01 Infection

SECTION 1

Infection 1.

Basics of Prescribing Antimicrobial Drugs Mahadev T Desai

2.

Rational for Antibiotics – Guidelines Mangesh Tiwaskar, Tanuja Manohar 6

3.

Pyrexia of Unknown Origin - Physician’s Challenge Asha N Shah

16

4.

Vector Borne Diseases Falguni S Parikh

20

5.

Tropical Fevers Smarajit Banik, Sabyasachi Mukhopadhyay

23

6.

Diagnostic Challenges of Malaria in India Sarita Behera

28

7.

Changing Profile of Dengue Infection in India Prasanta Kumar Bhattacharya, Aakash Roy

32

8.

Dengue Profile in Guwahati PC Bhattacharyya, Manabendra Nayak, Lalit Mohan Bhardwaj

35

9.

Leptospirosis in Current Status Shobha Manish Itolikar

39

10.

Management of Kala-Azar – from Bench to Bedside Shyam Sundar, Jaya Chakravarty

42

11.

Viral Hemorrhagic Fever Debasis Chakrabarti

45

12.

Swine Flu Bala Vinoth, D Suresh Kumar

50

13.

Clinical Presentation and Systemic Manifestations of Zika Virus Rajib Ratan Chaudhary

54

14.

Typhoid Fever: An Index of Sanitation in India K Nagesh

59

15.

Typhoid Fever – Recent Management Uttam Kumar Paul

64

16.

Atypical Presentation of Typhoid Fever: A Case Report J Bhagwan, A Bansal, S Bansal

68

3

17.

Current Management: Filariasis Manoranjan Behera, Sidhartha Das, Jayanta K Panda

70

18.

Invasive Fungal Infections Ayesha J Sunavala, Rajeev Soman

76

19.

Mucormycosis: A Challenge Not Limited to Diabetics Ketan Patel, Swati Gohel, Atul Patel

81

20.

Management of Sexually Transmitted Infections (STI) Nitin Sinha

84

C H A P T E R

1

Basics of Prescribing Antimicrobial Drugs

INTRODUCTION

Alexander Fleming at his 1945 Nobel Prize lecture so rightly predicted, “The time may come when penicillin can be bought by anyone in the shops. There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”

In 2010, India was the world’s largest consumer of antibiotics for human health at 12.9 x 109 units (10.7 units per person). The next largest consumers were China at 10.0 x109 units (7.5 units per person). Seventy-six percent of the overall increase in global antibiotic consumption between 2000 and 2010 was attributable to BRICS countries, i.e., Brazil, Russia, India, China, and South Africa.

Antimicrobial drugs are not antipyretics. It is high time that prescribing antimicrobial is taken seriously and not as knee jerk reaction for any febrile illness.

Mahadev T Desai

a.

Which class to choose?

Classification of antimicrobial drugs based on

•

Site / Mechanism of Action: e.g. drugs inhibiting the cell wall, drugs inhibiting protein synthesis, drugs inhibiting nucleic acid synthesis or function.

•

Molecular structure: Drugs having beta lactum ring (BL), beta lactamase inhibitors (BLI), aminoglycoside ring, macrolide ring, etc.

•

Spectrum of activity: Gram positive, Gram negative, Aerobic, Anaerobic.

b.

Spectrum of antimicrobial activities:

i.

Bacteriostatic or Bacteriocidal,

In immuno-competent patient and in minor illness bacteriostatic drugs are as good as bactericidal drugs.

•

Bactericidal drugs are those that kill target organisms. e.g. aminoglycosides, cephalosporins, penicillins, and quinolones.

•

Bacteriostatic drugs inhibit or delay bacterial growth and replication. e.g. tetracyclines, sulfonamides, and macrolides.

•

Some antibiotics can be both bacteriostatic and bactericidal, depending on the dose, duration of exposure and the state of the invading bacteria. e.g. aminoglycosides, fluoroquinolones, and metronidazole exert concentration-dependent killing characteristics; their rate of killing increases as the drug concentration increases.

ii.

Broad spectrum or Narrow spectrum

Broad spectrum anti bacterials are active against both Gram-positive and Gram-negative organisms e.g. tetracyclines, phenicols, fluoroquinolones, third and fourth generation cephalosporins.

Narrow spectrum anti bacterials have limited activity and are primarily useful against particular species of microorganisms e.g. glycopeptides are only effective against Gram-positive bacteria, Polymixins are active against Gram negative bacteria.

Aminoglycosides and sulfonamides are effective against aerobic organisms, and nitroimidazoles are effective against anaerobes.

DEFINITION

The word antimicrobial was derived from the Greek words anti (against), mikros (little) and bios (life) and refers to all agents that act against microbial organisms. The term “antimicrobials” include all agents that act against all types of microorganisms – bacteria (antibacterial), viruses (antiviral), fungi (antifungal) and protozoa (antiprotozoal).

This is not synonymous with antibiotics. Antibiotic was derived from the Greek word anti (against) and biotikos (concerning life). Thus, the word “antibiotic” refers to substances produced by microorganisms that act against another microorganism. By strict definition, antibiotics do not include antimicrobial substances that are synthetic (sulfonamides and quinolones), or semisynthetic (methicillin and amoxicillin).

CHECK LIST BEFORE PRESCRIBING AN ANTIMICROBIAL AGENT

For a successful outcome of an infectious illness, however minor or major, apart from the right diagnosis, the right drug in the right dose and for the right duration is very crucial.

One must take in to account various factors: 1) Drug factors, 2) Bug factors, 3) Patient factors 4) Combination of antimicrobial drugs and 5) Implications of abuse and misuse of antimicrobial drugs.

1.

DRUG FACTORS:

c. Indication of Therapeutic?

prescribing:

Prophylactic

or

INFECTION

4

Surgical antimicrobial prophylaxis should be given as per the national guidelines, taking in to account the local antibiogram.

Pharmacodynamics of a medicine correlates the concentration of the drug with its pharmacological or clinical effects. For an antibiotic, this correlation refers to the ability of the drug to kill or inhibit the growth of microorganisms. Antibiotics elicit their activity against bacteria by binding to a specific protein or structure in the organism.

-

Antimicrobials have to be administered within one hour before the incision

Remember: We should know RPC (Receptor binding (including receptor sensitivity),

-

Cefazolin (2 gm) or Cefuroxime (1.5 gm) or Cefaperazone + Salbactum (2 gm) are recommended for the most surgeries.

Post-receptor effects and Chemical interactions) of every drug that we use.

-

Single dose is recommended. Consider second intra-operative dose in prolonged surgery.

Antimicrobial drugs bring about their activities either by Concentration-dependant effect or by Time-dependant effect on organisms.

-

Duration of prophylaxis should not extend beyond 24 hours except for cardiothoracic surgery where up to 48 hours of prophylaxis is permissible.

d.

Pharmacokinetics (Pk) and Pharmacodynamic (Pd) parameters (Figure 1)

Concentration-dependant effect of antibiotics: Give High, Single daily dose: OD dose: Azithromycin, Levofloxacin, Aminoglycosides. Please do not prescribe. Azithromycin or Levofloxacin in twice a day dose.

•

Pk= What body does to a drug

Time-dependant effect of antibiotics: these drugs need to be given in divided doses:

Pharmacokinetics of a medicine deals with the movement of a drug from its administration site to the place of its pharmacologic activity and its elimination from the body.

BD, TDS or QDS doses e.g. Amoxicillin, Cephalosporin, Carbapenem.

When given intravenously, one should give infusion over 2 to 4 hours every 6 to 8 hourly.

Remember: We must be conversant with ADME (Absorption, Distribution, Metabolism, Elimination) of every drug that we use.

2.

BUG FACTORS (Table 1)

•

Pd= What a drug does to body

The dose and duration of antimicrobial drugs are different when given for prophylaxis than when given for therapeutic indications. Discussion about therapeutic indications is beyond the scope of this review.

a. Anticipated Organism(s) Antimicrobial Agents:

b.

Is the infection by one organism or multiple organisms (polymicrobial)?

Most infections can be treated with one drug.

However polymicrobial infections may require combination of different class of antimicrobial drugs or drugs working at synergistic or sequential manner.

3.

PATIENT (HOST) FACTORS

or

Immuno-competent

Patients having HIV infection, diabetes mellitus,

Gram Positive organisms

Gram Negative Organisms

Anaerobic organisms

Penicillin

Aminoglycosides

Metronidazole

1st / 2nd gen. Cephalosporines

Quinolones

Clindamycin

Macrolides

Extended spectrum

Penicillin

Tetracycline

2 /3 /4 generation cephalosporines

Newer Quinolone

Aztreonam

Linezolid

Imipenem

Vancomycin

Choramphenicol

rd

th

of

Every effort should be made to reach to the final diagnosis of the causative organism, pending which empiric antimicrobial may be started with provisional diagnosis of causative organism.

Table 1: Empirical choice of antibiotics till final reports are available

nd

choice

a. Immuno-compromised host

Fig. 1: Graph explaining drug distribution

and

receiving steroids or Immune-suppressant drugs should be considered as immuno-compromised host and should be treated accordingly b.

Special situations : pregnancy, children, renal failure, liver impairment

Special precautions have to be taken when antimicrobials are prescribed to pregnant women, children, elderly, and in presence of renal and hepatic impairment

c.

History of recent antibiotic exposure

Antimicrobial Stewardship Program places patient who has received antibiotics in previous 8 weeks in higher category and requires to be treated differently.

d.

Best time to take Antimicrobials?

Most antimicrobials are absorbed better when taken on empty stomach

Food, Antacids and Iron tablets reduce absorption of antibiotics.

4.

COMBINATION OF ANTIMICROBIAL DRUGS

Antibiotic combinations required and are lifesaving when indicated in situations such as

•

Seriously ill patients

•

Polymicrobial infections: burns, diabetic foot…

•

To achieve synergism

•

To prevent emergence of resistance as in case of Tuberculosis (TB)

•

Immunocompromised or Neutropenic patient with bacteremia

Rational combinations synergistic effects)

•

Sulfonamide + Trimethoprim

•

Amoxicillin + Clavulanate / Salbactum

•

Piperacillin + Tazobactum

Irrational combinations (Irrational parameters or No proven evidence)

•

Quinolone + Metronidazole / Tinidazole

•

Cefixime + Clavulanate

•

Cefixime + Ofloxacin

•

Cefpodoxime + Ofloxacin

•

Linezolid(600mg)+ Cefixime (200mg)

•

Azithromycin + Cefixime

5.

IMPLICATIONS OF ABUSE AND MISUSE

(Proven

additive

or

Pk/Pd

Unlike Nonsteroidal anti-inflammatory agents (NSAID) or other drugs which cause damage to individual patients and affect their families, misuse or abuse of antibiotics affect the society as a whole.

Important implications for the same may be as follows:

•

Adverse effects / Drug – Drug interactions

•

Extended hospital stay

•

Escalation of cost

•

“Collateral damage”: Ecological adverse effects of antimicrobial therapy

Selection of drug-resistant organisms & unwanted development of colonization or infection with MDR organisms

• Cephalosporins   risk of infection with VRE, ESBL, Acenatobacter & C. difficile Quinolones   risk of infection with MRSA, Pseudomonas aeruginosa •

Super-infection: Clostridium difficile

•

Resistance

A new era began in 2009, when New Delhi Metallobeta lactamase (NDM1) enzyme was isolated from Klebsiella pneumonie organisms. Later blaNDM1 gene was discovered which conferred resistance to carbapenems and all most all antimicrobial drugs.

The resistance quickly spread to other organisms.

NDM-1 began to be isolated from several other parts of India. Emergence of such bacterial species may be lethal for an individual patient and may lead to dangerous epidemics for society as a whole.

Avoiding use of unnecessary antibiotics in upper airway disease will be a great service to the society

CONCLUSIONS

Antimicrobial drugs are our treasured weapons to combat war against infectious agents. We must use our armaments judiciously and prudently. Prescribing antimicrobials for viral URTI and Gastroenteritis must be discouraged. Only rational combination of antimicrobial drugs should be prescribed. Always keep in mind Pk and Pd parameters.

If we miss the bus we have to blame our selves only. Save antimicrobials for our generation and more importantly, the next generation.

REFERENCES

1.

Center for Disease Dynamics, Economics & Policy (CDDEP).

2015. “State of the World’s Antibiotics, 2015.” CDDEP: Washington, D.C. 2. Laxminarayan R, Chaudhury RR. Antibiotic Resistance in India: Drivers and Opportunities for Action. PLoS Med 2016; 13: e1001974. doi:10.1371/journal.pmed.1001974 3. David Hooper, Shenoy Erica, Varughese Christy, Approach to therapy for bacterial diseases. Editors Dennis L. Kasper, Anthony Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Joseph Loscalzo. In Harrison’s Principles of Internal Medicine: 19th ed. Mc Graw Hill Education, New Delhi 2015: 930-46.

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CHAPTER 1

While prescribing antimicrobial to a pregnant woman or one who could be pregnant, one should be extremely careful in selecting a drug and must search for “Pregnancy Category” for prescribing such drug. In general prescribe only Category A and B drug. Reserve Category C drug for serious maternal infection.

C H A P T E R

2

Rational for Antibiotics – Guidelines

AN OVERVIEW OF BACTERIAL INFECTION

Bacteria, ubiquitous in nature, play an important role in maintaining the environment in which we reside. Only a small percentage of the world’s bacteria cause infection and disease. Bacteria are grouped as Gram positive and Gram negative based on the characteristics of their cell wall, as observed under a microscope after Gram staining (developed by HC Gram in 1882). Some bacteria which cannot be classified by Gram staining, e.g. Mycobacteria, requires special staining. Bacteria can also be classified as aerobes, obligate aerobes, facultative anaerobes and obligate anaerobes, based on their need for oxygen to grow.3 Clinical manifestations of bacterial infections: The human body, which contains about 1013 cells, routinely harbors about 1014 bacteria called as normal microbial flora. 4 Though all of the human organs are susceptible to bacterial infection, most often microorganisms stay in harmony with the host through mutual or commensal interactions.3,5 Each bacterial species has a predilection to infect certain organs and not others. For e.g. Neisseria meningitidis usually infects the meninges of the central nervous system causing meningitis or can infect the lungs causing pneumonia, however, it does not cause skin infection.3 Infectious disease is the clinically evident illness (viz. signs and symptoms) resulting from the infection, presence and growth of pathogenic bacterial agents in an individual host organism.5 The list of microorganisms infecting different sites of the human body are mentioned in Figure 1.6,7,8

ANTIBIOTICS - A BOON TO MANKIND

Infection was a major cause of morbidity and mortality, prior to the development of antibiotics. The treatment of infections faced a great challenge during those periods.9 Later in 1928, the discovery of Penicillin, a beta lactam antibiotic, by Alexander Fleming opened up the golden era of antibiotics.10,11,12 It marked a revolution in the treatment of infectious diseases and stimulated new efforts to synthesize newer antibiotics. The period between 1950s and 1970s is considered the golden era of discovery of novel antibiotic classes, with very few classes discovered since then.11,13 Table 1 enlists the different antibiotic classes with its mode of action and target infectious microorganisms.14 Antibiotics have played a vital role in achieving major advances in medicine and surgery. It has successfully

Mangesh Tiwaskar, Tanuja Manohar

prevented or treated infections that occur in patients with chronic diseases such as diabetes, end-stage renal disease or rheumatoid arthritis, complex surgeries such as organ transplants, joint replacements or cardiac surgery and in patients with chemotherapy treatments.15 Studies with antibiotics have also shown unexpected nonantibiotic effects that indicate a variety of other biological activities. The results exhibited a significant number of additional therapeutic applications of “antibiotics” as antiviral, antitumor or anticancer agents. In some cases, the alternative administrations have surpassed those of antibiotic activity in importance, such as in the treatment of cardiovascular disease or use as immunosuppressive agents. Unfortunately, the enormous requirement of these valuable drugs had a significant downside.1

ANTIBIOTIC RESISTANCE - MAGIC BULLETS AND MOVING TARGETS

The successful use of any therapeutic agent is always followed by the potential development of resistance to that agent from the time it is first employed.1 Alexander Fleming, who won a Nobel Prize for his discovery of Penicillin, had warned about the perils of antibiotic resistance.16 True to this prediction, resistance began to arise within 10 years of the large scale introduction of Penicillin.17 Initially, drug-resistant strains appeared in the hospitals, where most antibiotics were being used.

