Fishman's Pulmonary Diseases and Disorders - PART 16A

PART

XVI Infectious Diseases of the Lungs

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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SECTION SEVENTEEN

General Concepts

111 CHAPTER

Pulmonary Clearance of Infectious Agents Galen B. Toews

I. MECHANICAL DEFENSES Nasopharyngeal Airways Conducting Airways II. INNATE IMMUNITY Innate Immune Recognition Alveolar Macrophages NK Cells

Complement Alveolar Epithelial Cells III. INFLAMMATORY RESPONSES IV. ADAPTIVE IMMUNE RESPONSES Afferent Immune Response Regulatory T Cells V. CONCLUSION

The primary function of the lungs is the exchange of gases at a rate required to support tissue metabolism. During gas exchange processes, the lung is exposed to a varied burden of foreign materials, including infectious agents. In addition, the lung is repeatedly exposed to microbes via aspiration of secretions from the upper respiratory tract, particularly during sleep. The lung must defend itself against this potentially hostile environment to perform gas exchange adequately. This group of nonrespiratory functions has been collectively termed pulmonary host defenses (Fig. 111-1).

MECHANICAL DEFENSES Nasopharyngeal Airways Nasal hairs remove most particulates bigger than 10 µm.

Rapid airflow and quick changes in direction of the airstream

in the nose favor inertial deposition of large particulates; these particulates are cleared primarily by swallowing, sneezing, or coughing. Mucociliary clearance participates in the removal of particulates from the nasopharynx. Ciliated mucosa is present on the nasal septum and turbinates; mucociliary action sweeps mucus toward the posterior pharynx, where secretions are either swallowed or cleared from the throat.

Conducting Airways Mucociliary Escalator Most particulates larger than 2 µm in diameter affect the conducting airways. Mucociliary clearance and coughing are the principal means of mechanical defense (Fig. 111-2). The mucosa of the conducting airways is lined with mucus secreted by goblet cells, bronchial glands, and Clara cells. The mucous blanket is composed of two distinct layers: a watery sublayer, in which most ciliary movement takes place, and

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

1970 Part XVI

Infectious Diseases of the Lungs Innate Immunity

Macrophage

Initiation of Specific Immunity Dendritic Cell

Natural Killer (NK) Inflammation PMN Macrophage

T Cell

toxic oxygen radicals by stimulated neutrophils. Airway secretions also contain both serum-derived antiproteases (α1antitrypsin, α2 -chymotrypsin, and α2 -macroglobulin) and an airway epithelial cell-derived antiproteases (elafin). Elafin is produced by Clara cells in the airway.

Specific Immunity

INNATE IMMUNITY

Th2

B cell

Th1

Th1

Vessel γδ Antibody T cell

M

NO, O Enzymes Cytokines Antibacterial Lysis of infected target cytokines

Figure 111-1 Pulmonary immune defenses. Three immune defense systems protect the airways and lower respiratory tract.

Alveolar macrophages and pulmonary natural killer cells effectively remove certain microbes. Inflammatory responses, which lead to the recruitment of polymorphonuclear (PMN) leukocytes and monocytes, are crucial for the pulmonary clearance of most microbes. The initiation of specific immune responses requires dendritic cell–T lymphocyte interactions. Specific immune responses are required for effective pulmonary clearance of viruses, encapsulated bacteria, fungi and mycobacteria. The expression of immune responses requires the interaction of Th1 lymphocytes and macrophages and Th2 lymphocytes and B cells.

an upper viscous layer that is just penetrated by the ciliary tip.

Mucus is propelled up the respiratory tract by the pseudostratified ciliated epithelium that lines the conducting airways. Approximately 200 cilia are present on each ciliated cell. Ciliary length is approximately 5 to 6 µm, and ciliary frequency is 12 to 14 beats per seconds. Particulates can be cleared from the trachea with a half-time of 30 minutes and from distal airways with a half-time of hours.

Oxidants impair cilliary function and elastase damages cilia. Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1 increase cilia beating by a mechanism that is dependent on nitric oxide. Cigarette smoke adversely affects cells that produce mucus; mucus production is increased, and its biochemical and biophysical characteristics are altered.

Airway Secretion Airway epithelial cells secrete nonimmune host defense molecules. Iron is an essential ingredient for survival of many microbes. Iron is sequestered in cells or firmly complexes to transport proteins. Microbes compete for this iron with their own transport proteins, known as siderophores. Lactoferrin, found predominantly in the airways, and transferrin, found predominantly in the alveolar spaces, effectively complex any free iron in mucosal secretions, suppressing bacterial growth by making iron difficult for bacteria to obtain.

Lysozyme is secreted in large quantities in human airways (10–20 mg per day). Lysozyme catalyzes the hydrolysis of bonds between constituents of the cell walls of most bacteria and Cryptococcus neoformans and Coccidioides immitis. Lysozyme inhibits chemotaxis and the production of

Host defenses against invading microbial pathogens consist of two components: innate immunity and acquired immunity. Innate immune recognition occurs via germ-line encoded receptors that recognize conserved structures present on microorganisms (Fig. 111-2).

Innate Immune Recognition Microbial recognition is problematic because microbes evidence molecular heterogeneity and have high mutation rates.

The innate immune system recognizes a broad spectrum of pathogens using a repertoire of invariant receptors that recognize highly conserved microbial molecules including combinations of sugars, proteins, lipids, and distinct nucleic acid motifs. The receptors recognize molecular patterns and have, therefore, been termed pathogen recognition receptors (PRRs). Several hundred receptors accomplish the task of innate immune recognition. The ligands recognized by PRRs are pathogen-associated molecular patterns (PAMP). PAMPs share certain features. PAMPs are invariant structures shared by classes of pathogens, are produced only by microbes, and are essential for microbial pathogenicity or microbial survival. Cells that express PRRs include macrophages, dendritic cells (DCs), mast cells, neutrophils, eosinophils, natural killer (NK) cells, epithelial cells, and fibroblasts.

PRRs can be divided into three classes: secreted, endocytic and signaling receptors. C-reactive protein (CRP), mannan-binding lectin (MBL) and serum amyloid protein (SAP) are secreted pattern recognition molecules. CRP and SAP function as opsonins and bind to Clq to activate the classic complement pathway. MBL binds to mannose residues that are abundant on the surface of many microbes.

Macrophage mannose receptor (MMR) interacts with grampositive and gram-negative bacteria and fungal pathogens and mediates phagocytosis. Macrophage scavenger receptor (MSR) has broad specificity for a variety of ligands including double-stranded RNA, LPS, and lipoteichoic acid. Signaling PRRs induce expression of inflammatory cytokines and costimulatory molecules on antigen presenting cells following the recognition of PAMPs. Toll-like receptors (TLRs) are signaling PRRs. Thirteen TLRs have been described in mammals.

TLRs differ from one another in ligand specificity, expression patterns, and the genes they induce.

TLR2 recognizes a wide range of microbial products. These include lipoproteins/lipopeptides, peptidoglycan, lipoteichoic acid, lipoarabinomannan, and zymosan. TLR2 forms heterophilic dimers with other TLRs such as TLR1 and TLR6, likely accounting for its ability to recognize numerous

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Pulmonary Clearance of Infectious Agents

ROI Alveolar Macrophage RNI Toll-Like Enzymes Receptor CR Proteases Mannose FcγR Complement receptor Lymphocytes C5a C3b C5b,6,7,8,9 Membrane attack complex Transferrin Microbes

Endothelium

Complement

Dendritic cell Fibroblast

Epithelium

Surfactant Monocytes

Mast cell

γ δ T cell

Dendritic cell

Airway

Immunoglobulin Goblet cell NK cell NODE

Mucus

Lymphocytes

Nerve fibers

Monocyte

Bronchus associated Lymphoid aggregates

Figure 111-2 Resident defenses of conducting airways and alveoli. Conducting airways are lined by ciliated epithelium, which moves mucus generated by bronchial glands and goblet cells cephalad, where it is expectorated or swallowed. Airway macrophages ingest and kill small inocula of most aspirated and airborne bacteria. The alveolar spaces rely on innate immunity for the clearance of microbes that reach the alveolar surface. Alveolar macrophages are the first line of defense against microbes. Complement, surfactant, and iron-binding proteins are important humoral microbicidal factors.

ligands. TLR4 is an essential receptor for LPS recognition.

TLR4 also recognizes endogenous ligands such as heatshocked proteins and portions of fibronectin, hyaluronic acid, heparin sulfate, and fibrinogen. TLR5 recognizes flagellin, the principal structural component of bacterial flagella. TLR1, TLR2, TLR4, TLR5, and TLR6 are expressed on the surface of cells. TLR7, TLR8, and TLR9 are in the endosomal compartment and TLR3 is intracellular, although its exact location has not been defined. TLR3 recognizes double-stranded RNA (dsRNA) produced by most viruses during their replication.

TLR7 and TLR8 are structurally highly conserved proteins and recognize the same ligand in some instances. TLR7 and TLR8 recognize single-stranded RNA (ssRNA) from viruses such as human immunodeficiency virus and influenza virus.

TLR9 recognizes unmethylated CpG motifs in bacterial DNA. Mammalian DNA is methylated, whereas bacteria lack CpG methylation enzymes, allowing bacterial recognition.

Alveolar Macrophages Alveolar macrophages are a heterogeneous population of phagocytes that constitute the first line of defense against mi-

crobes that reach the alveolar surface (see Fig. 111-2). Alveolar macrophages are derived from monocytes and proliferating macrophage precursors in the interstitium of the lung. Alveolar macrophages undergo differentiation within the lung.

Alveolar macrophages have a life span of months to years.

The signals and ligands that modulate monocyte traffic into the normal lung have not been defined.

The microbicidal function of alveolar macrophage is dependent on four critical attributes. Macrophages recognize signals, ingest particulates, secrete mediators, and migrate in response to stimuli (Table 111-1). Macrophages recognize signals in their microenvironment via PRRs and surface receptors capable of binding specific ligands, including complement proteins, immunoglobulins, cytokines, PAMPS, and toxins. Activation of TLRs induces transcriptional activation of inflammatory mediators (TNF-α, IL-1, IL-6, IFN-α, IFNβ), chemokines, costimulatory molecules of T-cell activation (CD80, CD86), and signals that regulate the differentiation of lymphocytes (IL-4, IL-5, IL-10, IL-12), transforming growth factor (TGF-β and IFN-γ). Receptor-ligand interactions allow macrophages to ingest microorganisms and respond to cytokines and proteins.

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Infectious Diseases of the Lungs

Table 111-1 Secretory Products of Macrophages Cytokines, Growth Factors, and Hormones Growth factors GM-CSF M-CSF G-CSF Proteins involved in host defense and inflammation C1 C2 C3 C4 C5 Factor B Factor D Properdin C3b inactivation βIH Lysozyme Interferon-γ Fibronectin Lactoferrin Cytokines that promote acute inflammation and regulate lymphocytes TNF IL-1α/β IL-6 IL-8 IL-12 GROα/β/γ CTAPIII β-Thromboglobulin IP-10 MCP-1 MIP-1α MIP-1β Cytokines that inhibit acute inflammation and lymphocyte responses IL-10 TGF-β1 , -β2 , -β3 IL-1 receptor antagonist

Macrophages express two distinct receptors for the third component of complement. Complement receptor 1 (CR1) preferentially binds C3b and complement receptor 3 (CR3, Mo-1, MAC-1, CD11b/18) is a member of the β2 integrin family. CR3 is essential for migration of leukocytes functioning in cell-cell and cell-substrate adhesion. Genetic deficiency in the CD18 complex causes recurrent life-threatening infections.

Three Fcγ receptors recognize the Fc domain of immunoglobulin G (IgG). All FcRs function as signaltransducing molecules. FcγRI, FcγRII, and FcγRIII trigger

Reactive Oxygen Intermediates O− 2 H 2 O2 OH· Reactive Nitrogen Intermediates NO· NO2 NO3 Enzymes Active in Microbicidal Activity and Inflammation Acid hydrolases Acid phosphatases Cathepsins Cytolytic proteinase Hyaluronidase Lysozyme Phospholipase A2 Plasminogen activator Inhibitors of Enzymes α1 -Antiprotease α2 -Macroglobulin Inhibitors of plasminogen Inhibitors of plasminogen activator Lipomodulin Lipids Active in Host Defense and Inflammation PGE2 PGF2 α Prostacylin Thromboxane A2 Leukotrienes B, C, D, and E Mono-HETES Di-HETES PAF Lysophospholipids

both phagocytosis and cytolytic responses. Patients who lack FcγRI have no increased susceptibility to infection.

The redundancy of the three FcγRs may confer a selective advantage. The mannose receptor binds mannose and mediates phagocytosis of yeasts, zymosan particles, and Pneumocystis carinii (see Fig. 111-2).

Phagocytosis follows recognition of the microbe. Particle engulfment requires engagement of specific receptors and the generation of transmembrane signals that induce movement of the phagocyte plasma membrane over a ligand-coated particle. Phagocytosis requires sequential,

1973 Chapter 111

circumferential interaction of phagocyte surface receptors with complementary ligands on the surface of the particle.

The ingested microbe is initially contained within a phagosome that subsequently fuses with lysosomes. TLR stimulation is linked to phagosomal maturation. Resident alveolar macrophages require activation for microbicidal killing. Activation stimuli include microbial products, inflammatory cytokines and plasma proteins. IFN-α and/or IFN-β provide priming signals to augment macrophage microbicidal activity. GM-CFS is a potent stimulator of macrophage activation. Interactions with microbes lead to production of IFN-γ by NK cells.

Both oxidative and nonoxidative processes are used to kill ingested microbes. Alveolar macrophages have less antimicrobial activity than monocytes. Loss of granular peroxidase and a decrease in the magnitude of the respiratory burst account for a portion of the decline. Resident alveolar macrophages contain minimal myeloperoxidase (MPO): the MPO-H2 O2 -halide system is lest robust in resident macrophages than in recruited macrophages.

Microbes are also killed by macrophage-dependent nonoxidative mechanisms, including proteases, lysozyme, and defensins. Defensins are a multiple-member family of broad-spectrum cytotoxic peptides that kill many grampositive organisms (S. aureus, S. epidermidis, Streptococcus) and gram-negative species (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae). Defensins also kill fungi and inactivate certain viruses. Defensins are present in the alveolar macrophages of some species.

NK Cells NK cells are present within the lung. Active NK cells are located primarily in the interstitium of the lung. Pulmonary NK cells play a proactive role in influenza infections and in fungal infections. Engagement of TLRs induces macrophages to produce IL-12 and TNF-α which induce IFN-γ production

by NK cells. Early IFN-γ activates macrophages and enhances their microbicidal activity.

Complement Normal alveolar lavage fluids contain a functional alternative complement pathway. C3b, has opsonic activity and promotes receptor-mediated phagocytosis of microbes by macrophages. C5a is a chemoattractant for PMNs.

Alveolar Epithelial Cells Alveolar epithelial cells secrete proteins important in innate immune responses. SP-A and SP-D are members of the collectin family. SP-A facilitates alveolar macrophage and type 2 alveolar epithelial cell uptake of microbes. SP-A increases secretion of GM-CSF, promotes movement of alveolar macrophages and regulates macrophage oxidant production.

SP-D mediates agglutination of gram-negative bacteria.

Pulmonary Clearance of Infectious Agents

INFLAMMATORY RESPONSES A dual phagocytic system involving resident alveolar macrophages and recruited polymorphonuclear leukocytes (PMN) is required for the clearance of bacteria from the lower respiratory tract. Recruitment of PMNs into the alveoli is initiated by the generation of chemotaxins within the alveolar space (Fig. 111-3). A super-gene family of chemotactic cytokines, chemokines, possesses high degrees of specificity for inflammatory cells; accordingly they play important roles in the selective recruitment of blood-borne leukocytes to sites of inflammation. CXC, CC, C, and CX3 C chemokine families have been characterized. CXC chemokine family members (IL-8, MIP-2, GRO, ENA-78, NAP2) are chemotaxins for PMN. The CC family (MCP-1-4, RANTES, MIP1α and MIP-1β) are chemotaxins for macrophages, lymphocytes, basophils, eosinophils, and mast cells. Lymphotoxin is a C chemokine family member and fractalkine is a CX3 C chemokine.

Activation of TLRs on innate immune cells induces transcriptional activation of inflammatory genes. TLR activation induces TNF-α and IL-1, both of which induce gene expression and secretion of CXC chemokines from endothelial cells, fibroblasts and pulmonary epithelial cells. Macrophages also generate leukotriene B4, a potent chemotactic substance.

Sentinel dendritic cells and macrophages also produce IL-23 within a few hours after exposure to LPS and microbial products. This triggers rapid (hours) production of IL-17 from tissue resident α/β, γδ, and NK T cells. IL-17 promotes production of IL-1, IL-6, TNFα, and CXC chemokines from fibroblasts, epithelial cells and endothelial cells. Mice lacking the receptor for IL-17 evidence blunted G-CSF and MIP-2 responses, decreased neutrophil recruitment, have larger bacterial burden and worsening mortality in a murine model of Klebsiella pneumoniae infection. The alveolar capillary membrane is a dynamic assembly of innate immune cells that generate chemokines required to recruit specific inflammatory cells during microbial insults.

Neutrophils ingest microbes by phagocytosis. Effective killing requires products of granule constituents and molecular oxygen. Hydrogen peroxide and reactive oxygen intermediates are involved in neutrophil mediated killing. The MPO-H2 O2 -halide system is a crucial participant in oxygendependent killing by neutrophils. Granule components are also crucial in PMN mediated microbial killing. Lactoferrin chelates iron and lysozyme hydrolyzes bacterial cell walls.

Cathepsin G, elastase and cationic proteins found in azurophil granules kill bacteria. Human neutrophils contain defensins which kill gram-positive and gram-negative bacteria and fungi.

ADAPTIVE IMMUNE RESPONSES Microbial infections that elude the innate defense mechanisms and inflammatory responses generate a threshold

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Infectious Diseases of the Lungs

Microbes

AM Toll-like Receptor CR

TNF IL-1

Endothelium

LTB4 PMN CXC IL-1 IL-6 TNF

TNF IL-1

Mannose Fcγ R receptor IL-23 NK T cell

T cell

TNF IL-1

CC

IL-17 IL-17 IL-23

TNF IL-1

IL-17 NK T cell

T cell

Fibroblast

Epithelium

Monocytes PMN

Figure 111-3 Initiation of inflammatory responses in the lower respiratory tract. Chemotaxins are generated sequentially following the entry of bacteria or bacterial products into the alveolus. LPS stimulates alveolar macrophages to produce TNFα, IL-1β, IL-8, and leukotriene B4. TNFα and IL-1β induce gene expression and production of chemokines by epithelial cells and fibroblasts present in the alveolar-capillary wall and induce the expression of adherence molecules on inflammatory cells and endothelial cells. Microbes induce dendritic cells and macrophages to produce IL-23. IL-23 induces resident lymphocytes and monocytes to produce IL-17. IL-17 induces production of IL-1, IL-6 and CXC chemokines by parenchymal cells.

dose of antigen, which is needed to trigger adaptive immune responses. Adaptive immune responses consist of two major effector systems, antibody- and cell-mediated immunity, which are generated by antigen specific B and T lymphocytes, respectively. B and T lymphocytes rearrange their Ig and T-cell receptor (TCR) genes to maintain approximately 1011 different clones of B and T lymphocytes that express distinct antigen receptors. B lymphocytes recognize native antigens including carbohydrates, proteins, and simple chemical groups.

T-lymphocyte receptors recognize only peptides derived from protein antigens bound to cell-surface proteins from the major histocompatibility complex (MHC). Clones of lymphocytes are triggered by antigen-presenting cells (APCs) to proliferate and differentiate into effector cells. Antigenspecific lymphocytes remain expanded after elimination of an infection (memory lymphocytes). Memory lymphocytes provide a more rapid response to a second exposure to antigen.

Antigen-specific immune responses require at least 7 to 10 days for their development; this time is required for the proliferation and differentiation of antigen-specific T and B lymphocytes. During the development of specific immune responses, pathogens may continue to grow in the host or be held in check by innate and inflammatory mechanisms.

The generation of specific immune responses to infectious

antigens can be divided into three phases: the afferent phase, central control/processing phase, and efferent phase.

Afferent Immune Response Antigen presenting cells (APCs) provide an essential link between innate and adaptive immunity (Fig. 111-4). DCs are the most potent APC for T cells. DCs are bone marrow-derived cells which take up residence in peripheral tissues at epithelial borders throughout the mammalian host where they become specialized for recognition of pathogens and microenvironmental tissue damage. DCs signal the presence of “danger” to cells of adaptive immunity.

Two broad subsets of DC have been identified: myeloid DC (mDC) and plasmacytoid DC (pDC). mDC express CD11c, CD11b, varying levels of MHC class II and costimulatory molecules (CD40, CD80, and CD86). Human pDC express blood DC antigen (BDCA)2, whereas murine pDC express CD11c, GR-1, and B220. mDC contribute to a variety of T-cell responses or tolerance and pDC have been implicated in antiviral immunity and in murine models of asthma.

DC exist in both immature and mature forms. Immature DC are concerned mainly with antigen capture.

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Pulmonary Clearance of Infectious Agents

Alveolar Macrophage/Monocyte

Endothelium

LPS Receptor CR

Mannose receptor

Fcγ R

Down regulation of AM-mediated suppression GM-CSF

Microbes Microbes Dendritic cell

Fibroblast

Airway Macrophage

Mast cell γδ T cell

Epithelium

Monocytes

Monocyte PMN IL-1, GM-CSF, TNFα

Microbes Goblet cell

IL-12 T-bet STAT 4

Dendritic Cells Mucus

Lymphocytes

Lymphocytes

Monocytes

IFNγ

IL-23

Thp Nerve fibers

IL-12Rβ 2

Th

GATA 3 STAT 6 IL-4

Th2

Th17 IL-4

IL-17

IL-23R

NODE Bronchus associated Lymphoid aggregates

Figure 111-4 Initiation of specific immune responses in the lung. Dendritic cells located in the interstitium of the lung and in the airway epithelium function as sentinel antigen-presenting cells. Dendritic cells reside in close contact to airway epithelial cells, alveolar epithelial cells, and interstitial macrophages. Following exposure to microbial antigens, DC differentiation occurs as a result of exposure to cytokines produced by cells of the innate immune system (macrophages) and cytokine produced as a result of injury to epithelial cells. Differentiated DC migrates to local nodes and present antigen to naive T lymphocytes. The control of CD4 T-lymphocyte subset differentiation occurs via complex, cross-regulatory interactions mediated by lymphokines. The development of CD8 effector cells and plasma cells usually requires cognate interactions with DC4 regulatory T lymphocytes.

DC are mobilized from bone marrow precursors to peripheral blood in response to pulmonary inflammation. Monocytes contribute to the pool of newly recruited DC through transendothelial migration in which peripheral blood monocytes differentiate into tissue DC after crossing the vascular endothelium. CCR2 is a critical receptor in the recruitment of DC during inflammatory responses. CCR6 mediates recruitment of DC specifically to the airways and alveolar space in response to macrophage inhibitory protein (MIP)3α secreted by respiratory epithelial cells.

DC maturation is dependent on sensing of infection which may occur either directly by detection of pathogen products using TLRs or indirectly through exposure to endogenous danger signals such as material released from damaged cells. Ingested antigens are rapidly processed by one of two pathways. The endocytic pathways processe protein antigens obtained from the extracellular space in phagolysosomes converting them to small polypeptides. The polypeptides are

loaded on to MHC class II molecules to prime DC for further presentation to MHC class II restricted, CD4+ T helper lymphocytes. The endogenous pathway processes peptides from the intracellular environment and loads them onto MHC class I molecules for presentation to MHC class I restricted, CD8+ T cells. Mature DC up regulate MHC class II and costimulatory molecules allowing a phenotype focused on antigen presentation and the stimulation of na¨ıve T cells.

DC maturation is accompanied by changes in the expression of chemokine receptors. CCR1, CCR2, CCR5, and CCR6 are down regulated. CCR7 expression is enhanced allowing DC to respond to chemokine gradients of secondary lymphoid tissue chemokines (SLC/CCL21) and Epstein-Barr virus–induced molecule1 ligand chemokine (ELC/CCL19) emanating from local lymphatics and draining lymph nodes.

Mature DC leave the local inflammatory environment carrying their antigenic load to draining lymph nodes. DC–T-cell interactions within the draining lymph node are complex.

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T-cell stimulation, proliferation, and activation result if antigen recognition occurs. Induction of Th1, Th2, Th17, or T-regulatory responses may be the end result.

The engagement of TLRs on DCs leads to increased expression of MHC-peptide complexes and co-stimulatory molecules as well as the production of immunomodulatory cytokines, all of which have a profound effect on T-cell priming and differentiation. Triggering of the T-cell receptor (TCR) occurs following an interaction with an antigen/MHC complex and provides “signal one” to the T cell. T-cell maturation results in upregulation of important co-stimulatory molecules. Specifically, DC increase the expression of B7.1 (CD80) and B7.2 (CD86), which bind CD28 on T cells providing “signal two” to activate antigen specific T cells.

T-cell responses to pathogens are heterogeneous; three subsets of CD4 T helper cells have been defined on the basis of the cytokines they produce. Interleukin-12 (IL-12) is an innate immune response cytokine that drives Th1 polarization. IL-12 production by DC is tightly controlled, requiring a priming signal provided by microbial products or IFN-γ and an amplifying signal provided by T cells through CD40 ligand (CD40L). Cues other than IL-12 drive T-cell differentiation.

IL-23, which shares the p40 chain with IL-12 but pairs with a unique p19 chain, drives differentiation of inflammatory T cells capable of secreting large amounts of TNF and IL17. TLR3 and TLR4 potently act in synergy with endosomal TLR7, TLR8, and TLR9 in the induction of IL-12 p70 and IL23. The amounts of IL-12 and IL-23 induced by synergistic signaling are 50- to 100-fold higher than those induced by optimal concentrations of single agonists, leading to enhanced and sustained Th1-polarizing capacity. Since pathogens express several TLR agonists that may engage different TLRs at different times and in distinct cellular compartments, it is likely that “combinatorial codes” may exist by which DC discriminate pathogens for which a Th1 response is desirable.

IL-12 activation of STAT4 is necessary for differentiation of naive T cells into IFN-γ–producing Th1 cells. IFN-γ activates STAT1 and subsequently T-bet. T-bet activation is required for IL-12Rβ2 expression and IL-12 responsiveness. Th1 responses are characterized by the strong expression of IFN-γ, IL-2, and TNF-α. These cytokines in concert with simultaneous interactions between DC, Th1 cells, and CD8+ T cells result in the generation of antigen specific cytoxic T lymphocytes. The net result of the Th1 response is the generation of activated Th1 and cytotoxic T lymphocytes necessary for macrophage activation and effective cell-mediated immunity against predominantly intracellular pathogens.

Th2 responses are characterized by T-cell production of IL-4, IL-5, IL-10, and IL-13 as well as systemic IgE production and tissue eosinophilia. This response results in humoral immunity–mediated through interactions among DC, Th2 cells, and B cells. Th2 cell development is dependent on the transcription factors GATA3, STAT6, and IL-4.

It is increasingly evident that IL-23 has unique roles in regulating immunity. Whereas IL-12 drives classic Th1 responses characterized by IFN-γ production, IL-23 drives a T-cell population that produces IL-17 (Th17 cells). IL-17 is

a proinflammatory cytokine that induces G-CSF, GM-CSF, monocyte chemoattractant protein 1 (MCP-1), macrophageinflammatory protein-2 (MIP-2), IL-6, IL-8, neutrophil chemokine growth-related oncogene-α and PGE2 . The production of IL-17 by antigen-specific Th17 cells within a local tissue environment is important for both rapid recruitment of neutrophils to sites of acute infection and for continuous neutrophil recruitment. IL-23 induces IL-17 production in both CD4+ and CD8+ T cells.

Regulatory T Cells The immune system possesses various mechanisms to control and regulate the immune system to prevent and minimize reactivity to self-antigens or an overexuberant response to a pathogen. Avoidance of damage to the host is achieved by active suppression mediated by regulatory T (Treg) cell populations. Naturally occurring CD4+ CD25+ T reg cells are the best characterized subset. These cells represent 5 to 10 percent of the CD4+ T lymphocytes in healthy adult mice and humans. No characteristic stable surface marker has been ascribed to Treg cells. The forkhead/winged helix transcription factor, Foxp3, is specifically expressed by CD25+ Treg cells as well as CD25– T cells with regulatory activity. Foxp3 is thought to program the development and function of this subset of T cells. Naturally occurring Tregs suppress T cell proliferation by cell contact, membrane or soluble TGF-β and by secreted IL-10. A second population of regulatory T cells that produce IL-10 and secrete TGF-β have been described (IL-10 T reg). These cells are derived in culture and also express CD25. This second type of regulatory T cell also inhibits na¨ıve T-cell proliferation in vitro and suppresses experimentally induced autoimmune disease. These cells are Foxp3 negative. IL-10 Tregs suppress T cells via cell contact mediated mechanisms and secreted IL-10.

Efferent Immune Responses Migration of Effector Cells to the Lung

Antigen specific T cells must migrate via the blood stream to peripheral sites of ongoing infection (Fig. 111-5). Chemokine receptors are used, some of which are specific for Th1 cells. A subset of recruited DC remains in the lung rather than migrating to draining lymph nodes. These recruited nonmigratory pulmonary DC present antigen to newly recruited T cells to drive T-cell polarization and stimulate cytokine release. Cytokines produced by specific CD4 and CD8 lymphocytes play a central role in the recruitment of inflammatory mononuclear phagocytes and other effector lymphocytes. Monocytes and NK cells are recruited into the complex peripheral infectious environment.

Efferent T Cell Mediated Responses in the Lung Viral Infection

Viruses including influenza, parainfluenza, respiratory syncytial virus, Hantavirus, coronavirus (severe acute respiratory

1977 Chapter 111

Pulmonary Clearance of Infectious Agents DTH

IFNγ, TNFα/β

Lymphokine-mediated cytotoxicity

IFNγ, TNFα/β Th1

IL-2 IFNγ

IFNγ GM-CSF

Endothelium

IgG2a

Complement-mediated cytotoxicity

AM / Monocyte

•Antibody-dependent, cell mediated cytotoxicity •Phagocytosis •Intracellular killing

B Cell

LPS Receptor

IFNγ TNFα/β

CR

Mannose receptor

FcγR

CC Chemokines

TNF GM-CSF IFNγ Th17

Monocytes DC

IL-17 TNF

Fibroblast

IL-1 Epithelium

Monocytes PMN

MCP1-1 MIP1α RANTES

TNF GM-CSF IFN γ

Dendritic Cell (DC)

NODE

Monocyte

Granuloma Figure 111-5 Expression of specific immune responses in the lower respiratory tract. Activated T lymphocytes recirculate from draining regional lymph nodes and enter sites of microbial multiplication via a series of highly regulated events involving cytokines and adherence molecules expressed on both lymphocytes and endothelial cells. Activated Th0 or Th1 lymphocytes are stimulated by resident antigen-presenting cells to produce high levels of IFN-γ, GM-CSF, and TNF, which recruit and activate monocytes from the circulation. Adherence receptor ligand interactions between monocytes and endothelial cells are important in their recruitment. A unique subset of mononuclear cell chemotaxins (MIP-1α, MCP-1) are probably active in recruitment of mononuclear phagocytes. Recruited, activated mononuclear phagocytes are crucial to the clearance of certain pathogens. Th17 cells produce IL-17, which induces parenchymal cells to produce TNF-α, IL-1, IL-6, and CXC chemokines. These proinflammatory cytokines are important for continuous neutrophil recruitment during chronic infections.

syndrome), herpesvirus, and CMV cause significant pulmonary disease. Viruses are intracellular pathogens; the killing of virally infected cells by MHC class I restricted cytotoxic CD8 T lymphocytes (CTL) is required. CTL kill target cells by two mechanisms. Cytolytic mediators, including perforins and granzymes, are released from cytoplasmic granules. Perforins induce pore formation and osmotic cell lysis and granzymes are proteases that activate cell caspases, resulting in apoptosis. Killing of virally infected cells can also result from the direct induction of apoptosis by ligation of Fas by Fas ligand, which is up regulated and present on CTL. The development of cell-mediated immunity to viral infections precedes by mechanisms presented earlier, but may also precede locally within the lung. Lymphotoxin knockout

mice that lack lymphoid organs are capable of generating antigen-specific CD4+ T-cell responses. Priming occurred in bronchus-associated lymphoid tissue (BALT), a submucosal lymphoid tissue found in the major bronchi. Localized priming of the cell-mediated immune response may play a crucial role in viral host defense.

Memory T-cell responses are important in certain viral illnesses and following administration of antiviral vaccines.

Two subsets of memory T cells have been defined. Effector memory T cells are found within the lung, are short lived, retain markers of activation, and have effector functions; these cells lack expression of lymphoid trafficking molecules CCR7 or CD62L. Central memory T cells reside predominantly within lymphoid organs, persist for long periods of time, and express CCR7 and CD62L.

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Intracellular Pathogens Numerous strains of bacteria and certain fungi have evolved the capacity to invade and survive within host leukocytes, primarily macrophages, to evade recognition and elimination by innate immune responses. Cell-mediated immunity is required to successfully eradicate these microbes. Cytokines produced by CD4 and CD8 T lymphocytes play a central role in the activation of microbicidal function in phagocytic cells (see Fig. 111-5). IFN-γ produced by both CD4 and CD8 T lymphocytes is the most important macrophage activating factor. Macrophage activation is further enhanced by TLR stimulation and by inflammatory cytokines such as TNF-α and GM-CSF. Activated macrophages kill microbes. Intracellular microbes are exposed to toxic acid hydrolysis and cationic peptides in phagolysosomes. Expression of inducible nitric oxide synthase results in enhanced nitric oxide synthesis and the synthesis of reactive nitrogen intermediates that have antimicrobial properties. Induction of the respiratory burst results in generation of superoxide, hydrogen peroxide, and toxic reactive oxygen intermediates. The induction of macrophage apoptosis in response to intracellular infection

has been shown to be of importance in blocking cell-to-cell spread of certain intracellular infections.

Granuloma formation is an important mechanism of host defense to intracellular microbes (see Fig. 111-5). The recruitment of monocytes and lymphocyte populations to the site of infection is required for granuloma formation.

Macrophages coalesce into large, epithelioid and multinucleated giant cells. DC, CD4+ T lymphocytes, and CD8+ lymphocytes form a loose meshwork that serves to contain microorganisms. Granulomas are sites of ongoing production of inflammatory cytokines, including TNF-α, IFN-γ, and chemokines capable of recruiting additional effector cells.

Efferent B Lymphocyte--Mediated Immune Responses in the Lung Immunoglobulins are a major protein constituent of the fluid that lines the luminal surface of conducting airways and alveolar lining fluid. Effector functions for antibodies include opsonization, complement fixation, antibody-dependent cellular cytotoxicity (ADCC), agglutination and neutralization (Fig. 111-6). Approximately 20 percent of the total protein AM /Monocyte

Bone Marrow

Endothelium

CR

Microbes

•Phagocytosis •Intracellular killing

FcγR

Plasma Cell

B Cell

Dendritic cell Epithelium

Mast cell

Monocytes IL-1

Fibroblast

TNF

γδ T cell

Airway Macrophages

Plasma cell

S-IgA, IgE, IgG

Dendritic Cells

B Cells

Goblet cell

Mucus

Lymphocytes

T Cell

Nerve fibers Monocytes

Lymphocytes IL-5 IL-6 CD40L CD40 CTLA4 CD80(B7.1),CD86(B7.2) CD28 CD80(B7.1),CD86(B7.2) LFA-1 ICAM-1 or 2 CD4 or CD8 TCR

IL-4

CD2 CD5

Bronchus associated Lymphoid aggregates

MHC

B Lymphocyte

LFA-2 CD72 IL-4R

IL-4

NODE

Figure 111-6 Expression of B lymphocyte–mediated immune responses in the lower respiratory tract. Initial events in B-lymphocyte proliferation and differentiation occur in T lymphocyte–dependent areas of regional lymph nodes.

Proliferation, somatic hypermutation, and selection occur within the lymphoid follicle. B lymphocytes then migrate to bone marrow and to the lung, where they undergo differentiation to mature antibody-producing plasma cells.

Serum antibody that gains access to the alveolar spaces of uninflamed lungs is present in large amounts during intraalveolar infections processes. Antibodies neutralize pathogens and their toxins, activate complement, and function as opsonins to enhance macrophage recognition and ingestion of extracellular pathogens.

1979 Chapter 111

present in bronchoalveolar lavage fluid consists of IgG, IgM, and IgA. IgA is the predominant immunoglobulin in secretions of the trachea and major bronchi while both IgG and IgE are present as well. IgG is the predominant immunoglobulin in alveolar lining fluid.

Humans produce more IgA than any other Ig class.

The secretory IgA found in external secretions consists of two molecules of IgA that are held together by a joining chain and by a secretory component, a glycoprotein produced by epithelial cells. The role of IgA in pulmonary defenses remains enigmatic. The usual specificity of IgA antibodies is antiviral. Specific IgA antibodies against hemagglutinating antigen have been isolated from patients infected with influenza A. IgA may also be important in inhibiting bacterial adherence to the respiratory epithelium; it may also serve as an antitoxin, since specific IgA against Bordetella pertussis toxin has been isolated from the respiratory secretions of patients with pertussis. Although IgA is believed to fix complement poorly, IgA1 antibodies from volunteers vaccinated with meningococcal polysaccharide vaccine induced classic complement pathway–mediated killing of group C Neisseria meningitis.

Finally, IgA may also have a role as an opsonin, since human alveolar macrophages bear Fc receptors that bind either IgA1 or IgA2. Certain bacteria elaborate proteases that digest IgA; these proteases may provide a selective colonization advantage to the microbes.

Specific antibody is an important ingredient in lower respiratory tract defenses against extracellular microbes. Extracellular bacteria possess polysaccharide capsules that allow them to evade phagocytic cells. Antibodies function as: (a) opsonins that allow phagocytes to recognize and ingest microbes via the involvement of Fc receptors; (b) activators of complement, which enhances opsonization and leads to direct lysis of some bacteria; and (c) as neutralizing antibodies that neu-

Pulmonary Clearance of Infectious Agents

tralize pathogens or their toxins by binding to microbes or their products, thereby preventing injury to cells.

The role of antibody in resident bacterial defenses in the lower respiratory tract is uncertain. Immunoglobulins are clearly present in the epithelial lining fluid of the lower respiratory tract. Systemic immunization enhances pulmonary clearance of P. aeruginosa, P. mirabilis, and H. influenzae.

Enhanced clearance correlates with the appearance of antibodies in serum and bronchoalveolar lavage fluid, which are directed against the organisms. Antibody specificities of serum and alveolar antibodies are identical. Thus, it seems likely that alveolar antibodies are derived in large part from serum.

Serum IgG can clearly gain access to the alveolar space in normal subjects and during inflammation when large changes in alveolar permeability occur. Serum IgG can clearly and directly enhance bacterial clearance from the lower respiratory tract, since intravenous injection of a murine IgG monoclonal antibody specific for a cell surface–exposed epitope of nontypable H. influenzae resulted in enhanced pulmonary clearance. Accordingly, it seems likely that direct airway immunization would not be required to obtain protective antibodies in the lung.

CONCLUSION Infections are the most likely evolutionary driving force for the development of a complex system of pulmonary host defenses. A coordinated response of many different cells is required for the lung to clear pulmonary pathogens. An increasingly complex and potentially injurious cascade of host responses is mobilized following pulmonary microbial challenges (Table 111-2). Although the interactions of microbes

Table 111-2 Pulmonary Host Defense-Microbe Interactions Host Mood

Defense Mechanism

Timing

Microbial Behavior

Content

Mechanical: Epithelial barrier Mucociliary escalator

Continuous

Commensal

Irritated

Innate Immunity: Macrophages, NK cells, γ/δ T lymphocytes

Hours–days

Replication in the airway and alveolar space

Interested

Inflammation: Macrophages/PMN

Minutes–hours

Invasion

Angry

Antigen-specific immunity: DC; CD4, CD8 T lymphocytes; B lymphocytes

3–7 days

Tissue invasion/replication in phagocytes

Hysterical

Immunopathology: Macrophages; CD4, CD8 T cells; NK cells, B cells

Dissemination to many tissues

1980 Part XVI

Infectious Diseases of the Lungs

in the host are invariably complex, models of pulmonary infection have provided crucial information regarding the regulation of inflammatory and immune responses. These insights should eventually allow the development of rational strategies regarding vaccination and immunotherapy. The use of animal models offers the possibility of understanding the mechanisms that regulate immune responses sufficiently well so that the response to a specific antigen could be controlled.

A more complete understanding of host defense would allow the stimulation of deficient responses and the suppression of harmful responses to microbial pathogens and other antigens that enter the lung.

SUGGESTED READING Beutler B: Innate immunity: An overview. Mol Immunol 40:845–859, 2004.

Clark SW, Pavia D: Mucocilliary clearance, in Crystal RG, West JP (eds), The Lung: Scientific Foundations. New York, Raven, 1991, pp 1845–1859.

Fukao T, Matsuda S, Koyasu S: Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-γ production by dendritic cells. J Immunol 164:64–71, 2000.

Harrington LE, Hatton RD, Mangan PR, et al: Interleukin-17producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132, 2005.

Inaba K, Inaba M: Antigen recognition and presentation by dendritic cells. Int J Hematol 81:181–187, 2005.

Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995, 2004.

Kadowaki N, Ho S, Antonenko S, et al: Subsets of human dendritic cell precursors express different toll-like recep-

tors and respond to different microbial antigens. J Exp Med 194:863–869, 2001.

Kolls JK, Linden A: Interleukin-17 family members and inflammation. Immunity 21:467–476, 2004.

MacKenzie B, Kastelein RA, Kua DJ: Understanding the IL23-IL-17 immune pathway. Trends Immunol 27:17–23, 2006.

Martin TR, Frevert CW: Innate immunity in the lungs. Proceed Am Thorac Soc 2:403–411, 2005.

Mason C, Ali J: Immunity against mycobacteria. Semin Respir Crit Care Med 25:53–61, 2004.

Medzhitov R, Janeway C Jr: Innate immune recognition: Mechanisms and pathways. Immunol Rev 173:89–97, 2000.

Moser B, Wolf M, Walz A, et al: Chemokines: Multiple levels of leukocyte migration control. Trends Immunol 25:75–84, 2004.

Moser M, Murphy KM: Dendritic cell regulation of Th1-Th2 development. Nat Immunol 1:199–205, 2000.

Romani L: Immunity to fungal infections. Nat Rev Immunol 4:1–23, 2004.

Sallusto F, Lenig D, Forster R, et al: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712, 1999.

Schwartz RH: Natural regulatory T cells and self-tolerance.

Nat Immunol 6:327–330, 2005.

Vermaelen K, Pauwels R: Pulmonary dendritic cells. Am J Respir Crit Care Med 172:530–551, 2005.

Woodland DL, Randall TD: Anatomical features of anti-viral immunity in the respiratory tract. Semin Immunol 16:163– 170, 2004.

Zhang P, Summer WR, Bagby GJ, et al: Innate immunity and pulmonary host defense. Immunol Rev 13:39–51, 2000.

112 Approach to the Patient with Pulmonary Infection Jay A. Fishman

I. THE PATIENT WITH PNEUMONIA Host Defenses General Guidelines for Management of Pneumonia II. PULMONARY INFECTIONS: PATHOLOGICAL AND PATHOGENETIC FEATURES Bacterial Pneumonia Viral Infections of the Respiratory Tract Fungal Pneumonia Parasitic Pneumonia Radiographic Features of Pneumonia Miliary Pulmonary Disease

THE PATIENT WITH PNEUMONIA Pneumonia is a common cause of infection-related mortality and is one of the most important challenges in clinical medicine. Inappropriate treatment of pulmonary infection contributes to poor clinical outcomes and to the emergence of antimicrobial resistance. Pneumonia is defined as inflammation of the pulmonary parenchyma caused by an infectious agent. The clinical syndrome of pneumonia may include fever or hypothermia, sweats, rigors or chills, and pulmonary symptoms such as cough, sputum production, dyspnea, pleurisy or pulmonary lesions observed on radiographic examination. The diagnosis and management of pneumonia has been complicated by the discovery of newer pathogens, expanded antimicrobial resistance, increased populations of immunocompromised patients, and by newer diagnostic tools and antimicrobial agents.

Pneumonitis may be due to both infectious and noninfectious causes and only reflects inflammation. A variety of eponyms have been applied to various forms of pneumonia

Noninvasive Diagnostic Studies Invasive Diagnostic Procedures III. MAJOR CLINICAL SYNDROMES Community-Acquired Pneumonia Hospital-Acquired, Ventilator-Associated, and Nonresolving Pneumonias IV. NONINFECTIOUS PROCESSES MIMICKING PULMONARY INFECTIONS Drug-Induced Pneumonitis

that may reflect the epidemiology of the process and the likely causative organisms: aspiration pneumonia, communityacquired, nosocomial pneumonia, immunocompromised host, and atypical pneumonia (Table 112-1). These descriptions coupled with the radiologic appearance are useful in considering empiric therapy while awaiting microbiologic data. Consideration of potential immune deficits in each host will help to define the urgency of empiric antimicrobial therapies. These categories may be misleading, emphasizing the importance of definitive microbiologic diagnosis in optimizing clinical care (Table 112-2). Physical findings may also be unreliable—particularly since reliance on radiologic techniques has displaced the physical examination as an art form. Further, dual processes are common and physical findings are often muted in the immunocompromised host.

“Crackles” and rales are “heard” much more often than the actual frequency of pulmonary consolidation. Commonly, radiographic appearances are misconstrued as etiologic diagnoses: consolidation, bronchopneumonia, miliary patterns, nodules, abscesses, fluid collections, pleural effusions, interstitial pneumonitis, and lymphadenopathy. The goal of the

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1982 Part XVI

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Table 112-1

Table 112-2

Categorization of Pneumonia by Clinical Setting

Routine Evaluation of Patients with Suspected Pneumonia

Community-Acquired Pneumonia Typical (i.e., classic) pneumonia Atypical pneumonia Aspiration pneumonia

History Age Community (respiratory viruses, antimicrobial resistance) vs. hospital (ventilator) Pace of onset, dyspnea Recent infections (postviral pneumonia, endocarditis, aspiration) Recent hospitalization or exposure to medical facilities (extended care) Underlying conditions (mental status, immunity, cardiopulmonary, medications) Exposures (illness, children, institutions, animals, gardens, travel) Antimicrobial therapies, home infusion therapy, vaccinations Duration of hospitalization or endotracheal intubation

Pneumonia in the Elderly Community-acquired Nursing home residents Nosocomial Pneumonia Hospital-associated pneumonia Ventilator-associated pneumonia Health care facility associated pneumonia Pneumonia in Immunocompromised Hosts Immunoglobulin and complement deficiencies Granulocyte dysfunction or deficiency (cyclic neutropenia, chronic granulomatous disease) Cellular and combined immune deficiencies Neoplastic disease Solid organ and hematopoietic transplant recipients Untreated HIV infection Immune reconstitution syndromes (AIDS, neutropenia) Severe combined immunodeficiency (SCID) and congenital deficiencies Autoimmune and connective tissue disorders Other immunocompromised patients Cystic Fibrosis and Anatomic Disorders Bronchopulmonary sequestration

clinician is to define the etiology of pulmonary processes as rapidly as possible so as to facilitate management.

Host Defenses The presence of pneumonia should be taken as evidence of an immune defect relative to the epidemiological pressure of the microorganisms. A small inoculum of an organism of high intrinsic virulence (adhesion, invasive enzymes, motility, intracellular pathogens) may cause infection in a relatively normal host. Organisms of low virulence should cause infection only if there is an immune or anatomic predisposition to infection or with a high burden of organisms. Microorganisms may reach the lungs via the airways, bloodstream, or lymphatics.

Defects in specific components of the immune system (innate and acquired) predispose to specific types of infection (Table 112-3). An important first step in many infections is colonization of the upper airway via adhesion of organisms to

Physical Examination Laboratory Complete blood count with differential counts Electrolytes, liver function tests, blood urea nitrogen, creatinine Radiology PA and lateral chest radiograph Consider need for: Chest CT with contrast, echocardiogram, thoracentesis Microbiology Sputum Gram’s is stain, culture and sensitivity (susceptibility) Nasal swab (direct immunofluorescence) for respiratory virus panel (influenza, respiratory syncytial virus, parainfluenza, adenovirus) Blood cultures (2) Consider in appropriate setting: Pneumococcal urinary antigen Legionella urinary antigen Histoplasma urinary antigen Acid-fast smear (modified acid-fast smear) and culture Acute and convalescent sera (Mycoplasma, Chlamydophila, Q fever (Coxiella burnetti), Histoplasma, Coccidioides, Tularemia) HIV status Molecular assays (cytomegalovirus, Epstein-Barr virus)

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Approach to the Patient with Pulmonary Infection

Table 112-3 Infections Associated with Specific Immune Defects Defect

Common Causes

Associated Infections

Granulocytopenia

Leukemia, cytotoxic chemotherapy, AIDS, drug toxicity, Felty syndrome

Enteric gnr, Pseudomonas, S. aureus, S. epidermidis, streptococci, Aspergillus, Candida and other fungi

Neutrophil chemotaxis

Diabetes, alcoholism, uremia, Hodgkin’s disease, trauma (burns), lazy leukocyte syndrome, CT disease

S. aureus, Candida, streptococci

Neutrophil killing

CGD, myeloperoxidase deficiency

S. aureus, E. coli, Candida, Aspergillus, Torulopsis

T-cell defects

AIDS, congenital, lymphoma, sarcoidosis, viral infection, CT diseases, organ transplants, steroids

Intracellular bacteria (Legionella Listeria, mycobacteria), HSV, VZV, CMV, EBV, parasites

B-cell defects

Congenital/acquired agammaglobulinemia, burns, enteropathies, splenic dysfunction, myeloma, ALL surgery, sickle cell disease, cirrhosis

(Strongyloides, Toxoplasma), fungi (P. carinii, Candida, Cryptococcus) S. pneumoniae, H. influenzae, Salmonella and Campylobacter spp, Giardia lamblia

Splenectomy

S. pneumoniae, H. influenzae, Salmonella spp, Capnocytophaga

Complement

Congenital/acquired defects

S. aureus, Neisseria spp, H. influenzae, S. pneumoniae

Anatomic

IV/foley catheters, incisions, anastomotic leaks, mucosal ulceration, vascular insufficiency

Colonizing organisms, resistant nosocomial organisms

HSV, herps simplex virus; VZV, Varicella zoster virus; CMV, cytomegalovirus; EBV, Epstein-Barr virus.

the epithelial surfaces. These surfaces are normally protected against infection by mechanical clearance of organisms via the nose or oropharynx, local production of complement and immunoglobulin A (IgA), saliva, sloughing of epithelial cells, and bacterial interference by “normal flora”. Changes in these surfaces (diminished IgA secretion, changes in production of adhesins, fibronectin, altered lectin binding) predispose to adhesion of microorganisms. Organisms carrying enzymes that can degrade IgA exotoxins, adhesion proteins, or pili are favored in colonizing the respiratory epithelium. Mucociliary clearance may be disrupted by cigarette smoking, viral infection, Haemophilus influenzae, or Mycoplasma pneumoniae infection. Aspiration can result from altered closure of the glottis (neurological injury, sleep apnea, intubation, alcohol, anesthesia). Once past the glottis, most bacteria and viruses are small enough (up to 2 microns) to reach the alveoli unless impeded by alveolar lining fluid containing surfactant, immunoglobulin G (IgG), complement, and other proteins.

Surfactant includes a variety of components that serve to activate alveolar macrophage and neutrophil functions and may serve as an opsonin (SP-A and SP-D) for many types of or-

ganism. Organisms surviving the defenses of the upper airway are left to the cellular components of the lower airways including T- and B-lymphocytes, macrophages, and dendritic cells.

Pulmonary defense mechanisms are also disrupted by systemic infections (sepsis), acidosis, hypoxemia, pulmonary edema, malnutrition, uremia, age, and lung injury (acute respiratory distress syndrome, ARDS). Endotoxin and lipopolysaccharide diminish clearance of bacteria from the lungs. Viral infections may diminish neutrophil and macrophage functions, including phagocytosis, chemotaxis, and oxidative metabolism.

General Guidelines for Management of Pneumonia The individual with pulmonary infection often presents in an ambulatory setting. The evaluation of the patient with possible pneumonia depends on a series of questions that provide clues to management, including the need for hospitalization and selection of antimicrobial agents. Subsequently,

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microbiologic data provide the basis for adjusting antimicrobial therapy. The questions include: 1. Is the process life-threatening? a. Does the patient need to be admitted to the hospital? Does the patient have supports in the community? Can he/she manage oral medications, other therapies, and follow-up visits from home? b. What is the time course of the process? Is the infection rapidly progressive or gradual? Is there time to delay therapy or diagnostic procedures? c. Does the patient need supplemental oxygen, assisted ventilation, surgery, blood products, monitoring, or isolation?

2. Does the patient have immune deficits? Could the process be underestimated based on the absence of normal inflammatory responses?

3. What are the most common infections in the community or hospital or institution where this “infection” was acquired? In this appraisal, it is helpful to resort to clinical groupings: community-acquired, nosocomial (hospital, ventilator, health care facility), and pneumonia in the immunocompromised patient. Such groupings provide a guide to empiric therapy while evaluation is underway. It is important to understand the incidence of tuberculosis, acquired immunodeficiency syndrome (AIDS), respiratory viral infections, and antimicrobial-resistant organisms (Pneumococcus, Staphylococcus) in the community and of antimicrobial resistance in the institution.

4. What are the gross pathological and pathogenetic features of the pulmonary process? These may include frank pneumonia, focal infiltrate, lung abscess, chronic cavitary lesion, bronchiectasis, or miliary lesions. As a corollary, since pulmonary infections are occasionally generated by the hematogenous route, rather than by the bronchogenic route, consider possible extrapulmonary processes in the pathogenesis of pulmonary infection.

5. History: Are there clues to a specific etiology of infection and to the severity of the illness? a. Underlying clinical conditions: Chronic obstructive pulmonary disease (COPD), immune deficits, altered mental status, prior infections. b. Epidemiological history (i.e., travel, contacts, exposures, vaccines, medications, prior infections or hospitalizations): Has the patient traveled or does he/she have any hobbies (gardening, hiking, cooking) that might provide an epidemiological clue (Table 112-4)? c. Symptoms: Rate of progression, other systemic signs. Prior mild respiratory illness (“the flu”) with improvement and then rapid deterioration is suggestive of bacterial superinfection of viral pneumonitis, consistent with Staphylococcus

Table 112-4 Epidemiologic Exposures Associated with Pneumonia Pathogen

Epidemiology

Anthrax

Bioterrorism; animals, hides, raw wool, goat hair

Brucella sp.

Domestic animals, dairy products, abattoir, veterinarian

Chlamydophila psittaci

Birds: parrots, budgerigars, cockatoos, pigeons, turkeys

Coccidioidomycosis Southwest United States, Southern California, San Joaquin Valley Coxiella burnetii

Cattle, domestic animals, cats

Hantavirus

Rodent droppings/urine (virtually all states)

Histoplasmosis

Bird/bat droppings

Legionella

Contaminated aerosols

Leptospirosis

Rodents, animals, water contaminated by animal urine

Melioidosis

West Indies, Australia, Southeast Asia, South Central America—delayed onset post-exposure

Pasturella multocida

Dogs, cats

Plague (Yersinia, pestis)

Bioterrorism; squirrels, chipmunks, rabbits, prairie dogs, rats

Paracoccidioides

South America (Brazil)

Q fever

Goats, sheep, cattle, domestic animals (feces, amniotic fluid, placenta, milk)

Rhodococcus

Horses, soil, farms

Severe acute respiratory syndrome/ (SARS)

Endemic regions, nosocomial exposures

1985 Chapter 112

aureus or other bacterial infection. The abrupt onset of illness with recurrent (over several days) shaking chills, particularly if associated with mild diarrhea for 1 or 2 days, may suggest Legionnaires’ disease. Pneumococcal pneumonia may be associated with a single severe rigor with fever, often with symptomatic herpes labialis. Gastrointestinal symptoms and confusion may occur with any infection but are often notable with pneumococcal pneumonia and Legionnaires’ disease. The presence of extrapulmonary signs or symptoms is often a better clue to the nature of infection than are pulmonary symptoms.

6. Physical examination: Skin lesions (e.g., furuncles, endocarditis, or gram-negative sepsis), lymph nodes (symmetrical or regional), retinal examination, ear examination (bullous myringitis with Mycoplasma infection), periodontal disease or absent gag reflexes (with aspiration pneumonia), ipsilateral chest splinting, and neurological disease (pulmonarybrain syndromes) are often ignored but provide valuable clues. Dullness to percussion, bronchial breath sounds, and egophony (E to A changes) are suggestive of pulmonary consolidation but may be absent. Patients infected with Pneumocystis carinii, Mycoplasma, or viruses (or severe immune compromise) may have normal chest examinations despite abnormal chest radiographs and marked hypoxemia.

7. Basic laboratory data: Many systemic processes are reflected in abnormalities of blood counts, urinalysis, and routine blood chemistries. For example, the presence of mild liver function abnormalities might suggest Q fever, tularemia, miliary tuberculosis, or Legionnaires’ disease. The presence of pigmented casts in the urine and markedly elevated serum levels of creatine phosphokinase might focus attention on the possibilities of influenza virus pneumonia, Legionnaires’ disease, or a pulmonary infiltrate associated with intravenous drug abuse. Rapid screening tests (e.g., for respiratory viruses) are useful, but have limitations in terms of sensitivity.

8. Radiology: All patients with pneumonia merit chest radiography, preferably posterior-anterior and lateral views since portable films are often of limited value. Radiographs allow the physician to assess the severity of pneumonia and to distinguish this process from acute bronchitis; the latter, when infectious, is often viral in etiology. No radiographic findings are specific enough to define the microbial origin of a given pneumonia or pulmonary infiltrate. The only definitive way to obtain a specific etiologic diagnosis is through demonstration of the infecting organism—i.e., by examination of stained smears of sputum and pleural fluid or other biologic materials, by culture of respiratory secretions and blood,

Approach to the Patient with Pulmonary Infection

by demonstration of nucleic acids or proteins from an infecting microorganism, or by demonstration of an increase in antibody titer against the infecting microorganism. Nonetheless, the radiographic picture, taken along with other clinical information, can favor one or several etiologic agents. Involvement of multiple pulmonary lobes in the process and the presence of a pulmonary effusion are poor prognostic features. a. Define the radiographic pattern as either lobar (Fig. 112-1) or segmental consolidation, patchy bronchopneumonia, nodules (large, small, or miliary) (Fig. 112-2), or an interstitial process (Table 112-5). For example, many large, round pulmonary densities in a renal transplant recipient suggest Nocardia infection rather than Pneumocystis pneumonia, whereas in a heroin addict with cough, fever, and pleuritic chest pain, such densities suggest acute right-sided endocarditis rather than pneumococcal pneumonia. b. Compare with prior radiographs: Is the process old or new? Are there multiple processes? Has the patient had surgery in the intervening period? Is the spleen enlarged or absent? c. Confounding variables: Is it too early in the process to detect radiologic changes (first 18 to 24 h)?

Is the patient neutropenic (early viral or fungal pneumonitis) or otherwise immunocompromised (P. carinii pneumonia often occurs with minimal or no findings on plain chest radiographs)? Dehydration is commonly cited as a cause of false-negative radiographs, but, in general, this concept is probably overrated. d. Computed tomography (CT) scanning is sensitive to changes unrecognized in plain radiographs and may be useful in guiding invasive procedures.

9. How can a diagnosis be achieved most expeditiously? Is this likely to be a viral process that can be diagnosed in the office? Which invasive procedures are done well at your institution?

10. Examination of clinical specimens (appropriately stained smear of sputum or pleural fluid, blood buffy coat, skin lesions, throat swabs) often provides a provisional diagnosis. Examination of an appropriately stained smear of sputum can provide a shortcut to diagnosis if the findings are reasonably definitive. a. Gram-stained smears provide valuable information regarding the morphology and the tinctorial properties of bacteria (and some fungi) but also about the presence of polymorphonuclear leukocytes and squamous epithelial cells, the latter indicating that the specimen originated in the upper, rather than the lower, respiratory tract (Fig. 112-3). b. Other special staining methods, including Kinyoun and modified acid-fast stains for

1986 Part XVI

Infectious Diseases of the Lungs

B

A

C

Figure 112-1 A. Dense lobar consolidation involving right upper lobe and right middle lobe in an alcoholic patient with Klebsiella pneumoniae pneumonia. The minor fissure is bulging downward. (Courtesy of Dr. R. Greene.)

B. Same patient 7 days later. Despite antibiotic therapy, K. pneumoniae pneumonia progressed to become a necrotic process with formation of multiple abscesses. (Courtesy of Dr. R. Greene.) C. Sputum Gram’s stain from patient with K. pneumoniae infection reveals gram-negative rod forms with trace of a surrounding capsule.

mycobacteria can provide additional data. Actinomyces or Nocardia species and Wright-Giemsa or a variant such as Diff-Quik or direct fluorescent antibody staining of induced sputum samples for P. carinii or Legionella pneumophila may provide a diagnosis. c. Culture of sputum or blood or other bodily fluids may provide a specific etiologic diagnosis when evaluation of a sputum smear has not supplied a provisional diagnosis. The failure may be caused either because the infecting agent cannot be distinguished from components of the normal

upper-respiratory-tract flora which are incorporated in the specimen or because the particular microorganism is not visible on Gram-stained smear (e.g., Aspergillus species or M. pneumoniae). d. In some patients, an etiologic diagnosis cannot be made on the basis of initial smears or cultures. In such circumstances, a definitive diagnosis can sometimes be made by alternative means— e.g., urinary antigen tests for Legionella or Histoplasma infections, antigenemia or nucleic acid polymerase chain reactions for viral processes

1987 Chapter 112

Approach to the Patient with Pulmonary Infection

B

A

Figure 112-2 Miliary tuberculosis in a 45-year-old immigrant from Portugal with old calcified tuberculous empyema on the right. A. Fine nodularity present in both lungs. B. Arrows point to individual miliary lesions, which are more readily visible with added magnification. (Courtesy of Dr. R. Greene.)

(Tables 112-2 and 112-6) or, retrospectively, by serologic means, as in psittacosis, Q fever, or adenovirus pneumonia. Screening tests are highly useful for respiratory viruses (nasal swab coupled with immunofluorescence). Induced sputum examinations have a high yield for Pneumocystis and mycobacteria. e. Invasive diagnostic procedures: In patients who are critically ill or unlikely to tolerate invasive infections (immunocompromised hosts, recent major surgery, heart failure, COPD) it is reasonable to consider more invasive diagnostic procedures early in the clinical course. In such patients, only specific etiologic diagnoses can direct appropriate therapy. However, this observation illustrates the tension between empiric therapies and the risks inherent in invasive tests. Empiric antimicrobial therapies carry the risk of obscuring a specific microbiologic diagnosis as well as evoking drug-associated toxicities. Invasive diagnostic procedures are used to obtain uncontaminated lower-respiratory-tract secretions or pulmonary tissue for microbiologic and histologic analysis.

The selection of an invasive procedure should be based on the nature of the illness and the likelihood of success for each procedure afforded by the institution. Among the invasive procedures that are available are: (1) protected specimen brushing (PSB) (2) plugged telescoping catheter (PTC) sampling (3) standard bronchoalveolar lavage (BAL)

(4) protected bronchoalveolar lavage (P-BAL or PTC-BAL) (5) transtracheal aspiration (now uncommon) (6) fiberoptic bronchoscopy with transbronchial biopsy (7) needle biopsy of the lung (8) open lung biopsy via limited or video-assisted thoracotomy.

Important considerations in selecting an invasive procedure include the type and location of the pulmonary lesion, the ability of the patient to cooperate with the required manipulations, the presence of coagulopathies, and experience at the particular hospital in performing the particular procedure.

11. Antimicrobial therapy: In practice, initial therapy is empiric and based primarily on clinical clues. The selection of drug(s) for empiric therapy depends on the clinical setting and on the gravity of the pulmonary process. The selection of specific antimicrobial agents is considered in subsequent chapters.

PULMONARY INFECTIONS: PATHOLOGICAL AND PATHOGENETIC FEATURES Pulmonary infections can be categorized according to distinctive pathological, anatomic, and radiologic features. Some general patterns are presented below for their value in

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Table 112-5 Radiographic Features and Differential Diagnosis of Pneumonia in an Immunocompetent Host Consolidation/Focal opacity

S. pneumoniae, M. pneumoniae, H. influenzae, C. pneumoniae, Legionella sp., S. aureus, M. tuberculosis, and “atypical” mycobacteria (M. avium complex)

Cavitation

S. aureus, anaerobic bacteria, M. tuberculosis, gram-negative aerobic bacteria, Aspergillus sp., geographic/endemic fungi (H. capsulatum, C. immitis, B. dermatitidis)

Interstitial infiltrates

Viruses, M. pneumoniae, M. tuberculosis, geographic/endemic fungi, C. psittaci

Miliary

M. tuberculosis, geographic/endemic fungi, viruses, M. pneumoniae

Lymphadenopathy

M. tuberculosis, viral , Epstein-Barr virus, cytomegalovirus, rubella), geographic/endemic fungi, C. psittaci, cat-scratch disease.

differential diagnosis and are discussed in detail in subsequent chapters.

Figure 112-3 Three large oropharyngeal epithelial cells from a specimen of ‘‘sputum”that is inadequate for Gram’s stain analysis and culture because of its origin in the upper respiratory tract.

Note the large number of organisms agglutinated on the surface of the squamous epithelial cells (×400).

or other anatomic abnormality, or immune compromise of the host (Fig. 112-1).

Pneumonia may develop via the bacteremic route rather than the bronchogenic route. The clinical setting and the radiographic pattern usually suggest this type of pathogenesis. The intravenous drug abuser with S. aureus bacteremia and acute right-sided endocarditis presents with fever, cough, purulent sputum, a murmur of tricuspid insufficiency, numerous irregular infiltrates, and rounded densities on chest radiograph. Similarly, burn patients with Pseudomonas aeruginosa bacteremia and multiple nodular pulmonary densities are apt to have bacteremic Pseudomonas pneumonia with pulmonary bacterial arteritis. Septic pulmonary emboli, arising from septic thrombosis of the jugular vein may cause a clinical and radiographic picture suggestive of multifocal bronchopneumonia. On the chest radiograph, however, the lesions are nodular; histologically, they represent septic pulmonary infarcts (following emboli) upon which are engrafted pyogenic infection and abscess formation.

Bacterial Pneumonia Bacterial pneumonia commonly results from bronchogenic spread of infection following microaspiration of pharyngeal secretions. Such particles reach terminal airways and alveoli where they initiate infection, which has the anatomic distribution and radiologic appearance of subsegmental, segmental, or lobar consolidation. Pneumonia may be patchy, with a peribronchial and multifocal distribution, and occur in association with aspiration and bronchial plugging, superinfection of preexisting chronic bronchitis, diffuse acute tracheobronchial inflammation (e.g., influenza, parainfluenza), and with specific infecting microorganisms (e.g., oral anaerobic bacteria). The progression of a pulmonary infiltrate or lobar consolidation to parenchymal destruction (necrotizing pneumonia or lung abscess) is usually the consequence of one or more of three factors: the intrinsic virulence of the infecting organism(s), the presence of bronchial obstruction

Lung Abscess A lung abscess is an area of pulmonary infection with parenchymal necrosis. Lung abscesses may be solitary or may occur as multiple discrete lesions. Most often a lung abscess is secondary to aspiration of anaerobic or anaerobic and aerobic organisms which have colonized the upper-respiratory tract and may be associated with periodontal disease (Fig. 112-4). Superinfection of damaged or infarcted lung tissue (e.g., as occurs in aspirational pneumonia after chemical injury and anaerobic superinfection or primary anaerobic infection) progresses to necrosis and to microscopic foci of abscess formation. Confluence of small necrotic foci can either create one or more lung abscesses or lead to a progressively fibrotic, shrunken, and destroyed lobe. Pulmonary gangrene is an unusual consequence of severe pulmonary infection characterized by sloughing of a pulmonary segment or lobe. This

1989 Chapter 112

Approach to the Patient with Pulmonary Infection

Table 112-6 Assays for Viral Agents of Adults Culture Days to Positive

DFA/ Serology

Molecular Amplification∗

Nasopharyngeal wash/BAL

3–5

+/+

Qual

Fall/Winter

Nasopharyngeal wash/BAL

5–7

+/+

Qual

Parainfluenza(RNA)

Fall/Spring

Nasopharyngeal wash/BAL

5–7

+/+

Qual

Adenovirus (DNA)

All

Nasopharyngeal swab, stool

3–5

+/+

Qual/Quant

Measles (RNA)

All

Conjunct, nasopharyn; BAL, blood, urine

2–15

Fair −/+

N/A

EBV (DNA)

All

PBL-PCR, mono spot, serum

1–7

−/+

Qual/Quant (not well standardized)

CMV (DNA)

All

Blood, urine, BAL, saliva

2 (shell vial)–14

+/+

Qual/Quant antigenemia pp65

VZV (DNA)

All, Spring

Vesicle, throat, BAL, blood

Slow

+/+

Qual/Quant

HSV1, HSV2 (DNA)

All

Vesicle, BAL, blood

1–2

+/+

Qual/Quant (HSV1/2)

SARS Coronavirus (RNA)

All, Spring (Asia)

Qual

Human metapneumovirus (RNA)

All, Spring

Qual

Virus (Type)

Season

Culture/Specimen

Influenza A/B (RNA)

Winter

RSV (RNA)

∗ Qual:

qualitative assay; Quant: quantitative assay. Abbreviations: DFA, direct fluorescent antibody; BAL, bronchoalveolav lavage; RSV, respiratory syncytial virus; EBV, Epstein-Barr virus; PBL-PCR, pevipheral blood leukocytes – polymerase chain reaction; CMV, cytomegalovirus; VZV, varicella zoster virus; HSV, herpes simplex virus; SARS, severe acute respiratory syndrome.

process affects an entire segment or lobe secondary to thrombosis of both bronchial and pulmonary arteries followed by pulmonary infarction. The organism most commonly implicated has been Klebsiella pneumoniae, but others which have been implicated include Streptococcus pneumoniae, Escherichia coli, mixed anaerobes, H. influenzae, and S. aureus.

If there is some degree of ball-valve bronchial obstruction, air may enter while contained pus may fail to drain, producing the radiographic picture of an air-fluid level.

Other causes of lung abscess are (1) progression of a bronchogenic pneumonia due to a pathogen with necrotizing potential (e.g., K. pneumoniae, Fig. 112-1) or Nocardia asteroides in an immunocompromised patient, (2) bac-

teremic spread of infection, and (3) septic pulmonary emboli.

Lung abscesses complicating necrotizing pneumonia should be distinguished from pneumatoceles; the latter are thinwalled, air-filled structures that often develop early in the course of staphylococcal pneumonia, particularly in infants and young children, and usually disappear over the course of a few months.

Bronchitis and Bronchiectasis Acute bronchitis is an inflammatory process, usually of viral origin, confined to the bronchi and bronchioles; it does not extend appreciably to surrounding pulmonary parenchyma

1990 Part XVI

Infectious Diseases of the Lungs

A

B

Figure 112-4 Necrotizing pneumonia, probably secondary to aspiration in a 39-year-old man, smoker and drinker, previously healthy. Onset was with cough, shortness of breath, fever, and right-sided pleuritic pain. Despite antibiotics, signs and symptoms progressed to include high fevers, night sweats, greenish sputum, leukocytosis, and manifestations of hypertrophic osteoarthropathy. A. On admission, there was consolidation of right lower lobe, a right hilar mass (or adenopathy), and right pleural effusion. Mediastinoscopy and bronchoscopy revealed no tumor. B. Three months later, the process in the right lower lobe is more circumscribed. Right lower lobectomy revealed extensive necrotizing pneumonia, multiple abscesses, and ‘‘reactive” lymph nodes. Postoperatively, the patient was free of signs and symptoms, including hypertrophic osteoarthropathy.

and is not evident on radiographic examination. Purulent inflammatory secretions are common even though there may be no discernible bacterial infection. Such purulent secretions represent bacterial superinfection. The diagnosis of an acute exacerbation of chronic bronchitis is based solely on clinical grounds; the manifestations are increased cough, dyspnea, and enhanced production of purulent sputum, with or without fever, in a patient with COPD. Bacteriologic examination generally reveals large numbers of pneumococci or nontypeable H. influenzae, either as infecting organisms or as chronic colonizers of the bronchial tree. Patients with acute exacerbations of chronic bronchitis tend to improve with antimicrobial treatment while those with chronic bronchitis are less likely to improve with therapy.

Bronchiectasis is characterized by destruction of epithelial, elastic, and muscular elements of bronchi, resulting in their irreversible dilatation. The major proximate cause is repeated or chronic bacterial infection. However, predisposition to such infections may be a consequence of a variety of factors, including certain types of prior infection (pertussis, adenovirus, or rubeola infections, necrotizing pneumonia), bronchial obstruction, immunodeficiencies, congenital anatomic lung disease (e.g., congenital tracheobronchomegaly), and other hereditable disorders, such as ciliary dysfunctional states and α1 -antitrypsin deficiency. Currently, cystic fibrosis is the most common predisposing factor for bronchiectasis. As a result of repeated infections, stasis of se-

cretions, and peribronchial fibrosis, bronchi are grossly distorted or completely destroyed. Although pneumonia or lung abscess may accompany recurrent acute infections, exacerbations are usually confined to bronchial and peribronchial tissues.

Chronic Cavitary Disease Chronic cavitary pulmonary disease is most often due to tuberculosis, but may be seen in α1 -antitrypsin deficiency, echinococcal disease, Wegener’s granulomatosis, and other structural disorders. Tuberculosis commonly begins with a focus of pneumonitis, usually in the subapical posterior portion of an upper lobe. This patch of pneumonitis occurs at a latent site of earlier metastatic infection (Simon focus) produced by lymphohematogenous spread from primary pulmonary tuberculous lesions. Progressive caseation necrosis at this site, followed by drainage of caseous material through the bronchial tree, produces a cavity (Fig. 112-5). The cavity is encased in a rigid wall of fibrous tissue.

In addition to pyogenic lung abscess and pulmonary tuberculosis, other pulmonary infections can produce chronic cavities. These include Nocardia infections, Rhodococcus equi infections, actinomycosis, and chronic primary pulmonary mycoses (particularly histoplasmosis, occasionally coccidioidomycosis, uncommonly blastomycosis). Sporotrichosis can affect the lung and produce thin-walled cavities. Parasitic

1991 Chapter 112

A

C

infestation of the lung (paragonimiasis, echinococcosis) can also form cavities.

Pulmonary cavities may also occur in noninfectious disorders (e.g., Wegener’s granulomatosis, lymphoma or bronchogenic carcinoma, bland pulmonary infarcts, and intrapulmonary nodules of rheumatoid lung disease) (Fig. 1126). Such cavitary lesions, as well as the cystic lesions that occur in chronic pulmonary sarcoidosis (Fig. 112-7) and in the markedly dilated bronchi of saccular bronchiectasis, can be the sites of fungus balls. These represent tangled masses of fungal hyphae and debris lying freely within pulmonary cavities generally as noninvasive saprophytic growths in the immunologically normal host. Most often the mycotic agent is an Aspergillus species (usually A. fumigatus), and the fungus balls are called aspergillomas. Hemoptysis originating from the cavity wall is common and may be severe.

Miliary Lesions Hematogenous dissemination of tuberculosis can follow initial infection in children or adults. It also can result from breakdown of formerly quiescent sites of pulmonary or ex-

Approach to the Patient with Pulmonary Infection

B

Figure 112-5 Tuberculous cavities.

In each instance, the organisms were seen on smear and identified by culture.

A. Fifty-six-year-old African-American man. Cavity amid consolidation. B. Seventy-two-year-old African-American man. Bilateral, multiple cavities. C. Forty-eight-year-old African-American woman. Spread from original involvement of right upper lobe.

trapulmonary infection. Clinically unexplained fever may be accompanied by miliary lesions (which resemble millet seeds and are very small and uniform in shape) on the chest radiograph; histologically, these lesions are foci of granulomatous reaction (Fig. 112-2). Similar radiographic lesions also occur in the course of hematogenously disseminated bacterial and mycotic infections including cryptococcosis and histoplasmosis.

Viral Infections of the Respiratory Tract Respiratory viral infections are a major cause of morbidity worldwide. Patients present with cough, sore throat, bronchoconstriction, fever, rhinitis, and suffusion of mucous membranes. The majority of these infections are upper respiratory infections and of significance only as causes of discomfort and as predisposing conditions for infection of the lower respiratory tract. Spread is via aerosolized droplets and hand contamination. The most prominent viral pathogens include rhinovirus and coronavirus for which no specific antimicrobial therapies are available. Commonly, adenovirus,

1992 Part XVI

Infectious Diseases of the Lungs

A

B

C

D

Figure 112-6 Wegener’s granulomatosis. A. Onset with chills and fever in a previously healthy 64-year-old man.

Lung biopsy was interpreted as Wegener’s granulomatosis. Partial clearing in response to combined chemotherapy (cyclophosphamide and prednisone). B. Onset with malaise, headaches, and fever in a previously healthy 62-yearold woman. Bilateral maxillary sinusitis. Widespread nodular pulmonary infiltrates are most marked on the right.

C. Same patient as B after 3 years of intermittent combined chemotherapy. Bilateral large masses. D. Same patient as C, 2 months later. Necrosis within mass in left upper lobe has produced a fluid level.

parainfluenza virus, respiratory syncytial virus (RSV), and influenza virus may also cause this syndrome. Infections with respiratory viruses occur predominantly in the winter and early spring. Less commonly, reovirus, enteroviruses, metapneumoviruses, and picornaviruses may cause the same symptoms. Of nonviral etiologies, treatable infections with

M. pneumoniae and Chlamydophila (formerly Chlamydia) pneumoniae also cause significant upper- as well as lowerrespiratory infections. The predominant differential diagnoses for these infections include allergic, vasomotor, or atrophic rhinitis or nasal polyposis. These syndromes should be considered in patients with an atopic history and recurrent

1993 Chapter 112

A

Approach to the Patient with Pulmonary Infection

B

D

C

Figure 112-7 A to C. Chest radiographs illustrating the various stages of sarcoidosis. A. Stage I, bilateral hilar adenopathy. B. Stage II, bilateral hilar adenopathy with parenchymal infiltrates. C. Stage III, parenchymal infiltrates without hilar adenopathy. D. Transbronchial lung biopsy from a patient with sarcoidosis. Small arrows indicate granuloma with a surrounding rim of collagen (confirmed by positive trichrome staining). The large arrows indicate a granuloma without a surrounding rim of collagen. (Original magnification Ă—10.)

upper-respiratory infections. Although these infections are generally self-limited, common complications include sinusitis, otitis and bronchitis, exacerbations of chronic pulmonary disease (chronic bronchitis), asthma, and bacterial superinfection with pneumonia.

Viral Infections of the Lower-Respiratory Tract Influenza virus is an agent of the family Orthomyxoviridae that may be associated with sizable outbreaks or major epidemics of upper-respiratory infections. Influenza is classified into three subtypes based on antigenic differences: influenza

1994 Part XVI

Infectious Diseases of the Lungs

A, B, and C. Primary influenza viral pneumonia usually occurs in the setting of an outbreak of influenza A infections.

It impacts disproportionately on patients with underlying heart disease (mitral stenosis), chronic pulmonary disease, pregnancy, and immunocompromised individuals. Unlike secondary bacterial pneumonia after influenza—a complication that occurs after a period (1 to 4 days) of improvement following typical upper-respiratory illness—primary influenza pneumonia immediately follows typical influenza.

Two classes of drugs are available to treat influenza A including M2 matrix protein inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (zanamivir and oseltamivir). Resistance is emerging to both groups. Influenza A infects a wide range of species as hosts, including humans, pigs, birds, horses, and marine animals, whereas influenza B and C are generally restricted to humans. As a result, influenza A may move between host species, risking recombination, mutation (drift), and geographic spread. Pandemic influenza (e.g., avian influenza, H5N1) is most likely to arise in birds as all of the hemagglutinin and neuraminidase variants are carried in that population with viral replication in the gastrointestinal tract and secretion in high titers in feces.

The spread of mild variants of H5N1 influenza is common in some Asian populations.

Rarely, viral pneumonia develops in an otherwise healthy person in the course of systemic infection with viruses whose principal impact is extrapulmonary. Pulmonary infiltrates occur in 16 percent of young adults with varicella, but only 2 to 4 percent have clinical manifestations suggestive of pneumonia. Some cases of mild pneumonitis have been observed in patients receiving live varicella vaccine. Pneumonia in children with varicella is more likely to represent bacterial superinfection than primary viral pneumonia. On rare occasions, pulmonary infiltrates develop in patients with clinical infectious mononucleosis; the infiltrates represent atypical pneumonia due to Epstein-Barr virus (EBV).

A novel Hantavirus, Sin Nombre virus, emerged acutely in 1993, in the Four Corners area of New Mexico, Arizona, Colorado, and Utah. Cases had previously been reported worldwide but primarily in the west and southwestern United States. The Hantavirus pulmonary syndrome begins with a 3- to 6-day prodromal period consisting of myalgias and fever, sometimes accompanied by gastrointestinal symptoms.

The prodrome is followed by progressive cough, dyspnea, tachycardia, and hypotension. Bleeding may occur. Laboratory findings include hemoconcentration, leukocytosis, and thrombocytopenia. The chest radiograph demonstrates interstitial edema, peribronchial cuffing, and bilateral airspace (bibasilar and perihilar) disease. The picture of pulmonary edema (interstitial and alveolar) is consistent with a diffuse pulmonary capillary leak syndrome. The case fatality rate for the Hantavirus pulmonary syndrome is 50 percent. The principal host for Sin Nombre virus is the deer mouse, and infection is acquired through exposure to this rodent, to rodent excreta, or to contaminated dust.

Severe acute respiratory syndrome (SARS) is a viral respiratory illness that first appeared in southern China in

November 2002 before spreading globally. SARS is caused by a previously unrecognized coronavirus, called SARS-associated coronavirus (SARS-CoV). SARS-CoV is thought to be transmitted most readily by respiratory droplets. Illness usually begins with a high fever (measured temperature greater than 38.0◦ C with chills and malaise). Diarrhea occurs in approximately 10 to 20 percent of patients. After 2 to 7 days, SARS patients may develop a dry, nonproductive cough that may be accompanied by hypoxemia or progress to hypoxemia.

Ten to 20 percent of cases require mechanical ventilation.

Most patients develop pneumonia. The incidence of pneumonia is greatest in immunocompromised individuals. Between November 2002 through July 2003, 8098 people worldwide developed SARS and 774 died. No new cases were reported after July 2003.

Human metapneumovirus (HMPV) is a recently described but ubiquitous virus (Pneumovirinae subfamily, Paramyxoviridae family) which is recognized to be a major cause of acute respiratory infection, particularly in children and in immunocompromised individuals. The virus has phenotypic and clinical characteristics similar to those of RSV, often presenting with bronchiolitis. This virus may co-infect individuals with RSV. In the immunocompromised host, viral infection is most often due to cytomegalovirus (CMV) or communityacquired respiratory viruses, although varicella zoster and herpes simplex viral pneumonias do occur. In this population, the frequency, duration, and severity of viral illness exceed that of the general population. In the solid-organ transplant recipient CMV pneumonia occurs most often in seronegative (na¨ıve) recipients of donor organs from seropositive (latently infected) individuals. Conversely, in hematopoietic stem cell recipients, the seropositive recipient of seronegative cells is at greatest risk. The syndrome of hypoxia with diffuse, interstitial infiltrates may predispose to, or coexist with, a similar syndrome due to P. carinii. This syndrome is most severe in the lung transplant recipient. In contrast, CMV pneumonitis in the hematopoietic transplant recipient (bone marrow transplant) occurs with the activation of CMV in the seropositive recipient of cells from a seronegative donor. With engraftment, the na¨ıve immune system reacts against CMV antigens expressed in the lungs. Superinfection is common; graft-versus-host disease may complicate the differential diagnosis.

Fungal Pneumonia Fungal pneumonia occurs most often in immunocompromised hosts. However, in the normal host, infection due to the endemic or geographic fungi (Histoplasma capsulatum, Coccidioides immitis) or to Cryptococcus neoformans may be asymptomatic or may present with systemic signs often confused with acute bronchitis, viral infection, mycobacterial infection, or aseptic meningitis. Otherwise, fungal infection of the lungs is most common with anatomic defects (aspergilloma) or aspiration (Candida species) but is otherwise rare in individuals without immune defects. A few syndromes

1995 Chapter 112

merit consideration. P. carinii causes pneumonia with prominent hypoxia and often few physical or radiologic findings in immunocompromised individuals, particularly those on corticosteroids. Since this infection is easily prevented, consideration should be given to prophylaxis in any individual receiving chronic immunosuppressive therapy or with human immunodeficiency virus (HIV) infection or AIDS unresponsive to antiretroviral therapy.

Aspergilloma was traditionally considered to be a noninvasive colonization of pulmonary cavities. However, gross hemoptysis may complicate management and dissemination may occur at the time of surgical resection. Immune suppression may convert benign disease into invasive infection.

Mucormycosis (due to the Mucoraceae family) causes rapidly progressive sinus and lung infection that requires surgical resection for cure. This infection is most common in diabetics.

Fusarium species typically disseminate via the bloodstream, producing diffuse infiltrates.

Parasitic Pneumonia Parasitic pneumonia is uncommon without endemic exposures. Pneumonia generally occurs when the normal life cycle of the organism includes the lungs. Infection by Entaboeba histolytica causes pleuropulmonary disease as a result of (1) sympathetic reaction to an unruptured abscess within the liver; (2) empyema, after rupture of the liver abscess into the pleural space; or (3) parenchymal involvement with abscess, consolidation, or hepatobronchial fistula after rupture of a liver abscess. Amebae that have broached the mucosal barrier are thought to gain entry to the liver via the portal vein. Subsequent liver abscesses can be either purely amebic or mixed bacterial and amebic. Other less common routes exist, including hematogenous spread that can lead to metastatic abscesses of brain, lung, and other organs. Acanthamoeba species cause subacute meningoencephalitis or secondary keratitis often after hematogenous spread of dermal or pulmonary disease.

Some form of pulmonary complication occurs in 3 to 10 percent of patients with falciparum malaria. Noncardiogenic pulmonary edema can develop suddenly, even after appropriate antimalarial therapy has been instituted and even after parasites are no longer detected on blood smears. Acute acquired infection due to Toxoplasma gondii in the immunocompetent host is generally asymptomatic, with cervical lymphadenopathy as the hallmark of disease. It may be confused with mononucleosis caused by EBV or CMV. Fever, malaise, sore throat, and hepatosplenomegaly also occur, and the peripheral blood may manifest atypical lymphocytosis.

Rarely, acute acquired disease may present with severe dissemination, marked by pneumonitis, hepatitis, encephalitis, polymyositis, or myocarditis. In the immunocompromised host, acute toxoplasmosis is most often associated with necrotizing encephalitis as a result of brain cyst reactivation, although myocarditis, hepatosplenomegaly, fever, and interstitial pneumonitis are also common. Pulmonary infections due to migrating worms include a Loeffler-like syndrome with Ascaris lumbricoides, postobstructive pneumonitis and systemic

Approach to the Patient with Pulmonary Infection

sepsis due to Strongyloides stercoralis, cysts and nodules due to Echinococcus granulosus, Paragonimus westermani, Schistosoma species, and pulmonary eosinophilia in filariasis.

RADIOGRAPHIC FEATURES OF PNEUMONIA The radiographic features of pneumonia are discussed in detail elsewhere. No radiologic pattern provides a specific etiologic diagnosis. However, the radiographic pattern, combined with clinical and epidemiological information, can narrow diagnostic considerations while microbiologic data are being assembled. Several radiographic patterns can be helpful in categorizing infectious and noninfectious causes: (1) airspace or alveolar pneumonia, (2) broncho- or lobular pneumonia (Fig. 112-1), (3) interstitial pneumonia, and (4) nodular infiltrates. Although the chest radiographs of a particular patient may not fit neatly into one or another of these categories, identification of a predominant pattern can be helpful in directing attention to certain causes.

Alveolar Pneumonia This form of infiltrate occurs when certain organisms, notably S. pneumoniae, induce inflammatory edema in peripheral alveoli. When the extent of the consolidation involves an entire lobe, this is the classic lobar pneumonia. But more often the process is not that extensive, although the pathogenesis is the same. An air bronchogram is characteristic.

Loss of volume is absent or minimal during the acute stage of consolidation, but some atelectasis may develop owing to obstruction of bronchi by exudate during resolution of the process.

K. pneumoniae is another common cause of community-acquired pneumonia (CAP), which, like pneumococcal pneumonia, shows homogeneous parenchymal consolidation containing air bronchograms. Although K. pneumoniae pneumonia classically affects the right upper lobe and produces a dense, homogeneous lobar consolidation with bulging of the fissure, these features are not pathognomonic and cannot be relied on for diagnosis without supportive bacteriologic data (Fig. 112-1). The propensity for K. pneumoniae to produce tissue destruction and abscess formation may, in fact, result in a shrunken, rather than an expanded, lobe. Pneumococcal pneumonia may also cause bulging of the fissure, albeit less commonly and less prominently. Extensive alveolar consolidation may occur with a variety of other bacterial causes of pneumonia, including mixed anaerobes of aspiration pneumonia and a variety of gram-negative bacilli implicated in nosocomial pneumonias.

Occasionally, an unusual configuration of airspace consolidation, spherical pneumonia, occurs, particularly in children, with pneumococcal or H. influenzae pneumonia. It has also been reported with Q fever.

In the immunocompromised host, alveolar consolidation on the plain chest radiograph may be delayed and appreciated only by chest CT scan. Among infectious causes, bacterial agents are a major consideration. Common pathogens, such as S. pneumoniae, cause infection in this group of patients

1996 Part XVI

Infectious Diseases of the Lungs

A

B

C

Figure 112-8 A. Gram-stained smear of sputum from patient with pneumococcal lobar pneumonia (×1000). In this field there are numerous gram-positive, lancet-shaped diplococci and polymorphonuclear leukocytes. B. Gram-stained smear of sputum from patient with bronchopneumonia superimposed on chronic bronchitis. This field (×1000) is teeming with gram-negative coccobacilli.

Many polymorphonuclear leukocytes are present. Haemophilus influenzae was isolated from sputum as the predominant organism.

C. Gram-stained smear of sputum from patient with lobar pneumonia due to K. pneumoniae. In this field (×1000) there are moderate numbers of polymorphonuclear leukocytes and large, thick, gramnegative bacilli. (A to C Courtesy of H. Provine.)

which is often of greater severity than in the normal host and with less radiologic evidence for infection. Bacterial superinfection of viral processes (e.g., influenza, CMV) is also common. However, if the consolidation is lobar or multilobar, L. pneumophila is an important possibility. Other likely infectious agents are fungi (e.g., Aspergillus), Nocardia, and M. tuberculosis. Less often, viruses alone (e.g., CMV) elicit a predominantly alveolar pattern. Bilateral diffuse involvement with an airspace pattern resembling pulmonary edema is not uncommonly a feature of P. carinii pneumonia, but may also reflect viral or noninfectious etiologies.

Bronchopneumonia In bronchopneumonia, the focus of infection and the inflammatory response is in the bronchi and surrounding parenchyma. Consolidation is segmental in distribution, and involvement is patchy; segmental involvement may become confluent to produce a more homogeneous pattern. Bronchopneumonic patterns are commonly observed in pulmonary infections due to S. aureus or nonencapsulated H. influenzae. With S. aureus infections, macro- and microabscess formation may occur rapidly. Also, pneumatoceles occur during the first week of lung involvement in about half the children with S. aureus pneumonia. These cystic

spaces are believed to be the consequence of a check valve opening between a peribronchial abscess and an adjacent bronchus.

A bronchopneumonic pattern of consolidation is commonly observed when pneumonia is engrafted on underlying bronchiectasis or chronic bronchitis. In such predisposing circumstances, S. pneumoniae infection may produce a bronchopneumonic pattern rather than its usual lobar consolidation (Fig. 112-8). In the presence of underlying emphysema, the radiographic pattern of pneumococcal pneumonia may also be altered from its usual homogeneous pattern to one that contains multiple radiolucencies (representing unconsolidated emphysematous areas) that may be misinterpreted as abscesses.

Segmental bronchopneumonia is the radiographic picture in pneumonia due to C. pneumoniae (strain TWAR) or M. pneumoniae, and in many viral pneumonias. Any of the bacterial species that cause nosocomial pneumonia can produce a radiographic pattern of bronchopneumonic consolidation.

Interstitial Pneumonia (Peribronchovascular Infiltrate) A reticular or reticulonodular pattern of infiltration is the radiographic representation of interstitial inflammation—i.e.,

1997 Chapter 112

a peribronchovascular infiltrate. In otherwise healthy persons, M. pneumoniae is high on the list of communityacquired causes of a radiographic pattern of interstitial pneumonia. In some instances, interstitial infiltration progresses to produce patchy consolidation of airspaces, most often in the lower lobes. Pneumonias due to respiratory viruses sometimes have an interstitial pattern that progresses to patchy segmental consolidation or to diffuse airspace disease that resembles pulmonary edema. A variety of noninfectious causes of interstitial lung disease (e.g., hypersensitivity lung disease, collagen vascular disease, and sarcoidosis) may also produce a reticular pattern on the chest radiograph (Fig. 112-6).

In immunocompromised patients, particularly in those with AIDS, the infectious causes of interstitial pneumonia are broadened to include early P. carinii pneumonia and additional opportunistic viral agents (CMV, varicella-zoster, herpes simplex, and probably EBV and possibly HIV). Noninfectious causes of a reticular pattern on chest radiography in an immunocompromised host include drug-induced (bleomycin, methotrexate, etc.) pneumonitis, early radiation pneumonitis, and pulmonary edema.

Nodular Infiltrates Nodular infiltrates are considered here as well-defined large (greater than 1 cm on the chest radiograph), round focal lesions. Such a lesion may represent small aspirational abscesses (without air-fluid levels), a fungal or tuberculous granuloma, or a lesion of pulmonary nocardiosis. Multiple nodular infiltrates may also represent the necrotic lesions that develop in the lung secondary to the septic vasculitis produced by P. aeruginosa bacteremia or the consequences of fungemic spread of candidal infection from an infected intravascular catheter. Infected nodular pulmonary lesions are sometimes caused by septic pulmonary infarcts produced by infected emboli that originate from right-sided bacterial endocarditis, septic thrombophlebitis of pelvic veins, or septic jugular vein phlebitis. On rare occasions, similar nodular lesions are produced by necrotic (but not infected) pulmonary infarctions; primary or metastatic neoplastic lesions may have a similar appearance. Nodular lesions that undergo rapid necrosis with cavity formation can be a feature of Wegener’s granulomatosis (Fig. 112-5).

In the immunocompromised patient, nodular infiltrates may be due to bacteremic or fungemic spread of infection, most often as a result of nosocomial infection caused by an infected intravenous catheter. In this type of patient, nodular lesions should bring to mind the possibilities of pulmonary nocardial infection, aspergillosis, or other fungal infections. Tuberculous granulomas in the lungs may develop or enlarge in the immunosuppressed patient. Metastatic neoplasm or lymphoma sometimes presents a similar radiologic picture. Multiple small nodules, larger than miliary lesions but smaller than the gross nodular lesions described above, raise the possibility of varicella-zoster or CMV infection of the lung.

Approach to the Patient with Pulmonary Infection

Miliary Pulmonary Disease Disseminated miliary lesions of infectious nature suggest miliary tuberculosis, histoplasmosis, or blastomycosis in either the normal or immunosuppressed host. In the immunosuppressed patient, a miliary pattern may also occur in disseminated cryptococcal infection or bacteremic spread of bacterial or candidal infection (Figs. 112-2 and 112-4).

Computed Tomography Scanning In patients with pulmonary infections, CT scanning of the chest may be helpful in certain situations in determining whether pneumonia is necrotizing, consolidation secondary to bronchial obstruction (as by hilar lymphadenopathy or by endobronchial tumor), or if there is a relationship between a pleural effusion or an empyema or loculated fluid collections to parenchymal infections, if bronchiectasis is present, or whether circumscribed pulmonary densities represent a fungus ball within a cavitary lesion, and so forth. When small granulomatous lesions are present, CT scanning can provide information on the extent of the process. When a single nodule is present, CT scanning can assist in determining the best invasive diagnostic approach (needle, open biopsy). In particular, in immunocompromised individuals in which infiltrates are not appreciated on ordinary radiographs (e.g., P. carinii) may be demonstrated by CT scanning. This information greatly facilitates invasive procedures such as needle biopsy, video-assisted thoracoscopy, or bronchoscopy.

Noninvasive Diagnostic Studies Noninvasive studies can provide information indicating the specific microbial cause of a pulmonary infection or can narrow the field of likely etiologic agents.

Direct Examination of the Sputum Cytologic Examination

Examination of Gram-stained sputum smears can be of major value in pinpointing a bacterial cause of pneumonia and guiding initial and subsequent therapy. The quality of a sample of expectorated or induced sputum sample determines the value of the results that can be expected. Culture of sputum or nasopharyngeal secretions that consists principally of saliva is worthless. Cytologic examination provides an evaluation of the quality of the sample and its suitability for culture and interpretation of a Gram-stained smear made from it. Scanning of Gram-stained smears or application of specific quantitative criteria is helpful in selecting meaningful specimens for bacteriologic evaluation by smear and in culture. Squamous epithelial cells (normally exfoliated from the oropharynx), when present in numbers of 10 or more per low-power (Ă—100) magnification field, indicate that the specimen is unsatisfactory; culture of such a specimen correlates poorly with results from culture of a transtracheal aspirate (Fig. 112-3). The presence of numerous polymorphonuclear neutrophils on Gram-stained smear (10 to 25 or more per

1998 Part XVI

Infectious Diseases of the Lungs

low-power microscopic field) in the absence of an excessive number of squamous cells (see above) is indicative of a good specimen for bacteriologic evaluation.

Examination of Gram-Stained Smears for Bacteria

The oil immersion fields examined, and the immediately adjacent fields should not contain any squamous cells; each should also contain at least three or four neutrophils (in non-neutropenic hosts). The presence of squamous cells not only indicates that the specimen is derived from the upperrespiratory tract but also may be confusing to the uninitiated because of the large number of bacteria, often gram-positive diplococci, which might be mistaken for S. pneumoniae, adherent to the surface of these cells.

A variety of bacterial respiratory tract pathogens have rather characteristic morphologies and strongly suggest an etiologic role when present in a suitable specimen of sputum (or in a transtracheal aspirate) that contains the proper numbers of inflammatory cells. Such organisms include S. pneumoniae (gram-positive oval or lancet-shaped diplococci), H. influenzae (small, pleomorphic gram-negative bacilli), Moraxella catarrhalis (gram-negative, biscuit-shaped diplococci), or the similar-appearing Neisseria meningitis, enteric gram-negative bacilli (not distinguishable from one another with respect to species except for large encapsulated rods that are suggestive of Klebsiella), and S. aureus (large gram-positive cocci in small groups or clusters (Fig. 112-9). Since normal oral flora includes a variety of streptococcal species that are morphologically somewhat similar to S. pneumoniae, sputum smears may be misinterpreted. Thus, a definite predominance of gram-positive diplococci in multiple appropriate oil immersion fields needs to be observed in order to implicate S. pneumoniae (Fig. 112-7). A quantitative aspect to the evaluation has been suggested: at least 10 gram-positive

lancet-shaped diplococci per oil immersion field predict the isolation of S. pneumoniae from sputum cultures. With use of these criteria (numbers of polymorphonuclear leukocytes, absence of epithelial cells, and numbers of gram-positive lancet-shaped diplococci), the specificity of Gram’s stain for identifying S. pneumoniae is 85 percent, with a sensitivity of 62 percent.

Gram-stained smears can be helpful not only in the etiologic diagnosis of community-acquired bacterial pneumonia due to the usual respiratory pathogens but also in supporting a diagnosis of atypical pneumonia when sputum examinations repeatedly show neither neutrophils nor bacteria. Uncommon bacterial species may be implicated in a pulmonary infection on the basis of unusual morphology on Gram-stained smear. For example, irregularly staining, beaded, delicate gram-positive branching filaments suggest either Nocardia or Actinomyces (Fig. 112-10).

Several organisms, uncommon causes of pulmonary infection, have morphologic characteristics that may mimic other, more common respiratory pathogens. Pasteurella multocida and Acinetobacter species, both small gram-negative coccobacilli, have each been mistaken in sputum of patients with pulmonary infections for either H. influenzae or M. catarrhalis, or for a mixture of the two.

Sputum or pleural fluid with foul odor provides evidence of activity of anaerobic organisms in infective processes such as lung abscess, aspiration pneumonia, empyema, and, occasionally, bronchiectasis. In these settings, the findings on Gram-stained smear may corroborate the preliminary diagnosis. Organisms of the P. melaninogenicus-asaccharolyticus group are small, gram-negative coccobacilli. Fusobacterium nucleatum is a long, tapering, pale-staining gram-negative bacillus with irregularly staining gram-positive internal granules. Purulent secretions or pus from such anaerobic infections contain numerous neutrophils and usually a mixture

Figure 112-9 Staphylococcus aureus on Gram-stained smear from a drug addict with right-sided bacterial endocarditis. In this field (Ă—1000) there are polymorphonuclear leukocytes and clusters of gram-positive cocci. (Courtesy of H. Provine.)

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nosed by isolation of the organism from blood culture (lysis centrifugation method) or by histopathological diagnosis on biopsy. However, the organism can be demonstrated on acid-fast smears and culture of respiratory secretions even though there may be little radiographic evidence of pulmonary infection directly attributable to its presence. Modified Ziehl-Neelsen–stained smears are helpful in detecting Nocardia.

Fungal Wet Mounts (Potassium Hydroxide, KOH Preparations)

Figure 112-10 Actinomycosis in a 54-year-old chronic alcoholic man with pyorrheic gums who was admitted with signs of brain tumor. Chest radiograph shows mass in left lower lobe. Computed tomography is consistent with brain metastasis. Transthoracic needle aspirate revealed Actinomyces israelii.

of bacterial species, including anaerobic and microaerophilic streptococci on stained smear.

Examination of Ziehl-Neelsen or Fluorochrome-Stained Smears for Mycobacteria

The number of new cases of tuberculosis in the United States steadily declined over past decades, reaching a nadir in 1995.

During the period 1985 to 1991, the rate of development of new cases (often due to multidrug-resistant strains of M. tuberculosis) increased, primarily associated with microepidemics among the urban poor, racial and ethnic minorities, drug abusers, hospital and correctional facility populations, and patients with HIV infection. In patients with AIDS who have access to HAART (highly active antiretroviral therapies), the incidence of tuberculosis is decreasing. Pulmonary tuberculosis in the aforementioned settings may take the form of chronic cavitary tuberculosis or of forms more suggestive of pyogenic or atypical pneumonia—i.e., progressive primary tuberculosis and tuberculous pneumonia. Acid-fast smears of sputum can provide the very first evidence of this disease. Mycobacteria are seen on smears of about 50 percent of specimens that subsequently prove to contain M. tuberculosis. Most laboratories currently employ a fluorochrome stain with auramine-rhodamine (mycobacteria fluoresce orangeyellow) for initial examination of sputum or other body fluids. Atypical mycobacteria may be demonstrated on sputum smears of patients, usually older people, with slowly progressive pulmonary disease. In patients with AIDS, disseminated Mycobacterium avium-intracellulare infection is usually diag-

Fungal wet mounts, smears stained with Calcofluor white chemofluorescent agent or phase-contrast microscopy, are employed when epidemiological considerations suggest community-acquired pulmonary mycoses (particularly coccidioidomycosis and blastomycosis). They should be a routine part of evaluation of respiratory secretions and lung biopsy materials from immunocompromised patients in whom additional fungal pathogens (e.g., Aspergillus and Mucor) may be active. In patients with allergic bronchopulmonary aspergillosis, or with the unexpected detection of Aspergillus in sputum, fungal hyphae must be considered in the clinical context of each patient.

Direct Immunofluorescent Microscopy

Direct fluorescent antibody (DFA) staining can be useful in rapid diagnosis of respiratory tract pathogens. DFA staining reagents for L. pneumophila are commercially available.

Their use is not recommended in examination of sputum specimens because of the presence of cross-reacting species (Bacteroides species, Pseudomonas species, Bordetella pertussis) in the upper-respiratory tract. However, biopsy specimens of lung (needle, bronchoscopic, or surgical), bronchoscopic aspirates, BAL washings, and pleural fluid samples are suitable for DFA staining for L. pneumophila. Although a variety of stains (toluidine blue O, methenamine silver, WrightGiemsa, Diff-Quik, Calcofluor) are useful in identifying P. carinii in induced sputa or BAL specimens, or on imprint smears of tissue specimens, the most widely used diagnostic technique utilizes immunofluorescence with monoclonal antibodies against P. carinii. Rapid viral diagnosis (RSV, influenza, parainfluenza, adenovirus) by DFA can be applied to specimens from bronchial lavage or brushings or from nasopharyngeal swabs or washings. Anti–B. pertussis DFA may be used on nasopharyngeal aspirate smears in the presumptive diagnosis of pertussis.

Giemsa and Other Special Stained Smears for Diagnosis of Pneumocystis Infection

Since P. carinii pneumonia is an alveolar process, examination of routinely collected expectorated sputa for P. carinii is generally not regarded as rewarding in immunosuppressed patients with neoplastic disease or transplant recipients. In these patients, fiberoptic bronchoscopy and transbronchial biopsy, combined with BAL, provide the highest diagnostic yield. In patients with AIDS, however, induced sputum

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examination for P. carinii may be helpful. Sputum induction employing aerosolized, hypertonic saline provides a diagnosis in up to 80 percent of patients, particularly if coupled with microscopy of antibody-stained cytocentrifuged specimens.

Immunofluorescent assays, with monoclonal antibodies to P. carinii, of induced sputum have a sensitivity of 69 to 92 percent, compared with that of 28 to 80 percent for tinctorial stains. Toluidine blue O and methenamine silver stains stain only the cyst (less than 10 percent of the organism burden) and not the trophozoite forms of P. carinii. Giemsa and Diff-Quik stain trophozoites and intracystic sporozoites. If results of examination of induced sputum are negative and clinical circumstances warrant further attempts at diagnosis, follow-up bronchoscopy with transbronchial biopsy or BAL is performed. The sensitivity of each of these procedures for diagnosis of P. carinii pneumonia is more than 90 percent.

Special Microscopic Examinations

Occasionally, in the setting of apparent pulmonary inflammation with features atypical for infection, microscopic examinations using stains other than Gram’s stain may be indicated. For example, Wright-stained smears may show the presence of eosinophils in allergic pulmonary aspergillosis or other causes of pulmonary infiltrates that are accompanied by eosinophilia. Cytologic examination of exfoliated sputum using Papanicolaou’s stain may reveal a pulmonary neoplasm.

Birefringent calcium oxalate crystals (needlelike in rosettes or arranged like sheaves of wheat) in sputum cytologic specimens have been reported as suggesting pulmonary infection with Aspergillus (aspergilloma and, occasionally, invasive aspergillosis).

In the intubated or tracheotomized patient, whose tracheobronchial secretions commonly contain neutrophils and often some bacteria on Gram-stained smears, it may be difficult to distinguish between colonization and nosocomial pneumonia. The presence on light microscopy (×400) of characteristic elastin fibers with split ends (in a drop of tracheal aspirate to which a drop of 40 percent KOH has been added), in the appropriate clinical setting, is a strong indicator of a necrotizing pulmonary infection.

Intense bacteremia sometimes accompanies pulmonary infections, and the etiologic agent may be demonstrable on stained smears of the buffy coat of centrifuged blood: pneumococci have been identified in Gram-stained or Wright-Giemsa–stained smears of buffy coats from splenectomized patients; occasionally, M. avium-intracellulare has been found intracellularly in acid-fast stains of buffy coats from patients with AIDS. Additional special microscopic examinations may be indicated for immunocompromised patients who have patchy pulmonary infiltrates on the chest radiograph. For example, the presence of the hyperinfection syndrome of strongyloidiasis (often accompanied by E. coli bacteremia) can be established by the finding of filariform larvae in the sputum and in the stool after the latter is suitably prepared by concentration

techniques. Although eosinophilia is often present in patients with strongyloidiasis, it may be absent in the hyperinfection syndrome.

Sputum Cultures

In most patients with the common types of communityacquired and nosocomial bacterial pneumonia, the etiologic diagnosis can be made on the basis of the combined results of a Gram-stained smear of sputum and a proper culture of a suitable exudative portion of a freshly obtained sputum specimen. The criteria for a proper sample of sputum have been noted above. Culture entails streak dilution on blood agar and MacConkey media. Expectorated sputum should not be cultured anaerobically, since contamination with oral anaerobes is inevitable. Because patients with Legionnaires’ disease often have little sputum production, most attempts to isolate Legionella are limited to specimens obtained either by induced sputum samples, fiberoptic bronchoscopy or lung biopsy, or at thoracentesis. Cultures of such materials are plated on buffered charcoal-yeast extract (BCYE) agar. Occasionally, Legionella species can be isolated from sputum with the use of a semi-selective medium, either BCYE or BCYE-containing cefamandole, polymyxin B, and ansamycin. Culture is the most definitive method for diagnosis of Legionella infection.

Unfortunately, it may take 5 or more days for colonies to appear.

Cultures for mycobacteria are undertaken when clinical circumstances raise the possibility of pulmonary infections due to M. tuberculosis or atypical mycobacteria. Similarly, cultures of sputum for primary invasive mycotic agents (e.g., H. capsulatum, Blastomyces dermatitidis, and C. immitis) are dictated by clinical and epidemiological circumstances. In immunosuppressed patients, cultures of sputum are also directed toward uncovering a variety of opportunistic fungi, including Cryptococcus neoformans, Aspergillus species, and Mucoraceae.

Most hospitals do not have facilities for isolating viruses by tissue culture. This lack poses little problem in dealing with most community-acquired viral pneumonias, for which viral isolation is not necessary and the cost is prohibitive. However, viral isolation from throat washings is warranted in certain circumstances (e.g., to prove the presence of an outbreak of influenza), to establish that an outbreak among young children is due to RSV, and to identify a specific viral agent, such as an adenovirus, as the cause of a serious pneumonia that is not responding to antibacterial therapy. In immunosuppressed patients with pneumonia, a variety of opportunistic viral infections (CMV, RSV, varicella-zoster virus, herpes simplex) are diagnostic considerations. In vitro testing of CMV may provide data regarding susceptibility to antiviral agents. Most viral cultures and susceptibility (for CMV in particular) tests have been replaced by quantitative molecular amplification assays (polymerase chain reaction, PCR) or antigen detection systems (Table 112-6) that are more rapid and cost-efficient than culture systems.

Cultures are grown in cell lines susceptible to the viral infections under consideration in either standard

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“tube cultures” or “shell vial” cultures (rapid culture achieved by centrifugation of specimens against the cultured cells). Viral replication in the tissue culture can be confirmed within 48 h after inoculation with use of fluorescent monoclonal antibodies. Because CMV and herpes simplex are frequently present in the oral secretions of immunosuppressed patients, isolation of these viruses is apt to be meaningful only if the materials used for the isolation procedure were obtained either by bronchoscopy with protected specimen brushing (PSB) or with BAL, lung biopsy, or transtracheal aspiration.

Blood Cultures

Blood cultures should always be performed in patients with suspected bacterial pneumonia. Bacteremia occurs in approximately 30 percent of patients with pneumococcal pneumonia. Demonstration of bacteremia in other patients with pneumonia may indicate that the pulmonary infection is secondary to a focus of infection elsewhere (e.g., acute rightsided S. aureus endocarditis or P. aeruginosa infection of thermal burns). In patients with AIDS and disseminated M. avium-intracellulare infection, mycobacterial blood cultures are almost always positive. The lysis centrifugation technique permits ready and rapid isolation of the mycobacterium and quantifies the intensity of the bacteremia. L. pneumophila has been isolated with some frequency from automated radiometric blood culture bottles, but blind subculture onto BCYE agar is necessary because growth in the liquid medium does not achieve detectable levels.

Bacterial Antigen Detection in Sputum and Urine

The quellung reaction was extensively used in the preantimicrobial agent era to identify S. pneumoniae in sputum. It entails the use of light microscopy to detect capsular swelling after pneumococcal antiserum has been added to a loopful of sputum. The occurrence of the quellung reaction was shown to correlate closely with the presence of S. pneumoniae in sputum culture—in about 90 percent of the patients.

Pneumococcal antigens may be detected in the sputum of patients with pneumococcal pneumonia by enzyme-linked immunosorbent assay (ELISA), latex particle agglutination, or counterimmunoelectrophoresis. The first two are more readily available. ELISA is the most sensitive method. Antigen detection in sputum may have as high a sensitivity as 70 to 90 percent; but specificity is a problem, with about 20 percent false-positives, probably due in part to the difficulty in distinguishing oropharyngeal contamination and colonization (e.g., in patients with chronic bronchitis without pneumonia). Antigen detection in the urine has been less sensitive, and the sensitivity of antigen detection in the serum has been even lower.

A radioimmunoassay and an enzyme-linked immunoassay for L. pneumophila antigenuria are commercially available and provide a means of rapid (under 24 h) diagnosis of Legionella pneumonia, particularly in patients without sputum production. The sensitivity of the radioimmunoas-

Approach to the Patient with Pulmonary Infection

say is 89 to 95 percent, and the specificity is very high (estimated at 99 percent). The test is positive despite antimicrobial agent administration, and antigenuria may persist for weeks or months after recovery from pneumonia. It must be remembered that the assay is available only for L. pneumophila serogroup 1, and this serogroup is responsible for only 80 percent of L. pneumophila infections.

Rapid Viral Diagnosis by Antigen Detection

The need for methods that can rapidly identify viruses stems from the introduction of effective antiviral chemotherapy for several common viral agents. As noted earlier (“Direct Immunofluorescent Microscopy”), DFA can be used to detect viral antigens (adenovirus, influenza A and B, parainfluenza, and RSV, as well as CMV and herpes simplex virus [HSV]) in specimens of bronchial brushings, BAL, or nasopharyngeal washings. Enzyme immunoassay can also be used to detect viral antigens in respiratory secretions. The CMV antigenemia assay detects matrix protein pp65 and can be detected with the use of fluorescent or peroxidase-labeled antibody staining of peripheral blood neutrophils. This assay is semiquantitative. Quantitative and sensitive PCR assays are available for most clinically important viruses (see below, Table 112-6).

These are positive days in the advance of antigenemia assays, which are useful in management as well as diagnosis of acute infection. Strict criteria for CMV pneumonia include demonstration of the virus, typical cytologic changes, and absence of other evident pathogens. This is applicable in patients with AIDS, in whom CMV is frequently isolated but in whom CMV rarely causes pneumonia. In contrast, isolation of CMV from BAL fluid in blood or bone marrow transplant recipients with pneumonia is sufficient evidence to make the diagnosis and institute treatment, in view of the high frequency and mortality of CMV pneumonia in these patients.

Serologic Tests Serologic tests are sometimes of considerable help in establishing the causes of a number of pulmonary infections when the causative agents are difficult to isolate. However, this approach, requiring the demonstration of a fourfold or greater rise in titer between acute and convalescent samples, neither enables rapid diagnosis nor provides assistance in initial selection of antimicrobial therapy. Microimmunofluorescence serologic tests are of value in the diagnosis of psittacosis (Chlamydophila psittaci). A fourfold rise in IgG or the presence of IgM antibody indicates recent infection. The indirect immunofluorescent antibody test (fourfold titer rise to 1:128 or higher indicates recent infection) may provide a retrospective diagnosis of Legionnaires’ disease, but the antibody rise occasionally may not be demonstrable for 4 to 6 weeks after the clinical onset. Antibodies may persist for months or up to a year or more. Thus, a single titer of 1:256 or higher may reflect a prior Legionella infection. Cold agglutinins develop in about half the patients with M. pneumoniae pneumonia, but such antibodies occur in other conditions; complement fixation testing is the preferred diagnostic procedure. The

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most sensitive and specific serologic test for infection with C. pneumoniae is the microimmunofluorescence test. A fourfold rise in IgG titer or an IgM titer of 1:16 or more reflects an acute infection. The complement fixation test is usually used to confirm a diagnosis of Q-fever pneumonia, but microimmunofluorescence, microagglutination, and ELISA have been used to diagnose acute Coxiella burnetii pulmonary infection.

Tularemic pneumonia can be diagnosed serologically with an agglutination test for Francisella tularensis.

Serologic tests are also helpful in the diagnosis of invasive infection due to the primary pulmonary mycotic pathogens. Serum IgM precipitins (latex agglutination, immunodiffusion) appear with primary coccidioidomycosis.

Abnormally high complement fixation titers (at least 1:32) are present in most patients who have disseminated infection due to C. immitis. A fourfold increase in complement fixation titer to yeast and to mycelial phases of H. capsulatum (or possibly a single titer of 1:64 or higher) and the presence of H and M precipitin bands strongly suggest histoplasmosis.

Complement fixation tests for blastomycosis lack sensitivity and specificity: titers of at least 1:8 suggest recent or active disease, particularly if precipitins to the A antigen are also present. Cryptococcal antigenemia is detectable from latex particle agglutination in patients with cryptococcal pneumonia or disseminated cryptococcal infection. Sporotrichosis can be diagnosed with a serologic agglutination test when the titer is 1:80 or greater. Pulmonary toxoplasmosis is uncommon in seronegative individuals although acute toxoplasmosis is seen in endemic regions (the Caribbean, France) and after organ transplantation.

Serologic tests (paired acute and convalescent sera) may be helpful for the retrospective diagnosis of infections due to influenza A and B, RSV, adenoviruses, and parainfluenza viruses.

Molecular Diagnostic Testing A variety of nucleic acid target amplification tests (often PCR) are available for the direct detection of pulmonary pathogens.

PCR tests approved by the U.S. Food and Drug Administration can detect M. tuberculosis (as distinct from nontuberculosis mycobacteria) directly from sputum and BAL specimens.

These tests have shown a sensitivity of 90 to 100 percent in specimens that are acid-fast bacillus (AFB) smear–positive but a sensitivity of only 65 to 85 percent for specimens that are smear negative. Consequently, these PCR assays have been approved for use only on AFB smear–positive specimens. In some major medical centers, PCR assays for detection of C. pneumoniae and M. pneumoniae on nasopharyngeal or throat swab specimens are available to markedly shorten (by 1 to 2 days) the time required to isolate these organisms by culture (up to 3 weeks). Molecular detection of HSV, adenovirus, CMV, EBV, and other pathogens are used primarily with blood specimens but may also be used in BAL or cerebrospinal fluid samples. The interpretation of such assays used with respiratory secretions is nonstandardized and blood studies are preferred. Molecular amplification is under development for

many common pulmonary pathogens including P. carinii, L. pneumophila, and Candida and Aspergillus species.PCR tests are also under development for agents of bioterrorism.

Skin Tests of Delayed Hypersensitivity The tuberculin skin test is of great importance in the evaluation of a pulmonary infection of unknown origin. The intermediate (5 tuberculin unit) purified protein derivative (IPPD) test should be used if no information is available about previous testing. A positive test does not distinguish between prior and current infection, but in persons who are either less than 35 years old or members of high-risk groups (immigrant, HIV-positive), a positive reaction carries considerable diagnostic weight.

A negative second-strength PPD skin test in a patient who is not anergic is strong evidence against a tuberculous origin of a pulmonary process. However, several caveats are noteworthy: since it may take 4 to 6 weeks for the skin test to become positive, the tuberculin skin test may be initially negative in progressive primary pulmonary tuberculosis, and in the patient who was infected long ago, cutaneous hypersensitivity may wane; in the elderly person, in whom waning has occurred, repeat testing several weeks later may show a positive result (booster effect) even if the original IPPD skin test was negative.