Streptococcus pyogenes resistant to Sulfonamide emerged in military hospitals in the 1930s while Penicillin Resistant Staphylococcus aureus confronted London civilian hospitals shortly after the introduction of Penicillin in the 1940s. Similarly, Streptomycin-resistant Mycobacterium tuberculosis appeared in the community soon after the discovery of this antibiotic.18 Over the years, more and more microorganisms, exposed to more and more antibiotics, eventually developed resistance to nearly all antibiotics that have been developed.19 (Table 2 enlists the resistance mechanisms of commonly used antibiotics1) As a result, the optimism during the initial period of antibiotic discovery was tempered by the appearance of therapeutic resistant bacterial strains.18

FACTORS INTENSIFYING ANTIBIOTIC RESISTANCE

Irrational use of antibiotics contributes to dramatically increasing antibiotic resistance. Irrational antibiotic use is a worldwide problem that causes significant mortality, morbidity and increased health-care costs.20 Following are some of the factors that drive antibiotic resistance: Clinical over-prescription and public misconceptions:

7

CHAPTER 2

Fig. 1: Overview of bacterial infections6,7,8 Table 1: Mode of action and target of antibiotic classes Antibiotic class; example

Mechanism of action

Activity or target species

Sulfadrugs; Prontosil

Inhibition of dihydropteroate synthetase

Gram +ve bacteria

β-lactams; Penicillin

Inhibition of cell wall biosynthesis

Broad-spectrum activity

Aminoglycosides; Streptomycin

Binding of 30S ribosomal subunit

Broad-spectrum activity

Chloramphenicols; Chloramphenicol

Binding of 50S ribosomal subunit

Broad-spectrum activity

Macrolides; Erythromycin

Binding of 50S ribosomal subunit

Broad-spectrum activity

Tetracyclines; Chlortetracycline

Binding of 30S ribosomal subunit

Broad-spectrum activity

Rifamycins; Rifampicin

Binding of RNA polymerase β-subunit Gram +ve bacteria

Glycopeptides; Vancomycin

Inhibition of cell wall biosynthesis

Gram +ve bacteria

Quinolones; Ciprofloxacin

Inhibition of DNA synthesis

Broad-spectrum activity

Streptogramins; Streptogramin B

Binding of 50S ribosomal subunit

Gram +ve bacteria

Oxazolidinones; Linezolid

Binding of 50S ribosomal subunit

Gram +ve bacteria

Lipopetides; Daptomycin

Depolarization of cell membrane

Gram +ve bacteria

Fidaxomicin (targeting Clostridium difficile)

Inhibition of RNA polymerase

Gram +ve bacteria

Dairylquinolines; Bedaquiline

Inhibition of F1F0 – ATPase

Narrow-spectrum activity (Mycobacterium tuberculosis)

Gram+ve – Gram positive organism, S – Svedbergs unit, DNA – Deoxyribonucleic Acid, RNA – Ribonucleic Acid Source: Kim Lewis14

INFECTION

8

Table 2: Modes of resistance of commonly used antibiotics Antibiotic class (examples)

Mode(s) of resistance

β-Lactams (Penicillins, Cephalosporins, Penems, Monobactams)

Hydrolysis, efflux, altered target

Aminoglycosides (Gentamicin, Streptomycin, Spectinomycin)

Phosphorylation, acetylation, nucleotidylation, efflux, altered target

Glycopeptides (Vancomycin, Teicoplanin)

Reprogramming peptidoglycan biosynthesis

Tetracyclines (Minocycline, Tigecycline)

Monooxygenation, efflux, altered target

Macrolides (Erythromycin, Azithromycin)

Hydrolysis, glycosylation, phosphorylation, efflux, altered target

Lincosamides (Clindamycin)

Nucleotidylation, efflux, altered target

Streptogramins (Synercid)

C-O lyase (type B streptogramins), acetylation (type A streptogramins), efflux, altered target

Oxazolidinones (Linezolid)

Efflux, altered target

Phenicols (Chloramphenicol)

Acetylation, efflux, altered target

Quinolones (Ciprofloxacin)

Acetylation, efflux, altered target

Pyrimidines (Trimethoprim)

Efflux, altered target

Sulfonamides (Sulfamethoxazole)

Efflux, altered target

Rifamycins (Rifampin)

ADP-ribosylation, efflux, altered target

Lipopeptides (Daptomycin)

Altered target

Cationic peptides (Colistin)

Altered target, efflux

Source: Davies J and Davies D

1

patients with non-bacterial infections, a practice that has important repercussions

Table 3: Resistance mechanisms of P. aeruginosa Upregulation efflux pumps

Resistant to antibiotics

MexEF-OprN

Carbapenems and Fluroquinolones

MexCD-OprJ

Fluorquinolones and some β-lactams

MexAB-OprM

Sulfonamides, β-lactams, Cephalosporins, Fluoroquinolones, Macrolides, Novobiocin, Tetracycline & Chloramphenicol

MexXY-OprM

Aminoglycoside

Adapted from : Fair RJ et al21

There are a plethora of ways by which humans have inadvertently escalated the evolution of resistance.21 Inappropriate prescriptions and over use of antibiotics contributed to the promotion of bacterial resistance.15 Worldwide, it has been evaluated that half of all medicines are prescribed, dispensed or sold inappropriately, and that half of all patients fail to take their medicine properly.20 An estimated two-thirds of global antibiotic sales occur without any prescription, while studies in Indonesia, Pakistan and India show that over 70% of patients are prescribed antibiotics. A vast majority - up to 90% - of injections are estimated to be administered unnecessarily.22 The determinants of irrational antibiotic use are mentioned below: 20,22,23,24 •

Very short consultation time - does not allow proper diagnosis

•

Prescription of antibiotics for non-bacterial infections: Clinicians prescribe antibiotics to

•

Polypharmacy - Too many medicines are prescribed per patient (Lack of trust in or delayed lab results, fear of clinical failure)

•

Antibiotic injections are used where formulations would be more appropriate

•

Prolonged prophylactic therapy

•

Prolonged empiric antimicrobial treatment without clear evidence of infection

•

Failure to narrow antimicrobial therapy when a causative organism is identified

•

Prescriptions do not follow clinical guidelines

•

Patients self-medicate inappropriately

•

Patients do not adhere to prescribed treatment

oral

Antibiotic overprescribing is associated with other problems, apart from spreading resistance, viz. Increased medicalization of self-limiting infectious conditions, increase of more severe diseases, length of disease, risk of complications, mortality rate, healthcare costs, risk of adverse effects and re-attendance due to infectious diseases.25 Misuse by the food Industry: The use of antibiotics in animal feed stocks has also aggravated the spread of resistance. Especially, their use for non-curative reasons such as prophylaxis, metaphylaxis and growth promotion accounted for up to 50% of all antibiotic consumption in the early 2000s.21

Diminished pharmaceutical investment: Antibiotic development is no longer considered to be an economically wise investment for the pharmaceutical industry as they are not as profitable as drugs that treat chronic conditions, such as diabetes, psychiatric disorders, asthma or gastroesophageal reflux.15 Additionally, regulatory hurdles have also muted the interest of major pharmaceutical companies.21

The legacy of the past decades in terms of antibiotic use and misuse has added to the development of bacterial resistance towards multiple drugs.18

SUPERBUGS AND SUPER-RESISTANCE

Many of the bacterial pathogens related with the epidemics of human disease, subsequent to antibiotic use, have evolved into multidrug-resistant (MDR) forms. The term “superbugs” refers to microorganisms with heightened morbidity and mortality due to multiple mutations conferring high levels of resistance to the antibiotic classes specifically recommended for their treatment.1 Staphylococcus aureus (MRSA, VISA and VRSA): S. aureus, a Gram positive, facultative anaerobic pathogen with both hospital and community acquired strains, is one among the most notorious superbugs.1,21 Following the discovery of Penicillin, it seemed that S. aureus infections were controllable; however, it proved to be a shortlived one. The landmark discovery and introduction of Methicillin was anticipated to be a sure defense against the penicillinases, but the appearance of Methicillin-resistant S.aureus (MRSA) within 3 years inexorably led to other multiantibiotic-resistant variants.1 MRSA is resistant to certain antibiotics, such as Methicillin, Dicloxacillin, Oxacillin, Cloxacillin, Nafcillin and closely related classes of drugs, such as Cephalosporins. The use of more powerful drugs than necessary for less serious infections could be a cause of MRSA expansion.27 The development of resistance has led to the frequent use of Vancomycin to treat MRSA infections. This greatly increased selective pressure has resulted in the emergence of MRSA isolates with reduced susceptibility to Vancomycin (Vancomycin intermediate Staphylococcus aureus - VISA strains) and to the appearance of Vancomycin-resistant S. aureus (VRSA strains) with high-level resistance to Vancomycin.28 Resistant Enterococci Including VRE: Resistant Enterococci primarily comprises of two species, E. faecalis and E. faecium, both of which are Gram-positive, facultative anaerobic, opportunistic pathogens. Both E. faecalis and E. faecium have high levels of resistance rates (30–50%) against the aminoglycosides Gentamicin and Streptomycin.21 Streptococcus pneumoniae: S. pneumoniae is a Grampositive, aerotolerant, anaerobic, opportunistic pathogen.

Clostridium difficile: C. difficile is a Gram-positive, obligate anaerobic, spore forming opportunistic pathogen. C. difficile can be community acquired, but has a particularly high rate of acquisition in hospitals. Patients hospitalized for over four weeks have an approximately 50% chance of contracting C. difficile, a known causative agent for antibiotic associated diarrhoea.21 A study by Pepin J et al. 29 showed that administration of fluoroquinolones emerged as the most important risk factor for Clostridium difficileassociated-diarrhea caused by a hypervirulent strain of C. difficile. β-lactam and Quinolone Resistant Enterobacter: Enterobacter is a genus of Gram-negative, facultative anaerobic, opportunistic pathogens. They are mainly known to exhibit antibiotic resistance through expression of an extensive variety of extended spectrum β-lactamases (ESBLs) and Carbapenemases including, Klebsiella pneumoniae Carbapenemase, Oxacillinases and several metallo-β-lactamases (MBLs).21 MDR Pseudomonas aeruginosa: P. aeruginosa is a gramnegative, facultative anaerobic, opportunistic pathogen.

It naturally has a host of siderophores (Fe3+ carriers) and pigments that allow it to evade the innate immune system. Furthermore, it has particularly discriminating outer membrane porins that make its outer membrane impermeable and thus naturally resistant to many antibiotics. It has a high propensity to form biofilms that can increase resistances to antibiotics by 100 to 1000 fold.

P. aeruginosa also has an extremely comprehensive efflux pump system. Upregulation of the efflux pumps results in resistance to an array of antibiotics. 21 (Table 3) Resistant Escherichia coli: Antibiotic resistance of E. coli has risen rapidly due to horizontal gene transfer. ESBL positive strains in bacteraemias have shown high cross resistance to Cephalosporins, Fluoroquinolones and Gentamicin. E.coli strains in multiple continents have also acquired the New Delhi Metallo-β-lactamase-1 (NDM-1) enzyme from Klebsiella pneumoniae, which confers a broad resistance to all β-lactams including Carbapenems except for Monobactam and Aztreonam.21 MDR Acinetobacter, MDR and Pan-drug-resistant Klebsiella pneumoniae, Resistant Neisseria Gonorrhoeae & Mycobacterium tuberculosis (MDR-TBTB and XDRTBTB) are the other vital resistant bacteria dominating the headlines of alarming resistance.21 The growing numbers of antimicrobial-resistant pathogens place a significant burden on healthcare systems and have important global economic costs. It results in high mortality and morbidity rates, increased treatment costs, diagnostic uncertainties and lack of trust

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CHAPTER 2

Human independent resistance: Though there is a pronounced human contribution to the evolution of bacterial resistance, there is also resistance that occurs in nature in the absence of human interference.21 Bacteria can be either intrinsically resistant to certain antibiotics or can also acquire resistance to antibiotics.26

It has a polysaccharide capsule that makes it naturally resistant to phagocytes. About 40% of strains are no longer susceptible to Penicillin, and its Penicillin resistance often correlates with resistances to Macrolides, Sulfamides, older Tetracyclines and early generation Cephalosporins.

The strain is also resistant towards the third-generation antibiotics.21

infection by advising for a microbiological testing (staining of secretions/fluids/exudates, culture and sensitivity, serological tests and other tests).39 Microbiological testing helps to identify the specific etiologic agent and provides information about the in-vitro activity of antimicrobial drugs against the microorganisms identified.40 It also assists the clinicians to decide whether the patient should be prescribed antibiotics, as they are often under pressure from patients who believe they need antibiotics. A negative microbiology test report can make it easier for the clinician to refuse unnecessary prescription of antibiotic.

Additionally, if the patient needs treatment immediately, the test results can help in choosing the most appropriate agent.41

INFECTION

10

Fig. 2: Common illness which requires Antibiotic therapy38 in orthodox medicine.30 Considering the complications associated with increasing antibiotic resistance, its high time to promote judicious and optimized use of antibiotics worldwide.

GUIDELINES FOR ANTIBIOTIC STEWARDSHIP

The rise of antibiotic-resistant bacteria, which represents a serious threat to public health, can be overcome by promoting the optimized use of existing antibiotic agents and preventing transmission of drug-resistant organisms through control of infection.31,32 Rationalizing the use of antibiotics is an important patient safety and public health issue in addition to being a national priority.33 The following guidelines can help clinicians to ensure appropriate use of antibiotic therapy.