Fungal skin tests do not distinguish between current and past infection; indeed, active disease is often accompanied by a negative skin test. The coccidioidin skin test is the best of the available tests, but the diagnosis of coccidioidomycosis is not excluded by a negative test. Blastomycin and histoplasmin skin tests are of little value because of frequent falsenegative results and cross-reactions. Also, the performance of the histoplasmin skin test may falsely elevate antibody levels to the H. capsulatum mycelial antigen.

A negative skin test response to a specific antigen must be interpreted in light of possible anergy. A battery of control antigens (mumps, Candida, Trichophyton, streptokinase-streptodornase) serves to detect such anergy, but these reagents are increasingly unavailable and costly.

Invasive Diagnostic Procedures In certain circumstances, a more aggressive approach is required to uncover the etiology of pneumonia. This should be considered in any patient with immune deficiency or who is critically ill in whom rapid therapy is critical or in whom drug toxicity may be a major concern (e.g., renal transplant recipients). Such procedures are best done prior to the initiation of antimicrobial therapy. Such an approach may also be required if the patient’s condition continues to deteriorate despite empiric antimicrobial therapy. In the immunocompromised patient, early invasive diagnostic approaches are mandated by the large number of etiologic agents that may be responsible, the frequent involvement of many infectious or noninfectious agents in the pulmonary process, the multiplicity of antimicrobial choices available against different organisms, and the rapidity with which clinical deterioration may

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preclude further diagnostic and therapeutic actions. Among such invasive diagnostic procedures are bronchoscopy, BAL, open lung biopsy, transthoracic needle aspiration, and videoassisted thoracoscopy (VATS). A choice has to be made for one of several invasive procedures. The choice depends on the experience and skill with the different procedures at a given hospital. Also important in determining the proper procedure are the location and radiographic appearance of the pulmonary lesions. Fiberoptic bronchoscopy using specialized devices to shield against oropharyngeal contamination (protected specimen brushing) is used at some institutions to obtain tracheobronchial secretions for culture in certain acute bacterial pneumonias. A peripheral nodule or cavity (more than 1 cm in diameter) that is readily visualized on conventional (posteroanterior and lateral) radiographs and fluoroscopy, and is in an accessible location, may be aspirated and biopsied by a needle introduced percutaneously. A nodule that is inaccessible to needle aspiration, or a process placed peripherally, where the need for histopathology is not apt to be met by needle aspiration and biopsy, is best approached by open lung biopsy.

Flexible Fiberoptic Bronchoscopy with Lung Biopsy Fiberoptic bronchoscopy in conjunction with transbronchial lung biopsy provides an etiologic diagnosis in about 50 to 80 percent of immunosuppressed patients who do not have AIDS and in 60 to 90 percent of patients who do have AIDS, in whom P. carinii, CMV, and M. avium-intracellulare infections are common. Contraindications to transbronchial biopsy include inability of the patient to cooperate, marked hypoxemia, bleeding disorders (particularly those associated with hypoprothrombinemia, thrombocytopenia refractory to platelet transfusion, and uremia), and pulmonary hypertension. In such patients, correction of bleeding tendency and/or open procedures may be preferred. Fiberoptic bronchoscopy combined with transbronchial biopsy and segmental BAL is the usual initial invasive diagnostic procedure in the immunocompromised patient with an undefined diffuse pulmonary process. If this fails to provide a diagnosis, open lung biopsy is indicated.

Tissue specimens are processed for histopathological examination (hematoxylin and eosin stain, tissue acid-fast stains, Gomori’s methenamine-silver stain, periodic acid– Schiff stain, tissue Gram’s stain, and Dieterle silver stain).

Impression smears from tissues are made with sterile slides, which, after appropriate fixation, are stained with Giemsa, Gram, Ziehl-Neelsen, and methenamine silver (for P. carinii) stains, as previously described. As indicated, DFA staining for Legionella and monoclonal antibody staining for P. carinii are performed on separate impression smears. Appropriate cultures are made with tissue obtained either transbronchially or at open lung biopsy.

Bronchoalveolar Lavage

In patients with AIDS, fiberoptic bronchoscopy coupled with wedged, terminal, subsegmental BAL has proved particu-

Approach to the Patient with Pulmonary Infection

larly useful, providing a diagnosis in more than 95 percent of cases of Pneumocystis pneumonia. BAL alone, without transbronchial biopsy, is often substituted in patients who are thrombocytopenic, on mechanical ventilation, or severely hypoxemic. It should be noted that the yield in non-AIDS immunocompromised hosts is significantly less than in AIDS. Biopsy is often needed in this population. The material obtained by BAL is processed for smear and culture. As indicated earlier, a variety of stains are available for demonstrating the presence of Pneumocystis in the cytocentrifuged material.

Stained cytocentrifuged BAL specimens can also be helpful in establishing other diagnoses: Papanicolaou’s stain is useful in detecting neoplastic cells and in identifying viral cytopathic effects in epithelial cells.

In at least two-thirds of immunosuppressed patients with CMV pneumonia, the diagnosis can be made from the finding of inclusion bodies in cytocentrifuged BAL specimens and with immunofluorescent monoclonal antibody staining.

CMV is isolated more often on culture in these patients, but culture alone is not sufficient to establish the diagnosis, since viral isolation may represent only viral shedding in the presence of pulmonary disease due to other causes.

Invasive Diagnostic Testing in Ventilator-Associated Pneumonia

Protected specimen brushing (PSB) with quantitative culture and protected-catheter BAL, also with quantitative culture, have been employed to obtain bacteriologic information while minimizing opportunity for contamination from colonization of the upper airway in patients with ventilatorassociated pneumonia (VAP). The role of quantitative diagnostic techniques in the evaluation of patients with hospitalacquired pneumonia (HAP) and VAP remains controversial (discussed below) because of questions of reproducibility and the optimal threshold concentration of bacteria. In at least one study, tracheal aspirate cultures correlated with PSB cultures in patients with VAP, suggesting no added value to use of such an invasive procedure to direct initial therapy. The routine use of such tests requires standardization of techniques at the institutional level.

Percutaneous Transthoracic Needle Lung Biopsy Percutaneous needle biopsy is often the invasive diagnostic procedure of choice for a sizable (greater than 1 cm) pulmonary nodule or cavity that is located peripherally. The use of smaller-gauge needles has reduced the frequency of pneumothorax as a complication. Diagnostic yields of 60 to 80 percent have been obtained in immunocompromised patients with pneumonia. This procedure has also provided the diagnosis in 70 percent of patients in whom the underlying lesion was granulomatous. The small core of tissue and aspirated fluid is examined by stained smear and culture for various infectious agents (see “Flexible Fiberoptic Bronchoscopy with Lung Biopsy”). Cytologic examination should be done for neoplastic cells. Because of the nature of the specimen, however, histopathological examination is generally fruitless.

In patients in whom respiratory status is tenuous, or in whom

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lymph node biopsy or sampling of pleural fluid may be desired, VATS or open biopsy may be preferable.

Open Lung Biopsy Open lung biopsy and more recently VATS, provides the most definitive procedure for histopathological diagnosis in the immunocompromised host. It provides sufficient lung tissue for diagnosis and also makes it possible to sample several different sites. It is particularly suitable for evaluating processes that may not be infectious (e.g., neoplasm such as Kaposi’s sarcoma, antineoplastic drug toxicity, drug hypersensitivity, and lymphocytic interstitial pneumonia). Open lung biopsy has provided a specific diagnosis in 60 to 90 percent of nonAIDS immunocompromised patients. Major advantages include specimen size and the ability to control bleeding, air leaks, and the airway. Its disadvantages relate to the thoracotomy: the need for general anesthesia, the inherent delay in preparing the patient for the surgical procedure, the need for intubation, the usual placement of a chest tube, and postoperative splinting due to incisional pain. Some of these complications are decreased in VATS. The mortality from the procedure is about 1 percent. Bleeding is a complication in about 1 percent of patients and delayed pneumothorax in about 9 percent. For the patient in whom the pace of the illness does not allow this sequential approach, open lung biopsy may have to be the first choice. It is also preferred in the patient who is unable to cooperate with fiberoptic bronchoscopy or in whom thrombocytopenia or hypoxemia pose additional problems for transbronchial biopsy.

Processing of lung biopsy specimens should include special stained imprint smears for P. carinii, bacteria (including Nocardia and mycobacteria), fungi, and viral inclusion bodies; cultures for bacteria, viruses, fungi, and mycobacteria; and tissue sections stained for histology and for infectious agents.

MAJOR CLINICAL SYNDROMES Community-Acquired Pneumonia Approximately 1 million people are admitted to the hospital each year for pneumonia. Initial evaluations of pulmonary processes in the outpatient setting revolve around an assessment of whether the individual merits admission to the hospital for management. Clinical judgment is the most important guide to appropriate care. This judgment is based on whether the patient can manage at home (needs oxygen or intravenous antimicrobials, weakness, cannot eat independently or take oral medications, other preexisting medical or psychiatric conditions, substance abuse, home supports) and whether the patient is at risk for disease progression.

Many factors have been implicated in risk for death due to pneumonia. These include both common (alcoholism) and less common (immune deficiency) underlying conditions (Table 112-7). The PORT (Pneumonia Outcomes Research

Table 112-7 Underlying Conditions Contributing to Adverse Outcomes from Pneumonia Alcohol consumption Increasing age Leukopenia Congestive heart failure Coronary artery disease Diabetes mellitus Immune compromise Neurological disease Active malignancy Clinical signs including: dyspnea/tachypnea, hypothermia, chills, hypotension, confusion or altered mental status Laboratory tests: hyponatremia, hyperglycemia, azotemia, hypoalbuminemia, liver function test abnormalities Radiographic infiltrates and pleural effusions, post-obstructive pneumonia Microbiology: gram-negative bacilli, S. aureus, mixed flora (aspiration), bacteremia

Team) Severity Index (PSI) is a quantitative tool that assesses the severity of a patient’s illness, prognosis, and the need for hospitalization. This index provides the basis of North American practice guidelines for community-acquired pneumonia (CAP).

For more than half of the patients with CAP, no causative pathogen can be identified. Up to 15 percent of CAP cases are due to aspiration or mixed bacteria. In most series, 20 to 65 percent are due to S. pneumoniae (pneumococcus).

Approximately 15 percent of patients have definable, nonbacterial etiologies such as M. pneumoniae, C. psittaci, or viruses.

These atypical pathogens are difficult to diagnose (and therapy, while universal, is often of less than certain value). The atypical pathogens, the pneumococcus and Legionella species, and aspirational events account for many of the undiagnosed cases of CAP. Certain uncommon causes may be endemic, in particular geographic niches, including Coxiella burnetii (in Nova Scotia) or Francisella tularensis in Little Rock, Arkansas.

Thus, a major variable is the regional incidence of endemic infections including tuberculosis, and the episodic occurrence of epidemic infections such as outbreaks of influenza virus or Hantavirus.

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CAP is a major cause of infectious morbidity and mortality. Depending on the causative organisms, the mortality of CAP ranges from 10 to 15 percent for pneumococcal infection to 60 percent for P. aeruginosa. Adverse clinical prognostic factors included co-morbid conditions (neurological or neoplastic disease, cirrhosis, congestive heart failure, respiratory compromise, diabetes, hepatic and renal dysfunction, immune deficiency), bacteremia, and multilobar involvement. S. pneumoniae is the preeminent bacterial cause of CAP. H. influenzae, usually unencapsulated strains, may produce pneumonia in patients with chronic bronchitis or in the chronic alcoholic. Apart from S. pneumoniae, however, the most important pathogen in this type of patient, by virtue of its virulence and special antimicrobial agent susceptibilities, is K. pneumoniae. During an outbreak of influenza viral infections, bacterial superinfections often occur, usually in the elderly or in patients with chronic cardiopulmonary disease. Patients with secondary bacterial pneumonia often have up to 4 days of clinical improvement after the initial influenzal illness before the onset of overt pulmonary infection. The superinfecting microorganisms are the pathogens that would ordinarily colonize the upper airways but opportunistically invade a tracheobronchial tree that has been recently damaged. These organisms include S. pneumoniae, H. influenzae, S. aureus, Streptococcus pyogenes, M. catarrhalis, and K. pneumoniae. The use of antimicrobial agents at the time of the initial respiratory infection not only is useless against viral influenza but also may selectively promote the emergence of a more resistant bacterial flora in the respiratory tract. S. aureus is a very uncommon cause of CAP. Indeed, the occurrence of several cases of S. aureus pneumonia in the community during the winter months is usually a good indicator of the presence of an ambient influenza outbreak. Pneumonia due to S. pyogenes is quite uncommon.

Usually it occurs as a superinfection in a patient with influenza or as a primary pneumonia in the course of a regional outbreak of group A streptococcal infections (as still occurs from time to time when a new M-antigenic type appears in a community).

Atypical Pneumonia Syndromes and Endemic Mycoses In the evaluation of patients with CAP, it is often helpful to consider separately a group of patients whose illness is characterized by minimal sputum that does not reveal a predominant microbial etiology on routine smears (Gram’s stain, Ziehl-Neelsen) or cultures (including for mycobacteria and Legionella). The clinical onset of illness is generally subacute with a radiologic picture consisting of patchy infiltrates or an interstitial pattern than a lobar consolidation. Fever and peripheral leukocytosis are less common or intense than in common bacterial pneumonias. For convenience, this grouping has been designated atypical pneumonia.

The entities in the category of atypical pneumonia are heterogeneous (Table 112-8). The syndrome may account for up to 60 percent of cases of CAP. M. pneumoniae is the causative agent in about 25 percent of the cases of atypical

Approach to the Patient with Pulmonary Infection

Table 112-8 Causes of “Atypical Pneumonia” Mycoplasma M. pneumoniae Chlamydophila C. psittaci (psittacosis), C. pneumoniae Respiratory tract viruses Influenza, adenovirus, respiratory syncytial virus, parainfluenza virus Bacteria Legionella, F. tularensis, Y. pestis, B. anthracis Fungi Histoplasma, Blastomyces, Coccidioides, Pneumocystis Aspiration pneumonitis Sterile or mixed upper respiratory and oral flora Other viral agents Varicella-zoster, measles, Epstein-Barr virus, cytomegalovirus, metapneumovirus, Hantavirus Rickettsia C. burnetii (Q fever)

pneumonia. Respiratory viruses are responsible for about another 30 percent. However, the predominant etiologic agent varies with the season and the prevalence of influenza viruses in the community. This information should direct the initial evaluation (e.g., nasal swab for respiratory viruses).

Chlamydophila pneumoniae (formerly known as Chlamydia strain TWAR) is an infectious agent that can be spread from person to person and appears to be responsible for 12 to 21 percent of cases of atypical pneumonia. This form of pneumonia typically occurs in young adults as a sporadic mild pneumonia, but may have enhanced severity when coinfecting individuals with pneumococcal infection. In adults, M. pneumoniae pneumonia, in contrast to bacterial pneumonia, often begins insidiously with malaise, fever, and prominent headache. Sore throat is common, but coryza is minimal or absent. Nonproductive cough develops over the next few days and is the hallmark of this disease. Skin rash (erythema multiforme) and bullous myringitis, usually appearing late in the course of illness, are uncommon findings but, when present, do suggest the diagnosis. Mini-outbreaks of M. pneumoniae infection in households, schools, and military camps may not be appreciated because of the long incubation period (3 weeks) and variation in clinical presentation.

Q fever, due to C. burnetii, is suspected on the basis of epidemiological clues. Transmission of this disease to humans occurs as a result of inhalation of aerosols from surroundings

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contaminated by placental and birth fluids of infected livestock (cattle, sheep, goats), wild rabbits, and domestic animals (cats). Veterinarians, ranchers, taxidermists, and others who handle livestock are at particular risk. Since the incubation period of Q fever is approximately 20 days, a source of exposure may be overlooked. Although the clinical picture resembles that of M. pneumoniae pneumonia, the onset may be more abrupt, with chills and high fever. Liver function abnormalities or clinical hepatitis in a patient with atypical pneumonia is suggestive of Q fever. In some geographic areas (Australia, France), hepatitis has been the most frequent clinical presentation of C. burnetii infection; in others (Spain, Nova Scotia), pneumonia has been the major presenting sign.

Chlamydia trachomatis causes pneumonia in the newborn but has not been proved to be a cause of pneumonia in adults. C. psittaci, the causative agent of psittacosis, is spread to humans by avian species. Although psittacine birds (parakeets, parrots) are the major reservoir, human infection can be acquired from pigeons, sparrows, and turkeys.

In a patient with atypical pneumonia, the clinical features that raise the possibility of this etiology are relative bradycardia, splenomegaly and hepatomegaly, and hepatic dysfunction. C. pneumoniae produces atypical pneumonia without the usual bird-to-human transmission of C. psittaci infection.

Legionella infections (due to L. pneumophila and other Legionella species) account for 2 to 4 percent of cases of atypical pneumonia. Although Legionella is an important nosocomial pathogen, it is also responsible for communitybased sporadic cases and major outbreaks. The occurrence of summer outbreaks associated with the use of air conditioners, pooled water, and evaporative condensers should call attention to this possible cause of pneumonia. Various extrapulmonary manifestations are common with Legionnaires’ disease including relative bradycardia, diarrhea for 24 h at the onset of illness, confusion and obtundation, mild renal dysfunction (azotemia, microscopic hematuria, proteinuria), acute rhabdomyolysis, and mild hepatic dysfunction. Although many of these manifestations also occur with other pneumonias, the coincidence of several of these features should raise the possibility of Legionella infection. This is particularly important in view of the fact that the antimicrobial therapy (macrolides, fluoroquinolones) for Legionnaires’ disease differs from that for the more common bacterial pneumonias. The mortality from Legionnaires’ disease, if inadequately treated, can be as high as 15 percent.

Recurrent chills, which occur over several days in Legionnaires’ disease, are rare in pneumococcal pneumonia unless septic complications (e.g., endocarditis and pericarditis) develop. Although the initial radiographic picture of Legionella pneumonia is often that of an interstitial, segmental, or bronchopneumonic pneumonia, if the disease is untreated, it progresses to lobar or multilobar consolidation, a picture that mimics pneumococcal or Klebsiella pneumonia.

The other noteworthy bacterial types of atypical pneumonia are those due to F. tularensis (tularemic pneumonia), Yersinia pestis (plague pneumonia), and Bacillus anthracis (anthrax pneumonia). These are all singularly uncommon

causes of pneumonia, and the principal clues to diagnosis again derive from epidemiological considerations. Exposure to F. tularensis comes through contact with tissues of an infected animal (rabbit), animal bites (coyote, cat), inhalation of infectious aerosols, tick or deerfly bites, or ingestion of contaminated water or poorly cooked meat from an infected animal. Ulceroglandular tularemia, or the typhoidal form of tularemia, may be complicated by patchy pulmonary infiltrates. Indeed, it is likely that typhoidal tularemia often represents infection initially acquired via the bronchogenic route.

Plague is less common than tularemia in the United States and is strictly localized to southwestern states, including California. The diagnosis should be considered in a person from an endemic area who has a septic illness (septicemic plague) or painful localized lymphadenopathy with fever (bubonic plague) and a history of bites by rodent fleas or of handling tissues of infected animals, such as prairie dogs or coyotes.

Pneumonia occurs as a complication in 10 to 15 percent of patients with bubonic or septicemic plague. Primary (inhalation) pneumonic plague is extremely rare and occurs only as a result of exposure to aerosolized particles from an infected animal or following close contact with cases of plague pneumonia. Anthrax pneumonia (inhalation anthrax) is also extremely rare in this country; it is a consequence of the inhalation of anthrax spores during the processing, or use, of goat skin, hair, or wool (usually imported from the Middle East, Asia, or Africa).

The principal clues to the presence of pulmonary mycoses are epidemiological. Thus, the principal endemic areas for histoplasmosis in the Western Hemisphere are in the midwestern United States and Central America. However, disease can be found in other locales and after travel. The organism is present in high concentrations in soil sites where avian, chicken, or bat excrement has accumulated. Movement of soil in such endemic areas by cleaning chicken coops, knocking down old starling roosts, or cleaning out old attics or basements can expose people to high concentrations of airborne spores that, when inhaled, produce an acute pneumonia. Atypical pneumonia in a person with this type of geographic exposure, or in a spelunker, should automatically raise the possibility of histoplasmosis. Blastomycosis occurs throughout most areas of the United States, but the endemic area is principally in the southeastern and south central areas.

Rural exposure to soil contaminated with animal excrement appears to be a risk factor. Skin lesions, either verrucous or ulcerative, are the most common extrapulmonary manifestations of blastomycosis and afford a clinical clue to diagnosis.

Coccidioidomycosis is endemic in the southwestern United States (California, particularly the San Joaquin Valley, and Arizona) and in neighboring portions of Mexico. Infection is usually acquired in these areas by inhalation of highly infectious arthrospores. Occasionally, major dust storms carry the arthrospores considerable distances from their soil source and produce unexpected outbreaks of infection. Archeological digs sometimes cause infection in those living elsewhere who receive an artifact uncovered in the explorations. Erythema nodosum may be associated with any of the primary

2007 Chapter 112

pulmonary mycoses, but most often with coccidioidomycosis. The coincidence of this hypersensitivity skin lesion and an atypical pneumonia syndrome in a person from an endemic area suggests the possibility of one of these pulmonary mycoses.

Paracoccidioidomycosis (South American blastomycosis) is endemic to Brazil (predominantly), and in Colombia, Venezuela, and Argentina. This disease is caused by Paracoccidioides brasiliensis. In adults, the manifestations of this disease are mainly pulmonary; radiographs show patchy or confluent areas of consolidation, often bilateral. Cases have occurred in North America and Europe, but in those instances, the patients had previously resided in endemic areas where initial infection presumably had been acquired.

Aspiration Pneumonia Aspiration pneumonia may occur after an overt episode of aspiration (e.g., of gastric contents) or of bronchial obstruction by a foreign body. More often the predisposing circumstances are clear-cut (e.g., alcoholism, nocturnal esophageal reflux, pyorrhea, a prolonged session in the dental chair, epilepsy, or chronic sinusitis in a patient with absent gag reflex). In these circumstances, since the pneumonia may develop more insidiously than after overt aspiration, the relationship of the developing pneumonia to the predisposing circumstances may not be appreciated at the time. For this reason, specific questioning regarding such possible pathogenetic factors and evaluation of the gag reflex should be part of the examination of any patient with pneumonia.

If untreated, aspiration pneumonia may progress rapidly to a necrotizing process that is usually due to anaerobic organisms. The process may involve a pulmonary segment, a lobe, or an entire lung, with ultimate extension to the pleura (“putrid empyema”); in some patients, the necrotizing pneumonia culminates in lung abscesses. In others, aspiration produces an illness of several weeks’ duration that is characterized by malaise, productive cough, and low-grade fever. If a chest radiograph is first taken after several weeks of untreated illness, it may show little, if any, evidence of pneumonia but will clearly identify a well-formed lung abscess.

In community-acquired aspiration pneumonia, bacteriologic studies provide a statistical basis for selecting initial antimicrobial therapy. Anaerobic bacteria are etiologically implicated in about 90 percent of community-acquired aspiration pneumonias and lung abscesses. In 40 to 65 percent of these patients, anaerobic organisms are the sole infecting agents; in 40 to 45 percent, the cause is a mixture of anaerobes and aerobes. The most common anaerobes are Prevotella melaninogenica, Bacteroides species, Porphyromonas species, Fusobacterium species, peptostreptococci, peptococci, and microaerophilic streptococci. β-Lactamase– producing Bacteroides species, P. melaninogenica, and members of the Bacteroides fragilis group are present in about 15 percent of cases. P. melaninogenica may be the most important contributor in such mixed infections. The aerobic indigenous flora in mixed aerobic-anaerobic infections are

Approach to the Patient with Pulmonary Infection

Streptococcus viridans, M. catarrhalis, and Eikenella corrodens.

A rare form of anaerobic aspiration pneumonia (actinomycosis) that is community-acquired is that due to Actinomyces israelii, part of the normal flora in the gingival crevice or may contribute to chronic sinus infection. The direct extension of such a necrotizing pneumonia to the pleura and chest wall is a characteristic finding that strongly suggests the diagnosis of actinomycosis.

Although anaerobic members of the oropharyngeal flora have a preeminent role in community-acquired aspiration pneumonia and lung abscess, occasionally colonizing gram-negative enteric bacilli such as K. pneumoniae, E. coli, and Proteus species may be the cause (notably in alcoholics).

Persistence of a necrotizing pneumonia or lung abscess despite antimicrobial therapy that would be expected a priori to be effective raises the possibility of an underlying obstruction, often in the form of bronchogenic carcinoma, particularly if the patient is edentulous.

Pneumonia in the Elderly CAP in the elderly (over 60 years) primarily affects two populations: one that lives at home and another residing in nursing homes. The latter, from the point of view of oropharyngeal flora and the extent of exposure to antimicrobial agents, is generally considered as a part of “Health Care–Associated Pneumonia” (HCAP), with a predisposition to nosocomial infection (see below) with an increased rate of antimicrobial resistance. The clinical features of pneumonia in the elderly may differ in presentation from that in younger people. Infection has a more gradual onset, with less fever and cough, often with a decline in mental status or confusion and generalized weakness, often with less readily elicited signs of consolidation on examination. Eliciting a deep breath from the patient may be helpful in demonstrating a localized wheeze or rales that might otherwise be undetectable. Among the bacterial causes of CAP in the elderly, S. pneumoniae is the most frequent, accounting for 30 to 60 percent of cases. H. influenzae, primarily nontypeable strains, is the second most common cause (about 20 percent). M. catarrhalis is another cause of pneumonia in this age group, primarily in patients with chronic bronchitis. Aspiration pneumonia due to mixed aerobic-anaerobic flora occurs in this age group, particularly because of the presence of a diminished gag reflex or impaired pharyngeal motor function.

In nursing home residents or persons with recent hospitalizations, increased oropharyngeal colonization with gramnegative bacilli occurs, due to antimicrobial exposure, or exposure to the hospital environment or to other recent patients.

Microaspirational events predispose to pneumonia due to species such as K. pneumoniae, E. coli and other Enterobacteriaceae, and P. aeruginosa. Such gram-negative bacilli have been implicated as the cause in 25 to 40 percent of elderly nursing home residents with pneumonia. S. aureus is responsible for 2 to 10 percent of cases of CAP in the elderly overall, more commonly in nursing home residents and during community outbreaks of influenza. Common forms of CAP are also seen in the elderly.

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SUSPECTEDHAP, VAP, OR HCAP

Lower Respiratory Tract Sample for microscopy, Culture (quantitative or semiquantitative), and susceptibility data, blood cultures, radiography

Negative smears and low suspicion for infection

Serial clinical evaluations, microbiologic data, no empiric antimicrobials

Improved

Culture +

Narrow Spectrum of Antimicrobial therapy, consider duration of therapy

High Suspicion or positive smears Empiricantimicrobial therapy

Daily clinical assessment, review of laboratory data (microbiology, purulence of sputum, CBC, oxygenation, hemodynamics and organfunction), chest radiograph

NO CLINICAL IMPROVEMENT BY 48-72 HOURS

Culture -

Were Optimal Cultures Obtained?

Reculture, Consider Narrowing Therapy, Assess Sputum Purulence .Alternative Diagnoses?

Culture -

Adjust/Optimize antibiotics, Seek other sites of infection, other processes, additional pathogens

Culture -

Reculture, See Noninfectious Processes, Che Susceptibility Da Other Sites Of Infection

Figure 112-11 Paradigm for the evaluation of patients with nosocomially acquired pneumonia. Careful reassessment of patients on a daily basis is needed to assure an adequate response to therapy. Clinical judgment is the best guide to the use of empiric therapy.

Hospital-Acquired, Ventilator-Associated, and Nonresolving Pneumonias The hospitalized patient with pneumonia poses the dual challenge of infection with nosocomial pathogens and the presence of concomitant processes—the “sick” patient (Fig. 11211). Nosocomial pneumonia occurs at a rate of 5 to 10 cases per 1000 hospital admissions. The incidence increases 6- to 20-fold in patients receiving assisted ventilation. Hospitalacquired pneumonia (HAP) develops over 48 hours into hospitalization while VAP occurs more than 48 to 72 hours after endotracheal intubation. HCAP includes patients with infection developing within 90 days of hospitalization, residents in a nursing home or long-term care facility, or those who have had recent exposure to hemodialysis, intravenous antimicrobial therapy, chemotherapy, wound care, or hospitalassociated clinics. HAP accounts for up to one-fourth of intensive care unit infections. VAP occurs in up to one-fourth of intubated patients in some series, generally in the first 4 days of intubation.

Early-onset (first 3 days) nosocomial pneumonia is more often due to organisms without antimicrobial resistance including S. pneumoniae, H. influenzae, and M. catarrhalis. Community-acquired atypical pathogens (Mycoplasma, Chlamydophila) may also lead to early hospitalization. Beyond 5 days of hospitalization, or in those with recent hospitalization or with prior antimicrobial therapy, infection is more often due to multidrug-resistant (MDR) organisms (K. pneumoniae, other Enterobacteriaceae, Acinetobacter species, and P. aeruginosa) and mortality is increased. Attributable mortality for nosocomial pneumonia approaches 50 percent.

In practice, pneumonia is defined as the presence of a new or progressive radiologic infiltrate coupled with evidence that the infiltrate is infectious in origin—fever higher than 38◦ C, leukocytosis or leukopenia, and/or purulent secretions. Two out of three criteria are generally considered adequate. Tracheal aspirates will generally contain the offending organism(s) but may be contaminated by uppertract flora, notably flora associated with tracheobronchitis.

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Semiquantitative cultures are used to discriminate between pathogens and commensals. Gram staining of such specimens provides added information about host response (neutrophils and macrophages) and predominant bacterial forms.

In immunocompromised hosts, fungal smears and cultures, cultures and microscopy for Legionella, Nocardia, and mycobacteria should also be obtained. A good sputum specimen or an aspirate lacking bacteria or inflammatory cells (in a non-neutropenic host) should suggest other diagnoses (nonbacterial or noninfectious). While the majority of HAPs are bacterial, nosocomial infection due to respiratory viruses and Legionella species are common. A negative Gram’s stain of a good tracheal aspirate has a strong negative predictive value (approximately 94 percent) for VAP. Some friction exists between strict advocates of microbiologic evaluations and care which is based on clinical expertise. In practice, neither is sufficient, per se. Lower respiratory tract cultures must be obtained prior to the initiation of antimicrobial therapy, but should not delay the initiation of therapy in critically ill patients or in those with evidence of sepsis. Respiratory specimens may be obtained bronchoscopically or nonbronchoscopically, and cultured semiquantitatively or quantitatively, based on local expertise and availability. All patients with nosocomial pneumonia should also have blood cultures, chest radiography, arterial oxygenation levels, and diagnostic thoracentesis if large pleural effusions are present.

The use of semiquantitative cultures and clinical judgment results in the inappropriate use of broad-spectrum antimicrobial therapy in some patients with either minor infections or colonization in the setting of other pulmonary inflammatory processes: drug reactions, cancer, ARDS, congestive heart failure, pulmonary thromboembolus, hemorrhage, or even viral infection. However, depending on the patient mix of the institution (acuity, immune deficits) this approach is generally appropriate.

A narrower spectrum of initial antimicrobial therapy is possible by using quantitative cultures of invasive (endotracheal aspirates, BAL, or PSB specimens) specimens from the lower respiratory tract. Bacterial growth above a predetermined threshold (e.g., 104 to 105 cfu/ml in BAL or 103 cfu/ml for PSB specimen) provides a basis for treatment. Quantitative approaches may suffer from poor reproducibility and the impact of recent antimicrobial therapies (e.g., the use of empiric antimicrobial agents entails the risk of false-negative cultures and under-treatment of specific pathogens or patients). Pneumonia “in evolution” or patchy processes may confound quantitative approaches. This approach risks delays in therapy while awaiting culture data. This reservation is addressed in part by using detection of intracellular organisms (in 2 to 5 percent of cells) on Gram’s stained smear as a basis for empiric therapy. Sensitivity and specificity of various methods of collection and analysis vary greatly—but can be standardized within an institution.

Use of appropriate antimicrobial agents initially has a major beneficial impact on patient survival. Prior antimicrobial therapy and colonization patterns must be considered as

Approach to the Patient with Pulmonary Infection

risk factors for antimicrobial-resistant pathogens. The major pathogens in “hospital-acquired” pneumonia vary among institutions and within hospitals. Thus, empiric therapies must be individualized by institution as well by patient. Initially, broad-spectrum antimicrobial therapy directed at the likely pathogens (by clinical assessment) and at the predominant resistant flora of the given institution is likely to avoid inappropriate selection of agents. This approach must be coupled with “de-escalation” of therapy based on culture data.

Initial therapy should utilize appropriate doses of bactericidal therapies (including loading doses). If the patient has recently received antimicrobial therapy, drugs from a different class should be used in initial therapy. In normal hosts, sputum Gram’s stains are useful in gauging response to therapy (disappearance of neutrophils) while chest radiographs and oxygenation are helpful in evaluating response to therapy. Reevaluation of antimicrobial selections must be made as microbiologic data become available and the clinical progress of the patient is observed.

MDR pathogens provide special challenges. Risk factors for MDR-infection include recent hospitalization or antimicrobial therapy, exposure to certain clinical environments (dialysis, clinic, home IV therapy), and to immune compromise (Table 112-9). In intensive care units, Burkholderia (formerly Pseudomonas) cepacia, Stenotrophomonas (formerly Xanthomonas) maltophilia, and Acinetobacter baumannii (formerly Acinetobacter calcoaceticus variant anitratus) have been implicated in localized outbreaks of nosocomial pneumonia. Combination therapy for gram-negative bacterial pneumonia is generally reserved for two situations: suspected Pseudomonas pneumonia or for the initial therapy of nosocomial pneumonia while susceptibility data are pending. Community- and hospital-acquired Staphylococcus aureus is increasingly resistant to methicillin (MRSA). Both vancomycin and linezolid are reasonable alternatives for MRSA in this setting and some preliminary data suggest that linezolid may be advantageous in ventilator-associated infection. Strategies for empiric therapy are discussed in Chapter 115.

Nonresolving pneumonia occurs as a result of inappropriate antimicrobial therapy, superinfection, inadequate host response, obstruction, empyema, noninfectious processes, or recurrent infection. Inappropriate antimicrobial therapy includes inadequate dosing, agents that fail to penetrate infected lung tissue (often aminoglycosides), or the use of agents to which the organisms are or have become resistant. Empyema or loculated infection may occur during the course of appropriate therapy for pneumonia. Relapsed infection is common in intubated patients colonized with resistant microorganisms. Superinfection with resistant organisms (including fungi, Mycobacterium tuberculosis) may occur in the hospital setting as well as viral co-infection with community-acquired respiratory viruses. Untreated bacteremia (due to endocarditis, abdominal abscess, catheter-associated infections) or septic pulmonary emboli may cause persistent lung infections. In the compromised host, repletion of antibodies, neutrophils (colony-stimulating factor), treatment of concomitant viral

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Table 112-9 Factors in the Emergence of Antimicrobial Resistance Increase in “high-risk� (immunodeficient) population Prolonged survival of persons with chronic diseases Greater severity of illness of hospitalized patients Newer devices and procedures in use Increased introduction of resistant organisms from the community

of noninfectious etiologies of pulmonary disease increases if the Gram-stained smear and culture of sputum are unrevealing, if the initial response to empiric antimicrobial therapy proves unsatisfactory, or if radiographic findings are atypical. Similar histologic appearances result from both infectious and noninfectious etiologies. The presence of a maculopapular skin rash, generalized lymphadenopathy, joint or rheumatologic symptoms, and/or peripheral eosinophilia should suggest hypersensitivity. However, as noninfectious and infectious processes often coexist, it is essential to exclude infectious causes of pulmonary dysfunction before treating hypersensitivity reactions. Immunosuppressive agents, notably corticosteroids, reduce inflammation due to both infectious and noninfectious causes.

Congregate facilities (e.g., jails, day care centers)

Drug-Induced Pneumonitis

Increased use of antibiotics in animals and agriculture

Noncytotoxic Drugs Drugs producing pulmonary reactions may be considered in two categories: noncytotoxic and cytotoxic drugs. Noncytotoxic drugs that cause hypersensitivity pneumonitis include antimicrobials, anticonvulsants, diuretics, antiarrhythmics, tranquilizers, and antirheumatic agents (Table 112-11).

Among the most common pulmonary reactions are those due to sulfa drugs, phenytoin, nitrofurantoin, and amiodarone.

Sulfasalazine (and other sulfonamides) can produce hypersensitivity lung disease that includes cough, fever, dyspnea, and peripheral hazy acinar or diffuse reticular infiltrates on the chest radiograph. Phenytoin can produce hypersensitivity responses in the lungs 3 to 6 weeks after initiation of therapy. Fever, cough, and dyspnea are accompanied by radiographic findings of bilateral acinar, nodular, or reticular infiltrates. Nitrofurantoin can produce two patterns of pulmonary reaction: (1) acute, which occurs within 2 weeks after starting therapy and consists of dyspnea, nonproductive cough, chills, fever, crackles, eosinophilia, and diffuse interstitial or patchy infiltrates (often with pleural effusion); and (2) chronic, which is less common and occurs after months to years of continuous treatment. The picture of the chronic form is one in which exertional dyspnea and nonproductive cough appear gradually and are unaccompanied by fever; the pattern is not that of an acute pulmonary infection but, rather, the pattern of diffuse interstitial pneumonitis or pulmonary fibrosis. Amiodarone may be associated with pulmonary side effects that often occur after 5 to 6 months of therapy. Exertional dyspnea, nonproductive cough, malaise, and fever (in about half the patients) are gradual in onset, over weeks to several months. The radiographic findings include peripheral areas of consolidation that primarily affect the upper lobes.

In some instances, coarse reticular interstitial infiltrates are present. Withdrawal of the medication, coupled with the administration of corticosteroids, usually leads to complete resolution. Other common forms of drug-induced hypersensitivity pneumonitis include those due to hydrochlorothiazide and gold salts. Hydralazine, procainamide, and isoniazid are capable of inducing a lupus-like syndrome which may include pleuropulmonary involvement.

Physician practices that contribute to inappropriate antibiotic use Providing antibacterial drugs to treat viral illnesses Using inadequate diagnostic criteria for infections that may have a bacterial etiology Providing expensive, broad-spectrum agents that are unnecessary Prescribing antibiotics at an improper dose or duration Lack of rapid, accurate diagnostic tests to distinguish between viral and bacterial infections Selection of antibiotic-resistant genes via abuse of antimicrobial agents Ineffective infection control and isolation practices and compliance

infections (HIV, CMV), and repeat culturing may assist in management. Obstruction or empyema must resolve to allow resolution of infection. Recurrent infection may be observed if the patient is aspirating, has sinusitis, has a misplaced feeding tube, has airway compromise, or has pulmonary infarction. Additional cultures and radiologic studies (CT scans, decubitus films) may assist in defining lung processes which fail to respond to therapy. Bronchoscopic evaluation and, in selected patients, lung biopsy may assist in management.

NONINFECTIOUS PROCESSES MIMICKING PULMONARY INFECTIONS The list of noninfectious disorders that mimic pulmonary infections is extensive (Table 112-10). These should be considered in the course of taking the initial history. The likelihood

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Approach to the Patient with Pulmonary Infection

Table 112-10 Noninfectious Causes of Febrile Pneumonitis Syndrome (Mimics of Pulmonary Infection) Drug-induced pulmonary disease Extrinsic allergic alveolitis

Lymphocytic interstitial pneumonia (LIP) Desquamative interstitial pneumonia (DIP) Giant-cell interstitial pneumonia (GIP)

Acute eosinophilic pneumonia

Pulmonary neoplasms Carcinoma or lymphoma Kaposi’s sarcoma in AIDS

Pulmonary infiltrate with eosinophilia (“PIE syndrome”)

Sarcoidosis

Chronic eosinophilic pneumonia

Pulmonary infarction

Interstitial lung disease associated with autoimmune/ connective-tissue disorders Systemic lupus erythematosus Polymyositis-dermatomyositis Mixed connective-tissue disease

Acute chest syndrome in sickle cell crisis

Interstitial lung disease associated with pulmonary vasculitis Wegener’s granulomatosis Lymphomatoid granulomatosis Churg-Strauss syndrome (allergic angiitis and granulomatosis) Polyangiitis overlap syndrome

Acute respiratory distress syndrome (ARDS) associated with: Extrapulmonary sepsis Oxygen toxicity, chemical inhalation or aspiration, or aspiration of gastric contents Pancreatitis Fat embolization Shock of various etiologies Drug overdose Chest trauma

Injury due to inhaled toxic gases, dusts, chemicals

Intersitital lung disease associated with pulmonary airway disease Allergic bronchopulmonary aspergillosis Bronchocentric granulomatosis Bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia Acute or subacute interstitial pulmonary fibrosis (IPF, Hamman-Rich syndrome) Chronic interstitial pneumonias of unknown origin Usual interstitial pneumonia (UIP)

Cytotoxic Drugs Three clinical and pathological patterns characterize cytotoxic drug–induced pulmonary disease: chronic pneumonitis with pulmonary fibrosis, acute hypersensitivity lung disease, and noncardiogenic pulmonary edema (Table 112-12).

A variety of predisposing factors may contribute to the development of these reactions. The cumulative dose of certain drugs (e.g., bleomycin, busulfan, and carmustine) appears to be particularly important. Combined exposures (e.g., Adriamycin and bleomycin) with dual patterns (cardiac failure and pulmonary injury) are common.

Radiation pneumonitis Lipoid pneumonia (exogenous or endogenous)

Pulmonary leukoagglutinin transfusion reactions Miscellaneous Pulmonary alveolar proteinosis Plasma cell granuloma Histiocytosis X Idiopathic pulmonary hemosiderosis Goodpasture’s syndrome Rheumatic pneumonia (in acute rheumatic fever)

Syndrome of Acute or Chronic Pneumonitis with Fibrosis

All cytotoxic drugs capable of inducing pulmonary disease can produce pneumonitis with fibrosis. The clinical manifestations develop over weeks to months and include nonproductive cough, progressive dyspnea on exertion, fatigue, and malaise. End-inspiratory crackles are audible on examination. The radiographic findings are consistent with those of an interstitial inflammatory process and pulmonary fibrosis.

Fever is not common in this process except for the disease due to cyclophosphamide; over 50 percent of patients with pulmonary fibrosis due to cyclophosphamide exhibit fever.

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Table 112-11

Table 112-12

Noncytotoxic Drugs Capable of Inducing a Picture Resembling Pulmonary Infection

Cytotoxic Drugs Capable of Inducing a Picture Resembling Pulmonary Infection

Antimicrobial agents Nitrofurantoin Penicillins, cephalosporins Sulfasalazine, other salfonamides Minocycline, tetracycline Amphotericin B (acting with leukocyte transfusions) Para-aminosalicylic acid

Acute or Chronic Pneumonitis with Pulmonary Fibrosis Antimicrobial agents Bleomycin, mitomycin, neocarzinostatin Alkylating agents Busulfan, cyclophosphamide, chlorambucil, melphalan, chlorozotocin Nitrosoureas Carmustine (BCNU), semustine (methyl CCNU), lomustine (CCNU), chlorozotocin Antimetabolites Methotrexate, azathioprine, mercaptopurine, cytosine arabinoside, 6-thioguanine Miscellaneous Vinblastine, VM-26, vindescine

Anticonvulsants Phenytoin Carbamazepine Diuretics Hydrochlorothiazide Antiarrhythmics Amiodarone Tocainide Narcotics Heroin Methadone Propoxyphene Cocaine Anti-rheumatic agents Gold salts Penicillamine Naproxen Drugs that can induce a lupus erythematosus-like syndrome Hydralazine Procainamide Isoniazid Chlorpromazine Others: Sirolimus

Distinguishing between the effect of the drugs and the underlying disease process is often difficult.

Syndrome of Hypersensitivity Lung Disease

Methotrexate, bleomycin, and procarbazine cause an acute syndrome of dyspnea, nonproductive cough, fever, and occasionally pleuritic chest pain. The presence of blood eosinophilia and a skin rash suggests a hypersensitivity reaction. The radiographic findings include a diffuse reticular pattern and, in some patients, bilateral acinar infiltrates.

Hypersensitivity Lung Disease Antimetabolites Methotrexate Antimicrobial agents Bleomycin Miscellaneous Procarbazine Noncardiogenic Pulmonary Edema Antimetabolites Methotrexate, cytosine arabinoside Alkylating agents Cyclophosphamide Miscellaneous VM-26

Extrinsic Allergic Alveolitis (Hypersensitivity Pneumonitis)

Inhalation of organic dusts may produce chills, fever, nonproductive cough, dyspnea, and pulmonary crackles within hours of exposure to organic dusts or vapors. The chest radiograph usually shows bilateral patchy acinar infiltrates, suggestive of pulmonary infection. The history of a specific exposure provides the clue to diagnosis, particularly when such episodes have been recurrent. Farmer’s lung is due to hypersensitivity to moldy hay containing Thermoactinomyces species and Micropolyspora faeni. “Air-conditioner” or “humidifier” lung is associated with exposure to similar moldy antigens stemming from occult microbial growth on airexchanging systems in offices and homes. In other hypersensitivity pneumonitides, the offending antigens may be avian in origin (pigeon breeder’s disease) or due to other environmental fungi which contaminate natural products in industry (e.g., maple bark stripper’s lung; moldy sugar cane in bagassosis).

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Silo-filler’s disease is an acute syndrome that mimics acute bacterial or viral pneumonia clinically and radiologically following exposure to nitrogen dioxide. A degenerative interstitial pneumonitis–like picture may result from exposure to organic (e.g., wood, mycotoxin-containing) and inorganic (e.g., silicates, tungsten carbide) dusts. Severe interstitial disease and organizing pneumonia have occurred among workers exposed to aerosols of organic chemicals (designed to polymerize on mixing) used in textile dyeing.

INJURY DUE TO INHALED TOXIC GASES, DUSTS, CHEMICALS

CHRONIC AND ACUTE EOSINOPHILIC PNEUMONIA Chronic eosinophilic pneumonia usually has a course of weeks to months, characterized by fever, night sweats, nonproductive cough, and dyspnea. Pulmonary crackles are variably present. Chest radiographs show a characteristic pattern of peripheral acinar infiltrates that usually involve the upper lobes and resemble the appearance of butterfly pulmonary edema. Peripheral blood eosinophilia is common. Occasionally, chronic eosinophilic pneumonia has an acute onset. Even though the onset in such instances is acute, the course, if untreated (corticosteroids), is prolonged, as in typical chronic eosinophilic pneumonia. Acute eosinophilic pneumonia was initially described as an acute febrile illness with severe hypoxemia, diffuse pulmonary infiltrates, increased numbers of eosinophils in BAL fluid, and prompt response to corticosteroid therapy without relapse. Drug hypersensitivity may be the cause in some instances. A subset has been described with the same acute onset with high fever, a radiologic picture of micronodular and diffuse ground-glass infiltrates, and spontaneous improvement without relapse.

The term pulmonary infiltrates with eosinophilia (PIE syndrome) is used to encompass a wide range of definable clinical entities such as acute eosinophilic pneumonia, chronic eosinophilic pneumonia, allergic pulmonary aspergillosis, and Churg-Strauss vasculitis (see below). However, PIE syndrome should be used to refer to a syndrome consisting of fleeting pulmonary infiltrates, dry cough and mild wheezing, low-grade fever, and blood and pulmonary eosinophilia. Loeffler’s syndrome, a form of PIE, may be associated with parasitic infestation (migration or hypersensitivity) with Ascaris lumbricoides, Strongyloides stercoralis, Ancylostoma duodenale, Toxocara canis, and others, or due to drug hypersensitivity. Tropical eosinophilia is a similar syndrome, endemic in India and southern Asia, Africa, and South America, and most likely due to filarial infection.

PULMONARY INFILTRATE WITH EOSINOPHILIA

INTERSTITIAL LUNG DISEASE ASSOCIATED WITH CONNECTIVE TISSUE DISORDERS AND PULMONARY VASCULITIS A variety of connective tissue

disorders and vasculitides mimic pulmonary infections. Systemic lupus erythematosus may be associated with transitory infiltrates, interstitial disease, or frank consolidation of a noninfectious nature. Interstitial pneumonitis occurs in 5 to 10 percent of patients with polymyositis and may be mistaken for a pulmonary infection, since pulmonary manifestations and fever may precede muscle weakness.

Approach to the Patient with Pulmonary Infection

Three types of vasculitis commonly mimic pulmonary infection. Wegener’s granulomatosis involves the lung in approximately 95 percent of cases. Radiologically, the lesions appear as patchy infiltrates or as nodular lesions that may progress to cavities or lung abscesses. Superinfection of Wegener’s granulomatosis of the lungs is common. Allergic angiitis and granulomatosis (Churg-Strauss syndrome) occurs in the setting of asthma and peripheral eosinophilia. It characteristically involves the lungs, producing pulmonary infiltrates associated with granulomatous and vasculitic lesions.

The polyangiitis overlap syndrome combines some of the characteristic features of classic polyarteritis nodosa and of allergic angiitis and granulomatosis; in some instances pulmonary impairment is a prominent feature.

INTERSTITIAL LUNG DISEASE ASSOCIATED WITH PULMONARY AIRWAY DISEASE Allergic bronchopulmonary aspergillosis, character-

ized by cough, bronchospasm, fever, and intermittent pulmonary infiltrates, can suggest pulmonary infection, although an accompanying eosinophilia provides a clue to the true nature of the process. Eosinophilia may be absent in patients receiving corticosteroid therapy. Bronchocentric granulomatosis, a necrotizing process of unknown cause affecting small bronchi may be associated with fever in some patients.

The pulmonary lesions vary from mucoid impaction to diffuse and nodular infiltrates.

Bronchiolitis obliterans is an occasional complication of pulmonary viral or bacterial infections, cocaine toxicity, drug hypersensitivity, connective tissue disease, inhalation of chemical irritants; or the disease can occur without apparent cause. It is a common presentation of lung injury and chronic rejection of transplanted lungs. It may present with patchy areas of pneumonitis, necrosis of bronchiolar epithelium, and occlusion of terminal airways by granulation tissue. Bronchiolitis obliterans-organizing pneumonia (BOOP) refers to instances in which the presence of organizing inflammatory polypoid masses in distal bronchioles and alveolar ducts is accompanied by a chronic pneumonitis with lipid-laden macrophages. Although many patients with BOOP respond promptly to corticosteroids, occasional patients undergo a rapidly progressive course even with intensive therapy.

CHRONIC INTERSTITIAL PNEUMONIAS OF UNKNOWN CAUSE A variety of interstitial pneumonias, known as usual interstitial pneumonia (UIP), lymphocytic interstitial pneumonia (LIP), desquamative interstitial pneumonia (DIP), and giant cell interstitial pneumonia (GIP), are conditions of unknown origin that are defined on histologic grounds. Most often they present clinically as subacute or chronic processes characterized by progressive dyspnea, cyanosis, nonproductive cough, pulmonary crackles, and a radiographic picture of diffuse reticulonodular infiltrates (more prominent at the lung bases) or a “ground-glass” pattern without fever. Thus, the clinical picture may not suggest pulmonary infection. In some patients, the onset is rapid and accompanied by fever suggesting an acute respiratory infection.

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Bronchial obstruction by a bronchogenic carcinoma may produce obstructive pneumonia (“drowned lung”) or atelectasis. Fever and signs of consolidation/atelectasis may fail to respond to antimicrobial therapy.

Recurrent pneumonia in the same portion of the lung should suggest this possibility. Hodgkin’s disease and non-Hodgkin’s lymphoma may present with fever, cough, dyspnea, and pulmonary lesions suggesting infection. In Hodgkin’s disease, a single mass lesion may be present and cavitate, suggesting a lung abscess.

PULMONARY NEOPLASMS

SARCOIDOSIS In the patient with sarcoidosis and interstitial lung disease, fever is uncommon unless hilar adenopathy or other features, such as erythema nodosum, are also present.

Consequently, this process is usually not mistaken for a primary pulmonary infection.

PULMONARY INFARCTION Fever, dyspnea, pleuritic chest pain, leukocytosis, and segmental pleural-based infiltrates (and possibly accompanying pleural effusion) of pulmonary infarction suggest the presence of pulmonary infarction due to pulmonary embolus or septic emboli. Similar features are observed with pneumococcal pneumonia. The presence of blood-streaked sputum in this syndrome may suggest the possibility of S. pyogenes pneumonia with hemorrhagic tracheobronchitis. Occasionally, multiple round radiographic infiltrates in the lungs of a febrile, dyspneic patient with pulmonary emboli may suggest lung abscesses due to aspiration or septic emboli.

Exogenous lipoid pneumonia results from inhaling or aspirating fatty materials (oily nose drops, mineral oil). Endogenous lipoid pneumonia (often called “cholesterol pneumonia”) consists of chronic inflammatory foci containing cholesterol and its esters, derived from destroyed alveolar walls located either behind a bronchial obstruction or in lung parenchyma at a site of chronic suppuration. Sputum, fineneedle aspirates, or BAL specimens may reveal macrophages containing lipoid vacuoles, as demonstrated by fat stains (Sudan, oil red O).

LIPOID PNEUMONIA

The acute phase of radiation pneumonitis usually develops within 3 or 4 months after initiation of radiation therapy. It is characterized by fever, dyspnea, cough, and radiographic changes (infiltrates or ground-glass density) sharply demarcated geometrically to the portal of irradiation rather than to natural pulmonary anatomic divisions. This reaction might be mistaken for a bacterial pneumonia. The late phase of radiation pneumonia, characterized by pulmonary fibrosis, occurs 9 months or more after radiation therapy and is not accompanied by fever.

RADIATION PNEUMONITIS

Pulmonary alveolar proteinosis usually begins slowly, with dyspnea as the principal symptom. Radiographic features are those of a bilateral diffuse, predominantly perihilar airspace disease.

The radiographic, but not the clinical, manifestations

may suggest pulmonary infection. Fever is usually absent.

However, pulmonary alveolar proteinosis may be associated with hematologic malignancies, which are associated with fever including lymphoma or acute leukemia. In addition, pulmonary alveolar proteinosis is sometimes complicated by pulmonary infections—e.g., nocardiosis (most frequently), cryptococcosis, aspergillosis, tuberculosis, pneumocystosis, and histoplasmosis.

Plasma cell granuloma is a postinflammatory pseudotumor of the lung. The combination of cough, fever, and radiologic changes of atelectasis and consolidation suggests the diagnosis of pulmonary infection associated with bronchial obstruction. This process is very similar to the previously described cholesterol pneumonia.

Eosinophilic granuloma of the lung (pulmonary histiocytosis X) usually is manifested as a noninfectious interstitial pulmonary process with dyspnea and nonprogressive cough.

In about 15 percent of patients, however, fever does occur, suggesting the possibility of pulmonary infection. The radiographic findings are those of small nodules and reticulation or honeycombing; these findings in the febrile patient may suggest the diagnosis of miliary tuberculosis, invasive mycotic infection, Rhodococcus equi, or viral disease (e.g., varicellazoster).

Many unrelated conditions involving the lungs primarily or having their initial impact elsewhere have in common the capacity to cause diffuse damage to the alveolar-capillary membrane and produce noncardiogenic pulmonary edema. The process progresses rapidly with inflammatory cell infiltration and pulmonary fibrosis. Extensive pulmonary infiltrates are evident on chest radiographs. Superinfection of lungs injured by ARDS, often by nosocomial pathogens, is common. Many of the underlying processes that produce ARDS are associated with fever, including pancreatitis, peritonitis, endocarditis, severe thermal injuries, as well as fulminant bacterial or viral infections.

ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)

PULMONARY LEUKOAGGLUTININ TRANSFUSION REACTIONS An acute pulmonary reaction may follow receipt of a blood transfusion with which there has been passive transfer of leukoagglutinins and antibodies cytotoxic to recipient lymphocytes.

The clinical picture of an abrupt onset of chills, fever, tachycardia, cough, and dyspnea, accompanied by numerous fluffy and nodular perihilar infiltrates on radiograph, may easily be mistaken for an acute pulmonary infection. Pulmonary hemorrhage may also affect such patients, particularly after hematopoietic transplantation.

MISCELLANEOUS MIMICS OF PULMONARY INFECTION

SUGGESTED READING Arancibia F, Bauer TT, Ewig S, et al: Communityacquired pneumonia due to gram-negative bacteria and

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Pseudomonas aeruginosa: Incidence, risk, and prognosis.

Arch Intern Med 162:1849, 2002.

Bartlett JG, Breiman RF, Mandell LA, et al: Practice guidelines for the management of community-acquired pneumonia in adults: Guidelines from the Infectious Disease Society of America. Clin Infect Dis 31:347, 2000.

Beckham JD, Cadena A, Lin J, et al: Respiratory viral infections in patients with chronic, obstructive pulmonary disease. J Infect 50:322, 2005.

Esper F, Martinello RA, Boucher D, et al: A 1-year experience with human metapneumovirus in children aged <5 years.

J Infect Dis 189:1388, 2004.

Fine MJ, Auble TE, Yealy DM, et al: A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 336:243, 1997.

Francis JS, Doherty MC, Lopatin U, et al: Severe communityonset pneumonia in healthy adults caused by methicillinresistant Staphylococcus aureus carrying the PantonValentine leukocidin genes. Clin Infect Dis 40:100, 2005.

Friedman ND, Kaye KS, Stout JE, et al: Healthcare-associated bloodstream infections in adults: A reason to change the accepted definition of community-acquired infections.

Ann Intern Med 137:791, 2002.

Heyland DK, Cook DJ, Griffith L, et al: The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. Critical Trials Group. Am J Respir Crit Care Med 159:1249, 1999.

Hutt E, Kramer AM: Evidence-based guidelines for management of nursing home-acquired pneumonia. J Fam Pract 51:709, 2002.

Ibrahim EH, Sherman G, Ward S, et al: The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 118:146, 2000.

Jokinen C, Heiskanen L, Helvi J, et al: Microbial etiology of community-acquired pneumonia in the adult population of 4 municipalities in eastern Finland. Clin Infect Dis 32:1141, 2001.

Kollef MH: Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients.

Clin Infect Dis 31(Suppl 4):S131, 2000.

Luna CM, Vujacich P, Niederman MS, et al: Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest 111:676, 1997.

Approach to the Patient with Pulmonary Infection

Mandell LA, Marrie TJ, Grossman RF, et al: Canadian guidelines for the initial management of community-acquired pneumonia: An evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. The Canadian Community-Acquired Pneumonia Working Group. Clin Infect Dis 31:383, 2000.

Marrie TJ, Poulin-Costello M, Beecroft MD, et al: Etiology of community-acquired pneumonia treated in an ambulatory setting. Respir Med 99:60, 2005.

Mason CM, Nelson S: Pulmonary host defenses and factors predisposing to lung infection. Clin Chest Med 26:11, 2005.

Niederman MS, Mandell LA, Anzueto A, et al: Guidelines for the management of adults with community-acquired pneumonia: Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 163:1730, 2001.

Rello J, Sa-Borges M, Correa H, et al: Variations in etiology of ventilator-associated pneumonia across four treatment sites: Implications for antimicrobial prescribing practices.

Am J Respir Crit Care Med 160:608, 1999.

Tablan OC, Anderson LJ, Besser R, et al: Healthcare Infection Control Practices Advisory Committee, Centers for Disease Control and Prevention. Guidelines for preventing health-careâ&#x20AC;&#x201C;associated pneumonia, 2003: Recommendations of the CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep 53:1, 2004.

Trouillet JL, Chastre J, Vuagnat A, et al: Ventilator-associated pneumonia caused by potentially drug-resistant bacteria.

Am J Respir Crit Care Med 157:531, 1998.

Wattanathum A, Chaoprason C, Nunthapisud P, et al: Community-acquired pneumonia in southeast Asia: The microbial differences between ambulatory and hospitalized patients. Chest 123:1512, 2003.

Williams JV, Wang CK, Yang CF, et al: The role of human metapneumovirus in upper respiratory tract infections in children: A 20-year experience. J Infect Dis 193:387, 2006.

Woo PCY, Lau SKP, Tsoi H, et al: Clinical and molecular epidemiological features of coronavirus HKU1-associated community-acquired pneumonia. J Infect Dis 192:1898, 2005.

Wunderink RG, Waterer GW: Community-acquired pneumonia: Pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. Infect Dis Clin North Am 18:743, 2004.

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113 The Radiology of Pulmonary Infection Reginald E. Greene

I. IMAGING MODALITIES II. GENERIC LUNG FINDINGS ASSOCIATED WITH PNEUMONIA Peripheral Airspace Consolidation Pneumonia (Lobar Pneumonia) Centrilobular and Peri-bronchiolar Opacity Pneumonia (Bronchopneumonia)

This chapter aims to provide clinicians with a framework for analyzing images of pulmonary infection by focusing on generic pathogenetic categories that can be identified on computed tomography (CT). The focus is on the role of chest imaging in the diagnosis of pneumonia, the identification of common etiologic classes of infection, and notation of pertinent non-infectious differential diagnoses. A detailed examination of the imaging findings of the entire range of potential causes of lung infection is beyond the scope of this chapter.

IMAGING MODALITIES Imaging is an essential tool in the management of patients with pneumonia. The main roles of imaging are to independently detect, corroborate, and localize clinically suspected pneumonia, estimate the severity and extent of disease, identify categorical abnormalities that can narrow the range of likely etiological infectious agents, and differentiate pneumonia from non-infectious etiologies that may be responsible for the clinical and imaging findings. Follow-up imaging is used to estimate response to treatment, exclude complications of pneumonia, and document clearing of the initial imaging abnormality. Pneumonias that respond clinically to treatment can often take 8 weeks or more to clear on plain film radiography, and even longer on CT, usually long after the clinical status has returned to normal. Return to an imaging baseline

Nodular Pneumonia (Round Pneumonia) Micronodular Pneumonia Diffuse Opacification Pneumonia Ancillary Findings Associated with Pneumonia IV. CONCLUSIONS

condition is particularly slow in patients with co-morbidity or severe infections.

Plain chest radiography is the basic tool for imaging patients with suspected pneumonia. The findings can justify a working clinical diagnosis and help form the basis for initial management. In some cases atypical or otherwise worrisome findings of plain film radiography point to a need for supplementary CT to rule out complicated infection or other disease. This sequence occurs more often in older patients, and those with co-morbidities than in previously healthy young patients.

CT is the imaging gold standard for evaluation of lung disease in general, and chest infection in particular. It provides the highest level of global specificity and sensitivity for the diagnosis of pneumonia. In a few specific circumstances CT findings may warrant the start of preemptive antimicrobial therapy when etiological, microbiological, or histopathological proof of diagnosis is lacking. The present generation of 4- to 64-slice multidetector CT scanners can provide highspeed, single-breath, volume acquisitions that can be viewed as 2.5 mm or finer reconstructed sections. If these images are obtained after delivery of intravenous iodinated contrast medium, and there is careful control of the patientâ&#x20AC;&#x2122;s breathhold during the scan, then adequate anatomic detail can be obtained to evaluate the lung, pleura, mediastinum, and great vessels for infection. The categories of imaging findings discussed in this chapter may at times be identifiable on plain film radiography when fully developed, but the basis for their discussion relies on the CT technique.

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B

A

C

Figure 113-1 18FDG-avid macronodular C. neoformans infection. A. Plain chest radiograph with a macronodular opacity in the left upper lobe (arrow) in an asymptomatic mildly immunosuppressed solid organ transplant recipient.

B. CT scan confirms a well defined macronodule in the left upper lobe (white arrow). C. Positron emission tomography (PET) with 18 fluorodeoxyglucose (18FDG) shows normally high metabolic avidity of the cardiac ventricular musculature, and moderate avidity of the left upper lobe nodule due to Cryptococcus neoformans.

Other imaging modalities are at present used infrequently for evaluation of suspected pneumonia. Ultrasound is a standard modality for detecting and tapping pleural effusions, but it is not employed in the diagnosis of pneumonia. Magnetic resonance imaging (MRI) is rarely employed to detect or further assess patients with a clinical diagnosis of infection except when critical extension or dissemination is suspected. Positron emission tomography (PET) with 18 fluorodeoxyglucose (18FDG) is increasing used as a sensitive method of detecting metabolically active tumor lesions, but it has yet to find a definable role in clinical evaluation of inflammation and pneumonia. Anecdotal studies of patients with chronic and acute inflammatory lesions and infections have identified a wide spectrum of lung lesions that are 18FDGavid (Fig. 113-1).

GENERIC LUNG FINDINGS ASSOCIATED WITH PNEUMONIA Six common imaging categories of pneumonia are discussed, each of which has a distinctive pathogenesis, typical gross pathology, and characteristic imaging findings: the first two are most common: (1) peripheral airspace consolidation pneumonia (lobar pneumonia); and (2) centrilobular and peribronchiolar opacity pneumonia (bronchopneumonia).

The next three categories are less common but no less important: (3) nodular pneumonia; (4) micronodular pneumonia (miliary pneumonia); and (5) diffuse lung opacification pneumonia.

Several factors that limit this type of categorical analysis must be recognized; imaging findings vary between patients with pneumonia of the same etiology; imaging findings vary over time as pneumonias evolve, and different categories of imaging findings may be encountered in any single snapshot of a patient with pneumonia. Although no single imaging category can completely characterize a single etiologic kind of pneumonia, it is useful to think in terms of the predominant imaging finding when evaluating the likely pathogenesis and etiology of a likely pneumonia while taking into account the clinical context in which it occurs. One or more types of etiologic agents are more likely than others in each category of pneumonia when the clinical background is taken into account: immunocompetent versus immunocompromised, previously healthy versus having co-morbidity, acquisition of infection inside of the hospital, i.e., nosocomial pneumonia (NP) versus acquisition in the wider community, i.e., community-acquired pneumonia (CAP), and the presence of local epidemic infections.

Peripheral Airspace Consolidation Pneumonia (Lobar Pneumonia) Overview and Pathogenesis Peripheral airspace consolidation is a characteristic imaging category of pneumonia that is commonly encountered in all patient groups. It is an especially common primary pneumonia caused by bacteria in previously healthy patients with CAP. It is also called lobar pneumonia because it is often essentially confined to a single peripheral lung region without prominent involvement of the bronchial tree.

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The pathogenesis and imaging of peripheral airspace consolidation pneumonia is unique. It is the result of airborne infection initiated by microbes that reach and settle in the peripheral alveolar airspaces. From there the pneumonia spreads into adjacent alveoli by traversing collateral channels of ventilation, such as the pores of Kohn and canals of Lambert. Spread by this way from alveolus to alveolus results in characteristic involvement that parallels the pleural surface, and ultimately extends toward the more central regions of the lung in centripedal fashion. As the infection progresses, gas in the peripheral airspaces is replaced by exudate. This process of accretion tends to preserve or slightly expand without distorting the normal anatomic contours of the affected lung.

The relatively unaffected bronchi remain relatively gas filled, and become surrounded by consolidated alveoli. At the leading edge of a consolidation there is generally a patchwork of individually spared and affected lung.

Etiologies Outside of neonates, Streptococcus pneumoniae is the most common bacterial etiology of peripheral airspace consolidation pneumonia, as well as the most common cause of bacterial pneumonia acquired outside of hospitals in previously healthy patients (Fig. 113-2). It accounts for a large fraction of the etiologically proven, bacteremic, life-threatening pneumonias. In CAP and NP of patients with co-morbid conditions, peripheral airspace consolidation may be caused by opportunistic gram-negative enteric bacteria of the Enterobacteriaceae family such as, Klebsiella, Enterobacter, Escherichia, Citrobacter, and Serratia, as well as by Legionella pneumophila (Fig. 113-3). Large peripheral airspace consolidation is also a presenting imaging category in primary tuberculosis, in which case it affects primarily the lower lobes, middle lobes, and/or anterior segments of the upper lobes.

It is usually associated with mediastinal lymphadenopathy,

Figure 113-3 Community-acquired lobar pneumonia caused by Legionella pneumoniae in patient with co-morbidity. Communityacquired lobar pneumonia caused by Legionella pneumoniae in patient with co-morbidity due to chronic granulomatous vasculitis. There is peripheral airspace consolidation (lobar) pneumonia containing prominent air bronchograms (black arrow). There is also patchy ”spillover” pneumonia associated with ground glass and tree-in-bud opacities along the posterior chest wall (small black arrows), as well as a small layering pleural effusion.

especially in pediatric patients. Lobar pneumonia can also be a component of the imaging findings in endemic fungal infections, and in immunocompromised patients with invasive fungal infection. Less commonly it can result from a wide variety of viral infections such as adenovirus, Hantavirus, and the coronavirus of severe acute respiratory syndrome (SARS).

Imaging

Figure 113-2 Lobar pneumonia due to S. Pneumoniae in previously normal host. Severe community-acquired lobar pneumonia with bacteremia due to S. pneumoniae in a previously healthy 30year-old man. There is dense consolidation of the right upper lobe with prominent air bronchograms (white arrow). Layered pleural fluid is present along the right posterior chest wall (black arrow).

The characteristic imaging finding of peripheral airspace consolidation pneumonia is opacification of the peripheral airspaces often with visible air-filled proximal conducting airways, i.e., “air bronchograms.” Where fully developed, exudate causes complete opacification of the involved lung such that all the underlying pulmonary vasculature of the affected region is totally obscured. Where the consolidation is incomplete the affected lung may exhibit ground-glass opacification, in which case it does not completely obscure underlying vasculature. At the leading edge of spread of infection, there

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is generally a patchwork of affected and spared secondary lobules, i.e., lung regions of 10 to 25 mm on a side that are marginated by pulmonary septations. Specific identification of peripheral airspace consolidation is facilitated by recognition of internal air bronchograms that are in most cases identifiable. Atelectasis and significant local loss of lung volume are usually absent.

Peripheral consolidative pneumonia differs notably from bronchopneumonia (which will be described subsequently) in that it primarily affects peripheral airspaces rather than bronchi/bronchioles and peri-bronchial airspaces, and is not usually associated with loss of volume or atelectasis of the affected lung. It differs also from macronodule pneumonia (which will be described subsequently) in that even when large its lung opacification does not tend to substantially distort the pre-infection anatomic shape of the involved area.

The absence of air bronchograms does not per se exclude consolidation; air bronchograms may be absent when consolidation results from central bronchial occlusion or causes exudative impaction of proximal bronchi within the affected lung. Cavitation, necrosis, and pleural effusion are sometimes features of peripheral airspace consolidation pneumonia, particularly when the infection is caused by aggressive or necrotizing bacterium, such as Staphylococcus aureus, mycobacteria, and anaerobic enteric bacilli such as actinomycetes. The association of lymphadenopathy is common in mycobacterial, endemic fungal, and other less common infections such as tularemia.

Non-Infectious Etiologies

Non-infectious simulators and etiologies of peripheral consolidation include localized aspiration, atelectasis, hemorrhage, hydrostatic edema, alveolar-capillary leak edema, postobstructive pneumonitis, bronchiolo-alveolar cell carcinoma, lymphoma, and bronchiolitis obliterans organizing pneumonia (BOOP). Air bronchograms are often present in nonobstructive atelectasis in the absence of infection. In such cases of atelectasis is recognized by crowding together of the air-filled bronchi that are be visible within the atelectatic lung.

The air bronchograms of pure airspace consolidative pneumonia are normally distributed or splayed apart. Bronchioloalveolar cell carcinoma is suspected by atypical clinical presentation and failure to respond to antibiotic therapy.

Centrilobular and Peri-bronchiolar Opacity Pneumonia (Bronchopneumonia) Overview and Pathogenesis Like lobar pneumonia, centrilobular and peribronchiolar opacity pneumonia (bronchopneumonia), a characteristic imaging category of pneumonia that is commonly encountered in all patient groups. It is an especially common imaging category in CAP that follows viral infection. It is also called bronchopneumonia because it is associated with acute infection of the walls of bronchioles that spreads into the peri-

bronchiolar alveoli, and often involves the lung in a patchy multifocal distribution (Fig. 113-2).

Etiologies Many patients with community-acquired bronchopneumonia have mild and self-limited disease attributable to respiratory viruses, including epidemic influenza, adenovirus, rhinovirus, and respiratory syncytial viruses (RSV) (Fig. 1133). Some of these viruses can produce more serious primary pneumonia, as well as set the stage for bacterial or other etiology superinfection pneumonia, especially when there are co-morbid conditions. Severe acute respiratory syndrome (SARS), a newly identified coronavirus infection, can produce severe viral pneumonia with a broad spectrum of imaging findings, including bronchopneumonia.

Other organisms that commonly cause bronchopneumonia include Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, and Neisseria catarrhalis (Moraxella catarrhalis). Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa are also common causes of nosocomial (and ventilator-associated) bronchopneumonia, and of community-acquired bronchopneumonia in patients with co-morbid conditions. These latter pneumonias are associated with necrosis, abscess formation and pleural effusion.

The role of Staphylococcus aureus in the etiology of bronchopneumonia in the ventilator-associated milieu pneumonia (VAP) is controversial because airway recovery of the organism is not usually associated with the characteristic imaging signs of CAP caused by that organism in patients without co-morbid conditions, i.e., rapid development and necrosis. The organisms that cause peripheral airspace consolidation pneumonia are not restricted from also causing bronchopneumonia when bronchioles are already inflamed by recent infection.

Imaging On initial imaging bronchopneumonia is different from lobar pneumonia; it causes centrilobular opacities, as well as peri-bronchiolar opacities rather than affecting subpleural lung as in lobar pneumonia, and it tends to be multifocal and patchy in distribution rather than localized to any one lung region. Centrilobular opacities include centrilobular nodules, and small branching tubular opacities (tree-in-bud opacities), each of which is found within the center of the secondary pulmonary lobule (Fig. 113-4).

Centrilobular nodules are very small well- or ill-defined rounded opacities situated in the center of a secondary lobule (defined by its arterial/bronchial core, and/or straight septal walls with pulmonary veins at its corners). The nodules are usually only in (2â&#x20AC;&#x201C;3 mm) in diameter but may grow large enough to fill entire lobules (10â&#x20AC;&#x201C;24 mm), at which size they are often considered to be macro-nodules. Because small centrilobular nodules are located at the center rather than at the periphery of the secondary pulmonary lobule, they do not normally abut the visceral pleural surface, but usually stand off about 5 mm from it. Centrilobular nodules are considered

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Figure 113-4 Viral bronchopneumonia. Centrilobular and peribronchial opacity pneumonia (bronchopneumonia) after a 1week viral type prodrome with fever and cough. One of many bilateral patches of bronchopneumonia in the left lower lobe is characterized by branching small tubular opacities (black arrow) attributed to thickened, dilated and impacted bronchioles (treein-bud opacities) that simulate game ‘‘Jacks,” i.e., six-pronged three-dimensional metal crosses with bulbous ends. There is also a thickened bronchial wall leading to, and surrounded by the same tubular bronchiolar opacities (white arrow).

to be axial views of bronchiolar wall thickening, impaction and distention at bifurcations, and may present in clusters.

Branching centrilobular tubular opacities (tree-in-bud opacities) are very small cylindrical, branching structures with bulbous ends that equate to longitudinal projection of the bronchiolar thickening, exudative filling, and distention.

Peribronchial and peribronchiolar lung opacities are much larger than centrilobular opacities that develop from the coalescence of affected alveoli that open directly into respiratory bronchioles (Fig. 113-5). When secondary lobular involvement is complete, there is total opacification of a secondary lobule. When local alveolar involvement is incomplete, there may be ground-glass opacification of the lobule such that background vasculature is still visible. In lobar pneumonia, progression of infection tends to spread subpleurally and centripetally. In bronchopneumonia, progression of infection tends to spread centrifugally to affect secondary lobules distributed axially along bronchovascular bundles.

In most cases centrilobular nodules and tree-in-bud opacities are seen in combination. Common infectious etiologies of centrilobular opacities include a wide range of bacterial, mycobacterial, viral, and fungal etiologies that are caused by acute or chronic bronchiolar inflammation/infection.

The Radiology of Pulmonary Infection

Figure 113-5 Peribronchial consolidation due to viral pneumonia. CT scan one week after onset of fever; cough with a confirmed diagnosis of Influenza B and Mycoplasma pneumoniae. There are multifocal, bilateral peribronchial consolidations, one of which is in the right lower lobe (large black arrows) with prominent air bronchograms and bronchial wall thickening (curved white arrows). Centrilobular opacities, including nodules (short arrow) and branching tree-in-bud opacities, are also present.

They are also often seen in infectious pneumonias associated with bronchiectasis or cystic fibrosis. In Mycoplasma pneumoniae infection, tree-in-bud opacities are a common feature, and are often found in association with centrilobular nodules.

In some infections tree-in-bud opacities may be seen as a predominant feature, as in acute bronchiolitis, bronchogenic tuberculosis, and infections by atypical mycobacteria (Fig. 1136). In patients with HIV infection (CD4 T-lymphocyte count less than 200/mm3 ), disseminated bronchogenic tuberculosis, and disseminated atypical mycobacterial infection may be manifested by diffuse tree-in-bud opacities. The high CT attenuation of these opacities is ascribed to caseous necrosis material impacted within bronchioles (Fig. 113-7). In progressive primary or post-primary tuberculosis bronchogenic spread into other regions of the lung occurs when infected liquefied caseous material gains access into bronchial tree to be coughed or expectorated into other lung regions. In addition to centrilobular nodules, tree-in-bud opacities, multiple fluffy 5- to 10-mm “acinar” nodules may be detected adjacent to a source consolidation or cavity.

Regional atelectasis is common imaging finding in bronchopneumonia due to multiple small airway occlusions by exudates. Some infections may produce necrosis, cavitation, pleural effusion, bronchopleural fistula, and empyema.

Post-primary tuberculosis is a centrilobular process that when latent may include scarring, atelectasis, bronchial wall thickening, bronchiectasis, architectural distortion, and local pleural thickening, especially in the lung apices or superior segments of the lower lobes. Active post-primary tuberculosis usually results from reactivation of a dormant

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These cavities indicate activated latent post-primary tuberculosis, and can be detected twice as often, and more accurately differentiated from paracicatricial emphysema and fibrosis

by CT than by plain film radiography (Fig. 113-8). Other findings in active post-primary tuberculosis include poorly defined centrilobular 5- to 8-mm nodules, consolidation, and granulomas.

Non-Infectious Etiologies Non-infectious simulators and etiologies of centrilobular and peri-bronchial opacities include aspiration pneumonia, itself a frequent non-infectious cause of bronchopneumonia, as well as a facilitator of superinfection. Other causes include bronchiolo-alveolar cell carcinoma, non-infectious granulomas due to pneumoconiosis, sarcoidosis, respiratory bronchiolitis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), asthma, autoimmune disease, and bronchiolitis obliterans. They can also be found in patients with small mucous airway plugs and other endobronchial disease.

Nodular Pneumonia (Round Pneumonia) Figure 113-6 Bronchogenic tuberculosis. CT scan with disseminated bilateral high density tree-in-bud opacities (white arrow), centrilobular nodules (black arrow), and bronchial wall thickening (curved arrow) in a patient with advanced HIV infection and bronchogenic tuberculosis.

focus when cellular immunity deficiency lowers specific cellular immunity to tuberculosis, such as in debility or advanced AIDS. Active post-primary tuberculosis begins with ulceration of one or more bronchioles (2- to 4-mm diameter) that progress by coalescing into larger bronchocentric cavities.

Figure 113-7 Widespread centrilobular opacities and bronchiectasis in chronic Mycobacterium avium complex (MAC) infection. CT scan of elderly female with widespread centrilobular opacities, including tree-in-bud opacities (black arrows), and lingular bronchiectasis (white arrow) due to chronic Mycobacterium avium complex (MAC) infection.

Overview and Pathogenesis Nodular pneumonia is predominantly made up of circumscribed, ovoid opacities greater than or equal to 1 cm diameter that may at times be quadrilateral shaped and marginated by septal walls. This imaging type of is not as common as the two previously discussed types of pneumonia, but its finding as acute pneumonia may portend aggressive, potentially lifethreatening pneumonia. The nodules may be bronchocentric in location, but are often are subpleural whether the portal of entry is by way of the vascular route such as in septic emboli, or via the inhalational route, as in Staphylococcus aureus pneumonia and invasive pulmonary aspergillosis (Fig. 1139). They represent circumscribed foci of pneumonia forming in the distal airspaces or foci of pneumonia forming at the termination of pulmonary arteries.

Etiologies In a CAP setting, nodular pneumonia is often caused by Staphylococcus aureus in which case the lesions tend to enlarge rapidly and cavitate (Fig. 113-10). S. aureus is relatively more common among children and infants than among adults.

Other causes of round pneumonia include Actinomycetes, Nocardia, Aspergillus, Legionella spp., Q fever, M. tuberculosis, and viruses. Among pediatric-aged patients, nodular pneumonia may be due to measles virus. In the nosocomial setting, and in the immunocompromised patient, nodular pneumonia may be due to inhaled or bacteremic seeding of the lungs by gram-negative opportunistic intestinal organisms, opportunistic gram-negative enteric bacteria of the Enterobacteriaceae family such as, Klebsiella, Enterobacter, Escherichia, Citrobacter, and Serratia, especially when there is bowel distention or obstruction. In patients with mild reduction in defense against infection, such as that due in alcoholism, liver dysfunction, diabetes, wasting or chronic lung

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B

Figure 113-8 Centrilobular opacities and cavity in reactivation of latent post-primary tuberculosis. A. Nonimmunocompromised patient with abnormal nodular opacities characteristic of latent post-primary tuberculosis in the posterior segment of the right upper lobe. The presence of new cavitation of a â&#x20AC;&#x2DC;â&#x20AC;&#x2DC;tuberculomaâ&#x20AC;? indicates reactivation of latent tuberculosis (white arrow). B. More caudally in the same lobe, there are multiple centrilobular opacities indicative of endobronchial spread from the cephalad thick-walled cavity identified in Fig. 113-3A. There is a very large centrilobular nodule that approaches the major fissure (long arrow), bronchial wall thickening (short arrow), and many branching centrilobular tubular opacities (tree-in-bud) indicative of bronchiolar thickening, dilatation, and impaction (curved arrow).

disease, and in AIDS patients with CD4+ greater than 200 c/ml, nodular pneumonia is often due to bacterial pneumonia. In severely immunosuppressed AIDS patients with CD4+ less than 200 c/ml, and in solid organ transplant recipients, nodular pneumonia may also be due to mycobacterial or fungal infection, including Mycobacterium avium complex

Figure 113-9 Macronodular pneumonia. Multiple subpleural macronodular opacities (arrows) in a patient with acute onset of fever, shaking chills, fever, and cough productive of green sputum likely due to bacterial pneumonia that responded promptly to vancomycin therapy. Respiratory secretions and blood were culture-negative.

Figure 113-10 Cavitating Staphylococcal aureus macronodular pneumonia. Large subpleural mass-like macronodule with multiple gas pockets in this previously normal 39-year-old patient with sputum positive for S. aureus. The findings are characteristic of lung abscess before complete excavation.

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*

* N

* Figure 113-11 Septic emboli. Multiple predominately subpleural nodular opacities of varying sizes and stages in a patient with positive blood cultures for methicillin-resistant S. aureus (MRSA) and beta hemolytic Streptococcus. These findings are characteristic of septic emboli. There is a wide disparity in the size and stage of infection; some nodules are three times the diameter of others; some nodules are partially solid; others are partially fluid filled; and others are totally gas-filled, and have thin walls. There is a layered left pleural effusion likely due to unroofing of an infected cavity, a common feature.

(MAC), M. tuberculosis, Cryptococcus sp., Blastomyces sp., Histoplasma capsulatum, C. immitis, or Aspergillus spp. (Fig. 113-1). In heart, lung, and other solid organ transplant recipients, nodular pneumonias found shortly after surgery nodular pneumonia is most often due to bacterial infection, especially gram-negative intestinal bacteria. During the initial 3 months after lung transplantation, the risk of CMV pneumonia is high enough that even an uncharacteristic nodular presentation must be considered as possible CMV pneumonia.

Figure 113-12 Halo sign in angioinvasive aspergillosis. CT scan of patient with hematopoietic malignancy and prolonged neutropenia demonstrating a macronodule (N) surrounded by a halo of ground-glass opacity (â&#x2C6;&#x2014; ) in a patient with angioinvasive aspergillosis.

presentation. Thus, the absence of at least one macro-nodule argues against the diagnosis of angioinvasive aspergillosis.

Although other etiologies, such as mucormycosis, may cause halo signs in this group of patients, the prior probability of such infections is very much lower. The air crescent sign is an indicator of late angioinvasive pulmonary aspergillosis, usually after recovery from neutropenia (Fig. 113-13).

Non-Infectious Etiologies

Imaging In intravenous drug abusers nodular pneumonia can indicate septic emboli, particularly when the nodules are multiple, subpleural, and of varying size often from less than 10 mm in diameter to greater than 3 cm. Ultimately, the nodules cavitate late in the course of disease. Sometimes a feeding vessel can be seen extending to a nodule (Fig. 113-11).

Among severely immunocompromised patients with a compatible illnesses suffering from hematological malignancy with severe or prolonged neutropenia, or allogeneic hematopoietic stem cell transplant recipients, the presence of one or â&#x20AC;&#x153;halo signs,â&#x20AC;? i.e., macronodules (greater than or equal to 1 cm) with perimeter of ground-glass, is virtually diagnostic of early angio-invasive pulmonary aspergillosis (Fig. 11312). Pre-emptive targeted treatment of such patients based on the presence of a halo sign is associated with improved treatment response and outcome. It is notable that 90 percent of such patients with angioinvasive aspergillosis have one or more macronodular lesions with or without halo signs at

The most common simulators and non-infectious etiologies of nodular pneumonia include bland pulmonary infarcts, granulomatous vasculitis, primary lung cancer, and pulmonary metastases. Often a biopsy is necessary to make the diagnosis.

Micronodular Pneumonia Overview and Pathogenesis Micronodular pneumonias are an uncommon but important group of pneumonias. Micronodules are nodules 9 mm or less in diameter, ill- or well-defined, and of random distribution.

The most important infectious etiologies of micronodular pneumonia include: (1) miliary pneumonia; and (2) intermediate micronodular pneumonias. These micronodules are generally diffuse, bilateral, and widely distributed. They are variously distributed along the bronchovascular bundles, interlobular septal walls, and costal and interlobar fissural pleural surfaces.

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Intermediate Micronodular Pneumonia

S

These are micronodules are of intermediate size and somewhat larger than those most characteristic of early miliary nodules. They range in average size from 5 to 7 mm. These are often ill-defined. The prototypical viral causes of intermediate micronodule pneumonia are herpes simplex and varicella zoster pneumonias. In the patient with varicella skin lesions, intermediate-sized random lung nodules are virtually diagnostic of varicella pneumonia (Fig. 113-15). This appearance can also be found in hematogenous dissemination of fungal pneumonias, and other late disseminated infections. Intermediate nodules can be caused by bronchogenic tuberculosis, but these are restricted to centrilobular location. Non-infectious causes most often are due to metastatic neoplasms.

Diffuse Opacification Pneumonia

Figure 113-13 Air crescent sign in late angioinvasive aspergillosis. CT scan of patient with hematologic condition late in the course of angioinvasive aspergillosis after recovery from neutropenia demonstrates a cavitary macronodule with an air crescent at 10 to 1 oâ&#x20AC;&#x2122;clock (arrows) outlining a central necrotic sequestrum (S).

Etiologies Miliary nodules are random micronodular opacities (1â&#x20AC;&#x201C;5 mm) that are associated with a small but important group of disseminated miliary infections, including those caused by disseminated M. tuberculosis, non-tuberculous mycobacteria, and fungi (Fig. 113-14).

Imaging Miliary Nodules

Miliary tuberculosis is the prototypical example of miliary pneumonia that results from lymphohematogenous dissemination. Like bronchogenic tuberculosis, miliary tuberculosis can result from either progressive primary or re-activated post-primary tuberculosis. The numerous 1- to 5-mm randomly distributed nodules of military tuberculosis can usually be detected 3 to 6 weeks after lymphohematogenous dissemination. Some nodules are subpleural in location; some are septal thickening, and some are bronchovascular.

Ground-glass opacities may be seen. As the infection progresses, the nodules tend to increase in size and coalesce.

The primary non-infectious etiologies include disseminated hematogenous metastases from cancers of the thyroid, kidney, or the breast. Under other clinical circumstances, miliary nodules may be identified in coal workers pneumoconiosis, silicosis, berylliosis, sarcoidosis and Langerhansâ&#x20AC;&#x2122; cell histiocytosis, and silicosis, but such nodules tend not to be randomly distributed.

Overview and Pathogenesis Diffuse opacification pneumonia is a group of pneumonias of variable etiology that may have a diffuse or widespread multifocal bilateral distribution associated with ground-glass opacification, septal widening and/or frank consolidation.

Sometimes the lesions are limited to discrete secondary lobules leaving multiple areas of spared lung (Fig. 113-16).

Etiologies This type of pneumonia can be caused by Mycoplasma pneumoniae pneumonia, Respiratory syncytial virus (RSV), Ebstein-Barr virus (EBV), Herpes Simplex virus (HSV), adenovirus, and other viruses. These viruses may also cause a wide variety of other imaging types of findings. In pneumonias caused by Cytomegalovirus (CMV) diffuse groundglass opacification heralds a poor prognosis (Fig. 113-17).

In Pneumocystis jiroveci pneumonia, patchy diffuse groundglass opacities often demonstrate spared regions, prominent septal thickening, bulla, and thin-walled cysts (Fig. 113-18).

Less common causes of diffuse ground-glass attenuation, include infections due to fungi which most often focal or multifocal.

Imaging The imaging elements of diffuse lung opacification include ground-glass opacification, septal thickening, and a variety of centrilobular airspace opacities. Ground-glass attenuation is intermediate lung opacification that unlike consolidation does not completely obscure underlying pulmonary vasculature. This can result from parenchymal abnormalities that are beyond the spatial resolving power of CT, i.e., alveolar wall inflammation, alveolar wall thickening, partial airspace filling, or a combination of multiple causes, in which extensive bilateral ground-glass opacities progress into complete consolidation. Most infectious causes of diffuse lung opacification may also at different times be multifocal, and less commonly be localized.

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Figure 113-14 Miliary cryptococcal pneumonia. Immunosuppressed 62-year-old man under chemotherapy for metastatic pancreatic carcinoma. Disseminated cryptococcal infection was diagnosed by isolating cryptococcus from bronchoalveolar lavage, and detecting cryptococcus antigen in cerebrospinal fluid. CT scan demonstrates myriad randomly distributed 1- to 3-mm micronodules distributed throughout both lungs. Such miliary micronodules, although not easily distinguished from small end-on vessels on a single CT section, are more obvious when a stack of sections are viewed in rapid succession at which time the micronodules are found to be small spheres, not part of a longitudinal vascular structure.

Figure 113-15 Diffuse small nodules in varicella virus pneumonia. Thirty-nine-year-old woman whose son had chickenpox 2 weeks before she developed a new chickenpox lesion on her neck, cough, nausea, vomiting, headache, chills, and malaise. Chest radiograph demonstrates widespread small nodular opacities approximately 5 to 7 mm in diameter. A CT scan was not deemed necessary because of the characteristic radiographic findings of varicella zoster virus (VZV) pneumonia, the skin lesions, and the high clinical likelihood of varicella zoster virus (VZV) infection. The patient rapidly responded to intravenous acyclovir therapy.

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A

B

Figure 113-16 Lobular ground-glass opacities in viral pneumonia. Multifocal, bilateral patchy lobular ground glass opacification of secondary pulmonary nodules in the right upper lobe attributed to respiratory syncytial virus (RSV) pneumonia in immunocompromised patient under treatment for metastatic breast cancer. CT scan of the chest demonstrates two of many ground glass opacified secondary pulmonary lobules ( A and B ). The flat sides of the lobules indicate the sites of the septal margins of the lobules (arrows). The ground-glass opacity only partly obscures the underlying lung parenchyma.

Non-infectious Etiologies Non-infectious causes of diffuse opacification include pulmonary edema, drug-induced lung disease, hypersensitivity pneumonia; pulmonary hemorrhage, diffuse aspiration, diffuse alveolar damage, and other diffuse interstitial lung diseases, such as lymphocytic interstitial pneumonia and pulmonary alveolar proteinosis.

Ancillary Findings Associated with Pneumonia

Figure 113-17 Diffuse ground-glass opacity in cytomegalovirus pneumonia. Widespread ground-glass opacity with prominent inter- and intra-lobular septal thickening sparing the anterior lung in an elderly patient with cytomegalovirus pneumonia (CMV) while under radiotherapy for residual chordoma.

Figure 113-18 Diffuse ground-glass opacity Pneumocystis jiroveci pneumonia. Diffuse ground-glass opacification predominantly involving the subpleural (cortical) lung sparing the central lung at the time of first detection of Pneumocystis jiroveci pneumonia in a patient with advanced AIDS.

A wide variety of ancillary imaging findings may provide useful additional clues to etiologic causes of pneumonia. These include: atelectasis or other evidence of reduced lung volume; cavitation (which is suggested by lucency within lung

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opacity); or pleural effusion (which is suggested by a meniscus contour or smooth thickening of the pleural space); pericardial effusion or pericarditis (which is suggested by pericardial widening or enlargement of the cardiac silhouette); and mediastinal and/or hilar or perihilar lymphadenopathy.

Atelectasis Atelectasis refers to airlessness of a portion of lung. Crowded air-filled bronchi, and appropriate shift of lung contours toward the area of atelectasis may be diagnostic, e.g., pleural fissures, mediastinum, and diaphragm. When atelectasis is due to total airway occlusion, such as in proximal bronchogenic carcinoma, mucous plug, or aspirated foreign body, air bronchograms are usually absent. Atelectasis is a common feature of bronchopneumonia; it is not usually a prominent feature of peripheral airspace consolidation pneumonia. Atelectasis per se needs to be differentiated from pneumonia.

Bronchiectasis/Bronchiolectasis Bronchiectasis/bronchiolectasis refers to abnormal dilatation of the airway. It implies air- or fluid-filled and widened tubular, varicose, or cystic. Bronchiectasis is recognized by an airway diameter significantly greater than its paired pulmonary artery. Varicose and cystic bronchiectasis implies destructive pneumonia or other inflammation, such as due to granulomatous pneumonia, or prior radiation therapy. In acute pneumonia, cylindrical, often “reversible” bronchiectasis may be identified.

Cavitation Cavitation refers to abnormal non-anatomic lucency of lung usually within a lung opacity that makes up its wall. It is often devoid of normal internal vasculature. In uncomplicated bullous lung disease no significant wall thickness is present, and residual internal vasculature may be identified. Necrotizing cavitation may be caused by aspiration or pneumonia due to gram-negative intestinal bacteria, and mixed anaerobic oral flora. Cavitation suggests aggressive bacterial infections infection by bacteria such as S. aureus and gram-negative bacilli, and granulomatous infections, such as due to mycobacteria and fungi.

Lymphadenopathy Lymphadenopathy is inferred on plain film radiography by unilateral or bilateral nodular enlargement of the mediastinum and hilar regions. On plain film radiography these findings often cannot be differentiated from vascular enlargement. Contrast-enhanced CT is much more sensitive than non-contrast CT scan in the detection of lymph node enlargement.

In general, mediastinal adenopathy can be found in a wide variety of different types of pneumonia associated with sympathetic or complicated effusions, but it is especially common in patients with primary infection due to M. tuberculosis. The absence of acquired specific cellular immunity to

M. tuberculosis is responsible for the peripheral airspace consolidation and lymphadenopathy that are characteristic of primary tuberculosis. Lymphohematogenous dissemination results in characteristic mediastinal and hilar adenopathy with low-density necrotic centers, and rim enhancement in contrast-enhanced CT. Lymphadenopathy is also found in atypical mycobacterial infection; fungal infection due to Histoplasma capsulatum and Coccidioidomycosis immitis; viral infection due to HIV, CMV, and EBV; and bacterial infection associated with sepsis, e.g., pneumonia due to staphylococci, beta-hemolytic streptococci, and tularemia. In P. jiroveci pneumonia, lymphadenopathy often calcifies.

Non-infectious causes of hilar and mediastinal lymphadenopathy include bronchogenic carcinoma, lymphoma, sarcoidosis, metastatic cancer, lymphatic spread of tumor, pneumoconiosis, such as due to silica (in which case “eggshell” calcification, small lung nodules, and conglomerate masses may be seen), and interstitial pulmonary fibrosis.

In congestive heart failure non-pathologic lymph nodes can significantly enlarge, and reduce in size after diuresis.

Pleural and Pericardial Abnormality Pleural fluid is identified by abnormal fluid separation of the visceral and parietal pleural surfaces. It is likely to be free flowing if it is gravitationally dependent, and tapers out smoothly against gravity. Uniform meniscal opacity is usually identified in gravitationally dependent lung regions, where it tends to separate the lung from the ribcage. Loculation is suspected when the fluid localizes in non-gravitational regions of the pleural space. Pleural fluid is the only radiographic finding that has thus far been found to be an independent predictor of outcome of CAP pneumonia. For this reason pleural effusion has been incorporated into a Pneumonia Severity Index. Pleural fluid accumulation is more likely to indicate progressive and/or necrotizing pneumonia.

Pleural thickening and empyema are higher than water density on CT. Abnormal enhancement of both the visceral and parietal pleura is an imaging sign of active pleuritis. Empyema fluid may have near-normal water density or increased density. Pleural hemorrhage tends to have high density on non-contrast–enhanced CT studies.

Pneumothorax in the context of pneumonia implies a bronchopleural fistula (BPF) usually from cavitating pneumonia. CT scan can help localize the source of a BPF, as well as detect a small pneumothorax.

Pericardial effusion, when large, can be suspected on plain-film radiography by a new globular cardiac silhouette, short-interval cardiac enlargement, or abnormal fluid density thickness between the visceral and parietal pericardium on the lateral chest radiograph. On CT pericardial fluid can be identified by fluid density (or higher than fluid density in the case of empyema or hemorrhage) within the pericardial sac. Active pericarditis is indicated by abnormal thickening and enhancement of the visceral and parietal pericardium.

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CONCLUSIONS Radiologic imaging is an essential diagnostic tool for the diagnosis and management of pneumonia. Uncommonly, under special clinical circumstances, imaging findings can be virtually diagnostic of a specific etiology of infection. However, in most cases imaging only narrows the range of likely etiologies of pneumonia, and provides insight into its pathogenesis by categorizing its predominant imaging features and integrating these findings into the prior clinical probabilities.

Radiologists need to be aware of each patient’s pertinent background information to provide insightful opinions regarding imaging findings.

SUGGESTED READING Aquino SL, Dunagan DP, Ciles C, et al: Herpes simplex virus pneumonia: patterns on CT scans and conventional chest radiographs. J Comput Assist Tomogr 22:795–800, 1998.

Dietrich PA, Jonhson RD, Fairbank JT, et al: The chest radiograph in Legionnaire’s disease. Radiology 127:577–582, 1978.

Ebbert JO, Limper AH: Respiratory syncytial virus pneumonitis in immunocompromised adults: Clinical features and outcome. Respiration (Herrlisheim) 72:263–269, 2005.

Eggli KD, Newman B: Nodules, masses and pseudomasses in the pediatric lung. Radiol Clin North Am 31:651–666, 1993.

Escuissato DL, Gasparetto EL, Marchiori E, et al: Pulmonary infections after bone marrow transplantation: Highresolution CT findings in 111 patients. Am J Roentgenol 185:608–615, 2005.

Fine MJ, Auble TE, Yealy DM, et al: A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 336:243–250, 1997.

Fishman JA, Rubin RH: Infections in organ transplant recipients. N Engl J Med 338:1741–1751, 1998.

Franquet T: Imaging of pneumonia: Trends and algorithms.

Eur Respir J 18:196–208, 2001.

Greene R, Schlamm HT, Oestmann J, et al: Imaging findings in acute invasive pulmonary aspergillosis: Clinical significance of the halo sign. Clin Infect Dis 44:373–379, 2007.

Herbrecht R, Denning D, Patterson TF, et al: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347:408–415, 2002.

Herold CJ, Sailer JG: Community-acquired and nosocomial pneumonia. Eur Radiol 14:E2–E20, 2004.

The Radiology of Pulmonary Infection

Horger MS, Pfannenberg C, Einsele H, et al: Cytomegalovirus pneumonia after stem cell transplantation: Correlation of CT findings with clinical outcome in 30 patients. Am J Roentgenol 187:W636–W643, 2006.

Im JG, Itoh H, Shim YS, et al: Pulmonary tuberculosis: CT findings-early active disease and sequential change with antituberculous therapy. Radiology 186:653–660, 1993.

Kantor HG : The many radiologic faces of pneumococcal pneumonia. AJR 137:1213–1220, 1981.

Kim EA, Lee KS, Primack SL, et al: Viral pneumonias in adults: Radiologic and pathologic findings. Radiographics 22:137– 149, 2002.

Kim JS, Ryu CW, Lee SI, et al: High resolution CT findings in Varicella zoster pneumonia. Am J Roentgenol 172:113–116, 1999.

Kuhlman JE, Kavuru M, Fishman EK, et al: Pneumocystis carinii pneumonia: Spectrum of parenchymal CT findings. Radiology 175,711–714, 1990.

Kwong JS, Muller NL, Godwin JD, et al: Thoracic actinomycosis: CT findings in eight patients. Radiology 183:189–192, 1992.

Long R, Maycher B, Dhar A, et al: Pulmonary tuberculosis treated with directly observed therapy: Serial changes in lung structure and function. Chest 113:933–943, 1998.

Oikonomou A , M¨uller NL, Nantel S: Radiographic and highresolution CT findings of influenza virus pneumonia in patients with hematologic malignancies. AJR 181:507– 511, 2003.

Quagliano PV, Das Narla L: Legionella pneumonia causing multiple cavitating nodules in a 7-month-old infant. Am J Roentgenol 161:367–368, 1993.

Reittner P, M¨uller NL, Heyneman L, et al: Mycoplasma pneumoniae pneumonia: Radiographic and high-resolution CT features in 28 patients. Am J Roentgenol 174:37–41, 2000.

Reittner P, Ward S, Heyneman L, et al: Pneumonia: Highresolution CT findings in 114 patients. Eur Radiol 13:515– 521, 2003.

Stanton MW: Improving Treatment Decisions for Patients with Community-Acquired Pneumonia. Rockville, MD, Agency for Healthcare Research and Quality, 2002. Whimbey E, Englund JA, Couch RB: Community respiratory virus infections in immunocompromised patients with cancer.

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114 The Pathology of Pulmonary Infection Richard Kradin

I. THE APPROACH TO TISSUE SAMPLING Transbronchial Biopsy Fine-Needle Aspiration Biopsy Transbronchial Needle Aspiration Biopsy Video-Assisted and Open Thoracoscopic Biopsy II. HANDLING OF BIOPSY TISSUES Preparing Histopathology Sections Histochemical Stains Hematoxylin & Eosin Tissue Gram Stain Gomori Methenamine Silver Periodic Acid Schiff Silver Impregnation Techniques

The pathology of lung infection reflects a composite of hostpathogen interactions. Distortions in pulmonary anatomy, decreased mucocilary clearance, and local and systemic abnormalities in cellular and humoral immune response all predispose to pulmonary infection. Although clinical history, radiographic findings, and noninvasive sampling of secretions often establish a diagnosis of infection, only tissue sampling affords the possibility of directly assessing pulmonary infection. As biopsy procedures have become progressively less invasive, there has been a tendency to focus primarily on the identification of the causative infectious agent as the sole end point of the diagnostic process. However, this goal potentially ignores the benefits of evaluating host-pathogen interactions.

This chapter reviews the basics that clinicians and pathologists must know about lung tissue sampling, the optimal diagnostic work-up of the lung biopsy, and the histopathology of infection.

Mucin Stains Acid-Fast Stains Immunohistochemical Techniques Electron Microscopy III. PATTERNS OF PULMONARY INJURY IN INFECTION Pulmonary Host Response Diffuse Alveolar Damage Bronchopneumonia Other Patterns of Inflammation Granulomatous Inflammation Fungus Balls Vascular Inflammation Pleural Infection

THE APPROACH TO TISSUE SAMPLING The optimal method of sampling infection (Table 114-1) is a function of host immune status, where the infection is located in the lung, and on whether it is localized or diffuse. Infections that cause diffuse pulmonary infiltrates in an immunosuppressed patient with HIV-1 infection often can be accurately diagnosed by the induction of sputum or by bronchoalveolar lavage (BAL). This is particularly true when the microbial burden is large, as it often is in P. jirocevi and mycobacterial infections. Noninvasive procedures are less sensitive than biopsy in diagnosing pulmonary fungal infections, e.g., aspergillosis, and do not differentiate between noninvasive and invasive disease. Lung biopsy is also indispensable in distinguishing infection from noninfectious lung injury in patients receiving chemotherapy, radiation, or immunosuppressive agents. Whereas clinicians tend to favor minimally invasive

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Table 114-1

and radiographic data, but even then there is risk that they will be inaccurately interpreted.

Approach to the Isolation of Pulmonary Microorganisms

Fine-Needle Aspiration Biopsy

Expectorated sputum Induced sputum Bronchoalveolar lavage Fine-needle aspirate (1 mm) Bronchial biopsy (1–3 mm) Transbronchial biopsy (1–3 mm) Transbronchial needle biopsy (1 mm) Video-assisted thoracoscopic biopsy (2–3 cm) Open-lung biopsy (2–3 cm)

techniques in the sampling of lung tissue, most pathologists favor generous tissue samples. In support of the latter preference, it may be argued that diagnoses based on larger tissue samples are more reliable, afford the opportunity to establish additional treatable diagnoses, and lead to more finely crafted therapeutic interventions.

Transbronchial Biopsy The optimal approach to lung biopsy depends on the specific clinical features of the case. Sampling error is a serious pitfall in pulmonary pathology. Since the lungs have roughly the surface area of a tennis court, diagnostic accuracy is inversely related to the size of the biopsy. Transbronchial biopsy (TBB) yields tissue fragments of 1 to 3 mm in diameter and preferentially samples peribronchiolar parenchyma of the lung.

The TBB is particularly effective in sampling diffuse peribronchiolar granulomatous and neoplastic disorders. Despite limitations imposed by its size, it has a high yield in identifying infection when pulmonary infiltrates are diffuse, e.g., in diffuse alveolar damage due to viral pneumonia but is far less reliable in the diagnosis of localized parenchymal infections.

Despite its advantages, the findings in TBBs are often nonspecific and even misleading. Peripheral lesions in the lung are difficult to sample by TBB and samples obtained by this approach often prove to be nondiagnostic or nonrepresentative. For example, an area of organizing pneumonia can represent a tissue response to a focus of infection or it may reflect noninfectious etiologies, including treatment effects, aspiration, or cryptogenic organizing pneumonia. The findings in a TBB must always be carefully correlated with clinical

CT-guided fine needle aspiration biopsies have a high yield in the diagnosis of peripheral nodular infiltrates. Samples may be semi-liquid or include a 1-mm core of tissue. The procedures are generally performed with the assistance of a cytotechnologist, so that rapid diagnoses can be proffered at the bedside from the preparation and examination of stained smears. FNA is helpful in isolating the cause of infection and may enable the cytopathologists to suggest the pattern of inflammation based on the types of inflammatory cells, and the presence or absence of fibrin, necrosis, and elastic fibers in the sample. However, the limited sampling often does not provide sufficient tissue to reliably assess the inflammatory response of the host.

Transbronchial Needle Aspiration Biopsy Transbronchial needle aspiration biopsies of regional lymph node groups generally add little to the diagnosis of pulmonary infection, in part, because nonspecific reactive lymphadenitis is common but also because the procedure yields artifacts that can present diagnostic difficulties for the surgical pathologist.

However, they may have a role in diagnosing infection in patients with AIDS, since approximately 50 percent of patients with tuberculous lymphadenitis were successfully diagnosed using this approach.

Video-Assisted and Open Thoracoscopic Biopsy Video-assisted thoracoscopic lung biopsies have largely replaced procedures involving open thoracotomy. This approach is associated with less overall morbidity and allows direct access to widely separated lung segments. The procedure yields wedge biopsies of 2 to 3 cm with little artifactual distortion. Although it may be bucking the current clinical tide to argue for larger rather than smaller biopsies, the slight potential increase in morbidity associated with VATS lung biopsy is often counterbalanced by less discomfort than TBB, increased diagnostic accuracy, and less doubt concerning the subsequent treatment.

HANDLING OF BIOPSY TISSUES Proper handling of the lung biopsy is critical for obtaining the highest diagnostic yield from tissue samples (Fig. 114-1).

The examination of touch imprints of lung biopsy tissue is a simple way for identifying organisms rapidly. At least 10 touch imprint slides should be prepared from areas of pulmonary consolidation. These can be stained rapidly for bacteria, mycobacteria, and fungi, in the surgical pathology suite or the microbiology laboratory. Concomitantly, portions of

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Figure 114-1 The diagnostic work-up of pulmonary infection.

a large biopsy (VATS or open) or separate biopsies (TBB or FNA) should be harvested for culture, ultrastructural analysis, and polymerase chain reaction (PCR) assays. In preparing lung tissue for culture, it should be finely minced rather than crushed, since some hyphal fungi, e.g., Zygomyces sp., fail to grow in culture after the tissue has been macerated. For VATS or open lung biopsies, the lung should subsequently be inflated with 5 percent formalin via a 23- to 25-gauge needle, in order to optimize the histology of the paraffin-embedded lung sections.

The pathologist who receives the lung biopsy for processing must ascertain which diagnostic tests were sent by the surgeon and be prepared to harvest additional samples for tests that may have been overlooked. It is substandard care for either a surgeon or a pathologist to place a lung biopsy directly into formalin fixative, without first considering the possibility of infection. If there are doubts concerning which diagnostic tests to order, the amount of tissue required for a test or how best to transport the specimen to the laboratory, brief discussions with the hospital microbiology laboratory or an infectious disease specialist will promptly eliminate them.

Preparing Histopathology Sections The scarcity of microorganisms in tissue biopsies creates a diagnostic challenge for the pathologist. In addition, previous

antibiotic treatment can sterilize inflamed tissues, making it difficult to identify the original cause of the infection in situ. For these reasons, an adequate sample of tissue obtained by biopsy is critical for the microscopic identification of infectious agents. The surgical pathologist must be prepared to review multiple sections in the routine assessment of infection. In some instances, it may be necessary to examine literally scores of sections in order to identify an organism in situ. Too often, busy surgical pathologists may conclude that the diagnosis of infection is primarily in the realm of the microbiology laboratory or that the laborintensive effort required to identify organisms in situ is not cost effective. This attitude is to be discouraged, since it is incorrect and limits the practice that is required in order to acquire expertise in the identification of microorganisms in situ.

Certainly, if the microbiology laboratory has previously identified the offending pathogen, it may not be necessary to go to extraordinary lengths in order to duplicate its results.

But in instances in which cultures were not obtained, or when pathogens require weeks to grow in culture, e.g., mycobacteria, or the organism isolated in the laboratory may represent a commensal or contaminant, the pathologist must be ready to undertake a detailed examination of multiple tissue sections. Since antimicrobial drugs have become increasingly selective, it is currently suboptimal to render a nonspecific

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Figure 114-2 A. The lung shows a miliary focus of necrosis and fibrin deposition. Intranuclear inclusions (arrow) of herpesvirus-1 are present. B. Note the presence of multiple amphophilic intranuclear inclusions of Herpesvirus-1 infection in the trachea of a patient receiving chronic ventilator support.

diagnosis of, e.g., “necrotizing granulomatous inflammation,” without a concerted effort to identify the offending pathogen.

The pattern of pulmonary inflammation suggests the primary route of infection in the lung. For example, Herpesvirus-1 may either show a miliary pattern of fibrinoid necrosis (Fig. 114-2) in patients with viremia, or primarily affect the tracheobronchial epithelium in patients who have been intubated for prolonged periods. Microbes tend to be compartmentalized in inflamed tissues, and substantial effort can be wasted in searching for organisms at high magnification, in areas of the tissue section where they are not likely to be found. For example, mycobacteria and fungi are almost always localized in areas of necrotic tissue, and it is unusual to find them elsewhere in the biopsy. Organisms, such as Rickettsia sp. and Bartonella sp. are angiotropic, and attention should be focused on foci of perivascular inflammation.

Virus tends to target specific areas of the lung and certain types of cells.

Histochemical Stains A number of histochemical stains are available for the demonstration of microbes in situ and their proper application can yield accurate and specific diagnoses in many cases (Table 114-2). However, the limits of this approach must be recognized, and the gold standard, in most cases, remains the isolation and biochemical or molecular identification of an organism.

Hematoxylin & Eosin Most of the stains to be discussed in this chapter are widely available in pathology laboratories. However, if only one was to be chosen, it would be the standard hematoxylin and eosin (H&E) stain. Table 114-3 lists the diagnoses

that can be established reliably by H&E staining, without the benefit of additional methods. They include cytopathic viral infections, most fungal infections, and all parasites.

Although it is not possible to speciate bacteria into gram-positive or -negative subsets by the H&E stain, bacterial colonies often can be identified by this approach. Most fungi are visible by H&E, with the notable exception of Histoplasma capsulatum; and the tinctorial properties of the fungi can be helpful in speciating. For example, the cell walls of Zygomyces sp. stain intensely basophilic with H&E (Fig. 1143), and the yeast of Candida glabrata show prominent amphophilic staining.

Tissue Gram Stain The tissue gram stain (Brown-Hopps and Brown-Brenn) identifies most bacteria and some fungi in tissue sections. It also can be used to demonstrate the spores of microsporidia.

Gram-positive organisms stain a deep magenta, whereas gram-negative bacteria are pale pink (Fig. 114-4). For this reason, gram-negative organisms can easily be missed in a low-power cursory screening of gram-stained sections. The phenomenon of gram stain-variability, in which colonies of gram-positive organisms show a range of staining from dark blue to pink, is common and can give the false impression of “mixed flora.” In such instances, only culture can reliably distinguish the actual additional presence of gram-negative bacteria. Although most fungi are weakly gram positive, most Candida sp. stain intensely positive, a fact that can be used to advantage in their identification.

Gomori Methenamine Silver Gomori methenamine silver (GMS) is the stain of choice for identifying fungi in tissue sections. Both fungal yeast and

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Table 114-2 Histochemical Staining Characteristics of Microbes Organism Virus Influenza SARS (Coronavirus) Adenovirus Cytomegalovirus

Staining Characteristics

Herpes virus Measles Respiratory Parainfluenza

No cytopathic change No cytopathic change H&E (smudge cells), IHC H&E (intranuclear and cytoplasmic inclusions) IHC; PAS and GMS (intracytoplasmic inclusions) H&E (intranuclear inclusions); IHC H&E (intranuclear inclusions, polykaryons) H&E (polykaryons); IHC syncytial virus H&E (intracytoplasmic inclusions)

Bacteria Gram-positive Gram-negative Legionella Nocardia Actinomyces Mycobacteria tuberculosis Atypical mycobacteria

Tissue gram, GMS (all) Tissue gram, GMS (some) Silver impregnation Tissue gram, GMS, modified ZN Tissue gram, GMS ZN and mod ZN, PCR Mod ZN, ±ZN, PCR

Fungi Histoplasma Cryptococcus Blastomyces Coccidioidomycosis Candida Aspergillus Zygomyces Pseudeallescheria Alternaria and dermatiacious fungi

GMS, PAS H&E, GMS, PAS, mucicarmine; Fontana, IHC H&E, GMS, PAS, mucicarmine (weak) H&E, GMS, PAS H&E, GMS, PAS, gram-stain; IHC H&E, GMS, PAS, IHC H&E, GMS, PAS H&E, GMS, PAS H&E, GMS, PAS, Fontana

Parasites Protozooa Metazoa Echinococcus Paragonimiasis Schistosomiasis

H&E, PAS, gram stain (microsporidia); IHC (toxoplasma) H&E, trichrome stain GMS in chitinous wall, modified ZN (hooklets) Ova birefringent Lateral and terminal spines stain with modified ZN

Table 114-3 Microbes That Can Be Identified with H&E Stain Cytopathic virus Bacteria in colonies or in “granules” Most fungi Parasites

hyphae stain intensely with GMS (Fig. 114-5). However, identification of speciating fungi in tissue sections is a challenging morphologic task (Table 114-4). Identification is based primarily on size, branching pattern, and mode of reproduction. Hyphal organisms, e.g., Aspergillus sp., Pseudallescheria sp., Fusarium sp., and the Zygomyces sp. are particularly difficult to distinguish based solely on morphology, especially when fragmented, and immunohistochemical methods or culture confirmation are required (Fig. 114-6).

Yeast forms are distinguished by size, pattern of budding, and affinity for special stains.

The GMS stain is generally counterstained with methyl green, which highlights the grey-black staining of fungi.

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Figure 114-3 A. The broad pauciseptate ribbon-like hyphae of Zygomyces (mucor) stain intensely basophilic with H&E. B. The 3 to 4 ÂľM yeast of C. glabrata (torulopsis) show amphophilic staining with H&E.

However, this does not allow for optimal visualization of pulmonary anatomic structures or assessment of the inflammatory response of the host. When desirable or necessary, the GMS can be counterstained with H&E. This technique diminishes modestly the sensitivity of fungal identification in situ, but greatly facilitates localization within the lung (Fig. 114-7).

In addition to staining fungi, GMS blackens grampositive bacteria and some encapsulated gram-negative bacteria, e.g., Klebsiella sp. and H. influenzae. Unfortunately, the

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stain also reacts with anthracotic pigment, microcalcifications, and hemosiderin, complicating the distinction between bacteria and nonbacterial structures. The identification of bacteria by GMS should be confirmed and complemented by tissue gram stain.

Most pathologists recognize that GMS reacts with both Actinomyces sp. and Nocardia sp.; however, this is not a specific feature of these organisms but instead reflects the fact that they are gram-positive filamentous bacteria. The GMS stain adds little to their specific identification but does enhance

C

Figure 114-4 A. Colonies of magenta staining gram-positive cocci line the alveoli in a lethal case of streptococcal pneumonia. B. Gram-negative rods are seen in the lumen of a bronchiectatic airway in a patient with cystic fibrosis and Burkholderia cepacia infection. C. The yeast (blastoconidia) of C. parapsilosis show gram-variable staining.

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Figure 114-5 A. Both pseudohyphae and yeast (blastoconidia) of Candida albicans are well demonstrated with GMS. B. Septate acute-angle progressively branching hyphae of Aspergillus fumigatus. C. Yeast forms of Blastomyces dermatitidis show broad based single buds and accentuation of thick cell wall with GMS. D. GMS shows intact and collapsed cyst walls (arrow) of Coccidioides immitis. Endosporulation is not obvious.

their visibility in tissue sections. Actinomyces sp. are invariably seen within granules lined by granulohistiocytic inflammation, often highlighted by the eosinophilic staining of the Splendore-Hoepllei phenomenon (Fig. 114-8). Nocardia in the lung are rarely localized to granules, and unlike Actinomyces sp., they are generally weakly acid-fast positive. GMS reacts variably with mycobacteria. The intracellular inclusions of cytomegalovirus (CMV)-infected cells are GMS-positive and must not be confused with intracellular Histoplasma capsulatum.

Periodic Acid Schiff Many pathologists prefer the periodic acid Schiff (PAS) stain with diastase digestion for the identification of fungal forms.

However, PAS should be used primarily to complement GMS, and not as a first-line screening tool, since the latter is more sensitive. However, PAS can add important morphologic details that assist with identification of fungi (Fig. 114-9). PAS stains the cytoplasm of Entamoeba intensely but

obscures the karyosome, a feature that is required for accurate diagnosis. The PAS stain also demonstrates the intracellular bacilli of Trophyrema whipelli (Whippleâ&#x20AC;&#x2122;s disease bacillus).

Silver Impregnation Techniques Silver impregnation techniques, including the WarthinStarry, Steiner, and Dieterle stains, are distinguished by their capacity to blacken all eubacteria, including mycobacteria. In practice, this stain is used to identify bacteria that cannot be visualized by tissue gram stain. This includes Legionella sp., Bartonella sp., and spirochetes (Fig. 114-10).

Mucin Stains Mucicarmine stains Cryptococcus sp. (Fig. 114-11). The central organism does not stain and the capsule is stained red.

Capsule-deficient variants generally infect hosts who can mount a granulomatous response. When yeast forms meet the

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Table 114-4 Fungal Identification in Tissue Organism

Size (Width µM)

Defining Morphology

Histoplasma capsulatum

2–5

Narrow-neck bud

Cryptococcus neoformans

5–20

Narrow-neck bud

Blastomyces dermatitides

15–30

Broad-based bud

Candida glabrata

3–5

Budding, no pseudohyphae

Candida sp.

2–3

Yeast, pseudohyphae, hyphae

Aspergillus sp.

3–5

Acute-angle branching, septate, conidial head

Zygomyces spp.

5–8

Right-angle branching, ribbons, pauciseptate

Pseudallescheria sp.

3–4

Acute-angle branch, septate, terminal chlamydospore, pigmented conidia

Fusarium sp.

4–5

Acute and right-angle branch, septate, narrowed branch points

Coccidioides immitis

20–200

size and morphologic criteria of Cryptoccocus on the GMS and PAS stains but do not react well with mucin stains. A FontanaMasson stain will demonstrate the premelanin substances expressed within the cell wall by all cryptococci. A careful examination of the mucicarmine stain will generally reveal a rim of weak staining, even in the capsule deficient organisms. Fontana-Masson is helpful in demonstrating dermatia-

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Endosporulation

cious fungi, when pigment is not convincingly discerned with H&E.

Acid-Fast Stains The Ziehl-Neelsen (ZN) stain and its modifications are useful in the identification of mycobacteria in tissue sections.

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Figure 114-6 A patient with chronic granulomatous disease and lung nodule. Lung biopsy showed (A) fragmented hyphal form with stubby right angle buds that were impossible to speciate with confidence with GMS. B. Immunostain for Aspergillus sp. was positive (arrow) and the microbiology laboratory isolated A. terreus.

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Immunohistochemical Techniques A variety of immunohistochemical techniques are currently available for the identification of organisms in tissue (Table 114-5). Unfortunately, the number of commercially available stains for specific organisms is limited. A large panel of specific reagents is available through consultation with the Pathology Division of the Center for Disease Control in Atlanta, GA, or other regional medical centers. Most antimicrobial immunostains can be applied to either frozen or formalin-fixed and paraffin-embedded tissues. Protein nucleotide agglutination (PNA) represents a new and potentially important breakthrough in the localization of microorganisms in tissue sections.

Electron Microscopy Figure 114-7 Patient with disseminated trichosporon infection.

GMS-H&E shows hyphae (arrow) in a blood vessel with surrounding hemorrhage. This preparation is helpful when there is doubt concerning the localization of organisms in the routine GMSmethyl green preparation.

M. tuberculosis stains avidly with ZN. Mycobacterial organisms vary in length and are often curved and beaded (Fig. 114-12). Modifications of the ZN (Fite-Farraco or Putt) can help to identify organisms that fail to stain following strong decolorization by acid. This includes some atypical mycobacteria and M. leprae. The morphology of the mycobacteria is generally not diagnostic; however, M. kansasii characteristically shows prominent â&#x20AC;&#x153;cross-linkingâ&#x20AC;? due to variable uptake of stain. As noted, Nocardia sp. generally stain with the modified ZN, a feature that can help to differentiate this organism from Actinomyces sp. The hooklets of Echinococcus sp. stain with the modified ZN; so do the shells or spines of Schistosoma sp.

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Ultrastructural examination can be adopted for the identification of microbes in tissue. The limiting factors in this approach include sampling and expense. Whereas ultrastructural examination has largely been replaced primarily by immunohistochemistry, it can still assist in the morphologic identification of virus and other organisms. In addition, when questions remain concerning the veracity of light microscopic findings, areas of interest can be excised from the paraffin block and examined by electron microscopy. Most organisms can be identified even though fixation and paraffin embedding procedures may be suboptimal.

PATTERNS OF PULMONARY INJURY IN INFECTION Pulmonary Host Response Before examining the patterns of inflammation that occur in pulmonary infection, it may be helpful to summarize the basic

B

Figure 114-8 A. Granule in patient with Actinomyces israelli. To the naked eye, these granules are bight yellow (sulfur granules). Microscopically the gram-positive filamentous organisms are coated with eosinophilic PAS+ material that is deposited on the surface of the granule, i.e., the Splendore-Hoepllei phenomenon. B. Loosely adherent grampositive filamentous organisms are seen in Nocardia asteroides pneumonia. Nocardia in the lung rarely forms true granules.

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Figure 114-9 A. PAS shows the cyst wall and endospores of Coccidioides immitis to excellent advantage. B. The karyosome (arrow) of Entamoeba histolytica is well seen in this H&E preparation but can be obscured by PAS.

blood at low mean arterial pressures to the alveolated surfaces, whereas the bronchial circulation arises from branches of the aorta and nourishes the airways and connective tissue stroma of the lung with oxygenated blood at systemic arterial pressures. All new growths within the lung, including fibroinflammatory responses to pulmonary infection, evoke neoangiogenesis from the bronchial circulation, so that areas of infected bronchiectasis, abscesses, and tuberculous cavities are all supplied by the systemic circulation. Deep and superficial systems of pulmonary lymphatics drain the lung from the level of the respiratory bronchioles, respectively, either toward lymph nodes at the hilum or centripetally along

mechanisms of pulmonary host defense. The pulmonary response to infection includes generic elements of both innate and adaptive immunity that are shared by all tissues in their response to a particular infectious agent. However, the morphology of immune responses is modified by the specific microanatomy of the lung.

The lung is an elastic organ, composed of asymmetric dichotomously branching conducting airways that lead to the gas-exchange surfaces. The airways and the alveoli are embedded in a connective tissue matrix that is supplied by two blood circulations. The pulmonary circulation arises from the right side of the heart and carries deoxygenated

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Figure 114-10 A. The coccobacilli of Legionella pneumophila are demonstrated by silver impregnation (Steiner). B. A pulmonary syphilitic gumma shows numerous spirochetes with silver impregnation (Warthin-Starry).

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Figure 114-11 A. The true capsule of Cryptococcus neoformans stains red with mucicarmine. B. GMS shows the staining of the organism but does not demonstrate the capsule. C. Capsule-deficient cryptococci stain with FontanaMasson. In most cases, careful examination, in retrospect, will reveal a faint mucicarminophilic capsule.

the pleural surfaces before emptying at the hilum. Lymphatic drainage plays an important role in the mechanism of disease. Streptococcal infections rapidly invade the pulmonary lymphatics, which transport bacteria to the pleural spaces to produce empyema. Inhaled anthrax bacilli drain rapidly to the local lymph nodes and lead to rapid dissemination of

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infection. Mycobacteria and fungi drain to the hilar nodes and, from there, disseminate to extrapulmonary tissues via the blood circulation.

The primary defenses of the airways include the olfactory hairs of the nasal passages and the mucociliary clearance mechanisms of the lower airways. Most microbes are

C

Figure 114-12 The Ziehl-Neelsen stain demonstrates (A) M. tuberculosis. B. M. kansasii shows a prominent crosslinked staining pattern. C. The hooklets (arrow) of Echinococcus granulosa stain with modified Ziehl-Neelsen (Fite).

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Table 114-5 Immunohistochemical Stains Commercially Available for Microbe Identification in Paraffin-Embedded Tissues Fungi

Virus

Aspergillus (genus only)

Herpesvirus-1 (cross-reacts Herpesvirus-2)

Cryptococcus

Varicella-Zoster

Histoplasma

Cytomegalovirus

Candida sp.

Respiratory syncytial virus

Coccidioides immitis

Adenovirus

Pneumocystis jiroveci

Ebstein-Barr (EBER)

Pseudallescheria boydii

Actinomycetes

Zygomyces (genus only)

Actinomyces israelii

Sporothrix schenkii

Actinomyces naeslundi

Trichosporon

Arachnia propionica

small enough (less than 5 ÂľM) to penetrate to the distal gasexchanging surfaces of the lung. However, the vast majority are excluded by the defenses of the upper airways or deposit along the conducting airways, and are cleared by the mucociliary escalator. Humoral factors, including sIgA and defensins that are released into the airways, limit penetration by microbes. Mucosal dendritic cells trap microbial antigens and carry them to the regional lymph nodes, where they are processed and presented to both T- and B-lymphocytes (Fig. 11413), affording the potential for specific adaptive anamnestic responses The gas-exchange surface consists of a fused epithelialendothelial basement membrane. Disruption or thickening of the gas-exchange surface is deleterious with respect to the diffusion of oxygen and carbon dioxide. For this reason, the surfaces of the alveoli are kept sterile by scavenging alveolar macrophages. These resident alveolar macrophages have the capacity to ingest inhaled particulates and to secrete monokines, including IL-10, that actively suppress local inflammation. Under conditions of health, the prevailing response is one of immunotolerance. However, when the alveolar lining is injured, or the number of invading organisms overwhelms the phagocytotic capacities of resident alveolar macrophages, neutrophils and exudate monocytes are recruited to the sites of inflammation. Even small numbers of virulent pathogens can greatly amplify inflammation via

the release by the host of chemokines, cytokines, and complement components. Although this response may increase the clearance of infection, the damage evoked by these factors can injure the lung irreversibly, leading to fibrosis. The lung biopsy affords a unique opportunity to assess the host inflammatory response, in addition to identifying the cause of infection (Table 114-6). It is ultimately, the most accurate mode of determining host immune competence in patients with immune deficits.

Diffuse Alveolar Damage A number of patterns of inflammation are unique to the lung.

The sine qua non of acute injury to the alveolar wall is the development of the hyaline membrane, composed of an extravascular fibrin coagulum admixed with the necrotic alveolar cell debris. Diffuse alveolar damage (DAD) is the most frequent pathological correlate of the adult respiratory distress syndrome (ARDS), although confluent bronchopneumonia can also yield this syndrome since it is impossible to distinguish DAD from localized acute lung injury in small biopsy specimens, radiographic and clinical confirmation always should be sought.

Virtually all viruses cause DAD. Influenza and coronarvirus are RNA viruses that yield DAD with no diagnostic cytopathic features (Fig. 114-14). Herpesvirus, adenovirus, varicella-zoster, measles and cytomegalovirus cause DAD, but also exhibit cytopathic changes that are diagnostic. Immunohistochemical techniques can be used to localize viral proteins within infected cells in situ.

Bacterial, fungal, or parasitic infections rarely cause DAD primarily, although Pneumocystis jiroveci is a wellrecognized cause. However, the presence of DAD is not limited to infection. Many inhaled toxins also produce DAD, and in patients who are immunosuppressed due to cancer therapy or organ transplantation, distinction can be difficult between DAD due to infection versus radiation, cytotoxic drug therapy, lung implantation injury, and diffuse gastric acid aspiration. Pulmonary infection can complicate DAD due to other causes, and the septic complications of extrathoracic infections can cause DAD.

Bronchopneumonia Bronchopneumonia is the most common pattern of inflammation caused by inhaled pathogens. Bronchopneumonia begins as infection with inflammation of the membranous small airways and then extends into the surrounding alveolar spaces. Bacterial bronchopneumonia due to pyogenic bacteria, including S. pneumonia, S. aureus, and Streptococci sp., often complicate viral tracheobronchitis, probably reflecting an acquired postviral defect in mucociliary clearance and barrier defense. Virtually all bacteria and fungi and many viruses can cause bronchopneumonia. The inflammatory response evoked by the pathogen is helpful in limiting the differential diagnosis. Both gram-positive and -negative bacterial infections evoke a brisk pyogenic neutrophilic response

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Figure 114-13 The cartoon shows the afferent and efferent pathways of adaptive pulmonary immunity via which entrapped antigens (Ag) are transported by dendritic cells (DC) to regional lymph nodes, presented to T- and Blymphocytes, and subsequently evoke a cellular anamnestic response by memory lymphocytes (ML ) upon rechallenge. (Adapted from Kradin RL, Robinson BWS (eds.): Immunopathology of the Lung. Boston: Butterworth-Heinemann, 1996.)

Table 114-6 Tissue Responses to Infection Type of Inflammation

Example

Exudative inflammation

Pyogenic bacteria

Necrotizing inflammation

Gram-negative bacteria, amebiasis

Granulomatous inflammation

Mycobacteria, fungi

Histiocytic inflammation

Rhodococcus, Legionella, Whipple’s

Interstitial inflammation

Pneumocystis

Cytopathic changes

Virus

No response

Host anergy

in the lung. Streptococcal pneumonia is distinguished by its tendency to produce a non-necrotizing lobar pneumonia, although in the current age of antibiotic treatment, bronchopneumonia is more common. Klebsiella sp. classically produces a hemorrhagic lobar pneumonia, with upper lobe predominance (Fig. 114-15). Necrosis of lung tissue with microabscess formation proceeding to cavitation can follow due to infection by aspirated mixed oral flora, Staphylococcal sp., Streptococcal sp., or gram-negative bacilli.

Herpes simplex virus evokes dense neutrophilic infiltrates in the airways with fibrinoid necrosis and karyorrhexis that histologically mimics bacterial bronchopneumonia (Fig. 114-16). But the presence of characteristic intranuclear viral inclusions distinguishes herpetic from bacterial infection. Adenovirus has a propensity to produce ulcerative bronchiolitis and bronchiolitis obliterans organizing pneumonia (BOOP). The characteristic nuclear inclusions disrupt the nuclear membrane to produce diagnostic “smudge cells.” Influenza, respiratory syncytial virus (RSV) and parainfluenza viruses can all present as bronchopneumonia with a lymphohistiocytic inflammation or progress to DAD. Mycoplasma and nonvirulent Chlamydia produce acute bronchiolitis with

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Figure 114-14 A. The lung in a lethal case of severe acute respiratory syndrome (SARS) shows diffuse alveolar damage with no cytopathic changes. B. Cytomegalovirus infection (CMV) with enlarged cell bodies, intranuclear (long arrow) and intracytoplasmic inclusions (small arrow), which are well seen with H&E. C. Confirmation can be established by immunohistologic demonstration of nuclear antigen. CMV can produce DAD, bronchopneumonia, or patchy nodular interstitial pneumonitis.

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Figure 114-15 A. Hemorrhagic lobar pneumonia due to Klebsiella pneumonia. B. Multiple lung abscesses with early cavity formation (arrow) due to methicillin-resistant Staphylococcal aureus.

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Figure 114-16 A. Herpesvirus-1 bronchopneumonia produces a pyogenic and necrotizing response. Viral inclusions are present (arrow). B. Adenovirus causes necrotizing bronchiolitis with surrounding fibrinous pneumonia. A diagnostic ‘‘smudge cell” is shown in the inset.

of central vascular plugging by organisms and surrounding necrotizing fungal pneumonia (Fig. 114-19). Fungal infection due to fungemic spread to the lungs from extrathoracic sites yields a lesion in which the fungi grow radially from a plugged pulmonary arteriole, producing a “sunburst” appearance.

Nematodes that have a larval developmental phase in the lung, e.g., Ascaris and Strongyloides, migrate through the airways toward the mouth, where they are either swallowed or expectorated. This process may be associated with wheezing, migratory pneumonia, and blood eosinophilia, a complex of findings termed Loeffler syndrome (Fig. 114-20). The presence of track-like necrotizing granulomatous bronchitis and bronchopneumonia with prominent eosinophilic infiltrates

interstitial lymphohistiocytic infiltrates. Legionella sp. characteristically exhibits a necrotizing bronchopneumonia with alveolar filling by fibrin and histiocytes (Fig. 114-17). The demonstration of this weakly gram-negative coccobacillus in tissue requires either silver-impregnation techniques or immunohistochemical staining. L. micdadei shows positivity on modified Ziehl-Neelsen stains.

Confluent bronchopneumonia mimicking lobar consolidation is a common finding at autopsy in immunosuppressed patients with fungal infection. Opportunistic molds such as Aspergillus, Zygomyces, Pseudoallescheria, and Fusarium (Fig. 114-18), often begin as airway infections and then rapidly invade blood vessels. This produces the characteristic gross appearance of a “targetoid” lesion, comprised

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Figure 114-17 A. Legionella pneumophila characteristically yields a fibrinous and histiocytic bronchopneumonia. Coccobacilli organisms are generally numerous but require silver impregnation for demonstration. B. L. micdadei stains with modified Ziehl-Neelsen.

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Figure 114-18 A. Pseudallescheria boydii (Scedosporium) at a dehisced anastomotic site of a recent lung transplant.

The organism is septate and branching and can be confused with Aspergillus sp. In this instance, prominent terminal chlamydospores (arrow), evoking the image of a tadpole, are a distinguishing feature. B. Fusarium sp. is septate, shows nonparallel walls, branches predominantly at right angles, and narrows at branch points (white arrow). Blastoconidia can be seen in most cases (red arrow).

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Figure 114-19 A. Targetoid infarct-pneumonia due to disseminated Aspergillus fumigatus. A small vessel is thrombosed (arrow) and the surrounding area shows necrotizing pneumonia. B. Branching hyphae of Aspergillus fumigatus are seen growing out of a small vessel with GMS.

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Figure 114-20 A. A small airway shows a prominent mucus plug. B. High-power reveals larval forms of Strongyloides.

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Figure 114-21 A. The lung in Pneumocystis jiroveci pneumonia shows filling of alveolar spaces by eosinophilic frothy material due to the presence of trophozoites. B. This appearance can be confused with pulmonary alveolar proteinosis or with fibrinous pulmonary edema (not shown). The organisms of P. jiroveci are demonstrated with GMS. Characteristic features include size (4 to 6 µM), absence of budding, ‘‘boat”-shaped cysts (white arrow), and pericapsular accentuations (red arrow).

should alert the diagnostic pathologist to the presence of a parasitic pulmonary infection.

Other Patterns of Inflammation A variety of other inflammatory reactions are seen in response to infection. Pneumocystis jiroveci pneumonia generally shows alveolar filling by a foamy exudate that con-

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tains innumerable trophozoites (Fig. 114-21). Pneumocystis pneumonia must be morphologically distinguished from pulmonary alveolar proteinosis that also can occur in the immunosuppressed host, as well as from fibrinous pulmonary edema. Necrotizing granulomas and cystic lesions also may be caused by Pneumocystis and can easily be mistaken for fungal yeast forms.

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Figure 114-22 A. Chronic infection with Histoplasma capsulatum shows a necrotizing granuloma with mummification. B. The wall shows a multinucleate giant cell and characteristic paucicellular hyaline fibrosis. The GMS stain reveals multiple 2- to 4-µM yeast, some of which have single narrow-necked buds (arrow).

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Figure 114-23 A. A bronchiectatic lung is infected with Mycobacteria avium/intracellulare complex (MAC). B. The inflammatory response in the non-immunosuppressed host includes primarily non-necrotizing granulomatous inflammation. When areas of necrosis are more prominent, M. tuberculosis, or other more virulent atypical mycobacteria, e.g., M. kansasii, or an abnormal host response, should be considered.

Granulomatous Inflammation Most necrotizing granulomas in the lung are caused by chronic mycobacterial or fungal infections. However, noninfectious diseases, e.g., Wegenerâ&#x20AC;&#x2122;s granulomatosis and rheumatoid nodules, can show comparable morphologic features. M. tuberculosis can affect the airways, lung parenchyma, and pleura. Miliary tuberculous granulomas in the lung indicate spread through the pulmonary blood circulation. Tuberculous necrosis destroys the underlying elastic framework of the lung and is generally referred to as â&#x20AC;&#x153;caseousâ&#x20AC;? necrosis, but this term should be restricted to describe the cheesy

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appearance of the gross lesion. Chronic pulmonary infection with Histoplasma capsulatum yields an unusual form of mummifactive necrosis, as well as a dense paucicellular fibrotic response that can, in most instances, be distinguished from tuberculosis (Fig. 114-22). Involvement of regional lymph nodes by H. capsulatum can lead to the development of broncholiths or to immune-mediated mediastinal fibrosis.

Atypical mycobacterial infection in the emphysematous or bronchiectatic lung is characterized by a considerable number of non-necrotizing granulomas centered on distorted airways (Fig. 114-23). Necrotizing granulomatous changes

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Figure 114-24 Patient with HIV-1 infection and (A) a cavitary lung nodule due to Rhodococcus equi. B. The host response includes histiocytic inflammation and small calcified concretions termed Michaelis-Guttmann bodies (arrows). C. The organism is a gram-positive coccobacillus that is also positive with the modified Ziehl-Neelsen stain (inset).

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The Pathology of Pulmonary Infection

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Figure 114-25 A fungus ball was identified in an area of cystic bronchiectasis. A. The fungus ball shows rings of ‘‘zonation” that include distorted fungal mycelial forms. B. Specific identification may require immunohistochemical (Aspergillus sp.) staining or culture. C. Occasionally, the conidial head (fruiting body) is present, which allows for speciation. In this case, the morphology is diagnostic of Aspergillus fumigatus.

suggest a more virulent atypical mycobacterial infection, e.g., M. kansasii or M. abscessus. Rhodococcus equi, a gram-positive, weakly acid-fast coccobacillus, can yield necrotizing histiocytic pulmonary inflammation, usually in the immunocompromised host. The host response is distinguished by the presence of microcalcifications termed Michaelis-Guttmann bodies (Fig. 114-24). Amebic pulmonary infection is virtually always the result of extension of a hepatic abscess through the diaphragm. The organisms produce liquefactive necrosis with granulohistiocytic inflammation but no tissue eosinophilia.

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Fungus Balls Aspergillus, Pseudallescheria, and the Zygomyces can produce fungus balls within pre-existing areas of lung cystification due to emphysema, old mycobacterial infection, or sarcoidosis (Fig. 114-25). The diagnostic morphologic features of the organisms are distorted by the mycelial growth so that either immunohistological staining or culture is required to establish the specific cause. Occasionally, a conidial fruiting body, which develops only in areas of high oxygen tensions, e.g., a cavity, enables accurate speciation of aspergillus in situ or

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Figure 114-26 A. Pseudomonas aeruginosa pneumonia produces necrotizing microvascular injury. B. A small pulmonary vessel contains a club-shaped zygomycosis. C. Granulomatous pulmonary arteritis in response to the ova of Schistosome mansoni.

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Figure 114-27 A. Tubercle in granulomatous pleuritis due to M. tuberculosis. B. Eosinophilic pleuritis in patient with Strongyloides stercoralis. Although no organisms were identified in the pleura, multiple parasites were identified in the stool. C. Multiple Aspergillus sp. hyphae are seen with GMS, lining the pleural surface in a young boy with leukemia.

helps to identify the pigmented conidia of Pseudallescheria boydii. The presence of birefringent oxalate crystals is particularly common with A. niger.

Vascular Inflammation Blood vessel involvement can occur as a necrotizing vasculitis associated with acute pneumonia in Pseudomonas and other gram-negative bacterial infections (Fig. 114-26). Penetration of blood vessels is a dreaded complication of infections by molds, such as Aspergillus, Pseudallescheria, Fusarium, and Mucor sp., Rickettsiae sp., Bartonella sp., and spirochetes target blood vessels where they cause endothelialitis. Granulomatous arteritis may be evoked in response to either the ova or larval forms of schistosomes. Unlike the ova of Paragonimus sp., schistosome eggs are not birefringent. Pulmonary arterial occlusion with distal ischemic infarction may be caused by the heartworm Dirofilaria immitis.

Pleural Infection Parapneumonic effusions may complicate bacterial pneumonias but are rarely biopsied, unless they lead to empyema or the production of a restrictive rind around the underlying lung. In most instances, an infectious cause has been identified and treated previously, so that identifying viable organisms in situ is uncommon. Mycobacteria, fungi, and parasites yield exudative effusions and necrotizing granulomatous inflammation, and their presence helps to narrow the differential diagnosis, even if organisms are not identified (Fig. 114-27). Tissue eosinophilia may be a clue to the presence of a parasitic infection, but can also occur in fungal and mycobacterial infections, in response to pleural metastases, and following pneumothorax.

SUGGESTED READING Chandler FW: Approaches to the pathologic diagnosis of infectious disease, in Connor DH, et al. (eds.), Pathology of Infectious Diseases. Stanford, CT, Appleton & Lange, 1997.

Chandler FW, Watts JC: Pathologic Diagnosis of Fungal Infections. Chicago, ASCP Press, 1987.

Harkin TJ, et al.: Transbronchial needle aspiration in patients infected with HIV. Am J Respir Crit Care Med 157:1913– 1919, 1998.

Jaffe J, Maki D: Lung biopsy in immunocompromised patients: One institution’s experience and an approach to management of pulmonary disease in the compromised host. Cancer 48:1144, 1981.

Kradin R: Pulmonary immune response, in Kradin RL, Robinson BWS (eds.): Immunopathology of the Lung.

Boston, Butterworth-Heinemann, 1996, 1–13.

Leslie KO, and Wick MR: Practical Pulmonary Pathology.

Philadelphia, Churchill Livingstone, 2005.

Marr K, Patterson T, Denning D: Aspergillosis. Pathogenesis, clinical manifestations, and therapy. Infect Dis Clin North Am 16:875, 2002.

Masur H, Shelhamer J, Parrillo J: The management of pneumonias in immunocompromised patients. JAMA 253:1769, 1985.

McKenna R Jr, Mountain C, McMurtey M: Open lung biopsy in immunocompromised patients. Chest 86:671, 1984.

Nasuti J, Gupta P, Baloch Z: Diagnostic value and cost effectiveness of on-site evaluation of fine needle aspiration specimens: Review of 5,688 cases. Diagn Cytopathol 27:1– 4, 2002.

Toledo-Pereyra L, et al.: The benefit of open lung biopsy in patients with previous non-diagnostic transbronchial lung biopsy: A guide to appropriate therapy. Chest 77:647, 1980.

115 Principles of Antibiotic Use and the Selection of Empiric Therapy for Pneumonia Michael S. Niederman

I. PRINCIPLES OF ANTIBIOTIC USE Mechanisms of Action Penetration into the Lung Antibiotic Pharmacokinetics and Pharmacodynamics II. FEATURES OF SPECIFIC ANTIMICROBIALS USED IN THE THERAPY OF RESPIRATORY INFECTIONS Macrolides (Including Azalides) and Tetracyclines Ketolides Trimethoprim-sulfamethoxazole (TMP-SMX) β-Lactam Antibiotics

Antibiotics are the foundation of therapy for respiratory tract infections, but the approach to their use varies with the type of pneumonia present (community acquired, health care– related, or nosocomial), as well as the age of the affected patient, the presence of various co-morbid illnesses and risk factors for infection by specific pathogens, and the severity of the acute illness. For most patients, initial therapy is aimed at a broad spectrum of potential pathogens and is empiric because the infecting pathogen is often not known. Therapy can be more specifically focused on the basis of results of diagnostic tests. In some cases, initial empiric therapy must be continued because no etiologic pathogen is identified. When a pathogen is defined, the term “appropriate” refers to the use of at least one antimicrobial agent that is active in vitro against the etiologic pathogen. The term “adequate” includes not only appropriate therapy, but also the use of that agent in the correct dose, via the right route, given in a timely fashion and with penetration to the site of infection.

Fluoroquinolones Aminoglycosides New Agents Active Against Methicillin-Resistant S. aureus Aerosolized Antibiotics for Respiratory Tract Infections III. PRINCIPLES OF THERAPY FOR RESPIRATORY TRACT INFECTIONS Community-Acquired Pneumonia Hospital-Acquired Pneumonia

Timely and appropriate antibiotic therapy can improve survival in patients with community-acquired pneumonia (CAP) and nosocomial pneumonia [hospital-acquired pneumonia (HAP)], and the benefits are most evident in patients who are not otherwise terminally ill. The term HAP includes pneumonia in nonventilated patients, ventilated patients (VAP), and a new entity health care–associated pneumonia (HCAP). HCAP includes patients coming from nursing homes, those in the hospital for more than 2 days in the past 90 days, those from dialysis centers, or those getting home wound care. Because of their exposure to the health care environment, those with HCAP are at risk for infection with drug-resistant pathogens, and the presence of this entity has blurred the distinction between CAP and HAP, since HCAP patients may reside in the “community,” but be infected with organisms very similar to those present in patients with HAP. In the setting of CAP, effective initial antibiotic therapy is associated with a marked improvement in survival,

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compared with ineffective initial therapy, particularly in patients with severe illness. Data on patients with severe CAP provide the most convincing argument for the use of empiric therapy. In several studies, identification of the pathogens causing severe CAP did not lead to an improved survival rate, whereas the use of a broad-spectrum, empiric regimen directed at likely pathogens reduced mortality. In patients with HAP and VAP, survival is improved with the use of antibiotics to which isolated pathogens are susceptible, compared with empiric, nonspecific therapy. In both forms of respiratory infection, the timing of appropriate therapy has also been identified as a determinant of outcome. Patients with CAP have a reduced mortality if initial antibiotic therapy is provided within 4â&#x20AC;&#x201C;6 hours of arrival to the hospital. In the treatment of VAP, data show that appropriate therapy should be given as soon as the infection is clinically identified and lower respiratory tract samples have been collected for culture. A delay of at least 24 hours in starting therapy is an important mortality risk factor in VAP. Even with the use of the correct agents, not all patients recover. The fact that some patients with HAP die in spite of microbiologically appropriate therapy is a reflection of the degree of antibiotic efficacy, as well as a reflection of host response capability (which may have a genetic determination in part), and the fact that not all deaths are the direct result of infection. In some patients with HAP, death is the result of underlying serious illness; the percentage of deaths that occur because of infection, termed the â&#x20AC;&#x153;attributable mortalityâ&#x20AC;? of HAP, has been estimated to be as high as 50 to 60 percent.

However, the use of timely appropriate antimicrobial therapy can reduce attributable mortality to as little as 20 percent.

In recent years, a number of paradigms for empiric therapy, in the form of guidelines for both CAP and HAP have been developed, but several caveats should be remembered.

First, although current guidelines for empiric therapy are evidence based, outcome studies are required to demonstrate their utility in clinical practice.Second, guidelines must be re-evaluated relative to local patterns of antibiotic susceptibility. In the case of CAP, the emergence of penicillin-resistant pneumococcus, community-acquired methicillin-resistant S. aureus, and epidemic viral illness (influenza, severe acute respiratory syndrome) may affect the selection of initial therapy, particularly if resistance is prevalent in a specific community.

In the setting of HAP, each hospital has its own unique flora and antibiotic susceptibility patterns; a knowledge of such patterns is essential.

This chapter examines the principles underlying antibiotic use, and then discusses the commonly used antibiotics for respiratory tract infections and the principles of empiric therapy for patients with both CAP and HAP.

PRINCIPLES OF ANTIBIOTIC USE Mechanisms of Action Antibiotics interfere with the growth of bacteria by undermining the integrity of their cell wall or interfering with

bacterial protein synthesis or common metabolic pathways.

The terms bactericidal and bacteriostatic are broad categorizations, and may not apply for a given agent against all organisms, with certain antimicrobials being bactericidal for one bacterial pathogen but bacteriostatic for another.

Bactericidal antibiotics kill bacteria, generally by inhibiting cell wall synthesis or interrupting a key metabolic function of the organism. Agents of this type include the penicillins, cephalosporins, aminoglycosides, fluoroquinolones, vancomycin, daptomycin, rifampin, and metronidazole. Bacteriostatic agents inhibit bacterial growth, do not interfere with cell wall synthesis, and rely on host defenses to eliminate bacteria. Agents of this type include the macrolides, tetracyclines, sulfa drugs, chloramphenicol, linezolid, and clindamycin. The use of specific agents is dictated by the susceptibility of the causative organism(s) in a given location to individual antibiotics. However, when neutropenia is present, or if there is accompanying endocarditis or meningitis, the use of a bactericidal agent is preferred. Thus, for most patients with pneumonia, it is not essential to choose a bactericidal agent. One additional consideration is that certain organisms, such as S. aureus, can produce toxins, and the optimal agent must be able to not only kill the bacteria, but also inhibit the production of disease-mediating toxins.

Antimicrobial activity is often described by the terms MIC and MBC. The term MIC defines the minimum concentration of an antibiotic that inhibits the growth of 90 percent of a standard-size inoculum, leading to no visible growth in a broth culture. At this concentration not necessarily all the bacteria have been killed. The term MBC refers to the minimum concentration needed to cause a 3-logarithmic decrease (99.9 percent killing) in the size of the standard inoculum, and generally all pathogenic bacteria are killed at this concentration. The MIC is used to define the sensitivity of a pathogen to a specific antibiotic, under the assumption that the concentration required for killing (the MIC) can be reached in the serum in vivo. However, these terms must be interpreted cautiously in the treatment of pneumonia, because the clinician must consider the MIC data in light of the penetration of an agent into lung tissues, with some agents achieving higher than serum levels at respiratory sites of infection, and others reaching lower levels.

In recent years, most respiratory infections have been dominated by concerns of antimicrobial resistance, and a new term has emerged, the mutant prevention concentration (MPC). The MPC is defined as the lowest concentration of an antimicrobial that prevents bacterial colony formation from a culture containing greater than 1010 bacteria. At lower than MPC concentrations, spontaneous mutants can persist and be enriched among the organisms that remain during therapy. The concept has been most carefully studied with pneumococcus and the fluoroquinolones. In general the MPC is higher than the MIC, implying that it is possible to use an antimicrobial to successfully treat an infection, but not to prevent the remaining organisms (which are not causing illness) from emerging as resistant, and persisting and spreading to other patients.

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Penetration into the Lung The concentration of an antibiotic in the lung depends on the permeability of the capillary bed at the site of infection (the bronchial circulation), the degree of protein binding of the drug, and the presence or absence of an active transport site for the antibiotic in the lung. In the lung, the relevant site to consider for antibiotic penetration is controversial and not clearly defined. Sputum and bronchial concentrations may be most relevant for bronchial infections, whereas concentrations in lung parenchyma, epithelial lining fluid, and cells such as macrophages and neutrophils are probably more important for parenchymal infections. The localization of the pathogen also may be important, and intracellular organisms such as Legionella pneumophila and Chlamydophila pneumoniae may be best eradicated by agents that achieve high concentrations in macrophages. Local concentrations of an antibiotic must be considered in light of the activity of the agent at the site of infection. For example, antibiotics can be inactivated by certain local conditions. Aminoglycosides have reduced activity at acidic pHs, which may be present in infected lung tissues. In addition, certain bacteria develop resistance by producing destructive enzymes (e.g., β-lactamases), altering the permeability of the outer cell wall, changing the target site of antimicrobial action, or pumping (efflux) of the antimicrobial from the interior of the cell. In all of these conditions, a high local concentration of antimicrobial may help offset the bacterial resistance mechanisms.

The concentration of an antibiotic in lung parenchyma depends on its penetration through the bronchial circulation capillaries. The bronchial circulation has a fenestrated endothelium, so antibiotics penetrate in proportion to their molecular size and protein binding, with small molecules that are not highly protein bound passing readily into the lung parenchyma. When inflammation is present, penetration is further improved. For an antibiotic to reach the epithelial lining fluid, it must pass through the pulmonary vascular bed, which has a nonfenestrated endothelium. This presents an advantage for lipophilic agents, which are generally not inflammation dependent. Agents that are lipophilic and thus inflammation independent for their entry into the epithelial lining fluid include chloramphenicol, the macrolides (including the azalides and ketolides), linezolid, clindamycin, the tetracyclines, the quinolones, and trimethoprim-sulfamethoxazole.

Agents that are poorly lipid soluble are inflammation dependent for their entry into the epithelial lining fluid and include the penicillins, cephalosporins, aminoglycosides, vancomycin, carbapenems, and monobactams.

The volume of distribution of an antibiotic reflects the compartment size of its distribution. If this value exceeds 3 L it implies distribution outside of the plasma. The poorly lipid soluble (hydrophilic) drugs diffuse freely into interstitial fluid, but do not penetrate cells. For these agents, only the free, non–protein-bound drug can be distributed out of the plasma. Some lipophilic agents, such as the macrolides and quinolones, are distributed extensively to body tissues, and the serum levels underestimate their effect at sites of infection,

Antibiotic Use and the Selection of Empiric Therapy for Pneumonia

an observation that can explain the efficacy of azithromycin, which achieves high intracellular concentrations in phagocytes, can treat pneumonia, but achieves relatively low serum levels. Volume of distribution also can be increased by obesity, and dosing based on ideal body weight may lead to underdosing, although basing doses of hydrophilic antibiotics on total body weight may result in overdosage.

Active transport can facilitate antibiotic entry into lung tissue and phagocytes. Agents that are concentrated in phagocytes in this manner include the macrolides, clindamycin, and the fluoroquinolones. Antibiotics, such as the β-lactams, that are not concentrated in phagocytes by active transport remain in the extracellular space, which constitutes 40 percent of the weight of bronchial tissue; thus, penicillins achieve only about 40 percent of their serum level in lung tissue. Considering all of these factors, some general categories can be established (Table 115-1). Drugs that penetrate well into the sputum or bronchial tissue include the quinolones, newer macrolides and azalides (azithromycin and clarithromycin), ketolides (telithromycin), tetracyclines, clindamycin, and trimethoprim-sulfamethoxazole. On the other hand, the aminoglycosides, vancomycin, and to some extent the β-lactams penetrate less well into these sites. With the use of once-daily aminoglycoside dosing, high peak serum concentrations can be achieved, but the alveolar lining fluid concentration in patients with pneumonia is only 32 percent of the serum level over the first 2 hours, but the two sites have more similar concentrations later in the dosing interval.

Since aminoglycosides require high peak concentrations for optimal killing (below), their poor penetration with systemic administration often makes this impossible, suggesting a potential role for delivery by the aerosol route (discussed below).

Table 115-1 Penetration of Antibiotics into Respiratory Secretions Good Penetration: Lipid Soluble, Concentration Not Inflammation Dependent Quinolones New macrolides: azithromycin, clarithromycin Ketolides (telithromycin) Tetracyclines Clindamycin Trimethoprim/sulfamethoxazole Poor Penetration: Relatively Lipid Insoluble, Inflammation Dependent for Concentration in the Lung Aminoglycosides β-lactams Penicillins Cephalosporins Monobactams Carbapenems

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Antibiotic Pharmacokinetics and Pharmacodynamics Pharmacokinetics is the study of the absorption, distribution, and elimination of a drug in the body, and the information can be used to describe the concentration in serum. Pharmacokinetics also includes the study of the concentration at other sites of the body, including the site of infection and the relationship between drug concentrations and their pharmacologic or toxic effect. For antibiotics, this means the relationship of antibiotic concentrations at the site of infection, compared with the MIC of the target organism. Pharmacodynamics refers to the action of a drug on the body, including its therapeutic effect.

The way in which an antibiotic reaches the site of infection, considering the frequency of administration and dose administered, can affect its ability to kill bacteria, thus defining a close relationship between pharmacokinetics and pharmacodynamics. Some agents are bactericidal in relation to how long they stay above the MIC of the target organism (time-dependent killing), whereas others are effective in relation to the peak concentration achieved (concentrationdependent killing). If antibiotic killing is time dependent, dosing schedules should be chosen to achieve the maximal time above the MIC of the target organism. Antibiotics of this type include the β-lactams (penicillins and cephalosporins), carbapenems, aztreonam, macrolides, and clindamycin. The rate of killing is saturated once the antibiotic concentration exceeds four times the MIC of the target organism. Therefore, the optimal dosing strategy is to dose often and not let trough concentrations fall below the MIC of the target organism. With these considerations in mind, continuous infusion of β-lactams is under study to optimize treatment with β-lactam agents. In spite of these considerations, for many organisms, the concentration of the antibiotic only needs to be above the MIC for 40 to 50 percent of the dosing interval, and possibly as little as 20 to 30 percent of the interval in the case of carbapenems. For the time-dependent killing drugs listed above, the pharmacodynamic parameter that best predicts clinical efficacy is the time above the MIC. When killing is concentration dependent, activity is related to how high a concentration is achieved at the site of infection and how great is the AUC, or the “area under the curve” (of drug concentration plotted versus time) in relation to the MIC of the target organism. Alternatively, the action of these agents can be described by how high the peak serum concentration (Cmax) is in relation to the organism MIC. Classic agents of this type include the aminoglycosides and fluoroquinolones, but the ketolides are also concentrationdependent antibiotics. For these types of agents, the optimal killing of bacteria is defined by the ratio of AUC to MIC, often referred to as the area under the inhibition curve, or the AUIC. The target AUIC for gram-negative bacteria is 125 or greater, whereas for most antibiotics that treat pneumococcus, the target value is at least 30. For both the aminoglycosides and quinolones, some studies have shown that efficacy also

can be defined by the ratio of peak serum concentrations to MIC (Cmax/MIC), aiming for a target of 12 for quinolones against pneumococcus. Optimal use of these agents would entail infrequent administration but with high doses—the underlying principle behind the once-daily administration of aminoglycosides. With once-daily aminoglycoside dosing regimens, the patient achieves a high peak concentration (maximal killing), and a low trough concentration (minimal nephrotoxicity), relying on the “postantibiotic effect” (PAE) to maintain the efficacy of the antibiotic after the serum (or lung) concentrations fall below the MIC of the target organism. If an antibiotic has a PAE, it is capable of suppressing bacterial growth even after its concentration falls below the MIC of the target organism.

Although most agents exhibit a PAE against grampositive organisms, a prolonged PAE against gram-negative bacilli is achieved by the aminoglycosides and fluoroquinolones For pneumococcus, a PAE exists for the macrolides/ azalides, clindamycin, vancomycin, quinupristin/dalfopristin, tetracyclines, and the oxazolidinones (e.g., linezolid) Most of the agents that kill in a concentration-dependent fashion have a prolonged PAE. Agents with little or no PAE against gram negatives are generally also agents that kill in a time-dependent fashion; thus, they are given several times daily. The β-lactams (including penicillins, cephalosporins, and monobactams) generally have little or no PAE against gram-negatives; one notable exception is imipenem, which has a modest PAE against Pseudomonas aeruginosa. In clinical practice, the use of once-daily aminoglycoside dosing has had variable benefits in both efficacy and toxicity, but the advent of this type of dosing regimen follows from an understanding of pharmacodynamic principles.

A phenomenon similar to PAE is termed postantibiotic leukocyte enhancement (PALE), which refers to the ability of functioning white blood cells to kill organisms while they are in the postantibiotic phase of growth. Thus, when the patient has functioning neutrophils, the PAE of some agents is extended by their PALE. Recently, some investigators have suggested that antibiotic therapy be chosen on the basis of another property of certain agents: their ability to stimulate inflammation and cytokine production in response to the presence of the bacterial cell wall lysis products that they generate. It has been known for many years that certain antibiotics liberate bacterial cell wall products that can interact with cytokine-producing cells, stimulating the production of high levels of cytokines such as tumor necrosis factor. In theory, this could lead to the development, or worsening, of the sepsis syndrome in patients immediately after therapy for pneumonia is started, a phenomenon seen in the therapy of Pneumocystis jiroveci pneumonia and pneumococcal meningitis, leading to recommendations to use corticosteroids with antibiotics when treating these infections. Other than in these situations, it is unclear if cytokine release is clinically relevant, but bactericidal antibiotics lead to more of a host inflammatory response than bacteriostatic agents; antibiotics that are cell wall active, and kill slowly, have been associated with the greatest cytokine

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release. In particular, if an antibiotic has a high affinity for bacterial penicillin-binding protein 3, it may kill slowly and lead to filamentous cell wall products that are potent stimuli for cytokine release. On the other hand, agents that kill rapidly and do not interact with penicillin-binding protein 3 are associated with lower levels of in vitro stimulation of cytokine production by host inflammatory cells. In addition to these considerations, the use of antibiotics that inhibit protein synthesis (linezolid, clindamycin) may have an advantage in toxin-mediated illnesses, such as those caused by certain strains of S. aureus, when compared with cell-wall active bactericidal antibiotics.

FEATURES OF SPECIFIC ANTIMICROBIALS USED IN THE THERAPY OF RESPIRATORY TRACT INFECTIONS Macrolides (Including Azalides) and Tetracyclines Macrolides are bacteriostatic agents that bind to the 50S ribosomal subunit of the target bacteria and inhibit RNAdependent protein synthesis. The macrolides traditionally have had good activity against pneumococci, as well as atypical pathogens (C. pneumoniae, M. pneumoniae, Legionella), but the older erythromycin-like agents are not active against H. influenzae, and have poor intestinal tolerance, so prolonged therapy is difficult. The new agents in this class include azithromycin (also referred to as an azalide) and clarithromycin. These agents have enhanced activity against H. influenzae (including β-lactamase–producing strains), although on an MIC basis, azithromycin is more active. Erythromycin is active against Moraxella catarrhalis, although the new agents have enhanced activity against this pathogen.

Among the new macrolides, azithromycin is more active against not only H. influenzae and M. catarrhalis, but also M. pneumoniae than clarithromycin. On the other hand, clarithromycin is more active against S. pneumoniae, Legionella, and C. pneumoniae.

Both of the newer agents have better intestinal tolerance than erythromycin and penetrate well into sputum, lung tissue, and phagocytes. Clarithromycin, which has an active 14-hydroxy metabolite that is antibacterial, is administered twice a day orally at a 500 mg dose for 7 to 10 days in the treatment of CAP and acute exacerbations of chronic bronchitis (AECB). A new preparation of extended-release clarithromycin is administered as a 1000 mg dose once daily and has been effective as a 7-day course of therapy for AECB. Azithromycin has a longer half-life than clarithromycin, and concentrates in tissues, achieving very low serum levels when administered orally. The dosing regimen for CAP is usually 500 mg daily for 3 days in outpatients, but a recent extended release preparation allows the administration of 2000 mg as a one-time dose for CAP. For the hospitalized patient, an intravenous preparation of azithromycin is available and is dosed as 500 mg daily, with the duration defined by the clinical

Antibiotic Use and the Selection of Empiric Therapy for Pneumonia

course of the patient, but usually for 7 to 10 days. Because of its intravenous administration, the serum levels achieved have been adequate for the therapy of bacteremic pneumococcal pneumonia.

Clinical studies of CAP have consistently shown a benefit of using macrolide therapy, usually in conjunction with a β-lactam, but the mechanism for this favorable effect is not known. Speculation has included the possibility of atypical pathogen co-infection, a possibility supported by studies that have found the benefit of the addition of macrolides to vary over the course of time. Another explanation has been that macrolides have anti-inflammatory effects, which may explain their benefit in improving quality of life in patients with cystic fibrosis. Macrolides have a myriad of other effects, including the interference with “quorum sensing” between bacteria, which could inhibit the in vivo proliferation of Pseudomonas aeruginosa after colonization has occurred.

Although macrolides remain an important therapeutic option for community respiratory tract infections, pneumococcal resistance is becoming increasingly common, being present in as many as 35 to 40 percent of all pneumococci, especially in patients who have received an agent of this class in the past 3 months. In addition, macrolide resistance also can co-exist with penicillin resistance, and as many as 30 to 40 percent of penicillin-resistant pneumococci are also erythromycin resistant. The clinical relevance of these in vitro findings remains to be defined. However, there are two forms of pneumococcal macrolide resistance, one involving efflux of the antibiotic from the bacterial cell, and the other involving altered ribosomal binding of the antibiotic. The former mechanism is associated with much lower levels of resistance than the latter, and is present in two-thirds of the macrolide resistant pneumococci in the United States. The latter form of resistance is fortunately less common, because if present, it is unlikely that macrolide therapy for pneumococcal infection would be effective.

The tetracyclines are also bacteriostatic agents that act by binding the 30S ribosomal subunit and interfering with protein synthesis. These agents can be used in CAP because they are active against H. influenzae and atypical pathogens, but in the United States pneumococcal resistance to tetracyclines may be approaching 20 percent, and may exceed 50 percent among organisms with high-level penicillin resistance.

Photosensitivity is the major side effect, limiting the use of these agents in sun-exposed patients.

Ketolides This new class of antimicrobials is a semisynthetic derivative of the macrolides, with a 14-member ring structure, and substitution of a keto group at the C3 site. These agents act to inhibit ribosomal protein synthesis in bacteria, by binding to two different sites on the 50S ribosomal subunit, and because of enhanced binding affinity and the binding to multiples sites, may be able to avoid some of the resistance problems associated with the macrolides. In addition, this class

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of antibiotics has a poor affinity for the pneumococcal efflux pump. Because of these characteristics, ketolides are active against pneumococci that are macrolide resistant by either the efflux or ribosomal mechanism. Ketolides are also active against H. influenzae, but in vitro activity is not quite as high as with azithromycin, and efficacy in AECB is an area that requires further data. In addition, these agents have activity against the atypical pathogens. In clinical trials, one ketolide, telithromycin, has been evaluated and has been dosed at 800 mg daily for 5 days in the therapy of AECB and 7 to 10 days for CAP, with good efficacy. Side effects are primarily intestinal, with nausea and diarrhea occurring in some patients, but visual disturbances, liver function abnormalities (including rare cases of liver failure), and electrocardiographic QT prolongation have been reported.

Trimethoprim-Sulfamethoxazole (TMP-SMX) This combination antibiotic has been used as a mainstay for the therapy of P. jiroveci pneumonia, and in the past was an effective agent for CAP and AECB because of its antimicrobial spectrum, ease of use, and low cost. It has bactericidal activity against pneumococcus, H. influenzae, and M. catarrhalis, but not against atypical pathogens. Recently, it has become less popular because of the emergence of pneumococcal resistance at rates of at least 30 percent, since 80 to 90 percent of organisms that are penicillin resistant are also resistant to TMPSMX. The sulfa component of the drug inhibits the bacterial enzyme responsible for forming the immediate precursor of folic acid, dihydropteroic acid. Trimethoprim is synergistic with the sulfa component because it inhibits the activity of bacterial dihydrofolate reductase. TMP-SMX is available in a fixed combination of 1:5 (TMP:SMX), and is dosed as either 80/400 mg or 160/800 mg orally twice a day for 10 days, but the dosage should be adjusted in renal failure. An intravenous preparation is also available. Side effects generally result from the sulfa component and include rash, gastrointestinal upset, and occasional renal failure (especially in elderly patients).

β-Lactam Antibiotics These bactericidal antibiotics have in common the presence of a β-lactam ring, which is bound to a five-membered thiazolidine ring in the case of the penicillins and a six-membered dihydrothiazine ring in the case of the cephalosporins. Modifications in the thiazolidine ring can lead to agents such as the penems (imipenem, ertapenem, and meropenem), whereas absence of the second ring structure characterizes the monobactams (aztreonam). These agents also can be combined with β-lactamase inhibitors such as sulbactam, tazobactam, or clavulanic acid, to create the β-lactam/ β-lactamase inhibitor drugs. These agents extend the antimicrobial spectrum of the β-lactams by providing a substrate (sulbactam, clavulanic acid, tazobactam) for the bacterial β-lactamase, thereby preserving the antibacterial activity of the parent compound. β-Lactam antibiotics work by

interfering with the synthesis of bacterial cell wall peptidoglycans by binding to bacterial penicillin binding proteins.

The penicillins used for respiratory tract infections include the natural penicillins (penicillin G and V), aminopenicillins (ampicillin, amoxicillin), antiStaphylococcal agents (nafcillin, oxacillin), anti-Pseudomonal agents (piperacillin, ticarcillin), and β-lactam/β-lactamase inhibitor combinations (ampicillin/sulbactam, amoxicillin/ clavulanate, piperacillin/tazobactam, and ticarcillin/clavulanate). Among the anti-Pseudomonal penicillins, piperacillin is the most active agent.

The cephalosporins span from first to fourth generation. The earlier agents generally were active against grampositives, but did not extend activity to the more complex gram-negatives, or anaerobes, and were susceptible to destruction by bacterial β-lactamase. The newer generation agents generally are more specialized, with broad-spectrum activity, and more mechanisms to resist breakdown by bacterial enzymes. The second generation and newer agents are resistant to bacterial β-lactamase, but recent data suggest that cefuroxime may not be an optimal pneumococcal agent if resistance is present. On the other hand, the third generation agents such as ceftriaxone and cefotaxime are reliable and active against penicillin resistant pneumococci, whereas ceftazidime is not reliable against pneumococcus, but is active against P. aeruginosa. The third-generation agents may induce β-lactamases among certain gram-negatives (especially the Enterobacteriaceae spp.), and thus promote the emergence of resistance during monotherapy. The fourth-generation agent, cefepime, is active against pneumococci and P. aeruginosa, but is also less likely to induce resistance among the Enterobacteriaceae than the third-generation agents.

Imipenem and meropenem are the broadest spectrum agents in this class, being active against gram-positives, anaerobes, and gram-negatives, including P. aeruginosa. They have shown efficacy for patients with severe pneumonia, both community-acquired and nosocomial. A non-Pseudomonal carbapenem, ertapenem, is also available and has been used effectively in the therapy of CAP. Aztreonam is a monobactam that is so antigenically different from the rest of the β-lactams that it can be used in penicillin-allergic patients.

It is only active against gram-negative organisms, having a spectrum very similar to the aminoglycosides.

Fluoroquinolones These bactericidal agents act by interfering with bacterial DNA gyrase and/or topoisomerase IV, leading to impaired DNA synthesis repair, transcription, and other cellular processes, resulting in bacterial cell lysis. DNA gyrase is only one form of a bacterial topoisomerase enzyme that is inhibited by quinolones, and activity against other such enzymes is part of the effect of a variety of quinolones. The earlier quinolones (e.g., ciprofloxacin and ofloxacin) are active primarily against DNA gyrase, which accounts for their good activity against gram-negatives. The newer agents (gemifloxacin, levofloxacin, and moxifloxacin) bind both DNA

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gyrase and topoisomerase IV, and have extended their activity to gram-positives, including drug-resistant Streptococcus pneumoniae (DRSP). Resistance to quinolones can occur through mutations in the topoisomerase enzymes, by altered permeability of the bacterial cell wall, or efflux of the antibiotic from the inside of the bacteria. The quinolones kill in a concentration-dependent fashion, and thus optimal antibacterial activity can be achieved with infrequent dosing, and high peak concentrations and high ratios of either AUC/MIC or Cmax/MIC. In addition, because quinolones have a postantibiotic effect (PAE) against both gram-positive and -negative organisms, they can continue to kill even after local concentrations fall below the MIC of the target organism. These properties make the quinolones well suited to infrequent dosing, with the ideal being once-daily dosing, particularly given the relatively long half-life of the newer compounds. The only factor limiting a switch to once-daily dosing for all quinolones is the toxicity associated with high doses of some agents (e.g., ciprofloxacin), particularly concerns related to neurotoxicity and possible seizures.

Two features of quinolones make them well suited to respiratory infections. First, they penetrate well into respiratory secretions and inflammatory cells within the lung, achieving local concentrations that often exceed serum levels. Thus, these agents may be clinically more effective than predicted by MIC values. This may explain the observation that quinolones are often better than other agents in prolonging the “disease-free” interval between exacerbations of COPD, a finding that has been demonstrated for moxifloxacin and gemifloxacin. Second, these agents are highly bioavailable with oral administration and thus similar serum and tissue levels can be reached if administered orally or intravenously. This allows for some “borderline” patients (e.g., nursing home patients) with pneumonia to be managed with outpatient oral therapy and maintain high therapeutic levels in the serum. In addition, the high bioavailability of these agents permits an easy transition from intravenous to oral therapy of inpatients with pneumonia, facilitating early discharge when the patient is clinically improving, and permitting ongoing oral therapy with maintenance of high serum levels.

The fluoroquinolones have excellent antimicrobial activity against β-lactamase–producing H. influenzae and M. catarrhalis, making them very useful for patients with AECB. However, the newer agents (gemifloxacin, levofloxacin, and moxifloxacin) extend the activity of the quinolones by having enhanced gram-positive activity, as well as by being more active against C. pneumoniae and M. pneumoniae, compared with older agents. The new agents are also highly effective against L. pneumophila and may be the drug of choice for this organism. However, if P. aeruginosa is the target organism (as it is in certain patients with CAP, AECB, and HAP), then only ciprofloxacin (750 mg twice-daily orally or 400 mg every 8 hours intravenously) or levofloxacin (750 mg orally or intravenously daily) are active enough for clinical use. Since the older agents, ciprofloxacin and levofloxacin, have borderline activity against the pneumococcus, if they are

Antibiotic Use and the Selection of Empiric Therapy for Pneumonia

used for AECB or CAP, the dose probably should be optimized to either 750 mg twice daily of ciprofloxacin for AECB or 750 mg once daily of levofloxacin for CAP or AECB. Among the newer agents, their in vitro activity against pneumococcus is variable, with the agents listed in the order of most to least active (on an MIC basis) as gemifloxacin, moxifloxacin, and levofloxacin. All of these agents also have long half-lives, generally allowing for once-daily dosing, although the half-lives of these drugs vary from as short as 6 hours for levofloxacin, to as long as greater than15 hours for moxifloxacin and gemifloxacin. The agents also differ in the degree of protein binding, with agents that have a low degree of binding having higher free concentrations in the serum.

The relevance of this feature to clinical outcome is uncertain, but agents like levofloxacin and moxifloxacin are not highly protein bound. Although the new agents are highly active against pneumococci, both penicillin-sensitive and -resistant organisms, there is some concern that with widespread use, pneumococcal resistance to these agents will increase, especially since recent data show that many pneumococci (up to 20 percent) have quinolone-resistance determinant genes present, but have not yet developed full resistance. However, with continued selection pressure due to widespread use, this may become an important clinical problem. With this in mind, pneumococci are more likely to be resistant to the agents with the lowest pneumococcal activity, and in parts of Asia pneumococcal resistance to quinolones has already developed at much higher rates than in North America, particularly to levofloxacin, and especially among patients who have been given repeated courses of therapy with this agent. Other risk factors for quinolone resistance among pneumococci are recent hospitalization and residence in a nursing home.

One major distinction among these new quinolones is their profile of toxic side effects. A number of agents have been removed from clinical use because of toxicities such as QT prolongation (grepafloxacin), phototoxicity (sparfloxacin), and liver necrosis (trovafloxacin). The side effects of the other new agents have been acceptable generally, but as with any therapy, the risks of use should be weighed against the benefits. There have been reports of drug-induced hypoglycemia, which may be a quinolones class-effect, but this problem is most common with gatifloxacin and has led to removal of this agent from clinical use. A recent study comparing moxifloxacin with levofloxacin in elderly hospitalized patients with CAP, and a high frequency of heart disease, showed comparable safety, including a low frequency for both drugs, of cardiac arrhythmias and Clostridium difficile diarrhea.

In clinical trials, all of the newer agents have been effective in the therapy of AECB with 5 days of therapy. In CAP, therapy is usually for 7 to 14 days, but levofloxacin at 750 mg daily can be used for 5 days. Levofloxacin, but not moxifloxacin, is renally excreted, and thus need dosage adjustment in patients with renal insufficiency. Currently there are no good studies of severe CAP showing efficacy of any of the quinolones as monotherapy, although in both nosocomial pneumonia and AECB, monotherapy has been tested and shown to be effective.

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Aminoglycosides These bactericidal agents act by binding to the 30S ribosomal subunit of bacteria, thus interfering with protein synthesis.

Aminoglycosides have primarily a gram-negative spectrum of activity and are usually used in combination with other agents targeting difficult organisms such as P. aeruginosa or other resistant gram-negatives. When combined with certain β-lactam agents they can achieve antibacterial synergy against P. aeruginosa. Amikacin is the least susceptible to enzymatic inactivation by bacteria, whereas tobramycin is more active than gentamicin against P. aeruginosa. Aminoglycosides penetrate poorly into lung tissue, and can be inactivated by acid pHs, which are common in pneumonic lung tissue. Thus, in a clinical trial of nosocomial pneumonia therapy, the use of an aminoglycoside with a β-lactam was no more effective than a β-lactam alone, and the combination regimen was not more effective in preventing the emergence of Pseudomonal resistance during therapy than was the monotherapy regimen with a β-lactam. In the treatment of bacteremic Pseudomonal pneumonia, aminoglycoside combination therapy may be more effective than monotherapy. Recent metaanalysis has suggested that the use of combination therapy with an aminoglycoside is of limited value, and may simply add to the risk of nephrotoxicity.

As discussed, aminoglycosides kill in a concentrationdependent fashion, and can be dosed once daily to optimize killing while minimizing toxicity (primarily renal insufficiency). In clinical practice, this has not been proved to occur, and once-daily dosing is comparable in efficacy and nephrotoxicity to multiple-dose regimens. When aminoglycosides are used, it is necessary to monitor serum levels to minimize the occurrence of acute renal failure. Peak concentrations correlate with efficacy, but only have meaning with multiple daily doses, and their utility in once-daily regimens has not been established. Trough concentrations are monitored to minimize toxicity and probably should be followed regardless of dosing regimen.

Because of poor penetration into tissues, some investigators have used nebulized aminoglycosides for the therapy and/or prevention of gram-negative pneumonia. This approach is discussed below.

New Agents Active Against Methicillin-Resistant S. aureus In the past several years, methicillin-resistant S. aureus (MRSA) has emerged as an important pathogen in patients with nosocomial pneumonia, particularly ventilatorassociated pneumonia (VAP), and recently has been described as a potential pathogen in patients with necrotizing postinfluenza pneumonia. In the past, vancomycin was the agent used most commonly for this pathogen. However, there have been concerns about the limited efficacy of vancomycin, primarily because of its poor penetration into respiratory secretions. Linezolid the first agent in a new antibiotic class, the oxazolidinones, is active against MRSA, and also may block the production of antibacterial toxins, such as the Panton-

Valentine leukocidin, which can be produced by community MRSA strains. The oxazolidinones act to inhibit bacterial protein synthesis, by binding to the 50S ribosomal subunit, and preventing the binding of transfer RNA and the formation of the 70S initiation complex.

Linezolid is not only active against MRSA, but also drug-resistant Streptococcus pneumoniae, and vancomycinresistant enterococci (VRE) (both Enterococcus faecium and Enterococcus faecalis). The agent has high bioavailability; thus, serum levels are the same with oral or IV therapy. Renal and nonrenal clearance occur, and dosing adjustment is not needed for patients with renal failure. Efficacy has been shown for nosocomial pneumonia and CAP, but one recent analysis suggested that linezolid may be superior to vancomycin for the therapy of VAP that is proved to be caused by MRSA. Side effects are not common and include nausea, diarrhea, anemia, and thrombocytopenia (especially with prolonged use).

It is also a weak monoamine oxidase inhibitor.

Quinupristin/dalfopristin has been tested in patients with VAP and was not as effective against MRSA as vancomycin, in spite of good in vitro activity. Several other agents in various stages of development have activity against MRSA, but they are not yet proved to be useful for the therapy of respiratory tract infections. These include daptomycin, which has been shown to be inactivated by pulmonary surfactant, thus explaining its lack of efficacy in pneumonia therapy trials. Tigecycline is available for non-respiratory tract infections, and its efficacy in the therapy of pneumonia is not yet known, although it does have in vitro activity against MRSA and many gram-negatives, including Acinetobacter spp., but not P. aeruginosa. Other agents currently in development are dalbavancin and telavancin.

Aerosolized Antibiotics for Respiratory Tract Infections Local administration of antimicrobials has been used in the therapy of bronchiectasis, especially in the setting of cystic fibrosis and the therapy of ventilator-associated pneumonia.

This approach is used to enhance the delivery of agents to the site of respiratory infection, especially for antibiotics that penetrate poorly into the lung. Direct delivery of antibiotics is usually achieved by nebulization, and this approach not only achieves high intrapulmonary concentrations, but may do so with low systemic absorption, and thus a reduced risk of systemic toxicity. The majority of studies of inhaled antibiotics have been done in nonventilated patients with cystic fibrosis, and chronic bronchial infection with Pseudomonas aeruginosa, and have used nebulized tobramycin, which has been shown to both improve pulmonary function, as well as decrease the density of P. aeruginosa in sputum and thus reduce the risk of hospital admission. The use of this approach in mechanically ventilated patients has been proposed for patients with either infectious tracheobronchitis or VAP, since both infections can involve highly resistant gram-negative bacteria, and the local delivery of antibiotics may effectively treat some pathogens that cannot be eradicated by systemic therapy.

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In mechanically ventilated patients, local antibiotic administration by instillation or nebulization has been used to prevent pneumonia. In general, this is not a recommended approach, because even when it has been successful, there has been concern about the emergence of multidrug resistant gram-negatives in those who subsequently do develop infection, and these organisms may be difficult to treat. Most studies in this population have involved either the aminoglycosides or polymyxin B. Only one prospective randomized trial has examined the impact of the adjunctive use of locally instilled tobramycin with intravenous agents in the management of VAP. Although the addition of endotracheal tobramycin did not improve clinical outcome compared with placebo, microbiologic eradication was significantly greater in the patients receiving aerosolized antibiotics.

In spite of these data, sporadic small and uncontrolled series have shown that when patients have VAP due to multidrug-resistant Pseudomonas aeruginosa or Acinetobacter spp., aerosolized aminoglycosides, polymyxin, or colistin may be helpful as adjunctive therapy to systemic antibiotics. One side effect of aerosolized antibiotics has been bronchospasm, which can be induced by the antibiotic or the associated diluents present in certain preparations. A specially formulated preparation of tobramycin for aerosol administration was designed to avoid this complication.

Although the optimal method of administration of aerosol therapy is unknown, most studies have shown that nebulization can be effective and achieve more uniform distribution than direct instillation. When aerosol therapy is used in mechanically ventilated patients, it must be carefully synchronized with the ventilator cycle, and the optimal delivery device is not yet defined. In an animal model, investigators found that using an ultrasonic nebulizer placed in the inspiratory limb of the ventilator circuit, proximal to the “Y-connector,” up to 40 percent of the administered dose can be retained in the lung, achieving tissue concentrations ten times higher than can be achieved with comparable doses given systemically, and with minimal systemic absorption.

To optimize delivery, inspiratory time may need to be as high as 50 percent of the ventilatory cycle and routine humidification should be stopped during antibiotic administration. In ventilated patients, the ventilator may need to be set with a tidal volume of 8 to 10 ml/kg, with no humidification system in use during the use of the ultrasonic nebulizer which should be set to deliver 8 L/min.

PRINCIPLES OF THERAPY FOR RESPIRATORY TRACT INFECTIONS Community-Acquired Pneumonia Selection of Initial Therapy Empiric therapy is selected by categorizing patients on the basis of place of therapy (outpatient, inpatient, intensive care unit), severity of illness, and the presence or absence of cardiopulmonary disease or specific “modifying” factors that

Antibiotic Use and the Selection of Empiric Therapy for Pneumonia

Table 115-2 Common Pathogens Causing CAP in Specific Patient Popoulations (in Order of Decreasing Frequency) Outpatient, No Cardiopulmonary Disease or Modifying Factors S. pneumoniae, M. pneumoniae, C. pneumoniae (alone or as mixed infection), H. influenzae, respiratory viruses, others (Legionella sp., M. tuberculosis, endemic fungi) Outpatient, with Cardiopulmonary Disease and/or Modifying Factors∗ All of the above plus: DRSP, enteric gram-negatives, and possibly anaerobes (with aspiration) Inpatient, with Cardiopulmonary Disease and/or Modifying Factors∗ S. pneumoniae (including DRSP), H. influenzae, M. pneumoniae, C. pneumoniae, mixed infection (bacteria plus atypical pathogen), enteric gram-negatives (which can include P. aeruginosa), anaerobes (aspiration), viruses, Legionella sp., others (M. tuberculosis, endemic fungi, Pneumocystis jerovici) Inpatient, with No Cardiopulmonary Disease or Modifying Factors All of the above, but DRSP and enteric gram-negatives are not likely. These patients are rarely admitted to the hospital.

Severe CAP, with no Risks for P. Aeruginosa S. pneumoniae (including DRSP), Legionella sp., H. influenzae, enteric gram-negative bacilli, S. aureus, M. pneumoniae, respiratory viruses, others (C. pneumoniae, M. tuberculosis endemic fungi) Severe CAP, with Risks for P. Aeruginosa All of the pathogens above, plus P. aeruginosa ∗ Some

patients in this category are now classified as having HCAP if they have risk factors such as: hospitalization in an acute care hospital for two or more days within 90 days of the infection; those residing in a nursing home or long-term care facility; those who have received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection; or individuals who have attended a hospital or hemodialysis clinic.

make certain pathogens more likely (Table 115-2). In the current guidelines for CAP management, patient risk factors for infection with drug-resistant pneumococcus, enteric gramnegatives, and P. aeruginosa have been identified. By using these factors, a set of likely pathogens can be predicted for each type of patient and this information can be used to guide therapy. If a specific pathogen is subsequently identified by diagnostic testing, then therapy can be focused. Risk factors, or “modifying factors” that increase the risk of infection with DRSP are: age greater than 65 years, β-lactam therapy within

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the past 3 months, alcoholism, immune suppressive illness (including therapy with corticosteroids), multiple medical comorbidities, and exposure to a child in day care. The modifying factors for enteric gram-negatives include residence in a nursing home, underlying cardiopulmonary disease, multiple medical comorbidities, and recent antibiotic therapy. The risk factors for P. aeruginosa infection are structural lung disease (bronchiectasis), corticosteroid therapy (greater than 10 mg prednisone per day), broad-spectrum antibiotic therapy for more than 7 days in the past month, and malnutrition. In addition, there are a number of other clinical conditions that are associated with specific pathogens, and these associations should be considered in all patients when obtaining a history. Examples include the association between S. aureus and post-influenza pneumonia, H. influenzae with underlying COPD, and oral anaerobes with the presence of poor dental hygiene.

Empiric therapy for outpatients with no cardiopulmonary disease or modifying factors should be with a new oral macrolide (azithromycin or clarithromycin) or a tetracycline. Although erythromycin has been used for these patients, its value is limited by its lack of coverage of H. influenzae, and a higher frequency of intestinal complications (nausea, vomiting) than with the newer macrolides. Therapy with an anti-pneumococcal quinolone (gemifloxacin, levofloxacin, or moxifloxacin) is not necessary in these outpatients, because they are not at risk for organisms, such as DRSP and enteric gram-negatives. However, outpatients with cardiopulmonary disease and/or modifying factors, should not receive macrolide monotherapy, but should be treated with either a selected oral β-lactam (cefpodoxime, cefuroxime, high-dose ampicillin [3 grams daily] or high-dose amoxicillin/clavulanate [up to 4 g daily]) combined with a macrolide or alternatively, they can receive monotherapy using an oral antipneumococcal quinolone (gemifloxacin, levofloxacin, or moxifloxacin). The ketolide telithromycin also can be used in this population as oral monotherapy for patients at risk for DRSP, but only if the patient has no risk factors for aspiration or for enteric gram-negatives but concerns about lung toxicity have limited its clinical utility.

For the non-ICU inpatient, therapy can be with an intravenous macrolide (azithromycin) alone, provided that the patient has no underlying cardiopulmonary disease, and no risk factors for infection with DRSP, enteric gramnegatives or anaerobes. Although very few patients of this type are admitted to the hospital, macrolide monotherapy has been documented to be effective in this patient population. Since the majority of inpatients have cardiopulmonary disease and/or modifying factors, they should treated with either a selected intravenous β-lactam (cefotaxime, ceftriaxone, ampicillin/sulbactam, or ertapenem) combined with a macrolide, or alternatively, monotherapy with an intravenous anti-pneumococcal quinolone (levofloxacin, or moxifloxacin) can be administered. From the available data, it appears that either regimen is therapeutically equivalent, and although not proved, it may be useful to use these two types of regimens interchangeably, striving for “antibiotic heterogene-

ity,” but being sure to select an agent in a different class from what the patient received in the past 3 to 6 months. Recent data have shown that if patients have received a macrolide, quinolones, or penicillin in the past 3 months, then a subsequent infection with pneumococcus is more likely to be resistant to the agent received in the past, than to other agents.

Although oral quinolones may be as effective as intravenous quinolones for admitted patients with moderately severe illness, most admitted patients should receive initial therapy intravenously to be sure that the medication has been absorbed. Once the patient shows a good clinical response, oral therapy can be started. Selected inpatients with mild to moderate disease can be treated initially with the combination of an intravenous β-lactam and an oral macrolide, switching to exclusively oral therapy once the patient shows a good clinical response.

In the ICU population, all individuals should be treated for DRSP and atypical pathogens, but only those with appropriate risk factors (see above) should have coverage for P. aeruginosa. As mentioned quinolone monotherapy has not been established as safe or effective for these patients, and monotherapy should not be used in any ICU admitted CAP patient. Those without Pseudomonal risk factors, should be treated with a selected intravenous β-lactam (cefotaxime, ceftriaxone, or ertapenem), combined with either an intravenous macrolide or an intravenous quinolone. For patients with Pseudomonal risk factors, therapy can be with a two-drug regimen, using an anti-Pseudomonal β-lactam (cefepime, imipenem, meropenem, or piperacillin/tazobactam) plus ciprofloxacin or high-dose levofloxacin, or alternatively, with a three-drug regimen, using an anti- Pseudomonal β-lactam plus an aminoglycoside plus either an intravenous non- Pseudomonal quinolone or macrolide.

Other Therapeutic Issues In addition to the general approach to therapy outlined above, CAP patients need timely administration of initial antibiotic therapy. Retrospective data have shown a reduced mortality for admitted CAP patients who are treated within 4–6 hours of arrival to the hospital, compared with those who are treated later. However, it is uncertain if these outcomes are related to the timing of therapy or whether the timeliness of antimicrobial administration is a surrogate marker of other relevant factors. In the empiric therapy of CAP, there is a limited need for routine therapy against MRSA; however, a new strain of this organism has been described to cause a severe, necrotizing form of CAP after influenza. Although the frequency of this organism is still low, vigilance is needed to see how common it becomes in the future. The algorithms presented above suggest that all patients should receive empiric therapy that provides coverage for atypical pathogens.

As mentioned, this recommendation is based on outcome studies, and may be explained by a high frequency of atypical pathogen co-infection. In fact, even with bacteremic pneumococcal pneumonia, mortality is reduced when a β-lactam is used with a macrolide, compared with when it is used as

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monotherapy. Another emphasis of the recommendations for empiric therapy is to use a highly active agent in all patients with risk factors for infection with DRSP. The reason for this recommendation is because if a patient is at risk for infection with DRSP, the use of a highly active agent is not only likely to minimize the risk of treatment failure, but may also rapidly and reliably eradicate pneumococcal organisms that have even low levels of resistance, so that there is less selection pressure for the emergence of organisms with higher level of resistance.

Hospital-Acquired Pneumonia How to Initiate Responsible Empiric Therapy (Table 115-3) Many studies have documented that mortality in HAP is increased if initial empiric therapy is incorrect, or if there is a delay in the initiation of therapy. In the American Thoracic Society/Infectious Disease Society (ATS/IDSA)guideline for

Antibiotic Use and the Selection of Empiric Therapy for Pneumonia

HAP, the terms “appropriate” and “adequate” therapy were defined. Appropriate refers to the use of an antibiotic that is active in vitro against the identified pathogen, the term “adequate” refers to not only using an antibiotic to which the organism is sensitive, but also using that therapy without delay, in the right doses, having it penetrate to the site of infection, and using combination therapy, if needed. For example, for critically ill patients with normal renal function who were effectively treated for nosocomial pneumonia in clinical trials, the correct doses, of common antibiotics include: cefepime 1 to 2 g every 8 to 12 hours; imipenem 500 mg every 6 hours, or 1 g every 8 hours; meropenem 1 g every 8 hours, piperacillin-tazobactam 4.5 g every 6 hours; levofloxacin 750 mg daily or ciprofloxacin 400 mg every 8 hours; vancomycin 15 mg/kg every 12 hours, leading to a trough level of 15 to 20 mg/L; linezolid 600 mg every 12 hours; and aminoglycosides of 7 mg/kg per day of gentamicin or tobramycin and 20 mg/kg of amikacin. However, it is still a challenge to use antibiotics adequately, without using them too widely, and

Table 115-3 Principles of Antibiotic Therapy for Hospital-Acquired Pneumonia Prompt empiric therapy: Initiate when there is clinical suspicion of infection Obtain a lower respiratory tract culture (sputum, tracheal aspirate, protected brush, BAL) prior to initiation of antibiotic therapy. Samples can be obtained bronchoscopically or nonbronchoscopically, culured quantitatively or semiquantitatively.

Use a narrow spectrum agent for patients only at risk for infection with “core pathogens,” and with no risk factors for MDR pathogens.

Options include: ceftriaxone, ampicillin/sulbactam, ertapenem, levofloxacin, or moxifloxacin. For penicillin allergiy, use a quinolone or the combination of clindamycin and aztreonam.

Use combination therapy with a broad spectrum regimen, containing at least two antimicrobials in patients with risk factors for MDR pathogens. Specific choices should be guided by a knowledge of local microbiology patterns.

Use an aminoglycoside or an antipneumococcal quinolone (ciprofloxacin or high dose levofloxacin), PLUS an anti-Pseudomonal β-lactam such as: cefepime, ceftazidime, imipenem, meropenem or piperacillin-tazobactam. If there is concern about MRSA, add either linezolid or vancomycin Use the correct therapy in recommended doses (see text).

Choose an empiric therapy that uses agents from a different class of antibiotics than the patient has received in the past 2 weeks.

Try to de-escalate to monotherapy after initial combination therapy, after reviewing culture data and clinical response.

If Pseudomonas aeruginosa, consider stopping the aminoglycoside after 5 days and finish with a single agent to which the organism is sensitive.

If a non-Pseudomonal infection, switch to a single agent that the organism is sensitive to, using: imipenem, meropenem, cefepime, piperacillin/tazobactam, ciprofloxacin, or high-dose levofloxacin.

The drug of choice for Acinetobacter is a carbapenem, but colistin should be oonsidered if there is carbapenem resistance.

Consider linezolid as an alternative to vancomycin in patients with proven MRSA VAP, those with renal insufficiency, and those receiving other nephrotoxic medications (e.g., an aminoglycoside).

Consider adjunctive aerosolized aminoglycosides in patients with highly resistant gram-negative pathogens.

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thus promoting antibiotic resistance, which is often driven by antibiotic use. Thus, the guideline emphasizes the need for a “de-escalation” strategy of usage, that generally urges prompt broad-spectrum empiric therapy whenever there is a clinical suspicion of infection, in order to avoid a delay of therapy, combined with a commitment to focus, narrow the spectrum, reduce the duration of therapy, or stop therapy once culture and clinical response information become available. Several studies have shown that it is possible to effectively treat VAP with 6 to 8 days of therapy, provided that the initial therapy is appropriate. The optimal duration of therapy for infections caused by P. aeruginosa and MRSA is still uncertain, but prolonged therapy may be no better than short duration therapy, in the absence of bacteremia.

Algorithms for Initial Empiric Therapy Once there is a clinical suspicion of HAP, the antibiotic choice falls into either a narrow spectrum of therapy or a broadspectrum regimen, directed at multi-drug resistant (MDR) pathogens. The narrow spectrum approach is used if the patient has a pneumonia that started in the first 4 days of hospitalization and there are no other risk factors for MDR pathogens. Risk factors include recent antibiotic therapy within the past 90 days, immunosuppressive illness or therapy (corticosteroids or chemotherapy), admission to a unit with a high rate of MDR organisms, recent hospitalization for two or more days within the past 90 days, residence in a nursing home or long-term care facility (i.e., the presence of HCAP); or regular visits to a hospital clinic or hemodialysis center. All others receive a broad-spectrum therapy approach.

The narrow spectrum therapy is directed at the “core pathogens,” such as non-resistant enteric gram-negatives, pneumococcus,H. influenzae, and methicillin-sensitive S. aureus. Recommended regimens are usually monotherapy with ceftriaxone, ampicillin/sulbactam, ertapenem, levofloxacin, or moxifloxacin. If the patient is penicillin allergic, a quinolone can be used, or the patient can get the combination of clindamycin and aztreonam. When the patient has risk factors for MDR pathogens, therapy is directed at not only the core pathogens, but also P. aeruginosa, Acinetobacter spp., and in many instances MRSA. To provide this spectrum of coverage, patients need to receive at least two, and often three antibiotics. The recommended therapy is to use either an aminoglycoside or an anti-Pseudomonal quinolone (ciprofloxacin or levofloxacin) in combination with an anti-Pseudomonal β-lactam (cefepime, ceftazidime, imipenem, meropenem, or piperacillin-tazobactam). If there are concerns about MRSA because of risk factors, a high local prevalence, or the presence of gram-positives on a gram stain of lower respiratory tract secretions, then a third agent, either linezolid or vancomycin, should be added.

The use of combination therapy is controversial, and as mentioned, there are limited data to show that the use of an aminoglycoside with a β-lactam is more effective than β-lactam monotherapy. Dual therapy may have value if

the patient is neutropenic, or if Pseudomonal bacteremia is present, but both situations are uncommon. Thus, the most compelling reason for using empiric combination therapy in patients with suspected MDR pathogens, is to provide a broad enough spectrum of agents to increase the likelihood that the initial therapy was appropriate. Once the organism is identified, it is possible to de-escalate, and if an aminoglycoside was used with a β-lactam, the maximal benefit may have been achieved after 5 days of dual therapy, and thus the aminoglycoside usually can be stopped at that point. Similarly, If a non-resistant gram-negative is identified, therapy can be with a single agent, and the ones that have been shown to be effective for critically ill mechanically ventilated patients are: ciprofloxacin, levofloxacin, imipenem, meropenem, piperacillin/tazobactam, and cefepime. Thus, it is usually possible to de-escalate to monotherapy with one of these agents as soon as culture data become available, or after 5 days of dual therapy with an aminoglycoside, if P. aeruginosa has been identified.

Other Principles of Antibiotic Usage for Hospital-Acquired Pneumonia In general, it is necessary to use an agent as empiric therapy that is in a different class of antimicrobial than the patient has recently received. A number of studies of HAP have demonstrated that recent therapy with an antibiotic (within the past 2 weeks) predicts a greater frequency that pathogens such as P. aeruginosa will be resistant to the agents recently used.

This applies to β-lactams, as well as to quinolones. In addition, some studies have shown that quinolones promote not only gram-negative resistance to quinolones, but also to β-lactams, and that their use can cause resistance to many types of β-lactam antimicrobials. With this in mind, it may be better not to use quinolones for a first episode of hospital infection, since it may make both β-lactams and quinolones less effective for a subsequent infection. If quinolones are not used for a first episode of infection, there will be more options available if the patient develops a second infection while in the hospital.

In the management of HAP, as clinical and microbiologic data become available, it is often possible to de-escalate therapy in the form of using less drugs, using agents of narrower spectrum, stopping therapy, or reducing the duration of therapy. The key decision point for manipulating therapy is on day 2 to 3 when a decision can be made about whether the patient is improving or not. This decision is made by assessing clinical features such as fever, leukocytosis, purulence of secretions, radiographic patterns, and oxygenation. In general, the best clinical predictor of response is improvement in oxygenation, which usually occurs by day 3 in survivors of VAP, but not in nonsurvivors. If the patient is improving, then cultures should be checked, and efforts made to deescalate and shorten duration of therapy. In some instances, all signs of pneumonia are gone by day 2 to 3, respiratory cultures are negative and in retrospect, the diagnosis was heart failure or atelectasis, and antibiotics can be completely stopped.

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SUGGESTED READING Andes D, Anon J, Jacobs MR, et al.: Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of respiratory tract infections. Clin Lab Med 24:477– 502, 2004.

Anzueto A, Niederman MS, Pearle J, et al.: Communityacquired pneumonia recovery in the elderly (CAPRIE): Efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy. Clin Infect Dis 42:73–81, 2006.

Badia JR, Soy D, Adrover M, et al.: Deposition of instilled versus nebulized tobramycin and imipenem in ventilated intensive care unit patients. JAC 54:508–514, 2004.

File TM, Niederman MS: Antimicrobial therapy of community-acquired pneumonia. Infect Dis Clin North Am 18:993–1016, 2004.

Finberg RW, Moellering RC, Tally FP, et al.: The importance of bactericidal drugs: Future directions in infectious disease.

Clin Infect Dis 39:1314–1320, 2004.

Goldstein I, Wallet F, Robert J, et al.: Lung tissue concentrations of nebulized amikacin during mechanical ventilation in piglets with healthy lungs. Am J Respir Crit Care Med 165:171–175, 2002.

Goldstein I, Wallet F, Robin AN, et al.: Lung deposition and efficiency of nebulized amikacin during Escherichia coli pneumonia in ventilated piglets. Am J Respir Crit Care Med 166:1375–1381, 2002.

Gruson D, Hilbert G, Vargas F, et al.: Strategy of antibiotic rotation: Long-term effect on incidence and susceptibilities of Gram-negative bacilli responsible for ventilatorassociated pneumonia. Crit Care Med 31:1908–1914, 2003.

Hoffken G, Niederman MS: Nosocomial pneumonia: The importance of a de-escalating strategy for antibiotic treatment of pneumonia in the ICU. Chest 122:2183–2196, 2002.

Houck PM, Bratzler DW, Nsa W, et al.: Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med 164:637–644, 2004.

Iregui M, Ward S, Sherman G, et al.: Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 122:262–268, 2002.

Lonks JR, Goldmann DA: Telithromycin: A ketolide antibiotic for treatment of respiratory tract infections. Clin Infect Dis 40:1657–1664, 2005.

Luna CM, Blanzaco D, Niederman MS, et al.: Resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome. Crit Care Med 31:676–682, 2003.

Martinez JA, Horcajada JP, Almela M, et al.: Addition of a macrolide to a B-lactam–based empirical antibiotic regi-

Antibiotic Use and the Selection of Empiric Therapy for Pneumonia

men is associated with lower in-patient mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 36:389–395, 2003.

Micek ST, Dunne M, Kollef MH: Pleuropulmonary complications fo Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus: Importance of treatment with antimicrobials inhibiting exotoxin production. Chest 128:2732–2738, 2005.

Michalopoulos A, Kasiakou SK, Mastora Z, et al.: Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Crit Care 9:R53–59, 2005.

Niederman MS, Craven DE, Bonten MJ, et al.: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388–416, 2005.

Nseir S, Di Pompeo C, Soubrier S, et al.: First-generation fluoroquinolone use and subsequent emergence of multiple drug-resistant bacteria in the intensive care unit. Crit Care Med 33:283–289, 2005.

Panidis D, Markantonis SL, Boutzouka E, et al.: Penetration of gentamicin into alveolar lining fluid of critically ill patients with ventilator-associated pneumonia. Chest 128:545–552, 2005.

Paul M, Benuri-Silbiger I, Soares-Weiser K, et al.: Beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: Systematic review and meta-analysis of randomized trials.

Br Med J 328:668, 2004.

Richter SS, Heilmann KP, Beekman SE, et al.: The molecular epidemiology of Streptococcus pneumoniae with quinolone resistant mutations. Clin Infect Dis 40:225–235, 2005.

Rothermel CD: Penicillin and macrolide resistance in pneumococcal pneumonia: Does in vitro resistance affect clinical outcome? Clin Infect Dis 38:S346–349, 2004.

Trouillet JL, Vuagnat A, Combes A, et al.: Pseudomonas aeruginosa ventilator-associated pneumonia: Comparison of episodes due to piperacillin-resistant versus piperacillinsusceptible organisms. Clin Infect Dis 34:1047–1054, 2002.

Vanderkooi OG, Low DE, Green K, et al.: Predicting antimicrobial resistance in invasive pneumococcal infections.

Clin Infect Dis 40:1288–1297, 2005.

Wilson R, Allegra L, Huchon G, et al.: Short-term and longterm outcomes of moxifloxacin compared with standard antibiotic treatment in acute exacerbations of chronic bronchitis. Chest 125:953–964, 2004.

Wunderink RG, Rello J, Cammarata SK, et al.: Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 124:1789–1797, 2003.

Yu VL, Chiou CC, Feldman C, et al.: An international prospective study of pneumococcal bacteremia: Correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 37:230–237, 2003.

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116 Vaccination against Pulmonary Infections Michael S. Simberkoff

I. VACCINES AGAINST BACTERIAL PULMONARY PATHOGENS Pneumococcal Vaccines Haemophilus influenzae, Type b Vaccine Pertussis Vaccine BCG Vaccine

Vaccines are an important, often recommended means of preventing pulmonary infections. There are several reasons to encourage their use.

1. Pulmonary infections, such as pneumonia, are associated with substantial morbidity. For example, recent data from the National Center for Health Statistics showed that respiratory diseases accounted for 11 percent of the hospitalizations in the United States during 2003. During that year, there were more than 1.4 million discharges from acute, non-federal health care facilities in the United States with pneumonia as the first diagnosis. The average length of stay for patients hospitalized with pneumonia was 5.5 days. Pneumonia disproportionately affects the elderly. In the study cited above, the rate of hospitalization for pneumonia for those who were 65 years of age or older was 224 per 10,000, over four times the rate in the population as a whole. In another population-based study conducted in the state of Washington, the rate of community-acquired pneumonia was 52.3 cases per 1000 person years among patients older than 85 years of age.

2. Pneumonia and influenza are, overall, the seventh leading causes of death in the United States, ranking behind heart, malignant, cerebrovascular, and chronic lower-respiratory tract diseases, accidents and diabetes mellitus. In 2003, the age-adjusted death rate for pneumonia in the United States was 21.4 per 100,000 population.

II. VACCINES AGAINST VIRAL PULMONARY PATHOGENS Influenza Vaccines Measles (Rubeola) Vaccine Varicella Vaccine Adenovirus Vaccine III. CONCLUSIONS

3. Pulmonary pathogens are increasingly resistant to commonly used antibiotics, even when acquired in the community. For example, investigators from the Centers for Disease Control and Prevention (CDC) recently reported that 24 percent of the bacteremic pneumococcal strains isolated during 1998 were resistant to penicillin and that 14 percent were resistant to multiple other antibiotics. Both of these numbers increased significantly during the period from 1995 to 1998. There was considerable variation in the prevalence of drug-resistant pneumococcal isolates from different parts of the United States, different age groups, and different racial backgrounds. Drug resistance was most common among the isolates from patients residing in Tennessee and Georgia, from patients who were very young and very old, and from white as compared to black patients.

4. Vaccines that are licensed for use in the United States are remarkably safe. Most produce transient local or mild and infrequent systemic reactions (described below).

5. The licensed vaccines are effective in preventing pulmonary infections and their complications. However, efficacy may vary in different patient populations. Specific examples will be discussed under individual vaccines.

6. Vaccines are generally inexpensive, whereas the pulmonary infections they prevent are often expensive to diagnose and treat. Further, infected patients are often unable to work for extended periods. Thus, use

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of vaccines to prevent pulmonary infections is costeffective for individual patients, employers, insurers, and society.

VACCINES AGAINST BACTERIAL PULMONARY PATHOGENS A number of microorganisms infect the lungs including a diverse group of bacteria, mycobacteria, mycoplasma, chlamydia, viruses, and some fungi. Streptococcus pneumoniae is the most commonly recognized cause of severe communityacquired pneumonia (CAP), occurring in 20 to 50 percent of cases. Haemophilus influenzae, Legionella species, and Moraxella catarrhalis are isolated in 3 to 10 percent of cases.

Vaccines against four pulmonary pathogens are available (Table 116-1). These are the S. pneumoniae (pneumococcal) polysaccharide and protein-polysaccharide conjugate vaccines, the H. influenzae, type b protein-polysaccharide conjugate vaccines, the Bordetella pertussis vaccines (whole cell and acellular), and the live bacille Calmette-Gu´erin (BCG) vaccine.

Pneumococcal Vaccines The pneumococcal vaccines are designed to elicit protective antibodies against the strains of S. pneumoniae that are commonly associated with invasive infection. At present, 83 pneumococcal serotypes are recognized by serological reactions with their capsular polysaccharide. Included among these are 19 serogroups consisting of 2 to 4 antigenically related serotypes. A 14-valent pneumococcal polysaccharide vaccine was licensed in the United States in 1977, a 23-valent polysac-

charide vaccine was licensed in 1983, and a 7-valent proteinpolysaccharide conjugate vaccine was licensed for use in infants and very young children in 2000.

The Advisory Committee on Immunization Practices (ACIP) recommended use of the 23-valent pneumococcal polysaccharide vaccine for immunocompetent individuals who are 65 years of age and older, for immunocompetent individuals who are between 2 and 64 years of age with chronic cardiac or pulmonary diseases, diabetes mellitus, cerebrospinal fluid leak, functional or anatomic asplenia, or those living in a chronic care facility. ACIP also recommended use of the vaccine for immunocompromised individuals 2 years of age and older, including those with human immunodeficiency virus (HIV) infection; leukemia, lymphoma, multiple myeloma or generalized malignancy; chronic renal failure or nephrotic syndrome; organ or bone marrow transplant recipients; and patients receiving immunosuppressive chemotherapy or corticosteroids. It recommended revaccination for those who were vaccinated at less than 65 years of age where 5 years or more have elapsed since last vaccinations.

Pneumococcal polysaccharides elicit a T-cell independent, B-cell response. Thus, responses to these vaccines are neither prolonged nor does revaccination elicit an anamnestic, booster response. Infants and young children (up to 5 years of age) respond poorly to the pneumococcal polysaccharide vaccine. Therefore, a 7-valent, protein-conjugate vaccine was developed to provide protection for them.

ACIP recommended use of the 7-valent pneumococcal vaccine for all children 23 months of age and younger and for children who are 23 to 59 months of age with chronic cardiac or pulmonary disease, cerebrospinal fluid leak, diabetes mellitus, renal failure or nephrotic syndrome, functional or anatomic asplenia, HIV infection, immuno- or complement

Table 116-1 Vaccines for Bacterial Pulmonary Pathogens Pathogen

Vaccine

Targeted Population

Frequency

S. pneumoniae

23-valent polysaccharide

Elderly (>65 years of age) Asplenia; chronic pulmonary, cardiac or renal diseases; diabetes; HIV Children 2 months to ≤5 years of age

Administer once; repeat once after 5 years

7-valent protein-conjugate

2, 4, 6, and 12–15 months

H. influenzae, type b

Protein-conjugate

Children 2 months to <5 years of age

2, 4, 6, and 12–15 months

B. pertussis

Acellular purified

Children 2 months to <5 years of age

2, 4, 6, and 12–18 months

M. tuberculosis

Bacille Calmette-Gu´erin (BCG)

Not recommended in United States

Once in infancy

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deficiency, or diseases associated with immunodeficiency or immunosuppressive therapy such as leukemia and lymphoma or those affecting transplant recipients.

Pneumococcal vaccines have proven to be effective in preventing invasive pneumococcal infections (proven bacteremia and/or isolation of the organism from normally sterile body fluids) in immunocompetent individuals. Their efficacy against noninvasive pneumococcal pneumonia and in immunocompromised individuals is more controversial. ¨ Ortqvist et al reported the results of a randomized, double-blinded trial comparing pneumococcal vaccine and placebo in nonimmunocompromised patients 50 to 85 years of age who were being discharged from hospitals in Sweden with a diagnosis of CAP. A total of 693 patients were randomized: 340 received vaccine, 353 received placebo. In the vaccine group 63 patients developed recurrent pneumonia and in the control group 57 patients developed recurrent pneumonia (relative risk [RR] = 0.83; 95 percent confidence interval [CI] 0.58 to 1.2). Pneumococcal pneumonia was diagnosed in 16 and 19 of the patients in the placebo and vaccine groups, respectively (RR = 0.78; 95 percent CI 0.40 to 1.51).

Thus, the pneumococcal vaccine did not appear to be protective against either pneumonia or pneumococcal pneumonia in this population.

Honkanen et al reported on a study in which patients 65 years of age and older living in Northern Finland were offered either a combination of influenza and pneumococcal vaccines (IPV, offered to those born in even years) or influenza vaccine (IV, offered to those born in odd years). Overall, 62 percent of the eligible populations decided to participate and there were 38,037 person-years of follow-up. There were 145 and 116 episodes of pneumonia in the IPV and IV groups, respectively (RR = 1.2; 95 percent CI 0.9 to 1.5). There were 52 and 40 episodes of pneumococcal pneumonia in the IPV and IV groups, respectively (RR = 1.2; 95 percent CI 0.8 to 1.9).

There were 2 and 5 episodes of pneumococcal bacteremia in the IPV and IV groups, respectively (RR = 0.4; 95 percent CI 0.1 to 1.9). Thus, the pneumococcal vaccine appeared to offer incremental protection against bacteremic disease only.

Nichol et al reported on a retrospective cohort study (1993–1995) conducted among adults 65 years of age and older with a diagnosis of chronic lung disease who were enrolled in a health maintenance organization in Minnesota.

Hospitalizations for pneumonia, influenza, and all deaths were assessed. Pneumococcal vaccination was associated with significantly lower risk of hospitalization for pneumonia (RR = 0.57; 95 percent CI 0.38 to 0.84) and for death (RR = 0.71; 95 percent CI 0.56 to 0.91). However, the authors noted that the patients who received pneumococcal vaccine were younger and had fewer co-morbid conditions than did the nonvaccinated cohort.

Jackson et al reported on a retrospective cohort study conducted between 1998 and 2001 among Group Health Cooperative member adults 65 years of age and older in Washington state. Pneumococcal bacteremia and CAP were the end points of the study. Receipt of pneumococcal vaccine was associated with a 44 percent reduction in the risk of pneumococ-

Vaccination against Pulmonary Infections

cal bacteremia (RR = 0.56; 95 percent CI 0.33 to 0.93). However, receipt of the vaccine was not associated with a reduced risk of pneumonia (RR = 1.04; 95 percent CI 0.96 to 1.13).

French et al reported on the results of a trial of pneumococcal vaccine among untreated HIV-infected patients in Uganda. A total of 1392 HIV-infected patients were enrolled: 697 received the 23-valent pneumococcal vaccine; 695 received placebo. Invasive pneumococcal infection occurred in 15 and 7 patients in the vaccine and placebo groups, respectively (hazard ratio [HR] = 1.47; 95 percent CI 0.7 to 3.3).

Pneumonia also was more frequent in the vaccine group (40 versus 21). Thus, pneumococcal vaccine offered no protection against invasive pneumococcal disease or pneumonia in this population of untreated HIV-infected patients.

Conaty et al conducted a review of cohort studies, casecontrol studies, and randomized clinical trials designed to study the efficacy of the pneumococcal polysaccharide vaccine in adult patients. Overall, these studies showed that the vaccine was effective against invasive pneumococcal diseases.

The pooled efficacies of the randomized clinical trials, casecontrol studies, and observational studies reviewed were 0.62 (0.37 to 1.04), 0.45 (0.36 to 0.56), and 0.47 (0.41 to 0.54), respectively. Excluding studies done among young, highincidence patients (e.g., South African gold miners), overall efficacy of the pneumococcal polysaccharide vaccine against all-cause pneumonia was less impressive. The efficacy of the vaccine in randomized, clinical trials was 0.97 (0.81 to 1.16), while its efficacy in the pooled cohort studies among the elderly was 0.68 (0.50 to 0.93).

Melegaro and Edmunds compared the published metaanalyses of pneumococcal polysaccharide vaccines in the elderly. These studies showed the vaccine to be effective against invasive disease in the general elderly populations (efficacy = 65 percent; 95 percent CI 49 to 92), far less effective in the high-risk elderly (efficacy = 20 percent; 95 percent CI−188 to −78), and generally ineffective against pneumonia (efficacy = 16 percent; 95 percent CI 50 to 53).

Fedson and Liss provided a critical analysis of the published results of trials and meta-analyses concerning pneumococcal polysaccharide vaccine efficacy and a counterpoint to some of their conclusions. These authors argued that many of the pneumococcal vaccine trials were underpowered and others used the wrong end points. For example, they contended that nonbacteremic pneumonia was a valid end point for studies because it could be diagnosed objectively by radiograph. However, they did not accept nonbacteremic pneumococcal pneumonia as a valid end point because recovery of pneumococcal isolates from sputum did not prove that this organism was present in the lung and causing the pneumonia seen on radiograph. Basically, they concluded (as did most authors) that pneumococcal vaccine is effective in preventing invasive complications of pneumococcal infection, but could make no firm conclusion about its efficacy against pneumonia. However, they contended that lack of proof of vaccine efficacy against pneumonia does not prove its lack of efficacy.

Data on efficacy of conjugate pneumococcal vaccines are less voluminous but point in the same general direction.

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The seminal study on efficacy and safety of the protein conjugate vaccine was reported by Black et al. It was a randomized, double-blinded trial in which infants enrolled in the Kaiser-Permanente health system in Northern California were randomly assigned to receive the 7-valent conjugatepneumococcal vaccine or meningococcal vaccine at 2, 4, 6, 12, and 15 months of age. Close to 38,000 infants were enrolled in the study and over 82 percent received 3 or more doses of the assigned vaccine. There were 40 cases of invasive disease caused by vaccine serotype S. pneumoniae. Thirtynine of these were in the meningococcal vaccine recipients.

The efficacy of the vaccine for fully vaccinated children was 97.4 percent (95 percent CI 82.7 to 99.9). The vaccine was highly effective against otitis media, reducing the number and severity of visits for this infection. The vaccine was well tolerated causing only slightly more local and systemic side effects than the meningococcal vaccine.

A conjugate pneumococcal vaccine also has been tested in developing countries. A trial conducted in The Gambia was reported by Cutts et al. In this trial, children 5 to 51 weeks of age were randomly assigned to receive 3 doses of a 9-valent conjugate pneumococcal vaccine or placebo. Over 8000 children were enrolled in each arm of the study. The primary end point of this study was radiologically confirmed pneumonia. Invasive pneumococcal disease, all-cause admissions, and death were secondary end points of this study. There were 333 children with radiologically confirmed pneumonia among the vaccine recipients and 513 among placebo recipients (vaccine efficacy [VE] = 37 percent; 95 percent CI 27 to 45). There were 9 and 38 cases of vaccine serotype-invasive pneumococcal infection among the vaccine and placebo recipients, respectively (VE = 77 percent; 95 percent CI 51 to 90). Compared to placebo the vaccine was 50 percent effective (95 percent CI 21 to 69) in reducing all invasive pneumococcal infection, 15 percent effective (95 percent CI 7 to 21) in reducing all-cause admissions, and 16 percent (95 percent CI 3 to 21) effective in reducing mortality in this patient population.

Use of the conjugate pneumococcal vaccine for children in the United States has yielded unanticipated benefits.

Two publications have documented a declining rate of invasive pneumococcal disease that has occurred among older adults as well as children. Both of these publications used data from the Active Bacterial Core Surveillance (ABCS) Network. This network is situated in eight areas: San Francisco; the state of Connecticut; Atlanta; Baltimore; Minneapolis-St. Paul; Rochester, New York; Portland, Oregon; and MemphisNashville-Knoxville, Tennessee. The combined populations of these areas is approximately 19 million with approximately 5 million individuals who are 50 years of age or older.

In the first of these, Whitney et al reported on ABCS Network data during the first year (2001) following licensure of the conjugate vaccine compared to prior years. They found that there was a dramatic reduction in the rates of invasive pneumococcal infection in children under 2 years of age.

They also found a small but significant reduction in invasive pneumococcal infections among adults.

The second report, by Lexau et al, provided follow-up data. In this study, the authors compared the rates of inva-

sive pneumococcal disease in the ABCS Network populations during the pairs of years 2000–2001 and 2000–2003 following introduction of the vaccine compared to 1998–1999. They found that there was a 28 percent reduction in the rates of all serotype-invasive pneumococcal infections, a 55 percent reduction in the rates of the vaccine serotype invasive infections, and a slight increase in the rate of invasive disease caused by serotypes not in either the conjugate or pure polysaccharide vaccines in adults 50 years of age and older. A highly significant reduction in the rate of invasive pneumonia (pneumonia plus isolation of S. pneumoniae from blood or pleural culture) infections in the 50 years of age and older population was observed. However, not all older adults were benefited.

The authors found that there was a significant increase in the rates of invasive disease among adults with HIV infection, diabetes mellitus, and immunosuppression such as Hodgkin’s disease, leukemia, multiple myeloma, dialysis, nephritic syndrome, or transplantation recipients.

Appropriate use of the pneumococcal vaccine has become an indicator of quality of care in many large health care organizations in the United States including the Veterans Health Administration (VHA), the American Hospital Association, and the Joint Commission on Accreditation of Health Care Organizations. VHA was among the first to establish pneumococcal vaccination as a measure of quality of care and to measure vaccination rates by an external peer review of patient (EPRP) records program. Jha et al reported that the pneumococcal vaccination rate among VHA patient records reviewed in fiscal year (FY) 2000 was 81 percent compared to the rate of 27 percent in FY 1995 ( p < 0.001), prior to the introduction of this measure.

In another study, Jha et al reported data on use of pneumococcal vaccine use in facilities that participated in the Hospital Quality Alliance Program (HQAP). Data were available from 3079 hospitals for 2004. They showed a lower rate of documented pneumococcal vaccine use than had the VHA study cited above. In 2004, less than 10 percent of the HQAP facilities had achieved a pneumococcal vaccination rate of 81 percent or more, the rate achieved by VHA facilities in 2000.

Finally, the National Health Interview Survey (NHIS) demonstrated that there are racial and ethnic disparities in receipt of pneumococcal vaccine. These NHIS data were collected in 2000 and 2001. They showed that both nonHispanic blacks and Hispanics were significantly less likely to report receipt of pneumococcal vaccine than were nonHispanic whites (odds ratio [OR] = 0.4; 95 percent CI 0.3 to 0.5 and OR = 0.4; 95 percent CI 0.3 to 0.5, respectively).

Pneumococcal vaccines are a remarkably safe and effective means of preventing invasive pneumococcal infections in children and adults. Their use is recommended for the very young, the elderly, and those at most risk from pneumococcal infections at all ages. Although it has not been proven that highly immunosuppressed patients respond to and are optimally protected by the vaccine, much broader use of these vaccines in the populations at risk should be encouraged.

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Haemophilus influenzae, Type b Vaccine H. influenzae is a common cause of pneumonia and bronchitis. Although many of the isolates from the respiratory tract are nontypeable, H. influenzae, type b (Hib) has been frequently associated with bacteremic pneumonia. For example, Farley et al found a total of 47 cases of invasive H. influenzae infection in patients 18 years of age or older in metropolitan Atlanta during the period from December 1, 1988 to May 31 1990 and calculated that the annual incidence was 1.7 cases per 100,000 population. Bacteremic pneumonia accounted for 70 percent of the cases and 44 percent of the 29 pneumonia-associated blood isolates that were serotyped were Hib. Twenty-two of the cases reported by Farley et al occurred in adults over 60 years of age (incidence 5.6 per 100,000 per year), and 21 of the 22 cases were associated with bacteremic pneumonia. Patients with HIV infection are another group at particularly high risk for bacteremic Hib infection.

Safe, immunogenic, protein-conjugate Hib vaccines (HibCV) exist. These have been licensed for use in the United States since 1987 and have proven to be remarkably effective in preventing invasive Hib infections. For example, the Centers for Disease Control (CDC) estimated that the rate of invasive Hib infections in U.S. children under 5 years of age was 100 per 100,000 prior to licensure of the vaccine in 1987, whereas in 2003 the rate of all serotype-invasive H. influenzae infections in this age group was 1.9 per 100,000 (376 reported cases), of which only 32 (9 percent) were serotyped to be Hib. Unfortunately, not all groups have benefited equally from wide use of the HibCV vaccines. The rate of invasive H. influenzae infections did not improve among the elderly (those who are 65 years of age and older). Further, American Indians and Native Alaskan children benefited less than other racial groups.

The HibCV program has virtually eliminated Hib meningitis, one of the most serious infections of early childhood, from the United States It also has dramatically reduced the number of Hib respiratory infections that occur. For example, Zhou et al estimated that HibCV prevents 1106 and 1567 cases per year of epiglottitis and pneumonia, respectively and prevents 663 deaths.

The ACIP recently added a footnote to its recommendations for adult immunization. This footnote pointed out that the HibCV are licensed for children 6 to 71 months of age and that, though data on their efficacy do not exist in older children and adults, the vaccines are safe and immunogenic in many high-risk populations (e.g., those with sickle cell disease, leukemia, and HIV infection). Administration of the vaccine to these patients is not contraindicated.

Pertussis Vaccine Bordetella pertussis causes severe whooping cough in infants and young children. In recent years, however, clinical infections have been observed commonly in adolescents and young adults. For example, in the United States, a total of 11,647 B. pertussis infections were reported to the CDC in 2003, the highest number since 1964. Sixty-three percent of these infections occurred in persons who were 10 years of age and older.

Vaccination against Pulmonary Infections

Currently, no pertussis vaccines are licensed in the United States for persons 7 years of age and older.

The typical features of B. pertussis infection in infants and young children are a persistent, paroxysmal cough followed by inspiratory gasps (whoops), vomiting, cyanosis, and apnea. Complications of B. pertussis infections (e.g., pneumonia, seizures, and encephalopathy) are most common in infants less than 1 year of age and are associated with inadequate vaccination. Death occurs in 0.4 percent of cases.

Recently, Lee et al reported on the morbidity and medical and societal costs of B. pertussis infections among adolescents and adults in Massachusetts. Two-thirds of the patients had severe, long-lasting cough with 31 percent of adolescents and 41 percent of adults reporting episodes of “whoops”.

Seventy-nine percent of adolescents and 81 percent of adults were still coughing at the time of interview, an average of 41 and 48 days, respectively, after onset of this symptom. Adolescents missed a mean of 5.5 days of school whereas working adults missed a mean of 9.8 days of work as a result of their pertussis infections. The medical costs of infection were approximately $275 per case (mean $242 for adolescents; $326 for adults). The nonmedical costs per case were $155 and $447 for adolescents and adults, respectively.

An acellular pertussis (aP) vaccine is available and is recommended for use in infants and young children in the United States. Acellular vaccines are composed of purified components of the bacteria that are thought to elicit protective immunity. They contain a combination of the filamentous hemagglutinin (FHA); detoxified pertussis toxin (PT); and pertactin, an outer-membrane protein. The aP vaccine is generally combined with diphtheria and tetanus toxoid vaccines and is given to children at 2, 4, 6, and 15 to 18 months of age with a final booster at 4 to 6 years of age or entry into kindergarten.

Pertussis vaccines can produce significant side effects.

Local reactions include pain, tenderness, erythema, and induration at the inoculation site. Mild systemic reactions to pertussis vaccines include low-grade fever, drowsiness, fretfulness, and vomiting. Moderate to severe reactions include fever above 105◦ F, persistent inconsolable crying lasting at least 3 hours, and collapse (hypotonic-hyporesponsive episodes). Moderate to severe reactions are very uncommon with the acellular vaccine.

BCG Vaccine Strains of the attenuated bovine tubercle bacillus, originally developed by Albert Calmette and Camille Gu´erin (bacille Calmette-Gu´erin, BCG), are among the most widely used and studied vaccines to prevent pulmonary infection. Worldwide, BCG has been in use since 1921, and over 3 billion individuals have been vaccinated. Despite this long history, use of the vaccine remains controversial, and it is not recommended for prevention of pulmonary tuberculosis (TB) in the United States.

Colditz et al reported on a meta-analysis of 15 prospective trials and 10 case-control studies of BCG. The efficacy of vaccine in preventing TB was 51 percent in the

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prospective trials (RR = 0.49; 95 percent CI 0.34 to 0.70) for BCG recipients. The efficacy for preventing death was 71 percent (RR = 0.21; 95 percent CI 0.16 to 0.53). In case-control studies, the protective efficacy was 50 percent (RR = 0.50 (95 percent CI 0.39 to 0.64). Despite these data, use of the vaccine remains controversial.

One problem with BCG vaccine is that its observed efficacy varies greatly in different studies. Fine listed a number of possible reasons for the observed differences. These include: (1) differences in exposure of populations to nontuberculous mycobacteria (exposure to nontuberculous mycobacteria can affect the immune responses induced by BCG); (2) differences in the strains of BCG used (different strains elicit different immune responses); (3) differences in the age at which BCG was administered (BCG is most effective when given early in childhood and when protecting against primary infection); (4) differences in the time from vaccination to development of TB (protection can wane with time); and (5) differences in the nutritional status of the vaccine recipients (immune responses diminish as a result of malnourishment).

Recently, Aronson et al reported results of a 60-year follow-up study of the efficacy of BCG among American Indians and Alaskan Natives (subjects who have an unusually high risk of TB as well as other infectious diseases). This trial was originally conducted in Alaska, Arizona, North and South Dakota, and Wyoming between 1935 and 1938. It involved American Indian and Alaskan Native children and adults 1 month to 20 years of age who, prior to entry into the study, did not react to a second strength (250 TU) purified protein derivative (PPD) skin-test and who, upon entry, were given a single dose of BCG or saline placebo. The 60-year follow-up study showed that the overall incidence of TB was 66 and 138 per 100,000 person-years in the vaccine and placebo groups, respectively (efficacy 52 percent; 95 percent CI 27 to 69). Efficacy was observed for pulmonary and for extrapulmonary TB. Efficacy of BCG declined over time for men, but not for women.

BCG is not recommended for control of TB infection in the United States. Instead, a vigorous program of detection and treatment of latent and active TB is recommended for high-risk patients in high-risk settings (e.g., prisons, health care facilities) and for known contacts of patients (including infants and children) with active TB infection. However, research is recommended to develop an improved vaccine that would be effective in controlling latent TB infection.

VACCINES AGAINST VIRAL PULMONARY PATHOGENS Although most viral respiratory infections are transient and benign, some can be associated with serious complications.

Vaccines have been developed to prevent infections or limit the morbidity of some viral infections (Table 116-2). The most important of these are the vaccines against influenza, measles (rubeola), and chickenpox (varicella). An adenovirus vaccine was used exclusively in the military. However, it is no longer being manufactured and supplies have been exhausted.

Influenza Vaccine Influenza viruses cause significant morbidity in all groups, but they are a particularly important cause of serious illness among aged and debilitated patients. For example, Thompson et al estimated that approximately 36,000 respiratory and circulatory deaths occur in the United States each year as a result of influenza virus infection. Over 90 percent of these occur in individuals 65 years of age and older. Further, the annual rates of influenza associated deaths in the United States increased steadily over the decade of the 1990s. This has increased the urgency for improving the influenza prevention and treatment programs.

Three distinct types of influenza virus exist: influenza A, influenza B, and influenza C. Influenza A viruses are

Table 116-2 Vaccines for Viral Pulmonary Pathogens Pathogen

Vaccine

Targeted Population

Frequency

Influenza virus

Trivalent inactivated, whole or split Trivalent Live-attenuated

Persons ≥6 months of age

Annually

Healthy persons 5–49 years of age

Annually

Measles (rubeola)

Live-attenuated vaccine

All children Susceptible adolescents and adults

1st dose: 12–15 months 2nd dose: 4–6 years of age

Chickenpox (varicella)

Live-attenuated vaccine

All children Susceptible adolescents and adults

1st doses: 1–12 years of age 2nd doses: 6–8 weeks apart

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classified into subtypes on the basis of two surface antigens: hemagglutinin (H0, H1, H2, H3, H4, H5, etc.) and neuraminidase (N1, N2, etc.). Immunity to these antigens, especially the hemagglutinin, reduces the chance and severity of infection. Influenza A and influenza B viruses undergo antigenic variation (drift and shift), although the latter has more stability. For the past two decades, two subtypes of influenza A and one of influenza B have circulated in the global community. However, an influenza A (H3N2) virus has been the predominant cause of morbidity and mortality.

Influenza virus infections can be prevented or controlled by annual vaccination. They also can be prevented or controlled by appropriate use of antiviral agents: amantadine or rimantadine for influenza A; oseltamivir and zanamivir for influenza A or influenza B. Two types of influenza vaccines exist: inactivated influenza vaccine and live-attenuated influenza vaccine (LAIV). Both are produced from egg-grown viruses that are highly purified. Inactivated virus vaccines are further divided into whole and split virus preparations. The latter are recommended for infants and children 6 months to 5 years of age because they are less likely to cause febrile reactions.

Every year, three influenza virus strains (usually two influenza A strains and one influenza B strain) are included in the vaccine preparations. For the past several years, the trivalent vaccine has consisted of an (H3N2), an (H1N1) influenza A, and an influenza B virus strain. These are chosen for the vaccine preparation on the basis of global monitoring by the World Health Organization (WHO) and anticipation that these viruses will circulate in the United States and other parts of the Northern Hemisphere during the late fall, winter, and early spring influenza season. For the 2006– 2007 influenza season, the ACIP recommended vaccination for those at high risk of influenza and its complications as well as healthy adults over 50 years of age in October, November, and beyond throughout the influenza season.

Efficacy of the influenza vaccines has been difficult to assess because a number of agents can cause “flulike” symptoms and specific diagnostic tests (e.g., culture, serology) are rarely done in nonresearch, clinical situations. The ACIP estimated 70 to 90 percent efficacy of inactivated influenza vaccines in preventing illness in healthy adults over 65 years of age when the circulating viruses antigenically matched those used to prepare vaccine.

Bridges et al reported on a randomized, double-blind trial of inactivated influenza vaccine compared to placebo conducted among full-time, 18- to 64-year-old employees of the Ford Motor Company during the 1997–1998 and 1998– 1999 influenza seasons. End points of this study were clinically defined influenza-like illnesses (ILI), days ill, associated physician visits, and time lost from work during the influenza season. During the 1997–1998 season, vaccine recipients reported more ILI, days ill, physician visits, and days lost from work than did placebo recipients. These differences were not significant. However, during the 1998–1999 season, vaccine recipients reported significantly fewer ILI, days ill, physician visits, and days lost from work than did the placebo recipients ( p = <0.001 for each).

Vaccination against Pulmonary Infections

Demicheli et al reported results of a massive review and meta-analysis of the published literature on influenza control.

Their analyses showed that parenteral vaccines had efficacies against virologically confirmed and clinical ILI cases of 68 percent (95 percent CI 49 to 79) and 24 percent (95 percent CI 15 to 32), respectively. They also reviewed data on LAIV, reporting efficacies of 48 percent (95 percent CI 24 to 64) and 13 percent (95 percent CI 5 to 13) against virologically confirmed and clinical ILI cases, respectively.

Influenza vaccination reduces the risk of hospitalization for cardiac disease and stroke as well as for respiratory disease among the elderly. For example, Nichol et al reported the results of a cohort study involving community-dwelling adults 65 years of age and older. They found that the risk of hospitalization for cardiac disease was reduced by 19 percent ( p = <0.001) in vaccine recipients as compared to unvaccinated subjects. The risk of hospitalization for cerebrovascular disease was reduced by 16 percent ( p = 0.018) in the 1998– 1999 season and by 23 percent ( p = <0.001) in the 1999–2000 season. The risk of death from all causes was reduced in vaccine recipients by 48 percent and 50 percent during the 1998– 1999 and 1999–2000 seasons, respectively ( p = <0.001).

Influenza vaccines are less effective in elderly, debilitated individuals. Therefore, the ACIP strongly recommends annual influenza vaccine administration to all health care workers (HCW). Studies have confirmed the benefits of this strategy in long-term care facilities. For example, Potter et al reported on a study in which patients and staff of geriatric, long-term care facilities were offered influenza vaccine. Facilities were divided into those where patients and HCW received vaccine, patient received vaccine but HCW did not, HCW received vaccine but patients did not, and facilities in which neither patients nor HCW received vaccine. Vaccination of HCW was associated in a reduction in mortality from 17 percent to 10 percent (OR = 0.56; 95 percent CI 0.40 to 0.80) and in ILI (OR = 0.57; 95 percent CI 0.34 to 0.94). Vaccination of patients was not associated with an effect on mortality (OR = 1.15; 95 percent CI 0.81 to 1.64). In another study, reported

by Carman et al, the mortality of elderly patients in long-term care facilities was reduced from 22.4 percent to 13.6 percent (OR = 0.58; 95 percent CI 0.40 to 0.84) in facilities in which HCW were offered influenza vaccine.

The 2000 and 2001 NHIS data, referred to above, showed that non-Hispanic blacks were significantly less likely to report receipt of influenza vaccine than were non-Hispanic whites (OR = 0.7; 95 percent CI 0.6 to 0.8). However, there was no significant difference in the reported influenza vaccination rates for Hispanic and non-Hispanic whites (OR = 0.9; 95 percent CI 0.7 to 1.1).

Influenza vaccines are associated with relatively minor side effects. Local side effects of intramuscularly injected inactivated influenza vaccines, including soreness or swelling at the inoculation site, occur in 10 to 64 percent of patients, whereas systemic side effects (e.g., fever, malaise, and myalgia) are uncommon. Use of LAIV has been associated with runny nose or nasal congestion, headache, and low-grade fever. These were more often reported with the first dose of LAIV and were self-limited.

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Occurrence of Guillain-Barr´e syndrome (GBS) following influenza vaccination has been of concern since an association between swine influenza vaccine use in 1976–1977 and GBS was first noted. As a result, the CDC established a Vaccine Adverse Event Reporting System (VAERS). During the 1993–1994 influenza vaccination season, an increase in the number of GBS cases reported to VAERS was noted.