Evaluate the infection by clinical diagnosis: The communication occurring within the consultation influences the treatment decision both for and against antibiotic prescription.34 Initial clinical diagnosis of an infection should always precede the clinician’s decision to prescribe antibiotics.35 The clinician should always consider whether or not antibiotic therapy is even necessary for the patient by weighing the benefits (efficacy, rapid recovery and comfort of patient) against the risks (antibiotic resistance, adverse effects) and costs of treatment. At the same instance, clinician should also keep in mind that many infections are self-limiting and that most of the patients just require supportive therapy to deal with the symptoms.36 It is of utmost importance to highlight that a clinician should never prescribe antibiotics for non-bacterial infections such as cold, flu & sore throats. Antibiotics tackle bacteria and hence should be restricted for the treatment of bacterial infections only.37,38 (Figure 2) Select an appropriate antibiotic therapy: Following a proper clinical diagnosis, a clinician should decide whether to direct a patient to a definitive therapy or an empirical therapy or a prophylactic therapy.

Definitive therapy: When the etiology of the infection is known, the clinician should proceed with definitive therapy. Firstly, the clinician should confirm the bacterial

Empirical therapy: Clinician should reserve empirical therapy for critical patients, where time is inadequate for identification and isolation of the infection causing bacteria.39 Empiric prescribing is based on the clinicians working knowledge or experience of what is most likely to be the pathogen causing the patient’s condition. E.g. certain elements of the presenting illness (such as site of infection) can help the clinician to predict a broad group of pathogens such as: skin and soft tissue: Gram positive cocci, urinary tract: Gram negative bacilli, intraabdominal: Gram-negative, Gram-positive and anaerobic organisms.35 Therefore, a common approach can be prescribing a broad-spectrum antibiotic agent as initial empiric therapy with an intention to cover multiple possible pathogens commonly associated with the specific clinical syndrome.23 Simultaneously, the clinician should ensure that the samples for microbiological testing are collected before starting the empirical therapy.42 Once microbiological results have aided in identifying the etiological agent, every attempt should be made by the clinician to narrow the spectrum of the antibiotic.23 Prophylactic therapy: Antibiotic prophylaxis should be prescribed to susceptible patients to prevent specific infections that can cause definite detrimental effects.39 Susceptible patients include pre-surgical patients, immunocompromised patients and patients with traumatic injuries.23 The selection of an antibiotic for prophylaxis should be based on known or likely target pathogens, for a short duration of time. A single dose of antibiotic should be recommended for surgical prophylaxis. Longterm prophylaxis should be administered only when the benefits outweigh the risk of resistance selection or propagation.42 Criteria for choosing an antibiotic drug: Appropriate antibiotic selection is vital to facilitate successful treatment of infections and minimize the development of antibiotic resistance.43 Once the etiology of an infection is known, the clinician should recommend a most narrow spectrum antibiotic which is cost-effective and least toxic for the shortest duration possible.36 While prescribing an antibiotic, clinicians should consider the following treatment guidelines:

(Vancomycin/Teicoplanin) and Sulphamethoxazole + Trimethoprim.44

EFFICACY

•

However, in scenarios where the causative agent is not known and a delay in initiating therapy would be life-threatening or risk serious morbidity, broad spectrum antibiotics, based on the likelihood of the pathogen(s), should be prescribed.44 Clinician should also make it a point to de-escalate the regimen as soon as the etiological agent is known.35

•

Monotherapy or combination therapy: In order to evade antagonism between drugs and undesirable side effects of several antibiotics, it is prudent to use a single agent wherever possible in antibiotic treatment.44 However, there are situations when the use of an antibiotic combination is desirable.

The situations are:

•

To achieve synergistic effect against the infection: Synergy of antimicrobial agents infers that the combined effect of the agents is greater than the sum of their independent activities when measured separately. For instance, in the treatment of serious infections for which rapid killing is essential, the combination of certain β-lactams and aminoglycosides exhibits synergistic activity against a variety of Gram-positive and Gramnegative bacteria (e.g. combination of Penicillin and Gentamicin to treat endocarditis caused by Enterococcus species). The addition of Gentamicin to Penicillin has been shown to be bactericidal, whereas Penicillin alone is only bacteriostatic and Gentamicin alone has no significant activity.23

•

Combination therapy also shortens the course of antibiotic therapy, e.g. combination of Penicillin or Ceftriaxone with Gentamicin for 2 weeks results in more rapid clearance of the infecting microorganism as compared to Penicillin or Ceftriaxone alone for 4 weeks.23 Other combinations that act synergistically are as follows: β–lactam antibiotic + β–lactamase inhibitor, β–lactam antibiotic + Glycopeptide

•

When critically ill patients require empiric therapy before bacteriological diagnosis: Combination therapy can be used in hospitalassociated infections to ensure that at least 1 of the administered antibiotic agents will be active against the suspected organism(s). E.g. if a patient hospitalized for several weeks develops septic shock and the blood culture reports the growth of Gram-negative bacilli, it would be appropriate to provide initial therapy with 2 agents that have activity against Gram-negative bacilli, particularly P. aeruginosa, which is both a common nosocomial pathogen and frequently resistant to multiple agents. Thus in this scenario, a combination of an antipseudomonal β-lactam with a fluoroquinolone or aminoglycoside could be advisable.23

• To extend antibiotic spectrum during polymicrobial infections: When infections are caused by polymicrobes (more than one organism), a combination therapy can be preferred as it would extend the antimicrobial spectrum beyond that achieved by a single agent. Most intra-abdominal infections are usually caused by multiple organisms with a variety of Gram-positive cocci, Gram-negative bacilli and anaerobes. Antimicrobial combinations, such as a third-generation Cephalosporin or a Fluoroquinolone plus Metronidazole, can be used as a potential treatment option in these cases and can sometimes be more cost-effective than a comparable single agent (e.g., a Carbapenem).23 Bronchiectasis, peritonitis, urinary tract infections and otitis media are the conditions considered as polymicrobial infections.39 •

To prevent the development of bacterial resistance with long term therapy: The development of resistant mutants in a bacterial population is the result of selective pressure from antibiotic treatment.

While combining antibiotics with 2 different mechanisms of action, the chance of a mutant strain being resistant to both antimicrobial agents is much lower than the chance of it being resistant to either one. Additionally, use of combination therapy prevents the resistant mutant population from emerging as the dominant strain and causing therapeutic failure. This is the reason why, combination therapy is considered as a standard for the treatment of infections like tuberculosis and the human immunodeficiency virus, where treatment duration is prolonged, resistance can emerge relatively easily and therapeutic agents are limited.23

•

Efficacy at the site of infection & tissue penetration – An antibiotic which is effective at the infected site and exhibits adequate target tissue penetration should be the preferred therapy.45 Antimicrobial

CHAPTER 2

Narrow spectrum or broad spectrum: The spectrum of the antibiotic selected by the clinician should be the narrowest to cover known or likely pathogens. For instance, patients undergoing procedures associated with high infection rates, those involving implantation of prosthetic material and those in whom the consequences of infections are serious should receive perioperative antibiotics.

The prophylactic antibiotic(s) should cover the most likely organisms and be present in the tissues when the initial incision is made, with adequate serum concentrations maintained during the procedure.

In such situations, a single dose of a Cephalosporin (such as Cefazolin) administered within 1 hour before the initial incision is appropriate for most surgical procedures; this practice targets the most likely organisms (i.e., skin flora), while avoiding unnecessary broad-spectrum antimicrobial therapy.23

11

Good Good

Good

Poor

Good

Good

Poor Good Fair Good

Good

Good

Good

Good

Good

Poor Good Poor Good (in high doses) Poor

Good

Good

Good

Good

Source: Wasserman S et al35

CSF – Cerebrospinal Fluid, GFR – Glomerular Filtration Rate

Fair Good

Fair

Good

Good Good

Good Urinary

Soft tissue

•

The clinician should consider pharmacokinetic and pharmacodynamic factors in determining the drug dose.47 The dosage should be high enough to ensure efficacy and minimize the risk of resistance selection, and low enough to minimize the risk of dose related toxicity.42

•

The clinician should ensure the most appropriate route of administration in antibiotic treatment. Oral/ enteral route of administration should be preferred in patients with mild-to-moderate infections.35 When using oral therapy for invasive infections (such as pneumonia, pyelonephritis, or abscesses), clinicians should select an agent that has excellent absorption and bioavailability (i.e., the percentage of the oral dose that is available unchanged in the serum). Examples of antibiotics with excellent bioavailability are Fluoroquinolones, Doxycycline, Linezolid, Trimethoprim-Sulfamethoxazole and Metronidazole.23 Clinicians should reserve intravenous antibiotics for severe infection or for certain sites such as the CSF, bacteraemia, endocarditis and bone & joint infections.35 New microbiological or other information (e.g. fever defervescence for at least 24 hours, marked clinical improvement; low C-reactive protein) should often permit a switch to oral antibiotic(s), or switch to an intravenous narrow spectrum alternative or cessation of antibiotics (if no infection is present).44

•

Antibiotic treatment should generally be continued for a maximum of 5 days or a shorter period if this is clinically appropriate; however, some specific conditions require a longer course of therapy (viz. endocarditis, osteomyelitis etc.)48

Good (if normal GFR)

Good Good Good Lung

Good

Good

Poor

Good Good (in high doses) Poor CSF

Good (in high doses)

Good (in high doses)

Poor

Co-trimoxazole Aminoglycosides Co-amoxiclav

Ceftriaxone

Bactericidal vs bacteriostatic therapy: An antibiotic that is able to kill an organism instead of inhibiting its growth is preferred in few clinical settings. These include infections where the site of infection is not easily penetrated, e.g. in infections such as meningitis, endocarditis and osteomyelitis. Immunocompromised patients, in particular neutropenic patients, are also usually recommended for “cidal” therapy.46

DOSAGE, ROUTE OF ADMINISTRATION AND DURATION

Ampicillin Infection site

Table 4: Tissue penetration profile of few antibiotics

concentrations attained at some sites (namely, ocular fluid, cerebrospinal fluid (CSF), abscess cavity, prostate and bone) are often much lower than serum levels. For example, first- and secondgeneration Cephalosporins and Macrolides are not recommended for central nervous system infections as they do not cross the blood-brain barrier. Fluoroquinolones are preferred oral agents for the treatment of prostatitis because they achieve high concentrations in the prostate. Daptomycin, an excellent bactericidal agent against Gram-positive bacteria, is inactivated by the lung surfactant, hence it is not useful for the treatment of pneumonia.23,35 The tissue penetration profile of a few antibiotics are mentioned in the table below.35 •

Ciprofloxacin

Ertapenem

INFECTION

Meropenem Vancomycin

Linezolid

Daptomycin

12

13

CHAPTER 2

Fig. 3: Summary algorithm for rationale prescription of antibiotic therapy with caution when benefits overweigh the risks.

Penicillins, Cephalosporins and Ethambutol are safe in pregnancy. In lactating mothers, Sulfa, Tetracyclines, Metronidazole, Nitrofurantoin and Quinolones are contraindicated.39,49

PATIENT FACTORS

The clinician should consider the age of the patient, immune status, pregnancy and lactation, associated conditions like renal and hepatic function, epilepsy etc. while choosing the antibacterial agent.49 •

Age: Patients at both extremes of age handle drugs differently, primarily due to differences in body size and kidney function.39

•

Allergy or intolerance - Clinicians should routinely obtain an evaluation of history of antibiotic allergy or intolerance.23

•

Hepatic and renal function: Usually, dose is reduced to prevent accumulation and toxicity in patients with reduced renal or hepatic function.

However, sometimes doses might need to be increased to avoid underdosing young healthy patients with rapid renal elimination or those with rapid hepatic metabolism due to enzyme induction by concomitant use of drugs such as Rifampin.23

•

•

Pregnancy and lactation: Human studies on safety of antibiotics in pregnancy and lactation are scarce, hence clinicians should prescribe it with utmost caution.23 Drugs with known toxicity or unestablished safety like Tetracyclines, Quinolones, Streptomycin, Erythromycin and Clarithromycin are contraindicated in all trimesters while Sulfa, Nitrofurantoin and Chloramphenicol are contraindicated in the last trimester. Drugs with limited data on safety like Aminoglycosides, Azithromycin, Clindamycin, Vancomycin, Metronidazole, Trimethoprim, Rifampicin and Pyrazinamide should be used

Recent antibiotic use - Eliciting a history of exposure to antimicrobial agents in the recent past (approximately 3 months) can also help the clinician in selecting an antimicrobial therapy. Because the causative microorganism for a current episode of infection emerged under the selective pressure of a recently used antimicrobial agent, it is likely to be resistant to that drug and/or drug class, and an alternative agent should be used.23

MONITORING RESPONSE TO THERAPY

The need for an antimicrobial therapy should be reviewed on a daily basis by reviewing laboratory evidence.44,35 Response to therapy depends on the nature and sensitivity of the agent, specificity of the drug, bioavailability and dosage. Longer the doubling time of the organism, longer the time it takes to respond. Thus a Streptococcal pneumonia can respond within 24-48 hours, but tuberculosis may take 28 weeks to respond.

The clinician should wait for the adequate period before changing the drug (e.g. Streptococcal pneumoniae infections 24-48 hours; E. coli 24-48 hours; Salmonella

INFECTION

14

typhi 4-7 days; Mycobacterium tuberculosis 2-8 weeks etc.). Drugs should be changed midway only when there is absolutely no response or there is no expected response and the sensitivity report also suggests resistance.49 Since non-compliance is also one of the causes for treatment failure,50 the clinician should ensure patient adherence to the therapy. Treatment should be continued until all pathogens are eliminated from the tissues or until the infection has been sufficiently controlled for the normal host defenses to eradicate it.51 Additionally, clinicians should work together with patients to ensure safe antibiotic use. Clinicians should remind patients to avoid sharing of medications with anyone, to take antibiotics as prescribed and to discard unused medication.36 An example of the rationale usage of antibiotic is summarized in the algorithm below. (Figure 3) Taking everything into account, it is important for the clinician to implement the “7D’s of optimal antibiotic therapy: right Drug, right Dose, appropriate Direction (route of administration), De-escalation to pathogendirected therapy, and right Duration of therapy, watch for and consider Drug to drug interaction, always evaluate for possible immune Deficiency” to optimize antibiotic use in clinical settings.

CONCLUSION

user/medicine/MMI/Files/Bacteria_Table.pdf, viewed on August 27, 2016.

7.

Patras K. Polymicrobial Infections: Perhaps The Rule, Not The Exception. 2013, Available at http://schaechter. asmblog.org/schaechter/2013/08/polymicrobial-infectionsperhaps-the-rule-not-the-exception.html, viewed on August 27, 2016.

8.

Pathogen Regulation Directorate. Pathogen safety data sheet-Infectious substances. 2011, Available at http://www. phac-aspc.gc.ca/lab-bio/res/psds-ftss/myco-pneu-eng.php, viewed on August 27, 2016.

9.

Runcie H. Infection in a pre-antibiotic era. J Anc Dis Prev Rem 2015; 3:125.

10. Antibiotics: One of the Greatest Discoveries of the 20th Century, Available at http://www2c.cdc.gov/podcasts/ media/pdf/Antibiotics_Short.pdf, viewed on August 27, 2016.

11. Minikel E. Chemical biology 16: infectious disease.2015; Available at http://www.cureffi.org/2015/11/05/chemicalbiology-16/, viewed on August 27, 2016.

12. Caramia G, Ruffini E. Proper antibiotic therapy- From penicillin to pharmacogenomic. Minerva Pediatrica 2012; 64:225-237.

13. Aminov RI. A brief history of the antibiotic era: lessons learned and challenges for the future. Frontiers in Microbiology 2010;1:1-7.

14. Kim Lewis. Platforms for antibiotic discovery. Nature Reviews Drug Discovery 2013; 12:371–387.

Antibiotics, the magic bullets, have represented a great revolution for humankind. The discovery of antibiotics has determined a new era in the treatment of infectious diseases and in the quality of life.53 However, extravagant use of antibiotics has resulted in the rise of multi-drug resistant bacteria- the so called “superbugs”. Infections caused by these emerging superbugs require urgent action as these infections tend to last longer, can increase the risk for complications and may even cause death. Therefore, it is essential to use antibiotics in an optimal manner to prevent this rapidly growing issue. Only appropriate use of existing antibiotics can limit the spread of these superbugs. Antibiotics being a shared resource, should be preserved as a last weapon to treat patients and should be used only when the need is obligatory.

15. Ventola CL. The Antibiotic Resistance Crisis, Part 1: Causes and Threats. P T 2015; 40:277–283.

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16. Bushak L. A brief history of antibiotic resistance: How a medical miracle turned into the biggest public health danger of our time, Available at http://www.medicaldaily. com/antibiotic-resistance-history-373773, viewed on August 27, 2016.

17. Rosenblatt-Farrell N. The Landscape of Antibiotic Resistance. Environmental Health Perspectives 2009; 117:A244–A250.

18. Levy SB, Marshall B. Antibacterial resistance worldwide: causes, challenges and responses. Nature Medicine Supplement 2004; 10:S122-S129.

19. Nanotechnology solutions to combat superbugs 2013, Available at http://www.nanowerk.com/spotlight/ spotid=32188.php, viewed on August 27, 2016.

21. Fair RJ, Toi Y. Antibiotics and Bacterial Resistance in the 21st Century. Perspect Medicin Chem 2014; 6:25–64.

22. Rational use of medicines. The World Medicines Situation;2004, Available at http://apps.who.int/ medicinedocs/en/d/Js6160e/10.html, viewed on August 27, 2016.

23. Leekha S, Terrell CL, Edson RS. General Principles of Antimicrobial Therapy. Mayo Clin Proc 2011; 86:156–167.

24. Global Antibiotic Resistance Partnership (GARP) - India Working Group. Rationalizing antibiotic use to limit antibiotic resistance in India. Indian J Med Res 2011; 134:281– 294.

25. Llor C, Bjerrum L. Antimicrobial resistance: risk associated

with antibiotic overuse and initiatives to reduce the problem. Ther Adv Drug Saf 2014; 5:229–241.

26. Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV. Molecular mechanisms of antibiotic resistance. Nature Reviews: Microbiology 2015; 13:42-50.

27. Navidinia M. The clinical importance of emerging ESKAPE pathogens in nosocomial infections. Journal of Paramedical Sciences 2016; 7:43-57.

28. Gardete S & Tomasz A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest 2014; 124:2836–2840.

30. Santajit S, Indrawattana N. Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens. BioMed Research International 2016;2016(Article ID 2475067):8 pages, 31. Nathwani D, Sneddon J. Practical guide to antimicrobial stewardship in hospitals. Available at http://bsac.org. uk/wp-content/uploads/2013/07/Stewardship-BookletPractical-Guide-to-Antimicrobial-Stewardship-inHospitals.pdf, viewed on August 27, 2016.

32. Antibiotic Resistance Threats in the United States. 2013; Available at http://www.cdc.gov/drugresistance/threatreport-2013/pdf/ar-threats-2013-508.pdf#page=6, viewed on August 27, 2016.

33. Core Elements of Hospital Antibiotic Stewardship Programs, Available at http://www.cdc.gov/getsmart/ healthcare/implementation/core-elements.html, viewed on August 27, 2016.

34. Cabral C, Ingram J, Lucas PJ, Redmond NM, Kai J, Hay AD, Horwood J. Influence of Clinical Communication on Parents’ Antibiotic Expectations for Children With Respiratory Tract Infections. Ann Fam Med 2016; 14:141147.

35. Wasserman S, Boyles T, Mendelson M. A pocket guide to antibiotic prescribing for adults in South Africa 2014; Available at http://www.fidssa.co.za/Content/Documents/ SAASP_Antibiotic_Guidelines_2015.pdf, viewed on August 27, 2016.

36. Modern Approaches to Managing Bacterial Infections.

In: Tindall WN, Sedrak MM, Boltri JM. Patient-Centered Pharmacology: Learning System for the Conscientious Prescribe; Unit 2, Chapter 17, p 312-313.

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40. Washington JA. Principles of Diagnosis. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996.

41. Kolmos HJ, Little P. Should general practitioners perform diagnostic tests on patients before prescribing antibiotics?

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42. Moulds R, Rao G, Tevita S, Waqanibete I, Tikoduadua L, Wata T et al. Antibiotic Guidelines 2011; 3rd edition.

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43. Marcia Frellick. Clinicians and Antibiotic Prescribing: Should They Know Better? 2015; Available at http://www. medscape.org/viewarticle/837039, viewed on August 27, 2016.

44. National Treatment Guidelines for Antimicrobial Use in Infectious Diseases 2016; version 1, Available at http:// www.ncdc.gov.in/writereaddata/linkimages/AMR_ guideline7001495889.pdf, viewed on August 27, 2016.

45. General antibiotic prescribing pitfalls. Available at http:// www.jbpub.com/physicianspress/antibioticpitfalls.htm, viewed on August 27, 2016.

46. Ernst EJ. Infectious Diseases: Introduction. In Richard A, Quan DJ, Herfindal ET, Gourley DR, Zeind CS, Hudson JQ, Gourley GK et al. Textbook of Therapeutics: Drug and Disease Management; 8th edition, Lippincott Williams & Wilkins;2006. Chapter 72; p 1851.

47. Introduction to Pharmacokinetics and Pharmacodynamics.

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48. Catchpole C. In: Worcestershire Acute Hospitals NHS Trust. 2013; Titled as 5 day Stop/ Review Date Policy for Antimicrobial Prescriptions, viewed on August 27, 2016.

49. Kakkilaya BS. Rational Medicine. 2008, Available at http:// www.rationalmedicine.org/antibiotics.htm, viewed on August 27, 2016.

50. Kardas P. Patient compliance with antibiotic treatment for respiratory tract infections. J Antimicrob. Chemother 2002; 49:897-903.

37. Balzer D. Mayo Expert Discusses Antibiotics Overuse and Misuse. Available at http://newsnetwork.mayoclinic.org/ discussion/mayo-expert-discusses-antibiotics-overuseand-misuse/, viewed on August 27, 2016.

51. General principles of the treatment of infection. In Davey P, Wilcox M, Irving W, Thwaites G. Antimicrobial Chemotherapy; 7th edition. Oxford University Press. 2015; Chapter 13:p 137-138.

38. Antibiotics Aren’t Always the Answer. Available at http:// www.cdc.gov/features/getsmart/, viewed on August 27, 2016.

52. Doron S, Davidson LE. Antimicrobial Stewardship. Mayo Clin Proc 2011; 86:1113–1123.

53. Cascioferro S, Schillaci D. The Future of Antibiotic: From the Magic Bullet to the Smart Bullet. J Microb Biochem Technol 2014; 6:e118.

CHAPTER 2

29. Pépin J , Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium Difficile associated diarrhea: a cohort study during an epidemic in Quebec.

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C H A P T E R

3

Pyrexia of Unknown Origin Physician’s Challenge Asha N Shah

PUO(FUO) should be reserved for prolonged febrile illnesses without an established etiology despite intensive evaluation and diagnostic testing. FUO remains a challenging diagnostic problem with all the physicians.

With the development of better diagnostic techniques, the

Table 1: Definition of PUO Original (1961, petersdorf and Beteson)

• Temperature >1010 F(38.3 C) on several separate occasions • Fever lasting for more than 3 weeks • Evaluation of at least one week in hospital

Revised (1991)

• Temperature of >1010F on several separate occasions • Fever lasting more than 3 weeks • Evaluation of at least 3 outpatient visits or 3 days in inpatient care

New

• Temperature >1010F documented clinically on several separate occasions

cause of fever is often found before three weeks of illness and therefore only more difficult to diagnose cases meet the definition of FUO as given in Table 1.

The etiologies of the PUO have changed over time because of shifting disease patterns and new diagnostic techniques. In general, infection accounts for about 20–25% of cases of PUO in Western countries; next in frequency are neoplasms and noninfectious inflammatory diseases (NIIDs). In tropical and subtropical areas(INDIA), infections are a much more common cause of PUO), while the proportions of cases due to NIIDs and neoplasms are similar. Up to 50% of cases caused by infections in patients with PUO outside Western nations are due to tuberculosis, which is a less common cause in the United States and Western Europe.

CAUSES

More than 200 causes of PUO have been described in literature. The causes for PUO are extensive, but it is important to remember that PUO is far more often caused by an atypical presentation of a rather common disease than by a very rare disease.

1.

Bacterial: Tuberculosis, typhoid fever and other salmonelloses, Abdominal abscess, appendicitis, cholangitis, cholecystitis, endocarditis, epidural abscess, infected vascular catheter, infected joint prosthesis, infected vascular prosthesis, infectious arthritis, intracranial abscess, liver abscess, lung abscess, mastoiditis, osteomyelitis, pelvic inflammatory disease, prostatitis, pyelonephritis, urinary tract infection.

2.

Unusual infections: Actinomycosis, atypical mycobacterial infection, brucellosis, Campylobacter infection, Chlamydia pneumonia infection, chronic meningococcemia, gonococcemia, legionellosis, leptospirosis, Lyme disease, rickettsiosis, syphilis, tick-borne relapsing fever (Borrelia duttonii), Whipple’s disease (Tropheryma whipplei), yersiniosis.

3.

Parasitic: Malaria, Amebiasis, babesiosis, echinococcosis, malaria, schistosomiasis, strongyloidiasis, toxoplasmosis, trypanosomiasis.

• Duration of illness >3weeks • Non immunocompromised (neutropaenia>1 week ,known HIV, Hypogammaglobulinaemia or use of steroids >10mg *2weeks in 3 months prior to fever • Appropriate initial diagnostic work up does not reveal the etiology of the fever(erythrocyte sedimentation rate or C-reactive protein, hemoglobin, platelet count, leukocyte count and differentiation, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, antinuclear antibodies, rheumatoid factor, microscopic urinalysis, ferritin, three blood cultures, urine culture, chest X-ray, abdominal ultrasonography and tuberculin skin test.

4. Viral: Dengue, coxsackie virus infection, cytomegalovirus infection, Epstein-Barr virus infection, hepatitis (A, B, C, D, E), herpes simplex, HIV infection, parvovirus infection.

5.

Non infectious autoimmune diseases: Ankylosing

histiocytosis, multiple myeloma, myelodysplastic syndrome, myelofibrosis, non-Hodgkin’s lymphoma, plasmacytoma, systemic mastocytosis, vaso-occlusive crisis in sickle cell disease

Table 2: Potential Diagnostic clues Clues

Possible diagnosis

*Exposure • fresh water exposure

Leptospirosis

• living conditions (homeless)

Tuberculosis

• pets ,wild animals

10.

Defective thermoregulatory causes: Brain tumor, cerebrovascular accident, encephalitis, hypothalamic dysfunction

*Medical history • Abdominal disorders

Alcoholic hepatitis,

11.

Drug Fever: Barbiturates, carbamazepine, phenytoin, Carbapenems, cephalosporins, erythromycin, Isoniazid, Minocycline.

• History of transfusions

HBV, HCV, HIV

• Malignancy

Metastasis

• Psychiatric illness

Factitious fever

• Recent hospitalization

Nosocomial infection

*High risk behavior Abscess,endocarditis.

*Physical • rash(erythema multiforme,petechiae)

Adenovirus,herpes,tick borne

• Conjunctivitis/uveitis

Adult stills disease,SLE

• Hepatosplenomegaly

Lymphoma, Leptospirosis

• Polyarthralgia

IBD, Chikungunya

• Lymphadenopathy

Cat scratch disease,EBV,CMV

spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s disease, cryoglobulinemia, dermatomyositis, Felty syndrome, gout, mixed connective-tissue disease, polymyositis, pseudogout, reactive arthritis, relapsing polychondritis, rheumatic fever, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus.

6. Vasculitis: Allergic vasculitis, Churg-Strauss syndrome, giant cell vasculitis/polymyalgia rheumatica, granulomatosis with polyangiitis, hypersensitivity vasculitis, Kawasaki’s disease, polyarteritis nodosa, Takayasu arteritis.

7.

Granulomatous :Sarcoidosis

8.

Autoinflammatory syndrome: Adult-onset Still’s disease, CAPS (cryopyrin-associated periodic syndromes), Crohn’s disease, familial Mediterranean fever, hemophagocytic syndrome, juvenile idiopathic arthritis.

9. Malignancy: a. Haematological malignancyAmyloidosis, angioimmunoblastic lymphoma, Hodgkin’s disease, hypereosinophilic syndrome, leukemia, lymphomatoid granulomatosis, malignant

STUDIES

Evaluation

The most important and primary approach to these patients are thorough history taking, proper clinical examination and obligatory investigations. PDCs are defined as all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis are given in Table 2.

History: The history should include information about the fever pattern (continuous ,intermittent ,remittent or recurrent) and duration, previous medical history, present and recent drug use, family history, sexual history, recent and remote travel, unusual environmental exposures associated with travel or hobbies, and animal contacts.

One of the first steps should be to rule out factitious or fraudulent fever, particularly in patients without signs of inflammation in laboratory tests. All medications, including nonprescription drugs and nutritional supplements, should be discontinued early in the evaluation to exclude drug fever Physical examination: special attention to the eyes, lymph nodes, temporal arteries, liver, spleen ,sites of previous surgery, entire skin surface, and mucous membranes.

In patients without PDCs or with only misleading PDCs, fundoscopy by an ophthalmologist may be useful in the early stage of the diagnostic workup.

FDG PET SCAN

FDG-PET is based on the increased uptake of FDG (fluorodeoxyglucose) by activated inflammatory cells, which occurs in infection, NIID and malignancy. FDGPET/CT is a non-invasive imaging technique with high diagnostic yield and should therefore be performed early in the investigation of FUO. FDG-PET was helpful in 40% and FDG-PET/CT in 54% of cases. But in countries like India where FDG PET scans are not readily available ,relatively more cases of PUO remains undiagnosed.