However, a careful study reported by Lasky et al showed that there was not an increase of vaccine-associated GBS during that period.

Two recent problems have refocused attention on control of influenza virus infections. The first is the shortage of influenza vaccine that occurred during the 2004–2005 season because of the problems of one vaccine manufacturer. As a result of that shortage, strategies to prioritize and stretch the use of available vaccine were developed. Two studies examined the immunogenicity of intradermal rather than the traditional intramuscular inoculation with influenza vaccine.

These studies showed that a fraction of the conventional intramuscular dose elicited comparable seroconversion and presumed protective antibody titers when given intradermally. However, it was noted that reactions were more frequent following intradermal inoculations and that those over 60 years of age reacted less vigorously.

The second problem is the threat of avian influenza.

WHO reported a total of 132 human cases of avian influenza A (H5N1) in Hong Kong, Vietnam, Thailand, Cambodia, Indonesia, and Fujian Province, China between 1997 and August 2005. Of these, 64 patients (48 percent) died. Most of the cases occurred in individuals who had exposure to infected poultry. However, there were clusters of infection within families. In addition, there were at least two incidents of apparent transmission of avian influenza from an infected 11-year-old girl to her 26-year-old mother and to a 32-year-old aunt with whom the child was living. The mother provided 16 to 18 hours and the aunt 12 to 13 hours of unprotected nursing care to the child. The child and her mother died from the infection, whereas the aunt survived.

The emergence of avian influenza as a human pathogen has raised concerns about the possibility of an influenza pandemic. A pandemic occurs when a highly contagious disease with novel antigens is introduced into a population with little immunity and spreads rapidly to cause worldwide disease.

Influenza pandemics are known to have occurred in 1918, 1957, and 1968 when the H1N1, H2N2, and H3N2 influenza viruses were first introduced into the population, respectively.

These prior pandemics were associated with approximately 40, 1, and 2 million deaths worldwide, respectively. The avian influenza (H5N1) has novel antigens for humans; there is little or no immunity to it. To date, avian influenza (H5N1) has not proven to be highly contagious either from fowl-tohumans or human-to-human. If, however, this virus acquires the genes that allow it to spread more efficiently, it could very well cause a pandemic associated with staggering morbidity and mortality.

At present there are no Food and Drug Administration (FDA)-approved, effective human vaccines against avian in-

fluenza (H5N1). The National Institute of Allergy and Infectious Disease (NIAID) has announced plans to test the immunogenicity of a candidate vaccine, but is unclear as to whether this will produce the desired antibody response, whether it will be approved without a clinical test of efficacy, or when it might be approved for use in humans.

Measles (Rubeola) Vaccine Measles was a major cause of morbidity and mortality in the United States, and it remains an important pathogen in some other parts of the world. Before 1963, the year that a measles vaccine was introduced, approximately 400,000 cases of measles were reported annually in the United States, but as many at 3.5 million cases may have actually occurred. Prior to introduction of the vaccine, death occurred in 1 to 2 cases per 1000 measles cases in the United States. The risk of death was greater for infants, young children, and adults than it was for older children and adolescents. Death was usually associated with measles encephalitis or pneumonia. In 2003, there were only 56 cases of measles reported in the United States.

Twenty-four of these were internationally imported cases, and an additional 19 were the result of exposure to internationally imported cases. In 2003, there were two measles-associated deaths in the United States.

Pneumonia is common in patients with measles. A study of 3220 U.S. Air Force recruits with measles showed measles pneumonia in 106 (3.3 percent) cases. Quiambao et al reported on 182 children with measles associated pneumonia who were admitted to the Research Institute for Tropical Medicine in Alabang, Philippines; 17 percent of these children died. Co-infection with bacteria (Streptococcus pneumonia, Haemophilus influenzae, Staphylococcus aureus) or other viruses was common and more likely to result in death.

Two doses of the live-attenuated measles virus vaccine are recommended for all children, adolescents, and adults without a true contraindication. These include severe allergic reaction after a previous dose or dose component, pregnancy, or severe immunodeficiency (congenital, hematologic malignancy, long-standing immunosuppression). A dose of the measles vaccine, generally combined with attenuated mumps and rubella vaccines (MMR) is recommended for children 12 to 15 months of age. A second dose should be given at 4 to 6 years of age prior to entry into kindergarten. Most colleges require documentation of two doses of measles vaccine before admission.

Measles vaccine can cause low-grade fever in 5 to 15 percent of recipients. This generally lasts 1 to 2 days. A transient rash may also occur.

Varicella Vaccine The varicella-zoster virus (VZV) causes chickenpox in susceptible children and adults, and, as a result of latent infection in sensory ganglia, zoster in those who have had a previous case of chickenpox. Approximately 7 percent of healthy, young adults lack antibody to VZV.

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Primary VZV was considered to be a relatively benign disease of childhood. However, it was associated with greater morbidity and mortality in adults. For example, Weber and Pellechia reported that 16 percent of military personnel with primary VZV infection had radiographic evidence of pneumonia. A number of factors increase the risk of developing VZV pneumonia including cigarette smoking, pregnancy, and prolonged use of nasal or inhaled steroids, immunodeficiency, malignancy, and transplantation. Meyer et al reviewed 2262 deaths that were ascribed to varicella during the 25-year period (1970–1994) prior to licensure of the vaccine in the United States. Adults had 25 times the risk and children under 1 year of age had 4 times the risk of dying compared to children 1 to 4 years of age with varicella. Pneumonia was the most common complication of the primary varicella infection in those who died.

Recently, Danovaro-Holliday et al reported on an outbreak of varicella involving 18 Mexican-born young adults residing in Alabama. Five of the cases were severe, requiring hospitalization. One patient developed pneumonia and another GBS. Fortunately, all of the patients survived. In an editorial commentary that accompanied this report, Gershon et al urged a more aggressive approach to identifying and vaccinating susceptible adults.

Live, attenuated varicella vaccine was approved for use in the United States in 1995. The number of varicella cases reported in the United States in 1984 and 2003 were 221,983 and 20,948, respectively.

Varicella vaccine is lyophilized and must be stored in a freezer at –15◦ to –20◦ C until use. It must be given within 30 minutes of thawing and reconstitution. Healthy children 12 months to 12 years of age should receive a single subcutaneous dose of the attenuated vaccine while adolescents and adults should receive 2 subcutaneous doses 4 to 8 weeks apart.

Approximately 15 percent of children inoculated with the attenuated varicella vaccine develop low-grade temperature elevations and 7 percent develop a transient, mild varicella-like rash.

Recently, a more potent version of the attenuated varicella vaccine was shown to be effective in preventing zoster infections in healthy adults over 65 years of age. However, it is not known whether this vaccine will be of any benefit in preventing the rare pulmonary infections that complicate zoster.

Adenovirus Vaccine Adenoviruses cause respiratory infections in infants, children, adolescents, and young adults. They have been associated with pharyngitis, croup, bronchitis, and pneumonia. They are a particular problem in the military, where susceptible young men and women are brought together and where acute respiratory infections caused by adenoviruses types 4 and 7 are a leading cause of infirmary visits and hospitalization.

Inactivated vaccines, containing adenoviruses types 4 and 7 that were grown in monkey kidney tissue culture cells and then treated with formalin, were prepared and tested in

Vaccination against Pulmonary Infections

military recruits in the 1950s and early 1960s. Randomized, controlled studies showed the inactivated vaccines to be more than 90 percent effective in reducing confirmed adenovirus infections.

Problems in production and contamination with simian viruses hampered further development of the inactivated adenovirus vaccine. Subsequently, Gutekunst et al tested a live, enteric, type 4 adenovirus vaccine in a placebocontrolled trial among marine recruits. The vaccine was 100 percent effective in preventing febrile respiratory disease in which adenovirus type 4 was recovered, 67 percent effective in preventing all febrile respiratory disease requiring hospitalization, and 77 percent effective in preventing all respiratory disease during the observation period.

For years, the enteric adenovirus vaccine was used by the military to protect recruits from adenovirus disease. Unfortunately, vaccine production was halted in 1995. The supply of adenovirus vaccine that remained was used by the military to vaccinate a limited number of recruits during 1996–1998 but was exhausted by 1999. By 1997, outbreaks of adenovirus infections had reappeared among military recruits. For example, Ryan et al reported an outbreak of 571 confirmed cases of adenovirus infection among recruits at a center in Great Lakes, Illinois that occurred in the fall of 1997.

This outbreak was caused by adenovirus types 3 and 7. Similarly, Kolavic-Gray et al reported an outbreak of adenovirus type 4 infections that occurred in the fall of 1998 among U.S. Army recruits at Fort Jackson, South Carolina. This outbreak involved 678 recruits and caused 115 hospitalizations. In both of these outbreaks, respiratory symptoms were common.

CONCLUSIONS Use of vaccines to prevent pulmonary infections has not been adequately emphasized in the past. Vaccines are a safe, effective, and relatively inexpensive means of preventing pulmonary infections that can be debilitating and, in some cases lethal. A number of vaccines are available and should be used in appropriate patients. These include the 23-valent polysaccharide and 7-valent conjugate pneumococcal vaccines, conjugate H. influenzae, type b vaccine, the acellular pertussis vaccine, the trivalent inactivated and live-attenuated influenza vaccines, and the live-attenuated measles and varicella vaccines.

A number of challenges to achieving a fully successful vaccination program exist. First, it is clear that there must be incentives for manufacturers to develop and maintain production of vaccines. A limited market for military recruits was an inadequate incentive for the manufacturer to sustain production of the adenovirus vaccine. Further, for many years, millions of doses of the inactivated trivalent influenza vaccines were unused. It is clear that manufacturers must have incentives to go through the costly process of preparing and maintaining supplies of vaccines. Subsidies may be necessary

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to develop and sustain valuable vaccines with limited or unpredictable markets.

Second, there must be better incentives for health care providers to use or urge the use of existing vaccines. In 2006, Medicare will pay providers in New York City only $21.65 for administration of either the pneumococcal or trivalent influenza vaccines. This is less than the $23.08 that was paid for the same service in the same area in 2005. This cut in funding is not advisable. It is clear that there must be improvements in the financing of vaccination programs and/or development of alternate incentives (e.g., achievement of accreditation goals set by the Joint Commission on Accreditation of Healthcare Organizations, the American Hospital Association, and other organizations) to encourage provider participation in adult vaccination programs.

Finally, there must be better education of consumers and employers about the benefits of vaccination. Vaccination programs will be successful if there is demand for the vaccines.

The most successful programs occur among our infants and children because parents demand and states or schools require evidence of vaccination. Consumers must be convinced that they need to be up-to-date with recommended vaccinations.

Further, employers must be convinced that inexpensive vaccines can prevent illness and that healthy employees are more productive. Ultimately, patients are the beneficiaries of successful vaccination programs. Once this is recognized, they will demand the vaccines.

SUGGESTED READING Aronson NE, Santosham M, Comstock GW, et al: Long-term efficacy of BCG vaccine in American Indians and Alaskan natives: A 6-year follow-up study. JAMA 291:2086–2091, 2004.

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Bridges CB, Thompson WW, Meltzer MI, et al: Effectiveness and cost-benefit of influenza vaccination of healthy working adults: A randomized controlled trial. JAMA 284:1655– 1663, 2000.

Carman WF, Elder AG, Wallace LA, et al: Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: A randomized controlled trial.

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Danovaro-Holliday MC, Gordon ER, Jumaan AO, et al: High rate of varicella complications among Mexicanborn adults in Alabama. Clin Infect Dis 39:1633–1639, 2004.

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Farley MM, Stephens DS, Brachman PS, et al: Invasive Haemophilus influenzae disease in adults: A prospective, population-base surveillance. Ann Intern Med 116:806– 812, 1992.

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French N, Nakiyingi J, Carpenter LM, et al: 23-valent pneumococcal vaccine in HIV-1-infected Ugandan adults: Double-blind, randomized and placebo controlled trial.

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Gremillion DH, Crawford S: Measles pneumonia in young adults: An analysis of 106 cases. Am J Med 71:539–542, 1981.

Gutekunst RR, White RJ, Edmonson WP, et al: Immunization with live type 4 adenovirus: Determination of infectious dose and protective effect of enteric infection. Am J Epidemiol 86:341–349, 1967.

Gutts FT, Zaman SMA, Jaffar S, et al: Efficacy of ninevalent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: Randomised, double-blind, placebo-controlled trial.

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Honkanen PO, Keistinen T, Miettinen L, et al: Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older. Vaccine 17:2493–2500, 1999.

Jackson LA, Neuzil KM, Yu O, et al: Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med 348:1747–1755, 2003.

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Jha AK, Zhonge L, Orav J, et al: Care in U.S. hospitals— the Quality Alliance Program. N Engl J Med 353:265–274, 2005.

Kelley, PW, Petrucelli, BP, Stehr-Green P, et al: The susceptibility of young adult Americans to vaccine preventable

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infections: A national serosurvey of U.S. Army recruits.

JAMA 266:2724–2729, 1991.

Kovalic-Gray SA, Binn LN, Sanchez JL, et al: Large epidemic of adenovirus type 4 infection among military trainees: Epidemiological, clinical, and laboratory studies. Clin Infect Dis 35:808–818, 2002.

Lasky T, Terracciano GJ, Magder L, et al: The Guillain-Barr´e syndrome and the 1992–1993 and 1993–1994 influenza vaccines. N Engl J Med 339:1797–1802, 1998.

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˚ Helund J, Burman LA, ˚ et al: Randomized trial of ¨ Ortqvist A, 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Lancet 351:399–403, 1998.

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117 Microbial Virulence Factors in Pulmonary Infections Gregory Priebe Gerald B. Pier

I. GENERAL MECHANISMS OF INFECTIOUS PROCESSES IN THE RESPIRATORY TRACT

III. SPECIFIC VIRULENCE MECHANISMS OF MICROBIAL PATHOGENS

II. MOLECULAR FACTORS AND PROCESSES IN RESPIRATORY INFECTIONS

IV. EXAMPLES OF THE MOLECULAR PATHOGENESIS OF ACUTE AND CHRONIC BACTERIAL RESPIRATORY INFECTIONS

Beginning at birth, microbial organisms enter and leave the body, primarily on external or mucosal surfaces. Some of these predominantly commensal organisms become resident; others are transient; and still others establish latent foci in otherwise sterile spaces. Over a lifetime, a person is the reservoir for hundreds of strains of viruses, thousands of bacterial species, and a scattering of fungi and parasites. When these organisms violate their niche, invade, or produce toxic products, virulent interactions take place and occasionally lead to disease. Thus, organisms can cause disease without entering or adhering to tissues by releasing toxic products. However, many infections are preceded by attachment of organisms to surfaces, followed by their entry into cells or otherwise sterile spaces.

These processes of invasion are complex and involve factors present in both the host and the organism. Most organisms are cleared by a variety of nonspecific and specific mechanisms, with nonspecific mechanisms generally falling under the heading of innate immunity and the specific under adaptive immunity. In some situations, however, organisms are able to propagate and produce clinical symptoms. A number of pathological conditions in the host predispose to entry and survival of microbes, ranging from breaks in mucosal surfaces to defects in the immune system. Organisms become parasites when they express the requisite virulence determinants to gain entry and overcome or evade host defenses.

An important step in establishing infection occurs when the potential pathogen encounters the immune sys-

tem. There are numerous mechanisms whereby the immune system detects and tries to limit the extent of microbial challenge, including inflammation (acute and chronic), phagocytosis (neutrophils and macrophages), complement, and humoral and cellular immune responses. The immune system also maintains surveillance for organisms that invade phagocytes, propagate, and resist killing, and also for organisms that invade nonphagocytic cells. Means by which microbes can be controlled range from physical clearance mechanisms to phagocytosis (followed by oxidative or nonoxidative killing) to nutritional depletion (e.g., sequestration of iron, which is an essential nutrient for bacterial growth).

Microbes have evolved a variety of strategies to overcome host defenses, evade the immune system, scavenge for nutrients, and survive to spread to other hosts. These processes can lead to tissue damage and even death of the host.

However, ultimate survival of the microbe requires eventual spread to a new host. A new “generation” of microbes is established (by clonal division) approximately once an hour, whereas a new generation of humans occurs about once every 20 years. Thus, the microbes have a clear genetic advantage in selecting properties that enhance virulence and survival. In response, the human immune system has developed to present a variety of defenses against a broad range of pathogenic mechanisms. Infections can occur at specific sites on surfaces or within the body or involve local, distal (metastatic), or systemic spread. Infection can occur without damaging cells,

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through direct cellular damage by microorganisms or their toxins, or as a consequence of the immune response. When physiological disruption or cellular damage occurs, the host needs to recover and repair. In addition, the immune system attempts to recognize the pathogen and prevent reinfection.

Pathogens have also evolved a series of mechanisms to avoid immune detection, including local interference with immune processes, antigenic variation, and avoidance of inducing an immune response.

Organisms are constantly evolving to meet the demands and opportunities of modern society. Just as the cities of the Middle Ages brought together humans and rats and caused outbreaks of bubonic plague, the use of antibiotics, chemotherapy, and various medical devices has led to a number of new pathogenic interactions between microbes and humans. A key to understanding the pathophysiology of infectious diseases and appreciating the complexity of both the immune system and the microbial world is knowledge of the facts and processes of each; this knowledge base is necessary for an understanding of the ideas presented above and the conceptual basis of immunity and infection as related to respiratory tract infections.

GENERAL MECHANISMS OF INFECTIOUS PROCESSES IN THE RESPIRATORY TRACT The pathogenesis of acute and chronic microbial infections of the lungs entails complex interactions between the microorganisms and a variety of host defense mechanisms. The

general steps and molecular factors involved in the pathogenesis of microbes causing lung infections are summarized in Table 117-1. Although the alveolar spaces are generally sterile, low levels of microorganisms are continually inhaled into the lungs. Inoculation of the lungs can occur from a variety of sources, including aspirated upper-airway secretion or bacteria in small aqueous droplets inhaled directly via the nose or mouth. Most commonly, inhaled organisms, either alone or in association with particles of mucus, gain access to the lower airways. They are generally either cleared by mucociliary flow or scavenged by phagocytes (see Chapter 111). Particulates greater than 10 µm in diameter are deposited in the upper airways. Particles of less than 5 µm that are not cleared in the upper airways can be deposited in alveoli. Most particulate matter is not infectious, and only spores or organisms that remain viable can cause infection.

Thus, the pathogenesis of microbial infection will initially depend on a microbe’s ability to enter the respiratory system and avoid clearance by mechanical and innate immune mechanisms.

As noted above, microorganisms can reach the lower airways from various sources. Organisms in ambient air can be inhaled as droplet nuclei—particularly in closed environments, where density is great and infected individuals can deposit organisms into the air. Perhaps the most important source of organisms causing pneumonia is the flora of the upper respiratory tract. A large ecosystem of microorganisms that includes both pathogenic and nonpathogenic bacteria and fungi normally resides in the upper airways. The quantity and species diversity of many of these organisms can be stable over long periods, but transient colonization

Table 117-1 Steps and Molecular Factors for Infectious Microorganisms to Cause Lung Disease Step

Molecular Factors

Result

Attachment to or entry into the body

Pili, flagella, surface proteins, lipopolysaccharide (LPS), specific ligands for receptors on host cells or mucins

Establish organisms in a host

Multiplication

Iron-binding factors; quorum-sensing signals, biofilm matrix

Increase microbial numbers; activate other virulence systems; initiate clinical symptoms

Local or general spread into the lungs

Capsular polysaccharides, antiphagocytic factors, motility (pili and flagella), toxins

Evade defenses and the natural barriers to spread

Damage to lung tissue

Exotoxins (including type III secretion system), LPS, cytotoxins, immunosuppressive factors

Inflict basic pathology due to the infectious agent

Shedding (exit) from the body

None identified

Leave body at site and on a scale that ensures spread to a new host

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with a variety of microbes also occurs with some frequency, and these changes are often correlated seasonally and/or with concomitant infections with respiratory viruses. For example, Streptococcus pneumoniae and Neisseria meningitidis are more frequently isolated from the nasopharynx or throat during the winter months. In addition, organisms that make up the normal microbial flora in other parts of the body can be transferred to the lung, where they can cause infection. In early onset group B streptococcal pneumonia and sepsis in neonates, the organisms are transferred during birth from the vaginal canal of the mother to the respiratory tract of the infant.

Organisms causing infections at other body sites can spread to the lungs. Although not common, hematogenous spread from the bloodstream to the lungs can occur. The existence of heavy colonization or infection in the upper airways also increases the potential for infection in the lungs by a variety of mechanisms, mostly by a simple dose effect, whereby a large burden of potentially pathogenic organisms overwhelms the clearance mechanism of the lungs. Another mechanism for pneumonic infection can result from infections that perturb the specific and nonspecific defenses, leading to respiratory infection as a sequela of another pathogenic process. The most common example of this process is bacterial infection secondary to influenza virus. In fact, the neuraminidase of influenza virus has been shown to play a synergistic role in pneumococcal pneumonia models by cleaving the sialic acid residues on host glycoconjugates, thereby leading to increased adherence of the bacterium. Finally, any process that disrupts the physiological and physical barriers between the upper and lower airways can lead to infectionâ&#x20AC;&#x201D;for example, the placement of an endotracheal tube or changes in normal clearance mechanisms associated with cystic fibrosis.

Once a microorganism gains access to the lower respiratory tract, it must be able to attach to tissue factors, remain viable, and multiply. Usually organisms will either multiply locally, resisting local defenses, or spread to other body sites by traversing epithelial barriers that normally inhibit microbial spread. In order for extracellular organisms to multiply, they must scavenge for nutrients. Of particular note is the universal requirement for iron, which must be extracted from iron-binding molecules such as transferrin. Many bacteria produce iron-binding substances known as siderophores that have an affinity for iron of greater than 1018 M and bind to high-affinity receptors on the bacterial surface. Organisms must also avoid or resist opsonophagocytosis or be able to survive and multiply within phagocytes. Subsequent to microbial growth and resistance of host defenses, damage to the host tissues occurs. This process is aided by a variety of pathogenic factors and results in invasion of tissues often with destruction of cells. Secreted toxins can act locally and/or be systemically spread to cause clinical symptoms. Many gramnegative bacilli possess a type III secretion system which can function like a hypodermic needle to inject toxins directly into host cells. The potential for inflammation to cause tissue destruction can be a devastating consequence of microbial

Microbial Virulence Factors in Pulmonary Infections

growth in normally sterile lung sites. Finally, although not necessary for the pathological process to take place, most organisms that successfully multiply will have mechanisms with which to leave the body and transmit disease, thereby propagating their species.

MOLECULAR FACTORS AND PROCESSES IN RESPIRATORY INFECTIONS The study of pathogenic microorganisms has benefited greatly from the ability to identify microbial factors that are at work to elicit a particular pathological process. Often these factors by themselves are responsible for a particular aspect of the infectious process, whereas at other times these factors act in consort to promote microbial colonization, growth, infection, and ultimately host responses and disease.

The success of the microorganism in establishing infection (the presence of a microorganism in a tissue where it is not normally found) and causing disease (the signs and symptoms of clinical illness) is predicated on the organismâ&#x20AC;&#x2122;s ability to elaborate specific molecular factors that allow it to progress from the colonization to the disease state. Factors that inhibit or neutralize the hostâ&#x20AC;&#x2122;s response to eliminate the organism are also critical for pathogenesis. The ability of specific microorganisms to produce virulence or pathogenic factors is highly variable and is doubtless a major reason for the differences in pathogenicity among closely related strains of bacteria. Initially, most microbes that establish themselves in the respiratory tract will bind to host tissues, often in a specific manner. Pathogens will produce specific molecules to promote this process. Some potentially pathogenic microorganisms, such as S. pneumoniae and N. meningitidis, can establish colonization in the nasopharynx or throat without causing harmful effects. Almost everyone is colonized by these potential pathogens many times during life. Viruses and obligate intracellular parasites, such as Chlamydia, usually must find their way to the lower respiratory tract and invade a specific cell in order to start growing. Bacterial pathogens, such as Legionella pneumophila and Mycobacterium tuberculosis, need to encounter alveolar macrophages where they are ingested but resist destruction within these cells.

In some cases, as long as a potential pathogen confines itself to a local site, no disease will ensue. At other times, growth at the local site causes frank disease; this is the mechanism of group A streptococcal pharyngitis and whooping cough caused by Bordetella pertussis. In general, the nasopharynx and throat readily tolerate the presence of a dynamic bacterial population, comprising mostly nonpathogenic strains along with potential pathogens that do not spread to other tissues.

Most of the initial host response to pathogens in normally sterile sites, indicative of infection, involves the basic inflammatory responses of innate immunity. The microbes generally initiate this response by activating complement, binding quasi-specific host molecules such as mannose-binding

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lectin, and generating other tissue signals via cell-associated pattern-recognition molecules such as toll-like receptors that lead to an influx of inflammatory cells and serum factors into the site of infection. Inflammation leads to clinical symptoms in the form of a sore throat, sneezing, coughing, feeling of malaise, etc. Some particularly virulent microbes can produce much more serious disease rapidly as the organisms spread and cause inflammation diffusely throughout the respiratory tract. Failure to control microbial growth and sustained inflammation lead to pathological tissue destruction.

The balance between the host inflammatory response and microbial growth is the key factor in the disease process. As is often the case with microbial infection, inflammation is a double-edged sword, critically important for resolution of infection but also responsible for tissue damage.

SPECIFIC VIRULENCE MECHANISMS OF MICROBIAL PATHOGENS Much of our knowledge in the area of molecular mechanisms that microbial pathogens use to establish and cause respiratory infections is derived from studies of bacteria. In the case of viruses, clear factors, such as the neuraminidase and hemagglutinin proteins on the coat of the influenza virus, are needed to expose cellular receptors and promote viral binding, subsequent cellular invasion, viral replication, inflammation, and disease. All viruses causing respiratory infections must enter cells in some manner that includes binding of a specific viral factor to a specific host cellular receptor. Intracellular nonviral microbes such as Chlamydia are probably taken into cells nonspecifically by phagocytosis or endocytosis.

A fairly good understanding of the molecular basis for the pathogenesis of B. pertussis infection has been established.

B. pertussis binds exclusively to the cilia on ciliated respiratory epithelium using at least two bacterial cell-surface factors, designated pertactin and filamentous hemagglutinin (FHA).

A fraction of the organism’s cell wall, the muramyl dipeptide, is then extensively produced and secreted, and this factor is toxic to the ciliated tracheal cells. These cells are extruded from the epithelial surface, perhaps in an attempt to clear the bacteria from the respiratory tract. Secretion of pertussis toxin also contributes to the pathology. Pertussis toxin is composed of two subunits, designated A and B; the B subunit binds to receptors on host cells, allowing the A subunit to enter the cell. The A subunit transfers the ADP-ribosyl part of NAD to a membrane-bound GTP-binding protein that normally inhibits the enzyme adenyl cyclase. This leads to increased synthesis of cyclic adenosine monophosphate (cAMP). One recently described role of pertussis toxin is to inhibit neutrophil recruitment, thereby delaying antibodydependent clearance of the bacterium even in immune hosts.

Other extracellular pathogens that cause lung infections establish themselves in tissues by binding to either cellular receptors or factors in the mucus, notably mucin. Kri-

van and colleagues report that several bacterial pathogens that frequently cause pneumonia—including Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, and some Escherichia coli—bind specifically to terminal or internal Ga1NAc-β(1-4)-Gal sequences lacking sialic acid residues commonly found on cellular glycolipids in the respiratory tract. P. aeruginosa itself has been prominently studied in regard to binding to respiratory mucins as a mechanism to establish and maintain infection in the lung. Nontypeable H. influenzae also appears to use pilus-mediated adherence to human respiratory mucins to establish chronic infections in the lung.

Intracellular respiratory bacterial pathogens usually are ingested by alveolar macrophages and must resist phagocytic killing in order to establish infection and cause disease. M. tuberculosis enters these cells in the lower and middle airways with high airflow, as it is an obligate aerobic organism. Bacterial ligands and cellular receptors involved in this process are not fully characterized, although dendritic cellspecific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) on dendritic cells and macrophages appears to play a role. Following inhalation, most individuals will effectively clear or contain the tubercle bacilli, while in a minority the bacteria escape from the macrophage phagolysosome, or prevent its formation in the first place, leading to bacterial growth and host inflammation and resulting in lesions typical of tuberculosis. On the opposite side of the time spectrum from M. tuberculosis, inhaled spores of Bacillus anthracis are phagocytosed by alveolar macrophages but within 6 hours can germinate, escape from the phagosome, replicate within the cytoplasm, and escape from the macrophage to enter the lymphatics or bloodstream.

Respiratory pathogens elaborate additional virulence factors beyond those needed to establish infection in normally sterile tissues. Many respiratory bacterial pathogens are encapsulated—a critical factor in promoting bacterial resistance to phagocytic killing. Neutralization of this antiphagocytic property by specific antibody results in high-level host immunity. Successful vaccines against S. pneumoniae, H. influenzae type b, and certain serogroups of N. meningitidis have been developed by engendering capsule-specific immunity via immunization, and comparable vaccines against P. aeruginosa, K. pneumoniae, group B streptococcus, and S. aureus are in various stages of development and testing in humans. Many studies support a role for the M protein capsule-like antigen of group A streptococcus in preventing phagocytosis of this organism, although recent studies suggest that the nonimmunogenic hyaluronic acid capsule plays a more prominent role as an antiphagocytic factor for group A streptococci.

Regulation of the expression of virulence factors is tightly controlled by the pathogen via complex networks of two-component regulatory systems and other systems. In P. aeruginosa, quorum sensing (cell-density–dependent gene expression) via small organic molecules called acyl homoserine lactones has been shown to be important for virulence in

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pneumonia models both by regulating expression of secreted toxins and by inducing inflammation. S. aureus strains control virulence through regulatory peptides involved in activating and suppressing the accessory gene regulator (agr) network, with similar systems found in other gram-positive pathogens as well. Interfering with these systems with appropriate inhibitors holds promise for future therapeutic interventions in bacterial pneumonia.

Many respiratory pathogens, particularly P. aeruginosa and S. aureus, elaborate some very potent toxins. P. aeruginosa secretes an elastase that can interfere with innate immunity in the lung by cleaving surfactant protein D, thereby abrogating its role in bacterial clearance. In addition to secreted toxins, protein effectors of the type III secretion system of P. aeruginosa can be directly injected into host cells, injuring the alveolar epithelium and subsequently allowing the release of proinflammatory cytokines such as tumor necrosis factor–α (TNF-α) into the circulation, resulting in septic shock. The recent emergence of strains of communityacquired methicillin-resistant S. aureus (MRSA) that secrete the Panton-Valentine leukocidin, a pore-forming toxin specific for white blood cells, has been associated with severe cases of necrotizing pneumonia. The gram-negative endotoxin, also called lipopolysaccharide (LPS), can cause serious damage to lung tissues, although the lung seems relatively resistant to the effects of inhaled endotoxin when compared with the systemic response to circulating LPS.

EXAMPLES OF THE MOLECULAR PATHOGENESIS OF ACUTE AND CHRONIC BACTERIAL RESPIRATORY INFECTIONS Pneumococcal pneumonia is the prototypic acute bacterial respiratory infection. As important a pathogen as S. pneumoniae is in the respiratory tract, the understanding of how it causes pneumonia and sepsis is not extensive. The capsular polysaccharide is a critical virulence factor, but beyond this, the role of other bacterial products in pathogenesis is mostly unknown. The cell-wall bacterial phosphorylcholine of virulent S. pneumoniae has been shown to bind to the G protein–coupled platelet-activating factor (PAF) receptor following inflammatory activation of human cells. This leads to invasion of epithelial and endothelial cells, indicating a mechanism whereby S. pneumoniae could escape through the lung epithelium via the vascular endothelium into the circulation to cause sepsis. The fact that lung inflammation increases PAF receptor levels is likely another reason for the hypersusceptibility of people with viral upper respiratory infections to secondary infection with S. pneumoniae.

Chronic lung infections can be caused by a variety of bacterial pathogens, many of which occur in persons with underlying lung disease. Patients with chronic obstructive pulmonary disease are particularly susceptible to chronic infection with nontypeable H. influenzae, although beyond the propensity of the organism to bind to respiratory mucins, the

Microbial Virulence Factors in Pulmonary Infections

molecular bases for infection and disease are mostly unclear.

Interestingly, co-colonization experiments with H. influenzae and S. pneumoniae in mice have found that H. influenzae predominates due to H. influenzae-induced complementdependent phagocytic killing of S. pneumoniae.

Among patients with cystic fibrosis (CF), 80 to 90 percent will become chronically infected with P. aeruginosa.

This infection is currently the major factor limiting their life expectancy. A large research effort has focused on understanding how this pathogen infects the vast majority of patients with a genetic defect that does not appear related to chronic bacterial lung infection. In patients with CF, mutations are found in the CF transmembrane conductance regulator (CFTR) gene which codes for a large protein that regulates chloride ion secretions directly and also appears to affect the flow of other ions, such as sodium. Ninety percent of people carry at least one mutant CFTR allele that lacks the codon for the phenylalanine at position 508 (#F508 mutation), and about two-thirds of affected persons are homozygous for this mutation. The lack of phenylalanine at position 508 leads to an inability of the mature protein to get into the cell membrane.

The relationship of mutant CFTR and hypersusceptibility to chronic P. aeruginosa infection is undergoing intensive study. Pier and colleagues have proposed that clearance of P. aeruginosa from the lung following inhalation of bacteria is critically dependent on CFTR-controlled internalization of the bacterium by lung epithelial cells followed by rapid activation of innate immunity involving nuclear factor (NF)κB nuclear translocation and production of inflammatory cytokines such as interleukin (IL)-6, IL-8, and CXCL1. The combined effects of epithelial cell internalization and shedding along with rapid activation of innate immunity that most likely brings in neutrophils to phagocytose and eliminate any other extracellular bacteria can lead to efficient microbial clearance. Resolution of this response via apoptosis has also been shown to be important in the CFTR-dependent response of the lung to P. aeruginosa. The CFTR protein has been identified as the actual cellular receptor for clearance of P. aeruginosa from the lung. In a neonatal mouse model of clearance of P. aeruginosa from the lungs after nasal inoculation of bacteria, it was found that blocking of CFTR-mediated epithelial cell ingestion of P. aeruginosa led to higher bacterial burdens in the lung. Similarly, in transgenic CF mice there is reduced epithelial cell uptake of P. aeruginosa and increased overall bacterial burdens in the lung. Of note, there appears to be little to no binding of bacteria to tracheal epithelial cells in infected CF mice whereas extensive binding, ingestion, and shedding of P. aeruginosa by epithelial cells can be seen in tracheas of infected wild-type mice. Thus, in vivo, P. aeruginosa binding to CF epithelial cells is not observed, a situation completely consistent with results from histopathological examination of lungs taken at transplant or autopsy from CF patients, where P. aeruginosa also is not seen binding to the epithelium but rather encased in mucous plugs within the airways. Overall, the initial establishment of P. aeruginosa infections in the lungs of CF patients can be directly attributable

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to the lack of functional CFTR in cell membranes to bind to this microbe and initiate appropriate innate immune responses, which prevents efficient bacterial clearance from the lung.

The pathogenesis of chronic P. aeruginosa lung infections in CF patients is more extensive. After avoiding initial clearance, the bacteria adhere to mucins and become embedded in mucous plugs within the airways and eventually undergo a phenotypic conversion wherein they lose both their ability to produce the long O polysaccharide side chains that are usually on the LPS and acquire the ability to elaborate copious quantities of a bacterial exopolysaccharide called alginate. The hypermutable phenotype seen in P. aeruginosa strains from CF patients likely speeds this adaptation. Alginate is unable to provoke a protective antibody response in the host and encases the bacteria in microcolonies within a hypoxic microenvironment in the lung. Within this protective coating, phagocytes such as neutrophils are unable to ingest and kill the microorganisms. This leads to a vicious cycle of additional but ineffective inflammation and bacterial growth, the result of which is tissue destruction subsequent to the chronic inflammatory process. Alterations in the lipid A structure of the P. aeruginosa LPS in strains isolated from CF patients appear to confer resistance to antimicrobial peptides and a hyperinflammatory response. For most of the patient’s life, P. aeruginosa infection appears to remain confined to endobronchial surfaces, which become plugged with mucus while the airway tissues are being destroyed, although recently reported histopathological results from lungs of CF patients who died in the 1970s, prior to more modern medical management with aggressive antibiotic therapy used in some countries, also showed extensive alveolar involvement. The finding of quorum-sensing signals in the CF lung suggests that the P. aeruginosa may exist as a biofilm (defined as a structured community of bacteria encased in a self-produced matrix), which likely contributes to the recalcitrance of this infection to antibiotics. Thus, the pathogenesis of chronic P. aeruginosa infection in CF involves at least two components: an initial phase of hypersusceptibility to infection that is predicated on an inability of CF patients to kill or clear inhaled P. aeruginosa cells and a subsequent phase directly related to the bacterium’s ability to elaborate alginate, which allows the organism to resist host defenses while continuing to provoke inflammation that damages lung tissues.

From these two examples we garner some important insights into mechanisms whereby bacterial pathogens cause lung infections. Many of the principles apply to other types of pathogenic microbes that follow the basic scenario of entry, attachment, multiplication and survival, elicitation of inflammation, and ultimately tissue damage and compromise of respiratory function. Although each of these steps can often be characterized at a highly specific molecular level, usually using isolated factors such as toxins to elicit clinical symptoms of disease, the overall pathogenesis of disease requires that elaboration of molecular factors of pathogenesis be coordinated and that each step in the process occur under the proper

circumstances and at the right time. Research in identifying and understanding the microbe’s genetic and molecular factors that control and coordinate pathogenesis is in its infancy.

Presumably, greater understanding of particular factors and the interactions among both the factors and host tissues will lead to development of better vaccines and other therapies that will minimize the occurrence of microbial infections in the lung.

SUGGESTED READING Alcorn JF, Wright JR: Degradation of pulmonary surfactant protein D by Pseudomonas aeruginosa elastase abrogates innate immune function. J Biol Chem 279:30871, 2004.

Cannon CL, Kowalski MP, Stopak KS, et al: Pseudomonas aeruginosa-induced apoptosis is defective in respiratory epithelial cells expressing mutant cystic fibrosis transmembrane conductance regulator. Am J Respir Cell Mol Biol 29:188, 2003.

Cundell DR, Gerard NP, Gerard C, et al: Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377:435, 1995.

Dixon TC, Fadl AA, Koehler TM, et al: Early Bacillus anthracismacrophage interactions: Intracellular survival and escape. Cell Microbiol 2:453, 2000.

Donaldson SH, Boucher RC: Update on pathogenesis of cystic fibrosis lung disease. Curr Opin Pulm Med 9:486, 2003.

Ernst RK, Yi EC, Guo L, et al: Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa.

Science 286:1561, 1999.

Gillet Y, Issartel B, Vanhems P, et al: Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359:753, 2002.

Hoffmann N, Rasmussen TB, Jensen PO, et al: Novel mouse model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis. Infect Immun 73:2504, 2005.

Kirimanjeswara GS, Agosto LM, Kennett MJ, et al: Pertussis toxin inhibits neutrophil recruitment to delay antibodymediated clearance of Bordetella pertussis. J Clin Invest 115:3594, 2005.

Krivan HC, Roberts DD, Ginsburg V: Many pulmonary pathogenic bacteria bind specifically to the carbohydrate sequence GalNAc-beta(1-4)Gal found in some glycolipids.

Proc Natl Acad Sci USA 85:6157, 1988.

Kubiet M, Ramphal R, Weber A, et al: Pilus-mediated adherence of Haemophilus influenzae to human respiratory mucins. Infect Immun 68:3362, 2000.

Kurahashi K, Kajikawa O, Sawa T, et al: Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest 104:743, 1999.

Lyon GJ, Novick RP: Peptide signaling in Staphylococcus aureus and other gram-positive bacteria. Peptides 25:1389, 2004.

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Lysenko ES, Ratner AJ, Nelson AL, et al: The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces. PLoS Pathog 1:e1, 2005.

McCullers JA, Bartmess KC: Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae. J Infect Dis 187:1000, 2003.

Oliver A, Canton R, Campo P, et al: High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 288:1251, 2000.

Pier GB, Grout M, Zaidi TS, et al: Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 271:64, 1996.

Pier GB, Saunders JM, Ames P, et al: Opsonophagocytic killing antibody to Pseudomonas aeruginosa mucoid exopolysaccharide in older noncolonized patients with cystic fibrosis.

N Engl J Med 317:793, 1987.

Reiniger N, Ichikawa JK, Pier GB: Influence of cystic fibrosis transmembrane conductance regulator on gene expression in response to Pseudomonas aeruginosa infection of human bronchial epithelial cells. Infect Immun 73:6822, 2005.

Ritchings BW, Almira EC, Lory S, et al: Cloning and phenotypic characterization of fleS and fleR, new response regulators of Pseudomonas aeruginosa which regulate motility and adhesion to mucin. Infect Immun 63:4868, 1995.

Microbial Virulence Factors in Pulmonary Infections

Schroeder TH, Lee MM, Yacono PW, et al: CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proc Nat Acad Sci USA 99:6907, 2002.

Schroeder TH, Reiniger N, Meluleni G, et al: Transgenic cystic fibrosis mice exhibit reduced early clearance of Pseudomonas aeruginosa from the respiratory tract. J Immunol 166:7410, 2001.

Singh PK, Schaefer AL, Parsek MR, et al: Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407:762, 2000.

Smith RS, Harris SG, Phipps R, et al: The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl) homoserine lactone contributes to virulence and induces inflammation in vivo. J Bacteriol 184:1132, 2002.

Tailleux L, Schwartz O, Herrmann JL, et al: DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 197:121, 2003.

Wessels MR, Bronze MS: Critical role of the group A streptococcal capsule in pharyngeal colonization and infection in mice. Proc Natl Acad Sci USA 91:12238, 1994.

Worlitzsch D, Tarran R, Ulrich M, et al: Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 109:317, 2002.

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SECTION EIGHTEEN

Common Syndromes in Pulmonary Infectious Diseases

118 CHAPTER

Infections of the Upper Respiratory Tract Marlene L. Durand

I. THE COMMON COLD II. PHARYNGITIS III. ORAL CAVITY INFECTIONS IV. LARYNGITIS V. CROUP VI. EPIGLOTTITIS VII. BACTERIAL TRACHEITIS VIII. LARYNGEAL PAPILLOMATOSIS

Chronic Bacterial Sinusitis Complications of Bacterial Sinusitis Fungal Sinusitis X. EAR AND MASTOID INFECTIONS Auricular Cellulitis and Perichondritis Otitis Externa Acute Otitis Media Otitis Media with Effusion Chronic Suppurative Otitis Media Acute Mastoiditis Complications of Acute and Chronic Otitis Media

IX. SINUSITIS Acute Community-Acquired Bacterial Sinusitis Nosocomial Bacterial Sinusitis

Upper respiratory tract infections are the most common infections and the most frequent reasons for office visits in the United States. Most upper respiratory infections are minor and self-limiting, but some (e.g., peritonsillar abscess, epiglottitis, invasive fungal sinusitis) may be life-threatening.

THE COMMON COLD The common cold is a mild, self-limiting infection. Six major viral families are responsible: rhinovirus (30 to 40 percent of

cases); influenza virus (25 to 30 percent); coronavirus (10 to 15 percent); adenovirus (5 to 10 percent); parainfluenza virus (5 percent); and respiratory syncytial virus (5 percent). Each virus has several serotypes; rhinovirus has 100. Adults have an average of two to four colds and children six to eight colds per year.

In the United States, the incidence of colds is seasonal, with most occurring fall through spring. Young children are the main reservoir of respiratory viruses, and adults with children have more colds than those without. Transmission probably occurs either by inhalation of infectious droplets or by hand-to-nose “self-inoculation” after touching infectious secretions. The pathogenesis of rhinovirus

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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infections is thought to include viral entry into the nose followed by infection of the epithelial cells of the upper airway.

Symptoms (sneezing, nasal discharge and congestion, and a “scratchy” throat) develop 16 to 72 h after inoculation, and last for 1 to 2 weeks. The peak of rhinoviral excretion in nasal secretions coincides with the peak of clinical illness.

Complications of the common cold include bacterial superinfections of the upper respiratory tract, such as acute otitis media and acute sinusitis, and exacerbations of asthma.

Recent studies have demonstrated that rhinoviruses may be present in the lower airways during the common cold, and are a major cause of asthma exacerbations in children and adults.

Treatment of the common cold is symptomatic, with nonsteroidal anti-inflammatory drugs (NSAIDs) and antihistamines providing some benefit. Development of a vaccine is unlikely given the number of viral pathogens and serotypes.

Antiviral agents such as pleconaril have not provided sufficient benefit to outweigh risks or side effects. Herbal remedies, such as Echinacea, have shown no benefit. Careful handwashing and use of hand disinfectants may be the most effective preventive measures.

PHARYNGITIS Over 6 million adults visit primary care physicians annually for sore throats, and three-fourths receive antibiotics. Most cases of acute pharyngitis occur as part of the common cold and are caused by viruses such as rhinovirus, coronavirus, and parainfluenza virus. These cases are mild, nonexudative, and self-limiting. Patients with primary human immunodeficiency virus (HIV) syndrome may also have a nonexudative pharyngitis. A severe, usually exudative pharyngitis occurs in about half of patients with either adenovirus infection or Epstein-Barr virus mononucleosis. The pharyngitis seen in herpangina, due to group A coxsackievirus, is characterized by a vesicular enanthem. Lesions (usually only two to six) begin as papules on the soft palate between the uvula and tonsils. These vesiculate, then ulcerate. Primary herpes simplex virus may cause a severe vesicular or ulcerative pharyngitis; when there is an overlying exudate, it may mimic streptococcal pharyngitis.

Group A streptococcus (Streptococcus pyogenes) is the most important bacterial cause of pharyngitis because of its suppurative (e.g., peritonsillar abscess) and nonsuppurative complications (e.g., rheumatic fever, acute poststreptococcal glomerulonephritis). It causes 15 to 30 percent of cases of pharyngitis in children and 5 to 10 percent in adults (likely higher in parents of school-age children). Symptoms and signs vary. Patients may have a severe exudative pharyngitis accompanied by fever, leukocytosis, and cervical lymphadenopathy, or they may have a mild pharyngitis that mimics that of the common cold. Some patients with mild disease have a viral pharyngitis but are colonized with group A streptococci. These patients must also be treated for presumed streptococcal disease. Features independently associ-

ated with group A streptococcal pharyngitis include tonsillar exudates, cervical lymphadenitis, lack of cough, and history of fever. Diagnosis of streptococcal pharyngitis is made by culture or by rapid antigen detection test (RADT). The latter is 95 percent specific but not as sensitive as culture. Therefore, a negative test requires culture confirmation in children and adolescents, while a positive test is sufficient for the diagnosis. In adults, practice guidelines suggest that a negative RADT may not require culture backup, as the incidence of streptococcal disease is lower than in the pediatric population and the risk of rheumatic fever extremely low. Treatment is with oral penicillin (or erythromycin in penicillin-allergic patients) for 10 days, or with a single intramuscular dose of benzathine penicillin. Cephalosporins are very effective in eradicating streptococci, and cefdinir and cefpodoxime have Food & Drug Administration (FDA) approval for 5-day treatment courses, as does the macrolide azithromycin.

Other bacteria may also cause pharyngitis. Group C and G streptococci may cause an exudative pharyngitis and may be endemic or related to foodborne outbreaks. Arcanobacterium hemolyticum may cause an exudative pharyngitis along with a maculopapular rash, and typically occurs in children and young adults. Diphtheria, caused by Corynebacterium diphtheriae, is rare in the United States. Sore throat is a common symptom (in 90 percent), and findings include mild pharyngeal injection and an overlying adherent gray membrane (especially over the tonsillar pillars) that bleeds if removal is attempted. Yersinia enterocolitica may cause an exudative pharyngitis; an associated enterocolitis is more common in children than in adults. Neisseria gonorrhoeae may cause a mild pharyngitis, although most cases are asymptomatic.

Neisseria meningitidis has rarely been noted as a cause of pharyngitis, but it is often isolated from throat cultures because the meningococcal carrier state is common. Carriers are not treated except in epidemic situations or if they have had close contact with a case of invasive meningococcal disease. Chlamydia pneumoniae and Mycoplasma pneumoniae may cause a mild pharyngitis.

A peritonsillar abscess (quinsy) may follow untreated streptococcal pharyngitis or may be due primarily to mouth anaerobes. Patients have severe sore throat and trismus, and may speak with a “hot potato” voice. There is marked unilateral peritonsillar swelling and erythema, causing deviation of the uvula. The abscess should be aspirated or incised and drained by an otolaryngologist, and antibiotics active against streptococci and mouth anaerobes (e.g., ampicillinsulbactam) should be given.

ORAL CAVITY INFECTIONS The oral cavity extends from the lips to the circumvallate papillae of the tongue. Various streptococci (e.g., S. mutans, S. mitis, S. salivarius) and anaerobes (e.g., Peptostreptococcus, Veillonella, Lactobacillus, Bacteroides, Prevotella) heavily colonize this area, and are the main pathogens in dental and oral cavity infections. S. mutans is a major pathogen in dental

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cavities. Gingivitis and periodontitis are associated with anaerobic gram-negative rods such as Prevotella intermedia and Porphyromonas gingivalis. Mouth anaerobes are the major cause of Vincent’s angina (acute necrotizing ulcerative gingivitis, or trench mouth). Patients have gingival pain, halitosis, cervical adenopathy, and ulcerations of the interdental papillae. Treatment is with oral clindamycin or penicillin plus metronidazole.

Ludwig’s angina is a rapidly spreading cellulitis of the sublingual and submandibular spaces. It usually begins in the floor of the mouth from an infected mandibular molar tooth. The sublingual area becomes edematous, pushing the tongue to the roof of the mouth. The infection can cause acute airway obstruction. Patients present with fever, difficulty swallowing, drooling, and prominent submandibular and sublingual swelling. They should be admitted for airway monitoring, as intubation or tracheostomy may be necessary.

Intravenous antibiotics active against streptococci and anaerobes should be given. Surgical incision of the infected soft tissue compartment may be necessary. Noma, or cancrum oris, is a rare infection caused by mouth anaerobes, especially fusospirochetal organisms such as Fusobacterium nucleatum. It occurs mainly in malnourished children, and begins as a gingival ulcer that rapidly spreads as a necrotizing cellulitis of the lips and cheeks. Therapy includes intravenous penicillin, debridement, and correction of dehydration and malnutrition.

Primary herpes simplex infection may cause painful vesicles on the buccal mucosa as well as the lips and tongue, and should be treated with hydration and acyclovir. The most common fungal infection of the oral cavity is thrush, usually due to Candida species. It occurs most often in immunocompromised patients, but may occur in normal hosts after prolonged antibiotic therapy or in patients with asthma using inhaled steroids. Treatment is with topical (e.g., nystatin) or oral (e.g., fluconazole) antifungal agents.

LARYNGITIS Laryngitis, or inflammation of the larynx, is characterized by hoarseness. Acute laryngitis is usually caused by the same viruses that cause the common cold, and treatment is symptomatic. Hoarseness may accompany infections with human metapneumovirus, a virus identified in 2001 and primarily associated with bronchiolitis in young children. Herpes simplex virus may cause acute laryngitis; ulcerations or vesicles are typically seen. Streptococcal pharyngitis may be associated with laryngitis and should be treated with penicillin.

Corynebacterium ulcerans has been a rare cause of a membranous laryngopharyngitis that may mimic diphtheria. Some studies from Sweden have found Moraxella catarrhalis to be more prevalent in cultures of patients with laryngitis than in controls, but a review of randomized controlled trials found that antibiotics appeared to have no benefit in the treatment of laryngitis. Fungi such as Candida and Cryptococcus are rare causes of laryngitis.

Infections of the Upper Respiratory Tract

Patients with chronic hoarseness often have gastroesophageal reflux disease, but must be examined for laryngeal malignancies. In rare instances, fungi or mycobacteria may cause chronic laryngitis. In chronic progressive disseminated histoplasmosis, ulcers may occur on the larynx, as well as on the tongue, buccal mucosa, and gingiva. Blastomycosis may also produce laryngeal ulcers. Tuberculosis (TB) may cause laryngeal lesions that mimic a laryngeal neoplasm. Patients typically present with hoarseness but often lack systemic symptoms to suggest TB. They may have negative sputum smears for acid-fast bacilli and a clear chest radiograph. In a retrospective study of 22 patients with laryngeal TB, 9 had clear lungs and only 7 had active pulmonary TB. The patients with concurrent pulmonary TB characteristically had multiple ulcerative lesions on their vocal cords, while those with clear lungs had nonspecific, polypoid, single laryngeal lesions.

CROUP Croup, or acute laryngotracheobronchitis, is characterized by subglottic edema and occurs most often in children ages 3 months to 3 years old, with peak incidence in the second year of life. It is rare in children over age 6. Most cases occur in fall, winter, and spring; the most common cause, parainfluenza type 1, has caused biennial epidemics in the fall in the United States. Croup is characterized by fever, inspiratory stridor, and a “seal’s bark” cough. In severe cases, there is both inspiratory and expiratory stridor. There is typically a fluctuating course, and there can be alternating clinical improvement and worsening within an hour. Croup usually follows the onset of upper respiratory tract infection symptoms by 1 to 2 days.

The cause is nearly always viral, with parainfluenza virus types 1 through 3 accounting for the majority of cases; type 1 is the most common cause in the United States. Influenza virus, particularly type A, also causes croup and may be more severe.

Respiratory syncytial virus causes between 1 and 11 percent of cases, and typically affects children under age 1. Adenovirus, rhinovirus, enterovirus, and M. pneumoniae are rare causes.

The diagnosis of croup is based primarily on clinical grounds. A diagnosis of the viral etiology may be made by one of the rapid viral antigen detection techniques (e.g., RT-PCR) on nasopharyngeal swabs. The most important differential diagnosis in the acute clinical setting is epiglottitis (see below).

Children with epiglottitis usually lack the characteristic seal’s bark cough of croup, appear more toxic, and their illness worsens more rapidly.

Treatment of croup consists of nebulized racemic epinephrine, corticosteroids, and humidified air, although the value of humidified air has been questioned. A recent study of high vs. low humidity vs. mist therapy for croup in an emergency department found no difference in outcome between the three groups at 30 and 60 minutes, nor in the percentage of patients requiring hospitalization. Nebulized racemic epinephrine has a well-established role in treating croup, producing signs of clinical improvement within 30 minutes and with a duration of action of about 2 hours. Children should be

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monitored for rebound edema for several hours after initiation of therapy. Corticosteroids are also beneficial, with onset of action within 6 hours and duration of benefit 12 hours.

Oral or intramuscular dexamethasone has shown benefit for moderate to severe croup, and a single dose of oral dexamethasone is beneficial for mild croup.

examination reveals no impending airway compromise may be managed with close observation. Broad-spectrum intravenous antibiotics with activity against H. influenzae, such as ampicillin-sulbactam, should be given. If the patient with epiglottitis due to H. influenzae has household contacts that include an unvaccinated child under age 4, the patient and all members of the household should receive rifampin prophylaxis to eradicate carriage of the organism.

EPIGLOTTITIS Acute epiglottitis (supraglottitis) is a medical emergency, as it can rapidly lead to airway obstruction. It begins as a cellulitis between the base of the tongue and the epiglottis, pushing the epiglottis posteriorly. It then involves the epiglottis itself, with rapid swelling and airway compromise. Epiglottitis has become a rare disease in children since the advent of vaccination against Haemophilus influenzae type b (Hib) in 1985, which decreased the incidence of all types of invasive Hib disease by over 99 percent. In the prevaccine era, the incidence of epiglottitis was highest in children ages 2 to 4.

Disease in children is due to rare cases of Hib vaccine failure or to other organisms, including nontypeable H. influenzae. The incidence in adults has been increasing in the past 20 years, from 0.8 cases per 10,000 in 1986 to 3.1 in 2000.

Blood cultures are usually negative in adults and cultures of the epiglottis difficult or dangerous to obtain, so the etiology is often unknown. Pathogens isolated from throat cultures in adults with supraglottitis include H. influenzae, H. parainfluenzae, Streptococcus pneumoniae, group A streptococcus, and Staphylococcus aureus. Viral epiglottitis is very rare and poorly substantiated.

In children, the onset of symptoms occurs rapidly, usually within 6 to 12 h, and patients appear toxic. Patients are febrile, irritable, complain of sore throat and dysphagia, prefer to sit leaning forward, and may be drooling. Inspiratory stridor may occur, but the barking cough seen in croup is absent. Adolescents and adults usually have a less fulminant presentation, often with 2 to 3 days of symptoms. Severe sore throat, odynophagia, and fever are the main presenting symptoms, each occurring in 90 percent of adults in a recent study; muffled voice was present in 70 percent. In adults, diagnosis is made by direct flexible fiberoptic nasolaryngoscopy, a procedure that takes just minutes to perform in the emergency room by an otolaryngologist. A swollen, erythematous epiglottis is seen. Children suspected of having epiglottitis should be transported, sitting up, to the operating room for direct endoscopic visualization of the epiglottis. An uncuffed endotracheal (or nasotracheal) tube should be immediately inserted (or, if necessary, a tracheostomy performed) if a “cherry red” edematous epiglottis is seen. Lateral neck radiographs, used in the past to demonstrate the “thumb sign” of an edematous epiglottis, are rarely used now as they may be falsely negative and may cause a critical delay in securing the airway.

All patients with epiglottitis should be monitored in an intensive care unit. Children with epiglottitis should be intubated for airway protection, while adults whose endoscopic

BACTERIAL TRACHEITIS This rare disorder, sometimes called membranous croup, presents acutely like epiglottitis but primarily involves the subglottic region like croup. It may represent bacterial superinfection of a viral tracheitis. It usually affects children between 3 weeks and 13 years of age, and is uncommon in adults. Patients present with the acute onset of high fever, stridor, and dyspnea after a viral prodrome. They do not respond to racemic epinephrine or corticosteroids. On endoscopy, patients have a normal epiglottis but the subglottic trachea is covered with a thick exudate. Inspissated secretions may produce a pseudomembrane. Cultures of tracheal secretions yield S. aureus in half of the cases; other organisms include group A streptococcus, S. pneumoniae, and H. influenzae. Gram-negative bacilli have been rarely described. Most patients require immediate intubation; some require tracheostomy. Up to 60 percent will have concurrent pneumonia. Broad-spectrum intravenous antibiotics active against S. aureus and H. influenzae should be given, along with airway humidification and aggressive pulmonary toilet.

Inspissated or copious secretions may cause airway obstruction even in patients with an artificial airway; several patients have died because of this complication.

LARYNGEAL PAPILLOMATOSIS Recurrent respiratory papillomatosis (RRP) is a rare disease caused by human papillomavirus that involves the larynx, but also may involve the trachea and lungs. Human papillomavirus types 6 and 11 are the types usually responsible; type 11 tends to produce more aggressive disease and carry a higher risk (3 percent) for eventual malignant transformation. Patients typically present with hoarseness, but may present with airway obstruction. Disease tends to be more severe in children than in adults, with extensive involvement of the airway and multiple episodes of recurrent disease. Treatment is with endoscopically directed surgical excision of the papillomas. In some young patients, rapid regrowth of the papillomas requires surgical excision on a nearly monthly basis. Intralesional injection of cidofovir at the time of surgery has been helpful in prolonging the time to relapse in some patients. Adjuvant systemic therapies with reports of some success in reducing the frequency of recurrences include oral indole-3-carbinol, subcutaneous injections of interferon-α,

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and intravenous cidofovir. There are few randomized controlled trials of these agents, however, in this rare disease.

SINUSITIS The paranasal sinuses develop as outpouches of the nasal cavity. The maxillary and ethmoid sinuses are present at birth, the frontal sinus develops after age 2, and the sphenoid sinus develops after age 7. The sinuses are lined with respiratory epithelium that includes ciliated cells and mucus-producing goblet cells. The cilia normally move the mucous blanket toward the sinus ostia (and then to the nasopharynx) at a speed of up to 1 cm/min. Inflammation causes a marked decrease in the beat frequency of the cilia, as well as narrowing or obstruction of the sinus ostia due to mucosal edema. The resulting disruption of mucociliary transport results in sinusitis.

The most common cause of inflammation leading to acute sinusitis is a viral upper respiratory infection. Most adults with common colds have computed tomographic (CT) evidence of ostial obstruction and sinus abnormalities, although only about 0.5 percent of all colds are complicated by acute sinusitis. Viral infections increase the amount of mucus produced and may damage ciliated cells. Another predisposing factor for sinusitis is allergic rhinitis, which may cause ostial obstruction by mucosal edema or polyps. Dental infections, especially of the upper teeth that abut the maxillary sinus (second bicuspid, first and second molars), may cause some cases of maxillary sinusitis. Anatomic obstruction of the sinus ostia due to a deviated septum, tumor, granulomatous disease (e.g., Wegenerâ&#x20AC;&#x2122;s granulomatosis), or nasotracheal or nasogastric tubes may also lead to sinusitis. Barotrauma from deep-sea diving or airplane travel, chemical irritants, and mucus abnormalities (e.g., cystic fibrosis) are other risk factors for sinusitis.

Acute Community-Acquired Bacterial Sinusitis Symptoms of acute bacterial sinusitis include purulent nasal or postnasal drainage, nasal congestion, and sinus pain or pressure. The location of this pain depends on the sinus affected. Patients usually complain of pain in their cheek or upper teeth in maxillary sinusitis, the sides of the bridge of the nose in ethmoid sinusitis, supraorbital or frontal pain in frontal sinusitis, and retro-orbital, frontal, occipital, or vertex pain in sphenoid sinusitis. Fever occurs in about half of adults with acute sinusitis.

The diagnosis of acute bacterial sinusitis is often difficult on the basis of history and physical examination alone.

Identical symptoms may occur in patients with viral upper respiratory infections, although bacterial sinusitis should be suspected if the patient has had persistent symptoms for more than 7 days. The sensitivity and specificity of individual symptoms such as facial pain when bending forward, purulent rhinorrhea, and sinus tenderness are less than 70 percent, making these features of limited diagnostic usefulness. In evaluating

Infections of the Upper Respiratory Tract

a patient for sinusitis, the routine physical examination is usually not helpful. Nasal endoscopy is helpful as it usually shows purulent secretions emanating from the sinus ostia in acute sinusitis, but this procedure is performed mainly by otolaryngologists. Plain films of the sinus are helpful in diagnosing sinusitis only if there is complete sinus opacification, an air-fluid level, or mucosal thickening of at least 4 mm; sinusitis, however, may be present without these findings. Sinus CT is much more sensitive than routine radiographs, particularly for ethmoid and sphenoid disease, but not specific for acute bacterial sinusitis as viral sinusitis may also show similar changes.

The bacteriology of sinusitis has been well defined only for acute, community-acquired maxillary sinusitis. Sinus puncture studies of adults with this infection have revealed that over 50 percent of cases are due to S. pneumoniae or nontypeable H. influenzae. Other pathogens include other streptococci, anaerobes, Moraxella catarrhalis, and rarely S. aureus.

Anaerobes are more common in adults and M. catarrhalis is more common in children. Studies of sinuses other than the maxillary sinus are hindered by the difficulty of obtaining culture material that is not contaminated by nasal flora.

Treatment should be empiric and target the bacterial pathogens noted above. Oral therapy (e.g., amoxicillinclavulanate, cefuroxime, levofloxacin) for 10 days is sufficient except in severe disease or in patients who also have a complication of sinusitis (e.g., orbital sinusitis).

Nosocomial Bacterial Sinusitis Nosocomial bacterial sinusitis is usually seen in patients in the intensive care unit, and typically considered in those with fever of unknown origin. The incidence is higher in patients with nasotracheal tubes. It is also higher in patients with nasogastric tubes vs. those without, 20 vs. 12 cases per 1000 patient-days in one study. A sinus CT scan showing sinus opacification or an air-fluid level suggests the diagnosis.

Bedside nasal endoscopy performed by an otolaryngologist may be helpful in obtaining cultures, either by endoscopically directed cultures of purulent meatal secretions or by maxillary sinus (antral) puncture. Antral puncture may not be indicated in all intensive care unit patients suspected of having sinusitis, however. One study found that only 8 percent of antral punctures yielded positive cultures in patients with normal endoscopic examinations. The pathogens in nosocomial sinusitis are usually S. aureus and gram-negative bacilli, and often include antibiotic-resistant organisms. Empiric treatment should be directed against these organisms (e.g., intravenous vancomycin plus cefepime) until culture results are known.

Chronic Bacterial Sinusitis Chronic sinusitis is characterized by symptoms that last for weeks to months. Patients complain of persistent dull pain, postnasal drainage, foul odor and taste, and fatigue. True fever is rare, although many patients complain of having temperatures around 99â&#x2014;Ś F. Most patients have stable, low-grade symptoms punctuated by episodes of acute sinusitis. These

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episodes may be signaled by a change to purulent secretions and increased sinus pressure. A sinus CT scan is indicated in patients with chronic sinusitis, both to define the extent of disease and to exclude other causes of their symptoms.

Patients should be evaluated by an otolaryngologist to exclude conditions that may be causing obstruction, such as a deviated septum, nasal polyps, Wegener’s disease, or cancers such as adenocystic carcinoma.

The bacteriology of chronic sinusitis is not well defined. Most patients with chronic disease will have sinus cultures positive for bacteria, but whether these are colonizers or pathogens is not always clear. Patients without sinus disease also have positive cultures when cultures are obtained intranasally. Sinus cultures cannot be obtained without contamination by nasal flora, and since S. aureus is a nasal colonizer in 30 percent of the normal population, recovery of this organism is particularly difficult to interpret in the patient with chronic sinusitis. Coagulase-negative staphylococci are not sinus pathogens and should not be treated. Recently, there has been interest in fungi as the major pathogens in chronic sinusitis via a local allergic mechanism, since careful cultures of nasal mucus yield fungi in most patients. However, the same study that demonstrated the prevalence of molds in nasal mucus in patients with chronic sinusitis also recovered them in cultures from all of the normal controls, so causality has not been demonstrated. Studies of topical or oral antifungal agents for chronic sinusitis have been small or have not shown benefit over placebo.

Complications of Bacterial Sinusitis Orbital Cellulitis The most common complication of bacterial sinusitis is preseptal cellulitis or deeper orbital infection, conditions usually grouped under the heading “orbital cellulitis” (Fig. 118-1).

Most cases are secondary to ethmoid sinusitis, since the ethmoid is separated from the orbit by only a very thin plate of bone, the lamina papyracea. Preseptal cellulitis only involves the eyelids and surrounding skin anterior to the orbital septum, but not the structures of the orbit. The lids appear red and edematous, but vision is normal and there are no orbital findings. In patients with orbital cellulitis, subperiosteal abscess, or orbital abscess, the eyelids are also red and swollen, but examination of the eye reveals one or more orbital findings as well. These include proptosis, which may be only detectable by using a Hertel’s exophthalmometer, limitation of extraocular movements, and decrease in vision. In subperiosteal and orbital abscess, the abscess is almost always located medially or superomedially in the orbit (reflecting the involvement of the adjacent ethmoid sinus), and the eye looks “down and out.” Abscess cultures demonstrate that the major pathogens are S. pneumoniae, group A streptococcus, nontypeable H. influenzae, and S. aureus, and these are presumably also the major pathogens in sinus-related orbital cellulitis and preseptal cellulitis. Antibiotics should be directed against these pathogens. Blood cultures are usually negative in adults, but are positive in 4 to 8 percent of young children

Figure 118-1 Orbital complications of sinusitis. A. Preseptal cellulitis. B. Orbital cellulitis. C. Subperiosteal abscess. D. Orbital abscess. E. Cavernous sinus thrombosis. (From Chandler JR, Langenbrunner DJ, Stevens FR: The pathogenesis of orbital complications in acute sinusitis. Laryngoscope 1970; 80:1414–1428, with permission.)

with preseptal cellulitis, in whom this condition may be secondary to bacteremic seeding by S. pneumoniae, other streptococci, or nontypeable H. influenzae. A CT scan should be performed on any patient with orbital findings, and an orbital or subperiosteal abscess usually requires emergency surgical drainage. Some authors also advocate a CT scan for children with apparent preseptal cellulitis, as some have a subclinical abscess.

“Pott’s puffy tumor,” or subperiosteal abscess of the frontal bone, is a complication of frontal sinusitis. Patients present with frontal pain and a tender, doughy swelling over the forehead. Treatment consists of 6 weeks of intravenous antibiotic therapy, and surgical drainage of the frontal sinus and subperiosteal abscess may be necessary. Intracranial complications of sinusitis usually result from frontal or sphenoid sinusitis. These include epidural abscess, subdural empyema, meningitis, cerebral abscess, and dural vein thrombophlebitis. Because of the proximity of the sphenoid sinus to the cavernous sinus, sphenoid sinusitis also may cause cavernous sinus thrombophlebitis.

Fungal Sinusitis There are three forms of fungal sinusitis: allergic fungal sinusitis, sinus aspergilloma, and invasive fungal sinusitis.

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Allergic fungal sinusitis (AFS) is characterized by the presence of “allergic mucin” in the involved sinuses and is thought to be due to a local hypersensitivity reaction to fungi.

Mold spores are ubiquitous in the environment and in the nasal mucus, where they are trapped after being inhaled. Patients with AFS present with chronic sinusitis symptoms, and most have a history of nasal polyposis, aspirin allergy, and asthma. The CT typically shows inhomogeneous opacification of one or more sinuses, and there may be evidence of bony erosion of the sinus. Erosion is due to pressure necrosis, not fungal invasion. On magnetic resonance imaging (MRI), the affected sinus often appears black on T2 (“T2-weighted signal void”), a finding also seen in other types of fungal sinusitis.

The diagnosis of AFS may be suspected at surgery because allergic mucin is tenacious, with the consistency of anchovy paste. It has histological features similar to that of mucin found in allergic bronchopulmonary aspergillosis, with many eosinophils and Charcot-Leyden crystals. Fungal hyphae are found in the mucus of half of the cases, but there is no evidence of tissue invasion. Only half of cases have positive fungal cultures, and these grow molds such as Bipolaris, Curvularia, Alternaria, and Aspergillus. Surgical removal of the inspissated mucus, along with intranasal steroids or short courses of oral steroids, seems to be effective. There is no proven role for antifungal agents.

Sinus aspergilloma is a noninvasive fungal disease that may cause symptoms of obstruction and chronic sinusitis.

Usually only one sinus (most often maxillary) is affected, and symptoms are therefore unilateral. Surgical removal of the fungus ball is usually curative. Careful review of the pathological slides is required to verify that there is no tissue invasion.

Invasive fungal sinusitis carries a significant risk of mortality, in contrast to the other two benign forms of fungal disease. Estimates of mortality depend on the sinus affected and the immune state of the patient. In immunocompromised hosts, fungal disease presents acutely. Rhinocerebral mucormycosis is a life-threatening infection due to molds of the order Mucorales (Rhizopus, Mucor, Absidia). Approximately 70 percent of patients with mucormycosis have diabetes, while other risk factors include corticosteroid therapy or other immunosuppressant therapy, hematologic malignancies, and deferoxamine chelation therapy. Patients usually present with signs mimicking bacterial orbital cellulitis involving one eye, with swollen eyelids, proptosis, decreased extraocular movements, and decreased vision in that eye. In contrast with orbital cellulitis, eyelids may appear less red, unilateral frontal pain or temporal pain may be prominent, and there may be hypesthesia in the V1 or V2 distribution. If there are bilateral eye findings, involvement of the cavernous sinus should be suspected. Patients in whom the diagnosis is suspected should undergo immediate endoscopy by an otolaryngologist to look for a characteristic black eschar signifying infarcted intranasal or sinus mucosa. The eschar and adjacent tissue should be biopsied and examined for fungus on frozen section by a pathologist. On pathology, broad nonseptate hyphae are found invading tissue, often around

Infections of the Upper Respiratory Tract

blood vessels and nerves. In patients in whom the clinical suspicion for mucormycosis is high, the absence of a black eschar on clinical examination does not exclude the diagnosis, and biopsies of normal-appearing middle turbinate may yield the diagnosis. The absence of any evidence of sinusitis

by CT scan also does not exclude the diagnosis. Treatment of mucormycosis requires a combination of aggressive surgical debridement and intravenous amphotericin or liposomal amphotericin therapy. Voriconazole is not active against mucormycosis. Posaconazole is a new agent that may be effective in patients who fail debridement and amphotericin therapy.

Aspergillus and other fungi (e.g., Bipolaris, Curvularia, Exserohilum) may also cause invasive fungal sinusitis.

Immunocompromised patients, such as those who have received organ transplants, usually present acutely. Treatment is aggressive surgical debridement and systemic antifungal therapy. Normal hosts, in contrast, usually present subacutely, with weeks to months of symptoms. Fungi in the ethmoid and sphenoid sinuses may invade the orbital apex and cavernous sinus, affecting cranial nerves III, IV, V, and VI. Symptoms include headache, unilateral retroorbital pain, proptosis, ptosis, limitation of eye movement, decreased vision, and hypesthesia in the distribution of cranial nerve VI on the affected side. Symptoms of sinusitis are often absent. Diagnosis is suggested by the clinical findings and CT and MRI scans showing inflammation in the orbital apex or cavernous sinus. The diagnosis is made by demonstrating tissue-invasive fungi on pathology. Treatment is with appropriate systemic antifungal therapy (e.g., voriconazole for Aspergillus). Unlike immunocompromised patients with invasive fungal disease or patients with rapidly progressive mucormycosis, nonimmunocompromised patients may not require extensive surgical debridement as the disease is slowly progressive, allowing time for assessment of antifungal therapy.

EAR AND MASTOID INFECTIONS Auricular Cellulitis and Perichondritis In auricular cellulitis, the ear is usually red, edematous, hot, and mildly tender. The lobule is especially swollen and red.

There may be a history of minor ear trauma from earrings, scratching, Q-tips, etc. Treatment is with warm compresses and antibiotics (e.g., nafcillin) directed against S. aureus and streptococci.

Perichondritis is an infection of the perichondrium of the ear that is often accompanied by infection of the cartilage of the pinna (chondritis). It may lead to ear deformity due to necrosis of the cartilage. Patients present with a swollen, hot, red, and exquisitely tender pinna; the lobule is usually spared.

Usual causes include significant trauma to the ear (e.g., boxing) and burns. The most common pathogens are Pseudomonas aeruginosa and S. aureus. Intravenous antibiotics active against these organisms (e.g., ticarcillin-clavulanate or nafcillin plus ciprofloxacin) should be given for at least

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4 weeks. This infection must be distinguished from relapsing polychondritis, a rheumatologic condition.

Otitis Externa The external auditory canal is about 2.5 cm long. It is lined by a thin layer of skin, which covers cartilage in the lateral half of the canal and bone in the medial half. In the bony portion, the skin lacks a subcutaneous layer and is attached directly to the periosteum. This is an important feature in the pathogenesis of invasive otitis externa (see below). Glands secrete cerumen, which acidifies the canal and suppresses bacterial growth. Desquamated skin and retained moisture make the canal especially susceptible to P. aeruginosa, a hydrophilic organism.

Acute otitis externa, or swimmer’s ear, occurs mostly in summer months and is often a result of exposure to water.

It may be due to a decrease in canal acidity and the resulting bacterial overgrowth. The ear is pruritic and often extremely painful; the canal appears swollen and red. The usual pathogens are P. aeruginosa, S. aureus, and streptococci. Treatment consists of cleaning the ear (aural toilet) and topical antibiotic drops (e.g., ofloxacin 0.3 percent otic solution).

Herpes zoster oticus (Ramsay Hunt syndrome) is due to inflammation of the facial nerve by varicella-zoster virus.

It is characterized by vesicles in the ear canal or concha, severe otalgia, loss of taste in the anterior two-thirds of the tongue, and ipsilateral facial nerve paralysis. Treatment is with an anti-herpes agent (acyclovir, valacyclovir, or famciclovir).

Invasive (“malignant”) otitis externa (MOE) is a potentially life-threatening osteomyelitis of the temporal bone and skull base. First described in 1959, it occurs primarily in elderly diabetics and is nearly always caused by P. aeruginosa.

The infection begins in the external canal, then invades the adjacent soft tissues, petrous apex of the temporal bone, and eventually the skull base. The typical patient is an older diabetic whose diabetes is in good control, who presents with unilateral hearing loss, ear pain, and drainage progressive over the previous weeks to months. The symptoms may have been misdiagnosed as chronic otitis media, a condition not characterized by otalgia. There is often a history of irrigation of the ear canal for wax removal a few days before the onset of ear pain. On examination, the ear canal is edematous, and there is granulation tissue in the inferior wall about halfway down the canal (the area overlying the bony-cartilaginous junction). Some patients also present with unilateral facial paralysis from involvement of cranial nerve VII; other cranial nerves (VI, IX, and X) may also be involved. Fever occurs in less than half of patients and the white blood cell count is usually normal. The sedimentation rate is almost always very elevated, however, typically in the 80 to 100 range. A CT and an MRI scan are essential for defining the extent of involvement. Bony involvement is best seen on CT, while soft-tissue changes are best seen on MRI. Cultures should be obtained of ear canal drainage or of superficial biopsies of canal granulation tissue; more extensive surgery is not usually indicated. Nearly all cases are due to P. aeruginosa, but cultures are important in determining antibiotic sensitivity

and in excluding rare causes of invasive otitis (e.g., S. aureus, Proteus, Aspergillus). As soon as cultures are obtained, empiric treatment directed at Pseudomonas should be started.

Usually two-drug therapy is given, such as intravenous ceftazidime plus ciprofloxacin (orally), and therapy is continued for at least 6 weeks. Aminoglycosides should be avoided due to the toxicities associated with prolonged therapy, especially in the elderly diabetics with hearing loss who typify the patient with MOE.

Acute Otitis Media The middle ear is connected to the nasopharynx by the eustachian tube. Acute otitis media (AOM, Fig. 118-2), or infection of the middle ear, is thought to result from bacterial entry into the middle ear via the eustachian tube. It is often initiated by a viral upper respiratory infection, and is most common in fall through spring. The incidence of AOM decreases with age. More than two-thirds of children under age 3 have had at least one episode of otitis media, while the incidence in adults is only 0.25 percent. The most common symptoms are ear pain and decreased hearing. Children often have fever, but this is less common in adults. The tympanic membrane is usually red, opaque, and bulging. Spontaneous perforation of the tympanic membrane may occur, resulting in otorrhea and, frequently, decreased pain.

The bacteriology has been best defined in pediatric patients with AOM. The most common pathogens in nonneonates are S. pneumoniae (25 to 50 percent), H. influenzae (15 to 30 percent), and M. catarrhalis (3 to 20 percent).

Most of the H. influenzae strains are nontypeable, but about 10 percent are type B and these cases may develop bacteremia or meningitis. Group B streptococci and enteric gram-negative bacilli are important in neonates. Viruses are recovered, sometimes along with bacteria, in 25 percent of pediatric cases. H. influenzae and S. pneumoniae are the most common isolates in adults.

Treatment of AOM is usually empiric and should be directed against S. pneumoniae, H. influenzae, and M. catarrhalis. Approximately 50 percent of H. influenzae strains and 100 percent of M. catarrhalis strains produce β-lactamase, and approximately 30 percent of S. pneumoniae are not susceptible to penicillin (15 percent are highly resistant) due to altered penicillin-binding protein. Amoxicillin should not be effective for any of these resistant organisms, yet approximately 20 percent of children with S. pneumoniae, 50 percent with H. influenzae, and 75 percent with M. catarrhalis will clear their AOM despite no or ineffective antibiotic therapy. Therefore, recent practice guidelines by the American Academy of Pediatrics recommend amoxicillin as first-line therapy for most children with AOM at doses of 80 to 90 mg/kg/day. Amoxicillin-clavulanate is recommended for children who present with severe disease, defined as fever of 39o C or higher and/or severe otalgia, or for amoxicillintreatment failures as determined at 48 to 72 hours. For most children with non–type I allergy to penicillin, cephalosporins (cefdinir, cefpodoxime, cefuroxime) are recommended, and azithromycin or clarithromycin is recommended for those

2093 Chapter 118

with type I allergy. Ceftriaxone is recommended for children with severe disease and who are either penicillin-allergic with a non-Type 1 penicillin allergy or who have failed initial antibiotic therapy with amoxicillin-clavulanate. Clindamycin is recommended in patients who have failed therapy and have a type I allergy to penicillin.

Otitis Media with Effusion Otitis media with effusion (OME), also called serous otitis, refers to the persistence of middle-ear fluid without other signs of infection. This condition may occur spontaneously as a result of eustachian tube dysfunction, or may occur as a result of AOM. Approximately 50 percent of children will have OME in the first year of life, and 90 percent before school age. Diagnosis is made by otoscopy. Many episodes resolve spontaneously, but 30 to 40 percent have recurrent OME and 5 to 10 percent have OME episodes that last at least 1 year. The American Academy of Pediatrics published practice guidelines in 2004 that state that antihistamines and decongestants are ineffective, and that antibiotics and corticosteroids have no long-term efficacy and thus are not recommended routinely for treating OME. These guidelines recommend hearing tests for children with persistent OME at 3 months; decisions regarding the need for tympanostomy tube placement may be determined by these test results. Children with OME at special risk for developmental delays (e.g., who also have blindness, autism, Down’s syndrome) should have earlier hearing, speech, and language assessments.

Infections of the Upper Respiratory Tract

Chronic Suppurative Otitis Media Chronic suppurative otitis media (CSOM) is an inflammatory disease of the middle ear and mastoid characterized by tympanic membrane perforation, hearing loss, and persistent or recurrent otorrhea. It is associated with irreversible pathological changes of the mucosa of the middle ear and mastoid. There are two major subtypes of CSOM: CSOM with cholesteatoma and CSOM without cholesteatoma.

In CSOM with cholesteatoma, there is a perforation of the tympanic membrane, usually at the margin, which leads into a sac within the middle ear lined by skin. This sac constitutes a cholesteatoma, which contains desquamated keratin and may be superinfected with bacteria. Bacterial overgrowth results in purulent drainage via the perforation. An important feature of a cholesteatoma is its ability to enlarge by erosion of surrounding bone, which can result in serious intratemporal and intracranial complications.

In CSOM without cholesteatoma, there is a chronic central perforation of the tympanic membrane. Bacterial infection of the middle ear or mastoid can occur and leads to purulent drainage through the perforation (“active” chronic otitis media). Such drainage may be constant or episodic. The latter may be incited by an upper respiratory infection or by exposure of the ear canal to water.

The classic symptoms of both types of CSOM are painless otorrhea and hearing loss. Diagnosis is made with otoscopy. The appearance of the tympanic membrane varies with the type of CSOM (Fig. 118-2). Audiological assessment

Figure 118-2 Clockwise, from top left, tympanic membranes: normal ear, resolving acute otitis media, chronic suppurative otitis media (CSOM) with cholesteatoma, CSOM without cholesteatoma. (Courtesy of Steven D. Rauch, M.D.)

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Figure 118-3 Complications of chronic otitis media. (From Harris JP, Darrow DH: Surgery of the Ear and Temporal Bone. New York, Raven Press, 1993, with permission.)

usually reveals a conductive type of hearing loss. Cultures of ears with CSOM in both adults and children often yield S. aureus, Pseudomonas and other gram-negative bacilli, and anaerobes. Most cases of CSOM with cholesteatoma require a mastoidectomy and tympanoplasty to remove the cholesteatoma and reconstruct the middle-ear sound transmission mechanism. Cases of “active” CSOM without cholesteatoma are treated with ear cleaning and topical antibiotic otic drops. Oral antibiotics are also sometimes used.

The choice of antibiotics should be guided by culture results from the purulent middle-ear drainage, but most cases are treated empirically with a topical quinolone (e.g., ofloxacin 0.3 percent otic solution). Topical quinolones have proven to be nonototoxic and effective. Topical aminoglycoside therapy, commonly used in the past, is used infrequently now due to concern for ototoxicity. Surgery may be indicated in some cases of CSOM without cholesteatoma if medical therapy fails to control otorrhea or if surgery will improve hearing.

Acute Mastoiditis The mastoid is the portion of the temporal bone posterior to the middle ear that contains a honeycomb of air cells lined by low, cuboidal epithelium. These air cells connect with the middle ear. Some degree of mastoid mucosal inflammation invariably accompanies episodes of AOM and is also present in many cases of CSOM. A CT scan of a patient with a middleear effusion or infection will often also show opacification of the mastoid air cells without destruction of the cells, and this usually represents a sterile effusion in the mastoid rather than acute mastoiditis. In contrast, acute mastoiditis is an acute bacterial infection of the mastoid. Untreated, this infection often results in breakdown of the bony partitions between the mastoid air cells and can extend beyond the mastoid compartment. Acute mastoiditis has become rare in the antibiotic era, and occurs primarily in children. It occurs with the first episode of AOM in 10 to 50 percent of children, but may also occur with an episode of recurrent AOM. Patients present with pain, tenderness, and swelling over the mas-

toid. The pinna is pushed out and forward when there is a subperiosteal abscess or cellulitis. A CT scan may demonstrate bony destruction or a mastoid abscess. Major pathogens include Pseudomonas, S. pneumoniae, group A streptococcus, and H. influenzae. S. aureus and enteric gram-negative bacilli are seen in a small percentage of cases. Treatment is with broad-spectrum intravenous antibiotics directed against these organisms; surgery is also necessary in many cases and may include myringotomy, drainage of subperiosteal abscess, and mastoidectomy.

Complications of Acute and Chronic Otitis Media Otogenic complications are more likely to occur from chronic than from acute otitis media (Fig. 118-3). Extracranial complications include sensorineural hearing loss, labyrinthitis and the resulting vertigo, facial nerve palsy, and osteomyelitis of the petrous portion of the temporal bone. In mastoiditis, infection may track under the periosteum of the temporal bone and cause a subperiosteal abscess, or may break through the mastoid tip and cause an abscess in the neck deep to the sternocleidomastoid muscle (Bezold’s abscess).

Intracranial complications include epidural abscess, thrombophlebitis of the dural veins, meningitis, and temporal lobe abscess.

SUGGESTED READING American Academy of Pediatrics: Clinical practice guideline: Otitis media with effusion. Pediatrics 113:1412–1429, 2004.

American Academy of Pediatrics: Subcommittee on Management of Acute Otitis Media: Diagnosis and management of acute otitis media. Pediatrics 113:1451–1465, 2004.

Berger G, Landau T, Berger S, et al: The rising incidence of adult acute epiglottitis and epiglottic abscess. Am J Otolaryngol 24:374–383, 2003.

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Bisno AL, Gerber MA, Gwaltney JM Jr, et al: Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Disease Society of America. Clin Infect Dis 35:113–125, 2002.

Bjornson CL, Klassen TP, Williamson J, et al: A randomized trial of a single dose of oral dexamethasone for mild croup.

N Engl J Med 351:1306–1313, 2004.

Borish L, Rosenwasser L, Steinke JW: Fungi in chronic hyperplastic eosinophilic sinusitis: Reasonable doubt. Clin Rev Allergy Immunol 30:195–204, 2006.

Donaldson D, Poleski D, Knipple E, et al: Intramuscular versus oral dexamethasone for the treatment of moderateto-severe croup: A randomized, double-blind trial. Acad Emerg Med 10:16–21, 2003.

Falsey AR, Erdman D, Anderson LJ, et al: Human metapneumovirus infections in young and elderly adults. J Infect Dis 187:785, 2003.

Friedlander SL, Busse WW: The role of rhinovirus in asthma exacerbations. J Allergy Clin Immunol 116:267–273, 2005.

George DL, Falk PS, Umberto Meduri G, et al: Nosocomial sinusitis in patients in the medical intensive care unit: A prospective epidemiological study. Clin Infect Dis 27:463– 470, 1998.

Gwaltney JM Jr: The common cold, in Mandell GL, Bennett JE, Dolin R (eds), Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 6th ed.Philadelphia, Elsevier Churchill Livingstone, 2005, p 747.

Gwaltney JM Jr, Phillips CD, Miller RD, et al: Computed tomography study of the common cold. N Engl J Med 330:25–30, 1994.

Hafidh MA, Sheahan P, Keogh I, et al: Acute epiglottitis in adults: A recent experience with 10 cases. J Laryngol Otol 120:310–313, 2006.

Hayden FG, Herrington DT, Coats TL, et al: Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: Results of 2 double-blind, randomized, placebo-controlled trials. Clin Infect Dis 36:1523–1532, 2003.

Kaufmann D, Ott P, Ruegg C: Laryngopharyngitis by Corynebacterium ulcerans. Infection 30:168–170, 2002.

Knutson D, Aring A: Viral croup. Am Fam Physician 69:535– 542, 2004.

Infections of the Upper Respiratory Tract

Linder JA, Stafford RS: Antibiotic treatment of adults with sore throat by community primary care physicians: A national survey, 1989–1999. JAMA 286:1181–1186, 2001.

Marple B, Newcomer M, Schwade N, et al: Natural history of allergic fungal rhinosinusitis: A 4- to 10-year follow-up.

Otolaryngol Head Neck Surg 127:361–366, 2002.

Nadrous HF, Ryu JH, Lewis JE, et al: Cryptococcal laryngitis: Case report and review of the literature. Ann Otol Rhinol Laryngol 113:121–123, 2004.

Nalini B, Vinayak S: Tuberculosis in ear, nose, and throat practice: Its presentation and diagnosis. Am J Otolaryngol 27:39–45, 2006.

Nishiike S, Irifune M, Doi K, et al: Laryngeal tuberculosis: A report of 15 cases. Ann Otol Rhinol Laryngol 111:916–918, 2002.

Ponikau JU, Sherris DA, Kern EB, et al: The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 74:877– 884. 1999.

Reveiz L, Cardona AF, Ospina EG: Antibiotics for acute laryngitis in adults. Cochrane Database Syst Rev CD004783, 2005.

Rutka J: Update on topical ototoxicity in chronic suppurative otitis media. Ear Nose & Throat J 81(Suppl 1):18–19, 2002.

Scolnik D, Coates AL, Stephens D, et al: Controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: A randomized controlled trial. JAMA 295:1274–1280, 2006.

Shin JE, Nam SY, Yoo SJ, et al: Changing trends in clinical manifestations of laryngeal tuberculosis. Laryngoscope 110:1950–1953, 2000.

Simons E, Schroth MK, Gern JE: Analysis of tracheal secretions for rhinovirus during natural colds. Pediatr Allergy Immunol 16:276–278, 2005.

Turner RB, Bauer R, Woelkart K, et al: An evaluation of Echinacea angustifolia in experimental rhinovirus infections.

N Engl J Med 353:341–348, 2005. van Burik JA, Hare RS, Solomon HF, et al: Posaconazole is effective as salvage therapy in zygomycosis: A retrospective summary of 91 cases. Clin Infect Dis 42:e61–e65, 2006.

Vandenbussche T, De Moor S, Bachert C, et al: Value of antral puncture in the intensive care patient with fever of unknown origin. Laryngoscope 110:1702–1706, 2000.

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119 Acute Bronchitis and Community-Acquired Pneumonia Th omas J. Marrie

I. ACUTE BRONCHITIS

III. TREATMENT

II. PNEUMONIA Definition Epidemiology Clinical Manifestations Physical Examination Radiographic Diagnosis Etiologic Diagnosis Admission Decision Diagnostic Work-up Sputum Gram Stain and Culture

IV. ADJUNCTIVE THERAPY Treatment of Pneumonia in the Nursing Home

ACUTE BRONCHITIS Acute bronchitis is an inflammation of the tracheobronchial tree, usually in association with a generalized respiratory infection. It occurs most commonly during the winter months and is associated with respiratory viruses, including rhinovirus, coronavirus, influenza viruses, and adenovirus. Mycoplasma pneumoniae, Chlamydia pneumoniae, and Bordetella pertussis may also cause bronchitis. Secondary invasion with bacteria such as Haemophilus influenzae and Streptococcus pneumoniae may also play a role in acute bronchitis.

Cough is the most prominent manifestation of acute bronchitis. Initially, the cough is nonproductive, but later mucoid sputum is produced. Still later in the course of the illness, purulent sputum is present. Many patients with acute bronchitis also have tracheitis. Symptoms of tracheal involvement include burning substernal pain associated with respiration and a very painful substernal sensation with coughing.

Rhonchi and coarse crackles may be heard on examination of the chest; however, there are no signs of consolidation and the chest radiograph shows no opacity.

V. PREVENTION VI. QUALITY OF CARE MEASURES: PNEUMONIA End-of-Life Decision Making Specific Pathogens

Most cases of acute bronchitis require measures directed only at relieving cough. For patients with fever or a predominant tracheitis component and purulent sputum, the sputum should be gram stained and cultured. If there is a predominant microorganism seen in the presence of more than 25 polymorphonuclear neutrophils and fewer than 10 squamous epithelial cells per low-power field, antibiotic therapy directed against S. pneumoniae and H. influenzae should be instituted. Most patients, however, do not require antibiotic therapy for acute bronchitis; it is a self-limited disease.

PNEUMONIA Definition Pneumonia is defined as inflammation and consolidation of lung tissue due to an infectious agent. Pneumonia that develops outside the hospital is considered communityacquired pneumonia (CAP). Pneumonia developing 72 hours or more after admission to hospital is nosocomial, or hospital

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acquired. There is still some debate as to whether nursing home–acquired pneumonia should be considered community acquired or nosocomial pneumonia. For this reason, it is perhaps best to divide pneumonia into community acquired and institution acquired. (The latter includes hospitals, nursing homes, extended care facilities, psychiatric institutions, and rehabilitation facilities.) This chapter focuses on community-acquired pneumonia.

Epidemiology Pneumonia is a common disease. The overall attack rate is about 12 cases per 1000 persons per year. In adults, the rate of admission to hospital for treatment of pneumonia is low from age 17 to 55 years, at which point it begins to increase.

The attack rates are highest at the extremes of age. Pneumonia is the sixth leading cause of death in the United States. In a study recently carried out in Seattle, investigators found that the overall rate for CAP among those aged 65 to 69 years was 18.2 cases per 1000 person years compared with 52.3 cases per 1000 person years for those who were greater than or equal to 85 years. Just over 59 percent of episodes among seniors were treated on an outpatient basis and they estimated that there were approximately 915,900 cases of CAP among seniors annually in the United States. Data from the National Hospital Discharge Survey in the United States indicate that from 1990 to 2002 there were 21.4 million hospitalizations among those 65 years of age and over and infectious diseases accounted for 48 percent of these hospitalizations. Forty-six percent of the infectious diseases hospitalizations were due to lower respiratory tract infections and 48 percent of the infectious diseases deaths were due to these infections. In another study that also used the National Hospital Discharge Survey to examine pneumonia among those 65 years of age and older over the 15-year period 1988 to 2002, the investigators noted a 20 percent increase in pneumonia as a first or any listed diagnosis. They also observed that the in-hospital mortality rate was 1.5 times higher for pneumonia as a first listed diagnosis compared with the other most common causes of hospitalization.

The epidemiology of pneumonia has changed in recent years. This is due in part to changes in the population at risk and in part to the discovery of new microbial agents that cause pneumonia and changes in antimicrobial susceptibility of old microbial agents, such as S. pneumoniae, H. influenzae, and Staphylococcus aureus. Population changes include continued increase in the number and proportion of patients who are 65 years of age or older.

There has been a steady increase in the number of organ transplant recipients in the general population and in the number of patients with HIV infection. This has created a subset of patients with community-acquired pneumonia who may be infected not only with the traditional pathogens that cause pneumonia but also with opportunistic pathogens; furthermore, these patients may have severe or atypical presentations of this infection. Newer pathogens recognized as causing pneumonia include Hantavirus, SARS Co-V, human metapneumovirus, and S. aureus isolates carrying the Panton

Valentine leucocidin genes, some strains of which are also methicillin resistant. Pneumocystis jirovecii, previously a rare cause of pneumonia in intentionally immunocompromised patients, is a common cause of pneumonia in HIV-infected patients with CD4 counts of less than 200/µl.

In a study carried out in a Swedish town in which all persons 60 years of age and older were studied, independent risk factors for community-acquired pneumonia were: alcoholism, relative risk (RR) 9; asthma, RR 4.2; immunosuppression, RR 1.9; age greater than 70 years vs. age 60 to 69 years, RR 1.5.

Risk factors for specific etiologies of pneumonia may differ from those for pneumonia as a whole. Thus, dementia, seizures, congestive heart failure, cerebrovascular disease, and chronic obstructive lung disease were risk factors for pneumococcal pneumonia in one study. In other studies, cigarette smoking and asthma have been found to be independent risk factors for invasive pneumococcal disease. Among HIVinfected patients, the rate of pneumococcal pneumonia is 41.8 times higher than those in the same age group who are not HIV infected. However, with the advent of highly active antiretroviral therapy, the incidence of pneumococcal bacteremia among HIV infected persons has dropped from 24.1 episodes per 1000 patient years to 8.2 per 1000 patient years. Up until a recent study from the Centers for Disease Control, the effect of chronic illness on the incidence of invasive pneumococcal disease in adults was underappreciated.

In this study, the overall incidence rates of invasive pneumococcal disease was 8.8/100,000 adults. For those with diabetes it was 51.4; 62.9 for adults with chronic lung disease; 93.7 for those with chronic heart disease; and 100.4 among those who abused alcohol. The rate was highest in adults with solid cancer, 300.4, and HIV/AIDS, 422.9.

Risk factors for Legionnaires’ disease include male gender, tobacco smoking, diabetes, hematologic malignancy, cancer, end stage renal disease, and HIV infection. Risk factors for severe respiratory syncytial virus infection in elderly persons include the presence of underlying chronic pulmonary disease (odds ratio [OR] 3.97), functional disability (OR 1.67), and low serum neutralizing antibody titer (OR 5.89).

The usual risk factors for aspiration pneumonia are altered level of consciousness and various neurological diseases that interfere with the swallowing mechanism. Recently, there has been an association between the use of gastric acid suppressive drugs and aspiration pneumonia. The incidence rates of pneumonia in non–acid-suppressive drug users and those who used these agents was 0.6 and 2.45 per 100 person years, respectively. The risk seemed to be highest among those using proton-pump inhibitors.

There is seasonal variation in the rate of pneumonia.

Both attack rates and mortality rates are highest in the winter months. This is likely due to many factors, including more time spent indoors (crowding) and hence more opportunity for person-to-person spread of infectious agents. In a study carried out in Tennessee, the weekly frequency of invasive pneumococcal disease correlated with the weekly frequency of isolation of respiratory syncytial virus and influenza virus.

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Antimicrobial resistance of the common bacterial pathogens is also a key component of the epidemiology of CAP. Penicillin-resistant Staphylococcal pneumoniae (PRSP) is now a fact of life in most North American communities. Many of the PRSP isolates are resistant to three or more antibiotic classes (multidrug resistance). In one study, 14 percent of bacteremic S. pneumoniae isolates were resistant to penicillin, 12 percent to ceftazidime, and 24 percent to trimethoprim-sulfamethoxazole. In a recent study, the investigators examined 1817 S. pneumoniae isolates collected from patients with community-acquired respiratory tract infections at 44 U.S. medical centers during the winter of 2002 to 2003. The overall rates of resistance were as follows: penicillin 34.2 percent; ceftriaxone 6.9 percent; erythromycin 29.5 percent; clindamycin 9.4 percent; tetracycline 16.2 percent; and trimethoprim-sulfamethoxazole 31.9 percent. There was no resistance to the following agents: vancomycin, linezolid, and telithromycin. Multidrug resistance was present in 22.2 percent of the isolates and 2.3 percent of the isolates had ciprofloxacin MICs of greater than or equal to 4 µg/ml. These investigators also made the observation that since 1994 to 1995, rates of resistance to beta lactams, macrolides, tetracyclines, and trimethoprim sulfamethoxazole have plateaued or begun to decrease. In contrast, fluroquinolone resistance is increasing. Fortunately, it is possible to predict who is likely to have pneumonia due to PRSP. Previous use of beta lactam antibiotics, alcoholism, noninvasive disease, age of less than 5 or greater than 65 years, and immunosuppression are risk factors for PRSP pneumonia.

Acute Bronchitis and Community-Acquired Pneumonia

Nonrespiratory symptoms such as headache, nausea, vomiting, abdominal pain, diarrhea, myalgia, and arthralgia are also common symptoms in patients with pneumonia. It is wise to remember that the elderly complain of fewer symptoms with pneumonia than do younger patients.

In some instances extrapulmonary signs and symptoms may dominate the clinical picture. Thus, M. pneumoniae pneumonia may be complicated by a variety of neurological manifestations including encephalitis, meningitis, and cranial nerve palsies. In addition a maculopapular skin rash is not uncommon. Occasionally, Stevens-Johnson syndrome develops. Patients with Legionella pneumonia may have glomerulonephritis or cerebellar ataxia. One should also remember that pyogenic bacteria that cause pneumonia (S. aureus, S. pneumoniae) can cause metastatic infections such as endocarditis, brain abscess, and meningitis. Indeed, all patients with pneumonia and S. aureus bacteremia should have a careful evaluation for endocarditis.

Physical Examination Fever is usually present, but some patients may be hypothermic (a poor prognostic sign), and some (20 percent) are afebrile at the time of presentation with pneumonia. Crackles are heard on auscultation over the affected area of lung, and physical findings of consolidation (dullness to percussion, increased tactile, vocal fremitus, whispering pectoriliquy, and bronchial breath sounds) are present in about 20 percent of patients with pneumonia. A pleural friction rub is heard in about 10 percent of cases.

Clinical Manifestations Symptoms that are suggestive of pneumonia include fever, chills, pleuritic chest pain, and cough. The cough may be nonproductive (dry) or productive of mucoid or purulent sputum. It may be rusty in color and frankly bloody; in patients with a lung abscess (anaerobic infection), it may have a foul odor. The latter is suggestive of anaerobic infection.

Elderly patients complain of fewer symptoms than do younger patients. Indeed, those greater than 75 years of age with pneumonia had 3.3 fewer total symptoms than did patients aged 18 through 44 years with pneumonia.

For some time it was held that typical pneumonia (due to pyogenic organisms such as pneumococcus, staphylococcus, or H. influenzae) could be distinguished from that due to Mycoplasma pneumoniae, Legionella spp., and Chlamydia pneumoniae—so-called atypical pneumonia—on the basis of a distinct clinical presentation. Atypical pneumonia is said to be characterized by a more indolent illness than that of typical pneumonia, with a cough that is nonproductive or productive of mucoid sputum only. Careful studies have shown that one cannot reliably distinguish between typical versus atypical pneumonia on clinical grounds. However, this is not to say that a careful history and physical examination are not helpful in suggesting a cause of the pneumonia.

Table 119-1 gives a partial list of clues to the cause of pneumonia that may be obtained from the history and physical examination.

Radiographic Diagnosis A clinical suspicion of pneumonia usually prompts a chest radiograph. An opacity on the chest radiograph is considered the gold standard for the diagnosis of pneumonia. However, this opacity may be due to infection, infarction, hemorrhage, edema fluid, malignancy, or inflammation caused by a variety of processes, such as vasculitis or adverse drug reactions.

Several studies have shown that radiologists cannot differentiate bacterial from nonbacterial pneumonia on the basis of the radiograph. Representative chest radiographs of patients with pneumonia are shown in Figs. 119-1 to 119-4. For patients with pneumonia treated on an ambulatory basis, there is considerable disagreement (in up to 50 percent of cases) between the radiologist’s reading of the chest radiograph regarding the presence of pneumonia compared with that of the attending physician. In about 20 percent of patients with symptoms compatible with pneumonia and a chest radiograph read as normal or no pneumonia by the radiologist, computed tomography of the chest will be compatible with pneumonia. It is noteworthy that when patients who are admitted to hospital with a clinical diagnosis of pneumonia (radiologist says no pneumonia) are compared with those with radiologist-confirmed pneumonia, there is no difference in mortality between the two groups. While the percentage of patients with positive blood cultures does not differ between the groups, the microorganisms isolated do; about

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Table 119-1 Clues to the Etiology of Pneumonia from the History and Physical Exam Feature

Organism

Environmental Exposure to contaminated air-conditioning cooling towers, recent travel associated with a stay in a hotel, exposure to a grocery store mist machine, visit or recent stay in a hospital with contaminated (by L. pneumophila) potable water Pneumonia after windstorm in an endemic area Outbreak of pneumonia in shelters for homeless men, jails, military training camps Exposure to contaminated bat caves, excavation in endemic areas

Coccidioides immitis Streptococcus pneumoniae; Mycobacterium tuberculosis Histoplasma capsulatum

Animal contact Exposure to infected parturient cats, dog, cattle, sheep, or goats Exposure to turkeys, chickens, ducks, or psittacine birds

Coxiella burnetii C. psittaci

Travel history Travel to Thailand or other countries in Southeast Asia Pneumonia in immigrants from Asia, India, Africa

Burkholderia (Pseudomonas) pseudomallei (melioidosis) M. tuberculosis

Occupational history Pneumonia in a health care worker who works in a large city hospital with patients infected with HIV Host factors Diabetic ketoacidosis Alcoholism

Chronic obstructive lung disease

Solid organ transplant recipient (pneumonia occurring >3 months after transplant)

Sickle cell disease HIV infection with CD4 cell count <200/Âľl

Legionella pneumophila

M. tuberculosis

S. pneumoniae Staphylococcus aureus S. pneumoniae Klebsiella pneumoniae S. aureus S. pneumoniae Haemophilus influenzae Moraxella catarrhalis Pseudomonas aeruginosa (in the subset of patients with advanced COPD) S. pneumoniae H. influenzae Legionella spp.

Pneumocystis jiroveci Cytomegalovirus Strongyloides stercoralis S. pneumoniae P. jiroveci S. pneumoniae H. influenzae Cryptococcus neoformans M. tuberculosis Rhodococcus equi

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Table 119-1 (Continued) Physical findings Periodontal disease and foul-smelling sputum Bullous myringitis Absent gag reflex, altered level of consciousness, or a recent seizure Encephalitis

Cerebellar ataxia Erythema multiforme Erythema nodosum Ecthyma gangrenosum Cutaneous nodules (abscesses) and CNS findings

Anaerobes, may be mixed aerobic-anaerobic infection Mycoplasma pneumoniae Polymicrobial (oral aerobic and anaerobic bacteria) can be macro- or microaspiration M. pneumoniae C. burnetii L. pneumophila M. pneumoniae L. pneumophila M. pneumoniae C. pneumoniae M. tuberculosis P. aeruginosa Serratia marcescens Nocardia spp.

Source: From Marrie TJ. Commonly required Pneumonia. Clin Infect Dis 18:501â&#x20AC;&#x201C;515. 1994.

Figure 119-1 Right lower lobe pneumonia due to Coxiella burnetfi (Q fever). This young woman developed pneumonia after exposure to the products of conception of her infected pet cat.

60 percent of the isolates for those with definite pneumonia are S. pneumoniae compared with 31 percent for those with clinical pneumonia.

this is the organism causing the pneumonia, and not just a microorganism that had colonized the upper airway through which the sputum passed on its way to the specimen jar. For this reason, it is useful to categorize the etiology of pneumonia as definite or probable (Table 119-2).

The etiology of community-acquired pneumonia (CAP) as determined in prospective studies is given in Tables 119-3, 119-4, and 119-5. Table 119-4 shows data for patients with severe pneumonia requiring admission to intensive care units. Table 119-5 gives the etiologic data for bacterial pneumonia in patients with HIV infection. Early in the course of the HIV epidemic, P. jiroveci accounted for most cases of pneumonia. Now, with widespread use of prophylaxis to prevent Pneumocystis pneumonia, bacterial pneumonia is more common in HIV disease than previously seen (see Chapters 129 and 139). Indeed, the rates of pneumococcal pneumonia and H. influenzae pneumonia are 20 times higher among HIV-infected persons than in those of an ageand sex-matched population without HIV infection. In any young person with pneumococcal bacteremia, consider underlying HIV infection. However, one should not forget about P. jiroveci pneumonia, since many persons do not know they have HIV and this form of pneumonia is the presenting manifestation of HIV disease in these individuals. Likewise, one should never forget Mycobacterium tuberculosis as a cause of pneumonia, especially in the elderly.

Etiologic Diagnosis Pneumonia represents a difficult challenge for the clinician, since the etiology cannot be determined from the clinical presentation and data from microbiologic studies are not available for at least 48 hours. Even then, in the case of microorganisms isolated from the sputum, one cannot be sure that

Admission Decision Once a diagnosis of pneumonia has been made, the next decision is whether or not to admit the patient to the hospital.

Now, more than ever, there is considerable pressure to treat as many patients as possible at home. In order to do this, it is

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Figure 119-2 Serial chest radiographs of a 32-year-old nurse with Chlamydia psittaci pneumonia. She was severely ill with fever, chills, and headaches. She had severe fatigue for 8 months after this episode of pneumonia.

important to know the factors that are predictive of complicated course in pneumonia, some of which are given in Table 119-6. Several clinical rules that predict mortality have been developed that are often used to guide the admission decision. Two of these are the pneumonia severity index, often known as the PORT (patient outcomes research team) score (Tables 116–7 and 116–8) and the CURB-65 (confusion; urea; respiratory rate; blood pressure; age ≥65 years) rule (Table 116–9). The former, developed by Michael Fine and colleagues, assigns points to each of 20 different items

that had been shown to be associated with mortality (see Table 119-7). This system allows categorization of patients with pneumonia into five strata, with increasing risk for mortality from risk class I to V. Mortality is less than 1 percent for patients in risk classes I to III, but increases to 9 percent in class IV and to 27 percent in class V (see Table 119-8). Patients in risk classes I and II can usually be treated at home; those in risk class III may require a period of observation in the emergency room before a decision is made about the optimal site of treatment. Patients with pneumonia generally prefer to be

Figure 119-3 Chest radiographs showing rapidly progressive diffuse pulmonary opacities in a 22-year-old man with bacteremic Streptococcus pneumoniae pneumonia. This patient had had his spleen removed 6 years earlier. He rapidly developed septic shock and died about 8 hours after admission.

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Figure 119-4 Serial chest radiographs of a 40-year-old man with pneumonia due to Legionella pneumophila serogroup 6.

treated at home if it can be done safely. As more experience has been gained with this predicition rule, not unexpectedly we have learned that the rule is only a guide. It does not factor social circumstances into the score and since the score is heavily age dependent, many young patients fall into the first three classes when it is readily apparent that they should be admitted.

In the CURB-65 rule the score can range from 0 (none of the elements present) to 5 (all of them present). For a score

of 0 the mortality rate is 0.7 percent; 1 to 3.2 percent; 2 to 3 percent; 3 to 17 percent; 4 to 41.5 percent, and 5 to 57 percent (see Table 119-9).

However, the most important element in the admission decision is the physicianâ&#x20AC;&#x2122;s judgment. Prediction rules are no substitute for this. Functional status of your patient in the week prior to admission is also a powerful predictor of mortality. In one study, for those who were fully functional, the in-hospital mortality rate was 3.9 percent; for those

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Table 119-2 Guidelines for Determining the Degree of Certainty of the Etiology of CAP Definite Blood cultures positive for a pathogen Pleural fluid positive for a pathogen Presence of Pneumocystis jiroveci in induced sputum or in bronchoalveolar lavage luid A fourfold or greater rise in antibody titer to Mycoplasma pneumoniae, Chlamydia pneumoniae, Coxiella burnetii, or other pathogens for which serological testing is available.

Isolation of Legionella pneumophila or a fourfold rise in antibody titer or positive urinary antigen test for Legionella Positive direct fluorescence antibody test for Legionella plus an antibody titer of ≥1:256 for Legionella Serum or urine positive for Streptococcus pneumoniae antigen Isolation of Mycobacterium tuberculosis from sputum Amplification of nucleic acid of Legionella species from a nasopharyngeal swab specimen Probable Heavy or moderate growth of a predominant bacterial pathogen on sputum culture and a compatible Gram’s stain Light growth of a pathogen in which sputum Gram’s stain reveals a bacterium compatible with the culture results Amplification of nucleic acid of Mycoplasma pneumoniae; C. pneumoniae; influenza viruses A and B; parainfluenzae viruses 1,2,3; adenovirus, respiratory syncytial virus; human metapneumovirus from a nasopharyngeal swab specimen.

Aspiration pneumonia as diagnosed on clinical grounds.

Source: Modified from Fang GD, Fine M, Odoff J, et al: New and emerging etiologies for community-acquired pneumonia with implications for therapy: A prospective multicenter study of 359 cases. Medicine 69:307–316, 1990.

walking with assistance, it was 5.6 percent; for those who used a wheelchair, it was 20 percent; and for those who were bedridden, it was 25 percent.

Diagnostic Work-up Patients who are well enough to be treated as outpatients need minimal diagnostic work-up. This should include a chest radiograph, complete white blood count, electrolytes, creatinine, and oxygen saturation by pulse oximetry. It is worth noting that there is controversy as to whether or not all patients who present in an office setting and are suspected of having pneumonia should have the described work-up. How-

ever, there is no doubt that those who present to a hospital emergency department and are suspected of having pneumonia should at the very least have the work-up outlined in the preceding. In addition, all individuals who have pleuritic chest pain and symptoms and signs suggestive of pneumonia should have a chest radiograph, and pulmonary thromboembolic disease should be considered. Pulmonary infarction can mimic pneumonia on occasion. Despite the opinion of some experts, a sputum specimen should be submitted for culture whenever possible. Blood cultures should be done on all ambulatory patients with fever (oral temperature greater than or equal to 38◦ C) and suspicion of pneumonia.

In patients who are ill enough to be admitted to the hospital, two sets of blood cultures should be performed.

About 10 percent of patients with pneumonia have positive blood cultures. Streptococcus pneumoniae is the most common cause of bacteremic pneumonia, accounting for 60 percent of all cases. Despite the controversy about the utility of sputum gram’s stain and culture, this is still a useful test. Take the time to obtain the specimen yourself. One of the chief reasons why this test has fallen into disrepute is that collecting the specimen is a task assigned to other members of a busy health care team. A sample collected hours after antimicrobial therapy has been initiated is useless.

All patients who present to the hospital with pneumonia should have their oxygenation status assessed. This can by done by pulse oximetry, and a blood gas analysis should be obtained if the oxygen saturation is less than or equal to 90 percent. Patients with chronic obstructive lung disease should have blood gases done because hypercarbia can not be detected by pulse oximetry.

Sputum Gram Stain and Culture A sputum specimen should be cultured only if a smear of a representative portion shows more than 25 polymorphonuclear neutrophils and fewer than 10 squamous epithelial cells per low-power field. The gram stain on such a specimen is useful. If only one morphologic type of bacteria is seen in such a specimen, it is likely that this microorganism is causing the pneumonia. Indeed, in one study, when more than 10 gram-positive lancet-shaped diplococci were seen, the sputum was considered positive for pneumococci. This criterion was met in 62 percent of specimens that were culture positive for S. pneumoniae. The value of sputum culture in the diagnosis, management, and outcome of CAP remains a matter of controversy. The Infectious Diseases Society of America pneumonia guidelines recommend gram staining and culture of expectorated sputum for inpatients with CAP. The reasons for this recommendation are to permit optimal antibiotic selection directed to causative agent; limit injudicious antibiotic use in terms of cost, inducible resistance, and adverse drug reactions; allow for a rational basis for change from parenteral to oral therapy and any change in therapy necessitated by an adverse drug reaction; identify drug-resistant pathogens and monitor trends such as penicillin-resistant Streptococcus pneumoniae, beta lactamase–producing Haemophilus influenzae, or methicillin-resistant Staphylococcus aureus; and

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Table 119-3 Etiology of Community-Acquired Pneumonia Requiring Hospitalization: North America Reference

(Fang et al)

(Marrie et al)

(Bates et al)

No. of patients studied

359

719

151 (154 episodes)

No. (%) patients with sputum cultured

336 (94)

257 (36)

None∗

Location

Pittsburgh, PA

Halifax, NS

Little Rock, Ark

Time period of study

Jul 1/86–Jun 30/87

Nov 1/81–Mar 18/87

1985

118 (32.9) 10 (2.8)

340 (47) 74 (10.3)

75 (48.7) 10 (6.4)

39 (10.9) 12 (3.3) 7 (2) Not tested 12 (3.3) 39 (10.9) Not tested Not tested 9 (2.5) 24 (6.7) 4 (1.1) 22 (6.1) 19 (5.3) 0 0 0 Not tested 10 (2.8) 0 21 (5.9)

61 (8.5) 52 (7.2) 40 (5.6) 40 (5.6) 29 (4.0) 27 (3.7) 22 (3.1) 17 (2.4) 14 (1.9) 16 (2.2) 10 (1.4) 18/301 (6)† 13 (1.8) 0 0 0 Not tested 19 (2.6) 4 (0.6) 22 (3.1)

9 (5.8) Not stated 5 (3.2) 7 (4.5) 9 (5.8) 2 (1.3) 0 0 0 14 (9) 3 (1.9) 12 (7.8) Excluded 4 (2.6) 1 (0.6) 1 (0.6) 5 (3.2) 4 (2.6) 2 (1.3) 8 (5.2)

No. (%) with pneumonia of: Unknown cause More than one cause (polymicrobial) Streptococcus pneumoniae Aspiration Mycoplasma pneumoniae Influenza A virus Staphylococcus aureus Haemophilus influenzae Coxiella burnetii Influenza B virus Pneumocystis jiroveci Legionella spp.

Mycobacterium tuberculosis Chlamydophila pneumoniae Postobstructive S. epidermidis Aspergillus spp.

Nocardia spp.

Francisella tularensis Streptococcus spp.

Anaerobic bacteria Other aerobic gram-negative bacteria ∗ This

study did not use information from sputum cultures in determining cause. Some patients had a variety of invasive diagnostic procedures.

301 patients had serum samples tested for antibodies to Chlamydophila pneumoniae.

Sources: From Fang GD, Fine M, Orloff J, et al: New and emerging etiologies for community-acquired pneumonia with implications for therapy: A prospective multicenter study of 359 cases, Medicine 69:307–316, 1990; Marrie TJ, Durant H, Yates L: Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis 11:586–599, 1989; Bates JH, Campbell GD, Barren AL, et al: Microbial etiology of acute pneumonia in hospitalized patients.

Chest 101:1005–1112, 1992. † Only

prompt tracing of the contacts of those with Neisseria meningitidis pneumonia. On the other hand, the American Thoracic Society pneumonia guidelines recommend sputum culture only if a drug-resistant pathogen, or an organism not covered by usual empiric therapy, is suspected.

In patients with HIV infection, sputum production may be induced by inhalation of hypertonic saline, which irritates the tracheobronchial tree and produces bronchorrhea.

This results in a specimen that is useful for examination for P. jiroveci, thereby obviating the need for bronchoscopy.

Patients who are ill enough to require admission to an intensive care unit for the treatment of their pneumonia should have an aggressive diagnostic work-up. This will usu-

ally include at least a bronchoscopy, with use of a protected brush to sample respiratory secretions and brochoalveolar lavage. If this is carried out before the initiation of antibiotic therapy, the diagnostic yield is up to 80 percent. When this procedure is performed after 72 hours or more of antibiotic therapy, however, the microbiologic yield is much lower, 18 percent.

Transthoracic needle aspiration can be used when the basal segment(s) of the lungs is (are) consolidated. A 20-gauge 3.5-inch needle is used to inject 2 to 3 ml of nonbacteriostatic saline into the lung. This is then aspirated and placed into a blood culture bottle. The diagnostic yield from this procedure ranges from 33 to 85 percent. This procedure is

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Table 119-4

Table 119-5

Etiology of CAP in Patients Requiring Admission to an ICU

Etiology of Bacterial CAP in Patients with HIV Infection

Reference

(BTJ; PHLS)

(Torres et al)

(Pachon et al)

(Ortqvist et al)

No. studied

60

92

67

53

Mean age (yr)

54

53

56.8

No. (%) died

29 (48)

18 (20)

14 (21)

Reference

(Burack et al)

Location of study

San Francisco, CA

52

Period of study

May 1990–April 1991

13 (25)

No. of pneumonia episodes

216

Cause of pneumonia (no., %) Haemophilus influenzae Streptococcus pneumoniae Moraxella catarrhalis Other streptococcus Cause unknown Mixed infections Haemophilus spp.