TREATMENT

The emphasis in patients with PUO is on continued observation and examination with avoidance of “Shotgun” empirical therapy. However, vital signs instability or neutropenia is an indication for empirical

CHAPTER 3

Solid tumours - most solid tumors and metastases can cause fever. Those most commonly causing PUO are breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas

Brucellosis

• recent travel to areas with endemic diseases

• intravenous drug user

b.

17

Approach to patients of pyrexia of prolonged duration

18

Pa�ents with temperature >1010F on several occasions Comprehensive history and physical examina�on looking for diagnos�c clues Clues found?

yes

Order appropriate tests

INFECTION

No    

Perform minimum diagnos�c work up Complete blood count,chest radiography,urinalysis,urine culture ESR,CRP,electrolyte panel,liver enzymes LDH,crea�nine kinase,Blood cultures,ANA,RF, serological tes�ng(EBV,CMV,HIV) PPD test, interferon gamma assay(TB),abdominal and pelvic USG or CT imaging

No yes Diagnosis evident ?

Complete appropriate evalua�on and treatment Meets the defini�on of fever of unknown origin

Addi�onal diagnos�c work up  Measure ferri�n level  Cryoglobulins  An� neutrophilic cytoplasmic an�bodies  Serum protein electrophoresis  Complement studies  Thyroid tes�ng  At last, �ssue biopsy(lymph node ,liver temporal artery, bone marrow) or 18 FDG PET scan therapy with fluoroquinolone plus piperacillin. If Mantoux test is strongly positive and granulomatous disease is suggested (and sarcoid seems unlikely) then a therapeutic trial for tuberculosis should be undertaken with treatment continued for up to 6 weeks. A failure of the fever to respond over this period suggests other alternative diagnosis. A response of rheumatic fever and still’s disease to aspirin and NSAIDs may be dramatic.

Effects of glucocorticoids on temporal arteritis and polymyalgia rheumatica and granulomatous hepatitis are equally dramatic. Steroids are not to be given early in the course as they may mask various PDCs of the diseases. In patients with a suspected autoinflammatory disorder the interleukin-1 receptor antagonist, anakinra, can be tried.

Remission of symptoms is expected within 24–48 hours.

If anakinra is ineffective after two weeks of treatment,

a beneficial effect should not be expected and the drug should be stopped.

Patience, compassion, equanimity, vigilance and intellectual exibility are indispensable attributes for the clinician in dealing successfully with PUO.

PROGNOSIS

REFERENCES

1.

Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961; 40:1-30.

2.

Bandyopadhyay D, Bandyopadhyay R, Paul R, Roy D. Etiological study of fever f unknown origin in patients admitted to medicine ward of a teaching hospital of Eastern India. J Global Infect Dis 2011; 3:329-33

Longo D, Fauci A, Kasper D (Eds), Fever of unknown origin, Harrison’s Principles of Internal Medicine, 19th edition. McGraw Hill,e-chapter 26

4.

Bilgul Mete, Ersin Vanli, Mucahit Yemisen, Ilker Inanc Balkan, Hilal Dagtekin, Resat Ozaras, Nese Saltoglu, Ali Mert, Recep Ozturk, Fehmi Tabak Int J Med Sci 2012; 9(8): 682–689. Published online 2012 Oct 1. doi: 10.7150/ijms.4591

5.

Ergönül O, Willke A, Azap A, Tekeli E. Revised definition of ‘fever of unknown origin’: limitations and opportunities. J Infect 2005; 50:1–5.

6.

Varghese GM, Trowbridge P, Doherty T. Investigating and managing pyrexia of unknown origin in adults. BMJ 2010; 341:C5470.

7.

Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci 2012; 344:307–316.

8.

de Kleijn, EM, Vandenbroucke, JP, van der Meer, JW. Fever of unknown origin (FUO). I. A prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group. Medicine (Baltimore) 1997; 76:392–400.

19

CHAPTER 3

The overall prognosis of FUO is determined by the underlying disease. In patients in whom no cause of FUO can be established, prognosis is generally good and mortality is low. Up to 75% of patients experience spontaneous remission of fever, although this may take a long time. Treatment with NSAIDs or corticosteroids increases this proportion even further.

3.

C H A P T E R

4

Vectors are organisms that transmit pathogens from one infected individual to another causing serious disease in human population. Mosquitoes are the best known disease vectors. Others include ticks, flies, sandflies, fleas, bugs and some freshwater aquatic snails. Some of the world’s most destructive diseases are vector borne which account for over 17% of all infectious diseases.

Vector-borne diseases (VBDs) are among the most complex of all infectious diseases to predict, prevent or control. Not only is it difficult to predict the habits of the vectors, but most vector-borne agents can infect animals as well. Mosquitoes and ticks are notoriously difficult to reach and often develop resistance to insecticides. Almost all vector-borne pathogens are zoonoses which can live in animals as well as in humans. Only a few vector borne diseases can be prevented by use of vaccines.

Every year there are more than 1 billion cases and over 1 million deaths from VBDs globally.

Vector Borne Diseases Falguni S Parikh

authorities. Control of these diseases need unified efforts from medical fraternity, law makers and the community.

DENGUE FEVER

Dengue is a mosquito borne viral infection transmitted

by Aedes mosquito. It presents as fever and joint pains.

Acute febrile illness can vary in severity over 5–7 days.

Febrile Phase lasts 2–7 days after being bitten and can be biphasic. Headache, retro-orbital pain, joint pains, muscle and/or bone pain, rash, mild bleeding (nose or gums, easy bruising), neutropenia can occur with fever. Critical phase begins at defervescence, lasts 24–48 hours. Most patients improve but some may require hospitalization.

Warning signs include evidence of plasma leakage– abdominal pain, persistent vomiting (at least 3 episodes/24 hours), fluid accumulation, liver enlargement >2 cm, mucosal bleeding, lethargy or restlessness, hemoconcentration (high hematocrit) with rapid thrombocytopenia.

Rising deforestation and urbanization along with poor irrigation and water system, poor waste disposal and water storage are contributing to rise in Vector borne diseases. The World Health Day 2014 campaign, ‘small bite: big threat’ was aimed at raising awareness about the threats posed by insect vectors and the bacteria, viruses, and parasites they carry, and to motivate families and communities to protect themselves through simple measures.

Recovery phase is characterized by gradual reabsorption of extravasated fluid from plasma leakage over 48–72 hours; diuresis and stabilization of hemodynamic status.

Bradycardia is often observed.

Important vector borne diseases relevant for India are Malaria, Dengue fever, Japanese encephalitis, chikungunya , Kala Azar and lymphatic filariasis . The most widely known vector-borne diseases in the U. S. are West Nile virus, Lyme disease and Rocky Mountain spotted fever.

Global incidence of the disease has increased with half of the world’s population at risk. Dengue is endemic in India and outbreaks occur every year.

The risk of rare or new vector-borne pathogens continues to emerge and spread with rapid global travel and changes in agricultural practices and land use. In India urbanization, improper sanitation and widespread constructions cause breeding of the vectors which is a huge public health concern. The world’s fastest growing vector-borne disease is dengue, with a 30-fold increase in disease incidence over the last 50 years. The most deadly vector-borne disease, malaria, caused an estimated 627 000 deaths in 2012.The recent scare caused by Zika virus is a testimony to the fact that medical community needs to be always on the alert against vector borne diseases.

These diseases need to be notified to the local health

Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS) are severe forms of illness which can cause death. Secondary dengue infection is a risk factor for DHF.

The detection of dengue fever is by detection of NS1 antigen, IgM or IgG by ELISA method. The rapid tests for diagnosis of dengue are not reliable. The treatment of dengue fever is symptomatic mainly fluid resuscitation and antipyretics. Early detection and appropriate medical care reduce mortality in dengue fever. Recognizing warning signs for severe dengue and providing appropriate medical management can prevent morbidity and death.

Dengue Vaccine

Dengue vaccine development platform has progressed forward over the past few years, with a number of vaccine candidates in different phases of clinical trial.

Dengue vaccine is approved in some countries but it is not available for commercial use as yet in India.

CHIKUNGUNYA

Chikungunya is a viral disease transmitted to humans by infected mosquitoes. Chikungunya virus was first isolated from the blood of a febrile patient in Tanzania in 1953.

Currently in 2016, the big epidemic is going on and a total of 14656 clinically suspected have been reported.

It causes fever and severe joint pains. Patients also complain of muscle pains, nausea, rash and headache.

Joint pains can be very debilitating and may last from weeks to months. It shares some signs with Dengue.

The confirmation of Chikungunya is through any one of the following: 1.

Isolation of virus

2.

RT-PCR

3.

Detection of IgM antibody

4.

Demonstration of rising titre of IgG ( four fold)

There is no cure for the disease. Treatment is aimed at relief of symptoms. There is no vaccine for chikungunya.

Most patients recover fully however some may have joint pains for years. Neurologic, cardiac and ophthalmologic complications have been described. Some patients have persistence or relapse of rheumatologic symptoms in the months following acute illness. Mortality is rare and occurs mostly in older adults.

ZIKA VIRUS DISEASE

Zika virus disease is an emerging viral (flavivirus) disease transmitted through the bite of an infected Aedes mosquito. This is the same mosquito that is known to transmit infections like dengue and chikungunya. Zika virus was first identified in the Zika forest of Uganda in 1947.

World Health Organization has reported 22 countries and territories in Americas from where local transmission of Zika virus has been reported.

Zika virus can also be transmitted from pregnant patients to the fetus intrapartum and during the time of delivery.

The major cause of panic and concern caused by the Zika virus is the development of microcephaly and congenital central nervous system malformations in newborn.

Other neurological syndromes like Guillain Barre Syndrome has been found to be temporally associated with Zika virus infection.

A majority of those infected with Zika virus disease either remain asymptomatic (up to 80%) or show mild symptoms of fever, rash, conjunctivitis, body ache, joint pains. Zika virus infection should be suspected in patients reporting with acute onset of fever, maculo-papular rash and arthralgia, among those individuals who travelled to areas with ongoing transmission during the two weeks preceding the onset of illness.

Based on the available information of previous outbreaks, severe forms of disease requiring hospitalization is uncommon and fatalities are rare. Zika virus specific Igm antibodies develop towards end of 1st week , but are generally positive starting near 4 day post onsetof symptoms and continuing for 12 weeks. Zika MACELISA is used for qualitative detection of zika virus IgM antibodies in serum. There is no vaccine or drug available to prevent/ treat Zika virus disease at present. World Health Organization has declared Zika virus disease to be a Public Health Emergency of International Concern (PHEIC) on 1st February, 2016.

JAPANESE ENCEPHALITIS

It is a leading cause of vaccine preventable disease.

It is caused by a flavivirus which can cause severe inflammation of the brain. Epidemics of JE are reported from many parts of India. Uttar Pradesh and Assam contribute to 81% of total JE burden in the country.

Virus is transmitted by infected culex mosquito- culex tritaenorhynchus. It is maintained in a cycle between mosquitoes and vertebrate hosts like pigs and wading birds. Humans are incidental hosts.

It presents like acute encephalitis like illness. Diagnosis is suspected in individuals who live in or have travelled to a JE-endemic area. To confirm JEV infection and to rule out other causes of encephalitis requires a laboratory testing of serum or, preferentially, cerebrospinal fluid.

Severe disease is characterized by rapid onset of high fever, headache, neck stiffness, disorientation, coma, seizures, spastic paralysis and ultimately death. The case-fatality rate can be as high as 30% among those with disease symptoms.

Of those who survive, 20%–30% suffer permanent intellectual, behavioural or neurological sequelae such as paralysis, recurrent seizures or inability to speak.

There is no cure for the disease. Treatment is focused on relieving severe clinical signs and supporting the patient to overcome the infection.

Safe and effective vaccines are available to prevent JE. WHO recommends that JE vaccination be integrated into

21

CHAPTER 4

In India it reemerged in 2006 as epidemic after remaining quiescent for almost three decades. Analysis of the recent Indian epidemic has suggested that the increased severity of the disease is due to a change in the genetic sequence, altering the virus’ coat protein, which potentially allows it to multiply more easily in mosquito cells. In India the first isolation of the virus was done in Calcutta in 1963.In 2015 a total of 27,553 clinically suspected cases have been reported.

Zika virus disease has the potential for further international spread given the wide geographical distribution of the mosquito vector, a lack of immunity among population in newly affected areas and the high volume of international travel. As of now, the disease has not been reported in India. However, the mosquito that transmits Zika virus, namely Aedes aegypti is widely prevalent in India.

22

national immunization schedules in all areas where JE disease is recognized as a public health issue.

All travelers to Japanese encephalitis-endemic areas should take precautions to avoid mosquito bites to reduce the risk for JE. Personal preventive measures include the use of repellents, long-sleeved clothes, coils and vaporizers. Travelers spending extensive time in JE endemic areas are recommended to get vaccinated.

Prevention of vector borne diseases:

INFECTION

1.

Reduction /elimination of vector breeding sites near domestic and peridomestic areas.

2.

Regular emptying and drying of containers used for water storage.

3.

Straining of stored water to remove mosquito larva and avoiding storage for over a week.

8.

Education of community.

9.

Early diagnosis and appropriate treatment.

10.

Use of chemoprophylaxis and preventable vaccines when applicable.

REFERENCES

1.

Guidelines for vector borne diseases. National vector borne disease control programme. Ministry of health and family welfare, Govt of India (NVBDCP).

2.

Dengue. Simmons CP, Farrar J et al N Engl J Med 2012; 366:1423-1432.

3.

Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. Hadinegoro SR, ArredondoGarcia JL, Capeding MR et al. for the CYD-TDV Dengue Vaccine Working Group. N Engl J Med 2015; 373:1195-1206.

4.

World health organization- disease fact sheets

5.

Centers for disease control and prevention- disease fact sheets

4.

Use of larvicides - Gambusia and guppy fish which consume the larvae.

6.

5.

Use of mosquito repellants, clothing like long sleeve shirts and long pants to avoid bites for personal protection.

Centers for Disease Control and Prevention National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Vector-Borne Diseases (DVBD)

7.

Zika Virus. Peterson LR, Jamieson DJ, Powers AM Honein MA.N Engl J Med 2016; 374:1552-1563.

6.

Well screened areas indoors and use of bed nets,

7.

Avoid outdoor activities at dawn and dusk when mosquito activity is high.

Tropical Fevers

C H A P T E R

5

Smarajit Banik, Sabyasachi Mukhopadhyay

INTRODUCTION

Tropical fevers are defined as infections prevalent in and unique to tropical and subtropical regions. Some of these occur throughout the year and some are seasonal.

Every year different parts of India are affected by different seasonal fevers in the post monsoon period including dengue, malaria, scrub typhus, leptospirosis, typhoid fever and some other fevers leading to very high morbidity and mortality. Most of them are difficult to diagnose due to overlapping clinical presentations, and needs early empiric treatment solely on the basis of clinical evaluation during presentations. However one must remember that many common infections, such as influenza and tuberculosis, common in the tropics and may have atypical presentations confusing the clinicians.