Klebsiella pneumoniae Staphylococcus aureus Pseudomonas aeruginosa Serratia marcescens Neisseria meningitidis

4 (1.9) 66 (30.6) 1 (0.5) 15 (6.9) 54 (25) 13 (6) 42 (19.4) 4 (1.9) 10 (4.6) 5 (2.3) 1 (0.5) 1 (0.5)

No. (%) with pneumonia due to (six most common causes listed): Unknown 25 (42) 44 (48) 45 (67) 25 (47) Streptococcus pneumoniae 11 (18) 13 (14) 12 (17) 15 (28) Haemophilus influenzae 7 (12) Legionella pneumophila 7 (12) 13 (14) 7 (10) Mycoplasma pneumoniae 4 (7) 6 (7) 3 (5) Influenza virus 3 (5) 2 (4) Staphylococcus aureus 2 (3) 1 2 (4) Streptococcus spp.

3 (3) Chlamydophila psittaci 2 (4) Other aerobic gram negative bacilli 2 (3) 5 (5) 8 (12) Sources: From British Thoracic Society Research Committee and the Public Health Laboratory Service: The aetiology, management, and outcome of severe community-acquired pneumonia on the intensive care unit. Respir Med 86:7–13, 1992; Torres A, Serra-Battles J, Ferrer A, et al: Severe community-acquired pneumonia: Epidemiology and prognostic factors. Am Rev Respir Dis 144:312–318; 1991; Pachon J, Prados MD, Capote F, et al: Severe community-acquired pneumonia: Etiology, prognosis and treatment. Am Rev Respir Dis 142:369–373, 1990; Ortqvist A, Sterner G, Nilsson JA: Severe community-acquired pneumonia: Factors influencing need of intensive care treatment and prognosis. Scand J Infect Dis 17:377–386, 1985.

contraindicated in those who are receiving mechanical ventilation. Occasionally, patients with CAP require an open lung biopsy. However, this is usually a last resort in a patient whose condition continues to deteriorate and there is no etiologic diagnosis despite the usual work-up, including bronchoscopy.

An acute-phase serum sample should be obtained from all patients who are admitted to hospital with CAP. If the patient responds promptly to antibiotic therapy, there is no need to obtain a convalescent sample. If the patient responds poorly to therapy, however, a convalescent sample should be obtained 3 to 6 weeks after the acute-phase sample. The diagnostic battery ordered depends on local epidemiologic conditions. In general, M. pneumoniae, C. pneumoniae, Coxiella burnetti, Legionella pneumophila, adenovirus, influenza A and B viruses, parainfluenza viruses 1, 2, and 3, and respiratory syncytial virus antibodies can be measured in most laboratories. Antibody titers to S. pneumoniae pneumolysin and detection of immune complexes to this antigen may be a tool for diagnosis of pneumococcal pneumonia in those who do not have sputum available for culture.

L. pneumophila serogroup 1 infection can be reliably diagnosed from detection of antigen in urine with a radioim-

Sources: From Burack JH, Hahn JA, Saint-Maurice D, et al: Microbiology of community-acquired bacterial pneumonia in persons with and at risk for human immunodeficiency virus type 1 infection: Implications for rationale empiric antibiotic therapy. Arch Intern Med 154:2589–2596, 1994.

munoassay or an enzyme-linked immunosorbent assay. In the absence of an outbreak, Legionella spp. accounts for about 2 percent of cases of CAP. Thus, the dilemma is when to order this test. To some extent this depends on local epidemiology (in some hospitals the test is ordered for all patients sick enough to be admitted for treatment of CAP), but in general for patients with severe pneumonia this test probably should be done.

There is also a urinary antigen test for pneumococcal pneumonia. This test detects C polysaccharide, which is present in all serotypes of S. pneumoniae. It is reasonably sensitive and specific when bacteremic pneumococcal pneumonia is used as the gold standard. The question is, what is its usefulness in patients with negative blood cultures? There are false-positives in children with nasopharyngeal colonization with S. pneumoniae.

Multiplex polymerase chain reaction (PCR) is a tool that may be useful in the etiological diagnosis of CAP. Currently, from one specimen such as a nasopharyngeal swab or sputum, the following agents can be detected by multiplex PCR: M. pneumoniae; C. pneumoniae; Legionella spp.; influenza viruses A and B; parainfluenza 1,2,3 viruses; adenovirus; respiratory syncytial virus; human metapneumovirus; coronaviruses; and rhinoviruses. Using this technology, we have learned that viral pneumonia is more common in adults

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Table 119-6

Table 119-7

Risk Factors for a Complicated Course or Mortality in Patients with CAP

Community-Acquired Pneumonia Severity-of-Illness Scoring System: Assignment of Points∗

Age >65 years Comorbid illnesses that are likely to be made worse by the pneumonia, especially chronic renal failure, ischemic heart disease, congestive heart failure, severe COPD, concurrent malignancy Postsplenectomy state Altered mental status Alcoholism Immunosuppressive therapy Respiratory rate >30 breaths per minute Diastolic blood pressure <60 mmHg; systolic blood pressure <90 mmHg

Patient Characteristics Demographic factors Age Men Women Nursing home resident

Number of Points

Age in years Age in years minus 10 Age plus 10

Coexisting illnesses (definitions listed below) Neoplastic disease† 30 Liver disease‡ 20 Congestive heart failure§ 10 Cerebrovascular disease# 10 Renal disease¶ 10

Hypothermia Creatinine >150 mM/L or BUN >7 mM/L Leukopenia <3000/µl or leucocytosis >30,000/µl PO2 < 60 mmHg or PO2 >48 mmHg while breathing room air Albumin <30 g/l Hemoglobin <9 g/l Pseudomonas aeruginosa or Staphylococcus aureus as the cause of the pneumonia Bacteremic pneumonia Multilobe involvement on chest radiograph Rapid radiographic progression of the pneumonia defined as increase in the size of the pulmonary opacity of ≥50% within 36 h

Physical examination findings Altered mental status∗∗ Respiratory rate >30/min Systolic blood pressure <90 mHg Temperature <35◦ C (95◦ F) or >40◦ C (104◦ F) Pulse rate >125/min Laboratory and roentgenographic findings Arterial pH <7.35 Blood urea nitrogen >30 mg/dL (11 mmol/L) Sodium <130 mmol/L Glucose >250 mg/dL (14 mmol/L) Hematocrit <30% Partial pressure of arterial oxygen <60 mmHg Pleural effusion ∗ Based

than was previously recognized. However, more study is necessary before we know the role of multiplex PCR in our diagnostic armamentarium.

Other Tests C-reactive protein, serum procalcitonin, and neopterin have been used in an attempt to distinguish viral from bacterial infection. An ultrasensitive assay for procalcitonin looks promising in that at a level of less than or equal to 0.25 µg/L, antibiotic therapy has been successfully discontinued in

20 20 20 15 10

30 20 20 10 10 10 10

on Pneumonia Patient Outcomes Research Team (PORT) cohort study data. † Any cancer (except basal or squamous cell carcinoma of the skin) active at presentation or within 1 year of presentation for CAP. ‡ Clinical or histologic cirrhosis or chronic active hepatitis. § Diagnosis documented by history or by findings on physical examination, chest film, echocardiogram, multiple gated acquisition scan, or left ventriculogram. # Clinical diagnosis of stroke or transient ischemic attack, or stroke documented by MRI or CT. ¶ History of chronic renal disease or abnormal blood urea nitrogen and creatinine concentrations documented in this medical record. ∗∗ Disorientation as to person, place, or time that is not known to be chronic; stupor or coma.

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patients with pneumonia. The inference is that patients with this level of procalcitonin have viral pneumonia.

Table 119-8 30-Day Mortality Rate for Patients with Community-Acquired Pneumonia According to Risk Class in the Pneumonia Severity of Illness Scoring System Outpatients

Inpatients

Criteria

Mortality

Mortality

I

Age <50 years No existing illnesses or vital sign abnormalities

0

0.5%

II

<70 points

0.4%

0.9%

III

71–90 points

0

1.25%

IV

91–130 points

12.5%

9.0%

V

>131 points

NA

27.1%

Mean mortality rate

0.6%

8.0%

Risk class

Table 119-9 CURB-65 Rule Severity of Illness Scoring System for Community-Acquired Pneumonia Confusion : new mental confusion Urea >7 mM/L Respiratory rate >30 breaths per minute Blood pressure: Diastolic BP <60 mmHg or systolic blood pressure <90 mmHg Age ≥65 years of age Group 1: 0 or 1 of the above—mortality low—1.5%. Likely suitable for treatment at home.

Group 2: 2 of the above—mortality—9.2%. Hospitalization for treatment.

Group 3: 3 or more of the above—mortality—22%. Likely requires admission to ICU. Source: From Lim WS, van der Eerden MM, Laing R, et al: Defining community-acquired pneumonia severity on presentation to hospital: An international derivation and validation study. Thorax 58:377–382, 2003.

TREATMENT The initial therapeutic approach to pneumonia is empirical.

Categorize the severity of the pneumonia as mild, moderate, or severe. It is then usually self-evident where the patient should be treated; at home, in the hospital, or in an intensive care unit. Table 119-10 outlines the guidelines for initial antimicrobial therapy for community-acquired pneumonia as proposed by the American Thoracic Society and the Infectious Diseases Society of America. A key concept in selecting empiric antibiotic therapy is to inquire about antibiotic therapy in the past 3 months and then select an agent that has not been used in that time period. If a macrolide has been used in this time period, then 35 percent of S. pneumoniae isolates are resistant to a macrolide compared with 7 percent if the patient did not have macrolide therapy in this time period. For penicillin or a cephalosporin, resistance increases from 5 to 9 percent in this setting. Thus, use a different class of antibiotic than the one the patient received in the past 3 months.

Since in everyday practice an etiologic diagnosis is frequently not made, antibiotic therapy has to be empirical.

Osterheet et al. attempted to answer the question of whether combination therapy or monotherapy with a fluroquinolone (as recommended by the North American guidelines) is better than other therapy for the empiric treatment of CAP. They carried out a Medline search of studies published from January 1997 to April 2003. Only eight of the 135 articles fit their criteria for further analysis. In six of the eight studies, a significant reduction in all-cause mortality was found for patients treated with a combination of a beta lactam plus a macrolide or with monotherapy with a fluroquinolone. Three of these studies involved only patients with bacteremic pneumococcal pneumonia and in one study an effect was noted in one study year, 1993, but not in 1995 or 1997. Seven of the studies were retrospective and two involved administrative data bases. Clearly, a properly designed and conducted randomized clinical trial is necessary to answer this, the most fundamental question in the treatment of CAP. Data from several retrospective studies suggest that combination therapy of bacteremic pneumococcal pneumonia with a macrolide and a beta lactam is better than singleagent therapy. Unfortunately, we do not have randomized control data to advise us. Recent data indicate that intravenous cefuroxime should not be used to treat bacteremic pneumococcal pneumonia, because the failure rate is higher than with other regimens.

In one study, treatment of patients hospitalized with CAP with moxifloxacin was associated with faster resolution of symptoms compared with patients who were treated with ceftriaxone plus erythromycin.

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Table 119-10 Initial Empiric Antimicrobial Therapy for CAP Outpatient Previously healthy No recent antibiotic therapy: a macrolide, doxycycline telithromycin now known to cause hepatic necrosis.

Recent antibiotic therapy (within past 3 months). In general choose from a class of agents that the patient has not received within the past 3 months: a respiratory fluoroquinolone alone, an advanced macrolide (clarithromycin or azithromycin) plus high-dose amoxicillin, an advanced macrolide plus amoxicillin-clavulanate.

Co-morbidities such as congestive heart failure, chronic obstructive pulmonary disease, diabetes, or malignancy No recent antibiotic therapy: an advanced macrolide or respiratory fluoroquinolone Recent antibiotic therapy: Choose from a class of agents that the patient has not received within the past 3 months.

Suspected aspiration with infection: amoxicillin-calvulanate or clindamycin Influenza with bacterial superinfection: a vancomycin or linezolid or respiratory fluoroquinolone Inpatient Ward No recent antibiotic therapy: a respiratory fluoroquinolone, or an advanced macrolide plus beta lactam, cefotaxime, ceftriaxone ampicillin ertapenem for selected patients.

Recent antibiotic therapy: An advanced macrolide plus a beta lactam, or respiratory fluoroquinolone alone. (The regimen selected depends on the nature of the recent antibiotic therapy. Choose from a class of agents that the patient has not received within the past 3 months.

ICU Pseudomonas infection is not an issue: a beta lactam plus an advanced macrolide or respiratory fluoroquinolone Pseudomonas infection is not an issue but patient has a beta lactam allergy: a respiratory fluoroquinolone with or without clindamycin Pseudomonas infection is an issue: an antipseudomonal agent plus ciprofloxacin or antispseudomonal agent plus aminoglycoside plus respiratory fluoroquinolone or macrolide Pseudomonas infection is an issue and patient has a beta lactam allergy: aztreonam plus levofloxacin or aztreonam plus moxifloxacin or gatifloxacin with or without aminoglycoside Nursing home Treatment in the nursing home: a respiratory fluoroquinolone or advanced macrolide plus amoxicillin-clavulanate Hospitalized: same as ward or intensive care unit Source: From Mandell LA, Bartlett JG, Dowell SF, et al: Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 37:1405–1433, 2003; Mandell LA, Marrie TJ, Grossman RF, et al: Canadian guidelines for the initial management of community acquired pneumonia: An evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 31:383–421, 2000; Niederman MS, Mandell LA, Anzueto A, et al: American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 163:1730–1754, 2001; Mandell LA, Wunderink RG, Aazueto A, et al. Infectious Diseases Society of America/American Thoracic Society Guidelines in the management of community-acquired pneumonia. Clin Infect Dis 44:527–572, 2007.

Once an etiologic diagnosis has been made, treatment should be changed to the cheapest, narrowest-spectrum agent effective against that microorganism. For example, if penicillin susceptible S. pneumoniae is determined to be the cause of the pneumonia, penicillin therapy is still the most appropriate treatment.

The response of patients to treatment depends on the severity of the pneumonia and the presence of co-morbidities that may be made worse by the pneumonia. Outpatients with mild to moderate pneumonia do very well. Mortality is rare (less than 1 percent), and only about 4 percent of patients fail therapy and require hospitalization. The issue of the most appropriate treatment for patients with pneumonia due to PRSP is unclear. We do know that pneumonia due to this

microorganism can be treated successfully with high-dose intravenous penicillin. We also know that treatment with penicillin is not successful if there is concomitant pneumococcal meningitis. In this setting, vancomycin and ceftriaxone are recommended. If beta lactam antibiotics are used, the concentration of the antibiotic must exceed the MIC of S. pneumoniae 40 percent of the time for cure of pneumococcal pneumonia. In one study, high-dose amoxicillin was the most effective oral beta lactam antibiotic for the treatment of PRSP. Macrolide-resistant S. pneumoniae is also an issue in many communities. Because most cases of ambulatory pneumoniae are of unknown etiology and since there is less than 1 percent mortality among patients with pneumonia treated on an ambulatory basis, a worse outcome for

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macrolide treated patients vs. other antibiotics may not be detected unless large RCTs are performed. Currently, about 2 percent of penicillin-susceptible S. pneumoniae isolates are resistant to macrolides, 12 percent of isolates intermediately resistant to penicillin are resistant to macrolides, while 25 percent of isolates that are highly resistant to macrolides are resistant to penicillin. Macrolide susceptibility of S. pneumoniae is defined as an MIC of up to 0.5 mg/L. The mean MICs for strains resistant because of an efflux mechanism is 10 mg/L; this accounts for 55 percent of the macrolide resistance in S. pneumoniae. Modification of the target (ribosomal) site accounts for 45 percent of the resistance and results in MICs of 64 mg/L. Thus, strains with resistance due to efflux mechanism may very well respond to treatment with a macrolide, whereas those due to target alteration will not.

Resistance due to the efflux mechanism is more common in North America, while the reverse is true in Europe, i.e., most resistance is due to target alteration. Telithromycin, a new oral antibiotic, may be valuable for the ambulatory treatment of CAP in communities in which macrolide resistance is high.

Telithromycin, a semisynthetic derivative of erythromycin, is the first of a new class of antibiotics, the ketolides. The α Lcladinose at position three is replaced by a keto group that prevents telithromycin from inducing MLS B resistance and results in improved activity against certain macrolide resistant bacteria. It is noteworthy that constitutively resistant S. pneumoniae is highly susceptible to telithromycin, but S. pyogenes and S. aureus expressing constitutive MLS B resistance are also resistant to telithromycin. Telithromycin is not affected by macrolide efflux mechanisms in bacterial cells. The dose is 800 mg OD for 5 to 10 days. Diarrhea, nausea, and vomiting are the major side effects followed by headache and dizziness. It has also been associated with elevations in hepatic transaminases and prolongation of the QT interval. It is a strong inhibitor of cytochrome P450 3A4 isoenzyme. Therefore, it is important to monitor for potential drug interactions with medications that prolong the QT interval or are metabolized by the CYP system. There is no need for adjustment in dosage for renal or hepatic failure.

The overall mortality for those admitted to hospital for treatment of pneumonia is 8 to 10 percent. In patients with nursing home–acquired pneumonia, it may approach 40 percent. For many of these patients, pneumonia is the final common pathway for a variety of chronic debilitating illnesses.

A recent concept in therapy of pneumonia requiring hospitalization is early switch to oral antibiotics. Patients who are stable by hospital day 3 (as evidenced by temperature of 37.5◦ C or less for 16 hours, white blood cell count returning toward normal, normal hemodynamics, no requirement for auxiliary oxygen, no complications of pneumonia such as empyema, and ability to take antibiotics by mouth) can be switched to antibiotics and discharged shortly thereafter.

About one-third of patients qualify for this therapy. Prompt administration of antimicrobial therapy following a diagnosis of pneumonia intuitively makes sense. One study showed a lower mortality rate for elderly patients who received the first dose of antibiotics within 8 hours of presentation to an emer-

gency department. In another large administrative data base study of over 18,000 patients among the 24.4 percent who were receiving antibiotics prior to presentation, antibiotic therapy within 4 hours of presentation was associated with a reduction in length of stay but not in mortality. Among the 75.6 percent of patients who were not receiving antibiotics prior to admission, there was both a reduction in LOS and mortality for those who received their first dose of antibiotic within 4 hours of presentation.

In a study of 399 patients with CAP treated on an ambulatory basis, symptoms had resolved within 14 days in 67 percent. The mean time to return to work in this population was 6 days compared with a median of 22 days for those who required hospitalization.

Some patients see their condition fail to improve or indeed worsen during therapy. Table 119-11 gives the factors that should be considered in this setting. One should not forget methicillin-resistant S. aureus (MRSA) as a cause of failure of initial treatment in patients with CAP. Also, in those who are admitted from nursing homes, consider extended spectrum beta lactamase (ESBL) producing enterobacteriaceae. Radiographic evidence of resolution of pneumonia lags behind clinical resolution and correlates with age and the presence of chronic obstructive pulmonary disease (COPD). In general, those who are under 50 years of age and have no COPD show radiographic resolution of pneumonia within 4 weeks. In contrast, resolution requires 12 or more weeks for those with pneumonia who are older than 50 years and have coexistent COPD or alcoholism. In about 2 percent of patients, pneumonia is the presenting manifestation of carcinoma of the lung (postobstructive pneumonia). It is important to demonstrate that the pneumonia has resolved radiographically for those who are at risk for carcinoma of the lung. In general, all tobacco smokers and those who are 50 years of age or older and have pneumonia should have a chest radiograph to determine whether or not the pneumonia has completely resolved. Table 119-11 gives an approach to the patient whose pneumonia is not responding to therapy.

ADJUNCTIVE THERAPY In the PROWESS trial, drotrecogin alfa activated resulted in a 28 percent relative reduction in mortality among patients with severe CAP. Currently, patients with CAP and an APACHE II score of greater than 25 qualify for this drug, although the data suggest a beneficial effect beginning at an APACHE II score of 20. Tissue factor pathway inhibitor may also have a beneficial effect in severe pneumonia, and currently trials of this compound are underway.

Low-dose corticosteroid therapy is beneficial to those who are relatively adrenal insufficient (less than 9 µg/ml response in cortisol level to a dose of adrenocorticotrophic hormone). Hyperglycemia has been shown to be associated with higher mortality rates in patients who require hospitalization for community-acquired pneumonia, so it is likely that

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Table 119-11

control of hyperglycemia will be beneficial to patients with pneumonia and elevated blood sugar.

Considerations When Pneumonia Fails to Resolve or Worsens During Therapy

Treatment of Pneumonia in the Nursing Home

Reconsider the pneumonia diagnosis: Could this be pulmonary infarction, malignancy, vasculitis, drug reaction, or eosinophilic pneumonia?

Reconsider the etiologic diagnosis: Are you treating the appropriate microorganism(s)?

Remember that 10% of cases of community-acquired pneumonia are polymicrobial.

Tuberculosis can mimic pyogenic pneumonia. Also consider unusual organisms such as Actinomyces or Nocardia species.

Are you dealing with a resistant microorganism?

Streptococcus pneumoniae resistant to penicillin, erythromycin, and tetracycline is common in several European countries and the United States.

Has your patient developed nosocomial pneumonia?

Such an event is common, particularly in patients who require endotracheal intubation and assisted ventilation. Is your hospital’s potable water supply contaminated by Legionella spp.? If so, consider nosocomial Legionnaires’ disease. Nosocomial legionnaires’ disease should be a consideration anytime a patient with CAP is improving and develops nosocomial pneumonia.

Could this be postobstructive pneumonia (i.e., is endobronchial obstruction present)?

Have you considered empyema? Pus in the pleural space will continue to cause fever until it is drained.

Has metastatic infection occurred? Occasionally, patients who are bacteremic as a result of their pneumonia develop endocarditis, meningitis, septic arthritis, or a deep abscess such as splenic or renal abscess.

Always consider drug fever.

Sources: From Mandell LA, Bartlett JG, Dowell SF, et al: Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 37:1405–1433, 2003; Mandell LA, Marrie TJ, Grossman RF, et al: Canadian guidelines for the initial management of community acquired pneumonia: An evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 31:383–421, 2000, Niederman MS, Mandell LA, Anzueto A, et al: American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia.

Diagnosis, assessment of severity, antimicrobial therapy, and prevention.

Am J Respir Crit Care Med 163:1730–1754, 2001.

In one study, if more than two of the following factors were present—respiratory rate greater than 30 per minute, temperature greater than 100.5◦ F, pulse rate greater than 90 beats per minute, and feeding dependence and mechanically altered diet—the failure rate of therapy of pneumonia in the nursing home was high. It is important to take patients’ wishes into consideration in the decision to treat in the nursing home or transfer to the hospital. Treatment with ampicillin for nursing home–acquired pneumonia was associated with a significantly higher failure rate than was treatment with ceftriaxone. It seems that, given their antimicrobial spectrum and almost complete absorption following an oral dose, treatment of nursing home–acquired pneumonia with one of the “respiratory fluoroquinolones” is appropriate, although data from RCTs are still lacking for this group of patients.

PREVENTION Influenza vaccination of the elderly results in reduction in the rate of hospitalization for pneumonia and influenza by 48 to 57 percent. The role of pneumococcal vaccine has not been as clearly defined as that of influenza vaccine; however, the Advisory Committee on Immunization Practice recommends pneumococcal vaccine for persons older than 65 years of age. A somewhat unexpected benefit of the use of a protein-polysaccharide conjugated pneumococcal vaccine during childhood has been the reduction of invasive pneumococcal disease in 20 to 39 year olds and among those equal to or greater than 65 years of age. Indeed, in the United States, the incidence of invasive pneumococcal disease among adults 50 years and older declined from 40.8 cases/100,000 prior to the introduction of the vaccine to 29.4 only 4 years later. The rate of death following an episode of invasive pneumococcal disease among adults aged 50 years or older decreased from 6.9 to 5.7/100,000. The authors estimated 6250 fewer cases and 550 fewer deaths per year among those 50 years of age and older in the United States compared with the years prior to introduction of the conjugate vaccine.

Prevention of aspiration in those at risk (post-stroke, advanced Parkinson’s, and advanced Alzheimer’s disease) is difficult. Head positioning, stimulation techniques, exercises to enhance the swallowing reflex, and eating pureed foods can all help to reduce the risk of aspiration. In addition, intensive oral care (cleaning teeth after every meal with an applicator of povidone iodine, and frequent dental care to control plaque) reduced the rate of pneumonia from 19 percent in the control group to 11 percent in the treatment group.

Of course, all those who are asplenic should be vaccinated with pneumococcal vaccine, Hemophilus influenzae B vaccine, and meningococcal vaccine. If possible, this should be done prior to splenectomy.

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Patients with hypogammaglobulinemia should have periodic infusions of gammaglobulin in a regimen designed to keep the levels high enough to prevent infection.

QUALITY OF CARE MEASURES: PNEUMONIA The following have been adopted as quality of care measures for patients with CAP requiring admission to the hospital: blood cultures prior to administration of antibiotics; measurement of oxygenation status; administration of antibiotics within 4 hours of presentation to the emergency department; ascertainment of influenza; and pneumococcal vaccination status and administration of these vaccines as necessary. In addition, for those who smoke tobacco products, at the very least information about cessation, and preferentially counseling regarding cessation of smoking.

A number of studies have examined the effect of using guidelines on patient care, and while the designs have differed, there is a strong suggestion that following guidelines has a “halo effect” in improving patient care and results in decreased mortality and, in some instances, reduced length of stay.

End-of-Life Decision Making As indicated, many patients with CAP are elderly and many of these enter the hospital with advance directives. For all of these patients it is important to discuss life-sustaining measures such as assisted ventilation and admission to an intensive care unit should the need arise.

Specific Pathogens Streptococcus pneumoniae Streptococcus pneumoniae is still a common cause of pneumonia. Patients with bacteremic pneumococcal pneumonia are more likely to have diabetes mellitus, COPD, or alcoholism than those who have other causes of CAP. Capsular polysaccharide types 14, 4, 1, 6A/6B, 3, 8, 7F, 23F, and 18C are the most frequent causes of pneumococcal disease. Currently, 10 to 15 percent of S. pneumoniae isolates in the United States are intermediately or highly resistant to penicillin. These isolates are usually also resistant to erythromycin, tetracycline, and trimethoprim-sulfamethoxazole. Types 19A, 6A, 23, 19, 11, 6, 16, 9, and 14 are most frequently associated with penicillin resistance. The minimal inhibitory concentration (MIC) of penicillin for susceptible strains is under 0.06 µg/ml; isolates with MICs of 0.1 to 1 µg/ml are of intermediate resistance, and those with MICs of at least 2 µg/ml are highly resistant. These levels were established for central nervous system infections, for which trough concentrations of penicillin at 10 times MIC are necessary for cure. Generally, with intravenous antibiotics, high concentrations can be achieved in pulmonary tissue; therefore, even resistant strains of S. pneumoniae usually respond to treatment with high doses

of penicillin or third-generation cephalosporin. If there is concomitant meningitis, however, both a third-generation cephalosporin and vancomycin should be given. A number of observation studies have indicated that the combination of a macrolide and beta lactam results in lower mortality rates for patients with bacteremic pneumococcal pneumonia compared with monotherapy or therapy with other combinations.

Indeed, there is a suggestion that the combination of a beta lactam agent and fluoroquinolone results in higher mortality.

Staphylococcus aureus Pneumonia due to this agent is usually of sudden onset, affects persons with co-morbid illnesses (except during influenza outbreaks, when healthy young adults may be infected), and is frequently complicated by cavitation (20 percent), pneumothorax (10 percent), jaundice (8 percent), empyema (5 percent), acute renal failure (5 percent), and pericarditis (2 percent).

MRSA is a rare cause of CAP. It does occur, however, and once established in a region, it can be a major problem.

Vancomycin is used to treat MRSA, whereas cloxacillin or nafcillin is used to treat methicillin-susceptible strains. Surgical drainage is necessary for treatment of empyema. If multiple rounded opacities are seen in a patient with S. aureus pneumonia, suspect right-sided endocarditis. Toxic shock syndrome may complicate S. aureus pneumonia. Strains of S. aureus with the gene for Panton-Valentine leukocidin (PVL) have been described recently. PVL is an extracellular product of S. aureus. It is associated with primary skin infections such as furunculosis, and severe necrotizing pneumonia. In a recent report of eight cases of severe CAP caused by S. aureus strains carrying the PVL gene, six were fatal. The patients were all immunocompetent children or young adults.

All had a preceding influenza-like syndrome before developing pneumonia, and the six deaths occurred shortly after diagnosis. Necropsy showed diffuse necrotizing hemorrhagic pneumonia. In another study, PVL-positive infections were more often marked by temperature greater than 39◦ C ( p = 0.01), heart rate above 140 beats per min ( p = 0.02), hemoptysis ( p = 0.005), onset of pleural effusion during hospital stay ( p = 0.004), and leucopenia ( p = 0.001). The survival rate 48 hours after admission was 63 percent for the PVL-positive patients and 94 percent for PVL-negative individuals ( p = 0.007). Histopathological examination of lungs at necropsy from three cases of necrotizing pneumonia associated with PVL-positive S. aureus showed extensive necrotic ulcerations of the tracheal and bronchial mucosa and massive hemorrhagic necrosis of interalveolar septa.

Both methicillin-sensitive and methicillin-resistant strains have been described.

Haemophilus influenzae This cause of pneumonia is more common in older patients with COPD. Both type B and non-B strains can cause pneumonia. About 30 percent of all H. influenzae isolates now produce beta lactamase and hence are resistant to ampicillin and amoxicillin. Between 7 and 14 percent of H. influenzae

2113 Chapter 119

isolates are resistant to trimethoprim-sulfamethoxazole.

More than 90 percent of H. influenzae isolates are resistant to erythromycin; and 1 to 2 percent are resistant to tetracycline. Amoxycillin-clavulinic acid and a second- or third-generation cephalosporin reliably treat H. influenzae pneumonia.

Streptococcus pyogenes (group A streptococcus) This agent is uncommon as a cause of pneumonia. One of its presentations is pneumonia accompanied by explosive pleuritis. Cases of group A streptococcal pneumonia may be accompanied by “toxic strep syndrome.” Clindamycin, 600 mg given intravenously every 8 hours is superior to penicillin for the treatment of serious group A streptococcal infections. Of 2079 cases of invasive group A streptococcal (GAS) infection, 222 (11 percent) had pneumonia. The median age was 56 years. Underlying illness was present in 61 percent of cases.

Most cases were community acquired (81 percent). The case fatality rate was 38 percent for GAS pneumonia, compared with 12 percent for the entire cohort with invasive GAS infection. In 2002, the largest outbreak of 127 cases of GAS pneumonia in the United States occurred among military recruits in San Diego. The epidemic continued despite prophylaxis with penicillin and required additional prophylaxis to end it.

Mycoplasma pneumoniae This agent accounts for up to 30 percent of pneumonias treated on an outpatient basis. The extrapulmonary manifestations of M. pneumoniae are many and include cold agglutinin–induced hemolytic anemia, thrombocytopenia, encephalitis, cerebellar ataxia, Guillain-Barr´e syndrome, Stevens-Johnson syndrome, and myocarditis. This is primarily a disease of younger patients, but it accounts for 5 percent of all cases of pneumonia in persons 65 years of age or older. Macrolides (erythromycin, clarithromycin, and azithromycin) or tetracyclines are the treatment of choice.

Legionellaceae This family, which includes 29 species and more than 49 serogroups (there are 15 serogroups of L. pneumophila), causes two clinical syndromes: Legionnaires’ disease and a self-limited flu-like illness (Pontiac fever). L. pneumophila serogroup 1, the microorganism responsible for the 1976 outbreak in Philadelphia that gave this disease its name, accounts for 70 to 90 percent of the cases of Legionnaires’ disease. Legionnaires’ disease can be community or hospital acquired, and it can occur in sporadic, endemic, and epidemic forms.

Exposure to contaminated water (showers, cooling towers, or even ingestion of such water and subsequent microaspiration) is the prime mode of acquisition of this illness. Older age, male gender, immunosuppression (especially with corticosteroids), nosocomial acquisition, end-stage renal disease, and infection with L. pneumophila serogroup 5 are risk factors for death from this infection. On a molecular level, a mutation leading to a stop codon at position 392 resulted in a dysfunctional toll like receptor 5 protein unable to recognize flagellin.

This was a risk factor for Legionella pneumophila infection.

Acute Bronchitis and Community-Acquired Pneumonia

There is now considerable evidence that quinolone antibiotics are superior to macrolides for the treatment of Legionnaires’ disease. Azithromycin appears to be the macrolide of choice if this class of antibiotics is used. The disease may continue to progress for up to 4 days despite optimal therapy. Other options are doxycycline, 100 mg given twice intravenously in 24 hours and then 100 mg OD intravenously. Mild to moderately severe LD can be treated for 7 to 10 days while severe cases or LD in immunocompromised hosts should be treated for at least 21 days.

Hantavirus In May 1993, reports of deaths due to severe pulmonary disease were received by the New Mexico Department of Health.

Many of the affected persons were residents of the Navajo reservation located near the Four Corners area of New Mexico, Arizona, Colorado, and Utah. Within a few months a new Hantavirus (sin nombre, “no name” virus) had been isolated and shown to be responsible for this outbreak, which affected 17 persons. Hantavirus pulmonary syndrome (HPS) is characterized by a flu-like prodromal illness, followed by rapidly progressive noncardiogenic pulmonary edema. Fever, myalgia, cough or dyspnea, nausea or vomiting, and diarrhea are the most common symptoms. Hypotension, tachypnea, and tachycardia are the usual findings on physical examination. Leukocytosis (often with a severe left shift), thrombocytopenia (median lowest platelet count 64,500/mm3 ), prolonged prothrombin and partial thromboplastin times, and elevated serum lactate dehydrogenase concentration are the most common laboratory findings. The mortality was high (88 percent) in the Four Corners outbreak. The initial chest radiograph showed infiltrates in 65 percent and no abnormality in 24 percent of patients. Subsequently, 16 patients (94 percent) had rapidly evolving bilateral diffuse infiltrates.

In the few months after identification of this new Hantavirus, two more new Hantaviruses were identified in the United States and cases of HPS continue to be reported. The deer mouse, Peromyscus maniculatus, is the primary rodent reservoir for this virus.

Chlamydophila pneumoniae This intracellular pathogen of humans is spread by aerosols.

It causes sinusitis, pharyngitis, bronchitis, otitis media, and pneumonia. The last can be as a result of primary infection or as reactivation of latent infection. Primary infection affects mainly young adults and may be followed by reactive airway disease. Two weeks of treatment with doxycycline is adequate.

Clarithromycin is very active in vitro against C. pneumoniae, but whether it is superior to doxycycline is not known.

The reactivation type of infection occurs in older adults, often as part of a polymicrobial infection. The rate of C. pneumoniae in this setting is unknown.

Diagnosis is by isolation of the organism from respiratory secretions or by serology. A greater than fourfold rise in IgM or IgG by microimmunofluorescence test or a single IgM titer of at least 1:16 or an IgG titer of at least 1:512 is considered diagnostic.

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Severe Acute Respiratory Syndrome Coronavirus In November 2002 an outbreak of severe acute respiratory syndrome (SARS) started in Guangdong Province in southern China and spread worldwide, affecting more than 8000 persons. SARS was due to a novel coronavirus that jumped the species barrier from civet cats to humans. Patients with typical SARS usually present 2 to 10 days following exposure with nonspecific symptoms including fever, myalgia, headache, malaise, and chills. Three to five days later, a nonproductive cough and dyspnea develop. Twenty percent of patients subsequently develop worsening respiratory distress requiring admission to an intensive care unit. Approximately 10 percent of all patients die from progressive respiratory distress or complications of their hospital admission, typically around the third week of symptomatic illness.

Approximately 75 percent of patients have unilateral or bilateral infiltrates on chest radiograph at the time of presentation. The majority of those without visible infiltrates have ground-glass opacities detectable on high resolution computer tomography at the time of presentation or progress to develop radiographic infiltrates. Generally, radiographic opacities peak between 8 and 10 days after onset of illness and then improve, correlating with the worsening and improvement of respiratory symptoms, but progressive radiographic deterioration may occur associated with a more protracted clinical course. There is no effective antiviral therapy. The management of severe cases is that of the management of severe respiratory failure. Attention to infection control measures designed to prevent spread of SARS is most important.

Human Metapneumovirus Human metapneumovirus is a newly described member of the Paramyxoviridae family. Since its initial description in 2001, when it was isolated from nasopharyngeal aspirates of young children in the Netherlands, it has been described worldwide. Despite almost universal infection in early childhood, repeat infections do occur in adulthood, and it appears to account for about 2 to 3 percent of cases of pneumonia in adults. Unfortunately, there are no clinical or routine laboratory features that allow one to distinguish this type of pneumonia from bacterial pneumonia.

Mimivirus A giant virus that stains gram-positive with gram stain has been found in amoebae. This virus is an uncommon but definite cause of some cases of community-acquired pneumonia.

SUGGESTED READING Bates JH, Campbell GD, Barren AL, et al: Microbial etiology of acute pneumonia in hospitalized patients. Chest 101:1005– 1112, 1992.

British Thoracic Society Research Committee and the Public Health Laboratory Service: The aetiology, management, and outcome of severe community-acquired pneumonia on the intensive care unit. Respir Med 86:7–13, 1992.

Burack JH, Hahn JA, Saint-Maurice D, et al: Microbiology of community-acquired bacterial pneumonia in persons with and at risk for human immunodeficiency virus type 1 infection: Implications for rationale empiric antibiotic therapy. Arch Intern Med 154:2589–2596, 1994.

Fang GD, Fine M, Orloff J, et al: New and emerging etiologies for community-acquired pneumonia with implications for therapy: A prospective multicenter study of 359 cases. Medicine 69:307–316, 1990.

Fine MJ, Auble TE, Yealy DM, et al: A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 336:243–250, 1997.

Lim WS, van der Eerden MM, Laing R, et al: Defining community-acquired pneumonia severity on presentation to hospital: An international derivation and validation study. Thorax 58:377–382, 2003.

Mandell LA, Bartlett JG, Dowell SF, et al: Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 37:1405–1433, 2003.

Mandell LA, Marrie TJ, Grossman RF, et al: Canadian guidelines for the initial management of community acquired pneumonia: An evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 31:383–421, 2000.

Mandell LA, Wunderink RG, Aazueto A, et al. Infectious Diseases Society of America/American Thoracic Society Guidelines for the management of community-acquired pneumonia. Clin Infect Dis 44:527–572, 2007.

Marrie TJ, Durant H, Yates L: Community-acquired pneumonia requiring hospitalization: 5-year prospective study.

Rev Infect Dis 11:586–599, 1989.

Niederman MS, Mandell LA, Anzueto A, et al: American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention.

Am J Respir Crit Care Med. 163:1730–1754, 2001. ¨ ˚A, Sterner G, Nilsson JA: Severe communityOrtqvist acquired pneumonia: Factors influencing need of intensive care treatment and prognosis. Scand J Infect Dis 17:377– 386, 1985.

Osterheert JJ, Bonten MJM, Hak E, Schneider MME, Hopelman IM: How good is the evidence for the recommended empirical treatment of patients hospitalized because of community-acquired pneumonia? A systematic review. J Antimicrob Chemother 52:555–563, 2003.

Pachon J, Prados MD, Capote F, et al: Severe communityacquired pneumonia: Etiology, prognosis and treatment.

Am Rev Respir Dis 142:369–373, 1990.

Torres A, Serra-Battles J, Ferrer A, et al: Severe communityacquired pneumonia: Epidemiology and prognostic factors. Am Rev Respir Dis 144:312–318, 1991.

120 Acute Exacerbations of Chronic Obstructive Pulmonary Disease Fernando J. Martinez Jeffrey L. Curtis

I. DEFINITION II. IMPACT Pulmonary Function Health Care Utilization Health Status III. ETIOLOGY Viral Path ogens Bacterial Path ogens Environmental Exposures

Laboratory Physiologic V. TREATMENT Bronch odilators Steroids Antimicrobial Agents Mucolytics Oxygen Therapy Mechanical Ventilation Hospitalization Decision

IV. EVALUATION Clinical

DEFINITION Although the topic remains controversial, a generally accepted definition of acute exacerbations of COPD (AE COPD) is “a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.” It is important to exclude alternate causes of acute deterioration, including congestive heart failure, pneumothorax, and pulmonary emboli, among others. Two major approaches to defining an AE COPD have been advocated: symptombased and event-based definitions. Symptom-based definitions are the most frequently used, with most modifying the criteria of Anthonisen et al. Although symptom-based definitions are the most relevant to patient care, some investigators have documented that a significant proportion of patients with an AE COPD may not report these symptoms to health care professionals. To circumvent difficulties with

quantifying symptoms, event-based definitions have been utilized, particularly in clinical trials. This approach, which defines an AE COPD on the basis of health care utilization and therapy, may capture significantly fewer events. In fact, one group has compared symptom-based definition from daily diary cards to an event-based definition in a large, prospective study of an inhaled steroid/long-acting β-agonist; the correlation between the two definitions was quite weak. Accordingly, intensive investigation continues, seeking to develop optimal definitions both for clinical use and research studies.

The frequency and severity of exacerbations are quite variable among COPD patients. This variability may reflect the nature of data collection (prospective vs. retrospective), disease severity, medications administered, vaccinations, and smoking status. For example, investigators who identify AE COPDs through review of daily diary cards tend to identify more episodes per year. Studies that include patients with more severely impaired pulmonary function identify a greater number of yearly episodes.

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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IMPACT Pulmonary Function AE COPD episodes have been reported to result in measurable acute deteriorations in pulmonary function. Several groups have identified modest changes in pulmonary function, particularly in lung volumes, during the course of an AE COPD and its resolution. Importantly, persistent negative longitudinal effects of repeated AE COPDs have been reported by several groups; the additional decline in lung function averaged approximately 7 to 8 mL/year in FEV1 . As such, AE COPDs have measurable negative short- and long-term impacts on pulmonary function.

Table 120-1 Viral Pathogens Implicated in Exacerbations of COPD Rhinovirus Coronavirus Influenza A and B Parainfluenza Adenovirus

Health Care Utilization AE COPDs are also major source of health care expenditure.

Numerous groups have examined the economic impact of AE COPD on measures of health care utilization. In the United States in 1995, they were estimated to result in a total treatment cost of $1.2 billion in patients ≥ 65 years of age and $419 million in those < 65 years of age; these costs were predominantly for hospitalizations. A prospective Spanish study confirmed that patients who failed outpatient therapy, particularly those who required emergency department treatment and hospitalization, accounted for the majority of the total cost of care. Thus, patients with AE COPD, particularly those who require hospitalization, result in major health care expenditures.

Health Status The negative effects of AE COPD are particularly evident on health-related quality of life (HRQoL). Cross-sectional studies have reported reduced HRQoL during AE COPD, while longitudinal studies have found that HRQoL improves from exacerbation to recovery. The greatest improvement in HRQoL after a single episode occurs during the first 4 weeks, although HRQL continues to improve over 26 weeks.

A recurrence of AE COPD results in a markedly attenuated improvement.

ETIOLOGY

Respiratory syncytial virus Human metapneumovirus source: Adapted from Martinez FJ, Han MLK, Flaherty K, et al: Role of infection and antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease. Expert Rev Anti Infect Ther 4:101–24, 2006.

be associated with the production of eotaxin, eotaxin-2, and CCL5. Experimental evidence has confirmed that rhinovirus infection can infect the lower airways. It is evident that viral infection could account for the inflammatory response previously described as typical of AE COPD. Clinical data implicating multiple viral pathogens in AE COPD are increasing (Table 120-1). Early studies, which relied on serologic studies or viral cultures of the upper airway, reported a relatively minor role for viral infection. More recent studies have utilized more sensitive techniques for virus identification, including polymerase chain reaction (PCR).

Results have suggested that a much higher proportion of cases of AE COPD are related to viral infections (up to 60 percent in some series). As noted in Table 120-1, picornaviruses, respiratory syncytial virus (RSV), influenza and human metapneumoviruses have been identified most frequently. A prospective study of hospitalized patients with AE COPD found a viral pathogen in more than 48 percent of episodes (vs. 6.25 percent in the stable state), with a similar distribution of viral pathogens as previously noted; a clear relationship between viral infection and the inflammatory process was documented by this group (Fig. 120-1).

Viral Pathogens Viral infections are increasingly recognized as causative in AE COPD. Rhinovirus infection of the bronchial epithelium induces the expression of numerous proinflammatory genes, including IL-8, Groα, and ENA-78. In fact, induction of NF-κB and other transcription factors has been clearly demonstrated with several viruses, including rhinovirus, respiratory syncytial virus (RSV), and influenza infection. In addition, rhinovirus and RSV infection of bronchial epithelial cell lines can

Bacterial Pathogens The role of bacterial infection in individual AE COPD episodes remains controversial, in part due to the evolving diagnostic methods used to establish their etiologic role.

These methods have included sputum culture, bronchoscopic sampling, molecular epidemiologic studies of bacterial pathogens, identification of an immune response, and recording a response to antimicrobial therapy.

2117 Chapter 120 Assess patient Obtain ABG Begin O2 Assure PaO2 >8 kPa Adjust O2 to SaO2 90%

Hypercapnia?

(PaO2 >6.7 kPa) Yes No

pH <7.35? (with PaO2 >8 kPa)

No change in oxygen setting

Yes

No Reassess ABG in 1â&#x20AC;&#x201C;2 h Yes Hypercapnia?

(PaCO2 >6.7 kPa) No Maintain O2 SaO2 90%

Maintain O2 SaO2 90% Reassess ABG in 2h

pH <7.35? (with PaO2 >8 kPa)

Yes

Consider mechanical ventilation NPPV or intubation

No No change in oxygen setting

Figure 120-1 Proposed algorithm for the correction of hypoxemia in the acutely ill patient with AE COPD. ABG, arterial blood gas; NPPV, noninvasive positive pressure ventilation; O2 , oxygen; PaO2 , arterial oxygen tension; PaCO2 , arterial carbon dioxide tension; SaO2 , arterial oxygen saturation. (From Celli BR, MacNee W, committee members: ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932â&#x20AC;&#x201C;946, 2004.)

Sputum cultures have been the classic approach to identifying potentially pathogenic microorganisms (PPM) in AE COPD. Comprehensive reviews of comparative antimicrobial trials identified wide variable frequencies of PPM. The organisms most frequently isolated are non-typeable Haemophilus influenzae (NTHI), Moraxella catarrhalis, and Streptococcus pneumoniae. In general, greater airflow obstruction and prior use of antimicrobial agents identify COPD patients at higher risk for infection with Pseudomonas spp. or other enteric gram-negative rods.

Whether PPM are etiologic in AE COPD has been questioned, as early longitudinal studies showing that the frequency of bacterial isolation from sputum in a patient with AE COPD was no different from that of the stable state. Recent insights suggest that patients who have bacterial pathogens in the sputum during the stable phase have more frequent AE COPD and greater decline in lung function. These find-

Acute Exacerbations of COPD

ings imply that the results of earlier studies were heavily influenced by case selection. Moreover, sputum cultures have important limitations, e.g., seriously underestimating colonization with NTHI in comparison to PCR-based detection. Although bronchoscopically collected samples have confirmed that PPM are found in many patients with COPD at a stable state, the burden of organisms increased during AE COPDs. Recent longitudinal cohort studies that analyzed surface antigen diversity show that acquisition of a bacterial strain with which the patient had not been previously colonized more than doubled the risk of a clinical exacerbation.

Interestingly, the identification of a new NTHI strain was not associated with a symptomatic exacerbation in the majority of patients. This finding is consistent with evidence that H. influenzae and M. catarrhalis strains associated with symptomatic exacerbations appear to differ inherently from strains not associated with such a clinical response, in that they are more likely to lead to neutrophil recruitment and IL-8 release.

Further support for the importance of bacterial infection in the etiology of AE COPD comes from recent studies that confirmed a systemic immune response to homologous strains of H. influenzae and M. catarrhalis isolated simultaneously from sputum of patients during evaluation at time of stability and with symptomatic exacerbations. Demonstrating a systemic immune response has confirmed an interaction between bacterial and viral infections. It has been reported that almost half of exacerbations associated with a new NTHI strain are associated with evidence of acute viral infection. Overall, evidence of a viral infection was identified in 79 percent of patients with AE COPD. Taken together, these data strongly support a pathogenic role for bacterial pathogens in a large proportion of patients with AE COPD. Which patients are more likely to experience AE COPD as a result of bacterial infection has been addressed by numerous investigators. Sputum purulence has been examined most critically in the clinical setting; patients with purulent sputum have been reported to be more likely to have polymorphonuclear cells and organisms in sputum. A multicenter study reported that increasing sputum purulence, as defined by a semiquantitative colorimetric scale, was associated with bacterial growth. Furthermore, deepening sputum color (yellowish to brownish) was associated with increased yield of gram-negatives and P. aeruginosa/Enterobacteriaceae.

Importantly, the definition of color by patients and investigators was concordant in only 68 percent of cases without the aid of an objective color stick. A prospective study of 40 patients hospitalized for AE COPD provided sputum samples and underwent bronchoscopy with protected brush sampling (PSB). The concordance between sputum and PSB culture was high (k = 0.85, p < 0.002), while the presence of patient-reported sputum purulence was highly associated with positive PSB cultures (Fig. 120-2). The totality of these data suggests that new purulent sputum may identify a patient more likely to experience AE COPD related to bacterial infection.

2118 Part XVI

Infectious Diseases of the Lungs Antibiotic Group n/N

Study

Placebo Group n/N

Relative Risk (Fixed) 95% CI

Weight (%)

Relative Risk (Fixed) 95% CI

Bmes 1965a

1/29

5/29

18.0

0.20 [ 0.02, 1.61 ]

Nouira 2001

4/47

18/46

65.6

0.22 [ 0.08, 0.59 ]

Pines 1968

1/15

3/15

10.8

0.33 [ 0.04, 2.85 ]

Pines 1972

1/89

1/86

5.5

0.32 [ 0.01, 7.80 ]

100.0

0.23 [ 0.10, 0.52 ]

180 176 Total (95% CI) Total events: 6 (Antibiotic Group), 27 (Placebo Group) Test for heterogeneity chi-square=0.19 df=3 p=0.98 P=0.0% Test for overall effect z=.055 p=0.0004 0.001

0.01

0.1

Favours antibiotic

1

10

100

1000

Favours placebo

Figure 120-2 Comparison of effect of antibiotics versus placebo on short-term mortality during study intervention.

(From Ram FSF, Rodriguez-Roisin R, Granados-Navarrete A, et al: Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane Database Syst Rev 2006; Issue 3.)

Environmental Exposures Epidemiological studies and the inflammatory response provoked in patients with COPD by exposure to pollutants strongly support a role for environmental exposures in triggering AE COPD. Both particulate matter and nonparticulate gases have been implicated. For example, sulfur dioxide, ozone, black smoke, and nitrogen dioxide have been associated with an increased risk of admission to the hospital for COPD.

Observational studies suggest that a chest radiograph (CXR) identifies abnormalities leading to changes in management in suspected AE COPD in 16 to 21 percent of cases.

As such, an evidence-based review has suggested that CXR should be considered in AE COPD managed in the emergency room or hospital. Assessment of oxygenation, including arterial blood gas sampling in selected patients, adds valuable information in stratifying disease severity. Developing and validating cost-effective diagnostic algorithms is an important unmet research goal in AE COPD.

EVALUATION Clinical As noted, AE COPD is generally defined by a change in symptoms out of proportion to the usual daily variation, which may be considerable in a given patient. Given the central role of respiratory infection in AE COPD pathogenesis, in the absence of sputum purulence the diagnosis of AE COPD should be suspected and alternative diagnoses evaluated. Congestive heart failure, pneumothorax and pulmonary emboli are particularly important possibilities to exclude. In fact, pulmonary emboli have been identified in 25 percent of patients with COPD admitted with a severe exacerbation and no obvious evidence of infection. Previous thromboembolic disease and malignancy have been associated with pulmonary emboli in COPD patients. Similarly, the clinical history should be examined for risk factors for congestive heart failure.

Table 120-2 Potential Therapeutic Options for an AE COPD Managed in the outpatient Setting Patient education Check inhalation technique and reinforce correct use Consider use of spacer device Bronchodilators Short-acting β2 -agonists and/or ipratropium MDI with spacer or via handheld nebulizer as appropriate Consider adding long acting bronchodilator Corticosteroids Prednisone 20–40 mg orally/day for 10–14 days Consider use of an inhaled corticosteroid

Laboratory Given this differential diagnosis, focused laboratory testing is of value in the assessment of a patient with a suspected AE COPD. Recent data have suggested a valuable role for the measurement of natriuretic peptides in differentiating congestive heart failure from non-cardiac disorders in patients with acute breathlessness, including patients with AE COPD. Numerous investigators have confirmed that this neurohormone is elevated in patients with left ventricular dysfunction and correlates with severity as well as prognosis in CHF.

Antibiotics Can be considered in patients with altered sputum characteristics Choice of agent should be based on local bacterial resistance pattern and host characteristics source: Adpted from Celli BR, MacNee W, and committee members: ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004.

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Physiologic Physiologic changes have been demonstrated during an AE COPD. A modest improvement in pulmonary function, particularly in lung volumes, has been reported over the first two weeks after therapy for an AE COPD started. On the other hand, several observational studies have concluded that spirometric assessment at the time of presentation is of limited value in the care of patients with AE COPD.

TREATMENT Optimal therapy for AE COPD is multifactorial and depends, in part, on the site of therapy. Tables 120-2 and 120-3 enumerate suggested therapeutic options in patients with AE COPD treated as outpatients or in the hospital. The bases for these recommendations are discussed in individual sections.

Bronchodilators Both inhaled β-agonists and anticholinergic agents have been documented to decrease airflow obstruction during AE COPD. Systematic reviews suggest that short-acting

Table 120-3 Potential Therapeutic Options for an AE COPD Managed in the Inpatient Setting Bronchodilators Short-acting β2 -agonists and/or ipratropium MDI with spacer or via handheld nebulizer as appropriate Consider adding long-acting bronchodilator Supplemental oxygen Corticosteroids Prednisone 20–40 mg orally/day for 10–14 days if tolerated If patient cannot tolerate oral steroids equivalent dose intravenously for 10–14 days Consider using inhaled corticosteroid Antibiotics Can be considered in patients with altered sputum characteristics Choice of agent should be based on local bacterial resistance pattern and host characteristics source: Adapted from Celli BR, MacNee W, and committee members: ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004; Global Initiative for Chronic Obstructive Lung Disease.

Executive Summary: Global Strategy for the Diagnosis, Management, and Prevention of COPD. http://www.goldcopd.org. Accessed: July 24, 2006.

Acute Exacerbations of COPD

β-agonists and anticholinergic-inhaled bronchodilators have comparable effects on spirometry exceeding that of parenterally administered bronchodilators. Although the combination of an anticholinergic agent with a β-agonist has the potential for increased therapeutic benefit, studies combining agents from these classes have shown varied results, which, on average, do not seem to support the routine use of multiple agents for AE COPD. On the other hand, it is reasonable to add a second agent if a patient is experiencing suboptimal benefit on a single agent. The evidence for and against the utility of adding a methylxanthine to inhaled bronchodilators is also conflicting, although the high incidence of adverse reactions makes it difficult to recommend their routine use for AE COPD.

Steroids The role for systemic corticosteroids in AE COPD is becoming better defined. A systematic review suggested that systemic steroid use results in physiologic improvement over the first 72 hours and reduced the odds of a treatment failure over the subsequent 30 days (OR 0.48, 95 percent CI 0.34 to 0.68), but with an increased risk of adverse drug reaction (OR 2.29, 95 percent CI 1.55 to 3.38). The largest study in hospitalized patients confirmed that parenteral steroid use

Excerbation of COPD requiring ventilatory support

Contraindication for NPPV? Yes Intubate MV Weaning

No NPPV with monitoring

Improvement in pH, PaCO2 clinical status

Yes

No Intubate MV 48 h

Continue NPPV

Wean to complete disconnection

2-h T-tube trail Success

Failure

Disconnection MV

NPPV

Figure 120-3 Proposed algorithm for the use of noninvasive positive pressure ventilation (NPPV) during an AE COPD. MV, mechanical ventilation; PaCO2 , arterial carbon dioxide tension. (From Celli BR, MacNee W, committee members: ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004.)

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(methylprednisolone 125 mg/day for 3 days followed by either a 15-day or 8-week taper) was associated with a faster improvement in FEV1 , a lower number of treatment failures, and a shorter length of hospital stay, although with greater side effects (particularly hyperglycemia). Subsequently, others confirmed these findings while using lower doses for shorter periods, including patients being discharged from the emergency department. Non-controlled studies have suggested that prednisone therapy hastened AECB recovery (by 2.63 days) while prolonging time to the next event. Thus, the modest but proven efficacy of systemic steroids in severe AE COPD implies that modulating the host immune response may benefit some patients. It remains unclear how one can best identify which patient is most likely to benefit from parenteral steroids.

Antimicrobial Agents Given compelling data that bacterial infection is likely causative in approximately 50 percent of patients with AE COPD, it is not surprising that antimicrobial therapy has been intensively studied in this disease. Numerous placebo-

controlled trials of antibiotics in AE COPDs have been published over the past several decades. Systematic reviews of these trials have suggested a treatment effect, including a potential survival benefit (Fig. 120-3). There has been significant heterogeneity in the results of the individual studies, with none designed in an optimal fashion. The majority of recent international guidelines interpreted these data to suggest that antimicrobial agents provide additional benefit in selected patients. Most recommend the use of antimicrobials in patients with an AECOPD who are more likely to have bacterial infection (Table 120-4), i.e., those experiencing a change in sputum characteristics or multiple symptoms as defined

by Anthonisen et al. Serum procalcitonin has been shown by one group to define patients with AECOPD who have a higher likelihood of bacterial infection; additional, prospective investigation is required to better define this evolving technique.

The choice of antimicrobial agent remains contentious, although increasingly guidelines have taken the approach of stratifying patients according to the risk of treatment failure. One such schema is illustrated in Table 120-5. These stratification schemes have generally suggested features for a

Table 120-4 International Guideline Recommendations for the Use of Antimicrobial Therapy in an AE COPD Guideline, Year

Recommendation

Canadian Thoracic Society, 2003

“The Panel proposes that antibiotics should only be considered for use in patients with purulent exacerbations.”

Gold, 2004

“Antibiotics are only effective when patients with worsening dyspnea and cough also have increased sputum volume and purulence.”

American Thoracic Society/ European Respiratory Society, 2004

“[Antibiotics] May be initiated in patients with altered sputum characteristics.”

National Institute for Clinical Excellence, 2004

“Antibiotics should be used to treat exacerbations of COPD associated with a history of more purulent sputum.”

European Respiratory Society, 2005

“[Hospitalized patients with COPD exacerbations should receive antibiotics if] I. Patients with all three of the followings symptoms: increased dyspnea, sputum volume and sputum purulence (a type I Anthonisen exacerbation).

II. Patients with only two of the above three symptoms (a type II Anthonisen exacerbation) when increased purulence of sputum is one of the two cardinal symptoms.

III. Patients with a severe exacerbation that requires invasive or noninvasive mechanical ventilation.

IV. Antibiotics are generally not recommended in Anthonisen type II without purulence and type III patients (one or less of the above symptoms).

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Acute Exacerbations of COPD

Table 120-5 Potential Antimicrobial Options for an AE COPD Based on Host and Pathogen Factors Category Uncomplicated AECOPD Age < 65 years FEV1 > 50% predicted < 4 exacerbations/year No comorbid conditions

Complicated AECOPD Age > 65 years FEV1 < 50% predicted ≥ 4 exacerbations/year Comorbid conditions

Complicated AECOPD at risk for Pseudomonas aeruginosa infection FEV1 < 35% predicted Recurrent courses of antibiotics or steroids Bronchiectasis

Likely Pathogens

Antimicrobial Treatment

H. influenzae S. pneumoniae M. catarrhalis H. parainfluenzae Viral M. pneumoniae C. pneumoniae

Macrolide∗ Ketolides† Doxycycline 2nd or 3rd generation cephalosporin Respiratory quinolone†

H. influenzae S. pneumoniae M. catarrhalis H. parainfluenzae Viral M. pneumoniae C. pneumoniae Gram-negative enteric bacilli

Respiratory quinolone† Amoxicillin/clavulanate

H. influenzae S. pneumoniae M. catarrhalis H. parainfluenzae Viral M. pneumoniae C. pneumoniae Gram-negative enteric bacilli Pseudomonas aeruginosa

Fluoroquinolone with antipseudomonal activity‡

∗ In

active smokers H. influenzae infection is more prevalent—azithromycin and clarithromycin demonstrate improved in vitro activity. moxifloxacin, gatifloxacin, gemifloxacin, and telithromycin have activity against penicillin-resistant S. pneumoniae. ‡ Ciprofloxacin and levofloxacin have enhanced antipseudomonal activity.

Source: Martinez FJ, Han MLK, Flaherty K, et al: Role of infection and antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease.

Expert Rev Anti Infect Ther 4:101–124, 2006. † Levofloxacin,

high likelihood of infection with organisms that are not covered with standard antibiotic regimens (e.g., P. aeruginosa, drug-resistant bacteria) or host factors that predict treatment failure. The latter include worse lung function, increased frequency of exacerbation/office visits, ischemic heart disease and other comorbid conditions. The clinical implication of increasing antimicrobial resistance among common respiratory pathogens in patients with AECOPD remains unclear.

COPD patients are at higher risk for infection with resistant organisms. In data collected prospectively, patients with complicated AE COPD appear to experience an inferior clinical response rate compared with those with uncomplicated AE

COPD. The impact of utilizing different antimicrobial regimens based on different patient strata remains unproved.

Hence, tailoring the initial antimicrobial regimen selection in individuals at increased risk for treatment failure (Table 120-5) is an attractive concept that requires prospective validation.

Mucolytics An analysis of five randomized controlled trials concluded that pharmacological mucus clearance strategies did not shorten the course of treatment, but they may improve

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symptoms. The agents evaluated in these trials included domiodol, bromhexine, ambroxol, S-carboxymethylcysteine, and potassium chloride.

Oxygen Therapy Oxygen therapy has been described as a cornerstone of hospital treatment for COPD exacerbations. The benefits include decreasing pulmonary vasoconstriction, decreasing the right heart strain and possible ischemia, improving cardiac output, and subsequent oxygen delivery to the central nervous system and other vital organs. The concern regarding oxygen use is the relationship to hypercarbia and subsequent respiratory failure. A systematic review found that supplemental oxygen therapy increased PaCO2 in most patients, but most patients did not require subsequent mechanical ventilation.

Patients with combined baseline hypercarbia and more severe hypoxemia had the highest risk of requiring mechanical ventilation following the administration of supplemental oxygen.

Table 120-6 Indications and Contraindications to the Use of Nasal Positive Pressure Ventilation in a Severe AE COPD Criteria for consideration Moderate to severe dyspnea with use of accessory muscles and paradoxical abdominal motion Respiratory acidosis (pH ≤ 7.35) and hypercapni (PaCO2 > 45 mmHg) Respiratory frequency > 25 breath/minute Contraindications (relative/absolute) Cardiac or respiratory arrest Cardiovascular instability Failure of nonrespiratory organs Severe encephalopathy Severe hemorrhage of upper digestive system Uncooperative patient Recent facial or gastrointestinal surgery Craniofacial trauma, fixed nasopharyngeal abnormalities Obstruction of the upper airway High aspiration risk Inability to cooperate or protect the airway Extreme obesity Burns source: Adapted from Global Initiative for Chronic Obstructive Lung Disease: Executive Summary: Global strategy for the diagnosis, management, and prevention of COPD. http://www.goldcopd.org.

Accessed: July 24, 2006, Carrera M, Sala E, Cosio BG, et al: Hospital treatment of chronic obstructive pulmonary disease exacerbation: An evidence-based review. Arch Bronchoneumol 41:220–229, 2005.

Oxygen should be administered for patients with AE COPD with a goal oxygen saturation of 90 to 92 percent (PaO2 60 to 65 mmHg) under tightly controlled circumstances. Figure 120-3 illustrates an algorithmic approach to administering oxygen supplementation in a patient suffering from an AE COPD.

Mechanical Ventilation Noninvasive positive-pressure ventilation (NPPV) has the potential of resting fatigued muscles and thus preventing the need for endotracheal intubation and mechanical ventilation.

Decreased need for invasive mechanical ventilation and a potential survival advantage have been seen in several studies.

Expert opinion supports administration of NPPV in an ICU or other similar closely monitored setting for optimal results.

Criteria suggested to identify patients likely to benefit are enumerated in Table 120-6. A clinical practice guideline to the application and titration of this modality in AE COPD patient has been published. Patients who are intolerant of or do not benefit from NPPV should be considered for invasive mechanical ventilation (Table 120-7).

Table 120-7 Indications and Contraindications to the Use of Invasive Mechanical Ventilation in a severe AE COPD Absolute indications Cardiac or respirtory arrest Failure of noninvasive ventilation or contraindication to such Persistent, life threatening hypoxemia (Pao2 < 40 mmHg or Pao2 /Fio2 < 200) Worsening or severe respiratory acidosis (pH < 7.25 and hypercapnia—PaCO2 > 60 mm Hg) Contraindications (relative/absolute) Severe dyspnea with use of accessory muscles Respiratory rate > 35 breaths/min Somnolence, impaired mental status Cardiovascular complications Other complications (severe pneumonia, metabolic abnormalities, sepsis, pulmonary embolism, barotraumas, pleural effusion) source: Adapted from Global Intiative for Chronic Obstructive Lung Disease: Executive Summary: Global strategy for the diagnosis, management, and prevention of COPD. http://www.goldcopd.org.

Accessed: July 24, 2006; Carrera M, Sala E, Cosio BG, et al: Hospital treatment of chronic obstructive pulmonary disease exacerbation: an evidence-based review. Arch Bronchoneumol 41:220–229, 2005.

2123 Chapter 120

Table 120-8 Indications for Hospitalization in Patients with an AE COPD Presence of high-risk comorbid conditions Indequate response of symptoms to outpatient or emergency department management Marked increase in dyspnea Inability to eat or sleep due to symptoms Worsening hypoxemia Worsening hypercapnia Change in mental status Inability of patient to care for herself or himself Uncertain diagnosis Inadequate home care source: Adapted from Celli BR, MacNee W, and committee members: ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004.

Hospitalization Decision The decision to treat at home or in the hospital remains controversial with varying guidelines. General guidelines to aid in this decision are enumerated in Table 120-8.

SUGGESTED READING Allegra L, Blasi F, Diano PL, et al: Sputum color as a marker of acute bacterial exacerbations of chronic obstructive pulmonary disease. Respir Med 99:742–747, 2005.

Anthonisen N, Manfreda J, Warren C, et al: Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Int Med 106:196–204, 1987.

Blasi F, Ewig S, Torres A, et al: A review of guidelines for antibacterial use in acute exacerbations of chronic bronchitis.

Pulm Pharmacol Therapeut 2005.

Calverley P, Pauwels R, Lofdahl CG, et al: Relationship between respiratory symptoms and medical treatment in exacerbations of COPD. Eur Respir J 26:406–413, 2005.

Carrera M, Sala E, Cosio BG, et al: Hospital treatment of chronic obstructive pulmonary disease exacerbation: An evidence-based review. Arch Bronchoneumol 41:220–229, 2005.

Acute Exacerbations of COPD

Celli BR, MacNee W, committee members: ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004.

Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al: Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: clusterrandomised, single-blinded interventional trial. Lancet 363:600–607, 2004.

Doll H, Miravitlles M: Health-related QOL in acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease. A review of the literature. Pharmacoeconomics 23:345–363, 2005.

Global Initiative for Chronic Obstructive Lung Disease: Executive summary: Global strategy for the diagnosis, management, and prevention of COPD. http://www.goldcopd.org.

Accessed: July 24, 2006.

Kanner RE, Anthonisen NR, Connett JE : Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164:358–364, 2001.

Martinez FJ, Han MLK, Flaherty K, et al: Role of infection and antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease. Expert Rev Anti Infect Ther 4:101–124, 2006.

McCrory DC, Brown CD: Anticholinergic bronchodilators versus beta2-sympathomimetic agents for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;1.

McCrory DC, Brown C, Gelfand SE, et al: Management of acute exacerbations of COPD. A summary and appraisal of published evidence. Chest 119:1190–1209, 2001.

Niederman MS, McCombs JS, Unger AN, et al: Treatment cost of acute exacerbations of chronic bronchitis. Clin Therapeut 21:576–591, 1999.

Papi A, Bellettato CM, Braccioni F, et al: Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 173:1114– 1121, 2006.

Pauwels R, Calverley P, Buist AS, et al: COPD exacerbations: The importance of a standard definition. Respir Med 98:99–107, 2004.

Ram FSF, Rodriguez-Roisin R, Granados-Navarrete A, et al: Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane Database Syst Rev 2006; issue 3.

Ruchlin HS, Dasbach EJ: An economic overview of chronic obstructive pulmonary disease. Pharmacoeconomics 19:623–642, 2001.

Seemungal TAR, Donaldson GC, Bhowmik A, et al: Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161:1608–1613, 2000.

Sethi S, Evans N, Grant BJB, et al: New strains of bacteria and exacerbations of chronic obstructive pulmonary disease.

N Engl J Med 347:465–471, 2002.

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Sinuff T, Keenan SP: Clinical practice guideline for the use of noninvasive positive pressure ventilation in COPD patients with acute respiratory failure. J Crit Care 19:82–91, 2004.

Soler N, Agusti A, Angrill J, et al: Bronchoscopic validation of the significance of sputum purulence in severe exacerbations of chronic obstructive pulmonary disease (COPD).

Thorax Available at: doi:10.1136/thx.2005.056374. Published online 23 Aug 2006.

Stevenson NJ, Walker PP, Costello RW, et al: Lung mechanics and dyspnea during exacerbations of chronic obstructive

pulmonary disease. Am J Respir Crit Care Med 172:1510– 1516, 2005.

Tillie-Leblond I, Marquette CH, Perez T, et al: Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: Prevalence and risk factors. Ann Int Med 144:390–396, 2006.

Wood-Baker R, Gibson P, Hannay M, et al: Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006.

121 Pneumonia in Childhood Mark S. Pasternack

I. NEONATAL PNEUMONIA

IV. TUBERCULOSIS

II. PNEUMONIA IN EARLY INFANCY Chlamydia trachomatis Pneumonia Acute Viral Pneumonia Other Common Respiratory Viral Pathogens in Infancy Additional Respiratory Viral Pathogens Additional Causes of Pneumonia in Infancy

V. PNEUMONIA COMPLICATING CHILDHOOD VIRAL EXANTHEMS Varicella Measles

III. PNEUMONIA AFTER THE FIRST 6 MONTHS OF LIFE Bacterial Pneumonia Pneumococcal Pneumonia Haemophilus influenzae Pneumonia Staphylococcal Pneumonia Streptococcal Pneumonia Atypical Bacterial Pathogens

Pneumonia and influenza are the seventh leading cause of childhood death in the United States. Although in this country the impact on overall childhood mortality is limited (0.4/100,000 children annually), the worldwide mortality due to acute respiratory tract infections in childhood may exceed 2 million deaths annually. In addition, the morbidity of lower-respiratory tract infections (LRTIs) is substantial. For example, the hospitalization rate for influenza among U.S. children under the age of 5 is comparable to that of adults over the age of 50.

LRTIs in children may be organized as a collection of distinct clinical syndromes based on the age of the child and the clinical setting. Pneumonia is a rather common problem for the practicing pediatrician, yet its management is frequently problematic because of a paucity of objective data.

Historical information is often scant, especially when managing younger patients. The clinical and especially the radiologic features of pneumonia frequently are not closely correlated with particular etiologic agents, and it is often difficult or impossible to obtain sputum for microscopic analysis and culture. Rapid diagnostic methods detect only a fraction of

VI. ASPIRATION PNEUMONIA VII. PNEUMOCYSTIS JIROVECI PNEUMONIA (PCP) VIII. RECURRENT PNEUMONIA Recurrent Focal Pneumonia Recurrent Pneumonia in Different Locations Defects in Pulmonary Defenses Defects in Systemic Host Defenses

the common viral causes of LRTI, and similarly blood cultures identify bacterial pneumonia in a small subset of children, and then only after significant delay. Occasionally, pneumonia in early childhood and syndromes of recurrent pneumonia may reflect a congenital or acquired anomaly or a genetic disorder associated with impaired host defense. Thus, the management of pneumonia in children often presents a greater challenge to the clinician than do similar illnesses in adults.

NEONATAL PNEUMONIA Bacterial pneumonia in neonates generally follows acquisition of a pathogen during passage through the birth canal, and is a common focus of early onset neonatal sepsis. The incidence of neonatal bacterial infection is roughly 0.1 percent of all births, but is much greater in “high-risk” infants—infants delivered before the 36th week of gestation, after prolonged rupture of maternal membranes, maternal intrapartum fever, etc. At present group B streptococcus (Streptococcus

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agalactiae, GBS), especially serogroup III, is the most common cause of neonatal sepsis, resulting in up to 60 percent of episodes; enteric gram-negative bacilli (predominantly Escherichia coli) are responsible for roughly 25 percent of episodes, greatly exceeding Listeria monocytogenes.

The widespread adoption of universal third trimester maternal screening for GBS carriage and administration of intrapartum antibiotic therapy to GBS-positive mothers as well as to high-risk mothers at delivery has been successful in reducing significantly the incidence of all forms of invasive GBS disease over the past decade.

Early-onset GBS infection is commonly acquired intrapartum, with clinical evidence of sepsis appearing within the first few hours of life. In contrast, meconium aspiration is more common among term infants and is generally apparent in the delivery room. Respiratory distress, with grunting, flaring, and intercostal retractions, is the most commonly encountered sign of neonatal pneumonia. Thus, infants with GBS pneumonia cannot be readily distinguished clinically from those newborns with respiratory distress syndrome. The presence of fever or hypothermia, irritability, or hypotonia all point toward neonatal sepsis. The white blood cell count is frequently abnormal with either marked leukocytosis and an associated left shift with bands and earlier myeloid forms, or with leukopenia, but is not a reliable indicator of neonatal infection. Approximately half of the chest radiographs of infants with GBS pneumonia demonstrate symmetric ground-glass airspace infiltrates that are indistinguishable from the radiographic findings of hyaline membrane disease (Fig. 121-1).

The remaining infants have asymmetric lobar or multilobar consolidations which are typical of bacterial pneumonia.

The presence of a unilateral pleural effusion in a neonate with pulmonary infiltrates strongly suggests GBS pneumonia. Since the clinical features of GBS pneumonia overlap with those of respiratory distress syndrome, all infants with respiratory distress should undergo a “septic work-up” including blood, urine, and cerebrospinal fluid examination, followed by the empiric administration of ampicillin and gentamicin for 48 to 72 hours pending the results of the initial cultures. Infants requiring intubation and mechanical ventilation because of hypoxemia should also have endotracheally suctioned specimens sent for Gram’s stain and culture. These infants must be monitored for the development of enlarging pleural effusions, which may require drainage to improve ventilatory function, and for the development of metastatic skeletal infections or meningitis. The duration of therapy is determined in part by the presence of bacteremia and metastatic infection, since meningitis will require 3 weeks of therapy, and skeletal infection will require even longer treatment.

Low-birth-weight infants with protracted stays in a neonatal intensive care unit (NICU) are at risk for the late development of nosocomial pneumonia, particularly those infants requiring prolonged intubation in the setting of severe prematurity and respiratory distress, or those with anatomic (e.g., tracheoesophageal fistula, duodenal atresia) or neuro-

Figure 121-1 Early onset group B streptococcal pneumonia.

There are hazy symmetric ‘‘ground-glass” infiltrates bilaterally obscuring the cardiac silhouette. Note the presence of a small right pleural effusion.

logical defects resulting in aspiration. In such infants the spectrum of potential pathogens causing pneumonia is broad. In addition to the conventional neonatal pathogens, nosocomial flora may contain multiply resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), Enterobacteriaceae (Klebsiella, Enterobacter, Serratia), including extended spectrum β-lactamase producing organisms, or nonenteric gram-negative bacilli, such as Pseudomonas aeruginosa or Acinetobacter. Hence, potent broad-spectrum empiric antibiotic therapy such as vancomycin and gentamicin or amikacin, often with a broad-spectrum β-lactam agent such as cefepime or meropenem, should be given until a specific pathogen can be identified; antibiotic therapy can be modified at that time. The particular nosocomial

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pathogens which pose the greatest risks to infants with nosocomial pneumonia reflect colonization patterns which may vary among different hospitals, and so the empiric antibiotic therapy used in this situation is frequently nursery-specific.

Epidemics of nosocomial pneumonia often reflect breaches in standard precautions by physicians, nurses, or other direct care providers, and active surveillance for colonization of highly resistant pathogens as well as infections within NICUs, infant cohorting, and active hand disinfection programs are critical for controlling these outbreaks.

Congenital viral infections such as cytomegalovirus and rubella may occasionally be responsible for pneumonitis early in the neonatal period. Congenitally infected infants who have symptomatic tachypnea and/or hypoxemia in addition to the stigmata of congenital viral infection usually have extensive viral disease, with hepatosplenomegaly, microcephaly, and/or jaundice. Despite the radiologic findings of diffuse interstitial infiltrates, the clinical picture of systemic viral disease usually predominates, and frank respiratory failure is infrequent. In contrast, neonatal herpes simplex virus (HSV) infections are the consequence of intrapartum acquisition of virus through the birth canal of a (generally primarily) infected mother rather than a true congenital infection. Early onset herpetic infection can occur despite the absence of typical perinatal risk factors for bacterial sepsis. HSV pneumonitis in this setting is usually seen in early onset disseminated disease where the systemic features of fulminant herpetic infection with hepatitis, encephalitis, and myocarditis predominate. The prognosis in this setting is poor despite the availability of the nucleoside antiviral acyclovir. Rarely, hemorrhagic pneumonitis may be the sole manifestation of late-onset perinatal HSV infection. Similarly, early postnatal viral infections such as adenovirus may also result in fulminant respiratory failure in previously healthy full-term infants.

PNEUMONIA IN EARLY INFANCY The bacterial pathogens responsible for neonatal pneumonia are rarely encountered after the first month of life, since most episodes of bacterial pneumonia accompany the early onset form of neonatal bacterial sepsis. By the second month of life, infants have an increasing risk of developing viral infection as well as chlamydial pneumonia (Fig. 121-2). Despite the broad range of potential pathogens, the lungs of young infants have a limited repertoire in response to illness. The combination of diminutive airways, compromised further by inflammatory mucosal edema and/or intraluminal secretions, results in characteristic airway obstruction. Infants may wheeze, and chest radiographs demonstrate hyperinflation and interstitial infiltrates, with or without atelectasis. Patchy asymmetric airspace disease may be present as well. Thus, the nonspecific chest radiographic findings are not helpful in narrowing the differential diagnosis, and clinical and epidemiological features guide management and therapy.

Pneumonia in Childhood

Figure 121-2 Chlamydia trachomatis pneumonitis. This 12-dayold infant had stereotypic findings of hyperinflation and asymmetric interstitial infiltrates.

Chlamydia trachomatis Pneumonia Worldwide, C. trachomatis is the most common sexually transmitted pathogen. Vertically transmitted chlamydial pneumonia accounts for up to one-third of pneumonias in infants during the first 4 months of life. Infants generally acquireC. trachomatis during their passage through the birth canal from chronically (and usually asymptomatically) infected mothers, although horizontal infection in a nursery or at home due to inadequate handwashing is possible. The incidence of chlamydial infection is inversely proportional to the motherâ&#x20AC;&#x2122;s age and directly proportional to the number of her sexual partners. C. trachomatis LRTI can develop despite ophthalmia prophylaxis with silver nitrate solution or tetracycline or erythromycin ointments. When infected secretions are aspirated intrapartum, symptomatic LRTI may develop during the first month of life. More commonly, the conjunctivae and/or upper-respiratory tract mucosa are infected initially, with subsequent spread of infection following aspiration of infected upper-respiratory secretions. The illness progresses insidiously, with the gradual development of cough and congestion over several days, with low-grade or no fever. Respiratory distress is generally only mild to moderate unless there is concomitant infection with a second pathogen (such as respiratory syncytial virus) or there is an underlying pulmonary process such as bronchopulmonary dysplasia.

Chest auscultation generally reveals scattered rales, and the chest radiograph shows the nonspecific patchy pneumonitis and hyperinflation pattern described above. Infants often have mild leukocytosis, sometimes with modest eosinophilia.

Hyperglobulinemia is common but nondiagnostic. Only half of infants with chlamydial pneumonitis have associated conjunctivitis. The laboratory diagnosis of chlamydial pneumonia may be confirmed by antigen detection in nasopharyngeal swab samples using monoclonal antibody or nucleic acid

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detection methods, including polymerase chain reaction (PCR) technology. Systemic therapy with erythromycin (50 mg/kg/d divided q 6 h for 14 d) or azithromycin (20 mg/kg/d for 3 d) hastens resolution of symptoms. Infants with conjunctivitis should also receive topical therapy with erythromycin ophthalmic ointment or tetracycline solution.

Acute Viral Pneumonia Most episodes of pneumonia in infants over 2 months of age present as acute febrile illnesses and are due to viral pathogens.

Viral LRTIs may present primarily with clinical and radiologic features of bronchiolitis or with viral pneumonia and may be due to any of a variety of viral pathogens, requiring laboratory confirmation for definitive diagnosis. In addition to the traditionally recognized causes of viral pneumonia in infants and children (respiratory syncytial virus, parainfluenza viruses, influenza, and adenoviruses), which can be diagnosed by rapid antigen detection methods, molecular diagnostic approaches have identified important, newly recognized agents, such as human metapneumovirus and novel coronaviruses.

Respiratory syncytial virus and human metapneumovirus Respiratory syncytial virus (RSV) is the most important cause of LRTI in infants, and is responsible for the majority of hospitalizations for bronchiolitis among young children. Interestingly this incidence has risen steadily over the past 25 years.

Virtually all infections are symptomatic, although there is a clinical spectrum ranging from pure bronchiolitis, with wheezing, atelectasis, and hyperinflation as the dominant clinical features, to pneumonia, with true airspace disease.

Most infants possess features of both processes. RSV circulates widely every winter, although in a given community the peak incidence may shift anywhere from early fall to early spring in a particular year. There are two major RSV serotypes, with considerable genotypic variation within these groups, and in a particular year, a single RSV serotype may predominate. However, the immune response following RSV infection in infants is not significantly protective against symptomatic lower-respiratory tract disease following exposures during subsequent winters regardless of the circulating serotype. The interplay between RSV and the adaptive immune response of infants and children is quite complex, and specific modulation by the RSV envelope G glycoprotein of CD8+ and CD4+ Th1 function may be responsible for the lack of protective immune responses and a propensity for prominent allergic symptoms (Th2 responses). RSV pneumonia is not common until the second month of life, and it is believed that among term infants, transplacentally acquired anti-RSV antibodies may be protective. As the titer of protective antibody wanes, infants are at risk for more severe illness.

RSV infection generally begins with a brief prodromal illness with low-grade fever and nasal congestion and/or rhinorrhea. Within a day or two, infants develop increased fever (101â&#x2014;Ś to 103â&#x2014;Ś F) and progressive respiratory distress, with tachypnea and intercostal retractions. Approximately 1 per-

cent of infected infants develop respiratory distress requiring hospitalization.

Wheezing is prominent, and is believed to reflect mechanical obstruction of the airways due to inflammation, edema, and associated secretions, as well as true immunoglobulin E (IgE)-mediated allergic wheezing. The presence of rales reflects atelectasis and areas of pneumonitis. In very young infants, and in formerly premature infants, the initial presentation of RSV disease may be atypical, with little or no fever or wheezing, and with frequent but less specific episodes of apnea and bradycardia. High-risk infants (i.e., those with severe immunodeficiency states, primary congenital heart disease, particularly those with left to right shunts with pulmonary hypervascularity, pulmonary disease such as bronchopulmonary dysplasia, and low birth weight) are at particular risk for prolonged and life-threatening infection.

In general, RSV infection in children infected with human immunodeficiency virus (HIV) is well-tolerated, although prolonged viral replication and shedding may persist, with attendant risks of nosocomial spread. The specific diagnosis of RSV infection can be confirmed in 85 to 90 percent of cases by rapid antigen detection techniques such as enzymelinked immunosorbent assay (ELISA) or direct immunofluorescence of nasopharyngeal wash specimens. Specimens that are negative by rapid diagnostic methods can be cultured for RSV on Hep2 cells, with diagnostic syncytia appearing after 3 to 6 days. The treatment of RSV infection with the aerosolized nucleoside ribavirin is not often used at present due to concerns regarding efficacy, side effects, and potential teratogenicity risks for health care workers. Hospitalized infants with RSV pneumonia should be isolated (and cohorted if necessary) and placed under contact and respiratory precautions, since the virus can spread by large droplet, fomite, and aerosol. Long-term follow-up has suggested that recurrent wheezing and abnormalities in pulmonary function testing may be common in children after initial episodes of pneumonia and particularly after bronchiolitis, but whether this is a direct effect of RSV or other viral infection or whether subsequent chronic respiratory disease reflects an inherent underlying predisposition to asthma remains controversial.

Passive immunoprophylaxis of high-risk infants against RSV infection has been shown to be safe and protective. The use of a high-titered polyclonal human RSV immune globulin (requiring IV administration) for the first two winters of life has been supplanted by palivizumab, a humanized murine monoclonal antibody to the F surface glycoprotein of RSV (administered intramuscularly); a second-generation monoclonal antibody with enhanced affinity and neutralization is under clinical development.

Human metapneumovirus (HMPV), a syncytiumforming negative-strand RNA virus, characterized in 2001, with significant genetic relatedness to RSV, is now established as the second human pathogen within the viral subfamily Pneumovirinae. It has clearly been associated with bronchiolitis and viral pneumonia in young children as well as in the elderly and immunocompromised. Like RSV, HMPV has two major genotypes, and generally causes significant

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lower-respiratory tract disease in young children. It is estimated that HMPV is responsible for roughly 10 percent of LRTI infections requiring hospitalization in children, confirming that HMPV infections are an important public health issue. Dual RSV/HMPV infections may result in particularly severe illness, but data are limited. In contrast to RSV, rapid antigen-based diagnostic testing is not widely available for HMPV, and PCR-based methodologies are limited to research settings. Thus, most children with HMPV infection fall into the group of infants with typical bronchiolitis and/or viral pneumonia with negative studies. Potential therapeutic and immunoprophylactic strategies for HMPV are only beginning to be formulated.

Other Common Respiratory Viral Pathogens in Infancy Parainfluenza viruses The influenza viruses (of which there may be two type A strains and a type B strain circulating during a particular winter season) and the parainfluenza viruses (PIV, of which there are three major serotypes, 1, 2, and 3, and a less common serotype, PIV4), also are important causes of LRTIs in infants. Although PIV1 is commonly associated with croup (viral laryngotracheitis) among preschool-age children (especially in odd-numbered years), and PIV3 frequently mimics RSV and is more commonly associated with bronchiolitis and viral pneumonitis in the first year of life, all three serotypes may produce any syndrome of upper- and/or lowerrespiratory tract infection. Thus, bronchiolitis and/or viral pneumonia in infants, mimicking RSV infection, may be caused by a parainfluenza virus or even influenza. Although parainfluenza viruses are ubiquitous and responsible for limited serious morbidity among most infants, fulminant disease leading to respiratory failure and death can rarely occur even in the absence of underlying immunodeficiency. Distinguishing among these distinct viral etiologies is of some use in the severely ill, since neuraminidase therapy may be considered for influenza. Aerosolized ribavirin has had only anecdotal usage in parainfluenza virus infection, and is probably even less active in these infections than in RSV disease; thus specific antiviral therapy for PIV is limited to the very rare infants with life-threatening infections. Children with primary or acquired immunodeficiency are at increased risk for developing progressive and ultimately fatal infections with these respiratory viral pathogens, and efforts to establish a prompt etiologic diagnosis by rapid diagnostic testing or viral culture is crucial in order to institute prompt antiviral therapy.

Influenza Like RSV, influenza is a very important cause of lowerrespiratory tract disease in infancy. The remarkable morbidity of influenza in children is demonstrated by the hospitalization rates (approximately 250/100,000) of young children with influenza, rates that are comparable to those of adults over the age of 50. Careful statistics of fatal influenza in children have

Pneumonia in Childhood

been collected only recently, but in a single year (2003) at least 150 children in the United States died of influenza, and nearly half of these deaths occurred in previously healthy children.

Universal immunization of children 6 to 59 months of age, as well as their family members and caregivers, is currently recommended to prevent influenza in children. Prompt diagnosis of influenza is critical if antiviral therapy is under consideration, since the efficacy of antivirals decreases when therapy is instituted after 48 hours of symptoms. When suspicion of influenza is high, the diagnosis may be confirmed by rapid antigen detection testing and the illness treated by the administration of amantadine (8 mg/kg/d divided q 12 h) or, for children over age 1 year, oseltamivir. Antiviral therapies have only moderate activity, shortening the duration of typical influenza illness by about 1 day; it is not clear if they are effective in treating high-risk patients or reducing the incidence of complications and/or severe disease. Unfortunately, there appears to be a significant secular trend toward amantadine resistance among influenza A isolates, so that oseltamivir is becoming the gold standard of anti-influenza therapy. Treatment decisions should incorporate the latest sensitivity data from the World Health Organization (WHO) and/or the Centers for Disease Control (CDC).

Concern has been increasing about H5N1 highly virulent avian influenza strains since the first recent human cases were reported in Hong Kong in 1997. Unlike conventional influenza A, the H5N1 isolates have been notable for remarkable lethality (mortality rate greater than 50 percent among more than 250 reported cases), with particular virulence among infected children. H5N1 disease has a more prolonged incubation period (2 to 8 days), and has been associated with prominent gastrointestinal prodromal symptoms, although multifocal pulmonary infiltrates and respiratory failure follow. Although human-to-human spread of H5N1 virus has been documented as the result of prolonged intimate contact between a mother and her sick child, to date there is little evidence of human adaptation of these strains. H5N1 isolates are resistant to M2 channel inhibitors, and have variable sensitivity to oseltamivir, but neuraminidase inhibitor therapy has been offered as the only therapeutic option.

Additional Respiratory Viral Pathogens Adenoviruses are another important, but sporadic, cause of severe viral pneumonia in infants. The availability of rapid diagnostic tests is helpful from a diagnostic perspective, particularly since some infected children with prominent conjunctivitis and pharyngitis may be thought to have Kawasakiâ&#x20AC;&#x2122;s disease, but no specific therapies are available. An important new strain of human coronavirus (HCoV NL-63, a type I coronavirus) was recently cloned from infants with bronchiolitis using molecular biologic approaches. Like HMPV, HCoV NL-63 is responsible for up to 10 percent of lowerrespiratory tract illnesses (bronchiolitis and viral pneumonia) among hospitalized children whose conventional diagnostic studies are negative. The peak incidence of HCoV infection occurs among children under 2 years of age, similar to RSV

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and HMPV. A nonspecific DNA primer amplification strategy has also identified a novel respiratory tract parvovirus, human bocavirus, which has been detected in respiratory specimens from children with acute respiratory tract infections.

Bocavirus, like HMPV and HCoV NL-63, may be responsible for a significant fraction of LRTIs in hospitalized children.

Acquired cytomegalovirus pneumonia Occasionally, infants in the first two months of life have an indolent syndrome of interstitial pneumonitis which mimics chlamydial pneumonia but actually represents cytomegalovirus (CMV) pneumonia. In contrast to infants with congenital CMV, in whom pulmonary disease is associated with severe congenital infection, otherwise healthy infants may develop mild-moderate respiratory distress as the result of peripartum or neonatal acquisition of CMV through breast milk or, in premature infants, through blood transfusion. A single culture for CMV obtained at the time of respiratory symptoms cannot readily distinguish between postnatal primary infection and asymptomatic shedding of congenitally acquired CMV. Otherwise uncomplicated postnatal CMV pneumonia does not serve as an indicator of significant underlying immunodeficiency. Extreme low-birth-weight infants with perinatally or postnatally acquired CMV may have more severe chronic lung disease than uninfected infants, but the role of ganciclovir therapy in this population has not been studied.

Additional Causes of Pneumonia in Infancy Conventional clinical diagnostic techniques for chlamydial and viral pathogens fail to identify a pathogen in up to half of all cases of pneumonia in infants. As noted above, a significant fraction of these infections may be due to viral agents, such as HMPV and HCoV NL-63, for which routine testing is not available. Additional microbiological and serological analyses have suggested that occasional infants may have neonatal pneumonia due to Pneumocystis carinii and Ureaplasma urealyticum in addition to the conventional pathogens described above. Pneumonitis associated with these pathogens was not readily distinguished from infections due to C. trachomatis.

The short-term prognosis of these infections is presumably favorable, since diagnostic techniques to identify such infections are not employed in most centers, and infants with indolent pneumonia generally do well with supportive care.

PNEUMONIA AFTER THE FIRST 6 MONTHS OF LIFE After the first 4 to 6 months of life, C. trachomatis pneumonia is no longer observed. Longitudinal studies of LRTIs in infants and children using conventional microbiological and serological techniques to determine the specific etiologies of pneumonia in infancy fail to identify a specific pathogen in roughly half of all episodes. Combined antigen detection

testing, newer serological tests, and pneumolysin PCR testing identified approximately 80 percent of responsible agents, and multiplex PCR testing identified viral etiologies, due to the same viral pathogens that are responsible for viral pneumonia in early infancy, in approximately 90 percent of all episodes of pneumonia. Such intensive techniques commonly identify dual viral or mixed viral-bacterial infections. As noted above, recurrent symptomatic RSV disease in the second and third years of life is very common, and often results in clinically significant episodes of bronchiolitis and/or RSV pneumonia.

Since the related parainfluenza and influenza agents represent at least six immunologically distinct pathogens that circulate in epidemic fashion each year, it is not surprising that infants remain at risk to develop significant viral pneumonia. The diagnostic and therapeutic challenges of managing community-acquired pneumonia in children were recently summarized by McIntosh.

Bacterial Pneumonia Although far less common than viral pneumonia, bacterial pneumonia may be difficult to distinguish prospectively on clinical grounds from episodes of viral pneumonia. Both forms of pneumonia are common during the first two years of life after the neonatal period. Since the pathogenesis of bacterial pneumonia generally represents aspiration of pharyngeal pathogens, often in the setting of inflammatory edema and increased secretions triggered by an upper-respiratory tract infection, both processes may have similar initial prodromal findings associated with a low-grade fever. As the lowerrespiratory process evolves, infants and toddlers will have similar features of significant fever, tachypnea, and possible respiratory distress with acral cyanosis and intercostal retractions regardless of etiology. A few physical findings are helpful: diffuse wheezing, when present, usually reflects bronchiolitis, making RSV or other viral pathogens (especially HMPV, parainfluenza viruses, and to a lesser extent, influenza viruses) the likely cause of infection. Similarly, markedly asymmetric breath sounds, with unilateral percussive dullness or a unilateral pleural friction rub, strongly suggest bacterial infection with spread of disease to the pleural space. Laboratory findings are also often nonspecifically abnormal, since the presence of moderate leukocytosis (e.g., to 15,000) and band forms may be seen in either type of pneumonitis. Extreme leukocytosis, with abundant early forms, usually suggests a bacterial process, often with bacteremia and/or spread of infection to the pleural space. Blood cultures should routinely be obtained in children with high fever, leukocytosis, or moderate respiratory distress, since such cultures may represent the only ready approach to recovering a bacterial pathogen.

Chest radiographs are sensitive but surprisingly nonspecific in attempting to assess the etiology of pneumonia in children.

Although focal consolidation is usually caused by bacterial infection, viral pneumonia may present with a dense focal infiltrate (Fig. 121-3). Conversely, bacterial infection may be associated with patchy segmental infiltrates or even interstitial changes, particularly in younger children. Radiologic

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A

B

Figure 121-3 Viral pneumonia. A. This infant’s chest radiograph is notable for hyperinflation and asymmetric interstitial infiltrates, representing a combination of atelectasis and pneumonitis. B. The presence of focal consolidation does not reliably distinguish between bacterial and viral infection in young children. This child did not respond to intravenous antibiotic therapy, and adenovirus was recovered in anasopharyngeal specimen.

investigation is helpful in assessing the extent of disease and the presence of intrathoracic complications, but has a more limited role in determining the etiology of pneumonia. Thus, the pediatrician must often initiate antimicrobial therapy for possible bacterial pneumonia based on inconclusive clinical and laboratory findings. In patients sufficiently ill to require hospitalization who have difficulty clearing respiratory secretions, nasotracheal suctioning should be considered both for pulmonary toilet as well as for diagnostic testing (Gram’s stain and culture).

Even when these parameters point toward a bacterial process, identification of a specific pathogen remains problematic. Only the most severely ill infants and children

Pneumonia in Childhood

have bacteremia accompanying pneumonia. Unless a bacterial pathogen is recovered from the blood or from a site of a secondary infection (pleural fluid, joint fluid, cerebrospinal fluid), the specific etiology cannot be readily determined. It is not generally possible to obtain expectorated sputum, and invasive attempts at culture at the time of nasotracheal suctioning or bronchoscopy may be unrewarding because of the incidental recovery of pharyngeal flora, or because prior antibiotic therapy suppresses the recovery of the true pathogen in the lung. In general, rapid bacterial antigen detection techniques have not been helpful in determining the etiology of pneumonia in children because of limited sensitivity. Recovery of the pathogen from a sterile site facilitates antimicrobial susceptibility testing, but most episodes require empiric therapy.

The microbiology of community-acquired pneumonia in infancy and early childhood reflects pharyngeal carriage of respiratory pathogens, and the spectrum of causative agents resembles that seen with otitis media. The dissemination of antibiotic resistant strains of Streptococcus pneumoniae and S. aureus in recent years has complicated empiric antibiotic therapy for childhood pneumonia. Although amoxicillin is inexpensive and well-tolerated, one can predict that conventional dose amoxicillin therapy will be efficacious in less than 85 percent of cases. Since failure of initial oral therapy may lead to hospitalization and greatly enhanced morbidity and expense, one should consider high-dose amoxicillin (approximately 100 mg/kg/d) to cover possible penicillininsensitive S. pneumoniae isolates, or with more severe disease, an initial broad-spectrum oral agent, such as a secondor third-generation cephalosporin, to decrease the risk of primary antibiotic failure; macrolide resistance is generally high among pneumococci with reduced β-lactam susceptibility. Among hospitalized infants, the use of ceftriaxone has become increasingly popular since it is effective against β-lactamase–producing strains of Haemophilus influenzae and Moraxella and all but a small fraction of penicillinresistant pneumococci. Nevertheless, it has limited efficacy against conventional S. aureus pneumonia and no activity against MRSA. The β-lactam/β-lactamase inhibitor combination agents such as ampicillin-sulbactam are also popular although more costly, and are ineffective against fully penicillin-resistant pneumococci as well as MRSA.

Pneumococcal Pneumonia Pneumococci are the cause of most episodes of bacterial pneumonia in infants and children. The importance of polysaccharide-based serotype-specific opsonizing antibody, and the inability of children to mount anti-polysaccharide antibody responses in the first two years of life presumably explain why these encapsulated pathogens cause pneumonia so frequently. Pneumococci colonize the upper-respiratory tract, and spread contiguously to cause otitis media and sinusitis as well as pneumonia, or invade the bloodstream primarily from the pharynx or secondarily from the initial sites of invasive infection. Children with sickle cell disease or other

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hemolytic anemias associated with splenic dysfunction are at particular risk of life-threatening infection. The adoption of a heptavalent polysaccharide-carrier protein conjugated pneumococcal polysaccharide vaccine in 2000 into routine infant immunization practice has had a striking impact in reducing invasive pneumococcal infections due to these prevalent serotypes, but the decline in pneumonia episodes among immunized children was a more modest 17 percent overall (although the decline was 32 percent in infants under 1 year of age).

Haemophilus influenzae Pneumonia The routine use of conjugate H. influenzae type b (Hib) vaccine, the first polysaccharide-carrier protein conjugate vaccine, led to a marked diminution in pharyngeal carriage of Hib and a virtual disappearance of invasive Hib disease. Nevertheless, upper-respiratory carriage of nontypeable H. influenzae persists, and these strains continue to cause otitis, sinusitis, and pneumonia. The risk of bacteremia and metastatic infection is very low following nontypeable H. influenzae pneumonia, in contrast to the significant frequency of metastatic infections associated with Hib pneumonia. A significant fraction of these strains produce β-lactamase, requiring therapy with a second- or third-generation cephalosporin or a β-lactam/β-lactamase inhibitor combination. If an infant has proven invasive Hib disease, family contacts (as well as the index case) should receive eradicative therapy with rifampin.

Staphylococcal Pneumonia S. aureus pneumonia is associated with necrotizing infection in infants, just as in older patients. Nasal carriage may lead to the aspiration of staphylococci, particularly in the setting of an acute viral upper-respiratory tract infection. Severe systemic toxicity, respiratory distress, and clinical and/or radiologic evidence of necrotizing pneumonitis are common. Chest radiographs characteristically demonstrate focal airspace disease, often with lobar consolidation, associated with cavitation or the development of smaller subpleural pneumatoceles. Pleural space involvement is also common, and frequently patients with S. aureus pneumonia present with dyspnea due to a giant pleural effusion. Depending on the duration of illness before evaluation, the pleural effusion may be small or large, and free-flowing or loculated.

Later diagnosis is associated with larger and more viscid or even loculated pleural effusions. Pneumothorax or pyopneumothorax may develop, depending on the extent of subpleural necrotizing infection. These extensive abnormalities are not unique for staphylococcal pneumonia, and are occasionally encountered in the course of other bacterial infections in children, particularly in aspiration pneumonitis and, rarely, in pneumococcal disease. Traditionally, initial empiric antibiotic coverage with a second-generation cephalosporin such as cefuroxime or with ampicillin/sulbactam was reasonable. If staphylococcal disease was confirmed, antibiotic ther-

apy with high doses of a semisynthetic penicillin (nafcillin, 200 mg/kg/d), or a first-generation or second-generation cephalosporin (cefazolin, 100 mg/kg/d or cefuroxime, 150 mg/kg/d, respectively) were administered. In patients who have immediate hypersensitivity to β-lactam agents, parenteral clindamycin (40 mg/kg/d) is far easier to administer than vancomycin (30 to 40 mg/kg/d). However, the current epidemic of methicillin-resistant staphylococcal infections (MRSA) has complicated empiric management considerably.

Widespread MRSA disease is primarily due to the sudden appearance and rapid dissemination of MRSA infection among individuals who lack epidemiological risk factors for the acquisition of nosocomially spread MRSA. These communityacquired strains (CA-MRSA) are readily distinguished from nosocomial strains by greater susceptibility to other antistaphylococcal agents such as macrolides, clindamycin, and trimethoprim-sulfamethoxazole, as well as by the presence of the Panton-Valentine leukocidin (PVL), a potent virulence factor in CA-MRSA strains. In many communities, MRSA is now responsible for a majority of serious skin and softtissue S. aureus infections, and vancomycin is necessary when treating likely staphylococcal disease, especially necrotizing pneumonia.

The management of pleural space infection varies widely among institutions due to variations in local expertise as well as the paucity of controlled clinical trial data to establish best practices. Thoracentesis has the potential of confirming the microbiologic diagnosis and establishing antimicrobial susceptibilities, reducing respiratory distress by enhancing lung expansion, and preventing the evolution of a thick, loculated empyema which may be the source of continuing respiratory distress and ongoing infection. Thoracentesis under sedation or anesthesia, particularly when guided by ultrasound or computed tomography (CT) scan, is a generally safe procedure even in infants and young children. When the fluid is thin, free-flowing, and not grossly purulent, the initial drainage procedure aimed at evacuating the pleural space is generally sufficient. If the initial fluid is turbid or viscous, thoracostomy drainage (pigtail catheter vs. larger bore surgical thoracostomy tube) should be instituted. The clinical course following closed drainage procedures is usually one of gradual improvement; fever for a week or more is common. Although generally safe, the efficacy of thrombolytic therapy as part of the management of pediatric empyemas remains controversial. Unfortunately, many infants are referred to a tertiary care center after the development of established empyemas, and remain persistently febrile with an increasing erythrocyte sedimentation rate despite placement of an initial chest tube. Sometimes persistent loculated infection may be identified by ultrasound or chest CT scan and evacuated by additional drainage procedures, but often these infants will require video-assisted thoracoscopy (VATS) with evacuation of the loculated pleural space infection and placement of additional thoracostomy tubes or open thoracotomy and decortication. In some centers early utilization of VATS as the primary drainage procedure has reduced the length of in-hospital stay.

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Streptococcal Pneumonia Pneumonia due to group A streptococcal infection is, like staphylococcal disease, commonly associated with the development of pleural effusions. In contrast to staphylococcal pneumonia, where empyema is a relatively late complication of destructive subpleural infection, group A streptococcal pneumonia elicits a prompt and marked increase in lymphatic drainage. When the rate of inflammatory edema generation exceeds the fixed capacity of pulmonary lymphatic vessels to drain this fluid, the excess lymphatic drainage accumulates as a pleural effusion. These collections occur very frequently with group A streptococcal pneumonia, and may be considered a part of the process rather than a complication. The effusions are generally free-flowing and often sterile parapneumonic collections early in the course of infection. These collections may become infected as group A streptococci are carried to the pleural space, and may become exudative in character, resulting in frank empyemas requiring surgical debridement. Once again, early intervention by percutaneous drainage may obviate the need for more extensive surgical procedures late in the course of the infection. In addition to concerns regarding the local complications of group A streptococcal pneumonia, one must be vigilant for the possible systemic sequelae following group A streptococcal infection.

The expression of pyrogenic exotoxin A, particularly in M serotypes 1 and 3, has been associated with the development of streptococcal toxic shock syndrome, with scarlatiniform rash, shock, and multiple-organ system dysfunction.

Atypical Bacterial Pathogens The atypical bacterial pathogens Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila are often considered together as “atypical” pathogens because of their inability to grow on routine bacterial culture media, the prominence of nonproductive cough, and their responsiveness to macrolide therapy.

Mycoplasma pneumoniae The frequency of pneumonia due to the encapsulated bacterial pathogens such as pneumococci and H. influenzae decreases with increasing age, as do all invasive infections associated with these pathogens. Traditionally, young children with mycoplasma infection were thought to have mild or nonlocalizing infections, while school-age children developed “atypical pneumonia.” The syndrome of M. pneumonia in schoolage children, which is probably responsible for greater than 50 percent of all episodes of pneumonia in this age group, closely resembles symptomatic infection in adults who manifest an indolent influenzal illness, with fever, pharyngitis, myalgias, headache, and a progressive hacking nonproductive cough, or (in older children) a cough productive of mucoid or mucopurulent sputum. Although symptomatic atypical pneumonias were considered to be rare in young children, based on culture and complement-fixing antibody studies, more recent studies of pneumonia in young children,

Pneumonia in Childhood

using reverse transcriptase-polymerase chain reaction (RTPCR) or more sensitive serological assays, have demonstrated that roughly half of mycoplasmal and chlamydial infections develop in children under age 5, perhaps reflecting spread within day care centers. A variety of extrapulmonary features may be present, such as rash (including urticaria, maculopapular eruptions, erythema multiforme, and StevensJohnson syndrome), hemolytic anemia, bullous myringitis or meningoencephalitis, or rarely, hepatitis, perimyocarditis or arthritis. On occasion these features overshadow any mild pulmonary symptoms that a child may have, or occur in the absence of any respiratory tract complaints. Immunocompromised children and children with sickle cell disease may have more complicated illness, and Mycoplasma is a well-recognized cause of the acute chest syndrome. Indolent intrafamilial secondary spread of infection occurs regularly, with sequential illnesses occurring among siblings separated by intervals of 1 to 2 weeks. Physical examination is notable for fever and tachypnea, but there is often a paucity of adventitial sounds on chest auscultation. The radiologic features of M. pneumoniae may range from patchy asymmetric bibasilar infiltrates with plate-like atelectasis to dense focal airspace disease suggestive of bacterial pneumonia. Pleural effusions and hilar adenopathy may occur but are infrequently seen.

Laboratory diagnosis of M. pneumoniae infection currently relies generally upon nucleic acid detection technology such as RT-PCR; serological confirmation of mycoplasmal infection requires paired acute and convalescent specimens. The development of cold agglutinins, immunoglobulin M (IgM) antibodies reactive with autologous erythrocytes, occurs in a minority of patients and is not truly specific for mycoplasmal disease. Thus, the diagnosis of M. pneumoniae is a presumptive one in children, especially in outpatients, and the most likely cause of pneumonia in school-age children. The differential diagnosis of atypical pneumonia includes adenoviral infection and C. pneumoniae infection. Both mycoplasmal and chlamydial infections respond to macrolide therapy, as do many pneumococcal infections; consequently, macrolides are routinely administered for the treatment of pneumonia in school-age children. In children who are intolerant of erythromycin, the newer macrolide agents, clarithromycin or azithromycin, may be given. Alternatively, tetracycline administration may be considered in children over the age of 8 years of age.

Chlamydia pneumoniae pneumonia A second rather common cause of atypical pneumonia is attributed to the chlamydial species C. pneumoniae. C. pneumoniae infections have a broad spectrum of illness and range from asymptomatic seroconversion and mild isolated upperrespiratory tract syndromes (pharyngitis and/or sinusitis) to bronchitis and clinically significant episodes of pneumonia; it is thought to be responsible for over 10 percent of cases of community-acquired pneumonia in children over the age of 5 as well as in adults. Co-infection with Mycoplasma or S. pneumoniae or common viral pathogens often occur.

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Pneumonia due to C. pneumoniae in young children, once thought to be rare, is now recognized more readily by sensitive serological or nucleic acid techniques. Pharyngitis is more common with this agent than with M. pneumoniae, although in individual patients, distinction between these two illnesses using clinical criteria is difficult and not really necessary, since both agents respond to macrolide or tetracycline therapy.

Legionnairesâ&#x20AC;&#x2122; disease Seroepidemiological surveys of pediatric inpatients with pneumonia have documented a widely variable incidence (less than 2 to 52 percent) of L. pneumofila among children of all ages, presumably reflecting variation in environmental exposures. Although most children with Legionella infection are chronically ill due to a variety of underlying diseases, including hematologic malignancy and/or immunosuppression, no discrete pattern of underlying immunodeficiency has been specifically associated with the development of legionellosis. The clinical features of pediatric legionellosis mimic other bacterial processes, with fever, cough, and tachypnea, and are associated with unilateral or bilateral infiltrates, and cavitation or pleural effusion in a significant fraction of patients. Environmental exposures, particularly to contaminated sources of warm water, remain the dominant risk factor for Legionella infection. Nosocomial infections, including nosocomial pneumonia in premature infants in neonatal intensive care units, are an important problem.

Although macrolide therapy is beneficial, an extremely high index of suspicion is required to pursue this diagnosis among pediatric patients. Rapid diagnostic options include urinary antigen testing for L. pneumophila serogroup 1 and direct fluorescent antibody staining or PCR testing of secretions.

Culture of secretions on selective media and serological diagnosis (documenting either a high-titered acute specimen or a conventional rise or fall in paired serum samples) are also available. The presence of legionellosis among adults within a community due to an endemic source or an acute epidemic of legionellosis should alert pediatricians to the risk of L. pneumofila among children within the community.

Figure 121-4 Miliary tuberculosis. The miliary pattern is quite prominent in this radiograph. Routine chest radiography may be normal in miliary tuberculosis.

effective, presumably because of subtle developmental deficiencies of T-lymphocyte activation and/or macrophage mycobactericidal activity. As a result, mycobacterial proliferation at the site of primary infection may result in local spread of organisms (producing primary tuberculous pneumonia (Fig. 121-5) as well as spread through the regional lymph nodes (with early bacillary dissemination to extrapulmonary foci of infection). Infants and children with primary tuberculous pneumonia are often only mildly ill, with persistent

TUBERCULOSIS The prompt diagnosis and therapy of tuberculosis in children is particularly important since the development of lifethreatening complications such as tuberculous meningitis or miliary tuberculosis (Fig. 121-4) can develop soon after the clinical onset of primary tuberculous pneumonia in infants and young children. The development of tuberculosis in a child reflects the presence of a contagious individual within the patientâ&#x20AC;&#x2122;s circle of family, neighbors, or day care or school personnel. The pathogenesis of tuberculosis in young children is the same as for adults (i.e., one or a few M. tuberculosis bacilli are inhaled as small droplet aerosols and deposited within an alveolus, typically in a lower lobe). Unlike adults with primary tuberculous infection, in children the local and regional lymphatic barriers to mycobacterial dissemination are often less

Figure 121-5 Acute tuberculous pneumonia. This 15-year-old Haitian boy had slowly progressive fatigue, cough, and low-grade fever for 1 month prior to evaluation.

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cough in the setting of little or no fever despite (often repeated courses of) conventional oral antibiotic therapy. Chest radiographs demonstrating paratracheal or hilar adenopathy ipsilateral to an area of airspace consolidation strongly suggest possible mycobacterial infection. At times, atelectasis or lobar emphysema may be seen due to extrinsic compression of a bronchus by enlarged lymph nodes, and this may be accompanied by localized wheezing. The presence of pleural effusions or pulmonary cavitation is rare in children with primary tuberculosis. A positive tuberculin reaction usually develops within 4 to 6 weeks of initial infection, so that many children have a positive Mantoux test at the time they are evaluated for persistent respiratory symptoms. The presence of a compatible clinical illness with a positive Mantoux test provides presumptive evidence for M. tuberculosis infection.

Since young children lack a productive cough, confirmation of the diagnosis can be achieved in roughly half of cases through the culture of gastric aspirates obtained by nasogastric suction each morning on three successive days, or by bronchoscopy (usually reserved for children where the differential diagnosis may be broader or where airway compromise mandates bronchoscopy to exclude the presence of an obstructing foreign body). It is highly desirable to obtain an M. tuberculosis isolate for each child in order to confirm the diagnosis and determine antibiotic susceptibility, although this information generally can be extrapolated safely from a newly diagnosed index case.

The therapy of tuberculosis in children utilizes the same principles used to treat adult tuberculosis, but unique challenges arise due to the lack of pediatric formulations and limited outcomes data. Initial combination chemotherapeutic regimens should include isoniazid, rifampin, and pyrazinamide. In communities where there is significant concern regarding drug-resistant tuberculosis, such as among immigrants and in children residing with adults who have failed conventional therapy for tuberculosis (including patients with HIV infection), ethambutol should be included as a fourth initial agent until a childâ&#x20AC;&#x2122;s isolate has been studied for drug resistance. After a 2-month course of intensive (3- or 4-drug) therapy, in the absence of proven drug resistance, pyrazinamide and ethambutol may be stopped to complete a 6-month course of therapy. The incidence of isoniazid hepatotoxicity in children is considerably lower than in adult patients, but monitoring for hepatotoxicity in the setting of multidrug regimens is prudent. Although the ocular toxicities associated with ethambutol use cannot be elicited by history or color vision screening in young children, the incidence of this side effect is very low, particularly when ethambutol dosage is reduced to 15 mg/kg/d following an initial 4- to 6-week period of 25 mg/kg/d.

PNEUMONIA COMPLICATING CHILDHOOD VIRAL EXANTHEMS Both varicella and measles may be complicated by the development of primary viral pneumonia as well as life-threatening

Pneumonia in Childhood

bacterial superinfection. Pneumonia is a common complication requiring hospitalization among children with varicella (mean age 4 to 6 years) and measles (mean age 2 years), and occurs among normal as well as immunocompromised children.

Varicella Varicella pneumonia generally develops a few days after the onset of the typical bullous eruption, but can occur before the onset of the rash. Symptoms of dyspnea, cough, and tachypnea are associated with an interstitial and fine nodular infiltrate, and may be severe, requiring intubation and mechanical ventilation. The prognosis generally is favorable if the child can be supported adequately during the acute phase of the illness. Symptomatic pneumonitis in this setting should lead to the prompt institution of parenteral acyclovir therapy (30 mg/kg/d divided q 8 h). Bacterial superinfection occurs in a large fraction of children with varicella pneumonia. This complication is associated with the development of typical focal consolidation and can be accompanied by the development of a pleural effusion or frank empyema. The common bacterial pathogensâ&#x20AC;&#x201D;S. pneumoniae, S. pyogenes, S. aureus, H. influenzaeâ&#x20AC;&#x201D;are the usual etiologic agents, and require appropriate antibiotic coverage in addition to primary therapy with acyclovir. Although the risk of varicella pneumonia is extremely high in children receiving chemotherapy for hematologic malignancy, the risk of serious visceral complications is actually rather low in children with HIV infection. Neonates with peripartum exposure to maternal varicella are also at high risk of developing primary varicella pneumonia, and should be given zoster immune globulin at birth and parenteral acyclovir if they develop varicella.

Measles The epidemiology of measles pneumonia and its complications closely resemble the features of varicella pneumonia, although most cases of measles pneumonia are seen in younger children. In contrast to the low incidence of varicella pneumonia in children, radiologic evidence of pulmonary involvement is more frequently seen in measles (2.7 to 36 percent), although some children have few symptoms, and some children develop a croup syndrome rather than pneumonitis. Primary measles pneumonia is associated with a diffuse interstitial infiltrate, and may also be associated with the development of secondary bacterial pneumonia. Fulminant respiratory failure may develop in association with diffuse interstitial pneumonia, diffuse airspace consolidation consistent with the adult respiratory distress syndrome, bacterial pneumonia, and/or spontaneous pneumothorax prior to intubation and mechanical ventilation. As with varicella pneumonia, typical community-acquired bacterial pathogens are generally responsible for bacterial pneumonia, and may be associated with bacteremia. The acute mortality of measles pneumonia requiring intensive care support approaches 50 percent, and pulmonary fibrosis and/or bronchiolitis obliterans may develop during after the acute phase of illness.

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ASPIRATION PNEUMONIA Aspiration commonly is observed among children with strong clinical risk factors for this complication, so that the diagnosis of aspiration pneumonia is usually rather straightforward. Infants with neonatal asphyxia and other causes of profound neurological impairment frequently have feeding difficulties and may aspirate oral feeds or saliva. In these infants, fundoplication and placement of a feeding gastrostomy tube may reduce the risk of aspiration of gastric contents but not of oral contents. However, aspiration pneumonia may occur in otherwise normal infants (Fig. 121-6). Aspiration during or shortly after feeding is most commonly due to gastroesophageal reflux and is far less commonly due to tracheoesophageal fistulae or vascular ring anomalies. Thus, the occurrence of aspiration pneumonia in infants mandates an appropriate diagnostic evaluation in addition to antibiotic therapy. Similarly, infants with recurrent pneumonia may be aspirating despite the absence of apparent feeding difficulty, and should undergo a structural evaluation in addition to the screening studies for occult immunodeficiency. Aspiration pneumonia is also a common complication of status epilepticus and of posttraumatic neurological injury, and may be seen as a complication of general anesthesia, particularly after emergency procedures. Older children may develop aspira-

tion pneumonia as the result of alcohol or drug use or from primary neuromuscular disorders such as muscular dystrophy or myasthenia gravis, or generalized metabolic disease including the mitochondrial disorders. The radiologic features of aspiration pneumonia usually demonstrate the expected airspace consolidation in the dependent portions of the lung, recognizing that infants and children may be supine at the time of aspiration. Cavitation or pleural disease is infrequently seen at the time of initial evaluation, since the interval between the aspirational event and presentation with pneumonia is usually brief. A radiopaque foreign body is occasionally seen on chest radiograph and mandates prompt bronchoscopy.

The therapy of aspiration pneumonia depends on the child’s age and overall clinical status. Neonates are usually given ampicillin and gentamicin to treat the conventional neonatal pathogens, since infants are not usually colonized by anaerobic bacteria until the eruption of primary dentition. Colonization of the normal oropharynx by ampicillinresistant encapsulated pathogens such as H. influenzae or Moraxella catarrhalis or β-lactamase producing anaerobes offers a rationale for treating older infants and toddlers with a β-lactamase–resistant regimen such as ampicillin sulbactam or a combination of metronidazole together with ceftriaxone or cefuroxime. Chronically ill children have an increased risk of colonization by Enterobacteriaceae. In older children ampicillin-sulbactam or clindamycin (in β-lactam– allergic patients) may be considered for serious infections, and penicillin or ampicillin for milder episodes. A poor response to initial antibiotic therapy may be the result of inadequate antibiotic coverage or the presence of an obstructing endobronchial foreign body. Aspirated foreign bodies are particularly common in toddlers and preschool children who often place small objects in their mouths. Bronchoscopy is indicated in children who respond poorly to therapy or develop cavitation or empyema to exclude the presence of a foreign body as well as to obtain suitable endotracheal specimens for bacterial culture, and to improve bronchial drainage.

PNEUMOCYSTIS JIROVECI PNEUMONIA (PCP)

Figure 121-6 Aspiration pneumonia. This toddler presented with a loculated empyema (note multiple air-fluid levels) which grew mixed oropharyngeal flora in association with left lowerlobe pneumonitis.

Symptomatic infections in children due to P. jiroveci generally occur in infants rendered immunodeficient by profound malnutrition, and in children of any age with significant compromise of cell-mediated immunity due to underlying disease or to immunosuppressive chemotherapy (Fig. 121-7). A more benign form of PCP in normal infants has also been reported. The infantile form of P. jiroveci is an indolent and generally afebrile process manifested by progressive tachypnea and poor feeding over a period of weeks. In contrast, older children typically present with an acute febrile illness with nonproductive cough and tachypnea disproportionate to the bland physical examination and often mild symmetric interstitial and fine alveolar infiltrate present on chest

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risk factors, and recurrent infections distributed throughout the lungs suggest systemic causes of heightened susceptibility to infection.

Recurrent Focal Pneumonia

Figure 121-7 Pneumocystis jiroveci pneumonia in a teenager with acute leukemia. Depending on the extent of disease at the time of presentation, there may be predominance of interstitial or airspace disease. The radiographic findings are nonspecific, and may mimic viral pneumonitis and noninfectious causes of interstitial and alveolar lung disease such as drug hypersensitivity reactions.

Recurrent pneumonia in a single lobe may be due to a variety of intraluminal lesions, particularly the presence of a foreign body, or to extraluminal compression due to enlargement of perihilar or regional lymph nodes due to granulomatous infection or malignancy (Fig. 121-8). In addition, a variety of pulmonary or bronchial lesions may be responsible for recurrent infection. Bronchial stenosis and bronchiectasis (especially involving the right middle lobe bronchus) are the most common bronchial abnormalities responsible for recurrent focal pneumonia. Congenital lesions such bronchogenic cysts and pulmonary sequestra may present as recurrent or nonresolving pneumonia. Since these structures lack normal communications with functional bronchi, pneumonitis which develops in these regions as a result of contiguous spread of infection from normal lung is slow to resolve and frequently fails conventional medical therapy. Aspiration should be considered in the setting of recurrent basilar pneumonia. Evaluation of children with recurrent focal pneumonia should begin with chest CT scanning and bronchoscopy to identify obstructing intraluminal lesions, intrinsic bronchial abnormalities such as bronchiectasis, extrinsic bronchial compression, or

radiograph. The course of P. jiroveci infection in HIV-infected children may be quite variable, and resemble either the indolent progressive course seen in malnourished infants or the more rapidly progressive illness seen in older children. The diagnosis of PCP can be made noninvasively in older children by microscopic examination of induced sputum, but in infants and young children bronchoscopy or lung biopsy is required.

Trimethoprim-sulfamethoxazole therapy remains the mainstay of treatment, usually given at a dosage of 20 mg/kg/d of the trimethoprim component divided q 6 h for 2 to 3 weeks.

Children intolerant to sulfonamide therapy are usually given intravenous pentamidine 4 mg/kg/d for 2 weeks. Short-term administration of methylprednisolone (1 mg/kg q 6 h for 7 d, followed by 7-day tapering course) has been associated with improved survival in HIV-infected patients. Long-term prophylaxis (with trimethoprim-sulfamethoxazole or one of several alternate regimens) is essential to reduce the risk of relapse.

RECURRENT PNEUMONIA The occurrence of more than one episode of focal consolidative pneumonia, especially within a 1-year interval, raises concerns that a child may be experiencing recurrent pneumonia due to local or systemic risk factors. The radiologic distribution of these infiltrates directs the subsequent evaluation: recurrent pneumonia in a single lobe or lung suggests local

Figure 121-8 Recurrent pneumonia. This 5-year-old girl had three episodes of right lung consolidation, involving different lobes, shortly after immigrating to the United States from the Azores Islands. At bronchoscopy, cellophane tape was recovered from the right mainstem bronchus.

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congenital malformations and serves as the primary modality for the removal of retained foreign material. When pulmonary sequestration is suspected, vascular imaging by conventional contrast or magnetic resonance angiography demonstrates the aberrant systemic vascular supply associated with these lesions.

Recurrent Pneumonia in Different Locations Compromise of any of a variety of pulmonary or systemic host defense mechanisms may be associated with recurrent pneumonia, and in the setting of a such a generalized impairment, recurrent infections may occur anywhere in the lungs.

Defects in Pulmonary Defenses Abnormalities in the bronchial mucociliary transport system are important considerations. Children with cystic fibrosis (CF) first may become symptomatic beyond the neonatal period with recurrent bronchopneumonia rather than with a picture of steatorrhea and failure to thrive, as is common in neonates. A large number of distinct CF genotypes have been identified, and some are associated with a later and milder onset of respiratory symptoms; in fact, on occasion the diagnosis of CF may not become apparent until adulthood.

A family history of CF is often lacking among the families of children with CF. Initial episodes of pneumonia in these patients may be associated with conventional encapsulated bacterial pathogens or S. aureus; the development of chronic P. aeruginosa infection may be a relatively late event. The diagnosis should be explored with pilocarpine iontophoresis testing (“sweat test”) at a center experienced in the diagnosis of CF, with genetic screening considered for borderline tests.

In contrast, congenital abnormalities of the ciliary system are very rare. Kartagener’s syndrome of bronchiectasis, sinusitis, and dextrocardia is a subset of the group of immotile ciliary disorders. Such children often experience recurrent upper-respiratory tract infections such as sinusitis and suppurative otitis media in addition to recurrent pneumonia.

Ciliary disease can be assessed by analysis of ciliary beat frequency from nasal mucosal specimens. The classic method of diagnosing immotile cilia based on ciliary morphology requires electron microscopic analysis of a bronchial biopsy.

This procedure should be performed some weeks after recovery from an acute episode of pneumonia, since ultrastructural abnormalities may be seen after infection in the absence of a heritable ciliary defect. Tracheomalacia and tracheobronchomegaly (Mounier-Kuhn syndrome) also impair clearance of mucus and are associated with recurrent pneumonia.

Defects in Systemic Host Defenses Humoral immunodeficiency Humoral immunodeficiency states are the most common host defects associated with recurrent bacterial pneumonia.

A variety of different antibody deficiency syndromes have been identified. Bruton’s (X-linked) agammaglobulinemia is

the most extreme example with a virtual absence of all circulating immunoglobulins. The hyper-IgM syndrome is due to the inability of T cells to activate B cell CD40 which is necessary to drive B-cell differentiation to produce normal quantities of IgG and IgA antibodies. In these children with profound hypogammaglobulinemia, recurrent pyogenic infections, including recurrent pneumonia, develop after transplacentally derived maternal antibody wanes following the first 6 months of life. Common variable hypogammaglobulinemia and transient hypogammaglobulinemia of infancy have moderate reductions in IgG and IgM levels, and may have little or no IgA. In contrast to these more dramatic conditions, IgG subclass deficiency states, particularly of IgG2 and IgG4, have been associated with recurrent respiratory tract infections. Rarely, patients with normal IgG subclass levels have an isolated inability to mount IgG responses to the conventional encapsulated bacterial pathogens; this can be assessed by obtaining pre- and post-immunization titers after administering a bacterial polysaccharide vaccine. Definitive therapy with intravenous immunoglobulin (IVIG) administration can be cumbersome, especially in young children where peripheral venous access is problematic, and where central venous catheters have a significant rate of catheter-associated bacteremia. It is reasonable to offer a trial of chronic oral suppressive antibiotic therapy with a β-lactamase–resistant agent in patients with mild or moderate disease, and to reserve IVIG therapy only to children who fail to improve on suppressive antibiotics. Complement deficiency states, particularly C3, C5, and properdin deficiencies are rare heritable causes of recurrent bacterial infections as well. These patients have an increased incidence of a variety of soft tissue and systemic infections in addition to recurrent pneumonia.

Granulocyte disorders Quantitative and qualitative granulocyte abnormalities are rarely causes of recurrent pneumonia. Routine differential white cell counts will identify children with agranulocytosis; serial monitoring and bone marrow examinations will distinguish among cyclic neutropenia, immune neutropenia, and congenital agranulocytosis. In these children, pneumonia is often due to S. aureus or gram-negative bacilli, including Pseudomonas, or to fungal pathogens such as Aspergillus. If no response is seen to initial empiric therapy, bronchoscopy or lung biopsy may be necessary to guide further antibiotic therapy. A trial of granulocyte colony-stimulating factor (GCSF) is reasonable in this setting since the transient response in granulocyte number may hasten the resolution of the pneumonia. In contrast, children with chronic granulomatous disease (CGD) have a normal granulocyte number but impaired intracellular killing of bacteria. Like patients with complement deficiency, focal soft-tissue, skeletal, and lymph node infections may be seen in addition to recurrent pneumonia.

The use of interferon-γ and long-term antibiotic suppressive therapy has greatly improved the long-term outlook for such patients. Defects in granulocyte function may result in invasive pneumonia due to fungi as well as bacterial pathogens. As

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with neutropenic children, focal infiltrates which persist or progress (particularly with cavitation) despite reasonable initial empiric antibiotic therapy require vigorous investigation with chest CT scanning and biopsy.

Cell-mediated immunodeficiency Defects in T-cell function are associated with primary immunodeficiency diseases such as severe combined immunodeficiency and DiGeorge syndrome, lymphoid malignancies such as acute lymphoblastic leukemia, therapy with immunosuppressive agents for the treatment of a variety of inflammatory diseases and organ transplantation, and HIV infection.

The immunodeficient state triggered by acute systemic viral infection is transient and rarely associated with opportunistic pulmonary infection. Regardless of the initial mechanism of T-cell immunosuppression, these children are at risk of developing life-threatening pneumonia due particularly to common viral pathogens such as RSV, measles, and parainfluenza virus; fungal infections such as cryptococcosis or the endemic soil fungi; higher bacteria such as Nocardia asteroides and mycobacteria (both M. tuberculosis and atypical mycobacteria); and P. jiroveci. The radiologic features may point toward particular pathogens (e.g., focal infiltrates implicate fungal or bacterial pathogens, and diffuse infiltrates implicate viral pathogens or P. jiroveci) but the broad differential diagnosis, the possibility of polymicrobial infection and noninfectious processes such as drug hypersensitivity reactions, and the complexities of therapy mandate an invasive approach to diagnosis via bronchoscopy and/or open lung biopsy.

Human immunodeficiency virus HIV infection in children results not only in a heightened susceptibility to infection by P. jiroveci and other pathogens classically associated with T-cell immunodeficiency states, but also in an increased susceptibility to bacterial infection, with an increased risk of bacterial pneumonia and bacteremia due to encapsulated pathogens such as S. pneumoniae. Tuberculosis is another important pathogen among HIV-infected children living in resource-limited environments. In addition, lymphoid interstitial pneumonia, an infiltrative process possibly associated with Epstein-Barr virus infection, may be responsible for pulmonary infiltrates and respiratory distress in these children. Unlike adult HIV-infected patients, the risk of P. jiroveci pneumonia in HIV-positive infants is not closely correlated with the CD4 count. Infants with vertically transmitted HIV have an increased risk of acquiring PCP regardless of CD4 count during the first year of life. All infants born of HIV-infected mothers should begin P. jiroveci prophylaxis at 4 weeks of life, and continue treatment until 1 year of life, or until follow-up PCR testing is negative for HIV transmission at 4 to 6 months of age. The need for continued prophylaxis thereafter among HIV-infected infants is based on the CD4 count. The syndrome of recurrent bacterial infections, including pneumonia, in these infants, has become less common since the widespread introduction of highly ac-

Pneumonia in Childhood

tive antiretroviral therapy (HAART), and maintenance intravenous immunoglobulin (IVIG) therapy for HIV-infected infants is now rarely necessary. When HIV-infected children develop respiratory distress associated with diffuse interstitial and alveolar infiltrates, the broad differential diagnosis and the significant possibility of multiple concurrent processes warrants early consideration of an invasive biopsy process.

Depending on the severity and tempo of illness, an empiric trial of therapy for PCP may be given, with lung biopsy reserved for those patients who fail to improve.

SUGGESTED READING Apisarnthanarak A, Holzmann-Pazgal G, Hamvas A, et al: Ventilator-associated pneumonia in extremely preterm neonates in a neonatal intensive care unit: Characteristics, risk factors, and outcomes. Pediatrics 112:1283–1289, 2003.

Arnold JC, Singh KK, Spector SA, et al: Human bocavirus: Prevalence and clinical spectrum at a children’s hospital.

Clin Infect Dis 43:283–288, 2006.

Bhat N, Wright JG, Broder KR, et al: Influenza-associated deaths among children in the United States, 2003–2004. N Engl J Med 353:2559–2567, 2005.

Black SB, Shinefield HR, Ling S, et al: Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 21:810–815, 2002.

Braciale TJ: Respiratory syncytial virus and T cells: Interplay between the virus and the host adaptive immune system.

Proc Am Thorac Soc 2:141–146, 2005.

Brook I: Anaerobic pulmonary infections in children. Pediatr Emerg Care 20:636–640, 2004.

Diep BA, Sensabaugh GF, Somboona NS, et al: Widespread skin and soft-tissue infections due to two methicillinresistant Staphylococcus aureus strains harboring the genes for Panton-Valentine leucocidin. J Clin Microbiol 42:2080– 2084, 2004.

Graham SM: HIV and respiratory infections in children. Curr Opin Pulm Med 9:215–220, 2003.

Greenberg D, Chiou CC, Famigilleti R, et al: Problem pathogens: Paediatric legionellosis—implications for improved diagnosis. Lancet Infect Dis 6:529–535, 2006.

Hammerschlag MR: Pneumonia due to Chlamydia pneumoniae in children: Epidemiology, diagnosis, and treatment.

Pediatr Pulmonol 36:384–390, 2003.

Henrickson KJ: Parainfluenza viruses. Clin Microbiol Rev 16:242–264, 2003.

Hoyert DL, Mathews TJ, Menacker F, et al: Annual summary of vital statistics: 2004. Pediatrics 117:168–183, 2006.

Jennings LC, Anderson TP, Werno AM, et al: Viral etiology of acute respiratory tract infections in children presenting to hospital: Role of polymerase chain reaction and demonstration of multiple infections. Pediatr Infect Dis J 23:1003–1007, 2004.

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Kahn JS: Epidemiology of human metapneumovirus. Clin Microbiol Rev 19:546–557, 2006.

Marais BJ, Gie RP, Schaaf HS, et al: Childhood pulmonary tuberculosis: Old wisdom and new challenges. Am J Respir Crit Care Med 173:1078–1090, 2006.

McIntosh K: Community-acquired pneumonia in children.

N Engl J Med 346:429–437, 2002.

Michelow IC, Olsen K, Lozano J, et al: Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 113:701–707, 2004.

Mulholland K: Global burden of acute respiratory infections in children: Implications for interventions. Pediatr Pulmonol 36:469–474, 2003.

Schultz KD, Fan LL, Pinsky J, et al: The changing face of pleural empyemas in children: Epidemiology and management.

Pediatrics 113:1735–1740, 2004.

Smith KC, Seaworth BJ: Drug-resistant tuberculosis: Controversies and challenges in pediatrics. Expert Rev Anti Infect Ther 3:995–1010, 2005.

Smyth RL, Openshaw PJ: Bronchiolitis. Lancet 368:312–322, 2006.

Thompson WW, Shay DK, Weintraub E, et al: Influenzaassociated hospitalizations in the United States. JAMA 292:1333–1340, 2004.

Vichinsky EP, Neumayr LD, Earles AN, et al: Causes and outcomes of the acute chest syndrome in sickle cell disease.

National Acute Chest Syndrome Study Group. N Engl J Med 342:1855–1865, 2000.

Waites KB: New concepts of Mycoplasma pneumoniae infections in children. Pediatr Pulmonol 36:267–278, 2003.

Wong SS, Yuen KY: Avian influenza virus infections in humans. Chest 129:156–168, 2006.

122 Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections Jay A. Fishman

I. HISTORY II. MICROBIOLOGY OF ASPIRATION PNEUMONIA III. MICROBIOLOGY OF EMPYEMA Anaerobic Bacteria in Empyema Non-anaerobic Infections IV. MICROBIOLOGY OF LUNG ABSCESS Path ophysiology of Aspiration, Empyema, and Lung Abscess Clinical Features of Aspiration and Anaerobic Lung Infections Other Aspiration Syndromes

V. RADIOLOGY AND DIAGNOSIS OF ANAEROBIC PLEUROPULMONARY INFECTIONS Radiologic Diagnosis Laboratory Diagnosis Diagnosis of Empyema VI. DIAGNOSIS OF LUNG ABSCESS Bacteriology VII. TREATMENT OF ASPIRATION PNEUMONIA AND ANAEROBIC LUNG INFECTIONS Prevention Antimicrobial Therapy Management of Empyema VIII. TREATMENT OF LUNG ABSCESS

Infection due to aspiration, lung abscesses, and empyema are important syndromes dominated, in part, by the unique role of anaerobic bacteria in the pathogenesis of each. Aspiration pneumonia refers to the pulmonary consequences that follow abnormal entry of fluid, particulate substances, or endogenous secretions from the upper airways or gastric contents into the lower airways. To develop aspiration pneumonia, there needs to be a compromise of the host defense mechanisms that normally protect the lower airways, including glottic closure, cough reflex, or other clearance mechanisms.

The material aspirated must generate an inflammatory response or cause obstruction. The nature of the pneumonia that develops depends on the inoculum and the host response.

Anaerobic bacteria are the most common pathogens in this setting, reflecting both pathogenic potential and importance in the normal flora of the upper airways. Risk factors for aspiration may be transient (anesthesia, intoxication) or persistent (e.g., neuromuscular disorders, achalasia) with the risk

for recurrence depending on recognition and resolution of the inciting defect.

Empyema refers to a purulent collection in any body site, but is commonly used to indicate infection of the pleural space. Empyema is commonly associated with underlying pulmonary parenchymal infection, but may also be associated with blood-borne infection, thoracic surgery, trauma, abdominal infection, or neoplasm. Lung abscesses reflect infection with an unusual microbial burden (e.g., acute aspiration), a failure in microbial clearance mechanisms (e.g., bronchial obstruction), or both, with necrosis of pulmonary tissue and formation of cavities containing necrotic debris or fluid (Fig. 122-1). The formation of multiple smaller (less than 2 cm) abscesses in pulmonary tissue is occasionally referred to as necrotizing pneumonia or lung gangrene. Both lung abscess and necrotizing pneumonia are manifestations of the same pathologic processes, and the distinction is, therefore, arbitrary. Failure to recognize and treat either empyema or

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A

B

Figure 122-1 A. Anaerobic pneumonia with abscess formation in a 48-year-old alcoholic man. The abscesses are located in the posterior segment of right upper lobe, a dependent segment that is seen best on lateral view (B).

lung abscess is associated with a poor clinical outcome. In the pre-antibiotic era, lung abscess was associated with a mortality approaching 40 percent. However, controversy exists over the best approaches to both processes in terms of antimicrobial selection and physical drainage.

HISTORY The clinical and bacteriologic features of anaerobic infections of the lung have been documented by extensive studies during two periods of investigation. The first was at the turn of the century, when anaerobic bacteria were initially reported as important causes of empyema. This early work continued through the late 1920s, when David Smith conducted classic studies on the pathogenesis of lung abscess. At that time, approximately one-third of patients with lung abscess died. Smith noted that the bacteria in the walls of the abscess at autopsy resembled the bacteria found in the gingival crevice, leading him to conclude that aspiration was the major mechanism in pathogenesis. He subsequently supported this hypothesis by inoculating the trachea of experimental animals with gingival crevice material to reproduce the se-

quence of events of pneumonitis, followed in 7 to 10 days by lung abscess formation. Bacteriologic studies of the inoculum showed that four bacterial species were critical, and all were anaerobic bacteria: a fusiform bacterium now recognized as Fusobacterium nucleatum, Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Peptostreptococcus, and an anaerobic spirochete. This study is one of the first demonstrations of bacterial synergy; the demonstration of two or more bacterial species is required to produce a pathologic process that could not be reproduced by any single component of the inoculum.

In the first two or three decades of the antibiotic era, the role of anaerobic bacteria in this and other pathologic processes was largely ignored. Patients with lung abscesses often had putrid sputum and no identifiable pathogen; these infections were frequently referred to as nonspecific lung abscess. Although the microbial cause was unknown, it was well established that these patients almost invariably responded to penicillin treatment. The role of anaerobes in empyema was also largely ignored. Much of this neglect is ascribed to the paucity of laboratories capable of cultivating oxygen-sensitive bacteria. Studies of anaerobic bacteria were spawned by the ability to culture anaerobes in clinical laboratories with the introduction of GasPak jars, the description of the taxonomy

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of these organisms, and the availability of new antimicrobial agents (clindamycin, metronidazole, cefoxitin) for therapy. The introduction and widespread use of transtracheal aspiration (TTA) in the late 1960s made it realistic to collect uncontaminated specimens from the lower airways that could be used for anaerobic cultures. TTAs are seldom performed at present, so anaerobic bacteria are rarely established as pulmonary pathogens. These organisms are often suspected on the basis of the etiologic route (oropharyngeal flora) of infection and their importance in patients with aspiration pneumonia, necrotizing pneumonia, lung abscess, and empyema.

MICROBIOLOGY OF ASPIRATION PNEUMONIA The establishment of anaerobic bacteria in pulmonary infections requires specimens of respiratory secretions that are devoid of contamination from the upper airways. The usual procedures satisfying this criterion are TTA, transthoracic aspiration, open lung biopsy, thoracentesis, and most recently, bronchoscopy with quantitative cultures. In addition, there must be appropriate laboratory expertise for cultivation of anaerobic bacteria. The incidence of anaerobic lung infections reported in published studies from the antibiotic era that satisfy both requirements is summarized in Table 122-1.

Most published reports deal with the role of anaerobic bacteria in aspiration pneumonia or lung abscess, and these show recovery rates ranging from 62 to 100 percent. The usual specimens in these studies are TTA and transthoracic aspiration. One of the best studies is by Beerens and TahonCastel, who used transthoracic needle aspiration to characterize the flora in lung abscesses; this series showed recovery of anaerobic bacteria, usually in pure culture, in 22 of 26 cases (85 percent).

There have been few studies to identify the frequency of anaerobic bacteria in unselected cases of communityacquired pneumonia. One was by Ries and co-workers, who performed TTAs in patients hospitalized with a diagnosis of pneumonia and recovered anaerobic bacteria in 29 of 89 cases (33 percent). A more recent study by Pollock and colleagues, using fiberoptic bronchoscopy with a protected catheter and quantitative cultures, showed recovery of anaerobes in 16 of 74 patients (22 percent). These two reports suggest that anaerobic bacteria are actually relatively common pathogens among patients with community-acquired pneumonia and presumably account for a substantial proportion of cases that are now considered enigmatic. In nosocomial pneumonia, a study by Bartlett and colleagues utilized TTA in 159 consecutive patients and showed anaerobes in 56 (35 percent).

Nevertheless, most of these patients also showed the concurrent presence of aerobic gram-negative bacilli or Staphylococcus aureus, with the clinical course determined largely by the aerobic pathogens.

Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections

Table 122-1 Incidence of Anaerobic Infection of the Lung Number of Patients With Anaerobes Total Lung abscess 53 22 9 37

57 26 10 41

Percent

93 85 90 90

Reference

Bartlett et al.

Beerens and Tahon-Castel Brook and Finegold Gudiol et al.

Aspiration pneumonia 61 70 87 17 17 100 29 47 62 69 74 93

Bartlett et al.

Gonzales-C and Calia Lorber and Swenson Brook and Finegold

Empyema 63 23 28 25 26 20

Bartlett et al.

Beerens and Tahon-Castel Sullivan et al.

Mavroudis et al.

Grant and Finley Lemmer et al.

83 45 72 100 90 70

76 51 39 25 29 29

Community-acquired pneumonia 28 89 33 Ries et al.

16 74 22 Pollock et al.

Nosocomial pneumonia 56 159 35

Bartlett et al.

MICROBIOLOGY OF EMPYEMA In the pre-antibiotic era, up to 11 percent of cases of pneumococcal pneumonia were associated with empyema; 64 percent of all cases of empyema were associated with Streptococcus pneumoniae. β-Hemolytic streptococci (15 percent) and staphylococci (8 percent) were the other organisms most commonly isolated from empyema fluid. In the 1960s and 1970s, with new culture techniques, one study found only anaerobic bacteria in pleural empyema fluid in 35 percent of cases, and a mixture of aerobic and anaerobic bacteria in 41 percent in a series of 83 medical patients who had not received antibiotics or surgical intervention (Tables 122-2 and 122-3; Figs. 122-2, 122-3, and 122-4). With the introduction of the sulfa drugs and penicillins, the expansion of thoracic surgery, and the emergence of antibiotic resistance in the

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Table 122-2 Bacteriology of Anaerobic Empyema: Predominant Flora Organism

No. Isolates

Anaerobic iolates Fusobacterium nucleatum Prevotella denticola-melaninogenica group Prevotella oris Prevotella intermedia-nigrescens group Prevotella oralis Prevotella buccae Bacteroides fragilis Other B. fragilis group Unidentifiable Bacteroides spp.

Bacteroides gracilis Campylobacter spp.

Peptostreptococcus micros Peptostreptococcus anaerobius Peptostreptococcus spp.

Peptostreptococcus magnus Streptococcus intermedius Eubacterium spp.

Lactobacillus spp.

Actinomyces spp.

Actinomyces odontolyticus Propionibacterium acnes Clostridium perfringens Clostridium spp.

19 10 9 8 4 3 5 6 4 3 3 9 5 4 3 5 7 7 4 3 4 3 3

Aerobic Isolates α-Hemolytic streptococcus Nonenterococcal group D streptococcus Coagulase-negative staphylococci Proteus spp.

21 4 4 3

source: Based on data of Cien R, Jousimies-Somer H, Marina M, et al: A retrospective review of cases of anaerobic empyema and update of bacteriology. Clin Infect Dis 20:S224–S229, 1995.

staphylococci, the isolation of S. pneumoniae decreased and that of S. aureus and other nosocomial pathogens in empyema fluids increased. In more recent studies of empyema, the pneumococcus accounts for only 5 to 10 percent of cases, while anaerobes are found in 25 to 40 percent. The highest yield reported in recent years is a collaborative study at Cook County Hospital in Chicago and two VA hospitals in Los Angeles. Anaerobes were recovered in 63 of 83 cases (76 percent).

Anaerobic Bacteria in Empyema The frequency of anaerobic infection of the lung and pleural space is a function of the colonization pattern of the individual patient, including the presence of hospital-acquired pathogens and the role of aspiration in many of these infec-

tions (Table 122-3). The most frequent isolates are the anaerobes Prevotella, Fusobacterium nucleatum, and Peptostreptococcus and the streptococci (Figs. 122-5 and 122-6). In early studies, the Bacteroides fragilis group was isolated from 15 to 20 percent of patients with anaerobic pleuropulmonary infections. However, later studies employing newer techniques and utilizing newer taxonomic criteria found B. fragilis group in only 6.8 percent of 46 patients with pleural empyema specimens. The B. fragilis group is important because of resistance to penicillin G (a property shared by a number of common anaerobes) and other antimicrobial agents. Subdiaphragmatic infection may extend to the lung or pleural space by way of lymphatics, directly through the diaphragm or defects in it, or by way of the bloodstream. Anaerobic pulmonary and pleural processes rarely extend to the chest wall unless associated with actinomycosis, tuberculosis, or tumor.

Non-anaerobic Infections In immunologically normal adults, the aerobic organisms currently most often associated with empyema and lung abscesses are S. aureus, β-hemolytic streptococci, and various gram-negative aerobic or facultatively anaerobic bacilli, particularly Pseudomonas aeruginosa, Escherichia coli, Klebsiella species, and other nosocomial enteric gram-negative organisms—reflecting infections associated with pneumonia treated with antimicrobial agents to which the causative organism is resistant, with thoracic surgery or high-grade bacteremias. Mixed aerobic-anaerobic infections are often related to subdiaphragmatic processes. Increasingly, Mycobacterium tuberculosis, Nocardia asteroides, and fungi have been identified. In the immunocompromised host, the infecting organisms will more often be gram-negative bacteria (especially Pseudomonas and Enterobacter) or Candida or Aspergillus species, or will be due to reactivation of latent or subclinical infections due to M. tuberculosis, Candida species, or the less virulent streptococci. In all hosts, the colonization pattern of the individual will often predict the causative organisms, even if these are not easily isolated.

MICROBIOLOGY OF LUNG ABSCESS In lung abscesses, anaerobes are recoverable from up to 89 percent of patients. In some patients, anaerobic organisms of presumably greater virulence (e.g., Fusobacterium nucleatum or Peptostreptococcus species) may be found as the sole infecting organism. In studies by Bartlett and coworkers, 46 percent of patients with lung abscesses had only anaerobes isolated in cultures, while an additional 43 percent had a mixture of anaerobes and aerobic bacteria. In addition to anaerobes, among the organisms often implicated in lung abscess formation or in necrotizing pneumonia are S. aureus, Streptococcus pyogenes, Klebsiella pneumoniae, and P. aeruginosa. Infrequently, other gram-negative bacilli, such as E. coli and Haemophilus influenzae type B, may cause pulmonary

0 2 45 5

1

3

13 24 2 27 17 6

6

Pigmented gram-negative anaerobic rods

Fusobacterium nucleatum

F. necrophorum

Peptostreptococcus

Microaerophilic streptococcus

Anaerobic, nonâ&#x20AC;&#x201C;spore-forming, catalase-negative, gram-positive rods

Clostridium

1

0

5

9

2

7

7

0

source: Based on data of Finegold SM: Anaerobic Bacteria in Human Disease. New York, Academic, 1977.

0

1

11

Bacteroides fragilis group

Tonsillitis, Tonsillectomy

Aspiration

Bacteria

Gingivitis, Dental Extraction, Pyorrhea

0

1

0

4

1

4

2

3

Bronchiectasis

0

2

4

2

2

4

0

1

Bronchogenic Carcinoma

15

1

0

10

0

4

0

3

Chest Trauma, Thoracotomy

Correlation of Infecting Organism and Conditions Underlying Anaerobic Pleuropulmonary Infection

Table 122-3

7

3

5

6

5

6

2

16

Peritoneal Infection or Source in Bowel

0

1

8

4

1

0

1

Pelv Infect

2145

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Pathophysiology of Aspiration, Empyema, and Lung Abscess The bacteria implicated in anaerobic lung infections represent the normal flora of the oral cavityâ&#x20AC;&#x201D;primarily the gingival crevice, where anaerobic bacteria are found in concentrations that approach the geometric limits with which bacteria occupy space: 10/g. Compromised consciousness or dysphagia predisposes most frequently to clinically significant aspiration. Common conditions associated with clinically significant aspiration include alcoholism, general anesthesia, seizure disorder, drug abuse, esophageal lesions, and neurologic deficits.

Numerous studies indicate that virtually all healthy persons aspirate, but that this is usually inconsequential. In one study, in which contrast material was placed in the mouths of sleeping patients, chest radiographs the following day showed contrast material in the lung in most of them, but there was no evidence of a disease process. Similarly, dye markers placed in the stomach of postoperative patients can be aspirated from the tracheobronchial tree at the time of surgery, indicating aspiration of gastric contents during general anesthesia in 7 to 16 percent. Scintigraphic methods have also been used to demonstrate frequent aspiration in patients with intubation of the airways or gastrointestinal tract. None of these studies have demonstrated any clinical consequences from this type of occult aspiration. The conclusion is that aspiration is relatively common, but usually resolves spontaneously. The decisive factor for the development of lung complications depends on the frequency, volume, and character of the material in the inoculum. The conditions cited in the preceding as causing clinically significant disease are associated with more frequent aspiration or aspiration of large volumesâ&#x20AC;&#x201D;factors that define the populations at greatest risk.

Figure 122-2 Large anaerobic empyema accompanying right middle-lobe pneumonia.

necrosis. Uncommon but important causes of cavitating pneumonia are N. asteroides, Paragonimus westermani, Legionella species, Burkholderia pseudomallei, and B. mallei (glanders), and tuberculosis. Certain fungal infections may cause cavitation in diabetic and immunocompromised hosts (e.g., the Mucoraceae, Aspergillus species). Entamoeba histolytica is an important, but uncommon, cause of lung abscess, almost always in the basilar portion of the right lower lobe.

A

B

Figure 122-3 Prevotella melaninogenica. A. Distinctive black colonies (on blood-containing medium); pigment is hematin. B. Microscopically, the organism is a coccobacillus.

2147 Chapter 122

A

B

C

D

Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections

Figure 122-4 Bacteriology of empyema and lung abscess. A. Fusobacterium nucleatum, microscopic morphology.

Organism is thin and delicate gram-negative bacillus with tapered ends (sometimes filamentous). B. Pleomorphic gram-negative bacillus with filaments containing swollen portions and with large round bodies. This appearance is seen with F. necrophorum, F. mortiferum, and F. varium. C. Pus showing microaerophilic streptococcus. D. Microscopic morphology of Bacteroides fragilis. Organism is an irregularly stained, gram-negative rod. Bipolar staining may be seen.

Additional conditions that appear to predispose to anaerobic infections include pulmonary infarction, obstruction due to carcinoma or a foreign body, and bronchiectasis. These conditions are associated with stasis or necrosis of tissue, which presumably accounts for the association with anaerobic infections.

A somewhat unique feature of anaerobic lung infections is the penchant for necrosis of tissue, resulting in abscess formation or a bronchopleural fistula associated with empyema. Virulence factors of anaerobic bacteria presumed to account for this association include the capsular polysaccharide of anaerobic gram-negative bacilli. The most extensively studied is the polysaccharide of Bacteroides fragilis, but the same observations appear to apply to P. melaninogenica and probably other anaerobic gram-negative bacilli as well.

The capsule consists of a family of polysaccharides composed of oligosaccharide repeating units with sugars containing positively charged free amino groups and negatively charged

carboxyl or phosphorite groups. These positive and negative charges mediate the capacity to induce abscess formation in experimental animals. Another virulence factor possessed by most anaerobic bacteria is the production of short-chain fatty acids that inhibit phagocytic killing at low pH levels. Shortchain volatile fatty acids are metabolic products of anaerobic bacteria that are used to classify these organisms taxonomically, and they appear to be responsible for the putrid odor that is often a characteristic feature of infections by these organisms.

Because the most important predisposing condition for lung abscess is aspiration, lung abscesses are most often located in the posterior segment of the right upper lobe, less often in the left upper lobe, and the apical segments of the lower lobes (Fig. 122-1). Periodontal disease is highly associated with lung abscess formation; in edentulous people, lung abscesses are uncommon and may suggest the presence of an obstructing lesion of the bronchus, pulmonary embolus,

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Infectious Diseases of the Lungs

B

Figure 122-5 Fulminating anaerobic pneumonia in a 44-year-old woman with onset of pneumonia 6 days before admission. A. Day of admission. Patchy consolidation in right lower lung field and behind the cardiac silhouette. B. One day after admission: Extensive patchy alveolar infiltrates bilaterally with areas of rarefaction on right suggestive of cavitation. The patient died 2 days later.

A

B

Figure 122-6 ‘‘Gangrene” of the lung after aspiration, anteroposterior (A) and lateral (B ) views. Extensive cavitation following necrotizing pneumonia in a 65-year-old man.

2149 Chapter 122

septic embolus, or unsuspected pathogen. Nosocomial aspiration often involves gram-negative bacteria, particularly organisms with hospital-acquired antibiotic resistance patterns.

Lung abscesses generally develop after inflammation produces tissue necrosis with cavitation. In the presence of pre-existing cavitary disease (emphysema or old tuberculous lesions), infection may proceed without frank necrosis. The abscess cavity may become lined with regenerated epithelium.

Local obstruction may produce bronchiectasis or emphysema in the surrounding lung.

The classification of lung abscesses is based on the duration and likely cause of the process. Acute abscesses are less than 4 to 6 weeks old, whereas chronic abscesses are of greater duration. Primary abscesses are infections due to aspiration or to pneumonia in the normal host; secondary abscess is due to preexisting conditions (obstruction, spread from an extrapulmonary site, bronchiectasis, immune compromise). Abscesses with foul odors associated with anaerobic organisms are often called putrid abscesses.

Clinical Features of Aspiration and Anaerobic Lung Infections Aspiration Pneumonia Common clinical features of anaerobic pulmonary infections are summarized in Table 122-4, which categorizes the patients with respect to pneumonitis, lung abscess, or empyema. Features of anaerobic infections that are nearly unique are the association with conditions that predispose to aspiration and infection in the gingival crevice, putrid discharge, and a high frequency of suppurative complications in late stage-disease.

Anaerobic lung infections may be acute, subacute, or chronic.

Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections

The first stage in the infection is pneumonitis. One review of 46 patients with anaerobic bacterial pneumonitis showed clinical features that were similar to those of pneumococcal pneumonia. The diagnosis was established by TTA, and the results in this group were compared with those in a second group of patients in whom TTAs yielded S. pneumoniae.

The two groups were similar in terms of age, changes on the chest radiograph, peak temperature, and peripheral leukocyte count. Significant differences in the group with anaerobic infections were the lack of rigors, a somewhat longer duration of symptoms before presentation, and a more frequent association with predisposing conditions for aspiration. An important point to emphasize is that patients seen in this early stage of infection rarely have the features that are commonly associated with anaerobic lung infections, such as putrid sputum, tissue necrosis with abscess formation, and a chronic course. These infections presumably account for some and possibly many of the cases of community-acquired pneumonia in which no etiologic diagnosis is established despite extensive study; such cases account for 40 to 50 percent of cases in most series.

The initial stage of pneumonitis is often more subtle or neglected, so that patients may not seek medical attention until the infection has been present for weeks or even months. These cases are more analogous to tuberculosis than to most bacterial infections of the lung. As noted, many of these infections progress to suppurative complications, with presentation as lung abscess or empyema. Generally, 7 to 14 days is required for cavity formation.

Nearly all patients with anaerobic lung infections have the usual constitutional findings for patients with infection (Table 122-4). A review of 193 bacteriologically confirmed cases showed that the mean peak temperature for hospitalized

Table 122-4 Clinical Features of Anaerobic Pulmonary Infections∗ Lung Abscess (83 pts)

Empyema (51 pts)

Pneumonitis (only) (79 pts)

Total (193 (pts)

Age (median)

52 yr

49 yr

60 yr

51 yr

Peak temperature (mean, ◦ F)

102.1

102.4

102.6

102.4

Peripheral leukocyte count (median/mm)

15,000

21,600

13,700

15,000

History of weight loss

36 (43%)

28 (55%)

3 (4%)

57 (30%)

Putrid discharge

41 (49%)

32 (63%)

4 (5%)

62 (32%)

Lethal outcome

3 (4%)

3 (6%)

3 (4%)

8 (4%)

∗ Based

on retrospective chart review of 193 cases established by recovery of anaerobes as dominant flora in TTA, pleural fluid, or blood culture. source: From Bartlett JG: Anaerobic bacterial infections of the lung. Chest 91:901–909, 1987; Bartlett JG: Anaerobic bacterial infections of the lung and pleural space. Clin Infect Dis 16:S248–S255, 1993; Marina M, Strong CA, Civen R, et al: Bacteriology of anaerobic pleuropulmonary infections: Preliminary report. Clin Infect Dis 16:S256–S262, 1993.

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Table 122-5 Classification of Aspiration Pneumonia Inoculum

Pulmonary Sequelae

Clinical Features

Therapy

Acid breathing

Chemical pneumonitis

Acute dyspnea, tachypnea; tachycardia; cyanosis, bronchospasm, fever Sputum: pink, frothy Radiographic: infiltrates in one or both lower lobes Hypoxemia

Positive-pressure Intravenous fluids Tracheal suction

Oropharyngeal bacteria

Bacterial infection

Usually insidious onset Cough, fever, purulent sputum Radiographic: infiltrate in dependent pulmonary segment or lobe ± caviation

Antibiotics

Inert fluids positivebreathing with isoproterenol

Mechanical obstruction Reflex airway closure

Acute dyspnea, cyanosis ± apnea Pulmonary edema

Tracheal suction Intermittent pressure oxygen and matter

Particulate

Mechanical obstruction

Dependent on level of obstruction, ranging from acute apnea and rapid death to irritating chronic cough ± recurrent superimposed infections particulate matter

Extraction of matter Antibiotics for infection

patients was 39.1◦ C, and all but five patients were febrile.

The average peripheral leukocyte count was 15,000/ml3 . Patients who presented with the suppurative complications had a longer duration of symptoms before presentation; this was commonly associated with other evidence of chronic disease, including weight loss and anemia. Another common feature of patients with suppurative complications was putrid sputum or empyema fluid, which was noted in 40 to 60 percent.

It should be emphasized that the putrid discharge in these cases is considered diagnostic of anaerobic infection, since aerobic bacteria are not capable of producing this characteristic odor either in vitro or in vivo. Thus, anaerobic bacteria may cause a diverse range of pulmonary infections, which may be acute, subacute, or chronic. The anaerobic etiology is rarely established or even suspected in patients with acute pneumonitis unless the appellation aspiration pneumonia is applied; in this case, anaerobes are the presumed pathogens in most community-acquired cases, and they may be contributing factors in many nosocomial infections. By contrast, anaerobic bacteria are readily recognized as probable pathogens in patients who have the late suppurative complications, such as lung abscess or empyema.

Other Aspiration Syndromes Aspiration Pneumonia Aspiration pneumonia refers to distinctive syndromes that are distinguished on the basis of the character of the inoculum,

which dictates the pathogenesis of pulmonary complications, clinical presentation, and management strategies (Table 1225). Aspiration pneumonia includes at least three different syndromes: chemical pneumonitis, bacterial infection, and airway obstruction.

Chemical Pneumonitis Chemical pneumonitis refers to the aspiration of an inoculum that is inherently toxic to the lungs. Examples include acid, animal fats such as milk and mineral oil, and volatile hydrocarbons. These substances are toxic to the lower airways, and they initiate an inflammatory reaction. The prototypic example based on extensive study is gastric acid pneumonitis as classically described by Mendelson and often referred to as Mendelson’s syndrome. This is a severe pneumonitis with fever and hypoxia and respiratory alkalosis, that generally either rapidly clears in 4 to 7 days in healthy hosts or may progress (e.g., with lung injury and superinfection) to pneumonia, lung abscess, or ARDS. Factors that contribute to hypoxemia are pulmonary edema, reduced surfactant activity, reflex airway closure, hyaline membrane formation, and alveolar hemorrhage. These patients’ pulmonary function tests show decreased compliance, abnormal ventilation-perfusion, and reduced diffusing capacity. The pathophysiology of gastric acid pneumonitis has been studied in experimental animals with intratracheal instillation of graded acid inocula.

This work shows that the pH must be 2.5 or less for the

2151 Chapter 122

inflammatory process to be initiated. There must also be a relatively large inoculum, usually 1 to 4 ml/kg. It is possible that smaller volumes initiate a less dramatic presentation or may go undetected. Support for this hypothesis is the observation of frequent bouts of pneumonitis and otherwise unexplained pulmonary fibrosis in patients with gastric reflux or esophageal disease.

The pathologic changes in acid pneumonia occur rapidly. Atelectasis occurs within seconds and is extensive by 3 min. There is also peribronchial hemorrhage, pulmonary edema, and bronchial epithelial cell degeneration. The alveolar spaces are filled with neutrophils by 4 h and hyaline membranes are seen within 48 h. Resolution begins by the third day and may be complete or may result in residual scarring of the pulmonary parenchyma.

Long-term follow-up studies in patients who have gastric acid pneumonia show either complete recovery or radiographic evidence of pulmonary fibrosis with abnormal gas exchange.

The diagnosis of acid pneumonia is usually presumed on the basis of clinical observations such as the abrupt onset of dyspnea in a patient who is aspiration prone and has radiographic evidence of infiltrates, usually in the lower lobes. Other characteristic clinical features are the rapid clearing of the infiltrates and progression to ARDS. Bronchoscopy demonstrates erythema of the bronchi, suggesting a “chemical burn.” Confirmation of the acid inoculum is not possible because of rapid neutralization by pulmonary edema fluid and bronchial secretions within minutes after aspiration.

The treatment of gastric acid aspiration includes tracheal suction to clear fluids and particulate matter that may be aspirated concurrently. Supportive care consists primarily of ventilatory support with positive pressure ventilation, and intravenous fluids due to decreased intravascular volume with hypotension. Corticosteroids have not be useful.

Antimicrobial agents are reserved for superinfection.

Mechanical Obstruction Aspiration pneumonia may involve fluid or particulate material. In this form of aspiration pneumonia, the inoculum is not toxic to the lung but may cause obstruction or reflux airway closure. In most cases there is only transient, self-limited hypoxemia due to rapid clearance. Some patients develop pulmonary edema, with hypoxemia and reduced compliance apparently due to an intrinsic pulmonary reflex closure. Other patients suffer sequelae due to failure to clear relatively large volumes of the aspirate, as with near drowning victims and patients with profound neurologic deficits or in coma. The obvious critical intervention is tracheal suction.

Aspiration with mechanical obstruction may also be associated with solid particles. Foreign-body aspiration is most frequent in children 1 to 3 years of age. The most common objects in the lower airways are vegetable particles, inorganic materials, and teeth. The severity of the obstruction depends on the relative size of the material aspirated and the caliber of the lower airways. Large objects may cause obstruction at the

Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections

level of the larynx or trachea, leading to sudden respiratory distress, cyanosis, and in some cases, aphonia. This is referred to as caf´e coronary syndrome because it often involves meat aspiration during restaurant dining and may simulate an acute myocardial infarction. Aspiration of smaller particles may result in complete obstruction of more distant components of the tracheobronchial tree or partial obstruction. Chest radiographs often show atelectasis or obstructive emphysema. An important clue in some cases is unilateral wheezing. Bacterial infection is not important in the early stages of obstruction, but is a common feature when obstruction has been present for more than 1 week. The most common pathogens are anaerobic bacteria from the upper airways. These patients may respond well to antibiotics, but often have recurrent infections in the same pulmonary segment. The most important therapeutic intervention is removal of the foreign body, usually with bronchoscopy.

Empyema and Lung Abscess The pathogenesis and presentation of both pleural empyema and lung abscesses are often indistinguishable. Shared presentations of empyema and lung abscess include the indolent development of symptoms, most often fever, sweats, cough, dyspnea, weight loss, and pleurisy; an association with conditions predisposing to aspirational events (altered consciousness, dysphagia, and gingivitis); and foul odors of sputum or breath associated with anaerobic bacteriology. Lung abscesses and empyemas often coexist. Both are generally associated with primary pneumonias.

The clinical presentation of empyema is determined by the underlying cause of infection. Empyema associated with aspiration pneumonia may develop over 1 to 3 weeks, usually with associated symptoms of pneumonia. The patient may have high fever and leukocytosis. Physical examination reveals dullness to percussion and decreased breath sounds on auscultation. These changes may be quite localized in the setting of loculated fluid. The empyema fluid is generally purulent by the time of detection, but pleural infection may be noted only after treatment for pneumonitis has failed to resolve fever or pleurisy. Empyema associated with thoracic surgery may be radiologically “hidden” in areas of the chest not drained by chest tubes or behind relatively benign pleural effusions. The patient may appear minimally toxic or severely ill, depending on the extent of the infection and organisms present. The presentation is modified by routine prophylactic antibiotic use, sedation, intubation, and antipyretics. Acute empyema may be seen in staphylococcal and streptococcal infections and following rupture of hepatic abscesses, especially those due to E. histolytica.

Lung Abscess The clinical presentation of lung abscess may be coincident with the initial presentation of pneumonia or other underlying condition, or may occur later in the clinical course. Suspicion may be heightened by the presence of conditions predisposing to aspiration or anaerobic pneumonia: alcoholism or other causes of altered consciousness, anaesthesia, dysphagia

2152 Part XVI

Infectious Diseases of the Lungs

B

A

C

Figure 122-7 Septic emboli due to Pseudomonas aeruginosa in a 33-yearold woman with sarcoidosis and pyelonephritis following spontaneous abortion. The patient presented with headache, fever, backache, and purulent sputum. Pseudomonas grew from the sputum culture. A. Chest radiograph before present illness. Bilateral hilar adenopathy of sarcoidosis. B. Posteroanterior view of chest shows bilateral cavitary lesions (arrows). C. Lateral view.

The lesions are more dramatically seen.

or pharyngeal dysfunction, gingivitis or pyorrhea, blunt or penetrating chest trauma or lung surgery, obstruction due to neoplasm, bronchiectasis, or pulmonary embolism. Bad breath or putrid sputum may be noted. However, the absence of a foul odor does not exclude the possibility of anaerobic infection, since certain anaerobes do not generate the end products of metabolism responsible for this type of odor, and communication may be lacking between the lesion and tracheobronchial tree. A change in sputum production, either increased or decreased, may be noted in patients with chronic bronchitis or bronchiectasis.

The patient with primary lung abscess gradually develops fever, cough, pleurisy, chest heaviness, shoulder pain, and malaise. Pneumonia may be present or suspected from history for a period of 1 to 3 weeks before the recognition of the lung abscess. By contrast, secondary lung abscessesâ&#x20AC;&#x201D;due, for example, to septic pulmonary emboli with infarctionâ&#x20AC;&#x201D;can evolve over 48 to 72 h (Fig. 122-7). Clinically, the distinction between primary and secondary abscesses may be inapparent at the time of presentation, but is important in the proper management of the patient. Thus, the patient with staphylococcal or streptococcal endocarditis may present with pneumonia,

2153 Chapter 122

lung abscess, and empyema. The main clue to the presence of underlying endocarditis may be the development of new lung abscesses during the course of therapy. The patient with lung abscesses complicating subdiaphragmatic infection (amebic abscess of the liver or pancreatic phlegmon) may have abdominal signs in addition to acute pulmonary disease. Seizures due to brain abscesses are occasionally the presenting clinical manifestation of bacteremia due to lung abscesses.

RADIOLOGY AND DIAGNOSIS OF ANAEROBIC PLEUROPULMONARY INFECTIONS Radiologic Diagnosis Chest radiographs in patients with anaerobic lung infections show infiltrates, with or without cavitation, that most frequently involve dependent pulmonary segments. The favored locations are the superior segment of the lower lobes or posterior segments of the upper lobes; these are dependent in the recumbent position. The basilar segments of the lower lobes are favored in patients who aspirate in the upright position.

The right lung is more frequently affected, owing to the more direct takeoff of the right mainstem bronchus.

With empyema, chest radiographs generally reveal fluid, most often in the costophrenic angles; free-flowing effusions layer on lateral decubitus radiographs. Loculations and pleural disease are often best defined by computed tomography of the chest, which should include the neck and diaphragms to rule out extrathoracic sites of infection. Spinal disease is better detected with magnetic resonance imaging (MRI). Before invasive diagnostic procedures, a careful history and physical examination may suggest a reason for the accumulation of pleural fluid. Non-infectious causes include bland pulmonary embolus, malignant effusion, benign postsurgical changes, pericardiotomy syndrome, collagen-vascular diseases (systemic lupus, rheumatoid arthritis), congestive heart disease, sympathetic effusion related to subdiaphragmatic disease (pancreatitis), leakage of ascites or peritoneal dialysis fluids, and hemorrhage (from venous access catheters or aortic tears). Infectious causes include extension of all classes of pulmonary infections from the lungs (parapneumonic), esophageal rupture, parapharyngeal space drainage, drainage or sympathetic effusion due to hepatic or subdiaphragmatic abscesses, septic metastasis, and direct infection via thoracic defects or chest tubes used for pleural drainage. Pyopneumothorax, in the absence of bronchopleural fistula, prior surgery, or prior thoracentesis, suggests the possibility of gas formation by bacteria implicated in the infection. Although nonspecific, pyo- pneumothorax suggests a component of anaerobic infection.

The classic radiographic appearance of a lung abscess is an irregularly shaped cavity with an air-fluid level inside.

Because the presentation is often indolent, numerous chest radiographs may be needed to follow the evolution of pneumonia into necrotizing pneumonia and then into a pulmonary

Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections

cavity (Figs. 122-5 and 122-6). Anaerobic infection is suggested by rapid pulmonary cavitation within a dense segmental consolidation; there may be rapidly enlarging nodular lesions, with or without cavitation. Although anaerobic pulmonary infections may be acute and fulminating, almost two-thirds of them have a subacute or chronic presentation.

Natural progression of virulent infection, delays in appropriate therapy, or tissue infarction may allow the underlying infection to progress into pulmonary gangrene (Fig. 122-4).

Seeding of infection or rupture of a lung abscess into the pleural space may cause empyema (Fig. 122-7). Up to one-third of lung abscesses may be accompanied by empyema. Solitary cavities are generally observed with primary lung infections, whereas many smaller collections may be found in metastatic infection. Chest tomography will define the size and location of abscesses, and may distinguish between related processes (empyema, infarction) better than conventional radiographs.

The common organisms and conditions associated with lung abscesses are listed in Table 122-6.

Laboratory Diagnosis Aspiration pneumonitis is a clinical diagnosis. It is generally assumed that there is an anaerobic component to pneumonia in patients with altered consciousness or after surgical procedures.

It is important to emphasize the utility of the Gramâ&#x20AC;&#x2122;s stain in making the diagnosis of anaerobic lung infection. Often culture data are not available to document the presence of such organisms. However, most anaerobic gram-negative bacteria have unique morphologic features that make them relatively easy to identify or suspect on direct Gramâ&#x20AC;&#x2122;s stain.

Peptostreptococci appear like their aerobic counterparts.

These are usually mixed infections involving multiple bacteria, and about half of the cases demonstrate mixtures of aerobic and anaerobic bacteria. Thus, the detection of polymicrobial flora or bacteria with the unique morphology of anaerobes on any specimen that is devoid of contamination by normal flora represents an important clue to the probable presence of anaerobic infection.

Determination of the microbiology of anaerobic infections of the lower airways requires a specimen devoid of contamination by the flora of the upper airways or quantitative cultures that distinguish pathogens from normal flora. Uncontaminated specimens that are considered valid for anaerobic culture include pleural fluid, transtracheal aspirates, transthoracic aspirates, and specimens obtained at thoracotomy. Quantitative cultures of specimens obtained at fiberoptic bronchoscopy, either by BAL or with the protected brush, may be used for this purpose also. Anaerobic bacteriology should not be used for bronchoscopic aspirates. It should be noted that quantitative culture of lower-airway secretions improves diagnostic accuracy with virtually any specimen that is subject to contamination, including expectorated sputum and tracheostomy aspirates. Most studies employing these techniques use them for detection of aerobic bacteria, and there are relatively few studies in which anaerobic cultures

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Table 122-6 Organisms and Conditions Associated with the Radiographic Appearance of Lung Abscess Infectious

Noninfectious and Predisposing Conditions

Bacteria Anaerobes; Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, streptococci, Legionella spp., Nocardia asteroides, Burkholdaria pseudomallei

Anatomic Fluid-filled cysts, bland infarction Bronchiectasis Vasculitis

Mycobacteria (often multifocal) M. tuberculosis, M. avium complex, M. kansasii, other mycobacteria

Goodpasture’s syndrome, Wegener’s granulomatosis, periarteritis Obstruction (neoplasm, foreign body)

Fungi Aspergillus spp., Mucoraceae, Histoplasma capsulatum, Pneumocystis carinii, Coccidioides immitis, Blastocystis hominis

Pulmonary sequestration Pulmonary constusion Carcinoma

Parasites Entamoeba histolytica, Paragonimus westermani, Strongyloides stercoralis (post-obstructive) Empyema (with air-fluid level) Septic embolism (endocarditis)

have been performed. It is important to emphasize the importance of obtaining specimens before inception of antibiotic treatment. Such specimens are not often obtained in clinical practice until the patient has developed complications of persistent infection (i.e., empyema or abscess). Thus, the anaerobic component of infection should be considered in management even if an aerobic organism is isolated.

It is essential that material obtained for culture be placed under anaerobic conditions promptly before transport to the laboratory. A sealed syringe provides the best container, with delivery of the specimen to the laboratory within 20 to 30 min for immediate plating. It is imperative that air bubbles be eliminated from the syringe and needle. Special anaerobic transport tubes are also available for brush or liquid specimens. It is important to obtain additional pulmonary specimens for culture and antibiotic susceptibility measurements from patients failing to respond to initial therapy (Fig. 122-8).

Such data may demonstrate the presence of unrecognized or antibiotic-resistant organisms. Most of these infections are polymicrobial, and many of the organisms grow slowly in vitro. Thus, it often takes several days to separate, identify, and report results of anaerobic cultures. There is great variation in the availability and quality of in vitro susceptibility tests. These factors illustrate the need for empiric decisions regarding antibiotic selection.

Diagnosis of Empyema The diagnosis of empyema is based on the characteristics of thoracic fluid. The urgency to diagnosis is due to the devel-

opment of pleural scar and of loculated effusions in the presence of undrained pus. Thus, diagnostic thoracentesis should be attempted unless the nature of the pleural fluid is clear or the clinical risk to the patient is too great. Pleural fluid should be prepared for Gram’s stain and cultures (routine, anaerobic, mycobacterial, and fungal), parasitologic examination when appropriate, fluid cell count and differential, cytology, pH, lactic dehydrogenase, and glucose measurements. Purulent fluid requires drainage. Empyema (defined in the preceding) is diagnosed on the basis of the neutrophilic predominance in fluids with more than 25,000 white blood cells per milliliter. Parapneumonic effusions will generally have lower white blood counts, negative Gram’s stains and cultures, a pH over 7.3, and glucose over 50 percent of serum glucose levels. Parapneumonic fluids may become infected over time.

Blood cultures and sputum cultures should be obtained as adjunctive guides to therapy.

DIAGNOSIS OF LUNG ABSCESS Microbiologic specimens from patients with lung abscesses should be obtained, if possible, without contamination by oral flora, especially after nosocomial colonization. Thus, invasive procedures are preferred to routine sputum samples. In particular, the diagnosis of anaerobic infection is complicated by the prevalence of large numbers of anaerobes as normal flora in the mouth and upper respiratory tract (Fig. 122-9). However, there may also be significant

2155 Chapter 122

A

B

C

D

Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections

Figure 122-8 Failure of penicillin therapy for anaerobic lung abscess in a 29-year-old alcoholic man. A. Admission chest radiograph reveals a radiolucent area within a zone of consolidation in the left upper lung field. B. Lateral view demonstrates multiple cavities. The patient was treated for 5 days with penicillin (6 million units per day intravenously), followed by the same dosage orally for 10 days. C. Radiographic infiltrate persists but no cavity is visible.

D. Six weeks after the cessation of penicillin therapy, the abscess has recurred in the same area. Marked pleural reaction is noted in the vicinity of the recurrent disease.

colonization with nosocomially acquired pathogens in hospitalized patients.

Blood cultures and sputum cultures should be obtained as adjunctive guides to therapy. When empyema or bacteremia complicates lung abscess, adequate specimens for microbiologic evaluation may be obtained from the blood or pleura. However, to obtain adequate specimens from the abscess, bronchoalveolar lavage, use of a protected doublelumen catheter, or percutaneous transthoracic aspiration under radiographic guidance is recommended. The specific procedure selected depends on the location of the infection and

the expertise of the institution. Specimens collected through a fiberoptic bronchoscope, using bronchoalveolar lavage or a plugged double-lumen sampling catheter with a protected sampling brush, are preferred; these require the use of quantitative cultures. Growth at a dilution of 10 from a protected brush represents approximately 10 to 10 organisms per milliliter in the lower respiratory tract. Recovery of nonbacterial and anaerobic bacteria from these specimens has not been well standardized. Specimens obtained from blind, deep suctioning via an endotracheal tube may also be useful if cultured quantitatively and examined microscopically.

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Table 122-7 Bacteriology of Anaerobic Lung Infections

Figure 122-9 Sagittal section illustrating presence of large numbers of organisms, including anaerobes, as indigenous flora in upper respiratory tract. (Values given as number of aerobic/anaerobic organisms per milliliter.) (Courtesy of P.D. Hoeprich.)

Bacteriology The bacteriologic findings in anaerobic lung infections from two large series are summarized in Table 122-7. Most of these infections involve multiple bacterial species, and approximately half of the patients have anaerobic bacteria combined with potentially pathogenic aerobic or facultative anaerobes.

Analysis of community-acquired infections involving only anaerobes versus those that are mixtures of aerobic and anaerobic bacteria shows common clinical features with no difference in terms of the frequency of suspected aspiration, indolent presentation, or the frequency of putrid discharge. The implication is that a putrid lung abscess with E. coli in expectorated sputum or anaerobic bacteria plus E. coli in a TTA should usually be considered an anaerobic infection. Caution is advised in applying these conclusions to nosocomial pulmonary infections, since this is a setting in which the aerobic component of the infection is probably more important.

The major bacterial isolates in patients with anaerobic lung infections are Peptostreptococcus, F. nucleatum, and P. melaninogenica. Aerobic and microaerophilic streptococci are commonly present, and may be contributing factors in the pathogenic events. At least 15 to 25 percent of anaerobic bacteria responsible for lung infections are resistant to penicillin, generally because of penicillinase production. These susceptibility data are rarely available in individual cases unless specifically requested.

TREATMENT OF ASPIRATION PNEUMONIA AND ANAEROBIC LUNG INFECTIONS Prevention Treatment is focused on optimal antimicrobial therapy and drainage of any abscess or empyema (see below). The re-

Bartlett

Marina et al.

Period reviewed

1968–1975

1976–1991

Patients

193

110

Total anaerobic isolates

461

404

38∗ 76 — — 56 37 126

18 63 40 23 34 138 39

18 18 5 8 10

12 22 1 22 9

Major isolates Gram-negative bacilli Bacteroides fragilis group Pigmented Prevotella† Nonpigmented Prevotella B. ureolyticus Fusobacterium nucleatum Bacteroides spp. (other) Peptostreptococcus/ peptococcus‡ Gram-positive bacilli Clostridium spp.

Eubacterium spp.

Actinomyces Lactobacillus Propionibacteria ∗ Numbers

indicate the total number of isolates. Some of the differences are due to taxonomic changes. † Pigmented Prevotella refers to organisms previously classified as B. melaninogenicus. ‡ Most peptococci have been reclassified as Peptostreptococcus.

versibility of underlying conditions predisposing to aspiration must be considered. It has recently been recognized, for example, that aspiration in lung transplant recipients is a major predisposing factor to graft injury and obliterative bronchiolitis. In the general patient population, nasogastricfeeding tubes, sedation, laying flat in bed while sleeping, reflux, and frequent choking are associated with aspiration, and should suggest strategies for remediation. Gastric surgery for obesity has also been associated with a high incidence of aspiration disease.

Methods to prevent aspiration have been most extensively studied in hospitalized patients, especially those who are aspiration prone. Most important is use of the semirecumbent or upright position. Additional factors that have variable degrees of success are tracheostomies, reduction of the stomach volume with suction or metoclopramide, feeding via gastrostomy tube, and neutralization of gastric acid with H2 blockers or antacids. Many of these procedures may alter colonization patterns and predispose to more significant infections. Neutralization of gastric acid may increase colonization of the oropharynx and increase the risk of bacterial infection following aspiration of gastric contents. Tracheostomy is useful

2157 Chapter 122

Aspiration, Empyema, Lung Abscesses, and Anaerobic Infections

Table 122-8 Antibiotic Treatment of Anaerobic Lung Infections: Results of Two Randomized Trials Number of Patients with Source

Treatment

# Pts

Failure

Relapse

Fever

Putrid Sputum

Levinson (1983)

Penicillin (6 mil units/d) Clindamycin (1.8 g/d)

21 17

5 (29%) 0∗

3 (19%) 0

7.7 4.7∗

7.8 4.1∗

Gudiol (1990)

Penicillin (12 mil units/d) Clindamycin (2.4 g/d)

18 19

7 (39%) 1 (5%)

2 (11%) 0

7.2 6.4

7.3 3.9∗

∗ Difference

for treatment favoring clindamycin is statistically significant.

in some patients with repeated aspiration, but inflation of the balloon may occlude the esophagus and promote aspiration of upper-airway contents. Patients who require nasogastric feedings are aspiration prone; percutaneous endoscopic gastroscopy is an attractive method to address this issue, but study results are quite variable. An alternative method sometimes favored is a feeding jejunostomy. The use of surgery with gastroesophageal reflux has given variable results.

Antimicrobial Therapy It is essential, whenever possible, to obtain microbiologic samples from the lungs and blood in advance of antimicrobial therapy. As for all pneumonias, inappropriate initial therapy has an adverse impact on outcome. The initial choice of antimicrobial agents should be guided by the Gram’s stain and the likely bacteriology of the infection, and then adjusted as culture data become available. The history and a review of old data may be useful in the selection of specific antibiotics. The standard drug historically for aspiration pneumonia and lung abscess involving anaerobic bacteria has been penicillin, usually given intravenously or with high-dose oral treatment. However, in the face of increasing penicillin resistance among S. pneumoniae and in 40 to 60 percent of strains of fusobacteria and P. melaninogenica as well as anaerobic gram-negative bacilli, alternatives should be considered for empiric therapy. In therapeutic trials in patients with lung abscess involving anaerobic bacteria (Table 122-8), clindamycin proved superior to penicillin in terms of response rates and time to defervescence. Alternative regimens that have been used successfully based on anecdotal experience include amoxicillin-clavulanate (Augmentin) and penicillin combined with metronidazole. Metronidazole should not be used as a single agent in patients with anaerobic lung infections, since there is a poor response in about 50 percent. The presumed explanation is the contributing role of aerobic and microaerophilic streptococci, which are resistant to this drug.

Many other antimicrobial agents are likely to be useful in anaerobic or mixed aerobic-anaerobic infections: combinations of a β-lactam with a β-lactamase

inhibitor (ticarcillin-clavulanate, ampicillin-sulbactam, amoxicillin-clavulanate, piperacillin-tazobactam), chloramphenicol, imipenem or meropenem, and second-generation cephalosporins such as cefoxitin or cefotetan. Macrolides (erythromycin, clarithromycin, and azithromycin) offer good in vitro activity against most strains except fusobacteria.

Tetracyclines show limited activity against many anaerobic bacteria in vitro; vancomycin is active only against grampositive anaerobes. Oxacillin and nafcillin are much less active. Drugs that have virtually no activity against anaerobes include aminoglycosides, first-generation fluoroquinolones, aztreonam, and trimethoprim-sulfamethoxazole. Some of the newer fluoroquinolones (gatifloxacin, moxifloxacin) have broad coverage that includes anaerobes.

The appropriate duration of therapy is dependent on the clinical and radiographic response of the patient. Patients should be treated at least until fever, putrid sputum, and abscess fluid have resolved, and any fluid collection has resolved or stabilized over 2 to 3 weeks. A minimum of 2 to 3 weeks of antibiotics is recommended. Longer courses are often necessary. Relapse is common and may involve organisms resistant to initial antibiotic agents (Fig. 122-8).

Management of Empyema The management of empyema includes antimicrobial treatment, identification and treatment of any anatomic processes, and drainage of the infected fluid. The approach to a specific patient is based on the clinical status of the patient as well as the microbiology of the infection. For example, patients with empyema following thoracic surgery and other hospitalized patients may have useful culture data available from chest tube drainage samples or sputum cultures to assist in the selection of antibiotics. The Gram’s stain may indicate the predominant organism type. Mixed aerobic and anaerobic organisms may be the first suggestion of esophageal tear or parapharyngeal infection. Fastidious organisms (S. pneumoniae, anaerobes) may be seen on Gram’s stain but not isolated in culture. Antibiotic susceptibility data should be used to guide therapy, especially in nosocomially acquired infection.

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Local administration of antibiotics (e.g., inhaled, instilled) is unnecessary and may be irritating; intrapleural injection of antibiotics should be reserved for pleural ablation (pleurodesis), as may be achieved with erythromycin.

Drainage of empyema fluid is recommended but controversial. Ten to twenty percent of empyemas require external drainage or surgical intervention. Noninfected parapneumonic pleural fluids resolve with appropriate treatment of the underlying infections. Drainage is required if infection or frank pus is present. In the presence of pleural fluid and unexplained fever, leukocytosis, or bacteremia, or in the postoperative patient, thoracentesis should be performed routinely. Diagnostic thoracentesis may be performed with a needle adequate for removal of all but the most viscous material. Highly viscous or purulent fluids and fluids with acid pH require the insertion of a chest tube via thoracostomy or the thoracoscopic drainage of the fluid.

In the early or exudative phase of parapneumonic effusion, the fluid is thin and serous or serosanguineous. This may resolve during appropriate antibiotic therapy either without drainage or with multiple needle aspirations. If the pH is over 7.3, this method may be preferred. If the pH is less than 7.0, however, complete drainage should be performed, often requiring closed chest tube insertion. If the pH is between 7.0 and 7.3, failure to demonstrate improvement of infection or inflammation on multiple thoracenteses over 3 to 4 days should lead to consideration of formal drainage, especially if the primary process is adequately treated. Loculation of pleural fluid or failure to respond to antimicrobial therapy may require either multiple thoracenteses guided by ultrasound or chest tomographic evaluation (CT scans) or surgical intervention (see the following). Bloody fluid or persistent parapneumonic fluid should prompt cytologic evaluation and CT scans for lung masses or undrained mediastinal or retrocardiac collections.

Empyema diagnosed later in the course, persistently infected pleural fluid, viscous fluid, or fluids with acid pH may require large-bore tube drainage. This heavily proteinaceous fluid is characteristic of the fibropurulent phase of the evolving empyema. Indications for closed chest tube placement include bronchopleural fistula with empyema, loculated fluid unresponsive to thoracentesis and antibiotics, the presence of blood clots, and rapidly accumulating empyema not otherwise manageable. Under suction, and with removal of the gellike material, pus, and clots, the lung expands and obliterates the empyema space. Failure to expand the underlying lung, persistence of drainage beyond 7 days, inability to achieve drainage assessed radiologically, fever without change in 2 to 3 days, or pus formation with persistent infection (as opposed to colonization of the chest tubes) necessitates a search for undrained foci of infection, failure to close a bronchopleural fistula or esophageal tear, undetected rupture of a lung abscess, or antibiotic failure. As the infection enters the chronic phase, open drainage with rib resection or pleurocutaneous fistula formation may be needed, with or without decortication, to achieve lung expansion and healing. Open drainage is obtained by making the pleura adherent to the chest wall

during the insertion of chest tubes directly into the empyema cavities. Drainage achieved too late in the course of infection may result in the development of pleural scar and fibrous peel with restrictive pulmonary physiology. Decortication may be needed to achieve sterilization of the pleural space and restore lung expansion. Thoracoscopic drainage of empyema has been used with excellent results at a number of institutions, particularly in children. Often, thoracoscopic drainage of empyema is used as a temporizing maneuver (e.g., following acute rupture of a lung abscess into the pleural space).

Patients achieving rapid re-expansion of the lungs may avoid open drainage procedures while achieving limited decortication and disruption of loculations. Alternatively, once a patient is stabilized and can better tolerate open drainage, or has demonstrated an inability to resolve the empyema without further drainage, surgical intervention may be needed. Early, aggressive treatment of empyema may reduce the duration of hospitalization and the risk of nosocomial superinfection.

TREATMENT OF LUNG ABSCESS The treatment of lung abscess must be guided by the microbiology and knowledge of any underlying or associated conditions that may predispose to the development of severe pulmonary infection. A small abscess in an otherwise healthy person may respond to conservative management with antimicrobial therapy and chest physical therapy. A rapidly expanding pulmonary abscess in an immunocompromised host (e.g., due to one of the Mucoraceae) requires urgent lung resection in addition to antimicrobials. Intermediate to these approaches is the use of bronchoscopic or radiographically guided catheter drainage of any fluid and necrotic debris.

In the absence of antibiotics, the mortality of lung abscess is approximately 33 percent. However, up to half of patients surviving a lung abscess acutely in the pre-antibiotic era had significant pulmonary complications, including recurrent infections and abscesses, pleural empyema and adhesions, chronic bronchitis, and bronchiectasis. The introduction of penicillin, orally or parenterally administered, resulted in resolution or collapse of the abscess in up to 90 percent of patients (although long courses of treatment were often needed). Therefore, these patients could avoid surgical resection.

The role of drainage or surgery is based on serial clinical assessments of the patient. Bronchoscopic drainage may be most useful in the relief of abscesses without air-fluid levels, which indicate the possibility of persistent connection with the bronchi. However, experience dictates caution with the bronchoscopic drainage of closed cavities; spillage of cavity contents into other lung segments may produce catastrophic pulmonary dysfunction. Further, there are few data to suggest that bronchoscopic drainage offers a significant advantage in terms of rapidity of recovery in the immunologically normal host. In patients with coexistent empyema and lung abscess, it is often useful to address drainage of the empyema first, stabilizing the patient, and then considering further procedures

2159 Chapter 122

for the lung abscess. In critically ill patients, or those with bronchial obstruction related to the abscess cavity, bronchoscopic drainage should be considered.

Bronchoscopy and chest CT have major roles in the evaluation of the patient failing therapy. Persistence of bacteremia or high-grade fevers after 72 h, or the absence of change in sputum production or character or in the radiographic images over 7 to 10 days suggests unappreciated anatomic or microbiologic problems. Obstruction or resistant organisms (including fungi, parasites, or mycobacteria) may be present. Multiple loculations may be present, or empyema, including drainage of the abscess into the pleural space, may develop. New sites of infection, including extrathoracic sites, may have developed in the bacteremic patient. Progression of pulmonary infiltrates may occur after the initiation of appropriate antibiotic therapy, reflecting the relatively poor activity of many antibiotics at the low pH levels of poorly ventilated and underperfused, infected lung tissues, as well as the delayed radiographic response to treatment.

Surgical resection of necrotic segments of lung is helpful if the response to antibiotics is poor, for large abscesses, or ventilation-perfusion scans suggest little residual lung function in a limited necrotic region. Infarcted lung or rapidly progressive infection may force surgical resection of the affected tissue. Surgery is also indicated if airway obstruction limits drainage. Such presentations are seen in the presence of tumor or a foreign body. In patients thought to be poor surgical risks, percutaneous drainage via catheters may be a useful temporizing measure. However, leakage of the abscess contents into the pleural space in such patients may be disastrous and must be avoided.

Mortality in patients with lung abscesses reflects the quality of the host’s inflammatory response and overall condition. Patients with large abscesses (over 5–6 cm), progressive pulmonary necrosis, obstructing lesions, aerobic bacteria, immune compromise, old age, or systemic debility, and those with major delays in seeking medical attention have a significantly increased mortality.

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Bartlett JG: Diagnostic accuracy of transtracheal aspiration bacteriologic studies. Am Rev Respir Dis 115:777–782, 1977.

Bartlett JG: Anaerobic bacterial infections of the lung. Chest 91:901–909, 1987.

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Bartlett JG, Finegold SM: Anaerobic infections of the lung and pleural space. Am Rev Respir Dis 110:56–77, 1974.

Bartlett JG, Finegold SM: Bacteriology of expectorated sputum with quantitative culture and wash technique compared to transtracheal aspirates. Am Rev Respir Dis 117:1019–1027, 1978.

Bartlett JG, Gorbach SL, Thadepalli H, et al: Bacteriology of empyema. Lancet 1:338–340, 1974.

Beerens H, Tahon-Castel M: Infections humaines a` bact´eries ana´erobies nontoxig`enes. Brussels, Presses Acad´emiques Europ´eenes, 1965, pp 91–114.

Berson W, Adriani J: Silent regurgitation and aspiration during anesthesia. Anesthesiology 15:644–649, 1954.

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Brook I, Finegold SM: Bacteriology of aspiration pneumonia in children. Pediatrics 65:1115–1120, 1980.

Bynum LJ, Pierce AK: Pulmonary aspiration of gastric contents. Am Rev Respir Dis 114:1129–1136, 1976.

Chapman RL Jr, Downs JB, Modell JH, et al: The ineffectiveness of steroid therapy in treating aspiration of hydrochloric acid. Arch Surg 108:858–861, 1974.

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Cohn LH, Blaisdell EW: Surgical treatment of nontuberculous empyema. Arch Surg 100:376–381, 1970.

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Ednie LM, Jacobs MR, Appelbaum PC: Activities of gatifloxacin compared to those of seven other agents against anaerobic organisms. Antimicrob Agents Chemother 42:2459–2462, 1998.

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Gudiol F, Manresa F, Pallares R, et al: Clindamycin vs. penicillin for anaerobic lung infections: High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus. Arch Intern Med 150:2525–2529, 1990.

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Henriquez AH, Mendoza J, Gonzalez PC: Quantitative culture of bronchoalveolar lavage from patients with anaerobic lung abscesses. J Infect Dis 164:414–417, 1991.

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123 Mediastinitis Mark E. Rupp

Mary L. Ricardo-Dukelow

I. MEDIASTINITIS Anatomical Considerations II. ACUTE MEDIASTINITIS Epidemiology and Path ogenesis Bacteriology

MEDIASTINITIS Mediastinitis can be conveniently organized into acute or chronic forms with etiologies, clinical presentations, and treatments that are strikingly different. Acute mediastinitis is a life-threatening infection that is increasingly recognized as a postoperative complication of cardiovascular surgery.

Other less common causes of mediastinitis include esophageal perforation and contiguous spread from oropharyngeal foci.

Regardless of the route of infection, a high-index of suspicion must be maintained for this clinical entity so that aggressive, potentially life-saving, measures can be promptly initiated.

Chronic mediastinitis, also known as sclerosing mediastinitis, fibrosing mediastinitis, or granulomatous mediastinitis, is a rare disorder that is most often due to Histoplasma capsulatum.

Anatomical Considerations Detailed descriptions of mediastinal anatomy are available; a thorough review of this material is beyond the scope of this chapter. However, a few fundamental points will be emphasized. The mediastinum is the region within the thorax between the pleural sacs (Fig. 123-1). It extends from the diaphragm inferiorly to the superior aperture of the thorax. The 12 thoracic vertebral bodies border the mediastinum posteriorly and the sternum and costal cartilages make up the anterior boundary. The mediastinum is arbitrarily divided into four subdivisions: superior, posterior, anterior, and middle. Structures within the mediastinum include the heart and

Clinical Manifestations and Diagnosis Treatment Antibiotic Prophylaxis Complications and Prognosis III. CHRONIC MEDIASTINITIS

great vessels, the esophagus, the distal portion of the trachea and mainstem bronchi, vagus and phrenic nerves, the thymic remnant, and the thoracic duct. These structures are surrounded by adipose tissue, loose connective tissue, and lymph nodes. The mediastinum communicates with the structures of the head and neck via several fascial planes and potential spaces (Figs. 123-2 and 123-3). The three major routes by which infection spreads from the head and neck to the mediastinum are (1) the pretracheal space, (2) the long fascial planes of the posterior neck, and (3) the viscerovascular or lateral pharyngeal space. The long fascial planes of the posterior neck extend from the base of the skull to the diaphragm and are made up of the retropharyngeal or retrovisceral space, the prevertebral space, and the danger space. Pearse attempted to delineate the relative importance of each route in the pathogenesis of mediastinitis and found the retropharyngeal space to be involved in 71 percent of cases followed in frequency by the lateral pharyngeal space (21 percent) and the pretracheal space (8 percent). Knowledge of these fascial planes and anatomic relationships helps one to understand the pathogenesis and potential complications of mediastinitis.

ACUTE MEDIASTINITIS Epidemiology and Pathogenesis Primary infection of the mediastinum is a rare event. Essentially all cases of mediastinitis are secondary to the spread of infection from other sites or direct inoculation due to trauma

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or surgery. The causes of mediastinitis are summarized in Table 123-1 and can be conveniently grouped into the following four categories: cardiothoracic surgery, esophageal perforation, head and neck infection, and infection originating at another site. The pathogenesis, clinical manifestations, and treatment vary with the underlying cause of mediastinitis.

These aspects are summarized in Table 123-2.

Figure 123-1 Anatomic boundaries and divisions of the mediastinum.

Figure 123-2 Cross-section of the neck at the level of the seventh cervical vertebrae demonstrating the potential spaces for spread of infection from the head and neck into the mediastinum.

Figure 123-3 Sagittal section of the head and neck showing relationship of the fascial spaces to the mediastinum.

Mediastinitis Secondary to Cardiothoracic Surgery Cardiothoracic operations are among the most common surgical procedures performed in larger hospitals. Coronary artery bypass grafting and cardiac valve replacement accounted for 30 percent of the procedures reported between 1992 and 2004 to the Center for Disease Controlâ&#x20AC;&#x2122;s National Nosocomial Infection Surveillance System. Because of the large number of median sternotomies that are performed, mediastinitis has predominantly become a postsurgical infection. Numerous studies have documented the incidence of mediastinitis following cardiothoracic surgery and the risk factors for development of this serious complication. In 1984 Sarr et al reviewed the available literature and found the incidence of mediastinitis to range from 0.4 to 5 percent of patients undergoing median sternotomy. Since then studies documenting the experience in over 400,000 patients have been published, with incidence rates ranging from 0.66 to 2.4 percent. The largest study to date was derived from the Society of Thoracic Surgeons National Cardiac Database and involved analysis of over 330,000 coronary artery bypass graft cases performed during 2002 and 2003. Major infection occurred in 11,636 patients (3.51 percent), 25.1 percent of which was attributed to mediastinitis. The incidence of mediastinitis during outbreaks has been as high as 5 to 23.7 percent.

Patients undergoing heart transplantation are at higher risk of developing mediastinitis, with frequencies of 2.5 to 7.5 percent. This risk of mediastinitis is further increased if a mechanical device, such as a left ventricular assist device or a total artificial heart, is used to support the patient awaiting a suitable donor heart. The frequency of mediastinitis in this circumstance ranges from 7.5 to 35.7 percent. Patients undergoing heart-lung transplantation appear to be at a roughly twofold greater risk of mediastinitis than those undergoing heart transplantation per se.

A number of factors have been identified as causes for an increase risk of mediastinitis. The studies examining these risk factors are primarily retrospective case-control studies; therefore, they are limited by the problems inherent in retrospective surveys. Risk factors can be divided into the following groups: preoperative, intraoperative, and postoperative (Table 123-3). Preoperative risk factors include diabetes mellitus, obesity, previous sternotomy, chronic obstructive pulmonary disease, cigarette smoking, low-cardiac output states, remote infection, history of endocarditis, method of hair removal, and prolonged preoperative hospitalization.

Intraoperative and surgical risk factors include complexity of surgery, type of bone-saw used, type of sternal closure, use of internal mammary arteries in coronary artery bypass

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Mediastinitis

Table 123-1 Causes of Acute Mediastinitis Esophageal Perforation Iatrogenic Esophagogastroduodenoscopy, esophageal dilatation, esophageal variceal sclerotherapy, nasogastric tube, Sengstaken-Blakemore tube, endotracheal intubation, esophageal surgery, paraesophageal surgery Swallowed Foreign Bodies Bones, coins, can pull-tabs, drug-filled condoms, swords Trauma Penetrating Gunshot wound, knife wound Blunt Steering wheel injury, seat-belt injury, cardiopulmonary resuscitation, whiplash injury, barotrauma

Spontaneous/Other Emesis, cricoid pressure during anesthesia induction, heavy lifting, defecation, parturition, carcinoma

grafting, use of bone wax, prolonged operative time, prolonged time on cardiopulmonary bypass, blood transfusions, indiscriminate use of electrocautery, and antibiotic prophylaxis. Postoperatively, patients at increased risk for mediastinitis require re-exploration to control bleeding, prolonged length of stay in the intensive care unit, mechanical ventilation for more than 24 to 48 hours, need for tracheostomy, use of cardiopulmonary resuscitation, and low cardiac-output states. However, agreement regarding these risk factors is not universal and their relative importance is undefined. For instance, even after three decades of surgical experience, it is unclear whether the use of internal mammary artery (IMA) grafts in coronary artery bypass surgery predisposes patients to mediastinitis. In 1972, based upon anatomical studies of sternal blood supply, Arnold suggested that the use of the IMA in coronary artery bypass procedures might lead to significant sternal ischemia and thus predispose patients to sternal osteomyelitis and mediastinitis. This suggestion has been supported by several laboratory and clinical studies. However, other investigators have not observed a significant increase in sternal wound infections in patients undergoing coronary artery bypass grafting when the IMA is used.

It is generally believed that the pathogenesis of postcardiac surgery mediastinitis is primarily due to the inoculation into the operative wound of organisms from the patient’s endogenous bacterial flora or from the surgical field. Bacteria are able to propagate in the relatively protected avascular area of the surgical wound and cause infection. Therefore, a number of the putative risk factors are attractive intuitively,

Head and Neck Infections Odontogenic, Ludwig’s angina, pharyngitis, tonsillitis, parotitis, epiglottitis Infection Originating at Another Site Pneumonia, pleural space infection/empyema, subphrenic abscess, pancreatitis, cellulitis/soft-tissue infection of the chest wall, osteomyelitis of sternum, clavicle, ribs, or vertebrae, hematogenous spread from distant foci Cardio thoracic Surgery Coronary artery bypass grafting, cardiac valve replacement, repair of congenital heart defect, heart transplantation, heart-lung transplantation, cardiac assist devices, other types of cardio thoracic surgery

such as the duration of the surgery, the complexity of the surgery, and the need for re-exploration. In addition, outbreaks of mediastinitis have been linked epidemiologically to sources such as bacteria from a particular surgeon’s hands or nares, lending support to the belief that intraoperative factors are important in the pathogenesis of mediastinitis. Following changes in the environment of the operating room, Ferrazzi et al observed a significant decrease in the incidence of gram-negative mediastinitis, without a significant change in the frequency of gram-positive infections. This observation supported the belief that many of these infections arise from gram-positive organisms resident on the patient’s skin.

Archer et al has demonstrated that patients are colonized by small numbers of antibiotic-resistant, coagulase-negative staphylococci which become the predominant species when subjected to the selective pressure of prophylactic antibiotics.

In addition, various immunosuppressive effects of cardiopulmonary bypass have been elucidated that may contribute to the pathogenesis of mediastinitis after surgery.

The importance of postoperative factors has also been emphasized by outbreaks of mediastinitis which have been linked to environmental sources, including contaminated tap water and poor hand-washing technique in the postoperative care of cardiac surgery patients. However, Kaiser has warned persuasively against taking a “make-a-change-and-see-whathappens” approach to the analysis of risk factors related to the pathogenesis of postoperative infection. Controlled prospective studies are needed to improve the identification of factors that influence postcardiac surgery mediastinitis.

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Table 123-2 Summary of Acute Mediastinitis Cardiovascular Surgery

Head and Neck Infection

Esophageal Perforation

Pathogenesis

Intraoperative wound contamination

Oral infection that extends to involve sublingual and submandibular spaces with spread through fascial planes of the neck into mediastinum

Inoculation of flora into mediastinum secondary to esophageal perforation

Clinical Presentation

Fever, chills, sternal instability, sternal wound drainage

Pain, fever, local signs and symptoms of infection

Pain, dysphagia, respiratory distress

Most Common Microbial Etiology

Gram-positive cocci: saureus (methicillin-sensitive or resistant), Coagulase-negative Staphylococcus, Streptococci, Gram-negative bacilli

Oral flora: Streptococcus viridans, peptococci, peptostreptococci, Bacteroides sp, Fusobacterium, Gram-negative bacilli

Similar to microbiology of head and neck infections

Risk Factors

Cardiac assist-device Low-cardiac output Prior heart surgery Length of surgery Co-morbid conditions Obesity Method of hair removal Prolonged preoperative hospitalization Poor hemostasis Hyperglycemia COPD Smoking

Conditions predisposing to dental infections or other head and neck infections: poor dentition, parotid stone, recurrent tonsillitis

Conditions predisposing to esophageal perforation: esophageal tumor, endoscopy, swallowed foreign body

Laboratory Testing and Findings

Leukocytosis Blood cultures (bacteremia observed in more than one-half of cases)

Leukocytosis Microbiologic cultures using anaerobic techniques

Leukocytosis Microbiologic cultures using anaerobic techniques

Radiologic Diagnosis

CT chest localized mediastinal fluid, pneumomediastinum

CT head and neck CT chest

Contrast esophagography, CT neck and chest

Surgical Treatment

Surgical debridement required Vacuum-assisted closure

Prompt surgical intervention when descending odontogenic or pharyngeal infection is observed

Prompt surgical intervention with drainage, debridement, and repair

Antibiotic Treatment

Initial broad-spectrum coverage, include vancomycin (or other anti-MRSA agent) if MRSA is likely; adjust antibiotics according to microbiologic data

Initial antibiotic coverage for oral flora including Bacteroides sp; pencillin G + metronidazole, clindamycin, or broad-spectrum β-lactam/β-lactamase inhibitor

Similar to antibiotic choice for head and neck infection

COPD, chronic obstructive pulmonary disease; CT, computed tomography; MRSA, methicillin-resistant S. aureus.

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Table 123-3 Risk Factors for Mediastinitis Preoperative

Preoperative New York Heart Association physiologic class ≥III Preoperative hyperglycemia Presence of one or more co-morbid conditions (pulmonary, hepatic, gastrointestinal, or malignant disease processes) Diabetes mellitus Obesity Previous sternotomy Chronic obstructive pulmonary disease (COPD) Cigarette smoking Remote infection History of endocarditis Method of hair removal Prolonged preoperative hospitalization

Intraoperative

Poor hemostasis at the time of closure Complexity of surgery Type of bone saw used Type of sternal closure Use of internal mammary arteries in coronary artery bypass grafting Use of bone wax Prolonged operative time Prolonged time on cardiopulmonary bypass Blood transfusion Indiscriminate use of electrocautery Inappropriate antibiotic prophylaxis Avoidance of staple use

Postoperative

Re-exploration to control bleeding Prolonged length of stay in the intensive care unit Mechanical ventilation >24–48 h Need for tracheostomy Use of cardiopulmonary resuscitation Low cardiac-output states Use of contaminated tap water to remove Betadine following cardiac surgery

Mediastinitis Secondary to Esophageal Perforation Prior to the development of cardiac surgery, perforation of the esophagus was the leading cause of mediastinitis, followed by suppurative infections of the oropharynx. In 1724 Herman Boerhaave graphically described the first case of mediastinitis due to spontaneous rupture of the esophagus in a Dutch admiral who died 18.5 hours after self-induced emesis. Since then this entity has been known as Boerhaave’s syn-

Mediastinitis

drome. Currently, esophageal perforation is most frequently due to iatrogenic etiologies. Flexible fiberoptic endoscopy of the upper-gastrointestinal tract is complicated by esophageal perforation in 0.074 to 0.4 percent of the procedures. The frequency of complication increases when sclerotherapy or dilatation procedures are performed. Swallowed foreign bodies, esophageal carcinoma, and nonsurgical trauma may also cause perforation of the esophagus and mediastinitis.

Depending on the site of the esophageal perforation, mediastinitis may result from migration into the mediastinum via the fascial planes of the neck or from direct spillage of esophageal contents into the posterior mediastinum. A necrotizing chemical mediastinitis ensues, followed by an aerobic and anaerobic bacterial mediastinitis.

Often a synergistic necrotizing form of mediastinitis occurs.

Spread of infection from the neck into the mediastinum is influenced by respiratory dynamics by which the negative intrathoracic pressure generated during respiration tends to force the infection into the mediastinum.

Mediastinitis Secondary to Head and Neck Infection or from Other Sites Before antibiotics were widely available odontogenic and pharyngeal infections caused between 10 to 31 percent of cases of mediastinitis. Fortunately, these infections have currently become a rare cause of mediastinitis. The prototypic odontogenic infection leading to mediastinitis is Ludwig’s angina which usually stems from an infection of the second or third mandibular molar to involve the sublingual and submandibular spaces. From these spaces, the infection can spread via the lateral pharyngeal space to involve the retropharyngeal space or carotid sheath and thus track into the mediastinum. During the antibiotic era approximately 3.5 percent of Ludwig’s angina cases have been complicated by mediastinitis. Mediastinitis resulting from infections which involve the lateral pharyngeal space may originate from a number of sources including the teeth, parotid glands, tonsils, or, rarely, from otitis or mastoiditis. Infections of the retropharyngeal space generally arise from perforation of the esophagus or by extension from pharyngitis, epiglottitis, or tonsillitis. From the long fascial planes of the neck, these infections spread readily into the superior mediastinum, or, if the danger space is involved, the posterior mediastinum. The pretracheal space descends into the anterior mediastinum and most often is involved in mediastinitis, which complicates surgery of the thyroid or trachea. Rarely is mediastinitis due to spread from other sites.

Instances have been described secondary to the following conditions: pneumonia, pleural space infection, osteomyelitis of the ribs, clavicle, sternum or vertebrae, subphrenic abscess, pancreatitis, cellulitis, and hematogenous seeding from distant foci.

Bacteriology The bacteriology of mediastinitis complicating cardiovascular surgery is strikingly different from mediastinitis secondary to odontogenic or other head and neck infections (Table 123-4). Mediastinitis secondary to cardiothoracic

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Table 123-4 Microbiology of Mediastinitis Organisms Frequently Recovered in Mediastinitis Secondary to Infection of the Head and Neck or Esophageal Perforation Anaerobic Gram-positive cocci Peptococcus spp.

Peptostreptococcus spp.

Gram-positive bacilli Actinomyces Eubacterium Lactobacillus Gram-negative cocci Veillonella Gram-negative bacilli Bacteroides spp.

Fusobacterium spp.

Aerobic or Facultative Gram-positive cocci Streptococcal spp.

Staphylococci spp.

Gram-positive bacilli Corynebacterium Gram-negative cocci Branhamella Gram-negative bacilli Enterobacteriaceae Pseudomonas spp.

E. corodans Fungi C. albicans

Clinical Manifestations and Diagnosis

Organisms Frequently Recovered in Mediastinitis Secondary to Cardiothoracic Surgery

Organism

surgery is predominantly due to gram-positive cocci and less often by gram-negative bacilli. A recent review of 316 consecutive patients with mediastinitis that occurred in fewer than 30 days after sternotomy revealed the most common causative microorganisms to be methicillin-susceptible Staphylococcus aureus (45 percent), methicillin-resistant S. aureus (16 percent), gram-negative bacilli (17 percent), coagulase-negative staphylococci (13 percent), and streptococci (5 percent). A case-control study examined whether risk factors for specific pathogens could be identified. Multivariate analysis revealed that diabetes, female gender, and age greater than 70 years were associated with infection due to methicillin-resistant S. aureus, whereas obesity was the only independent risk factor associated with infection due to methicillin-susceptible S. aureus. The bacteriology of mediastinitis secondary to extension from head and neck sources is somewhat more complicated. The majority of these infections is polymicrobic. Often a synergistic infection made up of a number of oral anaerobes and gram-negative bacilli is evident. The most frequently isolated organisms include viridans streptococci, peptococci, peptostreptococci, Bacteroides spp., and Fusobacterium. The relative frequency with which these organisms are isolated is difficult to determine due to the difficulty of obtaining reliable anaerobic culture data.

Range

Representative Rate

Gram-positive cocci S. aureus 7.1%–66.7% 25% S. epidermidis 6%–45.5% 30% Enterococcus spp.

8%–18.8% 10% Streptococci spp.

0%–18.2% 2% Gram-Negative Bacilli E. coli 0%–12.5% 5% Enterobacter spp.

4%–21.4% 10% Klebsiella spp.

0%–21.1% 3% Proteus spp.

0%–7.1% 2% Other Enterobacteriaceae 0%–20% 2% Pseudomonas spp.

0%–54% 2% Fungi C. albicans 0%–14.3% <2% Polymicrobial 0%–40% 10% Other Occasionally Reported: Acinetobacter, Legionella spp. B. fragilis, C. tropicalis, Nocardia spp. Kluyvera, M. fortuitum, M. chelonei, R. bronchialis Other Unusual Causes of Mediastinitis: Anthrax, brucellosis, actinomycoses, paragonimiasis

The clinical manifestations of mediastinitis also differ based on the underlying cause of disease. Patients who experience mediastinitis from extension of odontogenic or pharyngeal infections usually have obvious primary infections with significant pain, fever, and swelling of the affected site.

Esophageal perforation may be clinically obvious or inapparent. Early in the course of mediastinitis, signs and symptoms may be subtle, but as the condition progresses, patients note increasing chest pain, respiratory distress, and dysphagia. Chest pain is often the most prominent symptom and may localize depending on the portion of the mediastinum involved. In anterior mediastinitis, pain is often located in the cervical or substernal region. Pain due to posterior mediastinitis may localize to the epigastric area with radiation to the interscapular region. Pleuritic chest pain may also be experienced due to pleural effusion, a relatively frequent complication. Retroperitoneal extension may be accompanied by acute abdominal signs and may prompt needless exploratory laparotomy. Examination may reveal fever, tachycardia, crepitus, and edema of the chest or neck. “Hamman’s sign”, a crunching rasping sound heard over the precordium synchronous with the cardiac rhythm, due to emphysema of the mediastinum, may be audible in up to 50 percent of patients with pneumomediastinum. The heart sounds may be distant and dull. In the later stages of mediastinitis, signs of bacteremia and sepsis may predominate. The early diagnosis of mediastinitis in the infant or neonate may be particularly challenging. A peculiar, interrupted, staccato type of inspiration has been described in a number of patients. The signs and symptoms of mediastinitis in older children are similar to those in adults.

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A

B

Figure 123-4 A. Chest radiograph of elderly woman with esophageal perforation and mediastinitis. The patient had senile dementia and had unknowingly swallowed a portion of a broken glass jar resulting in esophageal perforation. The chest radiograph reveals a foreign body within the esophagus (arrow) and widening of the mediastinum. B . Computed tomography of the chest at the level of the sixth thoracic vertebrae demonstrating a large abscess within the posterior mediastinum and a left-sided pleural effusion. (Radiographs courtesy of Dr. J. Gurney, University of Nebraska Medical Center.)

Laboratory tests usually reveal a leukocytosis with a leftward shift evident on the differential blood count. Radiographically, plain films of the chest may reveal mediastinal widening, air-fluid levels, and subcutaneous or mediastinal emphysema. A lateral chest radiograph may be useful in demonstrating superior mediastinal gas not evident on upright films. In about 50 percent of instances of pneumomediastinum lateral views are required to establish the diagnosis. Examples of some of the radiographic manifestations of mediastinitis are shown in Figs. 123-4 and 123-5.

Complications of mediastinitis, such as pleural effusion or

Mediastinitis

Figure 123-5 Chest radiograph demonstrating pneumomediastinum (arrow). (Radiograph courtesy of Dr. J. Gurney, University of Nebraska Medical Center.)

pneumoperitoneum, may also be evident on the chest radiograph. Esophageal perforation is best demonstrated by contrast esophagography which reveals extravasation of dye in 59 to 100 percent of cases. It is recommended that a water-soluble contrast agent be used initially to detect gross extravasation due to the inflammation and granuloma formation evoked by barium. If extravasation is not observed, barium should be used to detect subtle defects, since it provides better definition of the anatomy. Computed tomography (CT) is often helpful for patients in whom the diagnosis is not evident either clinically or on plain films. Technetium-labeled white blood cell scans are reported to be helpful in the diagnosis of mediastinitis in special circumstances when CT scan is not readily available. The role of magnetic resonance imaging (MRI) in the evaluation of mediastinitis is not well-established.

Postcardiothoracic surgery mediastinitis usually becomes evident clinically within the first 2 weeks following surgery. However, rare instances have been described that presented more than 1 year postoperatively. Infections due to gram-negative organisms generally present earlier. One study found that all cases of mediastinitis that presented more than 2 weeks postoperatively were due to gram-positive organisms.

The presentation of mediastinitis may be fulminant or subtle. Some patients may present with sepsis without localizing signs. Some patients may experience more than normal postoperative pain which may be pleuritic in nature. Dysphagia is a rare complaint. Fever and an abnormal appearance of the surgical wound, characterized by erythema, cellulitis, or purulent discharge, are the most frequent signs of mediastinitis. Sternal instability, dehiscence, or bubbles emanating from the sternal wound are less frequent. Occasionally emphysema of the chest wall occurs.

Post-sternotomy mediastinitis presenting as a deep neck abscess without abnormal findings on examinations of the chest has been reported. Laboratory tests usually show a

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Figure 123-6 Chest radiograph of patient with mediastinitis following cardiac surgery. Dehiscence of median sternotomy is demonstrated by asymmetry of sternal wires. (Radiograph courtesy of Dr. J. Gurney, University of Nebraska Medical Center.)

moderate leukocytosis with a leftward shift of the white blood cell differential. Radiographically, mediastinal widening is a rare finding on plain chest films and routine radiographs are usually of very little use for the diagnosis of mediastinitis following cardiothoracic surgery (Fig. 123-6). CT scanning has proved to be helpful in many instances of postoperative mediastinitis, particularly in differentiating superficial wound infections from deeper retrosternal processes. However, normal postoperative collections of fluid and gas are at times difficult to differentiate from early signs of mediastinitis.

The diagnostic value of nuclear scans has been espoused by several investigators. Browdie et al evaluated the relative value of CT, indium-111 (111 In)–labeled leukocyte scanning, and epicardial pacer wire cultures in 24 patients undergoing evaluation for possible mediastinitis. They found that CT had a sensitivity of 67 percent and specificity of 71 percent, 111 In– labeled leukocyte scan was 83 percent sensitive and 100 percent specific; and epicardial pacer wire cultures were reported to be 100 percent sensitive and 92 percent specific. However, another investigator found that epicardial pacer wire cultures were associated with an unacceptably high false-positive rate.

The role of MRI is not well-defined; it is contraindicated in instances in which ferromagnetic metals are used in sternal wires, artificial heart valves, cardiac pacemakers, or vascular clips. Several investigators have found that mediastinal needle aspiration is useful for the diagnosis of mediastinitis. This method, which has been reported to be positive in 65.8 percent of patients, appears to be particularly useful in diagnosing mediastinitis before it becomes more clinically obvious.

Treatment Treatment that includes both medical and surgical techniques should be promptly initiated once the diagnosis of medias-

tinitis is made. In all cases aggressive supportive and nutritional therapy is required. Barrett is credited with documenting in 1946 the first successful treatment of mediastinitis due to esophageal perforation. Since then, most experts recommend aggressive surgical drainage, debridement, and repair in patients with mediastinitis secondary to esophageal perforation. However, based on experience with eight patients, Cameron et al identified a subset of patients that could be treated without surgical intervention. These patients will have a well-contained disruption of the esophagus, the abscess should drain back into the esophagus, minimal symptoms are present, and there should be minimal evidence of clinical toxicity. Shaffer et al expanded upon these recommendations based on the patients with esophageal perforation due to instrumentation detected before major mediastinal contamination. Santos et al have recommended transesophageal irrigation for patients in whom primary repair of the esophagus is not possible due to advanced local infection with extensive tissue necrosis.

As in patients with mediastinitis due to esophageal perforation, patients in whom the mediastinitis is secondary to descending odontogenic or pharyngeal infection require prompt surgical intervention. Because transcervical drainage is frequently inadequate, a transthoracic approach is generally necessary.

Although the importance of supportive therapy and surgical intervention cannot be overemphasized, administration of appropriate antibiotics is also an essential component of therapy. Empirical regimens are based upon the underlying etiology and should deal with the major pathogens listed in Table 123-4. Penicillin G has traditionally been the antibiotic of choice in the treatment of anaerobic infections that originate above the diaphragm and continues to exhibit excellent activity against most oral anaerobic bacteria. Unfortunately, oral Bacteroides spp. are increasingly resistant to penicillin G. Therefore, when infection with Bacteroides is suspected, treatment with metronidazole, clindamycin, or broad spectrum β-lactam/β-lactamase inhibitor antibiotics with activity against Bacteroides spp., as well as other oropharyngeal anaerobes, may be indicated. In addition, gram-negative enteric bacilli are often implicated in mediastinitis and should be taken into account in the initial empiric therapy. Antibiotic therapy should then be more specifically tailored to the infecting organisms when definitive culture results are available, but treatment directed against anaerobic oropharyngeal organisms should probably be continued due to the difficulty in obtaining reliable anaerobic cultures. Duration of therapy, which may range from weeks to months, is determined by the virulence of the bacteria, host factors, and the patient’s response to therapy.

The treatment of postcardiac surgery mediastinitis generally requires aggressive surgical drainage and debridement.

A small number of patients have been successfully treated via percutaneous catheter drainage. Two approaches have been used in the surgical management of postcardiac surgery mediastinitis—an open technique and a closed technique.

The open technique involves debridement of infected tissue

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and open packing of the wound with delayed closure. Disadvantages of this technique include respiratory insufficiency due to lack of mechanical support for the thorax, delayed healing and closure of the surgical wound, and hemorrhage from exposed vessels. The closed method involves debridement of affected tissues, closure of the sternum, and postoperative irrigation through drainage tubes within the mediastinum. Irrigants have included a variety of antimicrobial and antiseptic solutions, such as neomycin, gentamicin, bacitracin, polymyxin B, saline, and Dakin’s solution. The use of irrigants has been associated with a variety of complications including emergence of resistant organisms, pericardial and tissue toxicity, and systemic absorption and toxicity. The most commonly employed irrigant is povidone-iodine. Use of povidone-iodine has been associated with iodine toxicity, renal failure, metabolic acidosis, and seizures. Therefore, this agent must be used with caution, and it has been recommended that serum iodide concentrations be measured to insure that toxic levels are not reached. Durandy et al reported a closed technique that successfully used Redon drainage devices in 11 patients who did not require postoperative irrigation. A number of investigators have reported the successful use of muscle flaps and omental grafts in many instances at the time of initial debridement to close mediastinal wounds, with or without postoperative irrigation. Fuchs et al suggest that vacuum-assisted closure (VAC) is a promising new method for the therapy of mediastinitis. A retrospective analysis of 68 cases that compared VAC to conventional therapy with open packing revealed earlier microbiologic cure, more rapid decline in C-reactive protein, shortened hospital stay, earlier rewiring, and higher survival in the VAC group.

The use of parenteral antibiotics has remained a cornerstone of therapy. Generally, empiric therapy should be directed at staphylococci and gram-negative aerobic bacilli until definitive culture results become available. As with mediastinitis secondary to infection of the head and neck, the duration of therapy is determined by multiple factors and may be quite prolonged.

Mediastinitis

as a choice for prophylaxis in centers with a high frequency of infections due to methicillin-resistant staphylococci. The major disadvantages associated with the use of vancomycin are the long infusion time and the small number of patients who experience adverse events, such as hypotension and “red man syndrome”. In addition, the emergence of vancomycinresistant enterococci and staphylococci, due in part to the inappropriate overuse of vancomycin, must be considered as a long-term disadvantage to the use of vancomycin as a prophylactic agent.

Complications and Prognosis Complications of mediastinitis include extension of the infection into a number of contiguous structures and spaces including the pericardial space, resulting in pericardial effusion and tamponade, the pleural space, and the peritoneum, resulting in peritonitis. A major complication of postcardiac surgery mediastinitis is sternal osteomyelitis. Prior to the development of modern surgery and antibiotics, mediastinitis, due primarily to esophageal perforation, was regarded as uniformly fatal. Unfortunately, since the time of Barrett’s first successful surgical repair of the esophagus, morbidity and mortality have remained high, with many studies recording mortality rates of 30 to 50 percent. Survivors of mediastinitis usually have no permanent sequela. In examining the economic ramifications of mediastinitis, Loop et al found that the hospital charges for coronary artery bypass surgery patients who experience mediastinitis were 280 percent greater than patients with uncomplicated bypass surgery, and the median length of stay ranged from 38 to 51 days. The most important factor in determining outcome has been the length of time to diagnosis and initiation of definitive therapy. Other prognostic indicators have included blood urea nitrogen, white blood cell count, culture positivity, type of surgical repair, and cytomegalovirus shedding.

CHRONIC MEDIASTINITIS Antibiotic Prophylaxis Although cardiothoracic surgical procedures are categorized as clean procedures, and the risk of infection is low, the consequences of infection are devastating. Therefore, despite the lack of placebo-controlled studies documenting efficacy, antibiotic prophylaxis has become commonplace. Cefazolin has generally been regarded as the drug of choice for prophylaxis.

The use of vancomycin or second-generation cephalosporins, such as cefamandole and cefuroxime, has also been considered. Studies regarding the relative efficacy of first- and second-generation cephalosporins are conflicting, and no agent has conclusively been shown to be superior to another. In a comparison between vancomycin, cefazolin, and cefamandole, Maki et al demonstrated a significant reduction in postoperative wound infection in patients receiving vancomycin prophylaxis. Vancomycin should be considered

Sclerosing, fibrosing, or granulomatous mediastinitis are terms for a chronic form of mediastinitis characterized by an invasive and compressive inflammatory infiltrate as summarized in Table 123-5. The first report of this entity, which may cause up to 10 percent of all primary mediastinal masses, reportedly dates to a description by Ulmont in 1855. Although the etiology of up to 83 percent of patients with sclerosing mediastinitis remains obscure, many experts believe that most instances are secondary to infection with H. capsulatum. With careful analysis, up to 73 percent of patients previously characterized as nonspecific granulomatous mediastinitis can be reclassified as secondary to H. capsulatum by re-staining the tissue with fungal stains and thorough review of the pathological sections. Other infectious etiologies that have been reported to cause this condition include tuberculosis, actinomycoses, nocardiosis, blastomycosis, coccidioidomycosis,

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Table 123-5 Summary of Chronic Mediastinitis Pathogenesis

Lungs provide portal of entry, indolent/progressive inflammatory infiltrate

Clinical Presentation

Usually asymptomatic Mediastinal mass Superior vena cava syndrome Pulmonary venous obstruction (cough, dyspnea, hemoptysis)

Most Common Microbial Etiology

H. capsulatum

Laboratory Diagnosis

Histopathology of tissue Granuloma, lymphohistiocytic aggregates, diffuse mononuclear infiltrates Fungal cultures, Histoplasma urinary antigen

Radiologic Diagnosis

Chest radiograph Mediastinal lymphadenopathy, bronchial narrowing, pulmonary artery narrowing, superior vena cava narrowing, infiltrate with or without calcification

Surgical Treatment

Early surgical intervention may prevent end-stage fibrosis, stent placement for pulmonary artery or venous compression, Palmaz stents for superior vena cava syndrome

Antimicrobial Treatment

Usually not indicated

aspergillosis, and infection with Rhizopus spp. Older literature often lists syphilis as a prominent cause of granulomatous mediastinitis. However, this was based upon seropositivity without other supporting evidence. Other conditions that closely mimic this entity include sarcoidosis, silicosis, lymphoma, mesothelioma, and mediastinal fibrosis associated with radiation therapy, idiopathic retroperitoneal fibrosis, Reidelâ&#x20AC;&#x2122;s struma, or sclerosing cholangitis.

Approximately 40 percent of patients with sclerosing mediastinitis are asymptomatic and come to medical attention when a chest roentgenogram incidentally reveals a mediastinal mass. Symptomatic patients usually note symptoms related to invasion or obstruction of structures within or adjacent to the mediastinum. Sclerosing mediastinitis is the most common nonmalignant cause of superior vena cava syndrome and is responsible for up to 23 percent of cases.

These patients generally present with plethora and edema of the face, neck and upper torso, neck vein distention, headache, and visual disturbances. Patients with obstruction of the pulmonary arteries often present with cough, dyspnea, and symptoms consistent with right-sided heart failure.

Pulmonary infarction, although rare, has been reported to occur in patients with sclerosing mediastinitis. Pulmonary venous obstruction causes patients to experience cough, dyspnea, and hemoptysis. Patients with airway obstruction due

to sclerosing mediastinitis usually present with wheezing, cough, hemoptysis, and recurrent episodes of bacterial bronchitis or pneumonia. Patients complaining of dysphagia may have esophageal obstruction due to posterior extension of the mediastinitis.

Sherrick et al reviewed the radiographic findings in 33 patients with sclerosing mediastinitis. The findings included bronchial narrowing (33 percent), pulmonary artery narrowing (18 percent), esophageal narrowing (9 percent), and superior vena cava narrowing (39 percent). Two distinctly different patterns of pulmonary infiltration were noted: localized with calcification (82 percent) and diffuse without calcification (18 percent). The authors believed that the localized pattern was most often secondary to histoplasmosis while the diffuse pattern was more likely to be due to a noninfectious etiology.

Patients with sclerosing mediastinitis often have a mediastinal mass, most frequently located in the superior mediastinum at the level of the bifurcation of the trachea. CT frequently reveals calcification and delineates the extent of infiltration whereas MRI is superior for the assessment of vascular integrity. Ventilation-perfusion lung scans often reveal large perfusion defects due to obstruction of the pulmonary vessels.

The diagnosis of sclerosing mediastinitis requires pathological examination. The histological appearance is a

2171 Chapter 123

continuum which ranges from a predominantly granulomatous entity to an almost completely fibrosing process. The lesions include caseating granuloma, dense hyalinized collagenous tissue, and infiltrations of lymphocytes, plasma cells, and giant cells. Specific stains for fungi often reveal organisms consistent with Histoplasma, but cultures are usually negative.

The pathological features of this disease suggest a marked inflammatory reaction. Several different mechanisms have been proposed to explain the pathology of fibrosing mediastinitis. Some investigators believe that a caseous lymph node from primary infection with Histoplasma ruptures into the mediastinum evoking an intense inflammatory reaction.

A second hypothesis invokes the development of a delayed hypersensitivity reaction due to the spread of soluble Histoplasma antigens into the mediastinum. Another explanation proposes that fibrosing mediastinitis represents an abnormality of collagen production and organization similar to idiopathic retroperitoneal fibrosis or Riedel’s struma. Noguchi et al have implicated the eosinophil in the pathogenesis of fibrosing mediastinitis by demonstrating eosinophils or major basic protein in tissue specimens from five of seven patients with fibrosing mediastinitis.

No controlled trials of medical or surgical therapy have been conducted for the treatment of fibrosing mediastinitis.

Although there is some anecdotal evidence of a beneficial effect of antifungal agents, most experts believe that there is little evidence of an active infection at the time of presentation and that antifungal agents are not indicated. Because the natural history of this disease is variable, with some patients progressing to compression of vital structures whereas others seem to have self-limited disease, it is difficult to make recommendations regarding the timing of surgical intervention. It has been suggested that early surgical intervention and removal of granulomatous tissue may prevent the development of subsequent end-stage fibrosis and involvement of vital structures. Clearly, patients experiencing obstruction or invasion of mediastinal structures require intervention, even though such surgery is often difficult and results are at times less than optimal. The superior vena cava syndrome, due to fibrosing mediastinitis, has been successfully alleviated through use of Palmaz stents. Therapy with corticosteroids does not appear to have a role in the treatment of fibrosing mediastinitis.

SUGGESTED READING Archer GL, Armstrong BC: Alteration of staphylococcal flora in cardiac surgery patients receiving antibiotic prophylaxis. J Infect Dis 147:642–649, 1983.

Arnold M: The surgical anatomy of sternal blood supply. J Thorac Cardiovasc Surg 64:596–610, 1972.

Barrett NR: Report of a case of spontaneous perforation of the oesophagus successfully treated by operation. Br J Surg 35:216–218, 1947.

Mediastinitis

Boerhaave H: Artocis, nec descripti prius Morbi Historia, Secundem Artis Leges Conscripta, Ludg., Batav, 1724.

Browdie DA, Bernstein RW, Agnew R, et al: Diagnosis of poststernotomy infection: Comparison of three means of assessment. Ann Thorac Surg 51:290–292, 1991.

Cameron JL, Kieffer RF, Hendrix TR, et al: Selective nonoperative management of contained intrathoracic esophageal disruptions. Ann Thorac Surg 27:404–408, 1979.

Centers for Disease Control and Prevention: National nosocomial infections surveillance (NNIS) system report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 32:470–485, 2004.

Dodds Ashley ES, Carroll DN, Engemann JJ, et al: Risk factors for postoperative mediastinitis due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis 38:1555–1560, 2004.

Durandy Y, Batisse A, Bourel P, et al: Mediastinal infection after cardiac operation: A simple closed technique. J Thorac Cardiovasc Surg 97:282–285, 1989.

Feldman R, Gromisch DS: Acute suppurative mediastinitis.

Am J Dis Child 121:79–81, 1971.

Ferrazzi P, Allen R, Crupi G, et al: Reduction of infection after cardiac surgery. Ann Thorac Surg 42:321–325, 1986.

Fowler VG, O’Brien SM, Muhlbaier LH, et al: Clinical predictors of major infection after cardiac surgery. Circulation 30:(Suppl):I358–365, 2005.

Fuchs U, Zittermann A, Stuettgen B, et al: Clinical outcome of patients with deep sternal wound infection managed by vacuum-assisted closure compared to conventional therapy with open packing: A retrospective analysis. Ann Thorac Surg 79:526–531, 2005.

Hamman L: Spontaneous mediastinal emphysema. Bull Johns Hopkins Hosp 64:1–21, 1939.

Kaiser AB: Risk factors for infection in cardiac surgery: Will the real culprit please stand up? Infect Control 5:369–370, 1984.

Loop FD, Lytle BW, Cosgrove DM, et al: Sternal wound complications after isolated coronary artery bypass grafting: early and late mortality, morbidity, and cost of care. Ann Thorac Surg 49:179–187, 1990.

Maki DG, Bohn MJ, Stolz SM, et al: Comparative study of cefazolin, cefamandole, and vancomycin for surgical prophylaxis in cardiac and vascular operations. J Thorac Cardiovasc Surg 104:1423–1434, 1992.

Noguchi H, Kephart GM, Colby TV, et al: Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis. Am J Pathol 140:521–528, 1992.

Pearse HE Jr: Mediastinitis following cervical suppuration.

Ann Surg 108:588–611, 1938.

Quirce R, Serano J, Arnal C, et al: Detection of mediastinitis after heart transplantation by gallium-67 scintigraphy. J Nucl Med 32:860–861, 1991.

Santos GH, Frater WM: Transesophageal irrigation for the treatment of mediastinitis produced by esophageal rupture. J Thorac Cardiovasc Surg 91:57–62, 1986.

Sarr MG, Gott VL, Townsend TR: Mediastinal infection after cardiac surgery. Ann Thorac Surg 38:415–423, 1984.

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Shaffer HA, Valenzuela G, Mittal RK: Esophageal perforation.

Arch Intern Med 152:757–761, 1992.

Sherrick AD, Brown LR, Harms GF, et al: The radiographic findings of fibrosing mediastinitis. Chest 106:484–489, 1994.

Trouillet JL, Vuagnat A, Combes A, et al: Acute poststernotomy mediastinitis managed with debridement and closed-drainage aspiration: Factors associated with death in the intensive care unit. J Thorac Cardiovasc Surg 129:518–524, 2005.

124 Microbiology and Infection in Cystic Fibrosis Scott H. Donaldson Richard C. Boucher

I. DIAGNOSIS

IV. TREATMENT OF LUNG DISEASE

II. PATHOGENESIS OF INFECTION CFTR and Epithelial Transport Airway Surface Liquid Regulation in Normal and CF Airways

V. ANTIBIOTICS

III. SECONDARY PATHOGENIC STEPS: MUCUS, PSEUDOMONAS, AND INFLAMMATION Clinical Aspects

Cystic fibrosis (CF) was first described as a unique disease entity in 1938. Patients typically presented with intestinal obstruction or malnutrition and died from overwhelming pneumonia within the first year of life. Postmortem studies revealed that CF was a multisystem disease characterized by mucous obstruction of pancreatic ducts, airways, and the gut early in life. Over the last 40 years, the median survival with CF has increased dramatically from 6 years in 1955 to 36 years in 2005. The improvement in CF outcomes has paralleled advances in antibiotic therapies, nutritional approaches, and the collection of clinical expertise into specialized treatment centers. These have been summarized by Voynow elsewhere in this volume. As CF patients survive longer, lung disease characterized by polymicrobial infection and progressive antimicrobial resistance have become prominent in patient management. Further, a multitude of pulmonary and non-respiratory complications are encountered.