APPROACH TO A PATIENT WITH TROPICAL FEVER SYNDROME

In approaching a acutely ill febrile patient, a detailed medical history should be aimed at eliciting the presence of any underlying conditions, associated with increased risk of infections such as diabetes, neoplastic conditions, HIV infection, splenectomy, and pregnancy. Arthropod bites, sexual exposure, occupational risks, animal contact, and immunization and drug history should be specifically taken. The history of the current illness should pay attention on the duration (acute or chronic) and pattern of fever and geographic and travel history, both within and outside the country, to any specific endemic zone of some particular disease. Absence of a classical pattern of illness should not be counted to rule out any tropical infection (Table 1).

Localizing clinical symptoms and signs are very crucial, clues like headache; altered sensorium, myalgia and arthralgia; confusional states, seizures, photophobia, conjunctivitis; skin rashes and localised dermal lesions;

lymphadenopathy, hepatosplenomegaly; jaundice and anaemia (Table 3).

Knowledge of areas with recent outbreaks is very helpful in recognizing the clinical entity. The onset of illness in relation to known incubation periods and event of possible exposure can help to include or exclude various infectious diseases.

Only limited epidemiologic data is available from a few selected centres but the overall experience indicates that common tropical infections are dengue, malaria, rickettsial infections, leptospirosis, typhoid, bacterial sepsis and viral infections.

The tropical infections may be approached in the under the following syndromes.

1.

Acute undifferentiated fever: patients with acute onset fever without any localizing signs and symptoms for less than 2 weeks: malaria, dengue, leptospirosis, scrub typhus, typhoid, other common viral infections.

2.

Fever with rash / thrombocytopenia: Acute onset fever along with a transient skin rash or exanthems, might have thrombocytopenia (platelet count < 100,000) dengue, leptospirosis, measles, rubella, rickettsial infections, meningococcal infections, malaria (falciparum), other viral exanthems.

3.

Fever with ARDS: Acute onset fever with respiratory distress such as SpO2 <90% at room air or frank ARDS with PaO2/FiO2 ratio < 200 : scrub typhus, falciparum malaria, influenza (including H1N1), hantavirus infection, meliodosis, community acquired pneumonia.

4.

Acute Febrile encephalopathy / Acute encephalitic syndrome: Fever with altered mental status within 7 days of onset of fever.

Table 1: Usual incubation periods of some common tropical fevers Short (< 10 days)

Intermediate (1 â&#x20AC;&#x201C; 4 weeks)

Long (>1 month)

Variable

1. Arbo viral diseases

1. Malaria.

1. Brucellosis.

1. Filariasis.

2. Dengue.

2. Enteric Fever.

2. Leishmaniasis.

2. Brucellosis.

3. Chikungunya.

3. Leptospirosis.

3. Viral Hepatitis (B, E, A, C)

3. Amoebiasis.

4. CCHF.

4. Brucellosis.

5. Plague.

5. Toxoplasmosis.

6. SARS. 7. Tularaemia.

CCHF: Crimian Congo Haemorragic Fever.

4. Melioidosis.

24

Table 2 Type of exposure

Associated infections

INFECTION

Bites Mosquitoes

Malaria, dengue, viral encephalitis, yellow fever, filariasis, many arbovirus infections.

Ticks

Borreliosis (Lyme disease) rickettsioses, Crimian Congo haemorrhagic fever, Q fever, tularaemia, tick-borne encephalitis,

Biting flies

onchocerciasis, leishmaniasis

Fleas

Plague, tungiasis, murine typhus

Mites

Scrub typhus, rickettsial pox

Exposure to rodents and their excreta

Hantavirus infection, Haverhill fever, Lassa fever, leptospirosis, pasteurellosis, campylobacteriosis, yersiniosis

Ingestion Water (untreated)

Hepatitis A/E, cholera, noroviruses/calciviruses, salmonellosis, shigellosis, giardiasis, poliomyelitis, cryptosporidiosis, cyclosporiasis, dracunculiasis.

Dairy (unpasteurized)

Brucellosis, tuberculosis, listeriosis, Q fever, enteric bacterial infection(Salmonella spp., Shigella spp., Escherichia coli, Campylobacter jejuni, etc)

Raw or undercooked food (meat, fish, vegetables)

Helminth infections (ascariasis, trichinellosis, taeniasis, trichuriasis; cysticercosis), protozoa (amoebiasis, toxoplasmosis); viruses.

Freshwater skin & mucous membrane contact

Leptospirosis, schistosomiasis, free-living amoebic infection (Acanthamoeba spp., Naegleria fowleri, Balamuthia mandrillaris); environmental mycobacterial infection (e.g. M. marinum).

Sand/dirt/mud skin contact

Hookworm, strongyloidiasis, cutaneous larva migrans, leptospirosis, tungiasis, melioidosis; environmental mycobacterial and fungal infections

Injections, tattoos & body piercing, transfusions, acupuncture

Hepatitis B/C, HIV, malaria, mycobacteria (e.g. M. fortuitum, M. chelonei)

Sexual contact

HIV, hepatitis B/C, syphilis, herpes, disseminated gonococcal infections;

I.

Encephalitis â&#x20AC;&#x201C; HSV, Japanese B, enterovirus, west nile virus.

II.

Meningitis- S.pneumoniae, N. meningitides, H. influenzae.

III. Scrub typhus, encephalaopthy

cerebral

malaria,

typhoid

5.

Fever with multiorgan dysfunction:

I.

Bacterial sepsis, leptospirosis.

II.

Dengue, Hepatitis A or E with fulminant hepatic failure, Hantavirus infection.

III.

Macrophage activation syndrome.

malaria,

scrub

Table 3: Differential diagnoses of important physical findings that may be associated with some febrile illnesses.

Physical finding

Differential diagnosis

Lymphadenopathy

Plague, HIV, rickettsioses, brucellosis, leishmaniasis, dengue, infectious mononucleosis, tuberculosis,toxoplasmosis, tularaemia, anthrax, melioidosis, lymphatic filariasis

Hepatomegaly

Malaria, leishmaniasis, schistosomiasis, amoebic or pyogenic liver abscess, typhoid, hepatitis, leptospirosis, tuberculosis

Splenomegaly

Malaria, leishmaniasis, trypanosomiasis, typhoid, brucellosis, typhus, dengue, tuberculosis, toxoplasmosis, tularaemia, anthrax

Jaundice

Hepatitis, malaria, leptospirosis, relapsing fevers, enteric fever, dengue.

typhus,

Some specific exposures and associated infections are shown in Table 2.

I: ACUTE UNDIFFERENTIATED FEVER (TABLE 4)

Fever without any specific symptoms or localising signs is a common early feature of many infections, and clinical clues to the cause of such illnesses are likely to emerge as time progresses. It is important to consider infections that require specific urgent intervention. The common diseases

Table 4: Mentions the common causes of Acute undifferentiated fever Disease

Suggested investigations Raised transaminases, Blood culture; bone marrow culture; urine & stool culture; leucopenia, Typhidot®, a dot enzyme immuno assay offers simplicity, speed, specificity (75%), economy, early diagnosis, sensitivity (95%) and high negative and positive predictive values.

Culture and dark-field microscopy of blood not usually available; serology positive after 5-6 days of illness; prolonged PT(predictor of mortality), thrombocytopenia, elevated CPK with modest transaminase elevation.

A loop mediated isothermal system (LAMP) targeting the lipL41 gene is under evaluation.

Blood, sputum, pus culture; chest x-rays; serological test available in some countries.

Anemia, leucocytosis, elevated phosphatase and transaminases.

alkaline

Weil-Felix test is less sensitive and specific than specific serological tests; specific rickettsial IFA tests, IgM ELISA capture assay is most sensitive and should be requested.

Leucopenia, thrombocytopenia, relative lymphocytosis,, deranged hepatic and renal function tests, prolonged PT. Non-structural protein 1 antigen detection (Rapid card test) – Sensitivity 76-93%, Specificity >98%.

• IgM, IgG serology (IgG titer > 1:1280 is 90% sensitive and 98% specific).

CSF protein elevated, IgM capture ELISA Serum: sensitivity 85-93%, Specificity 96-98%, CSF: Sensitivity 65-80%, Specificity 89-100%.

MRI brain may show involvement of thalamus, brainstem, and basal ganglia.

Microscopy: Thick smears – parasite detection; Thin smears– species identification Quantitative buffy coat test, Rapid diagnostic tests (RDTs) – histidine rich protein, lactate dehydrogenase antigen based immune-chromatography (Level IA) Sensitivity and specificity > 95%. Malaria ruled out if two negative RDTs.

CHAPTER 5

Substantiating evidence, caveats, and clinical points Enteric fever Constipation more common than (typhoid and diarrhoea in early infection; relative paratyphoid) bradycardia; normal or low WCC; eosinophils absent; psychiatric symptoms may occur; dry cough is common; organomegaly less common now a days, rose spots in chest and abdomen in second week, caecal gurgling.6 Leptospirosis Early (4-7 days): non-specific flu-like illness, conjunctivitis, myalgia in calf and lumbar areas.

Remittent fever with headache, leucocytosis, maculopapular rash, lymphadenopathy, organomegaly is variably seen; in later immune phase, serious complications may occur eg. jaundice, hepato-renal failure, myocarditis, pulmonary haemorrhage, ARDS, Interstitial nephritis. arrythmias.

Melioidosis Underlying disease, notably diabetes or CKD, alcohol abuse, chronic liver or lung disease; age> 40 are risk factors.

Can be localized, septicaemic or chronic.

Pneumonia, multiple abcesses in liver, lung, spleen, kidneys, skin and septic arthritis.

Prevalent in foothills of Himalayas. Eschars are Rickettsial infections sometimes not detected in routine examinations; (scrub typhus) Fever with relative bradycardia, headache, apathy, lymphadenopathy and a dry cough.

Maculopapular rash on trunk and extremities, may develop Interstitial pneumonia, ARDS, myocarditis, meningoencephalitis, and AKI. Dengue Headache, fever with characteristic “Saddleback pattern”, malaise, poly-arthralgia, myalgia, conjunctivitis, abdominal pain,retroorbital pain and photophobia may be present. Morbilliform, blanching rash spreads centrifugally; petechiae, echymoses, purpura,bleeding from other mucosa. suspect development of Dengue shock syndrome if restlessness, prostration, hypothermia and narrow pulse pressure develops.

Japanese B Rural; summer epidemics in temperate Asia; encephalitis endemic in tropical Asia. Fever, headache, stupor, convulsions; polio-like disease in 15%; CFR up 30%, high rate of residual neurological deficit in survivors.

Malaria Paroxysm of fever, shaking chills and sweats occur every 48 or 72 h, depending on species.

Hepatosplenomegaly. Can be Manifestated as severe malaria: like • Cerebral malaria • Severe anemia • Hypoglycemia • Metabolic acidosis • AKI(serum creatinine > 3 mg/dl) • ARDS • Shock (“algid malaria”) • DIC • Hemoglobinuria • Hyperparasitemia (>5%).

25

INFECTION

26

Table 5: Causes of Fever and rash Petechial Rash

Maculopapular Rash Vesiculo-bulous Rash

Urticarial Rash

Erythematous Rash

Dengue Rubella Yellow Fever Atypical Measles.

EBV Meningococcaemia Rickettsiosis.

Parvo B 19 Rubeola Enterovirus Rubella Primary HIV Typhoid Chikungunya Leptospirosis Lyme Disease Chlamydia Mycoplasma Meningococcaemia

Adenovirus Enterovirus EBV HBV HIV Mycoplasma Lyme Disease

Enterovirus Streptococcal Staphylococcal Ehrlichiosis

Parvo B 19 Enterovirus HIV Staphylococcal Gonococcaemia Rickettsial Pox Varicella zoster Herpes simplex Mycoplasma

Table 6: Causes of fever and central nervous system signs and symptoms Syndrome

Pathogens or diseases

Substantiating evidence, caveats, and clinical points

Altered mental status; neuropsychiatric symptoms

Malaria

Coma is the extreme manifestation; residual neurological damage is uncommon

Typhoid fever

Neuropsychiatric symptoms are common; may mask the diagnosis.

Typhus (louse-borne)

Delirium, stupor are typical

Legionnairesâ&#x20AC;&#x2122; disease

Confusion is common in elderly patients; may be related to electrolyte disturbance

Brucellosis

Chronic fatigue, amnesia and depression are typical of chronic brucellosis, and may persist after treatment.

Arboviral infections: West Nile, St Louis, dengue, tickborne encephalitis, and others

AME is generally mild, but a small proportion of cases progress to more severe encephalitis. older patients are often more prone to develop this.

JE Virus.

Rapidly progressing signs and symptoms, residual motor and cognitive disability. High mortality rate observed.

Miscellaneous infections

Include mumps, LCM, HIV, secondary syphilis, enteroviruses, mycoplasmas.

Leptospirosis

Aseptic meningitis is typically a feature of the second phase of biphasic illness.

Rabies virus

acute encephalitis, heralded by headache, anxiety, sensory changes at bite site; excitement, aerophobia and hydrophobia; delirium, paresis, coma. Death in 2-6 days.

West Nile virus

Severe encephalitis in <1% of cases

Nipah virus

Causes severe and often fatal febrile encephalitis; animal hosts are fruit bats, pigs; outbreaks of NiV have occurred in Malaysia and Bangladesh.

Herpes simplex virus

Early onset of seizures and temporal and frontal lobe localising signs.

Acute meningoencephalitis (AME) or AES

Encephalitis

are malaria, dengue, rickettsial infections, leptospirosis, enteric fever.

II: FEVER WITH RASH / THROMBOCYTOPENIA (TABLE 5)

Causes of fever and rash can be life threatening and the extensive differential diagnosis makes the specific diagnosis very challenging. Thrombocytopenia usually occurs due to immune destruction, bone marrow suppression, DIC and sometimes due to hypersplenism.

The platelet counts can fall to as low as 5000/mm making

the patient predisposed to life threatening bleeding in the central nervous system or from the GIT. Both malaria and leptospirosis can have an associated derangement of the PT and APTT, whereas dengue usually presents with thrombocytopenia only. In a Mumbai study of patients with severe falciparum malaria738% had thrombocytopenia of which 6% required platelet transfusions.

III: FEVER WITH HEPATORENAL DYSFUNCTION

Diseases that can predominantly present with hepatorenal

dysfunction are falciparum malaria, leptospirosis, scrub typhus and hepatitis E or A with fulminant hepatic failure and/or the hepatorenal syndrome. Renal failure in patients with severe malaria presents with oliguria whereas patients with leptospirosis usually have a nonoliguric renal failure with hypokalemia where tubular dysfunction plays the role. Mild jaundice may also occur and common in enteric fever which could be due to hepatitis, cholangitis, cholecystitis or haemolysis.

Biochemical changes indicative of hepatitis are have frequently being reported during the acute stage of enteric fever.

REFERENCES

1.

Singhi S, Chaudhary D, Varghese GM, Bhalla A, Karthi N, Kalantri S, et al. Tropical fevers: Management guidelines.

Indian J Crit Care Med 2014; 18:62-9.