The pathogenesis and treatment of these issues are reviewed here.

VI. ANTI-INFLAMMATORY AGENTS VII. ANTIMICROBIALS IN THE TREATMENT OF ACUTE EXACERBATIONS VIII. CONCLUSIONS

DIAGNOSIS The diagnosis of CF requires either detection of two diseasecausing mutations in the CFTR gene, or a combination of a compatible phenotype with evidence for CFTR dysfunction.

CFTR genotyping is usually restricted to the most common mutations in a given population, and is reviewed elsewhere.

To date, more than 1500 individual CFTR mutations have been identified and are grouped into one of five classes based upon the effect that the mutation has on the resulting CFTR protein (Fig. 124-1).

PATHOGENESIS OF INFECTION CFTR and Epithelial Transport The CFTR gene encodes a cAMP-regulated chloride channel that appears to regulate other ion channels as well, including

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2174 Part XVI

Infectious Diseases of the Lungs Class IV: Defective Clconduction

CFTR Potentiator (Classes III, IV, V)

+

PKA

Class III: Defective regulation

Golgi

ER

Class II: Defective processing Class I: Defective protein synthesis

CFTR Corrector (Class II)

Stop mutation suppressor (Class I)

Class V: Reduced mRNA level

the epithelial sodium channel (ENaC) and calcium-activated chloride channel (CaCC). Therefore, CFTR plays a central role in the regulation of ion transport across airway epithelia.

In CF, dysregulation of airway surface liquid (ASL) volume occurs as a consequence of ion transport dysfunction, which in turn impairs mucociliary clearance and, therefore, lung defense.

Airway Surface Liquid Regulation in Normal and CF Airways Airway surfaces are coated with a thin layer of liquid, the ASL, which is composed of a periciliary layer (PCL) and a more viscous mucus layer. The mucus layer, which normally floats on top of the PCL, efficiently traps inhaled pathogens and particulates. The underlying PCL layer, in turn, provides a low viscosity environment in which cilia can beat freely and thereby propel the mucus layer toward the mouth. The PCL also acts as a lubricant layer that prevents adhesion of the mucus layer to cell surfaces. Therefore, proper regulation of ASL volume and the hydration of its component layers are critical to the maintenance of mucus clearance. Whereas an adequate PCL height is necessary to allow ciliary beating, adequate hydration of the mucus layer is a key determinant of its viscoelastic properties and transportability.

When considering the geometry and function of airways, it is clear that ASL volume must be regulated carefully.

A gross excess of ASL volume would block small airway lumens, and thereby interfere with gas exchange, whereas even modest reductions in ASL volume may not be adequate to support mucus transport, as described. Therefore, the ability

Figure 124-1 CFTR mutation classes. CFTR mutations are grouped into five classes, each characterized by a different problem in CFTR synthesis, maturation, regulation, or function as an ion channel. As shown, new therapies are being developed to target specific classes of CFTR mutations.

to add or subtract ASL volume is an important airway epithelial function that is carried out by active chloride secretion (in part via CFTR) and sodium absorption (via ENaC), respectively (Fig. 124-2 A). Normal airway epithelia blend these ENaC CFTR

MCC

CaCC

(â&#x2C6;&#x2019;)

pO2

A

C ENaC

CaCC

MCC

pO2 B

D

Figure 124-2 Relationship between ion transport and mucociliary clearance in normal and CF airways. A. In normal airway epithelia, CFTR and ENaC channels provide the pathways for coordinated chloride secretion and sodium absorption. The calciumactivated chloride channel (CaCC) is an important reserve pathway for additional chloride secretion. B . In CF, CFTR mediated chloride secretion is absent, as is the inhibitory effect this channel normally exerts over the ENaC. Preserved chloride secretion via CaCC partially compensates for the absence of CFTR. C . The normal airway epithelium maintains an adequate height of periciliary liquid, hydrates the overlying mucus layer, and thereby supports mucociliary clearance. D . In CF, the described ion transport abnormalities result in dehydration of the airway surface liquid components, impairs mucociliary clearance, and ultimately encourages the development of an anaerobic niche within airwayadherent mucus plaques.

2175 Chapter 124

activities in response to the local ASL environment, thereby maintaining an appropriate PCL height and adequate mucus hydration (Fig. 124-2C ). In contrast, CF epithelia hyperabsorb liquid due to dysregulation of ENaC and have lost the capacity to secrete liquid via CFTR (Fig. 124-2B). As a result, the PCL layer becomes volume depleted and the mucus layer becomes concentrated and poorly transportable (Fig. 1242D). These changes in the ASL compartment impair mucus clearance and predispose the patient to the development of chronic airway infections.

Chronic sinusitis Nasal polyposis

Chronic infections Bronchiectasis Pneumothorax Massive hemoptysis ABPA

SECONDARY PATHOGENIC STEPS: MUCUS, PSEUDOMONAS, AND INFLAMMATION As described, ASL dehydration produces progressive mucostasis and initiates a cascade of events that leads to clinically apparent CF lung disease. First, thickened mucus secretions eventually become adherent to airway surfaces with the loss of PCL volume, and begin to obstruct small airway lumens. Mucus plugs and plaques not only provide a protected environment in which bacteria can escape mechanical and immune-mediated clearance, but also create a unique environment that drastically alters bacterial gene expression.

Paradoxically, the center of a mucus plug is in fact anaerobic (pO2 less than 2 Torr) due to a combination of an increased diffusion distance for O2 as well as increased oxygen consumption by CF epithelia (owing to heightened Na+ transport). Within this environment, P. aeruginosa converts to an anaerobic mode of metabolism, increases alginate production, and ultimately establishes a biofilm structure. Organisms growing within the biofilm possess increased resistance to secondary host defense mechanisms (e.g., neutrophils and soluble antimicrobials), display vastly different antimicrobial sensitivity patterns, and are likely impossible to eradicate with antibiotic therapy. Ultimately, it is the persistent attempt but ongoing failure of neutrophils to clear this infection, accompanied by the release of proteases and other harmful substances, which destroys lung tissue and yields bronchiectasis.

Clinical Aspects Optimal care for the diverse manifestations and complications of CF poses a significant clinical challenge (Fig. 1243). This presentation focuses on management relevant to the risk for infection. An early, and perhaps primary, manifestation of CF lung disease is the development of airway obstruction with mucus driven by dehydration of airway surfaces, due to intrinsic ion transport abnormalities. With ASL volume depletion, mucus secretions become less transportable and ultimately adhere to airway surfaces, thus triggering further mucus accumulation and airway obstruction.

Coupled with this accumulation is the development of a neutrophil-predominant inflammatory process with mucus hypersecretion in response to inflammatory mediators. The intensity of inflammation in relationship to the burden of

Microbiology and Infection in Cystic Fibrosis

Biliary cirrhosis Steatosis

Pancreatic insufficiency CFRD

Nephrolithiasis Meconium ileus DIOS Malabsorption CBAVD

Figure 124-3 Multisystem manifestations of cystic fibrosis. Abnormal CFTR function in epithelial lined organs leads to a wide variety of manifestations in multiple organ systems.

identified pathogens is greater than in other childhood lung diseases and the tendency for the inflammatory process to persist after the apparent resolution of an acute infectious process is perhaps unique to CF. Interestingly, an animal model of CF lung disease, which exhibits ASL dehydration and mucus plugging, also develops chronic airway inflammation without readily identifiable bacterial infection. Current hypotheses to explain these findings include: (1) a low burden of typical bacteria avoids eradication in the dehydrated mucus environment of the CF lung and drives the inflammatory process in very early disease; (2) the presence of atypical, perhaps anaerobic, organisms are poorly identified with usual culture systems but dominate early disease and cause inflammation; and (3) intermittent events, including viral infections and/or gastric aspiration drive the inflammatory process early in life.

Regardless, these observations point to the very early onset of lung disease, even in asymptomatic infants, and the need to develop and institute effective interventions in this population.

Over a relatively short period of time, the CF lung becomes chronically infected with typical pathogens. In childhood, Haemophilus influenzae and Staphylococcus aureus are often identified first, typically followed by the establishment of chronic Pseudomonas aeruginosa infection. Pseudomonas may take many morphologic forms, including rough, smooth, and small colony variants, but typically evolves to a mucoid

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phenotype that signifies chronicity and the inability to eradicate this organism, even with aggressive antibiotic regimens.

An increased emphasis on early detection and eradication has emerged, therefore, to delay the negative effects of chronic Pseudomonas infection. Other important pathogens that are encountered in CF include a variety of gram-negative bacteria, especially Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and the Burkholderia cepacia complex (Bcc).

The Bcc is currently subdivided into at least 9 genomovars, but genomovars II (B. multivorans) and III (B. cenocepacia) are most prevalent in CF. Bcc infection is associated with worse pulmonary outcomes, rapidly becomes antibiotic resistant, and certain strains carry the risk of rapid nosocomial spread to susceptible hosts (including other CF patients).

Genomovar III is particularly problematic and is considered an absolute contraindication to lung transplantation at most centers because of the unacceptably high rate of early mortality due to sepsis. Mycobacterial pathogens are also encountered in CF, including M. avium complex and M. abscessus.

MAC is the most prevalent mycobacterial pathogen in CF, but often does not cause discernible clinical disease, as opposed to the much more problematic infection with M. abscessus. Treatment of M. abscessus is often very prolonged (months), toxic, and often does not yield eradication. Viral infections, although probably not more frequent than in other populations, do appear to cause more morbidity and may be an important trigger of lung disease exacerbations.

Fungi, particularly aspergillus species, are common colonizers but may cause allergic bronchopulmonary aspergillosis (ABPA).

Once the cycle of reduced mucus clearance, infection, and inflammation begins, progressive airway obstruction follows. This is manifested clinically by reductions in pulmonary function tests and radiographic changes. With spirometry, airflow rates reflecting the small airways (FEF25−75 ) are affected first and most severely, followed thereafter by reductions in the FEV1 and lesser changes in FVC. Routine spirometry, however, is often technically impossible in young children (less than 5 years) and is quite insensitive to the development of lung disease early in the course of disease.

Chest radiographs may first show signs of hyperinflation followed by interstitial markings that reflect the development of bronchiectasis, but this technique is also a relatively insensitive tool for the detection of mild/early disease. More recently, thin-section CT scanning has been used to clinically characterize CF lung disease and has also been used as a clinical trial outcome measure. This technique, especially when combined with expiratory images to detect air trapping, often detects significant foci of disease prior to the ability to detect global airway obstruction with spirometry. Once CF lung disease becomes more advanced, all of these assessments of disease severity reflect the progressive development of bronchiectasis.

Exacerbations of CF lung disease are extremely important events in the life of a CF patient. These periodic illnesses often remove the patient from their usual work or school activities, are associated with significant reductions in qual-

ity of life, exact a large financial toll in terms of health care costs, and are associated with reduced survival. Exacerbations are typically acute to subacute events that are superimposed upon a previously stable clinical baseline. Patients usually report increased cough, sputum, fatigue, and weight loss during these episodes. Fever, leukocytosis, chest pain, and new infiltrates on chest radiographs are less consistent findings with exacerbations. The inciting events that trigger an exacerbation have not been clearly defined, although acute respiratory viral infection may be one important cause in addition to inadequate use of preventative therapies. Because significant disease progression can occur without many symptoms in patients with mild disease, lung function testing as a “screen” for exacerbations/progression are particularly important in this setting.

Other respiratory manifestations of CF lung disease, besides bronchiectasis, include massive hemoptysis and pneumothorax. In chronically inflamed, bronchiectatic CF airways the associated bronchial arteries often become massively dilated. In the setting of increased infection/inflammation, a dilated bronchial artery may erode through the overlying mucosa and bleed—under systemic arterial pressure—into the airway lumen. Minor to massive hemoptysis may ensue, at times requiring bronchial artery embolization in order to halt the bleeding. Massive hemoptysis is increasingly common in older patients, with an average annual incidence of 0.87 percent. Antibiotic therapy, correction of coagulation defects, and temporary cessation of unnecessary airway irritants (e.g., inhaled antibiotics) and chest physiotherapy are also mainstays of treatment for massive hemoptysis in CF. Similarly, the incidence of pneumothorax also increases with the age of the patient. The annual incidence of this complication is 0.64 percent. In general, the management of pneumothorax in CF is not conceptually different than in other lung diseases. However, it should be recognized that, because of the inability of the lung to fully deflate in the setting of obstructive airways, even a small volume pneumothorax could in fact cause tension physiology. Also, because lung transplantation is often an eventual treatment consideration, persistent air leaks and recurrent pneumothoraces are preferentially dealt with via thoracoscopic approaches (bleb stapling and local pleurodesis) rather than with chemical or talc pleurodesis. These later approaches may significantly compromise the ability to excise the native lung at transplant.

ABPA complicates the clinical scenario of roughly 2 percent of CF patients. This syndrome, caused by allergic inflammation directed against colonizing fungi, may cause symptoms that mimic exacerbations of the underlying CF lung disease itself, and is therefore difficult to diagnose on clinical grounds. Laboratory tests, consequently, are quite useful. A total serum IgE level is often used as a screening test for the presence of ABPA and to track the level of disease activity. Classically, patients with active ABPA will have serum IgE levels greater than 1000 µg/L, although lesser elevations may also be observed in patients with active disease.

2177 Chapter 124

Immediate-type hypersensitivity reactions to an aspergillus skin test are sensitive but not specific for ABPA; therefore, a negative test can be used to rule out this entity. The demonstration of aspergillus-specific antibodies can be useful for the diagnosis of ABPA, as are the presence of sputum or blood eosinophilia. Of note, culture positivity for aspergillus may not always be demonstrated. Treatment is typically with systemic corticosteroids for fairly prolonged periods of time, although there is growing experience with the use of antifungal agents to limit the system exposure to corticosteroids.

Nasal and sinus disease are another troublesome respiratory manifestation of CF. Children in particular may experience recurrent nasal polyposis and require surgical removal of obstructing polyps. Sinus disease is nearly universal, either clinically or radiographically, and often requires chronic medical therapies (nasal steroids, antibiotics, nasal irrigation) as well as judicious use of surgery. It should be noted that the benefits of surgery for CF sinus disease are not well studied and often temporary. Overly aggressive surgical approaches may ultimately distort the underlying anatomy such that nasal/sinus mucus clearance mechanisms are disrupted and sinus symptoms recur and progress a short time after surgery.

Non-Respiratory Manifestations Multiple epithelial lined organs outside of the lung are also affected by the absence of a functional CFTR protein (Fig. 124-3). Despite differences in the details of how CFTR normally functions in each of these organs, a general theme of altered luminal contents (e.g., altered ion composition, volume, or viscosity), causing reduced transit through the organ and obstruction, exists.

Pancreas, Gut, and Nutrition The exocrine pancreas is affected in more than 90 percent of patients with CF. These issues are reviewed in detail elsewhere.

Steatorrhea, malnutrition, and fat-soluble vitamin deficiencies (A, D, E, and K) are common and patients may also develop intestinal obstruction as the result of the bulky, poorly hydrated intestinal contents. This syndrome, termed distal intestinal obstruction syndrome (DIOS), occurs in roughly 20 percent of patients and increases in frequency with age. DIOS may present with abdominal pain, constipation, right lower quadrant mass, nausea, and vomiting. It is usually treated with relatively large volumes of iso-osmotic polyethylene glycol colonoscopy preparations by mouth or NG tube in the non-vomiting patient, or by enema treatments and bowel rest. A meglumine diatrizoate (Gastrografin) enema may be both diagnostic and therapeutic in severe cases. Meconium ileus, a similar syndrome that presents in the days after birth, is nearly diagnostic for the presence of CF and should prompt definitive diagnostic testing.

Endocrine functions of the pancreas, which do not rely on the presence of patent pancreatic ducts, are typically preserved much later into life than exocrine functions. Over time, however, progressive destruction of islet cells leads to insulin

Microbiology and Infection in Cystic Fibrosis

deficiency and the onset of CF-related diabetes (CFRD). The incidence of CFRD increases with age, with 15.6 percent of patients older than 13 years receiving insulin therapy. Given the insidious nature of CFRD and controversy over the need for insulin in patients without fasting hyperglycemia, this estimate of the problem is likely quite low. CFRD is a very important problem because it is associated with accelerated rate of lung function decline, worsened nutritional status, and poorer survival. For unclear reasons, females with CF appear to be particularly vulnerable to the adverse effects of CFRD, as its presence is associated with more pronounced effects on survival and lung function than in males. Therefore, screening for CFRD is recommended for all CF adults on an annual basis. Monitoring and treatment of hyperglycemia induced by acute illness (e.g., during exacerbations) is also recommended to avoid impairment of immune function and facilitate the return to normal nutritional status. Because CFRD represents an insulin-deficient state, insulin in the preferred therapy. Given the need to maintain an adequate nutritional status, calorie-restricted â&#x20AC;&#x153;diabetic dietsâ&#x20AC;? are not indicated.

Rather, calorie-rich diets with adequate insulin coverage are prescribed. Interestingly, it appears that glycemic status can wax and wane in patients with CF over time, moving back and forth among normal glycemia, impaired glucose tolerance, and frank CFRD. Clearly, this CF manifestation warrants close, careful longitudinal assessments.

Hepatobiliary Disease Steatosis and focal biliary cirrhosis are the most common pathological abnormalities of CF associated liver disease.

Whereas severe malnutrition may contribute to fatty lesions in the liver, the absence of CFTR-mediated secretion by cells lining bile ducts is believed to cause the development of inspissated biliary secretions, which in turn leads to biliary cirrhosis. Portal hypertension and associated variceal bleeding occurs uncommonly, although roughly 2 percent of CF deaths are related to liver disease. Based on autopsy series, it appears that the prevalence of cirrhosis increases with age. Despite this observation, clinically apparent liver disease is usually diagnosed by the time patients reach adolescence and typically does not present de novo after age 20 years. Treatment of CF-associated liver disease with ursodeoxycholic acid can be considered. Although this treatment has the potential to prevent the development of cirrhotic lesions if started early in the course of disease, the unclear natural history and absence of factors that predict the development of clinically important disease makes this therapeutic decision somewhat difficult and controversial. Liver transplantation is an option for CF patients with end-stage liver disease and mild pulmonary dysfunction, and results are generally good. Liver failure may exceed pulmonary dysfunction requiring liver before lung transplantation.

Reproductive Tract and Other Manifestations Males with cystic fibrosis have an approximately 99 percent chance of being infertile. Women with CF, in contrast,

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have relatively intact intrinsic fertility. However, the presence of severe lung disease, CF-related diabetes, and significant malnutrition increase the risk of maternal morbidity and fetal intrauterine growth retardation. Other nonrespiratory manifestations include: (1) early and severe osteoporosis; (2) hypertrophic pulmonary osteoarthropathy; (3) cutaneous leukocytoclastic vasculitis; (4) calcium oxalate nephrolithiasis; (5) gallbladder abnormalities, including micro-gallbladder, stones and sludging; and (6) metabolic alkalosis and sweat loss syndromes in infants. A detailed review of these manifestations is beyond the scope of this chapter, but is presented elsewhere.

TREATMENT OF LUNG DISEASE The strategies for treatment of CF lung disease are reviewed elsewhere. Available therapies include airway clearance maneuvers and exercise, inhaled mucoactive substances, bronchodilators, antibiotics, and anti-inflammatory agents. A cornerstone in the treatment of CF lung disease is the use of maneuvers and/or devices that facilitate the clearance of airway secretions. Because CF secretions are dehydrated and difficult to clear, additional efforts above and beyond cough must be applied on a regular basis to prevent their accumulation. Although indicated in almost all patients with CF, it remains controversial whether chest physiotherapy is appropriate for asymptomatic infants with normal lung function.

Choices are often made based on an individual patientâ&#x20AC;&#x2122;s perception of efficacy and preference for assisted vs. independent modalities. Chest percussion and vibration, with or without postural drainage, have long been the traditional airway clearance modalities, and are favored by many patients, especially when they are ill. Negative factors pertaining to this mode of therapy is the need for a caregiver to perform the treatment and the additional risk of inducing gastroesophageal reflux and aspiration when using head-down tilt positions in infants. Exercise is an additional treatment modality that may augment airway clearance, while providing other beneficial effects as well. Anecdotal experiences have long supported the usefulness of exercise in CF lung disease, but short-term studies only showed improved exercise tolerance rather than more substantial pulmonary benefits. One long-term, randomized controlled study of an in-home exercise program in CF, however, demonstrated that children with mild to moderate lung disease who were assigned to at least three times per week exercise sessions had slowed decline of lung function over a 3-year period; therefore, a program that combines exercise with other airway clearance maneuvers should be considered.

Medications that impact mucus clearance and benefit patients with CF include dornase alfa and hypertonic saline. Dornase alfa is an inhaled recombinant human DNAse enzyme that hydrolyzes free DNA molecules present in CF airway secretions. Because DNA is exceedingly viscous, the action of dornase alfa improves the cough-clearance

of secretions and has been shown to improve lung function and reduce the frequency of exacerbations. The optimal time to initiate dornase alfa treatment is somewhat unclear. However, it has been shown that children (mean age 8.4 years) with mild lung disease (mean FEV1 95 percent predicted) have sustained improvement in lung function and reduced disease exacerbations over 2 years of observation when treated with dornase alfa, and separately was shown to prevent an increase in markers of inflammation (IL-8, free elastase) as assessed by bronchoalveolar lavage at 18-month intervals.

Inhaled hypertonic saline draws water into the luminal compartment, thereby improving the hydration of the periciliary layer and of mucus secretions. Unlike dornase alfa, hypertonic saline has been shown to acutely stimulate mucociliary clearance, as measured via studies that use inhaled radiotracer particles, and to have sustained effects on mucus clearance rates (greater than 8 hours) in patients with CF as well. Unfortunately, there are no data that support the use of other mucolytics, including N-acetylcysteine, and their use cannot be recommended at this time. Bronchodilators, particularly beta-adrenergic agonists, are very commonly used in the setting of CF lung disease, although data supporting their efficacy are mixed.

ANTIBIOTICS Antibiotics are a mainstay in the treatment of CF, and their use fulfills different purposes at different times. Oral azithromycin, although generally not active against the major colonizing organisms, has been shown to improve lung function and reduce exacerbations in CF patients with Pseudomonas infection when used chronically. The mechanism may be via anti-inflammatory actions. However, Pseudomonas growing under biofilm conditions has very different antimicrobial susceptibility patterns, and sensitivity to macrolides may actually occur under these conditions. Coexistent infection with mycobacteria is generally a contraindication to macrolide use and should be excluded prior to initiation of therapy.

Other oral antibiotics are also widely used in CF. Continuous use of anti-staphylococcal antibiotics was a common practice in the United States in patients who were infected with sensitive S. aureus species. This practice has fallen out of favor because of an absence of demonstrated benefit and an increased rate of Pseudomonas acquisition. Proponents of anti-staphylococcal treatment still exist, although this practice should be examined carefully, given the very real harm associated with an earlier acquisition of Pseudomonas.

Oral anti-pseudomonal agents are principally confined to the quinolone class of antibiotics. Quinolone use is associated with the rapid development of resistance and therefore should not be used chronically/prophylactically. Instead, inhaled antibiotics have become very important in the chronic management of CF. The inhaled route is attractive because

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higher concentrations of drug reach the endobronchial site of infection via the inhaled route, so microbial resistance may be overcome. Also, inhaled tobramycin is associated with low blood levels and much less systemic toxicity than with the intravenous route. Six-month studies of inhaled tobramycin demonstrated improved lung function and fewer exacerbations when used in a cycling fashion (i.e., 1 month on, 1 month off). A small increase in Pseudomonas resistance was observed over these relatively short duration studies, but did not affect efficacy over this time period. However, it is unknown whether the same efficacy profile will be preserved with longer-term use of inhaled tobramycin, especially in the face of the progressive antimicrobial resistance that is likely to occur over time. Therefore, whether prophylactic use every other month is superior to less frequent dosing, or even intermittent use for minor changes in symptoms or lung function, is unknown.

Colistin has seen considerable use for CF, particularly in Europe. There are substantially fewer data to support the safety and efficacy of colistin use. Because this agent has excellent in vitro activity versus Pseudomonas and is infrequently used as an intravenous agent to treat exacerbations, use in maintenance therapy has theoretical advantages. There are also concerns over whether colistin is adequately converted to the active form in sputum by local hydrolases, difficulty with bronchospasm in some patients, and the need for somewhat complicated regimens to get the powdered drug into solution while avoiding problematic foaming during delivery.

A number of other antibiotics are either being formally developed for use via the inhaled route or have a history of being nebulized without adequate research into its delivery, safety, and efficacy. With adequate testing, additional inhaled antibiotic agents should prove to be useful in the treatment of CF.

ANTI-INFLAMMATORY AGENTS Anti-inflammatory agents are an attractive option for the treatment of CF lung disease given the fact that persistent, neutrophil-predominant inflammation ultimately is the cause of airway destruction. Ibuprofen is currently the only available agent for chronic treatment with proven efficacy and safety in CF. In a long-term, prospective study ibuprofen slowed the rate of lung function decline, and the affect appeared to be greatest in younger patients with mild disease. Importantly, ibuprofen levels must be monitored during treatment, as therapy may be associated with gastrointestinal bleeding and renal dysfunction, whereas subtherapeutic levels are associated with a paradoxical increase in neutrophil migration, and super-therapeutic levels are more likely to yield toxicity (e.g., GI bleeding). Use of ibuprofen should be stopped during administration of other nephrotoxic agents, such as intravenous aminoglycosides. Inhaled steroids are of unproven benefit for the typical patient with CF.

Microbiology and Infection in Cystic Fibrosis

ANTIMICROBIALS IN THE TREATMENT OF ACUTE EXACERBATIONS The choice of antibiotics to treat an exacerbation should be made based upon the most recently available pretreatment sputum culture result. For mild exacerbations in a patient chronically colonized with Pseudomonas, an oral quinolone with antipseudomonal activity or inhaled tobramycin may be effective either as monotherapy or in combination. Combination therapy has the theoretical advantage of inducing less drug resistance, but this has not been well studied.

For more severe exacerbations, selection of empiric intravenous antibiotics should be based on prior antimicrobial susceptibility data and, generally, two drugs from different classes should be selected. This may lessen emergence of bacterial resistance; true synergy for Pseudomonas has been documented only between aminoglycoside and β-lactam antimicrobial agents. It is unclear whether in vitro testing of Pseudomonas under log-phase growth conditions is clinically relevant given the role of biofilm in growth in vivo. In patients with CF, some drugs, particularly aminoglycosides, are renally cleared faster than normal individuals and levels should be followed to guide dosage adjustments.

The treatment of other gram-negative infections (e.g., B. cepacia complex, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans) is similarly based on susceptibility patterns. Coinfection with S. aureus or, increasingly, with non-tuberculous mycobacteria, may merit separate therapy.

CONCLUSIONS A detailed understanding of the molecular events that underlie the pathogenesis CF lung disease is emerging. This knowledge is now guiding the development of new treatment strategies, using both existing and novel agents, to more effectively treat this disease. With the development of drugs that correct the earliest defects in CF, i.e., CFTR dysfunction and ASL dehydration, further increases in the already vastly improved survival with CF are predicted. It is likely, however, that improved survival will paradoxically increase the complexity of caring for adult patients with CF who continue to develop complications related to reaching older ages. Continued research, the identification of best available practices, and broader dissemination of expertise will certainly continue to drive improved outcomes in coming years.

SUGGESTED READING Aaron SD, Ferris W, Ramotar K, et al: Single and combination antibiotic susceptibilities of planktonic, adherent, and

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125 Bronchiectasis Alan F. Barker

Sheela Y. Ahmed

I. PREVALENCE III. CLINICAL FEATURES

VI. DIAGNOSIS OF BRONCHIECTASIS Chest Radiograph High-Resolution Computed Tomography Pulmonary Function

IV. CLASSIFICATION USING RADIOLOGY

VII. BACTERIOLOGY

V. PREDISPOSING OR ASSOCIATED FACTORS Infections Bronchial Obstruction Aspiration/Inhalation Airway Injury Cystic Fibrosis Young’s Syndrome Primary Ciliary Dyskinesia Allergic Bronchopulmonary Aspergillosis Inflammatory Disorders Hypogammaglobulinemia

VIII. TREATMENT Control of Infection Bronchial Hygiene Mucus Clearance Bronchodilators Anti-inflammatory Therapy Surgery Miscellaneous

II. PATHOPHYSIOLOGY

Bronchiectasis (broncos, airways; ectasia, dilatation) is a morphological term used to describe abnormal irreversibly dilated and often thick-walled bronchi. This is an anatomic definition and is thought to have evolved from Laennec’s original description in 1819 of ectatic bronchi in pathological specimens. Bronchiectasis represents the end stage of a variety of pathologic processes that cause destruction of the bronchial wall and its surrounding supporting tissues. The clinical manifestations include chronic cough and copious mucopurulent expectoration, often lasting months to years.

Bronchiectasis shares many features with chronic bronchitis, including inflamed and easily collapsible airways, airflow obstruction on spirometry, and frequent exacerbations. The distinction between the two processes is a matter of degree and extent of the abnormality. Patel et al. from St. Bartholomew’s Hospital in London evaluated the presence and extent of bronchiectatic changes in stable patients with moderate to severe chronic obstructive pulmonary disease (COPD). They showed that 50 percent of these patients had evidence of radiologic bronchiectasis, with high-resolution computed to-

mography (HRCT) changes seen most frequently in the lower lobes.

PREVALENCE Bronchiectasis was a common disabling and fatal condition in the pre-antibiotic era. It remains an important cause of suppurative lung disease in the developing world. More recently, the declining incidence of this disease in the developed world has led to repeated suggestions that it be considered an orphan disease. The decline has been variously attributed to the advent of improved living conditions, frequent and early use of antibiotics, improved sanitation and nutrition, and introduction of childhood immunization, particularly against measles and pertussis. In the United States, the prevalence has recently been estimated to be 52 per 100,000. A slight female preponderance has been suggested in two large series of patients. Bronchiectasis has been reported to act more

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virulently in women, but whether this represents an altered inflammatory-immune response, or there are environmental, genetic, and anatomic differences leading to this predisposition is not clear.

PATHOPHYSIOLOGY The abnormal bronchial dilatation in bronchiectasis principally affects the medium-sized bronchi, but often extends to the more distal bronchi and bronchioles. On gross examination of surgically resected or autopsied lungs, the affected bronchi and bronchioles are so prominent as to be visible all the way to the pleural surface. These dilated and ectatic bronchi are commonly filled with purulent secretions.

The affected bronchi show transmural inflammation, mucosal edema, cratering, ulceration, and neovascularization.

The bronchial epithelium may show a polypoidal appearance due to underlying granuloma formation and mucosal prominence, ridging due to bronchial smooth muscle hypertrophy, and pitting due to the dilated bronchial mucous glands.

Severe cases may show denudation of epithelial lining, with destruction of underlying elastic laminae, smooth muscle, and cartilage with fibrotic changes replacing these structures.

Dilated and tortuous bronchial arteries may be seen secondary to the development of extensive bronchial-pulmonary anastomoses.

Microscopically, bronchiectasis is associated with loss of cilia, cuboidal and squamous metaplasia, hypertrophy of bronchial glands, and lymphoid hyperplasia. Intense infiltration of the bronchial wall with neutrophils, lymphocytes, and monocytes is seen. It has long been recognized that these changes are associated with chronic bacterial infection. The concept of the “vicious cycle” proposed by Peter Cole and colleagues from the Brompton Hospital has largely been accepted over the last three decades. While acute inflammation is an important host defense against bacterial infection, if it fails to clear the infection, it can result in lung damage.

This theory proposed that chronic bacterial endobronchial infection and inflammation damage or destroy mucociliary defenses, leading to secretion stasis, which in turn propagates furthers bacterial infection, and increases airway inflammation and bronchial dilatation. Bacterial colonization and/or infection of the airways alone is not sufficient to produce true bronchiectasis. It seems likely that focal disturbances resulting in airway obstruction or impairment of drainage and/or systemic conditions, resulting in uncoordinated airway clearance or impaired immune response are required in addition to airway colonization and/or infection. The appearance of Pseudomonas aeruginosa in the respiratory tract of bronchiectasis patients on a chronic or recurring basis has been associated with worsening ciliary function and deleterious effects on host defenses, resulting in impaired healthrelated quality of life and worsened lung function. This may be due to the ability of this organism to release virulent exotoxins, form surrounding biofilms on tissue surfaces, and easily

develop hypermutable P. aeruginosa strains resistant to antibiotics, all factors perpetuating and propagating bronchial damage.

Angrill et al., in a study looking at parameters of bronchial inflammation and colonization in clinically stable bronchiectasis, demonstrated findings suggesting that airway inflammation may occur even in the absence of bacterial colonization. They found a higher percentage of airway neutrophils and higher concentrations of IL-8 and IL-6 in the BAL fluid of patients with bronchiectasis and negative microbial cultures, than in nonsmoking controls who had no evidence of respiratory disease.

CLINICAL FEATURES The classic clinical manifestations of bronchiectasis are daily cough and mucopurulent sputum production. Cough is invariably present and often may be the only symptom for years.

Purulent, tenacious sputum production, frequently worse in the morning (having accumulated during recumbency in sleep) is present in most patients. Sputum production may be intermittent, being affected by recurrent infections, bronchial plugging, and antibiotic therapy. “Dry bronchiectasis” presenting as cough, minimal sputum expectoration, and/or hemoptysis is occasionally described. Hemoptysis may be seen in 40 to 70 percent of patients and may vary from blood streaks to large clots. Increasing cough, dyspnea, and volume of sputum production, fever, hemoptysis, and chest pain are hallmarks of acute exacerbations. Often patients give a history of recurrent chest infections, although single episodes of severe pneumonia, tuberculosis, or pertussis with secondary pneumonia may also result in bronchiectasis.

Most patients have abnormalities on physical examination. Chest auscultation usually reveals findings of early and mid-inspiratory crackles as well as diffuse rhonchi and prolonged expiration. Bronchial breath sounds may be heard in severe cases or patients with a complicating pneumonia. Digital clubbing and hypertrophic pulmonary osteoarthropathy, although common in the pre-antibiotic era, are rarely seen now. In severe advanced cases, there may be evidence of respiratory insufficiency and cor pulmonale.

CLASSIFICATION USING RADIOLOGY Bronchiectasis may be classified by predisposing factors, pathological features, and radiographic appearance. Reid in 1950 described a correlation between pathological and bronchographic findings in bronchiectasis; since then, this has been the most widely used classification. There is considerable overlap and coexistence among the various forms of bronchiectasis. In cylindrical bronchiectasis, the bronchi are regularly outlined (tubular), dilated in diameter, with straight

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Bronchiectasis

chopulmonary sequestration too, may become infected and communicate with the bronchial tree, mimicking localized bronchiectasis.

PREDISPOSING OR ASSOCIATED FACTORS

Figure 125-1 Chest computed tomography. A. (Left chest) Cylindrical bronchiectasis: Dilated and thickened airways. B. (Right chest) Saccular or cystic bronchiectasis: Very dilated airways clustered into saccules, cysts, or grapelike clusters.

walls, often coming to a straight abrupt end, instead of a tapering end, due to obstruction of the peripheral bronchial tree by secretions, casts, and inflammatory wall edema. Varicose bronchiectasis (illusion to varicose veins) is marked by the presence of irregular dilatations, outpouchings, and tortuosity of the airways. Saccular (cystic) bronchiectasis is characterized by the presence of cystic distortion of the distal airways that may be focal or more generalized, resulting in saccules that appear as a cluster of grapes (Figs. 125-1 and 125-2). Traction bronchiectasis, a term used to describe the dilated airways seen in diffuse pulmonary fibrosis secondary to fibrous tissue traction and elevated negative intrathoracic pressure, should be distinguished from usual bronchiectasis, because of the lack of intrinsic airway pathology and paucity of sputum expectoration. Congenital bronchial cysts (central and peripheral) are developmentally abnormal cystic bronchial structures, often filled with mucus and lined with respiratory epithelium. While usually lacking connection with the parent bronchus and distal alveoli, if infected they may communicate and mimic localized bronchiectasis. Intralobar bron-

Previously bronchial damage secondary to childhood respiratory tract infections such as pneumonia, pertussis, complicated measles, and tuberculosis were implicated as common causes of bronchiectasis. However, with the early use of antibiotics and childhood immunizations, the focus has shifted from postinfectious to intrinsic causes. Often regarded as a condition in which extensive investigation is unlikely to yield treatable causes, recent studies have shown results to the contrary. Thus, Pasteur et al. in a study of a northern European cohort of bronchiectasis patients with a low incidence of HIV and tuberculosis were able to identify a cause in 47 percent of cases. Postinfectious causes (29 percent) were still the largest group. Li et al. in a study of 136 patients were able to find an etiologic cause in 101 (74 percent) cases, and in 77 cases these diagnoses had implications for treatment and prognosis. The etiologic distribution in these studies is detailed in Table 125-1.

Infections A number of pulmonary infections have been associated with the development of bronchiectasis. The association of

Table 125-1 Associated Factors or Etiology Author, years studied

Li (1986â&#x20AC;&#x201C;2002) Pasteur (1995â&#x20AC;&#x201C;1997)

Etiology or association

Patients (n = 136)

Patients (n = 150)

Immunodeficiency

46

12

0

5

Aspiration

25

6

Primary ciliary dyskinesia

20

3

Childhood respiratory infection

5

44

Congenital structural malformation

5

1

ABPA

0

11

Rheumatoid arthritis

0

4

Young syndrome

Figure 125-2 Chest computed tomography shows varicose bronchiectasis: dilated airways with irregular thickened mucosa.

Cystic fibrosis

Excluded

Idiopathic

35

80

0

2

Ulcerative colitis

4

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measles with bronchiectasis has been considered a complication secondary to the intense bronchial and peribronchial inflammation and epithelial proliferation. Complicating secondary infections with adenovirus, herpesvirus, and bacteria such as Staphylococcus aureus, Klebsiella pneumoniae, and P. aeruginosa possibly further contribute to the severity of a necrotizing bronchopneumonia.

Primary necrotizing bacterial pneumonias due to S. aureus, K. pneumoniae, and P. aeruginosa may result in bronchiectasis. Streptococcus pneumoniae, H. influenzae, and Moraxella infections typically do not cause bronchiectasis, but may be colonizers of bronchiectatic airways. Necrotizing anaerobic pneumonias secondary to aspiration or bronchial obstruction are often complicated by parenchymal destruction and bronchiectasis. Tuberculosis can result in bronchiectasis by several mechanisms. Bronchiectasis may be a consequence of tuberculous bronchitis, postobstructive bronchial damage secondary to post-tuberculous bronchial wall stenosis, and extraluminal bronchial obstruction by enlarged tuberculous lymph nodes.

The association of Mycobacterium avium complex (MAC) with bronchiectatic airways is well documented.

While traditionally considered a secondary pathogen in an abnormal host or a colonizer in damaged lungs (bullous emphysema, cavitary lung disease) it is now recognized that MAC or other environmental mycobacteria infection can cause bronchiectasis in apparently normal hosts. CT scan of the chest in such cases is relatively specific, showing small irregular nodules in the middle lobe or lingula, but other parts of the lung may be affected. The phenotype for MAC-associated bronchiectasis seems to involve predominantly slender white women 50 to 70 years old without underlying lung disease or immune compromise. It is likely that a narrow angulated middle lobe bronchus and ineffectual coughing due to increased airway collapsibility explain this syndrome.

Bronchial Obstruction Bronchial obstruction may result in the development of localized bronchiectasis. Various explanations have been advanced for this phenomenon. It has been suggested that following bronchial obstruction, airways proximal to the collapse are exposed to strong dilating forces caused by the difference in the atmospheric pressure in the bronchi and the negative pressure in the pleural space. Over time, these forces acting on weakened, inflamed airways may result in permanent and pathological airway dilatation. The presence of surrounding lung fibrosis, atelectasis, and loss of lung volume leading to regional increases in local retractile lung forces may also play a role. Animal experiments suggest that obstruction may facilitate the development of bronchiectasis by interfering with bronchial clearance and promoting bacterial infection, bronchial wall inflammation, and weakening.

Endobronchial adenomas, fibromas, chondromas, and lower respiratory tract papillomatosis causing partial airway obstruction and bronchiectasis have been described.

Localized bronchiectasis may also been seen in middle lobe syndrome, and is usually caused by intraluminal or extraluminal obstruction secondary to tumor, enlarged lymph nodes, or abnormalities of bronchial structure and branching.

Aspiration/Inhalation Airway Injury Aspiration or inhalation of foreign matter, such as noxious fumes or particulates into the airways, may result in bronchiectasis. This may involve aspiration of oropharyngeal secretions containing microaerophilic and anaerobic bacteria, which may result in a necrotizing pneumonia. Refluxed material from the esophagus or stomach containing food particles, gastric, biliary, and pancreatic secretions, and gut microbes may enter and damage airways, especially if the aspiration events are large and repeated. Depressed sensorium (stroke, alcohol and drug use, seizure, postanesthetic), brain stem dysfunction (amyotrophic lateral sclerosis, multiple sclerosis, syringomyelia), defective laryngeal function (postsurgery, postirradiation), esophageal disorders (dysmotility, gastroesophageal reflux disease [GERD], achalasia, tracheoesophageal fistula), and gastric disorders (gastric outlet obstruction) influence the likelihood and frequency of aspiration. Bronchiectasis may present years after foreign body aspiration (aspiration is often unrecognized), though bronchiectasis has been seen to occur in animals as soon as 2 to 8 weeks after experimental foreign body introduction into the bronchial tree. GERD is the most common condition in this category contributing to the risk of bronchiectasis, and several studies are available documenting increased frequency of reflux in patients with bronchiectasis, asthma, and pulmonary fibrosis, all chronic pulmonary inflammatory conditions. The cause-effect conundrum of GERD in these conditions is still being debated. However, given the high rate of association of GERD with bronchiectasis and the fact that it is often treatable, GERD evaluation should be part of the bronchiectasis work-up.

Cystic Fibrosis Cystic fibrosis (CF) and its variants are a common cause of bronchiectasis in the United States and other developed countries. This is a monogenic disorder that presents most commonly in childhood as a multisystem disease. However, 3 to 7 percent of patients with cystic fibrosis are diagnosed in adulthood, and due to improvements in therapy, 25 percent of childhood cases reach adulthood. This is an autosomal recessive condition resulting from a genetic defect located on chromosome 7 leading to a deficiency in the CF transmembrane regulator. However, more than 200 mutations in the CF gene have been identified and the specific manifestations, severity, and rapidity of progression of CF vary according to the genotype. Clues suggesting CF as a cause of bronchiectasis include upper lobe radiographic involvement and sputum cultures showing mucoid P. aeruginosa. Adults diagnosed with CF after the age of 20 are less likely than children to have homozygous cystic fibrosis transmembrane conductance regulator (CFTR)

2187 Chapter 125

mutation, pancreatic insufficiency (but not pancreatitis), and diabetes mellitus. The diagnosis of CF rests on a combination of clinical criteria accompanied by sweat chloride values above 60 mEq/L. However, normal sweat chloride values may be seen in patients with clinical manifestations of CF and genetically confirmed CF. Screening for other mutations in the CFTR gene may be necessary in these circumstances.

Young’s Syndrome Young’s syndrome consists of a combination of obstructive azoospermia (with normal spermatogenesis) and chronic sinopulmonary infections (bronchiectasis and sinusitis). This syndrome is distinguished from ciliary dyskinesia by its lack of ultrastructural ciliary abnormalities. Young’s syndrome is distinguished from CF by its lack of family history, absence of CF genetic mutations, the presence of normal sweat electrolytes, and normal pancreatic secretion. Typically, the pulmonary manifestations of Young’s syndrome appear usually in childhood and become milder in adulthood, although severe progressive cases have also been reported. Diagnosis is usually made when affected individuals are evaluated for infertility.

Primary Ciliary Dyskinesia Primary ciliary dyskinesia (PCD) is phenotypically and genetically a heterogeneous group of conditions. It has an autosomal-recessive inheritance pattern, although rarely other modes of inheritance, such as X-linked, are described.

It is estimated to affect 1:20,000 to 1:60,000 people, with approximately 12,000 affected people in the United States. The disease phenotype is caused by defects of respiratory cilia, sperm tails, and cilia of the embryonic node.

Currently three genes (DNAI1, DNAH5, and DNAH11) that encode for dynein proteins (axonemal and cytoplasmic) have been linked to recessive PCD. It is hypothesized that given the small numbers of well-characterized affected families, the large size of the dynein genes, the different dynein proteins present in the axoneme, and the large number of regulatory and structural proteins necessary for ciliary function, dynein mutations may not be the only cause of primary ciliary dyskinesia. Since its initial description in 1933, Kartagener’s syndrome (triad of situs inversus, bronchiectasis, and either nasal polyps or recurrent sinusitis) and the description by Afzelius in 1975 of the defects in the dynein arms underlying this condition, incomplete forms of this syndrome have increasingly been recognized. Thus, clinical findings may be varied in patients with PCD, including respiratory distress in neonates, recurrent respiratory tract infections, bronchiectasis, situs inversus, heterotaxia, infertility, and hydrocephalus, singly or in various combinations. In a study looking at 94 patients from 68 families, Noone et al. showed that cough was seen in 100 percent of patients, bronchiectasis (98 percent), sinusitis (47 percent), otitis media (92 percent), and situs inversus (46 percent).

Bronchiectasis

Exhaled nitric oxide (NO) may be used as a screening test, with levels of NO being characteristically low. Ciliated epithelial cells obtained from the inferior or middle turbinate using a sterile cytology brush may be studied for ciliary beat pattern and frequency using digital high-speed video imaging, when the dyskinetic cilia are seen to lack the classical sideway recovery sweep. Abnormalities in ciliary beat have been correlated to ultrastructural defects, and normal ciliary motion essentially excludes PCD. Axonemal structure of respiratory cilia may be visualized by transmission electron microscopy and defects in dynein arms, peripheral and central tubules, radial spokes, and basal bodies may be seen. No structural abnormalities are found in 3 percent of cases of PCD, and diagnosis may be confirmed by establishing dysmotility. Several of these tests are only available in research centers.

Allergic Bronchopulmonary Aspergillosis Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease caused by the ubiquitous fungus Aspergillus fumigatus and usually occurs as a complication of persistent asthma or cystic fibrosis. The excessive mucus production and impaired mucociliary clearance in these conditions allow the inhaled conidia of Aspergillus to persist and germinate, releasing exoproteases and other fungal products that further compromise clearance, breach epithelium, and activate immune responses. ABPA is characterized by a marked local and systemic eosinophilia, an elevated level of Aspergillus fumigatus–specific IgG and IgE antibodies, as well as a nonspecific elevation of total IgE. Clinically, ABPA manifests as recurring episodes of asthma, pulmonary infiltrates, and central bronchiectasis that may progress to fibrosis. Criteria have been established for the diagnosis of ABPA in the non-CF (Patterson criteria) as well as the CF population.

Inflammatory Disorders Inflammatory and fibrotic processes affecting large and small airways may be seen in several rheumatic diseases and idiopathic inflammatory states. Significantly higher frequencies of bronchiectasis (20 to 35 percent) have been found in rheumatoid arthritis (RA) patients undergoing HRCT, both in symptomatic (30 percent) and asymptomatic (8 percent) patients, and was independent of smoking status. Bronchiectasis may precede or follow the development of rheumatoid arthritis, and the coexistence of both conditions is considered to portend a reduced survival. Sj¨ogren’s syndrome may also be complicated by bronchiectasis presumed to be secondary to the effects of inspissated bronchial secretions causing atelectasis and bronchial wall destruction. Relapsing polychondritis may be complicated by bronchiectasis in regions of recurring pneumonia as well as regions free of infection. It is not clear whether the chondritis itself or the recurrent infections predispose to bronchiectasis. While pulmonary involvement in systemic lupus erythematosus is diverse, bronchiectasis by

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HRCT findings is less frequent than in patients with RA. Idiopathic ulcerative colitis has been reported to be associated with bronchiectasis. The pathogenesis remains unknown, although autoimmune and immune complex deposition theories have been proposed. This variant of bronchiectasis does not respond to colectomy and has been known to appear and progress after colectomy. Response to steroids is said to be dramatic. Bronchiectasis seen in sarcoidosis is usually traction bronchiectasis secondary to parenchymal and peribronchial fibrosis. Endobronchial sarcoid may result in localized bronchiectasis secondary to obstruction, atelectasis, and bronchial wall destruction.

Hypogammaglobulinemia Recurrent sinopulmonary infections and bronchiectasis are clearly associated with hypogammaglobulinemia. Several forms of antibody deficiency have been linked with the development of bronchiectasis, including X-linked agammaglobulinemia, common variable immunodeficiency, IgA deficiency, and IgG subclass deficiency (usually IgG-G2 and IgG-G4). The issue of subclass deficiency (in the presence of normal or near-normal levels of total IgG) as a cause of bronchiectasis is controversial due to the wide range of values in normal individuals and the difficulties involved in accurately measuring these levels. A challenge with common humoral bacterial antigens, such as capsular polysaccharides of H. influenzae and S. pneumoniae followed by measurement of antibody titers 6 weeks later, may help establish the presence of such a deficiency. Early diagnosis of these conditions and replacement with intravenous immunoglobulin significantly reduces infections and prevents bronchiectasis, although the efficacy of this treatment in patients with selective IgM, IgA, and IgG subclass deficiency remains controversial. Standard doses in adults of 300 mg/kg by intravenous infusion every 4 weeks have been proved to reduce rates and severity of respiratory infections, but higher doses of 600 mg/kg appear more efficacious in reducing respiratory exacerbations and preserving pulmonary function in some patients.

Chest Radiograph The chest x-ray may be abnormal and show the presence of increased pulmonary markings, ringlike structures, atelectasis, dilated and thickened airways (tram lines), and mucus plugging (finger-in-glove) appearance; however, the chest radiograph may be normal even in the presence of bronchiectasis.

High-Resolution Computed Tomography The HRCT has been proved to be a reliable and noninvasive method for assessment of bronchiectasis. HRCT can accurately (sensitivity of 97 percent) diagnose bronchiectasis, localize and describe areas of parenchymal abnormality, and identify bronchiolar abnormalities and mucus plugging to the level of fifth- and sixth-order bronchi. It also can identify focal areas of air trapping as an indicator of small airway disease. It is indicated in the evaluation of bronchiectasis when surgical resection is contemplated, bronchiectasis is strongly suspected clinically and routine chest radiographs are normal, and other parenchymal abnormalities have to be better defined.

Airway dilatation can be detected by finding tram lines or end-on-ring appearance. A luminal diameter more than 1.5 times the adjacent vessel is indicative of bronchiectasis (Fig. 125-1). Bronchial wall thickening may also be seen. Evidence of small airway plugging with debris (tree-in-bud) may also be seen (Fig. 125-3).

Reports are available suggesting that the distribution and pattern of bronchiectasis may be sufficient to implicate a specific cause. Cartier et al. found that bilateral predominantly upper lobe bronchiectasis is seen most commonly in CF and allergic bronchopulmonary aspergillosis, a unilateral upper lobe predominance in tuberculosis and a lower lobe predominance in childhood viral infections.

Pulmonary Function Pulmonary function is usually abnormal. The degree of impairment depends not only on the nature and extent of the

DIAGNOSIS OF BRONCHIECTASIS The diagnosis of bronchiectasis is based on history, clinical features, and radiologic demonstration of bronchiectatic airways. The diagnostic evaluation in these patients is largely aimed at identifying potentially treatable underlying causes of bronchiectasis. Thus, esophageal pH monitoring and ciliary analysis may be evaluated depending on the age of presentation; family history; other organ system involvement and level of clinical suspicion; total white blood cell count and differential for eosinophilia; immunoglobulin G, A, M, and E levels; serum Îą1 -antitrypsin levels; sputum cultures for bacteria, mycobacteria, and fungi; sweat chloride levels; skin prick tests or precipitins to Aspergillus spp.

Figure 125-3 Chest computed tomography. A. Extensive peripheral branching opacities of tree-in-bud. B. Extensive peripheral branching dilated and thickened airways.

2189 Chapter 125

Bronchiectasis

Table 125-2 Microbiology in Bronchiectasis Author, Year Mean Age (Y)

Li, 2005 12

Nicotra, 1995 57

Pasteur, 2000 58

Angrill, 2001 53

n = 136 (%)

n = 123 (%)

n = 150 (%)

n = 42 (%)

53 (40)

37 (30)

52 (35)

11 (26)

Pseudomonas aeruginosa

15 (11)

38 (31)

46 (31)

4 (9)

Streptococcus pneumoniae

23 (18)

13 (11)

20 (13)

6 (14)

Staphylococcus aureus

5 (4)

9 (7)

NA

NA

Moraxella catarrhalis

3 (2)

3 (2)

30 (20)

2 (5)

Nocardia

0

4 (3)

NA

NA

Anaerobes

1 (1)

2 (1)

NA

NA

Mycobacteria

0

49 (40)

NA

NA

Aspergillus

1 (1)

Microbiologic flora Hemophilus influenzae

Two or more organisms

21

morphologic abnormalities of bronchiectasis, but also on the presence or absence of associated chronic bronchitis, emphysema, and so on. Thus, patients with mild localized bronchiectasis and no chronic bronchitis may have normal lung function tests. Patients with diffuse involvement may show on spirometry a pattern of airways obstruction, with normal or reduced forced vital capacity (FVC), reduced forced expiratory volume in 1 s (FEV1 ), and reduced FEV1 /FVC ratio. In some patients with accompanying atelectasis, parenchymal and pleural scarring, restrictive or mixed/obstructive and restrictive physiology may be seen with reduced FVC and normal FEV1 /FVC ratios. Lung volumes may help identify restriction, as the total lung capacity (TLC), functional residual capacity, and residual volume (RV) are reduced. With mainly obstruction, air trapping is evident with increased residual volume and increased RV/TLC.

BACTERIOLOGY Patients with bronchiectasis are frequently found to be colonized by potentially pathogenic microorganisms. Thus even in stable conditions 60 to 80 percent of patients with bronchiectasis are known to be colonized. The most frequent microorganisms isolated are H. influenzae and P. aeruginosa

6 (5)

3 (2)

60

NA

1 (2) NA

and are often implicated as the cause of periodic exacerbations. Colonization with P. aeruginosa, in particular, has been associated with more severe impairment of lung function, more intense inflammatory response, and more extensive lung disease. Shah et al. showed an association between the isolation of S. aureus and the presence of ABPA or CF. Instances of airway colonization with other potential pathogens that may require specific treatment include Nocardia asteroides, Aspergillus fumigatus, and environmental Mycobacterium spp. Microbiologic flora isolated in three studies are shown in Table 125-2.

TREATMENT The treatment of bronchiectasis is aimed at controlling infection, reducing inflammation, and improving bronchial hygiene, with surgical resection of affected areas being useful in selected patients. With few clinical trials for guidance, treatment often has to be tailored to the specific needs, tolerances, and preferences of individual patients.

Control of Infection Since infection plays a major role in the causation and perpetuation of bronchiectasis, reducing the microbial load and

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associated inflammatory mediators remains a cornerstone of therapy. Antibiotics are indicated to treat an acute exacerbation. However, they have been used variably to prevent recurrent infections by suppression and/or elimination of attendant flora. Antibiotics are directed at commonly isolated pathogens such as H. influenzae, S. pneumoniae, and P. aeruginosa. Oral fluoroquinolones are often used as initial antibiotic choices for treatment durations of 10 to 14 days. In the face of failure to respond to treatment or the occurrence of frequent exacerbations over short periods of time, sputum cultures and sensitivity tests should be done to help define antibiotic selection and/or aid in alternate diagnoses, e.g., atypical mycobacteria or fungae. Severe exacerbations due to P. aeruginosa require the intravenous administration of two antipseudomonal antibiotics and potential hospitalization.

The role of prophylactic/suppressive antibiotics remains controversial. Several approaches to the prescription of suppressive antibiotics exist, including daily antibiotics, antibiotics given for 1 to 2 weeks each month, as well as more prolonged courses lasting weeks to months.

The use of daily, twice weekly, and thrice weekly azithromycin as a biological response modifier in CF and diffuse panbronchiolitis has generated considerable interest about a role in the treatment of bronchiectasis. A pilot trial reported decreased frequency of exacerbations, reductions in sputum volume, and improvements in quality of life and pulmonary function and reductions in levels of C-reactive proteins. Macrolides have been shown to have several biologic effects not related to antibacterial effect. These include effects on nuclear transcription factors with down-regulation of proinflammatory cytokines, suppression of iNOS, reduced adhesion molecule expression, reduced neutrophil chemotaxis and degranulation, cytoprotection against phospholipids, improvement in mucus rheology, reduction in bronchial hyperreactivity, effects on Pseudomonas biofilm production, and quorum sensing function.

Administration of antibiotic aerosols (chiefly tobramycin 300 mg nebulized twice daily against Pseudomonas) is effective in CF. Pilot studies of non-CF bronchiectasis have demonstrated a reduction in Pseudomonas density and even eradication of Pseudomonas in some patients, although side effects were also noticed, including increased cough, wheezing, dyspnea, tinnitus, voice alteration, and tobramycin resistance. The effects of other aerosolized antibiotics, such as aztreonam, colistin, and gentamicin alone or in rotation with tobramycin need to be assessed for efficacy and side effects.

MAC-associated bronchiectasis should be considered in patients not responding to antibacterial therapy. The diagnosis requires three or more independent sputum cultures (or two positive cultures and one positive smear) and radiologic evidence of progressive infiltrates, multiple nodules, and cavitation on chest imaging. In this setting MAC should be treated per American Thoracic Society guidelines with a macrolide, rifampicin, and ethambutol for at least 12 months

after culture negativity. Streptomycin should also be considered for the initial 8 weeks in patients with a substantial MAC burden, e.g., patients with persistent strongly positive sputum cultures and cavitary disease on radiology.

ABPA responds to oral prednisone in doses of 0.5 to 1 mg/kg per day. The addition of antifungal azoles (itraconazole 400 mg/day for 2 months; then 200 mg/day) may confer additional benefits in terms of reducing fungal burden, steroid dose, and exacerbations. Early and appropriate therapy for ABPA may prevent or delay permanent airway destruction. Because of its relapsing course, monitoring of clinical, radiographic, and serologic responses (IgE) is necessary.

Bronchial Hygiene Airway mucus clearance is a problem in bronchiectasis. Chest percussion and postural drainage have been the traditional method of facilitating mucus clearance. The onerous and labor intensive nature of physical therapy procedures such as chest wall percussion and postural drainage, and potential issues of hypoxemia and chest discomfort may result in poor patient compliance and the search for alternative therapies. Autogenic drainage, mechanical vibration with ultrasonic devices, positive expiratory pressure, and Flutter valve use without the assistance of another caregiver have been shown to achieve good chest clearance provided the patient has motivation, breath control, and the neuromuscular function to perform. An intrapulmonary percussive ventilation device and vibratory vest help provide mucus clearance in patients unable to perform the other techniques mentioned in the preceding. Studies document increased sputum expectoration using all these methods, with no method being demonstrably more effective or preferred.

Thus it is recommended that patients should choose their modality based on ability, motivation, preference, needs, and resources.

Mucus Clearance Mucus hypersecretion is a prominent feature of chronic inflammatory airways disease and little is known about the effects of current therapies for airways disease, because of the difficulties in quantifying mucus hypersecretion in clinical studies, both at baseline and in response to treatment. Maintenance of hydration with oral and/or intravenous fluids is considered useful in preventing inspissated sputum retention. Humidification of inhaled air or oxygen as an adjunct to chest physical therapy has been shown to significantly increase the wet weight of sputum produced. The use of nebulized normal or hypertonic saline and acetylcysteine may be considered as important adjuncts to chest physical therapy, although bronchospasm may be associated with the use of these agents. A randomized multicenter study evaluating the efficacy of aerosolized DNAse in non-CF bronchiectasis did not find it efficacious in this group of patients. Rather it was associated with increased pulmonary exacerbation

2191 Chapter 125

rates, hospitalizations, antibiotic use, and a fall in FEV1 and FVC.

Bronchodilators Bronchodilators such as beta agonists, anticholinergics, or theophyllines are frequently used in patients with bronchiectasis, since these patients show signs of airway obstruction and hyperreactivity. There are few reports documenting efficacy in bronchiectasis.

Anti-inflammatory Therapy Persistent endobronchial inflammation isknown to play a significant role in the pathogenesis of bronchiectasis, and anti-inflammatory therapy may be beneficial. The role of inhaled steroids (fluticasone) in bronchiectasis was evaluated

by Tsang et al., who found reduced sputum volume and purulence and reduced rates of exacerbations.

Surgery Bronchiectasis generally is a diffuse disease and surgical extirpation of affected areas is often not feasible. However, in selected cases surgical resection of the most severely affected segments, bleeding segments, or areas harboring resistant tuberculosis or atypical mycobacteria may confer significant benefits in terms of symptom control, reduction of tenacious sputum production, elimination of large-volume bronchial bleeding, reduction of acute infective episodes, and improved quality of life. The surgical approach varies according to the centers offering this treatment, with some preferring a video-assisted thoracoscopy approach, while others recommend the lateral thoracotomy approach. The complications associated with surgery include spread of infection, bleeding, prolonged air leak, and poor lung expansion following surgery.

Lung transplantation is now considered a viable option in advanced cases, when earlier the risks of persistence of infection in the face of prolonged immunosuppression seemed prohibitive. The outcomes of patients receiving lung transplantation in non-CF bronchiectasis were recently reported

by Beirne et al. Overall 1-year survival was 68 percent, and overall 5-year survival was 62 percent. Survival was higher in patients receiving two lungs, as was the FEV1 and FVC.

Miscellaneous While not evaluated specifically for bronchiectasis, vaccinations against S. pneumoniae and influenza should be considered in these patients. Smoking cessation should be emphasized as a matter of routine. Patients with advanced bronchiectasis with evidence of exercise and/or nocturnal desaturation should be considered for oxygen supplementation to delay the onset of pulmonary hypertension and cor pulmonale and improve exercise tolerance. Pulmonary rehabilitation and inspiratory muscle training may be considered, as these modalities have been documented to improve exercise tolerance.

Bronchiectasis

SUGGESTED READING American Thoracic Society, Medical Section of the American Lung Association: Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 156:S1, 1997.

Angrill J, Agusti C, De Celis R, et al: Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med 164:1628, 2001.

Angrill J, Agusti C, de Celis R, et al: Bacterial colonization in patients with bronchiectasis: Microbiological pattern and risk factors. Thorax 57:15, 2002.

Barker AF, Couch L, Fiel SB, et al: Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 162:481, 2000.

Beirne PA, Banner NR, Khaghani A, et al: Lung transplantation of non-cystic fibrosis bronchiectasis: Analysis of a 13 year experience. J Heart Lung Transplant 24:1530, 2005.

Cartier Y, Kavanagh PV, Johkoh T, et al: Bronchiectasis: Accuracy of high resolution CT in the differentiation of specific diseases. AJR Am J Roentgenol 173:47, 1999.

Cohen M, Sahn SA: Bronchiectasis in systemic diseases. Chest 116:1063, 1999.

Cymbala AA, Edmonds LC, Bauer MA, et al: The disease modifying effects of twice weekly oral azithromycin in patients with bronchiectasis. Treat Respir Med 4:117, 2005.

Eijkhout HW, Meer JW, Kallenberg CG, et al: The effect of two different doses of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized double blind multicenter crossover trial. Ann Intern Med 135:165, 2001.

Gilljam M, Ellis L, Corey M, et al: Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood.

Chest 126:1215, 2004.

Karakoc GB, Yilmaz M, Altintas DU, et al: Bronchiectasis: Still a problem. Pediatr Pulmonol 32:175, 2001.

Li AM, Sonappa S, Lex C, et al: Non CF bronchiectasis: Does knowing the aetiology lead to changes in management?

Eur Respir J 26:8, 2005.

Newall C, Stockley RA, Hill SL: Exercise training and inspiratory muscle training in patients with bronchiectasis. Thorax 60:943, 2005.

Nicotra B, Rivera M, Dale AM, et al: Clinical, pathophysiologic and microbiologic characterization of bronchiectasis in an aging cohort. Chest 108:955, 1995.

Noone PG, Leigh MW, Sannuti A: Primary ciliary dyskinesia, diagnostic and phenotypic features. Am J Respir Crit Care Med 169:459, 2004.

Oâ&#x20AC;&#x2122;Donnell A, Barker AF, Ilowite JS, et al: Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase. Chest 113:1329, 1998.

Pasteur MC, Helliwell SM, Houghton SJ, et al: An investigation into causative factors in patients with bronchiectasis.

Am J Respir Crit Care Med 162:1277, 2000.

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Patel IS, Vlahos I, Wilkinson TMA, et al: Bronchiectasis, exacerbation indices and inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170:400, 2004.

Reid LM: Reduction in bronchial subdivision in bronchiectasis. Thorax 5:233, 1950.

Rubin BK, Henke M: Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. Chest 125:70S, 2004.

Shah P, Mawdsley S, Nash K, et al: Determinants of chronic infection with Staphylococcus aureus in patients with bronchiectasis. Eur Respir J 14:1340, 1999.

Tsang KW, Tan KC, Ho PL, et al: Inhaled fluticasone in bronchiectasis: A 12 month study. Thorax 60:239, 2005.

Vendrell M, deGracia J, Rodrigo MJ, et al: IgG subclass deficiency with normal IgG levels in bronchiectasis of unknown etiology. Chest 127:197, 2005.

Wark PA, Hensley MJ, Saltos N, et al: Anti-inflammatory effects of itraconazole in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial. J Allergy Clin Immunol 111:952, 2003.

Weycker D, Edelsberg J, Oster G, et al: Prevalence and economic burden of bronchiectasis. Clin Pulm Med 12:205, 2005.

SECTION NINETEEN

Pulmonary Infections in Special Hosts

126 CHAPTER

Pneumonia in Surgery and Trauma Judith Hellman/Luca Bigatello

I. EPIDEMIOLOGY

V. CLINICAL FEATURES AND DIAGNOSIS

II. RISK FACTORS Preinjury Risk Factors Operative Risk Factors Trauma-Related Risk Factors Postinjury Risk Factors

VI. PREVENTION Preoperative/Intraoperative

III. PATHOGENESIS

VII. TREATMENT OF PNEUMONIA IN TRAUMA AND SURGERY PATIENTS VIII. CONCLUSIONS

IV. MICROBIOLOGY

Pneumonia is the most common infectious complication in surgery and trauma patients, and importantly impacts on morbidity and mortality. Most postoperative and posttraumatic pneumonias and are acquired more than 48 hours after hospitalization and therefore are defined as nosocomial pneumonias. Nosocomial pneumonia is reviewed in detail in Chapter 130. Ventilator-associated pneumonia (VAP) is a subset of nosocomial pneumonia that occurs in critically ill surgery and trauma patients who are intubated and on mechanical ventilation. Although community-acquired pneumonia rarely occurs in surgery and trauma patients, the pathogens that are involved in pneumonia that occurs early after hospitalization may be the same as those that cause community-acquired pneumonia.

Several terms are currently used to describe various different nosocomial pneumonias. Hospital-acquired pneumonia (HAP) occurs 48 hours or more after admission to

the hospital, and may or may not require treatment in the intensive care unit (ICU). Ventilator-associated pneumonia (VAP) occurs at least 48 to 72 hours after intubation. Health careâ&#x20AC;&#x201C;associated pneumonia (HCAP) occurs in patients who have had significant exposure to a health care facility, such as hospitalization within the 90 days prior to infection, residence in a nursing home or chronic care facility, recent treatment with intravenous antibiotics, or treatment in a hemodialysis unit.

Pneumonia is most often caused by gram-positive and -negative bacteria. Fungal and viral pneumonias are rare in surgery and trauma patients and generally occur in patients who are severely immunocompromised.

Numerous factors are involved in the development of pneumonia in surgery and trauma patients. Important host factors include age; pre-existing medical conditions; smoking; and pulmonary, nutritional, and immune status. Intubation

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and mechanical ventilation increase the risk of pneumonia.

Anesthesia increases the risk of developing pneumonia because there is the potential for aspiration during induction and intubation, particularly during emergency surgery and in patients with gastroesophageal reflux.

Making the diagnosis of pneumonia in surgery and trauma patients is fraught with difficulty because noninfectious pulmonary processes often have similar clinical and radiographic manifestations, and the respiratory tract may be colonized with bacteria that are not acting as pathogens.

Generally, the combination of clinical findings (fever, cough, sputum production, and respiratory dysfunction) and laboratory and radiographic data are used to make the diagnosis of pneumonia. However, this strategy likely results in an overestimation of the rate of pneumonia.

Guidelines have been published for the management of nosocomial pneumonia. These guidelines are evidence based as much as possible and were generated based on extensive review of clinical studies, and on expert opinions in areas that have not yet been fully investigated. The guidelines are included in publications that provide exhaustive reviews of nosocomial pneumonia, including epidemiology, microbiology, diagnosis, and treatment.

Management of pneumonia in surgery and trauma patients falls into two basic categories: prevention and treatment. Preventive strategies are implemented to reduce the likelihood of developing pneumonia. Postinjury interventions are used to minimize the risk of aspiration, facilitate secretion clearance, decrease colonization of the respiratory tract, and facilitate opening of small airways and alveoli.

Treatment of established pneumonia includes antimicrobials and supportive therapies. Early appropriate treatment has been shown to be important in reducing mortality. Initial antimicrobial therapy is generally empiric and has broad coverage of gram-positive and -negative bacteria, and possibly anaerobes. Antifungal and antiviral therapies may be appropriate in some situations. Subsequently, the antimicrobial regimen should be tailored based on response to empiric therapy and culture results.

EPIDEMIOLOGY Pneumonia is the most common cause of infection in surgery and trauma patients. The reported incidence and outcome of pneumonia following surgery and trauma depend on a variety of factors, including the diagnostic criteria for pneumonia, the surgical procedure or pattern and intensity of trauma, baseline host factors, and management strategies.

Not surprisingly, critically ill patients with pneumonia have a particularly high mortality rate. However, for unclear reasons, nosocomial pneumonia has not been shown to be an independent risk factor for death.

The incidence of pneumonia following trauma has been reported to be as low as 4 percent, and as high as 87 percent.

More recent studies suggest that the incidence in trauma patients is roughly 20 to 45 percent. The incidence of pneumonia

is higher in patients cared for in the ICU. Head trauma patients are at highest risk of developing pneumonia. Several factors may contribute to the increased risk of pneumonia in head trauma patients. Intubation and mechanical ventilation, which are frequently required in patients with neurotrauma are known to increase the risk of pneumonia. In addition, altered levels of consciousness or impaired swallowing/airway reflexes due to localized neurological injuries may predispose patients to aspirate by impairing mechanisms involved in protecting the airway and clearing respiratory secretions. Trauma patients who develop pneumonia have a high mortality, although pneumonia is often not the direct cause of death. The mortality rate in trauma patients who develop pneumonia has been reported at approximately 44 percent versus 19 percent in trauma patients without pneumonia. The mortality rate is higher in patients who are infected with Pseudomonas aeruginosa (P. aeruginosa) or when there is associated bacteremia.

Pneumonia is currently the most commonly diagnosed postoperative infection, surpassing surgical wound, urinary tract, and bloodstream infections, which were more common than pneumonia in studies in the 1960s to 1980s. The postoperative nosocomial pneumonia rate has been reported in the approximately 1.5 to 20 percent. Pneumonia occurs more frequently in surgery patients with pre-existing lung disease and patients who undergo major upper abdominal or thoracic surgery. The mortality associated with postoperative pneumonia varies in different studies and has been reported at 20 to 50 percent. In one study, the mortality rate was reported at approximately 20 percent in surgery patients who develop pneumonia, and 2 percent in surgery patients without pneumonia.

RISK FACTORS Numerous risk factors have been identified for the development of post-injury pneumonia (Table 126-1). Modifiable risk factors should be identified early so that preventive strategies can be implemented (Table 126-2). In some cases it may be appropriate to delay elective surgery to optimize the status of high-risk patients preoperatively.

Preinjury Risk Factors Risk factors for development of postinjury pneumonia vary between surgery and trauma patients. Factors that have been shown to be associated with the development of pneumonia in trauma patients include: age greater than 55 years, low Glasgow coma score, head trauma, high injury severity score, blunt injury, shock, and emergency intubation. Pneumonia occurs most frequently in neurotrauma patients, perhaps due to aspiration resulting from a decreased ability to protect the airway, and increased need for emergency intubation.

Factors that have consistently been shown to increase the patientâ&#x20AC;&#x2122;s risk of postoperative pneumonia include advanced age, pre-existing lung disease, a history of smoking,

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Table 126-1

Table 126-2

Factors that Increase the Risk for Nosocomial Pneumonia

Preventive Strategies

Baseline Characteristics of Patient Age >55–60 years Preexisting lung disease History of smoking Obesity Poor nutritional status Immunocompromise High ASA∗ class Operative Factors Emergency surgery Site/type of surgery: Highest with upper abdominal and thoracic surgery Anesthesia: General anesthesia Trauma-Related Factors Aspiration during trauma Injuries to abdomen Injuries to chest Low Glasgow coma score Post-Injury/Post-Operative Factors Prolonged intubation and mechanical ventilation Immobility Inadequate analgesia Enteral tubes and feeds Prior treatment with antibiotics Treatment with corticosteroids ∗ ASA

= American Society of Anesthesiologists.

obesity, poor baseline nutritional status, and immunocompromise. The baseline health status is clearly important. Additional factors that also have been reported to be associated with increased risk of postoperative pneumonia include weight loss over a 6-month period, long-term steroid use, recent significant alcohol use, and history of cerebrovascular accident or impaired sensorium. The American Society of Anesthesiologists physical status scale (ASA class) attempts to quantify patients’ overall status preoperatively by assigning a score of 0 (no significant baseline medical problems) to 5 (moribund with little chance of survival). Studies suggest that the risk of postoperative complications is increased in patients with a higher ASA class.

Pneumonia in Surgery and Trauma

Preoperative and Intraoperative Optimize pulmonary status Smoking cessation Bronchodilators for COPD Consider steroids for refractory wheezing in asthma patients Weight reduction Decrease risk of aspiration during induction of anesthesia and intubation in patients with GE reflux, gastroparesis, full stomach Metoclopramide to facilitate gastric emptying prior to induction Consider rapid sequence induction of anesthesia and intubation with cricoid pressure throughout Postoperative/Post-trauma Early ambulation Head of bed elevation Optimize analgesia Specialized beds: rotation and percussion Minimize antibiotics: limit duration of perioperative coverage if required Chest physiotherapy Oral antisepsis

been prepared for nonemergent surgery. Second, the nature of the process requiring emergency surgery is more likely to be associated with a worse overall physiological state. Third, patients undergoing emergency surgery often have a full stomach as they have not fasted preoperatively and may also have impaired gastrointestinal motility. This increases the risk of vomiting and aspiration during induction of anesthesia and endotracheal intubation.

The type of anesthetic may impact on postoperative pneumonia in patients who undergo nonemergent surgery.

Studies suggest that the risk of pneumonia is higher in patients who undergo general anesthesia alone versus spinal or epidural anesthesia with or without general anesthesia. Patients undergoing upper abdominal, thoracic, neck, peripheral vascular, and neurosurgery have an increased likelihood of developing postoperative pneumonia. The risk of pneumonia is highest following upper abdominal and thoracic surgery. The risk of postoperative pneumonia is also increased in trauma patients who undergo craniotomy.

Operative Risk Factors The frequency of pneumonia is increased in patients undergoing emergency surgery. Various factors may contribute to pneumonia in patients undergoing emergency surgery. First, because time will not permit preoperative optimization, patients may be physiologically worse than patients who have

Trauma-Related Risk Factors Pneumonia may result from aspiration at the time of or following trauma. Injuries to the chest or abdomen may predispose patients to respiratory infections because of inability to adequately clear secretions from the airways due to pain, and

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inability to maintain adequate expansion of distal airways and alveoli, which is presumed to lead to atelectasis and collapse.

Postinjury Risk Factors A variety of postoperative and post-traumatic causes may contribute to the development of pneumonia. Hospitalized patients have higher rates of colonization with gram-negative bacteria. The combination of increased oropharyngeal and gastric colonization, and decreased ability to clear secretions and fully expand small airways and alveoli probably contribute to the development of pneumonia. Normal host defenses that are designed to protect the airways from aspiration and facilitate clearance of microbes often are impaired. Factors that predispose include impaired immunity, the inability to protect the airway due to altered level of consciousness, inadequate cough and expansion of the lungs due to pain and splinting, and the presence of endotracheal tubes, which can provide a direct conduit for inoculation of microorganisms.

Immobility is an important factor in the development of pneumonia. Factors that contribute to immobility include inadequate pain control, weakness, alterations in level of consciousness, and the type of surgical procedure. Early ambulation and participation in efforts to mobilize secretions such as coughing or chest physiotherapy are important preventive measures. Adequate pain control to facilitate ambulation, coughing, and deep breathing decreases the likelihood of developing pneumonia in surgery and trauma patients.

However, if narcotics are used in excess, they can depress the level of consciousness and impair the ability to protect the airway, and hence increase the risk of pneumonia.

The presence of devices such as endotracheal tubes and nasogastric tubes increase the risk for pneumonia. Intubation and mechanical ventilation has been reported to increase the risk three- to 21-fold, and the risk also increases with longer duration of intubation. The presence of nasogastric tubes and the use of enteral feeding also increase the risk. However, avoidance of enteral feeding is not encouraged since poor nutritional status and alternative options for nutrition (e.g., parenteral feeding) also increase the risk of infection. The supine position has also been shown to increase the risk of pneumonia in intubated and nonintubated patients perhaps due to increased tendency of gastric contents to regurgitate into the oropharynx. Many ICUs currently have protocols for routinely maintaining patients in a semirecumbent position, with the head elevated to 30 to 40 degrees, rather than in a fully supine position.

Gastric colonization with bacteria also may contribute to nosocomial pneumonia. In general, the stomach has an extremely low pH, which minimizes bacterial colonization of the stomach. The use of agents that alkalinize the stomach in order to prevent gastric stress ulcers increases gastric colonization with bacteria. Some reports suggest that ICU patients who are treated prophylactically for stress ulcer have a higher incidence of pneumonia. However, the populations under study may differ, and some studies suggest that trauma

patients treated with H2 receptor antagonists are not at an increased risk of developing pneumonia.

The in-hospital use of antimicrobial agents has been associated with an increased risk of nosocomial infections, including nosocomial pneumonia. Particularly in critically ill mechanically ventilated patients, the prolonged use of antimicrobial agents is thought to favor selection and subsequent colonization of the airways with multidrug-resistant pathogens. The use of broad-spectrum antibiotics has been shown to promote the occurrence of VAP from resistant strains of P. aeruginosa, Acinetobacter spp., and methicillinresistant staphylococcus aureus (MRSA). A recent observational study of ICU patients identified the prolonged use of antibiotics and the use of quinolones as independent risk factors for the development of multidrug-resistant bacteria in tracheal aspirates, including MRSA, P. aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia. In patients with acquired multidrug-resistant organisms, the infections were related to these organisms, longer duration of mechanical ventilation, and longer stay in the ICU are required.

Other factors that have been shown to be important include reintubation, tracheotomy, use of positive endexpiratory pressure, intense sedation, and the use of corticosteroids, muscle relaxants, barbiturates, and inotropic agents.

However, many of these factors seem to reflect the poor overall status of the patient, and may not be directly responsible for causing pneumonia.

PATHOGENESIS Environmental factors, the surgical procedure, the pattern and degree of traumatic injuries, and patient characteristics play a role in the development of pneumonia in trauma and surgery patients. Early pneumonia may result from gross aspiration at the time of the trauma, or during induction of general anesthesia. General factors that may contribute to the development of pneumonia include aspiration of colonized oropharyngeal secretions or inhalation of aerosolized matter, the inability of the patient to clear secretions, and impaired host immunity. Inadequate secretion mobilization may result from abnormal mucociliary function, inactivity, supine positioning, and inadequate cough due to weakness or splinting from pain.

Severe tissue injury causes generalized dysregulation of immunoinflammatory responses, which contributes to the development of infections in patients undergoing surgery or who have experienced trauma. It is currently believed that tissue injury activates a biphasic inflammatory response in which initial generalized hyperinflammation is followed by immunodepression. The generalized inflammation, or systemic inflammatory response syndrome (SIRS), leads to activation of the coagulation and complement cascades, and is believed to cause disturbances in microvascular blood flow, impaired use of oxygen, and to be responsible for the multiple organ dysfunction syndrome (MODS).

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The anti-inflammatory response is characterized by increased levels of anti-inflammatory cytokines, decreased responsiveness of inflammatory cells to microbial toxins, and altered ratios of T-suppressor to T-helper cells. The immunodepression resulting from major trauma and surgery predisposes patients to the development of infectious complications, including pneumonia. Studies are currently underway to evaluate methods designed to restore proper balance to the immune system, so that there will be adequate defenses against infection without tipping the balance toward hyperinflammation (reviewed in Faist et al., 2004).

Numerous other factors also contribute to the development of pneumonia in particular situations. Prolonged intubation is known to increase the risk of VAP, probably through pooling and microaspiration of oropharyngeal secretions around the endotracheal tube cuff, and inoculation via devices such as suction catheters and bronchoscopes. Although there may be some advantage to the use of noninvasive ventilation in appropriately selected patients, studies do not support a strategy of noninvasive ventilation to avoid reintubation in patients who are failing extubation. In trauma patients with pulmonary contusions, lung lacerations, or pneumatoceles, the presence of blood or devitalized tissue provide conditions for bacterial growth leading to development of pulmonary infections.

MICROBIOLOGY Pneumonia following surgery and trauma is most often caused by a mix of bacteria. Particular pathogens vary with the duration of hospitalization prior to the onset of infection, antecedent antibiotic treatment, and exposure to health care facilities. Early-onset pneumonia, which occurs within 4 days of hospitalization in patients who have not received antibiotics, is more likely to be caused by non窶電rug-resistant bacteria that had colonized the patient prior to admission.

Pneumonia in the first week following trauma or surgery is most often caused by Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae.

Late-onset pneumonia, which occurs 5 or more days after admission, is more likely to be caused by multidrug-resistant bacteria. Common gram-negative bacterial pathogens include Escherichia coli, Enterobacter spp., P. aeruginosa, Acinetobacter spp., Klebsiella pneumoniae, and Citrobacter spp. S. aureus is the most common gram-positive pathogen in burn and surgical ICU patients. Methicillinresistant S. aureus (MRSA) has increasingly become a problem in ICU patients. Recent studies suggest that more than 50 percent of S. aureus infections in the ICU are caused by MRSA. MRSA is also a common pathogen in head trauma patients. Anaerobic bacteria also have been cultured from respiratory secretions of patients with pneumonia, and may be important in the development of lung abscesses.

Fungi such as Candida spp. and Aspergillus fumigatus may cause pneumonia in patients who undergo organ trans-

Pneumonia in Surgery and Trauma

plantation, are neutropenic, or are otherwise severely immunocompromised. Although Candida spp. often colonize the respiratory tract of hospitalized patients, true Candida pneumonia is rare in immunocompetent patients.

CLINICAL FEATURES AND DIAGNOSIS As mentioned, pneumonia in trauma and surgery patients is most often nosocomial, which is reviewed in detail in Chapter 130. Ventilator-associated pneumonia (VAP) is defined as pneumonia that occurs more than 48 hours after tracheal intubation. Since most clinical studies of nosocomial pneumonia have focused on VAP, our discussion of the diagnosis of pneumonia in surgery and trauma patients will focus on the entity of VAP. Unlike community-acquired pneumonia, the diagnosis of VAP is difficult, and is still the subject of much debate. Clinically, the diagnosis of VAP includes three main components: a new or worsening consolidation on the chest radiograph, local (bronchial secretions) and systemic signs of infection, and microbiological evidence of respiratory infection. However, in trauma and surgical patients, systemic signs of inflammation can be virtually indistinguishable from infection (fever, leukocytosis, tachycardia, etc.). At one time, a dispute existed between those who favored a clinical versus a bacteriological diagnosis; it is now clear that a purely clinical diagnosis is no longer acceptable because of its low specificity in hospitalized, mechanically ventilated patients. Radiographic findings are notoriously nonspecific in critically ill patients and in those that have sustained chest trauma. Noninfectious infiltrates may be present in patients with pulmonary contusions, atelectasis or lobar collapse, or during episodes of congestive heart failure. Therefore, the clinical findings must be associated with definite microbiological evidence of deep seeded respiratory infection.

The current diagnostic debate in the literature is concerned with the type of bacteriological methodology that should be added to the clinical findings suggestive of nosocomial pneumonia. Although lung biopsy could be considered the gold standard diagnostic test, it is risky and impractical in most situations. The main available alternatives include: (1) blind tracheal aspiration of tracheobronchial secretions; (2) specimens of the distal airways by biopsy obtained using either broncho-alveolar lavage (BAL) or protected specimen brush (PSB), and (3) blindly collected specimens of the distal airways, or mini-BAL (Table 126-3). The major recommendations by experts concerning the use of these techniques have been published recently and can be summarized as follows: 1. Whenever possible, a sample of the distal airways should be obtained before starting or changing antimicrobial therapy. In principle, bronchoscopic techniques seem to be more reliable than blind techniques because they can direct the collection of

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Table 126-3 Techniques Available to Sample Tracheobronchial Secretions to Diagnose Ventilator-Associated Pneumonia Advantages

Diagnostic Power

Disadvantages

Blind tracheal aspirate

Easy, safe, does not need a physician, rapid qualitative reading

High sensitivity (>90%), but high contamination rate—very low specificity

May lead to overuse of antimicrobial therapy

Bronchoscopic PSB

Lowest contamination from higher airways

Moderate sensitivity (90%), best specificity (≥90%)

24–48 hr wait for growth, technically difficult, expensive

Bronchoscopic BAL

Samples a large alveolar area, rapid qualitative reading

High sensitivity (>90%), moderate specificity because not protected

Time consuming, not ideal in unstable patients

Mini-BAL

Deeper than tracheal, protected, does not need a physician

Equivalent to BAL (small number of studies)

Blind, potential for inadequate sampling

specimens to the areas of the lung that the radiographs indicate are probably affected. However, this premise has not fully been confirmed by controlled studies. Non-protected specimens, such as those collected by simple bronchoscopy and BAL, can be contaminated by upper airway nonpathogens. The PSB yields the most specific results, but may decrease sensitivity somewhat because the specimen is limited in size and does not yield a result for 24 to 48 hours.

Moreover, the PSB technique is somewhat cumbersome and expensive. BAL samples a larger area of the lung (including alveolar epithelium), and can be plated immediately.

2. Nonbronchoscopic sampling techniques of the distal airways (mini-BAL) are becoming popular because they are less labor intensive and can be safely and effectively performed by nonphysicians. Commercially available mini-BAL catheters enable protected collection of samples. The obvious concern with the use of these catheters is that they cannot be directed visually into the specific areas of the lung. However, a recent study has indicated that BAL specimens obtained using blindly inserted mini-BAL catheters and using bronchoscopy are equivalent.

3. Blind tracheal aspiration has the obvious advantage of being simple to implement and inexpensive. It has a high sensitivity for pneumonia, but low specificity.

Consequently, blind tracheal aspiration tends to favor overuse of antibiotics, a known risk for nosocomial infection, including VAP. One situation in which tracheal aspirates may be almost equivalent in their specificity to the bronchoscopic techniques is during ongoing antimicrobial therapy, which tends to decrease the bacterial load in the airways.

4. Quantitative or semiquantitative cultures are suggested, as opposed to simple qualitative sampling.

5. Use of tracheal aspirates to guide therapy during the evolution of the process is not universally recommended, because of the lack of specificity of the technique, which will lead to unnecessary prolongation of therapy.

The distinction between aspiration pneumonitis and actual aspiration pneumonia can be difficult and is important in determining whether or not to initiate the use of antibiotics. Infectious and noninfectious pulmonary complications may result from aspiration during induction and tracheal intubation as well as at other times in the perioperative period.

Aspiration pneumonitis, or Mendelson’s syndrome, is a noninfectious chemical pneumonitis that results from aspiration of sterile gastric contents (reviewed in Marik PE, 2001). Aspiration pneumonia is an infectious process that results from aspiration of oropharyngeal or gastric secretions that contain bacteria. For both aspiration pneumonia and aspiration pneumonitis the chest radiograph may show an infiltrate in dependent portions of the lung, most often in the right lower lobe. Antibiotics are often begun in patients who have been witnessed to aspirate and are deemed to be at high risk of developing aspiration pneumonia; such patients include those who are immunocompromised or otherwise severely debilitated, are taking H2 blockers or antacids, and/or have preexisting pulmonary disease. Antibiotics are often withheld in patients who have been witnessed to aspirate, but that do not have significant risk factors for developing pneumonia. In such patients, antibiotics are initiated only if there is failure of the pneumonitis to improve after 48 hours of observation.

Complications of pneumonia include acute lung injury/acute respiratory distress syndrome (ALI/ARDS),

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empyema, lung abscess, and very rarely necrotizing (gangrenous) pneumonia.

PREVENTION Preoperative/Intraoperative Preoperative interventions, such as optimizing the pulmonary status, smoking cessation, and bolstering nutritional status may be indicated prior to elective surgery. Postoperative pulmonary complications have been shown to be decreased in COPD patients treated with bronchodilators preoperatively, and there is evidence that there are also fewer pulmonary complications in adequately treated asthma patients. In asthma patients with refractory wheezing, it may be appropriate to initiate corticosteroids prior to surgery and continue the steroids through the early postoperative period. Although smoking cessation has been shown to decrease the incidence of postoperative pulmonary complications, studies suggest that this decrease does not occur until more than 8 weeks following cessation.

Gastroesophageal reflux, gastroparesis, obesity, pregnancy, and emergency surgery increase the risk of aspiration during induction of general anesthesia and intubation. Measures to prevent reflux and aspiration should be considered preoperatively such as treating the patient with the promotility agent metoclopramide to facilitate gastric emptying. In addition, a rapid sequence induction with application of cricoid pressure should be considered in patients who are at high risk of vomiting and aspirating. The rapid sequence induction is generally accomplished by simultaneously providing the induction agent and muscle relaxant. In order to avoid distention of the stomach, the patient is then intubated without attempting to ventilate via a mask. Pressure is applied to cricoid cartilage on the anterior neck starting immediately before administration of induction agents throughout the entire induction and intubation to occlude the esophagus so that gastric contents do not reflux into the pharynx.

This method of induction can be risky and have catastrophic consequences in patients who cannot be intubated and cannot be ventilated by mask. Thus, modifications may be appropriate depending on the patientâ&#x20AC;&#x2122;s airway and pulmonary function/reserve.

A variety of interventions can be implemented following surgery or trauma to decrease the likelihood of developing pneumonia. The basic goals of these interventions are to: (1) prevent aspiration of colonized oropharyngeal or gastric secretions; (2) facilitate clearance of respiratory secretions; and (3) maintain adequate tidal volumes so that small airways and alveoli remain open to avoid atelectasis and collapse, which presumably provides good conditions for bacterial growth.

Although the general principles of prevention are similar, the strategies used to prevent pneumonia vary based on the clinical status of the patient. For instance, nonintubated patients actively participate in prevention, whereas intubated patients play a more passive role. Other strategies include minimizing

Pneumonia in Surgery and Trauma

the duration of intubation, using specialized beds for percussion and oscillation to facilitate clearance of secretions, and oral decontamination with antiseptic.

1. Early mobilization, including ambulation. Patients who are not intubated and who are physically able to do so should begin to mobilize as soon as feasible after surgery and/or trauma. The measures include sitting at the edge of the bed or in a chair, and if possible, ambulating.

2. Head of bed elevation. Studies suggest that the frequency of pneumonia is decreased in patients who are maintained in a semirecumbent position, with the head of bed elevated at least 45 degrees, than in patients who are fully supine.

3. Analgesia. Adequate analgesia is required after surgery and trauma to allow patients to clear secretions through coughing and mobilization, and facilitate ventilation and prevent or correct atelectasis and collapse. A properly titrated analgesic should alleviate pain without sedating the patient. Excessive oversedation may lead to aspiration due to inability to protect the airway. Epidural analgesia may be of benefit in both surgery and trauma patients; a properly functioning epidural catheter should provide excellent analgesia without significantly affecting the sensorium.

4. Rotational beds and percussion. Specialized beds often are used to limit pooling of secretions and facilitate the clearance of secretions. Options include turning the patient, changing posture, and percussion.

5. Chest physiotherapy (performed in both intubated and non-intubated patients). It is believed to assist with mobilization of respiratory secretions and to prevent or facilitate expansion of atelectatic and collapsed areas of the lung.

6. Oral antisepsis. Oropharyngeal colonization has been shown to be an independent risk factor for the development of gram-negative pneumonia in ICU patients. Although oral antisepsis using chlorhexidine has been reported to decrease the rates of nosocomial respiratory infections in patients undergoing cardiac surgery, until now studies in ICU patients have not confirmed a decrease in pneumonia.

TREATMENT OF PNEUMONIA IN TRAUMA AND SURGERY PATIENTS This section provides a general overview of the principles of treatment of pneumonia in surgery and trauma patients. A more comprehensive review of specific treatment protocols is discussed in Chapter 130. Early treatment with appropriate antibiotics significantly impacts on outcome, underscoring the importance of selecting particular antibiotics. Often

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initial treatment must be empiric, without definitive culture data to guide therapy. Most empiric treatment is broad, covering gram-positive and -negative bacteria, and possibly anaerobes. When culture and sensitivity data become available, there should be a de-escalation of antibiotics. The final regimen should target individuals pathogens based on sensitivities to individual antibiotics and the regimen should be least likely to facilitate colonization and/or infection with more resistant bacteria.

The empirical choice of antibiotics in trauma and surgery patients is influenced by a number of factors, including the duration of hospitalization or exposure to health care facilities before the pneumonia, previous antibiotic treatment, prior culture results, the likely mechanism of the pneumonia (aspiration versus hematogenous spread versus invasion via a wound), and the presence of severe immunosuppression. The severity of illness may also factor into decisions about the choice of antibiotics and may prompt earlier empirical initiation of antibiotics. Empirical choices of antibiotics also must take into account the local flora and antibiotic resistance patterns that can vary considerably between different hospitals and communities. Much of the literature concerning treatment has focused on VAP, from which diagnostic and treatment strategies have been extrapolated and applied to the larger population of patients with hospital-acquired pneumonia.

Postoperative and trauma patients with pneumonia fall into two broad categories, which have important treatment implications. One category includes patients who develop pneumonia early during their hospitalization and have not had recent exposure to health care facilities. These patients are unlikely to be infected with multidrug-resistant pathogens; consequently they are not treated with empirical regimens that target resistant bacteria. The other group includes patients who develop HAP and VAP later during their hospitalization, and who therefore are likely to be colonized/infected with drug-resistant pathogens. These patients should receive broad-spectrum empirical therapy that targets multidrug-resistant bacteria. Empirical treatment with two agents against resistant gram-negative bacteria should be considered in patients who are severely ill and/or are likely to be infected with multidrug-resistant bacteria. Empirical treatment of pneumonia in patients who have recently received antibiotic should include an agent from a different antibiotic class.

Comprehensive guidelines for management of HAP, VAP, and HCAP and a comprehensive review of ventilatorassociated pneumonia were recently compiled by a committee of experts from the ATS and IDSA. Important aspects of the guidelines include: (1) the early initiation of appropriate antibiotics; (2) tailoring empiric therapy to the likelihood of being infected with multidrug-resistant pathogens; (3) considering the use of combination antibiotic therapy for empiric or directed treatment of resistant gram-negative bacteria and for P. aeruginosa; (4) de-escalating therapy promptly when indicated by cultures of lower respiratory tract secretions and clinical response to therapy; (5) limiting the duration of

therapy for “uncomplicated” pneumonia to 7 to 8 days to reduce the development of multidrug-resistant pathogens; and (6) considering using linezolid in lieu of vancomycin for treating MRSA VAP.

CONCLUSIONS Pneumonia, a common problem following surgery or trauma, is associated with increased morbidity and mortality. Most instances of pneumonia in surgery and trauma patients are nosocomial because they occur more than 48 hours after admission to the hospital. However, pneumonia occurring early after surgery or trauma may be caused by the same pathogens that usually cause community-acquired pneumonia. Early pneumonia in patients who have not recently had significant exposure to a health care facility may be caused by non– drug-resistant microorganisms. Pneumonia that occurs later during hospitalization or in patients who have had significant exposure to health care facilities is more likely to be caused by antibiotic-resistant bacteria. This distinction has important implications when resorting to empirical antimicrobial therapy.

The diagnosis of pneumonia in patients who have experienced trauma or surgery can be difficult because the manifestations are non-specific. At present, the approach to the diagnosis is based on a combination of clinical, laboratory, and radiographic data. Sputum and blood cultures should be obtained before starting antibiotics to maximize the chance of identifying the pathogen. Initial treatment of pneumonia is usually empirical and uses broad-spectrum antibiotics that cover gram-positive and -negative aerobic and anaerobic bacteria. Subsequent antimicrobial therapy should be tailored to the pathogens identified in cultures of respiratory secretions or blood. Treatment with antiviral and/or antifungal agents may be appropriate in severely immunocompromised patients. When choosing antibiotics for the empirical treatment of pneumonia, it is important to take into account the local bacterial flora and patterns of antibiotic resistance.

SUGGESTED READING Arozullah AM, Khuri SF, Henderson WG, et al.: Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery.

Ann Intern Med 135:847–857, 2001.

Bochicchio GV, Joshi M, Bochicchio K, et al.: A timedependent analysis of intensive care unit pneumonia in trauma patients. J Trauma 56:296–301, 2004.

Boque MC, Bodi M, Rello J: Trauma, head injury, and neurosurgery infections. Semin Respir Infect 15:280–286, 2000.

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Bulger EM, Edwards T, Klotz P, et al.: Epidural analgesia improves outcome after multiple rib fractures. Surgery 136:426–430, 2004.

Chastre J, Fagon JY: Ventilator-associated pneumonia. Am J Respir Crit Care Med 165:867–903, 2002.

Craven DE, De Rosa FG, Thornton D: Nosocomial pneumonia: Emerging concepts in diagnosis, management, and prophylaxis. Curr Opin Crit Care 8:421–429, 2002.

Dupont H, Montravers P, Gauzit R, et al.: Outcome of postoperative pneumonia in the Eole study. Int Care Med 29:179– 188, 2003.

Esteban A, Frutos-Vivar F, Ferguson ND, et al.: Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 350:2452–2460, 2004.

Faist E, Angele M, Wichmann M: The immune response. In: Moore EE, Feliciano DV, Mattox KL (eds.), Trauma. New York, McGraw-Hill, 2004, 1383–1396.

Fourrier F, Dubois D, Pronnier P, et al.: Effect of gingival and dental plaque antiseptic decontamination on nosocomial infections acquired in the intensive care unit: A doubleblind placebo-controlled multicenter study. Crit Care Med 33:1728–1735, 2005.

Co-cleairs, Michael S. Niederman, Donald E. Graven: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and health care-associated pneumonia. Am J Respir Crit Care Med 171:388–416, 2005.

Hilbert G, Gruson D, Vargas F, et al.: Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med 344:481– 487, 2001.

Iregui M, Ward S, Sherman G, et al.: Clinical importance of

Pneumonia in Surgery and Trauma

delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 122:262–268, 2002.

Kobayashi M, Takahashi H, Sanford AP, et al.: An increase in the susceptibility of burned patients to infectious complications due to impaired production of macrophage inflammatory protein 1 alpha. J Immunol 169:4460–4466, 2002.

Kollef MH: Inadequate antimicrobial treatment: An important determinant of outcome for hospitalized patients.

Clin Infect Dis 31:S131–138:S131–S138, 2000.

Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 344:665–671, 2001.

Rodgers A, Walker N, Schug S, et al.: Reduction of postoperative mortality and morbidity with epidural or spinal anesthesia: Results from overview of randomised trials. Br Med J 321:1–12, 2000.

Tablan OC, Anderson LJ, Besser R, et al.: Guidelines for preventing health-care–associated pneumonia, 2003: Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep 53:1–36, 2004.

Tejada AA, Bello DS, Chacon VE, et al.: Risk factors for nosocomial pneumonia in critically ill trauma patients. Crit Care Med 29:304–309, 2001. van Loon HJ, Vriens MR, Fluit AC, et al.: Antibiotic rotation and development of gram-negative antibiotic resistance. Am J Respir Crit Care Med 171:480–487, 2005.

Wallace WC, Cinat ME, Nastanski F, et al.: New epidemiology for postoperative nosocomial infections. Am Surg 66:874– 878, 2000.

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127 Pulmonary Infection in Immunocompromised Hosts Jay A. Fishman

I. OVERVIEW II. GENERAL PRINCIPLES Opportunistic Infection Epidemiologic Exposures Net State of Immunosuppression Timetable of Infection III. MICROBIAL VIRULENCE AND INFECTION IV. PROTECTING THE PATIENT FROM INFECTION V. RECOGNITION OF NEW SYNDROMES VI. CONCOMITANT PROCESSES VII. PATIENT MANAGEMENT VIII. GENERAL CONSIDERATIONS IN SPECIAL HOSTS HIV Infection and AIDS Infection in Cancer Patients Clinical Approaches to Infection in the Cancer Patient Fever and Pulmonary Infiltrates Approach to Antimicrobial Therapy in Patients on Empiric Therapy

Non-infectious Etiology Idiopathic Pneumonia Syndrome Pulmonary Edema Syndromes New-Onset Airflow Obstruction and Obliterative Bronchiolitis Pulmonary Veno-Occlusive Disease Infectious Etiologies Pulmonary Function Testing in Hematopoietic Stem Cell Transplantation X. SOLID ORGAN TRANSPLANTATION Timetable of Infection Radiologic Clues to the Diagnosis of Pneumonia in the Organ Transplant Patient XI. PRIMARY IMMUNE DEFECTS Antibody (B-Cell) Deficiency Complement Disorders Cell-Mediated Immunity XII. DIGEORGE’S SYNDROME Phagocytic Defects

IX. BONE MARROW AND STEM CELL TRANSPLANTATION Temporal Sequence of Pulmonary Disease Syndromes Common Clinical Presentations

OVERVIEW Prolonged survival of individuals with AIDS, after solid organ and bone marrow transplantation, with connective tissue diseases, primary immune deficiencies, and after intensive chemotherapeutic regimens for cancer, has greatly expanded the population of immunocompromised hosts.

These patients are defined by their susceptibility to infection with organisms that have little native virulence for the normal host. The detection of underlying immune compromise has been facilitated by improvements in microbiologic techniques, particularly molecular assays, and advances in imaging. Survival has also been improved by the availability of new antimicrobial agents, including antifungal agents, macrolides, antivirals (ganciclovir, foscarnet, and oral agents),

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hematopoietic growth factors, and highly active antiretroviral therapies (HAART) for HIV infection. The major challenges in these populations include systemic infections for which adequate therapies have not yet been developed (e.g., hepatitis C virus) and the progressive antimicrobial resistance of common pulmonary pathogens, including Staphylococcus aureus, Enterococcus, Pseudomonas, and Stenotrophomonas (formerly Xanthomonas) spp., and selection of novel strains of bacteria, including non-tuberculous mycobacteria and Nocardia spp. In addition, the incidence has increased of strains of streptococci (including pneumococci) resistant to antimicrobial agents used for routine prophylaxis (i.e., trimethoprim-sulfamethoxazole and quinolones). With the changing health care scene, medical care of immunocompromised individuals is increasingly managed outside of academic centers. Therefore, information about the clinical management of these patients has become increasingly important to the entire spectrum of medical practitioners.

GENERAL PRINCIPLES Opportunistic Infection Opportunistic infection is defined as an infection occurring in an individual as a result of a compromised immune function that would not be expected to occur or would cause disease of lesser intensity in the presence of normal immune function. Thus, immunocompromised individuals are subject to the common infections that are present in the community, but these infections are likely to be of greater frequency or severity than in the immunologically normal host. In addition, infection in these patients may be caused by organisms of low native virulence or that cause insignificant disease in the normal host, including such organisms as Pneumocystis carinii (jiroveci) or cytomegalovirus (CMV).

The risk of infection in any patient is determined by the interaction of two factors: the potential pathogens to which the individual is exposed (epidemiologic exposures), and a measure of the individualâ&#x20AC;&#x2122;s susceptibility to infection, termed the â&#x20AC;&#x153;net state of immunosuppressionâ&#x20AC;? (Table 127-1). The occurrence of infection in an individual at a time when the immune status of the patient is thought to be nearly normal is evidence that either an excessive environmental exposure has occurred or that the immune status of the individual is depressed. Conversely, even minimal environmental exposures can cause invasive infection in an individual who is maximally immunosuppressed.

Epidemiologic Exposures Epidemiologic exposures of importance to the immunocompromised patient can be divided into two general categories: those occurring within the community and those occurring within the hospital. Exposures within the community vary based on such factors as geography and socioeconomic status.

Thus, opportunistic pathogens acquired in the community

Table 127-1 Factors in the Net State of Immune Suppression Immunosuppressive therapy: dose, duration, temporal sequence Underlying immune deficiency: autoimmune disease, functional immune deficits Mucocutaneous barrier integrity: catheters, epithelial surfaces, devitalized tissue, fluid collections Neutropenia, lymphopenia Metabolic conditions Uremia Malnutrition Diabetes Alcoholism with cirrhosis Viral infection: Cytomegalovirus Epstein-Barr Virus Hepatitis B and C Human immunodeficiency virus

include the geographically restricted systemic mycoses (blastomycosis, coccidioidomycosis, and histoplasmosis), Mycobacterium tuberculosis, Strongyloides stercoralis, Leishmania donovani, Pneumocystis carinii, Legionella species, and community-acquired respiratory viral infections (e.g., influenza, respiratory syncytial virus, and parainfluenza). Common viral agents may include herpes simplex virus, cytomegalovirus, varicella zoster, and hepatitis B and C viruses.

Due to the limited effectiveness of many vaccines in immunocompromised individuals, infections resulting from Streptococcus pneumoniae and Haemophilus influenzae are common.

Within the hospital, excessive environmental exposures can be divided into two general categories: domiciliary and non-domiciliary. Domiciliary exposures occur on the hospital unit where the patient is housed. When the air, food, equipment, or potable water supply is contaminated with pathogens such as Aspergillus species, Legionella species, or vancomycin-resistant enterococci, clustering of cases of infection in time and space are observed. As a result, an increased incidence of nosocomial pneumonia or catheter and wound infections may be seen. Non-domiciliary exposures occur when the patient is transported to contaminated operating rooms, radiology suites, or catheterization laboratories for procedures. Non-domiciliary outbreaks, although possibly more common, are more difficult to detect because of the lack of clustering on a particular hospital unit. The leading clue to the presence of a nosocomial hazard is the occurrence

2205 Chapter 127

of opportunistic infection in a patient whose net state of immunosuppression would not normally lead to such an event, or nosocomial infection with organisms not known to be present on the clinical unit on which the patient is housed.

Net State of Immunosuppression The net state of immunosuppression (Table 127-1) is a concept that describes all of the host factors that determine infectious risk, including: the dose, duration, and temporal sequence in which immunosuppressive drugs are deployed; injuries to the primary mucocutaneous barrier to infection (e.g., indwelling catheters, gastrointestinal or bronchial anastomoses in organ transplant patients); neutropenia or lymphopenia; underlying immune deficiency; pulmonary aspiration injury; metabolic problems, including protein-calorie malnutrition, uremia, and, perhaps, hyperglycemia; the presence of devitalized tissues, and fluid collections (hematoma, effusions, ascites); and infection with immunomodulating viruses (cytomegalovirus or CMV, Epstein-Barr virus or EBV, hepatitis B or HBV, hepatitis C or HCV, and the human immunodeficiency viruses, HIV-1 and -2), which predispose to other opportunistic infections, and also to graft rejection and graft-vs-host disease. The sum of the congenital, metabolic, operative, and surgery-related factors is the patient’s net state of immune suppression. Generally, more than one factor is present in each host; the identification of the relevant factors, and correction when possible, are central to the prevention and treatment of infection in these hosts.

For example, in the alcoholic patient with hepatitis C and cirrhosis who has undergone liver transplantation, the socalled net state of immune suppression includes immunosuppression needed to maintain graft function, immune deficits caused by cirrhosis and chronic illness; immunologic and inflammatory effects of infection by hepatitis C virus; exposure to, and colonization with, community-acquired and nosocomial organisms; and new infections (e.g., spontaneous peritonitis) that may occur during the prolonged waiting period for a compatible organ. When the organ for transplantation does become available, it may arrive contaminated by organisms acquired by the donor during hospitalization. This gravely ill patient is then subjected to a major surgical procedure. After surgery the lungs are apt to be compromised, recovery of function in the allograft is often slow, immunosuppressive drugs are initiated, biliary (T-tube), intravenous, and urinary catheters are placed, and major incisions need to heal. Drug toxicities at this stage are common, often resulting in neutropenia and hepatitis. Biliary function and anastomotic integrity are assessed by injecting contrast dye into ducts and tubes (e.g., T-tube cholangiogram) that are colonized by native and nosocomial organisms. The sum of the underlying, operative, and transplant-related factors is the net state of immune suppression. Thus, the spectrum of susceptibility to infection is a continuum from individual deficits (e.g., viral upper respiratory infection that paves the way for bacterial superinfection) to multiple simultaneous deficits (e.g., the transplant recipient).

Pulmonary Infection in Immunocompromised Hosts

Timetable of Infection In the broad spectrum of immunocompromised hosts, the risks of infection may be relatively stable over time, as in the diabetic with vasculopathy and neuropathy who is prone to skin and soft tissue infections. The risks of infection may be time limited, as in the postsurgical patient without complications or in the autologous bone marrow transplantation recipient with effective engraftment. The risk of infection may be cumulative and progressive, as in the AIDS patient, in whom infection is a function of declining immunity (without therapy), falling CD4 lymphocyte counts, rising viral loads, and the effects of other persistent infections (CMV, Cryptosporidium) (Fig. 127-1). In these individuals the occurrence of new infections suggests the progression of immune compromise.

The risks may also be progressive but not cumulative. Thus, the risks of infection in the recipient of allogeneic stem cell or solid organ change predictably with time as a function of the evolving condition of the patient. For example (Fig. 127-2), in the early phase after hematopoietic stem cell transplantation (HSCT), infection is often the result of nosocomial exposures during neutropenia. Subsequently, following marrow engraftment but in the absence of preformed cellular immunity, viral pneumonitis (CMV) and hepatic veno-occlusive disease may occur. Finally, during the development of, and treatment for, acute and chronic graft-vs-host disease, susceptibility to infection is a function of immune suppression and mucosal injuries (possibly from chemotherapy, radiation, or infections such as C. difficile colitis).

With standardized immunosuppressive and chemotherapeutic regimens, specific types of infections often occur in a predictable pattern (time line) as a reflection of the specific risk factors (surgery, immune suppression, acute and chronic rejection, re-emergence of underlying diseases, viral infections—see Figs. 127-1 and 127-2) present at each phase of the post-transplantation course. The patterns have been altered by the availability of a broader range of immunosuppressive and chemotherapeutic agents, the use of stem cells instead of marrow for transplantation, and antimicrobial prophylaxis. However, the general concepts and major determinants of infection remain the same—the exogenous immune suppression or chemotherapy and any additional immune suppression used to treat either graft rejection or graft-vshost disease. Superimposed viral infections will enhance the risk of infection at any point along the time line.

Because each risk factor renders the patient susceptible to infection by new groups of pathogens, infections occurring with the “wrong” pathogen or at the wrong time suggest an undiscovered immune deficit (fluid collection, neutropenia) or an unusual epidemiologic exposure. the occurrence of specific infections can be prevented by the use of antimicrobial prophylaxis, vaccines, and behavioral modifications (e.g., no raw vegetables or digging in gardens without masks). This results in a shift to the right of the time line—infections generally observed later in the course of disease or therapy are observed at the appropriate time in the absence of infections that tend to occur earlier but have been prevented by a variety of preventive

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Figure 127-1 The progression of AIDS-associated conditions.

Solid Organ

Acute rejection

Chronic rejection

Graft derived (leaks, hematoma, obstruction, mucosal, catheters. drains)

Technical

Community Exposures, Recurrent Disease, Tumors (Lymphoma) Anastomosis (lung, vascular) Aspiration

0

1

2

3

4

5

6

7

8

9

10

MONTHS Transplant

Bone Marrow, Stem Cell

Interstitial Pneumonitis Neutropenia

Acute GVHD and Treatment

Chronic GVHD and Treatment

In-dwelling Catheters Transfusions Blood Products Community Exposures, Relapsed Disease, Secondary Malignancy

Figure 127-2 The timeline of conditions predisposing to infection in solid organ transplantation (above the timeline) and in bone marrow and stem cell transplantation (below the timeline). Patients will vary in individual susceptibility patterns.

1 yr

2207 Chapter 127

measures. the timetables presented in Figs. 127-1 and 127-2 are useful in a number of regards: 1. Developing a differential diagnosis for infectious syndromes by time post-transplant: What type of infection is most likely at various times after transplantation.

2. Identification of excess epidemiologic hazards Nosocomial: Aspergillus, MRSA, VRE: Clustered in time and space, by inpatient unit, procedures, or surgical suite Community: Influenza, RSV, Legionella outbreaks Individual: Unique exposures, travel, occupational hazards 3. Excessive immune suppression: Too many infections, too severe, or at the wrong time on time line suggests that a problem exists with immunosuppressive regimens used by a program.

MICROBIAL VIRULENCE AND INFECTION The risk of infection in any individual patient depends not only on the sum of the immune deficits and the nature, duration, and intensity of the exposures to potential pathogens, but also on the virulence of the organism. Recent data suggest that the specific host-pathogen interactions are a critical factor in the development of infection. Such factors as the distribution of toll-like receptors, microbial production of biofilm, or antimicrobial resistance influence the pathogenesis of infection. Host cells may enhance the virulence of the invading organism by the induction of genes in that organism that contribute to bacterial persistence or invasion.

Thus, resistance to phagocytosis is induced by target cells in Yersinia infections. Also, the survival of uropathogenic E. coli in urine and the growth of pili for attachment are induced by contact with the targeted uroepithelial cells. Another example of the host-pathogen interaction is the role of cytomegalovirus (CMV) in transplantation. CMV is the cause of common clinical syndromes that frequently occur in immunocompromised patients. Among these are pneumonitis, hepatitis, glomerulonephritis, gastritis, colitis, retinitis, and mononucleosis-like syndromes. CMV also induces an array of host responses (i.e., neutropenia, immune suppression, upregulation of histocompatibility antigens and other cell surface antigens, TNFα secretion, graft rejection) that contribute to the host’s susceptibility to infection (Table 127-2). Thus, the concept of immune status balanced against epidemiologic exposure may be incomplete: The immunoregulatory effects of some pathogens and the interaction of the organisms with the “correct” target cells of the host are best regarded as only part of the response to opportunistic infection.

Physical defects may also contribute to virulence. Foreign materials (vascular grafts, sutures, and eye or limb prostheses) may provide a nidus for infection by an organism that would not be capable of causing infection under normal

Pulmonary Infection in Immunocompromised Hosts

Table 127-2 Effects of Viral Infection in the Immunocompromised Host Direct causation of invasive viral infection Immunomodulatory effects Systemic immune suppression—opportunistic infection Allograft injury Cellular effects—up-regulation of surface antigens and graft rejection Oncogenesis and cellular proliferation Hepatitis B: hepatocellular carcinoma Epstein-Barr virus: B-cell lymphoproliferative disease (PTLD) Papillomavirus: squamous cell carcinoma, anogenital cancer HHV8 (KSHV): Kaposi’s sarcoma, effusion lymphoma Cytomegalovirus: accelerated atherogenesis, bronchiolitis obliterans

conditions. Local immune defects coupled to physical factors may predispose to life-threatening infection. Thus, corticosteroid eye drops used for inflammation due to prosthetic lens implants may lead to eye infections with Streptomyces, Bartonella, Sporothrix, and Fusarium species. Salmonella infection in the organ transplant recipient “homes” to vascular anastomoses and may persist despite appropriate therapy, causing mycotic aneurysms.

PROTECTING THE PATIENT FROM INFECTION Although the clinical care of the compromised host has improved, flaws in the armamentarium against infection have been highlighted by the emergence of bacteria and fungi that are resistant to common antimicrobial agents. For example, increasingly Streptococcus pneumoniae and Neisseria gonorrhoeae are detected that are resistant to penicillin, fluoroquinolones, and macrolides; enterococci are resistant to β-lactam antimicrobials, macrolides, vancomycin, teicoplanin, linezolid, quinupristin-dalfopristin, and aminoglycosides; Pseudomonas and enteric gram-negative bacteria are resistant to broad-spectrum β-lactam agents; and azoleresistant yeasts, all of which are routinely isolated both in the community and hospitalized patients. Moreover, decreases in the acquisition of infection by compromised hosts can only be accomplished by complete reverse precautions that entail the use of laminar airflow rooms and access to the patient only via glove-ports or the use of gowns, gloves, masks,

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caps, and shoe covers. This practice reduces the incidence of hospital-acquired infection (as distinguished from spread of endogenous infection) by up to 50 percent, to the approximate rate of such infections in granulocytopenic patients.

However, the practice of complete reverse precautions is very costly and reduces patient contact by health care providers. Consequently, protection against both acquired and endogenous infections has fallen onto the broad use of prophylactic antimicrobials. Such oral agents as trimethoprim-sulfamethoxazole, quinolones, acyclovir (and related agents), and azole antifungal drugs now have widespread use in the management of both inpatients and outpatients. Oral decontamination regimens (i.e., nonabsorbable antimicrobials) have not been proved to prevent disease beyond limited periods of time, and are poorly tolerated because of taste, consistency, malabsorption of glucose and xylose bases, and cost. Moreover, the use of such prophylactic agents contributes to the emergence of antimicrobialresistant organisms.

RECOGNITION OF NEW SYNDROMES The identification of new infectious disease syndromes has often occurred in individuals with immune deficits. Thus, the cluster of cases of Pneumocystis carinii pneumonia in homosexual males was the first indicator of a new viral pathogen (HIV-1), and the role of Cryptosporidium as a common cause of diarrhea in both normal and compromised individuals was elucidated as a result of diarrheal disease in AIDS patients in the 1980s. Similarly, many uncommon bacteria (Bartonella species, Rhodococcus equi), viruses (Kaposiâ&#x20AC;&#x2122;s-associated human herpesvirus 8, polyoma viruses), fungi (Penicillium), and parasites (Microsporidia) have been identified in immunocompromised patients. Thus, a continuing lookout for new pathogens or novel presentations of known pathogens is essential for the care of the immunocompromised patient. Often, infection in immunocompromised hosts presents without the expected signs and symptoms of infection. This lack of clinical manifestations may delay identification of the critically ill patient. In the outpatient setting, the practitioner must have a low threshold for performing tests (e.g., blood counts, cultures, radiographs) on patients with minimal complaints.

CONCOMITANT PROCESSES Early and aggressive therapy of infection is required in the immunocompromised patient. Thus, most febrile or possibly infected patients are treated empirically while awaiting data that identify specific pathogens. The occurrence of multiple simultaneous infections or conditions often complicates and delays appropriate therapy (Fig. 127-3). For example, CMV infection may complicate the treatment of graft rejection or

Figure 127-3 Chest radiograph of a 48-year-old heterosexual man with community-acquired pneumonia unresponsive to therapy. The patient was diagnosed as having AIDS on the basis of HIV seropositivity, CD4 lymphocyte count of 113 per milliliter, and Pneumocystis carinii and Mycobacterium avium-intracellulare complex pneumonia.

graft-vs-host disease and contribute to the pathogenesis of Pneumocystis or Toxoplasma pneumonia.

The radiologic appearance of pneumonia is altered by immune suppression (Fig. 127-4) (see also Chapter 114). Radiographic patterns may change during the care of the patient (e.g., cavitation of pulmonary nodules after the resolution of neutropenia). Noninfectious causes of pulmonary infiltrates may coexist with infection, and atypical patterns predominate. Drug toxicities (bleomycin, Cytoxan, sulfa drugs), leukoagglutinin reactions, radiation injury, pulmonary emboli, and lesions of metastatic cancer may coexist with opportunistic infection (Fig. 127-5). The typical evolution of pulmonary infection may be altered by the presence of underlying (e.g., interstitial) pulmonary disease as well as by diminished inflammatory responses. It is commonly necessary to repeat tests, to utilize computed tomography (CT), or invasive diagnostic modalities (biopsy) in the evaluation of the patient who is unresponsive to therapy. In the compromised host with fever and pneumonitis, chest radiographs may be difficult to interpret.

Complications of therapy may contribute to the development of new infections: Trimethoprim-sulfamethoxazole can cause pneumonitis, hepatitis, or Stevens-Johnson syndrome; ganciclovir can cause neutropenia; transfusion reactions can cause pulmonary infiltrates and hemolysis; cyclosporine can cause hemolytic-uremic syndrome; antimicrobials can contribute to thrush and C. difficile colitis.

2209 Chapter 127

Pulmonary Infection in Immunocompromised Hosts

PATIENT MANAGEMENT

Figure 127-4 Chest radiograph of an AIDS patient with atypical cryptococcal pneumonia. Diffuse interstitial infiltrates may be observed in fungemic patients with primary or secondary pulmonary infection.

Figure 127-5 Chest radiograph of a 36-year-old homosexual man not known to be HIV-1 infected, with bilateral nodular infiltrates due to pulmonary Kaposiâ&#x20AC;&#x2122;s sarcoma.

Antimicrobials alone may not suffice in the treatment of infection in the immunocompromised host. Improvement in host responses is often needed to clear ongoing infection. Infections may respond to a decrease in exogenous immune suppression, correction of neutropenia by growth factors, or treatment of simultaneous infections that predispose to superinfection (e.g., respiratory syncytial virus, CMV).

Drainage of collections of infected fluid such as a hematoma or a lymphocele, or removal of drains or catheters enhances the treatment of infection. Identification of metastatic sites of infection (e.g., infections of the central nervous system due to Nocardia or Cryptococcus species) may facilitate management. Synergistic antimicrobial therapy must be used when available. Compromises often must be made. The loss of renal function due to antimicrobials used in the treatment of fungal infections significantly hinders patient management.

However, progression of a fungal infection while on inadequate doses of amphotericin must be avoided.

Infection must be prevented in the susceptible host, since antimicrobials are often ineffective during acute infection. Whenever possible, vaccines should be given before immune suppression or splenectomy. During immune suppression, only killed or conjugate vaccines should be used. Repletion of immunoglobulin deficiencies (after BMT or solid organ transplantation) and the use of specific hyperimmune globulins (i.e., for exposure to varicella or for CMV) may help to prevent infection. Similarly, in patients susceptible to infection, the use of antimicrobials to prevent common infections is cost effective. The use of preemptive therapies based on tests that demonstrate the presence of infection (e.g., the administration of ganciclovir in patients with evidence of CMV infection by antigenemia assays or polymerase chain reaction studies) allows the interruption of infection before disease becomes manifest clinically. Similarly, routine surveillance cultures have been useful to detect specific pathogens in subgroups of patients (e.g., neutropenic patients with Aspergillus colonization) or in specific geographic regions.

The clinical evaluation of the patient prior to immune suppression may be very helpful in preventing disease. Patients with cystic fibrosis or chronic bacterial sinusitis may become colonized in the airways or sinuses with Pseudomonas or Aspergilluss pecies. These colonizing organisms may reactivate during immune suppression. Careful evaluation by radiography and invasive cultures may prevent major infection. Similarly, patients who are not immune to varicella zoster may benefit from vaccination. Patients seronegative for Toxoplasma gondii or CMV are at high risk of reactivation in the presence of an organ transplant from a seropositive donor. Similarly, seropositive patients with AIDS or before seronegative bone marrow transplantation are at high risk for reactivation disease due to Leishmania, CMV, or Toxoplasma.

In endemic areas, transfusions and transplants may provide entry of T. gondii, Trypanosoma cruzi (Chagasâ&#x20AC;&#x2122; disease),

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Leishmania species, Acanthamoeba, Naegleria, Strongyloides stercoralis, Taenia species, or Echinococcus species with exacerbation of infection by immune suppression. A careful clinical history and pretreatment of known infections or specific antimicrobial prophylaxis may prevent such complications of immune deficiency. Serologic tests are often useful in the stratification of risk for infection in the immunocompromised host.

GENERAL CONSIDERATIONS IN SPECIAL HOSTS The spectrum of common infections varies with specific immune defects in each type of host (Table 127-3) and are considered subsequently.

HIV Infection and AIDS The management of HIV infection has been dramatically altered for those individuals with access to antiretroviral therapies and is covered in detail by Fangman and Sax in Chapter 128. Anti-HIV therapy should be started before the immune system is irrevocably compromised. Most practitioners are treating all individuals with progressive HIV infection, and all HIV-infected individuals with CD4 counts below 200/mm3 . HAART has resulted in the recrudescence of immunity as manifested by rising CD4+ lymphocyte counts and diminished signs of opportunistic infection and cancer associated with severe T-cell deficits. Treatment of HIV infection with highly active antiretroviral therapy (HAART) with reversal of immune deficiency appears to eliminate the risk of Pneumocystis pneumonia (studied up to 2 years) in AIDS patients with and without prior Pneumocystis pneumonia.

The risk of Mycobacterium avium complex, tuberculosis, and

Table 127-3 Infections Associated with Specific Immune Defects Defect

Common Causes

Associated Infections

Granulocytopenia

Leukemia, cytotoxic chemotherapy, AIDS, drug toxicity, Felty syndrome

Enteric gnr, Pseudomonas, S. aureus, S. epidermidis, streptococci, Aspergillus, Candida, and other fungi, S. aureus, Candida, streptococci

Neutrophil Chemotaxis

Diabetes, alcoholism, uremia, Hodgkinâ&#x20AC;&#x2122;s disease, trauma (burns) lazy leukocyte syndrome, CT disease

Neutrophil killing

CGD, myeloperoxidase deficiency

S. aureus, E. coli, Candida, Aspergllus, Torulopsis

T-cell defects

AIDS, congenital lymphoma, sarcoidosis, viral infection, CT ds, organ transplants, steroids

Intracellular bacteria (Legionella, Listeria, mycobacteria), HSV, VZV, CMV, EBV, parasites (Strongyloides, Toxoplasma), fungi (P. carinii, Candida, Cryptococcus)

B-cell defects

Congenital/acquired agammaglobulinemia, burns, enteropathies, splenic dysfunction, myeloma, ALL surgery, sickle-cell anemia, cirrhosis

S. pneumoniae, H. influenzae, Salmonella, and Campylobacter spp., Giardia lamblia

S. pneumoniae, H. Influenzae, Salmonella spp., Capnocytophaga.

Splenectomy

Complement

Congenital/acquired defects

S. aureus, Neisseria spp., H. influenzae, S. pneumoniae

Anatomic

IV/Foley catheters, incisions, anastamotic leaks, mucosal ulceration, vascular insufficiency

Colonizing organisms, resistant nosocomial organisms

2211 Chapter 127

cytomegalovirus (CMV), has also decreased. Thus, prophylactic (both primary and secondary) and therapeutic regimens must be considered in light of the individual’s immune status. Not all patients respond to HAART or maintain viral suppression during therapy. The specifics of antiviral therapy are not considered here.

One of the features of HAART is a syndrome of intensified inflammatory responses referred to as the immune reconstitution syndrome, which generally occurs within the first 3 months of starting effective antiretroviral therapy. This is thought to represent a hyperacute response to pathogens to which the HIV-infected individual has been exposed. It has been observed in P. carinii pneumonia, cytomegalovirus retinitis and vitreitis, disseminated Mycobacterium avium complex (MAC) as pneumonitis and lymphadenitis, cryptococcosis with meningitis and necrotizing lymphadenitis, and with acceleration of hepatitis C virus infection, including cryoglobulinemia and renal failure. Thus, effective antiviral therapy may result in more intense symptoms and unusual manifestations of some opportunistic infections while the overall incidence of new infections has declined.

HIV testing should be considered for all persons either in high-risk groups or with unusual infections. Highrisk groups include intravenous drug users, sexually active homosexual or bisexual men, hemophiliacs or individuals requiring blood or clotting factors, persons with sexually transmitted diseases (especially syphilis), pregnant women, health care workers with exposure to body fluids or needle stick injury, and all patients with conditions commonly associated with AIDS (Table 127-4). Testing for HIV infection is generally divided into viral culture assays (uncommon now that molecular resistance tests are available), antibody tests, and specific, quantitative (molecular) viral tests, including molecular antiviral susceptibility testing. Most patients produce antibodies to HIV within 6 to 8 weeks, and almost 100 percent have detectable antibodies by 6 months after exposure. These tests are well standardized and easy to perform, but are troubled by false-positives (cross-reacting antibodies) and falsenegatives (e.g., in the early period). Between 4 and 20 percent of Western blot tests are indeterminate because of seroconversion in progress, loss of antibody in advanced HIV disease, cross-reacting antibodies in pregnancy, blood transfusions, autoantibodies from collagen vascular disease, infection with HIV-2, recent influenza vaccination, or trial HIV vaccines.

These subjects should be retested and inconclusive assays resolved with specific viral (molecular, p24 antigen, or culture) testing. Specific viral tests include the p24 antigen detection, molecular amplification by PCR, and culture-based assays.

These are positive earlier than the antibody tests and therefore may be useful in primary infection before the development of antibody; they have high sensitivity (95–99 percent) and are often useful when the Western blot is indeterminate. Quantitative techniques are very useful in assessing the response to antiviral therapy and disease progression.

Measures of HIV viral RNA in plasma may not correlate with the CD4 lymphocyte count. The CD4 count provides a surrogate marker for the response to antiviral therapy and

Pulmonary Infection in Immunocompromised Hosts

Table 127-4 When to Suspect HIV Infection and AIDS History High-risk behaviors or exposures Unsafe or promiscuous sex Sex with prostitutes Sex with person at risk for HIV Injection drug use Blood or blood product transfusion between 1975 and 1985 (especially in high-prevalence areas) Blood clotting concentrate transfusion before January 1985 Sexually transmitted disease Tuberculosis, especially extrapulmonary Racial and ethnic minority populations in highprevalence areas of HIV disease Homeless persons in high-prevalence areas of HIV disease Individuals from high-prevalence areas for heterosexual transmission Symptoms and signs Acute retroviral syndrome Unexplained constitutional symptoms Fatigue, malaise, fever, diarrhea, night sweats, anorexia, weight loss Lymphatic Persistent generalized lymphadenopathy Dermatologic manifestations Infectious Severe herpes simplex (oral, anogenital), oral or genital candidiasis, staphylococcal skin infections, herpes zoster (especially recurrent), superficial dermatophytoses (tinea nail infection), molluscum contagiosum, warts, condyloma acuminata, oral hairy leukoplakia (EBV), necrotizing gingivitis or periodontitis Kaposi’s sarcoma, petechiae (ITP), seborrheic dermatitis, psoriasis (new or worsening), eosinophilic folliculitis, severe drug eruptions, aphthous ulcers, intraepithelial neoplasia Neurologic conditions Cranial neuropathy, Guilian-Barr´e syndrome, aspectic meningitis, peripheral neuropathy, myopathy, cognitive impairment Laboratory findings Unexplained anemia, leukopenia, lymphocytopenia, atypical lymphocytosis, thrombocytopenia CD4 lymphocytopenia Polyclonal hyperglobulinemia Elevated blood urea nitrogen or serum creatinine, proteinuria, hypoalbuminemia Elevated lactate dehydrogenase Hypocholesterolemia and hypertriglyceridemia

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the risk of infection and death. At present, the best predictive value of testing is the combination of viral load with CD4 lymphocyte enumeration. Viral RNA levels in long-term nonprogressors are consistently under 10,000 copies per milliliter, whereas progression and immunologic deterioration are often associated with loads over 50,000 to 100,000 copies. Patients with viral loads of 10,000 to 50,000 are considered at intermediate risk. Viral load changes generally precede CD4 count changes. Immune alterations due to infection (e.g., cytomegalovirus) or immune modulation therapy (interferons) are not yet interpretable.

Immunization is a part of the routine management of AIDS. In general, HIV-infected persons are susceptible to the same community-acquired respiratory pathogens (with additions) as the normal host but with a greater severity of disease. Thus, patients should be vaccinated early in the course of disease when they are clinically stable. Live vaccines are generally contraindicated, but measles vaccine is generally well tolerated in children, and MMR is recommended for unvaccinated adults born after 1957 or vaccinated between 1963 and 1967. The efficacy of vaccination in this population is not clear; HIV viral loads may temporarily increase after vaccination. However, general practice suggests that pneumococcal, influenza (inactivated whole virus and split virus vaccines), Haemophilus influenzae, hepatitis B recombinant vaccine, and MMR be given as indicated.

Underlying lung disease is common in HIV-infected patients even before the development of opportunistic infection.

Although FEV1 and FVC are nearly normal, 11 to 13 percent of patients with CD4 lymphocyte counts below 200 per mm3 or with a history of AIDS-associated extrapulmonary diseases (including thrush and varicella zoster infections) and weight loss have decreased DlCO measurements. Intravenous drug users have a higher incidence of abnormal FVC, FEV1 , and DlCO measurements (33.3 percent), consistent with patterns of cigarette smoking and racial distribution. Thus, susceptibility to pulmonary infection is further exacerbated in this population and the importance of vaccination increased.

Opportunistic Infections in AIDS The problem of opportunistic infection in the untreated or newly diagnosed AIDS patient is unique because of the progressive decline in immune function when compared with the intermittent compromise seen after chemotherapy or the relatively stable immunosuppression used after solid organ transplantation. This progression appears to have been reversed by HAART, but such therapies are far from universally available. Specific opportunistic infections depend on the nature and duration of immune suppression as well as on the infectious exposures of the patient (Table 127-5). As a result of the progressive and cumulative risks, the incidence of opportunistic infections increases over time. A time line exists for the common infections and noninfectious manifestations seen in progressive AIDS, relating to the total CD4 lymphocyte count as a measure of susceptibility (Fig. 127-1). In an individual, the time line is also related to the patient’s viral load, but an exact correlation does not exist. The specific

Table 127-5 Infectious Agents Commonly Associated with AIDS Viral (with HIV-1, HIV-2) Cytomegalovirus Herpes simplex Varicella zoster Epstein-Barr virus Parvovirus B19 HHV-6, HHV-8 HTLV-1, HTLV-2 Protozoan Toxoplasma gondii Cryptosporidium Isospora belli Microsporidium Cyclospora Fungal Candida spp.

Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatidis Aspergillus spp.

Petriellidium boydii Coccidioides immitis Penicillium spp.

Pneumocystis carinii Sporothrix schenckii Bacterial Mycobacterium avium-intracellulare complex M. tuberculosis Legionella spp.

Nocardia asteroides Encapsulated gram-positive bacteria Salmonella spp.

Rhodococcus equi Bartonella spp.

Campylobacter spp.

pattern of opportunistic syndromes changes for individual patients, but it reflects the overall progressive immunological deterioration of untreated AIDS. Many opportunistic pulmonary infections in AIDS patients were initially assumed to be reactivation of latent infection. However, some of these processes—including P. carinii, T. gondii, tuberculosis, and histoplasmosis—represent a mix of both new exposures and old disease. Similar observations have been made in terms of the drug susceptibility of mycobacterial isolates in recurrent disease (Fig. 127-6). The clinical manifestations of opportunistic infections in AIDS are

2213 Chapter 127

A

Pulmonary Infection in Immunocompromised Hosts

B

Figure 127-6 Chest radiographs of a 39-year-old man with AIDS on zidovudine, ritonavir, and trimethoprimsulfamethoxazole prophylaxis, and with a CD4 lymphocyte count of 89/ml. The patient presented to the outpatient clinic with low-grade fever, fatigue, and mild cough. A. Physical examination and chest radiograph were unremarkable. The patient was anergic on both PPD and control skin testing. Induced sputum examination was negative for bacteria, for P. carinii, and by mycobacterial stains. Blood cultures for mycobacteria were obtained. B. Ten days after initial presentation, the patient was admitted to the hospital with minimal dyspnea and cough; chest radiograph was remarkable for bilateral pulmonary reticulonodular infiltrates. Bronchoalveolar lavage samples were positive for mycobacteria. The organisms were subsequently identified from cultures of both blood and sputum as M. tuberculosis, resistant to both isoniazid and ethambutol. Induced sputum sample cultures remained negative for mycobacteria.

altered by prophylactic and therapeutic regimens, adverse drug reactions, and drug interactions. Toxicities of both prophylactic and therapeutic drug regimens (particularly rash, marrow suppression, and hepatic toxicities) are much more frequent in HIV-infected patients and are exacerbated by the simultaneous need for antiviral therapies.

Continued primary prophylaxis in AIDS patients who maintain CD4 lymphocyte counts above 200/mm3 for over 3 to 6 months and with low or undetectable viral loads appears to be unnecessary, at least for P. carinii and mycobacterial infections. For other infections and secondary prophylaxis, the data are less clear. Up to 15 to 20 percent of AIDS patients have more than one opportunistic infection at one time. The spectrum of clinical diagnoses in pulmonary disease in AIDS includes bacterial infection (45.5 percent), P. carinii pneumonia (27 percent), Kaposiâ&#x20AC;&#x2122;s sarcoma (7 percent), bronchitis (5 percent), M. tuberculosis (4.3 percent), other mycobacteria (4 percent), lymphoma (2.1 percent), and a variety of other processes. Common community-acquired upper respiratory infections, manageable on an ambulatory basis, constitute more than 50 percent of respiratory illnesses

in HIV-infected persons. The incidence of fungal infections varies by geographic region, whereas the rate of demonstration of viral pulmonary infection is closely related to the diagnostic testing techniques used at each center and seasonal variation.

Approaches to the Diagnosis of Opportunistic Pulmonary Infections in AIDS With the wide array of potential pathogens causing disease in HIV-infected patients, the frequency of atypical and multiple infections, and the urgency to diagnosis of infection in the immunocompromised host, a systematic approach to lung disease in these hosts is imperative. A few general rules are useful.

1. Prophylaxis is generally effective. When failure of prophylaxis occurs, it is usually due to noncompliance, malabsorption of drugs, emerging antimicrobial resistance, or coinfection or tumor that alters the local environment. For example, it is often impossible to eradicate Candida esophagitis unless erosive

2214 Part XVI

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esophageal herpes simplex virus infection is also treated. Pneumocystis is difficult to treat in the presence of CMV infection or bronchial obstruction.

2. Specific therapies for individual infections have a high incidence of adverse reactions in the HIV-infected patient. Thus, presumptive or empiric therapy without microbiologic confirmation, although often appropriate, has a greater risk in this population than the normal host.

3. The utilization of newer diagnostic tests has improved the care of AIDS patients. The interpretation of some tests is unclear, and the availability of some tests (urinary Histoplasma antigen or immunoperoxidase stains for T. gondii) is not universal. The induced sputum examination has been very useful in the early, noninvasive diagnosis of Pneumocystis infection, and for mycobacterial disease in the absence of spontaneous sputum production. The sensitivity of sputum induction for Pneumocystis infection approaches 90 percent, but the negative predictive value of the test is only 50 percent. The cost and sensitivity of this procedure cannot be justified for the routine diagnosis of bacterial infections, particularly in persons capable of producing sputum samples. The use of more invasive tests, such as bronchoscopy, with the obvious limitations of cost and risk to the patient, has the advantage of providing subglottic specimens and the potential for diagnosis of a broader range of pathogens. The interpretation of positive cultures for CMV or MAC may

be uncertain without tissue histopathology for confirmation. In patients with a rapidly deteriorating clinical condition or a failure to respond to initial therapy, bronchoscopy with biopsy or needle aspiration may be preferable to bronchoalveolar lavage or sputum induction as an initial procedure. In general, noninvasive, nuclear isotope–based radiologic tests are rarely useful in the diagnostic evaluation of pulmonary disease in AIDS patients.

4. The rate of progression of infection is often a clue to the type of disease. Thus, community-acquired pneumonia develops rapidly (2–5 days), whereas the initial episode of P. carinii pneumonia generally evolves more slowly (over 7–12 days) in AIDS (as compared with other compromised hosts). Fungal infection and mycobacterial infection are generally preceded by systemic complaints. Pyogenic pulmonary infection is generally associated with sputum production, whereas the “atypical” infections may have little or no sputum despite cough and dyspnea.

5. The radiographic pattern is often suggestive of the diagnosis (Table 127-6). All “typical” patterns are altered by progressive immune deficits and coexisting or prior lung disease. Diffuse infiltrates (alveolar or interstitial) may be seen with a homogeneous distribution, as in P. carinii, T. gondii, CMV, mycobacterial species, Histoplasma, or Coccidioides.

Drug toxicity may also cause pulmonary infiltrates.

Inhomogeneity with these pathogens reflects altered pulmonary parenchyma from previous disease,

Table 127-6 Roentgenographic Findings in Opportunistic Pulmonary Diseases in AIDS Diffuse Infiltrates

Cavitary Lesions

Hilar Adenopathy

Focal Infiltrates

Nodular Lesions

Pleural Effusions

Pneumocystis carinii

Tuberculosis

Tuberculosis

Legionella sp.

C. neoformans

Tuberculosis

Tuberculosis

Pyogenic bacteria

Lymphoma

Tuberculosis

H. capsulatum

Fungal

Toxoplasma gondii

Aspergillosis

Kaposi’s sarcoma

P. carinii

Tuberculosis

Pyogenic

Histoplasma capsulatum

Cryptococcus neoformans

Cryptococcus neoformans

Streptococcus pneumoniae

P. carinii

Lymphoma, Kaposi’s sarcoma

P. carinii and other agents

P. carinii Rhodococcus equi

HIV acute

Kaposi’s sarcoma

Lymphoma

sarcoma

Lymphocytic interstitial pneumonitis

Septic emboli (addicts)

EBV acute

Nocardia asteroides C. neoformans

Septic emboli

2215 Chapter 127

obstruction (e.g., with tumor, Strongyloides stercoralis), or upper-zone disease or pneumothorax in Pneumocystis pneumonia. Tumors may appear with interstitial radiographic patterns in HIV disease.

Lymphoid interstitial pneumonitis is an interstitial process of unknown origin that is seen in AIDS patients. Diffuse interstitial infiltrates are often due to P. carinii, but not in patients receiving TMPSMX prophylaxis and rarely without hypoxemia.

Thus, the presence of a sepsis-like picture with a diffuse interstitial infiltrate in a patient receiving antiPneumocystis prophylaxis might suggest mycobacterial disease, Legionella infection, or C. neoformans.

Focal airspace disease is most often seen with bacterial infections (pyogenic, mycobacteria, Legionella species), Mycoplasma pneumoniae (viral influenza, adenovirus, CMV), and mixed infections (e.g., CMV and P. carinii). Occasionally, primary cryptococcal pneumonia, Aspergillus infection, or obstructive disease presents with focal infiltrates. Each of these processes may evolve to frank cavitation, particularly infections due to pyogenic bacteria (Staphylococcus, Klebsiella, S. pneumoniae) or M. tuberculosis.

Small cavities are seen with P. carinii, mycobacteria, and metastatic tumors. Large cavities are uncommon: M. tuberculosis or aspergilloma is most often present. Nodular lesions can be seen with any of the metastatic tumors or hematogenous infections. Endocarditis, KS, toxoplasmosis, tuberculosis, MAC, and Cryptococcus may all progress from nodules to small cavities. In particular, unusual bacterial pathogens (Bartonella, Rhodococcus, Candida, and Salmonella) have been observed as pulmonary nodules associated with right-sided endocarditis in AIDS patients. Intrathoracic adenopathy is common in AIDS patients, most often with infections earlier in the course of disease (CD4 count greater than 400/ml) and with tumors late in disease. Fungal infections (Cryptococcus, Histoplasma, and Coccidioides), CMV, and mycobacterial infections may also cause adenopathy. Adenopathy should prompt invasive diagnosis in the absence of a clear etiology in AIDS. Pleural effusions are common with tuberculosis, other pyogenic bacterial infections, and tumors.

6. The CD4 lymphocyte count is a good indicator of susceptibility to specific infections, while the viral load is most closely associated with overall disease prognosis. Unresolving community-acquired pneumonia due to S. pneumoniae, H. influenzae, Mycoplasma, or Legionella species may be the sentinel infection of HIV disease. As host immunity declines, other opportunistic infections occur. M. tuberculosis, an organism of high virulence, causes infections at any CD4 lymphocyte count but occurs increasingly as the CD4 lymphocyte count falls below 500/ml (Fig. 127-6). In contrast, less virulent organisms cause dis-

Pulmonary Infection in Immunocompromised Hosts

ease only with greater degrees of immune compromise.

7. Chronic or recurrent sinus infection may provide a source of Pseudomonas or Aspergillus for pulmonary infection.

8. The spectrum of pulmonary disease varies by geographic region and by HIV transmission category.

9. Physical findings are often useful in establishing a differential for pulmonary disease in contrast, often, with other types of immunocompromised hosts.

Infection in Cancer Patients Immune Defects Due to Tumors and Chemotherapy The incidence of infection in cancer patients is determined in part by the nature of the underlying neoplasm. Studies of infection in cancer have focused on patients with leukemia and lymphoma, due to severe and predictable immune deficiencies. In a series by Bodey and colleagues, fatal infections in acute leukemics were caused by bacteria in 66 percent, fungi in 33 percent, viruses in 0.2 percent, and protozoa (including P. carinii, now considered a fungus) in 0.1 percent (Fig. 127-7). In contrast, fatal infection in lymphoma patients (86 percent) and solid-tumor patients (94 percent) were more often bacterial. In studies of cryptococcal infection in cancer patients, the rate of cryptococcal infection in chronic lymphocytic leukemia was more than double that in Hodgkinâ&#x20AC;&#x2122;s disease (24.3 versus 10.9 per thousand), and the rate in breast cancer was only 0.159 per thousand. Other tumors are also associated with specific infections. For example, lung cancer is associated with tuberculosis at a rate of 92 per 1000,

Figure 127-7 Lung abscess (arrow) in a febrile patient following intensive chemotherapy for relapsed acute myelogenous leukemia. Patient developed fever while granulocytopenic (less than 50 neutrophils/mm3 for 8 days) without localizing symptoms and a clear chest radiograph. When the neutrophil count exceeded 200/mm3 , a lung abscess was detected in the left upper lobe. Aspergillus fumigatus was detected in fluid obtained from the abscess via CT-guided percutaneous needle aspiration. The infection responded well to amphotericin B treatment.

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second only to the rate in patients with Hodgkinâ&#x20AC;&#x2122;s disease (96 per 1000) due to cellular immune deficits. Without therapy, the degree of depression in cellular immunity (delayed-type hypersensitivity) is more prominent in lymphoma, whereas humoral immunity is impaired to a greater degree in diseases affecting B-lymphocyte function, such as multiple myeloma and chronic lymphocytic lymphoma. Thus, the lymphoma patient is particularly susceptible to intracellular organisms, including Listeria monocytogenes, Mycobacterium tuberculosis, viruses, and fungi, whereas the myeloma patient is more apt to develop pneumonia or bacteremia due to Haemophilus influenzae, Streptococcus pneumoniae, and a variety of other acute bacterial infections. Acute leukemia is associated with a depression in the number and function of circulating granulocytes and is associated with severe pyogenic bacterial infections. Patients with acute and relapsed leukemia have demonstrated impaired phagocytosis and killing of fungi and bacteria by these cells, which may appear morphologically normal. These defects may persist well into periods of remission and may progress along with progression of the underlying disease.

The impact of the various forms of chemotherapy on host defenses must be added to those caused by the underlying malignancy. Multiple immune functions are impaired by chemotherapy, including the phagocytosis and killing of bacteria by neutrophils (corticosteroids, carmustine, radiation); antibody production (methotrexate, cyclophosphamide, L-asparaginase, 6-mercaptopurine); uptake and processing of antigen by macrophages (corticosteroids, cyclophosphamide, dactinomycin); recognition of antigens by T and B lymphocytes (corticosteroids, cyclophosphamide); and antigen-driven lymphocyte proliferation (methotrexate, 5-fluorouracil, fludarabine, cytarabine, L-asparaginase, dactinomycin, 6-mercaptopurine, hydroxyurea). Predisposition to infection induced by chemotherapy may mask more subtle defects due to underlying disease; e.g., the effects of granulocytopenia due to intensive chemotherapy generally predominate over the effects of underlying lymphoma or myeloma.

Neutropenia The most common predisposing condition for infection in the cancer patient is granulocytopenia; it is often due to chemotherapy and occurs while awaiting engraftment of hematopoietic transplants. The function of inflammatory cells and other immune (e.g., mucosal) barriers is also of great importance and are much more difficult to assess. The risk of infection increases as granulocyte counts decrease. Thus, the risk of infection in the patient with neutropenia (under 1000 total granulocytes per mm3 ) increases when granulocyte numbers fall further, to below 500/mm3 ; the risk is greatest when counts are lower than 100/mm3 . The many causes of neutropenia differ qualitatively (Table 127-7). They include iatrogenic neutropenias (chemotherapy, drug toxicities), aplastic anemia and other immune neutropenias, the hereditary and acquired cyclic neutropenias, and malignancy-

Table 127-7 Causes of Neutropenia Iatrogenic Cancer chemotherapy Drug toxities (TMP-SMX, chloramphenicol, gancicolovir, AZT) Infection Viral (cytomegalovirus, HIV, Epstein-Barr virus, hepatitis B) Parasitic (Leishmania) Bacteria (Clostridium) Acute neutropenia of sepsis/endotoxemia (gram-negative sepsis) Bone marrow failure of neonatal sepsis Immune Drug-induced autoimmunity (haptenic: penicillins, sulfa drugs) Aplastic anemia (includes idiosyncratic reactions: phenothiazines, chloramohenicol) Alloimmune neonatal neutropenia (maternal-fetal incompatibility) Congenital autoimmune neutropenia Primary autoimmune (systemic lupus erythematosus, Feltyâ&#x20AC;&#x2122;s syndrome, rheumatoid arthritis) Transfusion induced Antineutrophil antibody mediated Cyclic neutropenia (CD57 lymphocyte expansion) Hereditary Infantile genetic agranulocytosis Familial neutropenia Cyclic neutropenia (autosomal dominant) Old age

associated (especially acute leukemias) and infection-induced neutropenias. The rate of decline in white blood cell numbers and the duration of neutropenia influence the risk of infection. Thus, the patient with acute leukemia and rapidly falling neutrophil counts is at greater risk than the person in whom counts are falling slowly or are stable.

The Microbiology of Infection in Neutropenia and Cancer Pulmonary infections in patients with functional or quantitative defects in neutrophils can reach the lungs via inhalation, microaspiration of colonizing organisms, and bacteremia after non-respiratory penetration and bacteremia (e.g., from vascular catheters or disrupted mucosal surfaces).

Decisions about the management of these patients are often made empirically because of the urgency of therapy in

2217 Chapter 127

the immunocompromised host. Distinctions between pulmonary and extrapulmonary infections often become blurred in the attempt to treat most of the likely pathogens in a febrile neutropenic cancer patient. Often a specific, unsuspected pulmonary pathogen is detected on routine blood or urine culture or from a biopsy of an extrapulmonary infected site.

Common infections in the neutropenic host and cancer patient are most often the result of colonization with, and infection by, pyogenic bacteria, including S. pneumoniae, Staphylococcus aureus, the Enterobacteriaceae, Pseudomonas aeruginosa, H. influenzae, and Stenotrophomonas (formerly Xanthomonas) maltophilia. Common fungal pathogens include Candida albicans, Aspergillus species, C. krusei, C. glabrata, Mucor, Absidia, and Rhizopus species. The emergence of bacteria and fungi with antimicrobial resistance takes on special importance in the neutropenic host because therapy is generally empiric and is started before microbiologic data become available. The common “resistant” organisms include vancomycin-resistant Enterococcus faecium and faecalis (now also resistant to linezolid, quinupristin-dalfopristin), methicillin-resistant S. aureus, inducible chromosomal and acquired plasmids encoding β-lactamase in gram-negative bacteria, and azole (i.e., fluconazole) resistance to C. krusei and C. glabrata. In individual patients, the spectrum of colonizing organisms also changes over time, especially with antimicrobial use (and abuse). Seeding from blood-borne infection (e.g., due to vascular access catheters or localized infection) occurs most often with the organisms described in the preceding; other organisms are Candida and Aspergillus and, occasionally, mycobacteria. Patients with solid lung tumors may develop obstructive pneumonia or pulmonary hemorrhage, followed by superinfection with the flora of the upper respiratory tract and oropharynx (Fig. 127-8).

Fungi and Less Common Pathogens Combined cellular and granulocytic deficiencies are often present after chemotherapy. As a result, in addition to the common pathogens described above, pathogens normally controlled by cellular immune mechanisms (especially intracellular pathogens) can be detected; among these are M. tuberculosis, Brucella species, the geographic fungi, Cryptococcus neoformans, Strongyloides stercoralis, Salmonella, and Pneumocystis carinii. Unusual pathogens have been identified in increasing numbers of cancer patients with neutropenia. The classic presentations of pneumonia, inflammation and perforation of the cecum (often with Pseudomonas and anaerobes), and “typhlitis” (often Clostridium septicum) may be the first signs of life-threatening infection in a neutropenic patient. Atypical presentations of infection may be from a portal of entry other than the gastrointestinal tract or the lungs. Thus, the first clinical signs of infection may be “spontaneous” or line-associated bacteremia (Staphylococcus, enterococci, gram-negative rods, Bacillus, C. jeikeium, Candida species, Fusarium), skin lesions (gram-negative sepsis, Candida species, Nocardia asteroides, C. neoformans, herpes simplex or varicella zoster), gingivitis (anaerobes), hepatic dys-

Pulmonary Infection in Immunocompromised Hosts

Figure 127-8 Postobstructive pneumonia and lung abscess (arrow) in a 45-year-old man with adenocarcinoma of the lung in the right hilum. The abscess was drained via a bronchoscopic approach. Cultures of the abscess fluid grew common oral bacterial flora, including Prevotella melaninogenica and Bacteroides species.

function (hepatosplenic candidiasis), or seizures (Nocardia or Aspergillus species in brain abscess associated with a slowly progressive pneumonia) (Fig. 127-9).

Because of the widespread use of antibacterial agents, mucosal injury, use of intravenous catheters and bone marrow transplantation, fungal infections have occurred with increasing frequency, most often in acute leukemia patients and following stem cell transplantation and graft-vs-host disease (Table 127-8). C. glabrata and C. krusei that may carry resistance to fluconazole may develop during antimicrobial treatment. Although Mucoraceae (Rhizopus, Mucor, Absidia), like the Aspergillus species, may present with invasive disease of the sinuses and periorbital and frontal cortex in diabetics, they can also cause rapidly progressive hemorrhagic pneumonia with infarction and fungemia. Invasive disease of the sinuses and periorbital and frontal cortex is especially prevalent in neutropenic diabetics and in patients treated with deferoxamine, with prolonged corticosteroid therapy, or with broad-spectrum antimicrobials. The treatment of this invasive disease is surgical d´ebridement in addition to antifungal therapy. In patients with neutropenia or acute leukemia, a group of “benign” dermatophytes—including Trichosporon beigelii, Aureobasidium, Alternaria, Curvularia, Phialophora, Wangiella, and Cladosporium—have been associated both with disease of the skin and with invasive infection of the lungs, the sinuses, and the central nervous system. Occasionally infections are caused by “atypical fungi” (e.g., Saccharomyces cerevisiae, Pseudallescheria boydii, Cunninghamella bertholletiae, Drechslera, Fusarium species, Geotrichum candidum, and Penicillium species). Fusarium causes infection of

2218 Part XVI

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A

B

Figure 127-9 Multiple simultaneous infections in a 46-year-old man with Wegenerâ&#x20AC;&#x2122;s granulomatosis treated with cyclophosphamide and prednisone. The patient developed progressive pneumonia and neutropenia. Sputum cultures were unrevealing. A. Bronchoalveolar lavage revealed Nocardia asteroides (curved arrow) there was no clinical response to trimethoprim-sulfamethoxazole therapy. Bronchoscopic biopsy of a small abscess in the upper lobe (small arrow) revealed Fusarium species. B. Magnetic resonance imaging (MRI) of the brain revealed numerous small abscesses (arrows) diffusely distributed throughout the brain. These were initially thought to be consistent with infection due to Toxoplasma gondii. Brain biopsy revealed Nocardia asteroides.

the bloodstream and lungs that is indistinguishable from that due to Aspergillus, but with greater tendency to cutaneous involvement. The cardinal sign of Pneumocystis pneumonia is the presence of arterial hypoxemia out of proportion to physical or radiologic signs.

Viral Infections Viral infection has become increasingly prevalent in cancer patients. This is a reflection of prolonged T-cell defects, use of depleting antilymphocyte antibodies, and improved molecular diagnostic assays. Herpes simplex virus (HSV) and varicella zoster virus (VZV) are frequently reactivated during periods of neutropenia or as a sign of the presence of new malignancies. Patients who are undergoing chemotherapy for Hodgkinâ&#x20AC;&#x2122;s disease or who have received bone marrow transplants are at greater risk than other immunocompromised hosts (35â&#x20AC;&#x201C;50 percent in the first year). Specific antiviral prophylaxis is effective in reducing the incidence and severity of these relapses. Most often, these viruses cause painful, but relatively benign, skin or mucosal (especially esophageal, gastrointestinal, and perianal) lesions. These lesions may progress in neutropenic patients and the skin rash may become more diffuse, with hemorrhagic or nonhemorrhagic lesions extending beyond dermatomal limits.

Systemic dissemination to visceral organs occurs in 10 per-

cent of patients with disseminated skin disease commonly involving the liver, lungs, brain, or gastrointestinal tract. Nasal, oropharyngeal, or esophageal HSV or VZV infections may spread directly to the lungs with the development of vesicular lesions in the trachea, or may cause viral pneumonitis in the parenchyma as a result of viremia secondary to cutaneous reactivation. Primary varicella pneumonia may accompany chickenpox in adults and in the compromised host.

Pulmonary invasion occurs within the first 7 days of illness, with mortality approaching 18 percent. Chest radiographs reveal nodular or interstitial infiltrates in up to 16 percent of adults with chickenpox, whereas only 10 to 25 of these have clinical symptoms. Pulmonary invasion by HSV and VZV in the neutropenic host should be considered a life-threatening emergency.

In hematopoietic stem cell and bone marrow transplantation (BMT) recipients, CMV pneumonitis occurs in the CMV-seropositive recipient of CMV-seronegative cells.

Because much of the lung injury is due to immune responses to CMV antigens, the full pneumonitis develops not during lymphopenia but, rather, with the engraftment of the marrow and with the re-emergence of immune function. Viral replication is not needed for CMV pneumonitis to occur. In the granulocytopenic host, pulmonary CMV infection may be fatal.

2219 Chapter 127

Table 127-8 Factors in the Development of Fungal Infections in Cancer Patients Age/performance status Prior chemotherapy or radiotherapy: dose and duration Steroids Purine analogues Prior infections (specific isolates) Recent antimicrobial use (resistance) Broad-spectrum antimicrobials Prophylactic agents Functional immune status (cell number, activity) Hematopoietic transplantationâ&#x20AC;&#x201C;related Delayed engraftment or function of marrow Graft-vs-host disease and treatment Degree of donor-recipient histocompatibility mismatch Insufficient dose of stem cells (CD34) Total T-cell number Integrity of mucosal barriers (catheters, gastrointestinal) Neutropenia (severity, duration > 2 weeks) Hospital environment Home environmentâ&#x20AC;&#x201D;hobbies, travel Nonhematopoietic organ failure (e.g., dialysis) Other simultaneous infections (e.g., cytomegalovirus)

Parasitic Infection The predominant parasitic infection enhanced by immune compromise is that due to S. stercoralis, a nematode that infects more than 100 million people worldwide, producing lifelong infection. Strongyloides is distinguished by its ability to complete the replicative cycle within the human host. Malnutrition is a major cofactor; neutropenia and corticosteroids are common coinducers of parasite replication. In the normal pattern of infection, the filariform larvae penetrate the skin, follow the veins to the lungs, and are then swallowed, entering the small intestine. The hyperinfection syndrome is the result of activation in the gastrointestinal tract by immune suppression, which causes penetration or transudation of worms across the wall, carrying gastrointestinal organisms with them. Peritonitis, bacteremia, and gram-negative, eosinophilic meningitis may result. Pneumonia may result from bacteremia or obstruction of small airways and pneu-

Pulmonary Infection in Immunocompromised Hosts

monitis; the pulmonary infection fails to resolve without therapy directed at eliminating the nematode.

In endemic regions, activation of Toxoplasma gondii, Chagasâ&#x20AC;&#x2122; disease (T. cruzi), pulmonary or disseminated microsporidiosis or cryptosporidiosis (rare), leishmaniasis, and acute infection with Acanthamoeba and Naegleria species (primary amebic meningoencephalitis) must be considered in the differential of systemic and pulmonary infections.

Splenectomized hosts are at special risk for intense infection due to babesiosis, malaria, and ehrlichiosis.

Clinical Approaches to Infection in the Cancer Patient Clinical Signs of Infection Clinical recognition of infection is often delayed in the neutropenic or cancer patient because the inflammatory response is diminished (decreased numbers or mobilization of granulocytes) and the usual signs of infection are absent. Thus, in neutropenic patients, pneumonia may not be associated with sputum production and radiologic changes. In the febrile neutropenic patient with leukemia, the source of obscure infection is often the perineal and perirectal areas; less common are infections of the urinary tract, skin (including venous lines and wounds), and the lungs. In nonhematopoietic cancer patients, however, pulmonary infections predominate. A site of origin for a febrile episode is undetermined in 20 to 50 percent of patients. Many sites of infection are detected only at autopsy, notably in patients with disseminated fungal or combined fungal and bacterial infections. Mortality in the febrile neutropenic population is 30 to 50 percent. Noninfectious causes of fever are common; among them are pulmonary thromboembolism, tumor, radiation pneumonitis, atelectasis with pulmonary edema, drug allergy or toxicity, and pulmonary hemorrhage. Often, the resolution of fever in response to a trial of antimicrobials is the only evidence of infection.

Initial Management of the Cancer Patient with Fever: Stratification of Risk Each patient presenting with signs of infection must be evaluated in terms of the perceived risks of infection and noninfectious causes of fever and for the presence of neutropenia or other immune dysfunctions. Attempts to manage patients with greater efficiency and to shorten hospital stays have led to the development of critical pathways, which include standard patterns of evaluation and treatment for many patients, including those with cancer. Such uniform approaches are useful in establishing a minimal standard of care, but they do not address concerns about the pitfalls of failing to individualize therapy.

The safe application of critical pathways for the outpatient management of neutropenic patients necessitates careful stratification of these compromised patients by experienced clinicians in terms of their risk for infectious complications.

Any sign of infection requires at least a brief hospitalization

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(1–3 days), with careful evaluation. However, many experienced oncologists now manage some febrile neutropenic patients as outpatients. Any febrile neutropenic patient—or patient in whom absolute neutrophil count (ANC) is expected to fall below 1000/mm3 —with localizing signs (headache, altered mental status, rash, dyspnea, chest pain, pain over an indwelling catheter site, pulmonary infiltrates) should be considered for emergency admission. In particular, patients with leukemia or lymphoma, uncontrolled metastatic cancer, recent need for antimicrobials, or ANC under 100 (or expected to fall below 100) are generally considered higherrisk patients and are best managed as inpatients until clinically stable. Patients with a history of frank rigors or hypotension merit admission. Any febrile cancer patient needs an assessment of vital signs, oxygen saturation, complete blood count with differential, electrolytes and blood urea nitrogen and creatinine (for obstruction by tumor or acute drug toxicity), blood cultures (at least one peripheral and one from any indwelling catheter), urine sediment examination and culture, sputum Gram’s-stain examination and culture, and chest radiograph. After a careful physical examination, the threshold for lumbar puncture and determination of serum or spinal cryptococcal antigen should be low. The patient’s history and medical record should be reviewed, with attention to current drugs, recent chemotherapy (especially corticosteroids), recent microbiologic data, and antimicrobial use, allergies, and exposures.

Empiric Use of Antimicrobials in Fever and Neutropenia After appropriate smears and cultures have been obtained, empiric antimicrobial therapy in the febrile neutropenic patient is essential. The specific antimicrobials selected for routine use in the febrile neutropenic patient remain controversial. Ultimately, this is because many combinations appear to work equally well, and there are few studies of various combinations in identical patient populations using the same entry and end point criteria. The antimicrobials selected must cover previously documented infections or surveillance culture data, physical findings, known hospital flora, and potential community exposures.

Initial therapy should assume that the organisms causing infection are likely to be resistant to current prophylactic or therapeutic antimicrobials. Many infections are loculated and require drainage (sinusitis, postobstructive pneumonitis) (Fig. 127-8). Patients thought to be at low risk for infection or other complications (nonleukemic, underlying cancer not progressing, no serious coexisting illness, no recent infections or courses of antimicrobials, expected ANC to remain above 100) may be considered for home management after 24 h (to await blood culture data), based on the clinical assessment.

In these patients, empiric antimicrobials might include ticarcillin (or ticarcillin-clavulanate, piperacillin with or without tazobactam, ceftriaxone) plus gentamicin (or tobramycin or amikacin). Monotherapy with cefepime, ceftazidime, or carbapenems has also been found to be effective in medical centers that do not have nosocomial flora resistant to these

agents. Optimal antimicrobial therapy should include synergistic therapy for Pseudomonas infection in medical centers in which this organism is prevalent or if the patient is profoundly neutropenic. The routine use of quinolones or aztreonam for initial therapy in high-risk patients has not been well studied and is not recommended, especially for patients receiving these agents for prophylaxis.

A decision regarding the use of coverage for gram-positive organisms, including MRSA or VRE (e.g., vancomycin) is made based on the possibility of catheter-associated infection and clinical judgment. Such patients might include those with skin wounds, decubitus ulcers, or indwelling vascular access catheters. Gram-positive bacterial infections generally progress more slowly than do gram-negative infections.

Therefore, the routine use of vancomycin in these patients does not appear to be justified, because of the increased risk of vancomycin-resistant enterococci. Routine surveillance for VRE may be of assistance in adjusting the regimen if fever persists.

If an abdominal or anaerobic bacterial source is suspected, clindamycin or metronidazole can be added. Anaerobic infections other than those due to Bacteroides fragilis are uncommon as a source of major morbidity in these patients. Restrictions on the use of clindamycin have been instituted at many centers because of outbreaks of C. difficile colitis. Topical oral antifungal therapy (clotrimazole, nystatin) is commonly administered with broad-spectrum parenteral antimicrobials. Antimicrobials may be adjusted on the basis of microbiologic data or if the patient is afebrile for 7 to 10 days with the ANC over 500 and increasing.

Fever and Pulmonary Infiltrates Pulmonary disease in the cancer patient is clinically challenging, owing to the large array of processes that may cause radiologic infiltrates (Table 127-9). Non-infectious causes of pulmonary infiltrates and fever (edema, cancer, radiation injury, drug toxicity, leukoagglutinin transfusion reaction, pulmonary embolus, hemorrhage, alveolar proteinosis) are common (up to 25 percent) and may closely mimic infection (discussed also in Approach to the Patient with Pulmonary Infections). Conversely, the absence of inflammatory cells or mobilization may mask signs of significant infection. In the patient undergoing chemotherapy or in the neutropenic host, cough, sputum, radiologic infiltrates or cavitation, and fever may all be absent. Infection may spread to the chest from contiguous structures (e.g., perforation of the esophagus due to Aspergillus) or may complicate anatomic changes (e.g., bronchial obstruction in lung cancer).

Radiologic Clues to Diagnosis A number of clues are available to assist in the differential diagnosis of pulmonary infiltrates in cancer patients. For example, the clinical and radiographic appearance and progression of disease may suggest a diagnosis based on the time course and nature of the infiltrate (Table 127-9 and Chapter 114). In general, acute processes include both bacterial infections and

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Pulmonary Infection in Immunocompromised Hosts

Table 127-9 Common Causes of Pneumonia in Cancer Patients Based on Radiographic Abnormalities and Disease Progression Common Cause by Rate of Disease Progressionâ&#x2C6;&#x2014; Abnormality on Chest Radiograph

Acute (<24 h)

Subacute-Chronic

Consolidation

Bacteria (include Legionella) pulmonary embolus, hemorrhage, pulmonary edema

Fungi, Nocardia, tuberculosis (drug, virus [RSV], P. carinii, radiation)

Interstitial infiltrate

Pulmonary edema (include drug) Leukoagglutinin reaction (bacterial)

Viral, Pneumocystis, radiation, drug (fungi, Nocardia, tuberculosis, tumor)

Nodular infiltrate

Bacteria, edema (CMV, VZV)

Tumor, fungal, Nocardia, TB Pneumocystis (CMV)

â&#x2C6;&#x2014; Common

causes (and less common in parentheses) in the absence of specific epidemiologic exposures or past history.

noninfectious injuries, such as pulmonary embolus or edema.

Subacute processes include P. carinii, viral, Mycoplasma, or Nocardia or Aspergillus infections. More chronic processes include drug-induced, radiation-induced, mycobacterial, nocardial, or malignant invasion of the lungs.

In particular, bronchial obstruction by tumor or enlarged lymph nodes may cause atelectasis or postobstructive pneumonia. The underlying process may be suggested by pneumonia that fails to respond to antimicrobial therapy or recurs in the same location after successful treatment. Tumor masses, especially those due to lymphoma, may cavitate, giving the appearance of a lung abscess. Finally, it is important to bear in mind that a chronic process may be superinfected by an acute bacterial, viral, or drug-induced lung injury.

The clinical assessment coupled with the radiologic pattern of lung disease is usually the basis for forming a differential diagnosis for the patient with fever and pneumonitis. Computed tomography (CT scans) has greatly improved differentiation of some processes. For example, in patients with simultaneous processes affecting the lung (e.g., aspiration and tumor), CT scans may disclose distinctive patterns of parenchymal involvement (consolidation and infiltrative lesions with associated adenopathy) better than do conventional chest radiographs. Subtle interstitial infiltrates (P. carinii) or nodules (Cryptococcus) are better detected by CT scans than by conventional radiographs.

Noninfectious Pneumonitis After a dose of radiation greater than 2000 rads, radiation injury is common. The injury may become evident either acutely or more than 6 months after the initial exposure.

The acute form of radiation pneumonitis may present as a bronchitis or esophagitis with dry cough, fever, fatigue, hypoxemia, and dyspnea that develop over 6 to 12 weeks.

The histologic picture reveals vascular damage, mononuclear

infiltrates, and edema. The severity of lung injury due to radiation appears to correlate with the rapidity of the withdrawal of steroid therapy, but it may also reflect the emergence of the underlying inflammatory response. Radiation fibrosis usually occurs in 6 to 9 months, and pulmonary function may take up to 2 years to plateau.

Acute, drug-induced lung disease may reflect hypersensitivity to chemotherapeutic agents or sulfonamide agents.

Methotrexate, bleomycin, and procarbazine can cause a syndrome of nonproductive cough, fever, dyspnea, and pleurisy with skin rash and blood eosinophilia. Chest radiographs demonstrate diffuse reticular infiltrates. Cytoxan may cause a syndrome of subacute pulmonary disease with interstitial inflammation and pulmonary fibrosis, with fever, dyspnea, fatigue, and cough. Drug toxicity for agents such as bleomycin, BCNU, and CCNU may be related to the cumulative dose (for bleomycin, over 450 mg) and patient age. Synergistic toxicity for the lung occurs between radiation and a variety of chemotherapeutic agents (e.g., bleomycin, mitomycin, and busulfan) and supplemental oxygen use. A variety of non-infectious processes may mimic infection. Alveolar proteinosis may be associated with hematologic malignancies or accompany infection due to Nocardia or, less often, Cryptococcus, Aspergillus, M. tuberculosis, and Histoplasma.

Pulmonary infarction may mimic infections by causing hemoptysis, leukocytosis, pleuritic chest pain, and segmental pleural-based infiltrates on the chest radiograph.

Approach to Antimicrobial Therapy in Patients on Empiric Therapy Empiric therapy must be individualized. In a patient receiving empiric therapy who becomes afebrile on antimicrobials by 72 h and with a neutrophil count above 500 per mm3 , the antimicrobials may be stopped after 7 days and the patient re-evaluated if no localizing source is found or untreated

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pathogens detected. Patients who are clinically well and who become afebrile with neutrophil counts of 100 to 500 per mm3 should be afebrile for 5 to 7 days before antimicrobials are stopped in order to re-evaluate sources of infection. If the patient is not clinically well (e.g., has mucositis, fewer than 100 neutrophils per mm3 , or unstable vital signs), the antimicrobials should be continued until the patient is stable and afebrile for 48 to 72 h.

Unless a specific source of infection is located and the pathogen(s) identified, patients with persistent fever and neutropenia should have antimicrobials broadened 48 to 72 h after the start of therapy. The options include: (1) addition of vancomycin (or other gram-positive agent if colonized with resistant organisms such as VRE); (2) addition of antianaerobic therapy for oral mucositis or gingivitis, abdominal pain, or perirectal tenderness; (3) expansion of gramnegative bacterial coverage (generally adding a second agent from a different class of antimicrobials); (4) consideration of antiviral therapy in patients with esophagitis or a history of HSV or VZV or at risk for CMV infection; and (5) addition of antifungal therapy. The toxicities of antifungal agents must be considered carefully in these patients, notably those with decreased renal function or systemic fungal infection.

The use of amphotericin B products (lipid-associated) or deoxycholate form must be in full dose and patient must be well hydrated with attention must be paid to magnesium and potassium maintenance. Slowly advancing doses of this drug have been advocated without supporting data and entail the disadvantage of delay in achieving adequate therapy.

Voriconazole (and other azoles) have significant interactions via the hepatic P450 metabolic system and the incipient has been associated with cardiac arrhythmias in renal dysfunction. The echinocandins have fewer drug interactions but are rarely the drug of choice for initial therapy of filamentous fungal infection. The Mucoraceae lack susceptibility to both voriconazole and echinocandins. Cryptococcus lacks susceptibility to echinocandins.

Special attention must be paid to any symptoms of pulmonary disease, the presence of new pulmonary infiltrates on chest radiographs, or the presence of sinus or CNS symptoms in patients with persistent fevers. New infiltrates should prompt examinations of sputum and procurement of specimens (open biopsy, thoracoscopic biopsy, or bronchoscopy, preferably with biopsies, or needle aspirates under tomographic guidance) for histologic and microbiologic evaluation.

BONE MARROW AND STEM CELL TRANSPLANTATION Temporal Sequence of Pulmonary Disease Syndromes The patterns of infection in hematopoietic transplantation have shifted due to earlier engraftment with hematopoietic stem cell transplantation (HSCT) compared with bone marrow transplantation (BMT) and the use of non-myeloablative

Table 127-10 Pulmonary Complications in BMT/HSCT Pulmonary edema syndromes (engraftment syndrome) Infectious pneumonia Bacterial Fungal Viral Protozoal Idiopathic pneumonia Oral mucositis Pulmonary veno-occlusive disease Bronchopneumonia Idiopathic pneumonia Viral pneumonia Airflow obstruction (obliterative bronchiolitis) Obstructive airflow among marrow recipients with chronic GVHD.

transplantation (Fig. 127-2). The impact is apparent in the shorter duration of neutropenia in the initial phase, earlier engraftment—but has not decreased the incidence of graftvs-host disease (GVHD) or the infections associated with immunosuppressive treatment of GVHD (Table 127-10). Specific pulmonary complications can be grouped according to the status of the individual patient: pre-engraftment neutropenia (1–4 weeks), engraftment (fever and cytokine release, renal dysfunction), early and late post-engraftment (up to approximately 26 weeks and 1 year), and late infections (based on the status of host immunity and epidemiology).

Although this division is clinically useful, overlap occurs in the timing of specific complications, and the categorization of pulmonary complications is often arbitrary, since the cause of many respiratory abnormalities is uncertain. Inadequate tools are available to accurately assess the individual’s immune function. T-cell depleted grafts and patients treated with Tcell depleting antibodies have less GVHD but more viral and fungal infections. Treatments including B-cell depletion have more bacterial infections due to encapsulated organisms. Prophylaxis served only to delay infection and to select resistant organisms unless immune function is restored. Killed organism vaccination is appropriate by one year post-transplant with use of live vaccines reserved until immune function has normalized, generally by two years post-transplantation.

In the early phase, neutropenia predominates with mucositis (and aspiration) being common, herpes simplex (in seropositive recipients), idiopathic pneumonia (respiratory viruses, cytomegalovirus [CMV], pulmonary edema), Aspergillus infection, and line-associated infections (Candida,

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Pulmonary Infection in Immunocompromised Hosts

Figure 127-10 Diagnostic approach to pulmonary infiltrates after hematopoietic stem cell transplantation. 1. Diuretics often indicated in the first 30 days after transplantation. 2. Choice of procedure often influenced by results of CT scan of thorax.

gram-positive and -negative bacteria). Viral pathogens predominate after engraftment but before T-cell function normalizesâ&#x20AC;&#x201D;CMV, varicella zoster virus (VZV), adenovirus (and other respiratory viruses), but also Pneumocystis carinii (jiroveci, PCP), Toxoplasma gondii and moulds (Figs.

127-10 and 127-11). Routine prophylaxis (trimethoprim-

A

sulfamethoxazole, antivirals) is generally effective in preventing such infections. Late and uncommon infections may occur at any time in the post-HSCT course notably in those with persistent immune deficits. Such individuals are at persistent risk for infections due to Legionella, Nocardia, Mycoplasma, Mycobacteria, Strongyloides stercoralis,

B

Figure 127-11 Adenovirus pneumonia during week after marrow engraftment following allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia. A. Routine chest radiograph reveals diffuse pneumonia while B. CT scan demonstrates bronchiolitis. The patient failed to respond to cidofovir therapy but cleared infection after infusion of autologous stem cells.

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Cryptosporidium species, Epstein-Barr virus (EBV, posttransplant lymphoproliferative disorder or PTLD), and in those with hypogammaglobulinemia, encapsulated organisms including Streptococcus pneumoniae, Neisseria meningitis, and Haemophilus influenzae.

The most important characteristic that separates patients receiving allografts from those receiving syngeneic or autologous marrow or stem cells is the occurrence of GVHD in the former group. Syngeneic and autograft recipients share early risk factors such as neutropenia with patients receiving allogeneic transplants, and are at risk of early pulmonary complications, such as bacterial or fungal pneumonia and non-infectious treatment-related pulmonary injury. Transplant recipients who have delayed engraftment or subsequent marrow failure are at continued risk of bacterial or fungal infection. Allogeneic marrow recipients with GVHD have continued abnormalities in immune function that increase the risk of opportunistic infections. Among patients with chronic GVHD, infection and pneumonia due to encapsulated organisms (e.g., Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus) appear related to deficiencies in specific antibody production, use of anti-CD20 antibodies, resistance to common antimicrobials used for prophylaxis, and possibly continued defects in macrophage and NK cell functions.

the time of presentation of pulmonary complications. Routine chest radiographs are obtained frequently during the first weeks of neutropenia and often provide the first indication of pulmonary impairment.

Diffuse Infiltrates Diffuse infiltrates are common radiographic abnormalities noted in marrow recipients. However, these infiltrates are most often nonspecific. Infectious causes for diffuse infiltrates have been documented in fewer than 20 percent of marrow recipients undergoing open lung biopsy within 30 days after marrow transplantation. Within this early period, pulmonary edema syndromes predominate. The edema may be associated with cardiac decompensation or intravascular volume excess, or with acute respiratory distress syndrome (ARDS) and pulmonary capillary leak due to treatment-related toxicities or sepsis syndrome. Infections presenting with diffuse infiltrates within the first weeks after transplantation include respiratory viral causes, such as respiratory syncytial virus, while cytomegalovirus is uncommon (Fig. 127-11). Alveolar hemorrhage may contribute to the radiographic infiltrates in the presence of thrombocytopenia, regardless of the cause of the lung injury.

After marrow engraftment, infections are a major reason for diffuse radiographic abnormalities. Cytomegalovirus was common in the past, but it is now unusual in patients receiving appropriate prophylaxis. Diffuse pneumonia due to bacterial infections (occasionally disseminated nontuberculous mycobacterial disease, Mycoplasma or Chlamydophila) also is unusual; however, diffuse involvement with fungus may occur in as many as 20 percent of diffuse infiltrates and may be extremely difficult to detect.

Common Clinical Presentations Signs and symptoms of pulmonary disorders related to marrow and hematopoietic stem cell transplantation are often nonspecific (Fig. 127-12). Tachypnea is common, as are fever, cough, and rales. However, any or all of these may be absent at

A

B

Figure 127-12 A. Diffuse process on plain radiograph of Pneumocystis pneumonia 8 weeks following hematopoietic stem cell transplantation for T-cell lymphoma. B. CT scan revealed pattern most consistent with aspiration pneumonia.

Bronchoalveolar lavage revealed Pneumocystis and antimicrobial-resistant Klebsiella pneumoniae. Treatment of both processes resulted in resolution of infection.

2225 Chapter 127

Focal Lesions Focal parenchymal infiltrates are frequently due to infection regardless of the time of presentation after transplant. Focal consolidations or masses are related to local fungal infection in 80 percent of marrow transplant recipients receiving broadspectrum antimicrobials. Other causes are Legionella species, Nocardia, relapse of lymphoma in patients transplanted for that disorder, bronchiolitis obliterans with organizing pneumonia (BOOP), and, rarely, infarct due to thromboembolic disease.

Aspiration Desquamation of the oropharyngeal mucosa is a frequent complication after intensive chemotherapy, and the stomatitis is often referred to as mucositis. It develops within the first week after radiotherapy and reaches its greatest severity after 10 to 14 days, and impaired mucociliary clearance is common.

Recurrent aspiration of oropharyngeal contents is common among transplant recipients with oral mucositis due to sedation, poor cough reflex, and dysphagia. These patients may present with basilar infiltrates or consolidation.

Pleural Effusions Pleural effusions are common in the first weeks after marrow transplantation and are rarely related to an identifiable infectious source. Pleural effusions may be associated with fluid retention of any cause, especially with ascites secondary to hepatic veno-occlusive disease (HVOD). HVOD may occur in as many as 60 percent of patients after total-body irradiation or in association with GVHD. Characteristics include weight gain within the first weeks after transplantation and elevation of the serum bilirubin, which usually precede the development of pleural effusions. The effusions are frequently bilateral. Bilateral pleural effusions in the presence of weight gain can be approached conservatively without diagnostic thoracentesis. Cautious diuresis coupled with treatment of GVHD often produces satisfactory results. Small effusions are common and may be associated with treatment-related pleuropericarditis or thromboembolic events, but a specific cause is seldom determined. A large unilateral or rapidly accumulating effusion in the presence of fever or ipsilateral chest pain may represent hemorrhage or infection and should be evaluated promptly by thoracentesis.

Non-Infectious Etiology Non-infectious causes of lung injury after marrow and hematopoietic stem cell transplantation include a spectrum of syndromes: idiopathic pneumonia, alveolar hemorrhage, pulmonary edema, obliterative bronchiolitis, or BOOP. Idiopathic pneumonia is characterized as a syndrome of hypoxemia and radiographic nonlobar infiltrates in the absence of congestive heart failure and without evidence of an infectious origin. It is included as a form of â&#x20AC;&#x153;interstitialâ&#x20AC;? pneumonia.

The term interstitial pneumonia in marrow transplant recipients refers to the syndrome of diffuse inflammatory pul-

Pulmonary Infection in Immunocompromised Hosts

monary disease presenting with fever and tachypnea. This term includes noninfectious causes, as well as infectious pneumonia due to viruses (CMV) or protozoa. To avoid the ambiguity of the term interstitial in relation to inflammatory disorders of the lung, it is preferable to classify the clinical conditions as diffuse pneumonia on the basis of the radiographic presentation. Most non-infectious causes of lung injury are attributed to treatment-related toxicities. Alkylating chemotherapy agents and ionizing irradiation are likely contributors; however, ARDS secondary to sepsis syndrome also may occur. While pneumonia is associated with the presence of GVHD, whether GVHD causes a direct lung injury is unproved. The role of unrecognized infections remains a concern.

Idiopathic Pneumonia Syndrome The largest studies of idiopathic pneumonia after allogeneic marrow transplantation estimate the incidence at 12 to 17 percent. The spectrum of idiopathic lung injury is referred to as a syndrome (idiopathic pneumonia syndrome, or IPS) in recognition of the multiple causes and varied clinical presentation of this process (Table 127-11). The diagnosis of IPS is defined by a bronchoalveolar lavage (BAL) that does not reveal an infection in the presence of nonlobar radiographic infiltrates and physiological changes consistent with pneumonia. A common series of laboratory evaluations is presented in Table 127-12. Many clinicians use IPS only to describe noninfectious lung injury occurring within the first 3 to 4 months after transplantation.

Table 127-11 Criteria for Diagnosis of Idiopathic Pneumonia Syndrome Evidence of widespread alveolar injury Multilobar infiltrates on chest radiograph or computed tomography Symptoms and signs of pneumonia Evidence of abnormal physiology and Absence of active lower respiratory tract infection documented by Negative bronchoalveolar lavage Lung biopsy or autopsy with examination of stains and cultures for bacteria, fungi, and viruses, including cytomegalovirus (CMV) centrifugation culture, cytology for viral inclusions and Pneumocystis carinii, and immunofluorescence monoclonal antibody staining for CMV, respiratory syncytial virus, influenza virus, parainfluenza virus, and adenovirus

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Table 127-12 Routine Laboratory Evaluation of Bronchoalveolar Lavage Specimens in Marrow and Stem Cell Transplant Recipients Pathology∗ Wright-Giemsa stain Papanicolaou stain Silver stain Modified Jimenez stain (or other suitable for detecting Legionella) Fluorescent antibody stain for Pneumocystis Microbiology Stains Gram’s Wet mount KOH or calcofluor white Modified acid-fast Fluorescent antibody stain for Legionella Antigen/molecular Mycoplasma PCR Legionella urinary antigen Cryptococcal serum antigen Culture Bacterial (aerobic), semi-or quantitative method Fungal (consider epidemiology: Aspergillus, Histoplasma, Mucor—do not grind) Legionella (chocolate yeast extract) Mycobacterial culture Nocardia/actinomyces Virology Fluorescent antibody stains†: CMV HSV Adenovirus, RSV, parainfluenza, and influenza (direct fluorescent assay) Culture or ELISA and/or molecular assay CMV HSV Adenovirus RSV, parainfluenza, and influenza viruses (in appropriate clinical setting) ∗ Fluorescent antibody stains may be supplemented or replaced by enzyme immunoassays (EIA) or molecular tests. † If available. Culture may be replaced with fluorescent antibody stains or EIA alone if culture facilities are unavailable.

The causes of diffuse idiopathic pneumonia are often multiple, and include treatment-related toxicities due to radiation or chemotherapeutic agents. However, sepsis-related pulmonary toxicity may account for a proportion of cases of diffuse idiopathic pneumonia with histology consistent with

ARDS. Although GVHD is associated with an increased incidence of idiopathic lung injury, it is unclear whether this is a cell-mediated immune response to the lung or related to an increased incidence of sepsis in these immunosuppressed patients. Also, administration of large volumes of blood products during the transplantation procedure may lead to pulmonary vascular injury through leukoagglutination reactions. Other unusual causes of non-infectious diffuse pneumonia after marrow transplantation are leukemic infiltration due to relapse of primary malignancy, injection of malignant cells with reinfused autologous marrow, and fat embolization due to marrow infusion. Several cases of fat embolization have been associated with pulmonary hemorrhage and steroid administration.

The clinical presentation of IPS is nonspecific. Most patients develop a syndrome of fever, nonproductive cough, and tachypnea. Hypoxemia with hyperventilation is common.

The onset is most often rapid, occurring over a few days. Occasionally, insidious onset similar to that of idiopathic pulmonary fibrosis is seen. Median onset is within the first 3 weeks of transplantation, but it may occur up to months later.

The chest radiograph shows diffuse intra-alveolar and/or interstitial infiltrates. The presentation is not sufficiently distinct to be readily differentiated from that of pulmonary edema syndromes or diffuse infectious pneumonia. Marked tachypnea in the absence of radiographic infiltrates should raise the suspicion of obstructive airway disease or pulmonary veno-occlusive disease rather than idiopathic pneumonia.

IPS after marrow transplantation represents a histologic spectrum ranging from a primarily interstitial reaction with diffuse or focal widening of the alveolar septa and interstitial spaces with mononuclear inflammatory cells and edema to diffuse alveolar damage (DAD) with alveolar epithelial necrosis, intra-alveolar hyaline membranes, edema and hemorrhage, and type 2-cell hyperplasia. The predominantly interstitial presentation has been referred to as idiopathic interstitial pneumonia, whereas the pathology of diffuse alveolar damage is identical to that of ARDS. Variable degrees of alveolar hemorrhage may be seen with either of these presentations. By definition, all microbiologic and histologic evaluations for infectious agents (viral, protozoal, fungal, and bacterial) are negative in idiopathic pneumonia. The importance of a thorough microbiologic examination lies in the fact that these histologic presentations are similar to those of infectious pneumonia, especially cytomegalovirus pneumonia.

Mortality from idiopathic lung injury after marrow transplantation remains over 70 percent. The diagnosis of idiopathic lung injury rests largely on the results of BAL. Lung biopsy (transbronchial or open) appears to add little to the diagnostic sensitivity of BAL for infection in the presence of diffuse parenchymal infiltrates. At present, histopathology does not help to direct therapy in idiopathic lung injury after hematopoietic stem cell transplantation. Lung biopsy should be considered in cases with patchy or multifocal infiltrates because of the higher incidence of infection and concern for false-negative results from BAL. There are no

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randomized studies of treatment of idiopathic lung injury after marrow transplantation. High-dose corticosteroids (ranging from 1 to 16 mg/kg per day of methylprednisolone) and other forms of intensive immune suppression are commonly used.

and should prompt a trial of diuretic therapy and a search for other signs of GVHD (GI, liver, skin) before consideration of invasive diagnostic procedures. Noninvasive assessment of cardiac function with ultrasonographic or radionuclide techniques is often warranted to guide treatment.

Pulmonary Hemorrhage

New-Onset Airflow Obstruction and Obliterative Bronchiolitis

Robbins and colleagues described a potentially specific form of idiopathic pneumonia: diffuse alveolar hemorrhage (DAH). The syndrome consisted of progressive dyspnea, hypoxemia, cough, and a progressively bloodier return from BAL in autologous marrow recipients, usually within 2 weeks of transplant. The incidence of DAH was 20.5 percent and was associated with age over 40 years, high fever, transplantation for a solid tumor, severe mucositis, white blood cell recovery, and renal insufficiency. Thrombocytopenia was a common finding, and patients with (DAH) received more platelet transfusions than patients without DAH. It is unclear whether this hemorrhagic pneumonia represents a unique syndrome or represents severe lung injury in the presence of a bleeding diathesis.

Pulmonary Edema Syndromes Biventricular failure after transplantation is often iatrogenic and associated with excessive fluid administration and an increase in total body weight. Radiographic evidence of pulmonary edema after marrow transplantation has been reported in up to 50 percent of patients, most occurring in the second week. Close attention to the total amount of sodium and fluids administered can lead to dramatic reduction in the incidence of pulmonary edema. Also, pulmonary edema may be associated with left ventricular decompensation related to cardiotoxic cytoreductive regimens, including anthracyclines in excess of 500 mg/m2 and high-dose cyclophosphamide.

Posttransplantation cardiac and pericardial toxicity occur in 4 to 10 percent of cases, usually associated with total-body irradiation and cyclophosphamide, often in the setting of prior anthracycline administration. The utility of cardiac imaging studies before transplantation to predict heart failure is limited.

The most frequent noncardiac association with pulmonary edema states is HVOD. The syndrome is often associated with interstitial pulmonary edema, the formation of pleural effusions, and renal failure. Noncardiac pulmonary edema also develops in association with acute GVHD and may be due, in part, to DAD and capillary leak. The presentation of pulmonary edema is nonspecific and usually occurs within 30 days after marrow infusion. Marrow recipients are often febrile and tachypneic at this time in the transplant course, and recipients of allogeneic marrow may display evidence suggestive of acute GVHD. Thus, the distinction between pulmonary edema and idiopathic pneumonia often cannot be made with certainty without pulmonary artery catheterization. However, recent increase in total body weight appears to correlate well with total-body fluid accumulation

About 10 percent of allogeneic marrow recipients with chronic GVHD are likely to develop airflow obstruction consistent with obliterative bronchiolitis. However, the reported incidence of obliterative bronchiolitis varies, in part, with the method used to identify the presence of the disease. Possibly because of decreased airway diameter. The onset of progressive airflow disease is related to the development of GVHD. Factors associated with the increased risk of GVHD, such as increasing age and HLA-nonidentical marrow grafts, are not independent risk factors for the development of obliterative bronchiolitis. The cause of obliterative bronchiolitis after marrow transplantation is unknown.

The main manifestation of new-onset airflow obstruction is the insidious onset of tachypnea, dyspnea on exertion, and dry, nonproductive cough. Fever is uncommon.

Although the chest radiograph is commonly interpreted as normal, high-resolution chest CT often reveals parenchymal hypoattenuation and segmental bronchial dilatation. Auscultation of the chest may reveal scattered expiratory wheezing and occasionally diffuse inspiratory crackles, but results are sometimes normal. Arterial blood-gas analysis reveals moderate hypoxemia and, in the later stages, hypercarbia. Systemic evidence of GVHD is usually present. The major differential diagnoses of the gradual onset of nonspecific respiratory symptoms in the presence of a normal chest radiograph include pulmonary veno-occlusive disease and pulmonary embolism. Obliterative bronchiolitis is characterized by reduction in expiratory airflow on spirometry and increases in residual lung volumes not found in the other two diseases.

Obstruction may be recognized incidentally as a result of coinfection due to respiratory viruses or Pneumocystis.

Patients with early onset of airflow obstruction after marrow transplantation tend to have a rapid decline in pulmonary function and a fatal outcome. These patients may not survive long enough to develop manifestations of chronic GVHD but usually display acute GVHD after BMT or HSCT. It is possible that infection plays a role in the development of the airflow obstruction in some of these patients. Marrow and stem cell recipients with later onset of airflow obstruction tend to have a more gradual decline in lung function. Airflow may stabilize in 50 percent of these patients.

There are no prospective trials of treatment for newonset airflow obstruction. At present, the accepted approach to these patients is to aggressively control with immunomodulating agents the chronic GVHD that most often accompanies the airflow obstruction. Treatment usually consists of increased immunosuppression. Reversal of the airflow obstruction is uncommon. The usual goal of management

2228 Part XVI

Infectious Diseases of the Lungs

is stabilization of the obstruction. For this reason, prompt recognition and treatment for this progressive process are critical. Supportive measures include prophylaxis against Pneumocystis carinii pneumonia and S. pneumoniae infection, inhaled bronchodilators, supplemental immunoglobulin administration to maintain normal serum levels, and prompt treatment of intercurrent infections.

Pulmonary Veno-Occlusive Disease Pulmonary veno-occlusive disease (PVOD) is a rare complication of treatment with chemotherapeutic regimens, and as a solitary pulmonary complication, PVOD is an uncommon but potentially catastrophic complication after transplantation. The primary histologic lesion of PVOD—obstruction of the pulmonary veins and venules by loose intimal fibrosis proliferation—may be difficult to detect with hematoxylin and eosin stains alone, and specific stains for elastic tissues, such as Verhoff–van Gieson stain, are required to demonstrate the fibrotic reaction in the veins. The typical presentation of PVOD is that of insidious dyspnea on exertion and resting tachypnea within 3 to 4 months after transplantation. Significant hypoxemia may occur along with hyperventilation. The chest radiograph is often unrevealing. On cardiac exam, there is evidence of pulmonary hypertension. Auscultation of the lungs is often normal, although scattered inspiratory crackles may be heard. Noninvasive examinations, echocardiography, perfusion-ventilation nucleotide scans, and electrocardiograms are nondiagnostic. Pulmonary function testing may be consistent with mild restrictive defect, but airflow obstruction, suggesting obliterative bronchiolitis, is absent. BAL has failed to demonstrate pathogens or inflammatory cells. The diagnostic procedure of choice is a pulmonary angiogram.

Right heart catheterization reveals elevated pulmonary artery pressure, with normal pulmonary artery wedge pressures.

Angiography excludes the presence of thrombi as a cause of the pulmonary hypertension. In most cases presenting after treatment for malignancy, the disease follows an insidious course, with progressive hypoxemia and dyspnea on exertion due to pulmonary hypertension. Some patients recover with high-dose corticosteroid therapy or other immunosuppressive therapy.

Infectious Etiologies Cytomegalovirus and Viral Pneumonias The incidence of cytomegalovirus (CMV) pneumonia has declined significantly in recent years with routine prophylaxis and monitoring. Most CMV infection occurring in seropositive patients is due to reactivation of latent infection. In the seropositive recipient of a seronegative allograft, pneumonitis may be severe. The risk of infection in seronegative patients with seronegative marrow or stem cell donors is attributable to blood product exposure, and this risk can be virtually eliminated by use of screened seronegative or filtered blood products.

Clinical Presentation

The clinical presentation of CMV pneumonia is not distinct from that of other entities associated with diffuse pneumonia. Patients with CMV pneumonia may have nonproductive cough, dyspnea, hypoxemia, or fever, with a median onset of 60 days after marrow transplant. Onset within the first 2 weeks is unusual. The period of risk of CMV pneumonia generally ends by approximately the fourth or fifth month after transplant, although later cases occur among patients with chronic GVHD or after autologous transplant. The chest radiograph generally shows bilateral infiltrates; in later stages, diffuse consolidation occurs. Unilateral, focal, and even nodular infiltrates have been seen in the early stages.

Treatment of proved CMV pneumonia remains disappointing despite the availability of effective antiviral agents, including ganciclovir, cidofovir, and foscarnet and CMVspecific immunoglobulins. Early therapy (any effect takes at least 5 days) should allow survival of up to 80 percent, but poor outcomes are common, notably in patients with respiratory failure at time of initial treatment. CMV pneumonia can be prevented in most cases with the prophylactic administration of ganciclovir or oral valganciclovir to seropositive recipients.

Most seropositive patients who are at the highest risk of developing CMV pneumonia can be prospectively identified by CMV antigenemia or molecular assays on blood or sputum.

Prospective use of these techniques after allogeneic transplantation permits preemptive treatment with ganciclovir, which appears to eliminate the incidence of CMV pneumonia. The side effects of the antiviral agents (neutropenia, thrombocytopenia, renal toxicity, neurotoxicity, magnesium wasting) may be limiting.

Other Viral Infections: RSV, Parainfluenza, Adenovirus, HSV, HHV-6 The respiratory viruses, particularly respiratory syncytial virus (RSV), influenza, parainfluenza (PIV), adenovirus (AV), picornaviruses, and human metapnuemovirus (hMPV), are increasingly recognized as significant pathogens in these populations. Nosocomial transmission from infected health care workers has been documented. Respiratory syncytial virus (RSV) is the most common respiratory viral pathogen in transplant recipients, but little progress has been made in managing RSV infections. Influenza annually causes increased morbidity and mortality in transplant recipients.

M2 and neuraminidase inhibitors, alone or in combination, result in shorter duration of viral replication, decreased progression to lower tract disease, and reduced mortality.

Parainfluenza (PIV) continues to be recognized as a significant pathogen that is a risk factor for the development of acute and chronic rejection. Therapeutic options remain limited for PIV infections. Adenovirus has recently been shown to cause asymptomatic viremia in association with respiratory infection that resolves without therapy. Approximately 20 percent of marrow transplant patients with adenovirus infection develop pneumonia (Fig. 127-11). Cidofovir appears to be the drug of choice in managing disseminated or

2229 Chapter 127

life-threatening adenoviral infections, but not all strains are susceptible. Rhinoviruses have recently been recognized to cause significant lower tract disease and increased mortality.

Human metapneumovirus (hMPV) and coronaviruses, including severe acute respiratory syndrome (SARS)-associated coronavirus, have been recently discovered and are increasingly recognized as significant pathogens in immunocompromised hosts. Therapeutic options for both viruses are not yet clearly defined.

Pneumonia due to herpes simplex virus (HSV) or varicella zoster virus (VZV) occurs uncommonly. HSV pneumonia is generally due to contiguous spread of virus to the trachea or aspiration from the oropharynx, although it may be due to generalized infection with viremia. Pneumonia due to VZV occurs among patients with disseminated infection and viremia. Both situations have become exceedingly uncommon with the advent of acyclovir treatment and, in the case of HSV, acyclovir prophylaxis. Human herpesvirus 6, the cause of childhood roseola (exanthema subitum), has been detected in the lungs of some patients with idiopathic pneumonia. It is unclear whether this virus is a cause of pneumonia or merely latently reactivated, since virtually all adults are seropositive for the virus.

Fungal Infections

Fungal infections are reviewed in detail elsewhere. Major risk factors for invasive fungal infections are the level and duration of neutropenia, age of the patient, the presence of GVHD, total number of other infections, and immunosuppressive administration after BMT or HSCT (Table 127-8). The frequency of Aspergillus infections is similar in recipients of allogeneic and autologous transplants, but they occur during periods of neutropenia before engraftment among autologous marrow recipients and after engraftment and during GVHD among allogeneic recipients.

Pulmonary Infection in Immunocompromised Hosts

Pulmonary Function Testing in Hematopoietic Stem Cell Transplantation Pulmonary function testing (PFT) is a standard part of the pretransplant evaluation at many centers. The results form baseline data for comparison with later testing, and have been used as an indication to exclude a candidate for transplantation. Abnormalities in the measures of airflow, lung volume, and diffusing capacity have been associated with increased risk of pulmonary complications after transplantation. After accounting for other clinical characteristics associated with death after transplantation (age, relapsed malignancy, HLAmismatched graft), restrictive lung defect (decreased total lung capacity), hypoxemia, and reduced diffusing capacity are associated with statistically increased risk of death, especially within the first few months after transplant. The risks associated with these PFT results are applicable to autologous as well as allogeneic marrow recipients, suggesting that they predict mortality due to treatment-related toxicities. Hypoxemia and reduced diffusing capacity were independently associated with death, each carrying risk.

PFT performed after marrow transplantation has consistently revealed reductions in lung volumes and diffusing capacities associated with total-body irradiation and intensive chemotherapy. PFT abnormalities have been reported to include declines in lung volume, gas diffusion, and airflow.

Losses of lung volume are more pronounced among patients who survive pneumonia after transplant. The declines in lung volume may be at least partly reversible within 2 years after transplantation, whereas the low diffusing capacity reportedly persists for several years. Development of airflow obstruction has been seen in approximately 10 percent of allogeneic marrow recipients in the presence of chronic GVHD and most often is related to obliterative bronchiolitis. Such PFT results strongly suggest that lung parenchymal and vascular injury are common features of marrow transplant, even in the absence of recognized infection or idiopathic pneumonia.

Nonbacterial Infections

Pneumocystis carinii pneumonia occurs in as many as 10 to 15 percent of HSCT recipients without the use of trimethoprim-sulfamethoxazole prophylaxis, although regional and center-to-center variations exist. Except for patients being treated for chronic GVHD (who remain at risk and who should continue to receive prophylaxis), the risk period for P. carinii pneumonia ends approximately 120 days after transplantation. Because it is highly effective, trimethoprimsulfamethoxazole is the prophylactic regimen of choice. Other regimens have been discussed elsewhere. Patients with allergies to sulfa may undergo desensitization so that prophylaxis with trimethoprim-sulfamethoxazole can be administered.

Most infections with Toxoplasma gondii infection have had only central nervous system disease diagnosed and treated during life, while involvement of heart and lungs may be documented at postmortem. Chest radiographs show diffuse, patchy involvement. These patients have also had concomitant bacterial or viral infections. Most infections have been fatal.

SOLID ORGAN TRANSPLANTATION Timetable of Infection As immunosuppressive regimens have become standardized in recent years, it has become apparent that different infectious processes occur at different points in the posttransplant course. That is, although pneumonia can occur at any point in the posttransplant course, the etiology of pneumonia varies depending on the amount of time that has passed since transplantation (Fig. 127-2).

Infections in the First Month after Transplantation In the first month after transplant, two major causes of pulmonary infection apply to all forms of organ transplantation.

The first is the recurrence of pneumonia that was present prior to transplantation (in the lung allograft donor or in the recipient), but was incompletely treated, and which may be

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exacerbated after transplant due to superinfection with nosocomially acquired gram-negative bacilli and fungal species.

This is most commonly seen in patients with end-stage liver or cardiac disease who require critical care support prior to transplant. Second, infection due to aspiration of nosocomial flora is often the result of postoperative vomiting (because of gastric distention or metabolic dysfunction) or due to a technical problem with the endotracheal tube in the perioperative period. The risk of antimicrobial-resistant pneumonia increases with the duration of the pretransplant hospitalization as well as with the duration of posttransplant intubation or ventilatory restriction (following the transplant operation).

Donor-derived infection has been recognized in many recipients of lung transplants (mycobacteria, Aspergillus, colonizing gram-negative bacteria), occasionally with rapid progression after transplantation. It is essential to distinguish early lung allograft dysfunction from diffuse infection due to donor-derived viruses (HSV, VZV, CMV, respiratory viruses) or other pathogens (e.g., Mycoplasma). Extensive pulmonary injury before transplant places the patient at high risk for postoperative pneumonia that is poorly responsive to therapy. In the special case of the lung transplant patient who may require prolonged intubation, bacterial pneumonia and infection that threatens the bronchial anastomosis, particularly with Aspergillus, are special concerns. These patients require exquisite attention to the technical aspects of the transplant procedure, to the management of the endotracheal tube, and the maintenance of pulmonary toilet (including, on occasion, repeated therapeutic bronchoscopy).

Notable by their absence in the first posttransplant month are the opportunistic infections, despite the fact that the highest daily doses of immunosuppression are administered during this first month. This emphasizes that it is the sustained exposure to immunosuppressive therapy, the area under the curve, that is the major determinant of the net state of immunosuppression.

Infections 1 to 6 Months after Transplantation In the period 1 to 6 months after transplant, the nature of pulmonary infection changes markedly. During this time period the immunomodulating viruses, particularly CMV, are of importance in terms of direct effects (invasive disease) and immunological or indirect effects (rejection, opportunistic infections). CMV can directly cause pneumonia itself; CMV may contribute to the incidence of graft rejection necessitating increased exogenous immune suppression and increasing the risk of opportunistic infection; or CMV (and the other immunomodulating viruses) are globally immunosuppressive and can enhance the likelihood of pulmonary infections due to Pneumocystis carinii, Aspergillus species, and Nocardia asteroides in the absence of an unusual epidemiologic exposure. Unlike the bone marrow transplant recipient, the risk of active CMV disease (as compared with viral secretion) in the solid organ transplant recipient is greatest in the CMVseronegative recipient of an organ from a seropositive donor.

Thus, CMV prevention and the utilization of diagnostic tech-

niques for CMV viremia (e.g., antigenemia assays, polymerase chain reaction testing, shell vial cultures with early antigen detection) are important parts of the therapeutic program.

During this period, in the absence of specific prophylaxis, significant nonviral pulmonary infections are also common including those due to P. carinii, Aspergillus species, endemic fungi (Histoplasma, Coccidioides) and Nocardia asteroides (Figs. 127-13 and 127-14). There is important regional variation in the occurrence of each of these pathogens.

At centers with high endemicity of these infections, low dose trimethoprim-sulfamethoxazole prophylaxis (which effectively eliminates Pneumocystis and nocardial infection) and epidemiologic protection against Aspergillus (as with a HEPA filtered air supply within the hospital) are effective, particularly in the context of effective CMV prevention.

Infections beyond 6 Months after Transplantation In the period more than 6 months after transplant, patients can be divided into two groups in terms of the forms of pulmonary infection that can develop. Most patients have a good result from their transplant and have good allograft function and receive relatively modest levels of maintenance immunosuppression. These patients are subject to communityacquired respiratory virus infection, particularly influenza and RSV, and pneumococcal pneumonia. The remaining patients have had a less positive outcome from their transplant; these individuals have less satisfactory graft function and require far more intensive acute and chronic immunosuppressive therapies to manage rejection. These patients, often termed “chronic ne’er do wells,” are the subgroup of transplant patients at highest risk for pulmonary infection with such organisms as Pneumocystis carinii, Cryptococcus neoformans, Nocardia asteroides, and Aspergillus species (Fig. 12715). For this subgroup of patients, prolonged trimethoprimsulfamethoxazole prophylaxis, epidemiologic protection, and a consideration of fluconazole prophylaxis are indicated.

Notable among the ne’er do well group is the liver transplant recipient with recurrent hepatitis C infection, the lung transplant with cystic fibrosis and resistant Pseudomonas or Stenotrophomonas infections, and the kidney transplant with chronic allograft dysfunction.

Radiologic Clues to the Diagnosis of Pneumonia in the Organ Transplant Patient The presentation and evolution of the chest radiograph provide important clues to both the differential diagnosis of pulmonary infection in the transplant patient and the appropriate diagnostic workup that should be undertaken (Table 127-13). The following radiologic parameters are useful in developing clinical-radiologic-pathologic correlations: 1. Time of appearance, rate of progression, and time to resolution of pulmonary roentgenographic abnormalities in relation to clinical events.

2. Distribution of radiologic abnormalities. An abnormality confined to one anatomic area is considered

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A

Pulmonary Infection in Immunocompromised Hosts

B

Figure 127-13 A 56-year-old man, lifelong resident of Kansas, presented 21/2 years after a renal transplant with fever, nonproductive cough, and 3-month weight loss. The chest radiograph was diffusely abnormal. A. Close-up reveals extensive micronodular disease. B. Peripheral blood smear shows a macrophage laden with Histoplasma capsulatum.

Treatment with liposomal amphotericin B resulted in clearing of the radiograph and cure of the infection.

Figure 127-14 Invasive pulmonary aspergillosis after liver transplantation. A diffuse Klebsiella pneumonia was treated, with a good clinical response to therapy. After 2 days without fever, the patient became febrile with increasing shortness of breath although the chest radiograph remained unchanged. One day after this radiograph was taken, the patient died. Autopsy revealed two processes in the lungs: a diffuse gram-negative pneumonia and focal areas of invasive aspergillosis restricted to the right lower and middle lobes. This figure illustrates the difficulty in differentiating the focal areas of Aspergillus superinfection from the primary bacterial process.

focal, whereas widespread lesions are considered diffuse. Abnormalities that are present in more than one area, but are countable, are termed multifocal. As visualized particularly on computed tomographic scanning (CT), abnormalities may be located centrally or peripherally or both.

3. Which of three types of pulmonary infiltrate is present? The first type is a consolidation, in which there is substantial replacement of alveolar air by material of tissue density, typically with air bronchograms and a peripheral location of the abnormality. The second type is peribronchovascular (or interstitial), in which the infiltrate is predominantly oriented along the peribronchial or perivascular bundles. Finally, nodular lesions are space-occupying, nonanatomic lesions with well-defined, more or less rounded edges surrounded by aerated lung.

4. Other characteristics. These include pleural fluid, atelectasis, cavitation, lymphadenopathy, and cardiac enlargement. Pleural fluid is a clue to congestive heart failure and fluid overload when bilateral, and to necrotizing or granulomatous infection, especially when associated with lymphadenopathy or cavitation, when unilateral.

By combining this classification with information concerning the rate of progression of the illness (Table 127-13), a useful differential diagnosis is then generated. Thus, focal or multifocal consolidation of acute onset quite likely is

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C A

Figure 127-15 Cryptococcus neoformans in an asymptomatic renal transplant patient. The patient presented with minimal complaint of nonproductive cough of a few weeksâ&#x20AC;&#x2122; duration. A. The chest radiograph was essentially clear other than a shadow in the right midlung field (arrow). B. Chest tomography revealed a nodular lesion in the right midlung field (arrow). Percutaneous needle aspiration of this lesion yielded Cryptococcus neoformans on fungal culture. C. India ink stain of cerebrospinal fluid from same patient reveals narrow-based budding yeast forms consistent with Cryptococcus neoformans.

B

caused by bacterial infection. Similar multifocal lesions with subacute to chronic progression are more likely secondary to fungal, tuberculous, or nocardial infections. Large nodules are usually a sign of fungal or nocardial infection in this patient population, particularly if they are subacute to chronic in onset. Subacute disease with diffuse abnormalities, either of the peribronchovascular type or miliary micronodules, is usually caused by viruses (especially CMV) or Pneumocystis carinii (or, in the lung transplant patient, rejection). Additional clues can be found by examining the pulmonary lesion for the development of cavitation, with cavitation suggesting such necrotizing infections as those caused by fungi, Nocardia, and certain gram-negative bacilli (most commonly with Klebsiella pneumoniae and Pseudomonas aeruginosa). The depressed inflammatory response of the immunocompromised transplant patient may greatly modify or delay the appearance of a pulmonary lesion on radiograph, particularly if neutropenia is complicating the effects of the antirejection therapy. CT of the chest has revolutionized the evaluation of these immunocompromised patients, and CT is particularly

useful when the chest radiograph is negative or when the radiologic findings are subtle or nonspecific (Fig. 127-15). An additional important application of CT in this patient population is defining the extent of the disease process. Particularly with opportunistic fungal and nocardial infection, precise knowledge of the extent of the infection at diagnosis, and the response of all sites to therapy, lead to the best therapeutic outcome, as therapy should be continued until all evidence of infection is eliminated, not just the primary site. CT findings are also quite useful in defining which invasive diagnostic procedure should be used to obtain diagnostic samples and in identifying the anatomic site at which sampling should be directed to optimize the diagnostic yield.

PRIMARY IMMUNE DEFECTS Primary immune deficiencies are defined as alterations in the immune system that are congenital, as opposed to those

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Pulmonary Infection in Immunocompromised Hosts

Table 127-13 Differential Diagnosis of Fever and Pulmonary Infiltrates in the Organ Transplant Recipient According to Roentgenographic Abnormality and the Rate of Progression of the Symptoms Etiology According to the Rate of Progression of the Illness Chest Radiographic Abnormality

Acute∗

Subacute-Chronic∗

Consolidation

Bacterial (including Legionnaries’ disease) Fungal Thromboembolic Nocardia Tuberculosis Viral Hemorrhage (Pulmonary edema) (Drug-induced, radiation, Pneumocystis tumor)

Peribronchovascular

Pulmonary edema (Leukoagglutinin, reaction bacterial)

Viral Pneumocystis (Fungal, nocardial, tuberculous, tumor)

Nodular infiltrate†

(Bacterial, pulmonary edema)

Fungal Nocardial Tuberculous (Pneumocystis)

∗ An

acute illness develops and requires medical attention in a matter of relatively few hours. A subacute-chronic process develops over several days to weeks. Note that unusual causes of a process are in parentheses. † A nodular infiltrate is defined as one or more large (>1 cm2 on chest radiography) focal defects with well-defined, more or less rounded edges, surrounded by aerated lung. Multiple tiny nodules of smaller size, as sometimes caused by such an agent as CMV or varicella-zoster virus, are not included here.

related to chemotherapy, autoimmune disease, organ transplant, or chronic systemic disease. Clinical problems that require evaluation of the immune system include chronic or recurrent bacterial or fungal infections of the skin, sinuses, and respiratory and digestive tracts and repeated infections with unusual viruses. Other suggestive signs and symptoms are persistent atypical rashes, chronic diarrhea, failure to thrive, paucity of lymphoid tissue, lymphadenopathy, chronic conjunctivitis, and unusual reactions to live virus vaccines. The evaluation of recurrent infections should analyze all compartments of the host defense system, including anatomic structures, mucociliary function, B- and T-cell activity, phagocytic cell function, and complement activity. Table 127-14 outlines both initial and confirmatory screening tests available to most clinicians.

Antibody (B-Cell) Deficiency Antibody deficiency states are among the most common of the primary immunodeficiency diseases. Although the defect in immunoglobulin production can occur at any point in B-cell maturation/activation or secretion of antibody, or even in T- and B-cell interaction, the end result is a decrease in serum antibody levels or the inability to respond to antigens with specific antibody. Patients typically present with recurrent sinopulmonary infections caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae (both type b and non-typable), and Staphylococcus aureus. Diseases caused by mycoplasma, enteroviruses, and

intestinal parasites also are seen occasionally. The incidence of autoimmune abnormalities and hematologic malignancies is also significant in patients with these defects. Treatment for most of these defects relies on the administration of gammaglobulin. Annual chest radiographs and pulmonary function tests are especially helpful, given that the lung disease in patients with hypogammaglobulinemia may be insidious in onset and progression.

X-Linked Agammaglobulinemia X-linked agammaglobulinemia (XLA or Bruton’s agammaglobulinemia) is a relatively common inborn error of immunity, occurring in 1 per 50,000 live births. A block in the normal maturation of immunoglobulin-producing B cells (block in VHDJH recombination) results in the absence or severe reduction of serum immunoglobulin, absence of circulating mature B cells, and absence of plasma cells in all lymphoid tissue. T-cell number and function are intact. Inheritance is sex-linked recessive, although a clinically indistinguishable syndrome with autosomal recessive inheritance has been observed in some patients. Recent studies have localized the defect to a protein tyrosine kinase gene (Bruton’s tyrosine kinase, btk) on the proximal region (q21.3–q22) of the X chromosome. After maternal antibody is consumed (usually after the first 4–6 months of life), patients develop sinopulmonary infections, bacteremia, and meningitis with encapsulated gram-positive and -negative bacteria, such as H. influenzae, S. pneumoniae, S. aureus, Pseudomonas aeruginosa, and

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Table 127-14 Immunologic Workup of Primary Immune Deficiencies Suspected Abnormality

Screening Tests

Confirmatory Tests

Antibody deficiency

Serum IgM, IgG, IgA levels IgG antibody response to protein (diphtheria, tetanus, influenza) and polysaccharide (pneumococcus, Hemophilus influenzae) antigens Isohemagglutinin titers for IgM antibody response Serum IgG subclass levels

B-cell enumeration (total B [CD20] surface IgM-, IgG-, IgA-, IgD-bea B cells) In vitro immunoglobulin synthesis

Cell-mediated immunodeficiency

Total lymphocyte count Delayed hypersensitivity skin tests (diphtheria, Tetanus, Candida, PPD, SK/SD for T-cell function) Tests for HIV antibodies

Enumerate total T cells and T-cell subsets (CD3, CD4, CD8) Measure T-cell function with mitogenic, antigenic, and allogenei (mixed lymphocyte reaction) respo lymphokine production, cytotoxic Assays for Th and Ts activity Enzyme assay (ADA, PNP) for ADA PNP deficiency

Complement deficiency

CH50 or CH100 for classical pathway activity APH50 for alternative pathway activity Serum C2, C3, C4, C5, and factor B levels

Other specific component levels C1 esterase inhibition levels C1 esterase functional component

Phagocyte defects

NBT test for respiratory burst activity (defect in CGD) Serum IgE levels for HIE

Leukocyte adhesive protein analysis: (CD11a/CD18, CD11b/CD18, and CD11c/CD18) Adherence and aggregation Chemotaxis and random motility Phagocytosis Assays for respiratory burst activity (chemiluminescence, oxygen radiography production) Bacterial killing test Enzyme assay (MPO, glucose-6-phosphate dehydrogenase) for phagocyte enzyme defects Cytochrome b or cytosolic protein measurement for CGD

Mycoplasma pneumoniae. Respiratory disease due to Pneumocystis carinii or gastrointestinal infection with Giardia lamblia is also commonly observed. Although viral infections are not typical, enterovirus (polio and echo) and hepatitis viruses may cause severe or fatal disease. Autoimmune diseases, such as rheumatoid arthritis, occur in up to 20 percent of patients, whereas lymphomas and other lymphoreticular malignancies occur in approximately 5 percent of cases. IgG levels are very low (less than 100 mg/dl), and IgA and IgM are often undetectable.

Common Variable Immunodeficiency Common variable immunodeficiency (CVI) is a common defect in general due to B-cell activation or differentiation defects, resulting in low serum levels of IgG and depressed levels of IgA or IgM. B cells may be normal, high, or low, and T-cell number and function, although usually normal at diagnosis, deteriorate with time. Although the disease is familial, it is not strictly X-linked or autosomally inherited. In some patients, the genomic defects of both CVI and isolated IgA deficiency appear to be localized to the major histocompatibility

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A

B

Figure 127-16 A. PA chest radiograph of an adolescent boy with common variable immunodeficiency demonstrating marked bibasilar opacification, atelectasis, and infiltrative changes. Sputum culture grew only H. influenzae (non-typable). B. Pulmonary function tests from the same patient demonstrate significant restrictive, obstructive disease, supported by RV/TLC measurements. Marked improvement in radiographs and pulmonary function tests occurred with the use of continuous, rotating ciprofloxacin, Ceclor, and Biaxin, in conjunction with aggressive chest percussion via a percussor vest and inhaled DNAse.

complex region of chromosome 6.The disease is characterized by the development of recurrent sinopulmonary infections or chronic bronchiectasis in childhood or adulthood. Chest radiograph findings consistent with atelectasis, bronchiectasis, and/or interstitial markings, along with pulmonary function tests revealing mild to severe obstruction and restrictive disease, are seen in 60 to 80 percent of CVI patients (Fig. 12716). A few patients with CVI present with infections with unusual organisms, such as P. carinii, mycobacteria, or fungi.

Recurrent attacks of both herpes simplex and zoster are not uncommon.

Pulmonary Infection in Immunocompromised Hosts

Selective IgG Subclass Deficiencies Patients with selective IgG subclass deficiencies have recurrent sinopulmonary infections associated with normal or decreased total concentrations of serum IgG, but with selective deficiencies of IgG subclass 1, 2, 3, or 4. Patients with IgG2 subclass deficiency can make antibody, but the spectrum of the response is decreased, resulting in recurrent infection. Recent studies suggest a critical role for IL-6 and IFN-Îł in enhancing IgG subclass production. Titers to bacterial polysaccharide antigens are low even after immunization, since antibody responses to polysaccharides reside predominantly in the IgG2 subclass. Titers to protein antigens such as tetanus or diphtheria toxoids may be normal. IgG2 subclass deficiency may be associated with IgG4 subclass deficiency, IgA deficiency, Wiskott-Aldrich syndrome, and ataxia-telangiectasia.

Persons with low or absent IgG2 or IgG4 appear to be particularly predisposed to recurrent or severe pneumonias and middle ear infections. Selective IgG3 deficiency is also associated with recurrent sinopulmonary infections, but the mechanism is not clear. These IgG3-deficient patients have normal responses to both common protein (Dt) and polysaccharide antigens; however, responses to influenza or rubella vaccine may be abnormal. Treatment is based on clinical findings of recurrent infections, rather than isolated laboratory abnormalities. It is important to document not only a low concentration of a subclass but also failure to make specific antibody when immunized, before immunoglobulin therapy is contemplated.

Selective IgA Deficiency This most common of all the inborn defects of humoral immunity, occurring in 1 per 700 persons, accounts for more than 1 percent of recurrent infections in children. The defect is assumed to be a differentiation block affecting IgAcommitted B cells. Typically, peripheral counts of patients with IgA deficiency show normal numbers of mature B lymphocytes, as well as normal numbers and proportions of CD4 and CD8 cells. Selective IgA deficiency has been defined as serum IgA less than 5 mg/dl in severe deficiency and greater than 5 mg/dl but less than 2 SD below the age normal mean in partial IgA deficiency. The diagnosis and treatment of IgA deficiency depend not only on the serum level of IgA but also on the history and results of related diagnostic studies, particularly the immune workup. In general, treatment relies on the administration of appropriate antimicrobials for acute infection or chronic suppressive therapy for chronic infection.

When IgA deficiency is associated with IgG2 deficiency, IVIG depleted of IgA may be indicated.

Hyper-IgM Immunodeficiency These patients have absent or markedly reduced IgA, IgE, and IgG levels, elevated levels of IgM, circulating mature B lymphocytes bearing IgM or IgD and plasma cells, as well as hyperplastic lymphoid tissue. Recurrent neutropenia, probably secondary to autoimmune phenomena, may coexist with the humoral defect. Because antibody protection for the

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gastrointestinal and respiratory tracts is normally provided

by IgA and IgG isotypes, patients with this syndrome are especially prone to respiratory and GI infections with pyogenic organisms. They are also predisposed to P. carinii pneumonia. As with other immunoglobulin deficiencies, patients with the hyper-IgM syndrome have very high rates of autoimmune (involving the formed elements of the blood) and lymphoproliferative disorders.

Complement Disorders Disorders due to primary deficiencies of complement components are rare causes of pulmonary infections. Complement function can be assessed by determining the total hemolytic activity in serum (CH50), which measures the ability of serum to lyse antibody-coated sheep cells. A low to absent CH50 suggests a deficiency in a classic pathway complement component. Levels of specific complement components can then be determined.

Congenital absence of C3 or consumption of C3 due to deficiency of factor I (C3b inactivator) results in a clinical picture like that seen in deficiency of the critical antibody opsonins, including infections due to pyogenic bacteria including severe and recurrent pneumonias due to S. pneumoniae, H. influenzae, and Enterobacteriaceae.

The terminal complement components, C5–9, form the cytolytic membrane attack complex (MAC), and deficiency of any one of these will block MAC formation. C5–9 deficiencies predispose to disseminated infection with N. meningococci and N. gonococci.

C1 esterase inhibitor deficiency results in persistent consumption of C2 and C4 by the C1 esterases, resulting in release of vasoactive kinins and the development of nonpruritic angioedema. Although angioedema can occur in any tissue, including the GI tract, edema of the upper airway can be life threatening. Diagnosis is suggested by family history (autosomal dominant state), edema without pruritus, and chronically decreased C4 and C2 levels, especially during the 24 to 72 h of the episode. Patients with the familial form of the disease have low to absent C1 esterase inhibitor concentrations. Angioedema with later onset, without a familial pattern, may be due to the absence of the functional component of the inhibitor, which may be associated with malignancy.

Treatment is with danazol or purified C1 inhibitor for acute attacks.

Cell-Mediated Immunity Although the most characteristic infections in patients with cellular immune deficiency are those caused by opportunistic intracellular pathogens, including protozoa (P. carinii and Toxoplasma gondii), fungi (Candida and Aspergillus species), viruses (particularly those of the herpesvirus family), and some intracellular bacteria (including Listeria and Mycobacteria species), defects in humoral or phagocyte defense mechanisms can also be seen.

DIGEORGE’S SYNDROME DiGeorge’s syndrome (DGS) is a constellation of abnormalities resulting from dysmorphogenesis of the third and fourth pharyngeal pouches. Patients have hypoplasia or aplasia of the thymus and the parathyroid glands, complex cardiac malformations, esophageal atresia, bifid uvulas, cleft palate, short philtrums, mandibular hypoplasia, hypertelorism, and lowset notched ears. The severity of immunologic manifestations varies from severe forms with complete thymic aplasia, resembling severe combined immunodeficiency disease (SCID), to only latent hypoparathyroidism, which may also be seen in relatives of patients with DGS. Most patients have partial T-cell function, which may improve with age, presumably due to the adaptation of functional extrathymic sites for T-lymphocyte maturation. T-cell numbers are typically reduced, with reduced percentages of CD3 and CD4 cells, but CD8 cells may be normal or even elevated. Patients with more significant CD4 T-cell deficiency seem to have more frequent and severe infections requiring hospitalization. Blymphocyte counts are usually normal; antibody production is also usually normal, but of poor biologic quality. Some patients may have low IgA or elevated serum IgE levels. Surviving infants often have the tendency to acquire parathyroid function, cell-mediated immunity, and functional T cells. Patients are prone to severe viral pneumonias, particularly those of the herpes and measles family. Pneumonias due to fungal and gram-negative bacilli and P. carinii also occur.

Severe Combined Immunodeficiency Disease SCID is a syndrome of heterogeneous lymphocyte stem cell defects that affect both T- and B-cell function, resulting in profound hypogammaglobulinemia and absence of T-cell function. Laboratory analysis may reveal lymphopenia (10– 20 percent) and normal or increased numbers of circulating B cells, but severely reduced IgG levels. In general, SCID syndrome patients present with a triad of mucocutaneous candidiasis, intractable diarrhea, and P. carinii pneumonia, evident shortly after birth or within 6 to 9 months of life and progressing to severe failure to thrive. Within a few days after birth, patients may also develop a morbilliform rash that is probably a manifestation of graft-vs-host disease (GVHD) from passively transferred maternal lymphocytes. Infections with a wide range of microbes occur in all forms of SCID, including viral pathogens, particularly herpesviruses (herpes, cytomegalovirus, and varicella), adenovirus, measles, influenza, and Legionella. Fatal giant-cell pneumonia has resulted from measles infection and live measles vaccination, and progressive vaccinia has occurred after smallpox vaccination.

Purine Nucleoside Phosphorylase Absence of the enzyme purine nucleoside phosphorylase (PNP) is associated with marked cell-mediated immunodeficiency but intact humoral immunity. The gene encoding the enzyme is localized to chromosome 14q13.1. Patients are

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prone to disseminated viral infections, P. carinii infection, mucocutaneous candidiasis, and chronic diarrhea. Neurologic disorders afflict more than 50 percent of patients, and more than a third of PNP patients develop autoimmune diseases.

Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome (WAS) is caused by a defect localized to the short arm of the X chromosome (Xp11.22– 11.3), resulting in severely impaired production of antibodies to polysaccharide antigens, as well as variable reductions of T-cell numbers and impaired mitogen responses that tend to worsen with age. Both T-cell numbers and function progressively decrease, and profound lymphopenia becomes apparent at approximately 6 years of age. Most patients have abnormalities of serum immunoglobulin levels, with low IgM and isohemagglutinin concentrations, a tendency toward elevated IgA and IgE levels, and normal or slightly depressed IgG levels. Males afflicted with this syndrome suffer from a triad of recurrent infections, thrombocytopenia, and a skin disease indistinguishable from atopic dermatitis. Typical infections include pyoderma or cellulitis associated with eczematoid eruptions, chronic otitis media with persistent otorrhea and/or mastoiditis, and chronic pneumonitis. Encapsulated pyogenic bacteria, such as S. pneumoniae, H. influenzae, herpesvirus, and P. carinii, are the most frequently identified pathogens.

Ataxia-Telangiectasia This syndrome (AT) is characterized by profound deficiencies of cellular immunity (including lymphopenia, defects in cutaneous anergy, decreases in Th:Ts ratios, decreases in cytotoxic T cells, and an increase in immature T cells with increased γ/# TCR expression), impaired humoral responses (thymic hypoplasia associated with IgA deficiency, IgE deficiency, and IgG2 and IgG4 subclass deficiency), and a constellation of progressive cerebellar ataxia with degeneration of Purkinje cells. The defective genes of the two most common AT variants map to chromosome 11q22.3, which may result in a recombination defect that interferes with the rearrangement of T- and B-cell genes, an inability to repair damaged DNA, and a failure of normal organ maturation. Telangiectasias, particularly ocular and cutaneous, and a high incidence of malignancies, particularly non-Hodgkin’s lymphoma, and breast cancer (in heterozygous female carries of the AT allele) are seen. AT is also associated with insulin-resistant diabetes mellitus, gonadal agenesis, premature aging, elevated levels of serum α1 -fetoprotein and carcinoembryonic antigen, and hypersensitivity of fibroblasts and lymphocytes to ionizing radiation, reflecting an inability to repair damaged DNA. Patients suffer from an increased incidence of bacterial and viral sinopulmonary infections, and many eventually develop chronic bronchiectasis. The most frequent pulmonary pathogens are S. aureus and other encapsulated bacteria. Concurrent IgG2 (50 percent), IgG4, and IgA deficiencies (70 percent) may be associated with the tendency toward recurrent

Pulmonary Infection in Immunocompromised Hosts

infections of the respiratory tract. Approximately 80 percent of patients have depressed IgE levels.

Phagocytic Defects Disorders of Phagocyte Numbers These disorders include cyclic neutropenia, Felty’s syndrome, Kostmann’s syndrome, Shwachman-Diamond syndrome, and autoimmune neutropenia. They are characterized by absolute PMN counts as low as 50 to 200/mm but typically lower than 1000/mm. Owing to the presence of a compensatory monocytosis, these disorders are associated with a low incidence of severe respiratory infections, although pneumonia is seen—as are furunculosis, subcutaneous abscess, and otitis media. Typical pathogens include S. aureus, P. aeruginosa, and enteric bacteria.

Defects of Phagocyte Function Chronic Granulomatous Disease

CGD is caused by a defect in a membrane-associated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytic cells, resulting in the failure of phagocytic cells to produce superoxide, hydrogen peroxide, and other reduction products of oxygen that are necessary for killing certain microbial species. Diagnosis is made by the inability of neutrophils to reduce nitroblue tetrazolium (NBT) from yellow to blue-black formazan and by the inability of neutrophils to kill staphylococci or other catalase-positive microorganisms. Additional laboratory findings suggestive of CGD include leukocytosis, elevation of erythrocyte sedimentation rate, abnormal chest radiographs, and hypergammaglobulinemia. Onset is typically in infancy, childhood or, less commonly, early adolescence, with a male-to-female ratio of 6:1. All forms of CGD are characterized by abscess formation at sites of bacterial tissue invasion and in lymph nodes, liver, and lung. Patients present with severe recurrent lymphadenitis and infections of the skin, sinopulmonary, and GI tracts. Severe and recurrent pulmonary infections occur in almost all patients with CGD, including bronchopneumonia, empyema, lung abscess, and hilar adenopathy syndromes.

Most young adult patients demonstrate chronic bilateral infiltrates, pulmonary fibrosis, or pulmonary calcifications associated with restrictive/obstructive disease. Aggregates of granulomas, leading to mechanical obstruction, may form as a response of activated macrophages to microbial persistence and chronic antigenic stimulation. S. aureus represents by far the most common cause of infections in CGD. Other catalase-positive and non–H2 O2 -producing organisms include Escherichia coli, Klebsiella, and Enterobacter species, Serratia marcescens, Salmonella, and Pseudomonas species.

Pneumonias in CGD patients may be caused by Mycobacterium tuberculosis, atypical mycobacteria, and P. carinii. In specific geographic locations, such as the southeastern United States, Chromobacterium violaceum has been recognized as the cause of infection in several CGD patients. Nocardia infection, particularly of the respiratory system, is also relatively

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A

Figure 127-18 PA chest radiograph in a patient with CGD demonstrating nocardial abscess of right upper lobe, extending into the anterior chest wall.

B

Figure 127-17 A. PA chest radiograph of a child with CGD who originally presented as an infant with recurrent pneumonia in the right upper lobe diagnosed radiographically as cystic adenomatoid malformation. Subsequent histologic examination and culture revealed this to be nocardial pneumonia. This radiograph reveals recurrent diffuse nocardial pneumonia. B. Pulmonary function tests from the same patient showing mild restrictive disease, probably secondary to right upper lobectomy and recurrent airspace disease.

common, as are fungal infections (Figs. 127-17 and 127-18).

Antimicrobials and interferon-Îł have been useful in therapy.

Glucose-6-Phosphate Dehydrogenase Deficiency

This is a variant of CGD, in which G6PD levels are less than 1 percent, and results in an inability to generate oxygen by products and a slightly milder form of disease than that in patients with CGD.

ratory tract infections, including recurrent or chronic otitis media, sinusitis, and pharyngitis, in addition to lower respiratory tract infections, including bronchopneumonia. Segmental or lobar lung involvement can account for up to 30 percent of documented infections. Most infections are due to S. aureus, H. influenzae, group A streptococcus, and gramnegative enteric organisms (Klebsiella, Proteus, Shigella, Pseudomonas). Aspergillus and Candida represent less common etiologic agents. Respiratory failure can occur with extensive histiocytic infiltration of the lungs during an accelerated lymphoma-like proliferative phase marked by widespread tissue infiltrates of lymphoid and histiocytic cells, usually without malignant histologic characteristics. Anemia, hypersplenism, and platelet dysfunction, associated with the accelerated phase, and albinism or hypopigmentation, due to abnormal fusion of melanocyte pigment organelles, are also seen.

Leukocyte Adhesion Deficiency

Chediak-Higashi Syndrome

CHS is a rare autosomal recessive defect characterized by abnormal fusion of azurophilic lysosomes of neutrophils and cytoplasmic granules of monocytes and lymphocytes. This defect results in impaired microbicidal activity of phagocytes due to the presence of giant lysosomal granules, which have abnormal post-phagocytic phagolysosome fusion and degranulation. In addition, neutrophil counts tend to be low, secondary to their rapid turnover. Chemotactic defects and impaired natural killer cell activity have also been noted. Patients present with recurrent skin and upper and lower respi-

Patients with this autosomal recessive disease lack or have markedly reduced Îą2 integrins, essential glycoprotein constituents of the CD11/CD18 receptor complex that mediates leukocyte adhesion. Recurrent necrotic and indolent infections of soft tissues, primarily in skin, mucous membranes, and the intestinal tract, are the clinical hallmarks of this disease. The recurrent infections reflect a profound impairment of leukocyte mobilization into extravascular inflammatory sites, despite peripheral blood granulocyte counts of 15,000 to 161,000/mm. A wide spectrum of gram-positive or -negative bacteria (S. aureus and gram-negative enteric bacteria) and

2239 Chapter 127

Figure 127-19 PA chest radiograph in a child with CD18 neutrophil receptor deficiency demonstrating extensive airspace disease due to probable candidal and pyogenic bacterial pneumonia.

Pulmonary Infection in Immunocompromised Hosts

A

fungal microorganisms (Candida and Aspergillus) infect LAD patients, similar to those with neutropenia syndromes (Fig. 127-19).

Hyperimmunoglobulin E Syndrome

Also known as the hyper-IgE (HIE) recurrent infection or Job’s syndrome, this unusual disorder, which appears to be autosomal dominant with incomplete penetrance, is lacking an exact immunologic defect. Serum levels of polyclonal IgE are markedly elevated (above 2000 IU/ml), but immunoglobulins other than IgE are normal. Complete blood counts and differentials are mildly abnormal, with occasional borderline neutropenia. Most patients have mild to moderate eosinophilia, despite lacking a significant history of classic allergic diseases.

All patients have chronically elevated erythrocyte sedimentation rates. Diagnosis of HIE can be established in patients (usually during infancy) with a history of staphylococcal infections of the skin and sinopulmonary tract, and IgE levels at least 10 times normal. Coarse facies, chronic eczematoid eruptions, cold cutaneous or subcutaneous abscesses, eosinophilia, and mucocutaneous candidiasis are also seen, as are recurrent bone fractures and osteopenia.

“Cold abscesses” are not seen in all HIE patients, but are rare in other immunodeficiency states. They can present in any part of the body as fluctuant masses, with little evidence of inflammation and often without fever. Drainage of these abscesses usually reveals large volumes of purulent material, which almost always grow S. aureus. Otitis externa and chronic otitis media, occasionally complicated by mastoiditis, are common in HIE patients. Recurrent bronchitis represents the most common pulmonary manifestation of HIE. Patients often suffer several days a month of productive cough, rarely associated with fever. Less commonly, pneumonia, with or without associated complications—including

B

Figure 127-20 A. PA chest radiograph in a patient with Job’s syndrome, after left upper lobectomy for bronchiectasis due to Aspergillus fumigatus, resulting in recurrent, severe hemoptysis.

Chest radiograph shows residual bronchopleural fistula with loculated air collection in the left upper lobe, extensive airspace disease in the left lower lobe, and pleural thickening. B. Pulmonary function tests from the same patient showing mild restrictive and obstructive disease despite his extensive left-sided pulmonary disease.

bronchiectasis, lung abscess, empyema, pneumatocele formation, and bronchopleural fistula formation—may represent serious and potentially devastating features in HIE patients.

S. aureus and H. influenzae are the most frequent causes of pneumonias in HIE, but fungal infections may complicate management (Fig. 127-20). Management relies on the use of narrow-spectrum antistaphylococcal prophylaxis, such as cloxacillin or dicloxacillin. Trimethoprim-sulfamethoxazole may also be employed as a prophylactic agent.

ACKNOWLEDGEMENT The author gratefully acknowledges the contributions of Stephen W. Crawford (Respiratory Disease in Bone Marrow and Hematopoietic Stem Cell Transplantation), and

2240 Part XVI

Infectious Diseases of the Lungs

Harry R. Hill and Kathleen D. Pfeffer (Pulmonary Infections in Patients with Primary Immune Defects) to the previous edition of this text who have provided material that has been adapted for this new edition.

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