2.

Ashish Bhalla, Mary John; Syndromic Approach to Tropical Infections. Update on Tropical Fever. Association of Physicians of India.

3.

Frean J, Blumberg L. Tropical fevers part A. Viral, bacterial and fungal infections. Primer of Tropical Medicine. Ch. 5A. Brisbane:ACTM Publication; 2005. p. 1-18.

4.

Rapid diagnosis of typhoid fever : Indian J Med Res 2006; 123:489-492.

5.

S Jog, R Soman, T Singhal ; Enteric Fever in Mumbai â&#x20AC;&#x201C; Clinical Profile, Sensitivity Patterns and Response to Antimicrobials. JAPI 2008; 56:237-240.

6.

Vatsal M Kothari, Dilip R Karnad, Lata S Bichile; Tropical Infections in the ICU. Review Article. JAPI 2006; 54.

7.

Rajneesh Joshi, SP Kalantri; Acute Undifferentiated Fever: Management Algorithm. Update on Tropical Fever. API. 1-14.

8.

Singh MP, Majumdar M, Singh G, Goyal K, Preet K, Sarwal A, et al. NS1 antigen as an early diagnostic marker in dengue: Report from India. Diagn Microbiol Infect Dis 2010; 68:50-4.

9.

Guidelines for the Treatment of Malaria. 2nd ed. Geneva: World Health Organization; 2010.

TREATMENT APPROACH

The treatment approach should be aimed at achieving a definitive diagnosis as soon as possible, however, it may not always be possible. The prime objective in the emergency room is to stabilize the patient by taking care of the vitals, establishing a patent airway, maintaining oxygenation and a mean arterial pressure to have adequate tissue perfusion. This should preferably be done without any attempts of invasive monitoring as the patients with tropical infections may have associated thrombocytopenia or coagulopathy. Invasive monitoring can be reserved for the very sick and to be performed carefully after baseline laboratory data is available. Due consideration to blood or blood component therapy should be given before taking

27

CHAPTER 5

IV: FEVER AND CENTRAL NERVOUS SYSTEM INVOLVEMENT

A wide spectrum of pathogens are involved in this constellation of syndromes, and certain cosmopolitan infections should always be kept as differential diagnosis regardless of the geographic location or origin of the patient, e.g. meningococci, pneumococci, Haemophilus influenzaeb, Listeria monocytogenes etc, in the case of acute purulent meningitis. Severe headache is common symptom in many infections, especially malaria, rickettsial infections, typhoid fever and influenza; likewise, feverish patients often have non-specific abnormalities of consciousness. The different patterns can be broadly divided into following CNS febrile syndromes: altered mental status without overt CNS invasion; acute meningoencephalitis or AES; haemorrhagic or eosinophilic meningitis; and encephalitis (Table 6).

up invasive procedures. Isotonic fluid is preffered with an aim of maintaining haematocrit <33. Antipyretics and cold sponging should be used for fever control. Paracetamol in the therapeutic dose of 3 to 4 gram per day is safe but higher doses should be avoided. With the availability of antigen based rapid diagnostic kits, ruling out malaria and enteric fever is easy and should be done.Empiric chloroquine/ quinine/ artesunate is not recommended as indiscriminate use may potentiate drug resistance. It is safe to initiate doxycycline and Ceftriaxone which is recommended in indian guidelines also. They are effective in typhus, leptospirosis, enteric fever and acute pyogenic meningitis. However, the patient should be reviewed for alternative diagnosis if patient does not respond to empiric drug therapy in 48 hours.

C H A P T E R

6

INTRODUCTION

Malaria is a life threatening protozoal disease, transmitted by the infected Anopheline mosquitoes, caused by parasites known as Plasmodium (P) falciparum, P.vivax, P.malarie and P. ovale. The fifth species of plasmodium detected infecting humans in South-Eastern Asian countries since 2004 is P.knowlesi, commonly known as “monkey malaria parasite”.1

GLOBAL SCENARIO

It is a major public health problem responsible for substantial morbidity, mortality and economic loss.

Its transmission is ongoing in 108 countries containing 3billion people, out of which 1.2 billion are high risk cases and causing 1 million deaths each year.2 In 2015 WHO documented 214 million symptomatic cases and 438,000 deaths from malaria.2 P.falciparum malaria is the predominant infectious disease in tropical and subtropical countries with an estimated global incidence of 207 million cases and 627,000 deaths reported in 2012.

(WHO)3

INDIAN SCENARIO

At present official figures for malaria in India, available at National Vector Borne Disease Control Programme

Diagnostic Challenges of Malaria in India Sarita Behera

(NVBDCP) indicate 0.7-1.6 million confirmed cases and 400-1000 deaths annually.

According to World Malarial Report 2014, 22% (275.5m) of India’s population, live in high transmission (>1 per 1000 population) areas, 67% (858.9m) live in low transmission (0-1cases per 1000 population) areas and 11% (137.7m) live in malaria free (0 cases) areas4 (Figure 1).

With a population of 36.7 million (3.5%) the state of Odisha contributes about 25% of the total annual malaria cases, more than 40% of P. falciparum malaria cases and nearly 20-30% of deaths caused by malaria in India, followed by Meghalaya, Mizoram, Maharashtra, Rajasthan, Gujarat, Karnataka, Goa, Southern Madhya Pradesh, Chattisgarh and Jharkhand that also report significant number of malaria cases and deaths.4

DIAGNOSIS OF MALARIA

Malaria cases are diagnosed clinically and supported by laboratory investigations.

Clinical Diagnosis

The earliest symptoms of malaria are very non-specific and variable that includes fever with chill and rigor, headache, dizziness, anorexia, nausea, vomiting, loose motion etc. and very often they are received in secondary and tertiary care centres with complications like cerebral malaria, renal failure, hypoglycaemia, anaemia, respiratory distress or septicaemia. Clinical diagnosis of malaria is challenging in most tropical countries as it needs high degree of suspicion in both endemic and non-endemic areas, because malaria alone and with complications can mimic many other diseases like dengue fever, leptospirosis, influenza, hepatitis, enteric fever, scrub typhus, all types of viral encephalitis and gastroenteritis.

It must be considered in the differential diagnosis of sepsis in pregnant woman arising in the uterus or urinary tract.

The non-specific nature of clinical signs and symptoms of malaria may promote indiscriminate use of antimalarials due to over-treatment or non-treatment of other diseases in malaria endemic areas.

Laboratory Diagnosis

Rapid and effective malaria diagnosis decreases both patient’s suffering and community transmission. In the laboratory, malaria is diagnosed using different techniques e.g.conventional microscopic diagnosis by staining thin and thick peripheral blood smears, quantitative buffy coat (QBC) method, and rapid diagnostic tests (RDT) and

Fig. 1: Malaria endemic areas in India

29

Table 1: Comparison of Rapid Diagnostic Tests for Malaria Antigens PfHRP2 tests

PfHRP2 and PMA test

pLDH test

Target antigen

Histidine rich protein 2 of P. falciparum,water soluble protein expressed on RBC membrane

Pan-specific Plasmodium aldolase. Parasite glycolytic enzyme produced by all species and PfHRP2

Parasite lactate dehydrogenase. Parasite glycolytic enzyme produced by all species

General test format

2 lines

3 lines

3 lines

Detects P. falciparumonly

Can detect all 4 species

Can detect all 4 species

Not detected

Detected; differentiation between the 3 not possible

Detected; differentiation between the 3 not possible

Mixed infections of P. falciparum with nonfalciparum species

Appear as P. falciparum;differentiation not possible

Appear as P. falciparum; Appear as P. falciparum; differentiation not possible differentiation not possible

Detection limit

>40-100 parasites/µL

Higher for P. vivax and other non-falciparum species

> 100-200 parasites/µL for P. falciparum andP. vivax; may be higher forP. malariae andP. ovale

Post-treatment persistence Reported up to 31 days of antigens

Reported; longer for pan specific antigenemia than for PfHRP2

Reported up to 1 -3 weeks

Cross-reactivity between malarial species

Reported

Reported

Reported

Cross-reactivity with auto antibodies

Reported, high (up to 83% with rheumatoid factor)

Not known

Reported. low (3.3% with rheumatoid factor)

Indication of viability of parasites

No

No

Positive test indicates presence of viable parasitemia

molecular diagnostic methods such as polymerase chain reaction (PCR) amplification of parasitic nucleic acid.

Peripheral Blood Smear Examinations

Accurate and timely diagnosis of malaria infections in febrile patients is a critical part of case management.

Microscopic examination of stained blood smear remains the gold standard practice for malaria till date. Though considered as advantageous for accurate identification, species detection, parasite density estimation, low cost test, its parasite detection limitation is estimated to be 4-20 parasites/μl blood but under field conditions a threshold of about 50-100 parasites/μl is more justified.5 More over its accuracy depends upon quality of microscope experience and training of microscopists and staining procedure and time consuming observations, added to that PHC’s clinic examine blood smears from a large no. of clinically suspected patients with the help of one or two trained microscopists resulting in misleading interpretation and under estimation of malaria parasite.6 At any parasitaemia, more is the no. of mature stage parasites poorer is the prognosis. In general if more than 50% of peripheral blood parasites are at the tiny ring stage (i.e diameter of nucleus is less than 50% of the diameter of cytoplasm rim), the prognosis is relatively good. If more than 20% of parasite contain visible pigment (i.e. mature trophozoites or schizonts), the prognosis is relatively bad.

The presence of malaria pigment on polymorphonuclear leucocytes (PMN) (neutrophils) is a useful indication of the diagnosis of malaria, especially in anaemic children and in patients of sever malaria with absent or low parasitaemia.1 If more than 5% PMN’s contains malaria pigment then prognosis worsens.

QBC Test

These technique uses epi-fluorescent microscope that detects malaria parasite DNA when stained with fluorescent dyes e.g. acridine-orange. It is a simple, rapid and sensitive test for diagnosing malaria but it requires specialised instrumentations which is more costly then conventional light microscopy and is poor at determining species and numbers of parasites.

Rapid Diagnostic Test (RDT)

Over past two decades RDTs for malaria case identification has been developed and tested as an alternative to microscopy. This is based on the principles of detection of antigen released from parasitized RBCs.The result is a coloured test line obtained in 5-20minutes.RDTs incorporate antibodies against Histidine rich protein2 (HRP2) specific for P.falciparum, Plasmodium specific LDH (pLDH) for all malaria species and also Plasmodium aldolase.

Several studies compared RDTs based on these antigens, with different results in terms of sensitivity, specificity,

CHAPTER 6

Capability Non-falciparum species

INFECTION

30

Table 2: Comparison of Peripheral Blood Smear Examination and RDTs for Malaria Peripheral Smear

Rapid Diagnostic Tests

Format

Slides with blood smear

Test strip

Equipment

Microscope

Kit only

Training

Trained microscopist

‘Anyone with a little training’

Test duration

20-60 minutes or more

5-30 minutes

Test result

Direct visualization of the parasites

Color changes on antibody coated lines

Capability

Detects and differentiates all plasmodia at different stages

Detects malaria antigens (PfHRP2/ PMA/pLDH) from asexual and/or sexual forms of the parasite

Detection threshold

5-10 parasites/µL of blood

1 00-500/µL for P. falciparum, higher for non-falciparum

Species differentiation

Possible

Cannot differentiate among nonfalciparum species; mixed infections of P.falciparum and non-falciparum appear as P. falciparum

Quantification

Possible

Not possible

Differentiation between sexual and asexual stages

Possible

Not possible

Disadvantages

Availability of equipment and skilled Unpredictable efficiency at low microscopists, particularly at remote and very high parasitemia; cross reactions among plasmodial areas and odd hours species and with auto-antibodies; persistence of antigens

Status

Gold standard

Not yet approved by the FDA

Cost per test

US$ 0.12-0.40

US$ 1 .20-13.50

positive and negative predictive values. Since 2010, WHO has recommended either RDT or microscopy for confirmation of suspected malaria cases before treatment.7 The RDT consumption has increased in developing countries for the past few years. The WHO has recommended a minimum standard of 95% sensitivity at parasite densities of 100/μl. Most RDTs today have achieved >95% sensitivity goal for P.falciparum but not for non P. falciparum5 (Table 1). RDTs, in field conditions require to be stable under extremes of temperature and humidity during use and storage.

In 2010, P.falciparum lacking pfhrp2 and/or pfhrp3 genes were first isolated from infected human subjects in the Amazon region of Peru.Other endemic regions also reported false negative results using RDTs based on pfhrp2 due to gene deletions.7 A lot of RDT negative cases often responding to antimalarias questions not only to establish the genetic make-up of Indian population but also to the humidity, temperature resistant RDT Kit’s standardisation.

Both microscopy and RDT cannot detect parasite densities of less than 100 parasites per ml particularly in field conditions where a symptomatic carriers have a much lower parasite density8 (Table 2).

Polymerised Chain Reaction (PCR)

During the past decade highly sensitive and specific

nucleic acid amplification techniques have been developed to detect malaria parasite those are PCR, quantitative PCR (qPCR), Reverse transcriptase PCR (RT-PCR).

But PCR & Loop mediated isothermal amplification (LAMP) are the techniques used for detecting parasite DNA. These are highly sensitive and vary useful for detectingmixed infections in particular at low parasitaemia where conventional microscopy or RDT will be of no help.

PCR detects< 10 parasite/μl, LAMP detects 5-10 parasite/μl and NASBA’s (Nucleic Acid Sequence Based Amplification) selection limit is < 1 parasite/μl. For field based epidemiological study PCR based methods are most useful to quantify, detect and diagnose low density parasitaemia whether asexual or gametocyte forms.

In developing countries these tests are performed in reference centres as it is impractical to use for diagnosis of malaria in standard clinical settings. At present according to WHO, molecular diagnostic tools based on nucleic acid amplification techniques don’t have a role in the clinical management of malaria.2

CONCLUSION

The foremost point in the malaria case management is prompt and accurate diagnosis that can be obtained by proper travel history, clinical diagnosis, confirmation by specific diagnostic procedures having high accuracy.

The diagnostic challenges in India can be alleviated

if a suitable, simple, sensitive and low cost diagnostic procedure with high specificity would be available.

5.

Chansuda Wongsrichanalai, Mazie J. Barcus, Sinuon Muth, Awalludin Sutamihardja, Walter H. Wernsdorfer: A Review of Malaria Diagnostic Tools: Microscopy and Rapid Diagnostic Test (RDT). Am J Trop Med Hyg 2007; 77 (suppl6), 119-127.

6.

Praveen K Bharti, Nipun Silawat, Puspendra P Singh, Mrigendra P Singh, Manmohan Shukla, Gyan Chand, Aditya P. Dash et al: Malaria Journal 2008; 7:126.

REFERENCES

1.

Nicholas J. White, Joel G. Breman: Malaria; Dennis L Kasper, Stephen L Hauser, J Larry Jameson, Anthony S. Fauci, Dan L Longo, Joseph Loscalzo: Harrisonâ&#x20AC;&#x2122;s principles of Internal Medicine, 19th edition, McGraw Hill Education, USA, 2015, 1368-1386.

2. www.who.int/malaria/media/world-malaria-report-2015/ en/ .

3.

http://www.malariasite.com/malaria-india/ .

8.

Eniyou C. Oriero, Jan Jacobs, Jean-Pierre Van Greetruyden, Davis Nwakanma, Umberto Dâ&#x20AC;&#x2122;Alessandro: Molecularbased isothermal tests for field diagnosis of malaria and their potential contribution to malaria elimination. J Antimicrob Chemother 2015; 70:2-13.

CHAPTER 6

4.

Praveen K Sahu, Sanghamitra Satpathi, Prativa K Behera, Saroj K Mishra, Sanjib Mohanty and Samuel Crocodile Wassmer: Pathogenesis of cerebral malaria: new diagnostic tools, biomarkers and therapeutic approaches: Frontiers in Cellular and Infection Microbiology,2015,vol 5,article 75

7. Tamaki Kobayashi, Dionicia Gamboa, Daouda Ndiaye, Liwang Cui: Malaria Diagnosis across the International centres of Excellence for Malaria Research: Platforms, Performance and Standardisation. Am J Trop Med Hyg 2015; 93 (suppl 3),99-109.

31

Changing Profile of Dengue Infection in India

C H A P T E R

7

Prasanta Kumar Bhattacharya, Aakash Roy

INTRODUCTION

Dengue, an arboviral infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes, has emerged as one of the most important mosquito-borne viral disease. It is a global public health problem causing 50 to 390 million annual infections ranging from dengue fever, dengue hemorrhagic fever (DHF), to dengue shock syndrome (DSS). Climatic change, spread of dengue vectors to new geographic locales, increasing international travel, global trade, and rural to urban migration have collectively brought about far reaching changes in the patterns and trends of dengue.

Dengue in India has dramatically expanded over the last few decades. Although a notifiable disease in India since 1996, the impact of dengue has been underestimated because of insufficient information from the national reporting systems. Between 2006 and 2012 the National Vector Borne Diseases Control Program (NVDCP) reported an annual average (±SD) of 20,474 (±13,760) dengue cases and 132 (±57) deaths caused by dengue, a

Table 1: Recent outbreaks of dengue and involved serotypes Year of study

Region

Predominant dengue virus serotype

2001

Gwalior, Madhya Pradesh

DENV-2

2003

Northern India (Delhi and Gwalior)

DENV-3

2003-05

Delhi

2003 DENV-1-4, 2005 DENV-3

2005

Kolkata

DENV-3

2006

Delhi

DENV-1 &3

2008

Delhi

DENV-1,2,3

2008

Ernakulam, Kerala DENV-2,3

2009

Delhi

DENV-1-4

2009-10

Pune, Maharashtra

DENV-4

2010-11

Delhi

DENV-1

2009-12

Uttar Pradesh

DENV-1,2,3

2013

Delhi

DENV-2

2015

Delhi

DENV-14, (DENV-2 predominant)

number which is still thought to be underestimating the full impact of the disease

BRIEF HISTORY OF DENGUE IN INDIA

The epidemiology of dengue in India has seen major evolution and changes. The first reported occurrence of dengue fever in India documents back to 1946. Since then there were no major outbreaks in the country for almost two decades. Calcutta faced a major epidemic in 1963– 1964. It gradually spread to involve parts of northern and southern India in 1967–1968 with cases being reported of all four serotypes (DENV 1-4) of dengue virus. This was followed by a relative period of quiescence of almost three decades. The next major outbreak of DF/DHF was reported from Delhi in 1996 where 10,252 cases and 423 deaths occurred. This outbreak was caused by DENV2, genotype IV strain of the virus. Similar strains of the DENV-2 were reported from central India and southern India, indicating that the predominant circulating strain in India that time was DENV-2.

Serotypes of the virus kept changing from year to year, and each time there was a change in serotype the areas reported a higher burden of dengue cases. In 2003, another major outbreak engulfed northern and central India (particularly in Delhi and Gwalior), and at this time, all four serotypes were seen for the first time in Delhi with the predominant serotype being DENV-3. The re-emergence of this epidemic strain of DENV-3 in Delhi in 2003 and its persistence in subsequent years marked a changing trend in DENV circulation, showing the shift in the epidemiology of dengue virus in India. Subsequently, all four serotypes were reported from various parts of the country. Distribution of various serotypes in some of the recent outbreaks in India is depicted in Table 1.

Concurrent infection with multiple serotypes of dengue was also seen. Thus, it became more evident that India had gradually moved to being a hyperendemic are of dengue virus infection.

Evolution of dengue case definition

Earlier guidelines classified dengue into three categories: •

Dengue fever (DF): an acute febrile illness

•

Dengue hemorrhagic fever (DHF grades 1 and 2): a syndrome characterized by increased vascular permeability

•

Dengue Shock Syndrome (DSS): a state of altered homeostasis with progression to hypovolemic shock (grades 3 and 4).

In 2009 the new revised clinical classification of dengue was proposed which now divides the clinical cases into two categories: dengue with or without warning signs, and severe dengue infection.

EVOLVING CHANGES IN DENGUE EPIDEMIOLOGY

The epidemiology dengue is complex and it involves host, viral and vector status that are further influenced by demographic, economic, behavioural societal factors. It is thus of utmost importance to understand the evolving pattern and trend of the epidemiology of dengue.

SEX PREDILECTION AND DENGUE

Males outnumber females in the majority of the reports of dengue outbreaks in India, and in a few studies the male to female ratio was as high as 3–5:1. An interesting finding however is an apparent difference between sexes in term of severity of illness and case fatality ratio. A previous study reported a higher rate of mortalities among females than males, suggesting different pathogenetic processes or immune response. Further research into determining the sex differences both in infection and severity of the disease is needed to assess the disease pattern in the community.

SEASONAL VARIATIONS IN DENGUE

The seasonal character of dengue epidemics in India has been documented by ecological studies. Outbreaks of DF and DHF most commonly occur during the warm and humid conditions of the rainy season which are favourable for abundant mosquito growth. In a study of the influence of climatic factors on the pattern of dengue infections, the interaction between rainfall, temperature and relative humidity were found to be associated with the distribution of serologically confirmed dengue cases with a peak occurrence rate at the end of the monsoon season during the months of October and November. In contrast, few studies have reported dengue outbreaks during the dry summer months from Rajasthan and Maharashtra indicating local variations in the pattern of outbreak.

RURAL-URBAN DISTRIBUTION

Historically dengue was considered an urban disease.

Rapid urbanization and unplanned constructions with deficient waste water management systems resulted in the ideal conditions for the proliferation and spread of the vector and the virus. While this is still the case, the disease has progressively made its presence felt in the rural settings. The first outbreak reported from a typically rural area occurred in northern India (Haryana) in 1996 and subsequent outbreaks in rural settings were reported from

33

SEROTYPE VARIATIONS IN DENGUE

The first serotype of dengue infection in India was DENV-1. DENV-2 emerged as the predominant serotype from the early 1970s to 2000, during which time it was responsible for the large epidemics of dengue. DENV-3 emerged as a predominant serotype in large outbreaks in 2003 and 2006. All four DENV serotypes were found to co-circulate in Delhi for the first time in 2003, which thus became a hyperendemic region for dengue. Co-circulation of multiple DENV serotypes has resulted in concurrent infection with more than one serotype, further leading to complexity in the serotypic distributions of dengue.

CLINICAL PRESENTATIONS AND SEVERITY OF DISEASE

A mild to moderate degree fever has been the most consistent finding in all the epidemics with an average duration of 5-7 days. Rashes, retro-orbital pain, myalgia, headache and vomiting have been the other traditional clinical presentations commonly documented in various studies. Thrombocytopenia has also been a classical laboratory abnormality frequently found in cases of dengue. Interestingly though not a criteria according to WHO, certain studies from Delhi have documented the presence of splenomegaly in a large number of cases.

Since the mid to late 1980s and early 1990s small numbers of severe dengue cases in the forms of DHF and DSS were reported gradually leading to the large epidemic in 1996.

This pattern of a gradual increase from small numbers of sporadic severe dengue cases occurring for several years, leading to a major epidemic is typical of every region where epidemic DHF has become established. Following the epidemic of DHF in 1996, two other large epidemics with substantial numbers of deaths occurred in 2003 and 2006. However, the subsequent years noted a decline in the case fatality rates. This is a feature which is perhaps contributed by the increased awareness of the disease and consequent improved diagnosis and management.

CONCEPT OF “EXPANDED DENGUE”

Expanded dengue is a terminology developed in the WHO guidelines of year 2012 to describe cases which cannot be classified either as DHF or DSS and incorporates atypical findings and presentations of dengue. These comparatively unusual presentations may be on account of several factors including co-infections, co-morbidities or complications of prolonged and sustained shock. Table 2 shows certain atypical manifestations of dengue.

CONCLUSION

In recent years the epidemiology of dengue infection has evolved rapidly. Progressively larger outbreaks are being

CHAPTER 7

CHANGES IN AGE DISTRIBUTIONS

Dengue has traditionally been a disease of early childhood with most cases of DHF/DSS occurring in children aged 2-15 years, adults being usually immune and escaped DHF, as they have acquired immunity against primary infection. However, there has been a significant increase incidence in the older age group in recent outbreaks of dengue.

Maharashtra and Tamil Nadu. The spread of dengue from urban to rural areas is related to both the phenomenon of peri-urbanization as well as improved reporting and surveillance systems. The gradual urbanization of the rural areas resulted in the proliferation of Aedes aegypti in such areas and has resulted in the transition of dengue from a primarily urban problem to a pan-India health concern.

INFECTION

34

Table 2: Atypical manifestations of dengue

REFERENCES

1.

Bethell DB, Gamble J, Pham PL, Nguyen MD, Tran TH, Ha TH et al. The non invasive measurement of the microvascular leakage in patients with Dengue hemorrhagic fever. Clin Infect Dis 2001; 32:243-53.

Organ system involvement

Clinical spectrum

Renal

Acute Kidney Injury, IgA nephropathy

2.

Cardiac

Conduction abnormalities, Atrio-ventricular dissociation

Chakravarti A, Arora R, Luxemburger C. Fifty years of dengue in India. Transactions of the Royal Society of Tropical Medicine and Hygiene 2012; 106:273-82.

3.

Gupta E, Ballani N. Current perspectives on the spread of dengue in India. Infection and Drug Resistance 2014; 7:33-7.

Neurological

Gullian Barre syndrome, acute encephalitis, encephalopathy, seizures

4.

Hepatic

Hepatic encephalopathy, acute liver failure

Gupta E, Dar L, Kapoor G, Broor S. The changing epidemiology of dengue in Delhi, India. Virol J 2006; 3:92â&#x20AC;&#x201C; 96.

5.

Auto-immune

Dysregulated immune response leading to systemic lupus erythematosus

Halasa YA, Dogra V, Arora N, Tyagi BK, Nandand D, Sheparda DS. Overcoming data limitations: design of a multi-component study for estimating the economic burden of dengue in India. Dengue Bull 2011; 35:1-4.

6.

Reported in a child with mucocutaneous involvement

Islam A, Abdullah M, Tazeen A, Afreen N, Deeba F, Naqvi IH, et al. Detection of All the Four Serotypes of Dengue Virus in New Delhi, India During Post Monsoon Season of 2015. Indian Journal of Health Sciences and Care 2016; 3:24-9.

7.

Evidence of pancytopenia with bone marrow haemophagocytosis

Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: past, present and future prospects. Clinical Epidemiology 2013; 299-309.

8.

Saxena P, Parida MM, Dash PK, et al. Co-circulation of dengue virus serotypes in Delhi, India, 2005: implication for increased DHF/DSS. Dengue Bull 2006; 30:283â&#x20AC;&#x201C;7.

9.

Shepard DS, Halasa YA, Tyagi BK, Adhish SV, Nandan D, Karthiga KS, et al. INCLEN Study Group. Economic and disease burden of dengue illness in India. The American Journal of Tropical Medicine and Hygiene 2014; 91:1235-42.

Kawasaki disease Haemophagocytic syndrome

observed, accompanied by a shift in the paradigm of the disease from urban to rural settings. Disease patterns are also evolving rapidly with circulation of multiple DENV serotypes and expansion of the profile of clinical presentations.

10. World Health organization Comprehensive guidelines for prevention and treatment of dengue and dengue hemorrhagic fever. New Delhi: WHO, SEARO; revised and expanded edition. SEARO Technical Publication Series No. 60, World Health Organization 2011.

Dengue Profile in Guwahati

C H A P T E R

8

PC Bhattacharyya, Manabendra Nayak, Lalit Mohan Bhardwaj

INTRODUCTION

The word ‘dengue’ is derived from the Swahili phrase Ka-dinga pepo, meaning “cramp- like seizure”. The first clinically recognized dengue epidemics occurred almost simultaneously in Asia, Africa and North America in the 1780s. The first clinical case report dates from 1789 of 1780 epidemic in Philadelphia is by Benjamin Rush, who coined the term ‘break bone fever’ because of the symptoms of myalgia and arthralgia. The term dengue fever came into use after 1828. In 1906, Aedes mosquitoes transmitting the dengue fever was confirmed and in 1907 Dengue was the second disease after ‘yellow fever’ that was shown to be caused by virus.

HISTORY

In India the first epidemic of clinical dengue-like illness was recorded in Madras in 1780 and first virologically proved epidemic of dengue fever (DF) occurred in Calcutta and Eastern Coast of India in 1963-1964.1 Dengue virus was isolated in Japan in 1943 by inoculation of serum of patients in suckling mice2 and at Calcutta in 1944 from serum samples of US soldiers. 3 The dengue haemorrhagic fever (DHF) started simmering in various parts of India since 1988. 4The major outbreak of DF/DHF was reported in Delhi and neighboring states in 1996. Data for the last 10 years reveal maximum numbers of cases due to DF/ DHF were reported in year 1996 (16,000) while the next increase was noted in 2003 (21,000). 5

VIROLOGY

Dengue virus is a RNA virus of the family flaviviridae.

The dengue virus genome contains 11,000 nucleotide bones. They have 3 different protein and molecules that form virus particles (C prM and E) and 7 other types of

Table 1: As per record of National Vector Borne Disease Control Program, Directorate General of Health Services, Ministry of Health and Family Welfare Dengue case details and death since 2010 in Assam Year

Case

Death

2010

237

2

2011

0

0

2012

1058

5

2013

4526

2

2014

27

0

2015

1076

1

2016

2099*

3

*Till 2nd October 2016

protein molecules (NS1, NS2, NS2b, NS3, NS4a, NS4b, NS5) that are found in infected host cells and are required for replication of virus. There are 4 strains of virus ex.

DEN1, DEN2, DEN3, DEN4. All four serotypes can cause full blown disease. Infection with 1 serotype is believed to produce lifelong immunity to that serotype, but he can be infected with other serotype in future. It is transmitted mainly by Aedes aegypti mosquito and also by Aedes albopictus. A mosquito that takes a blood meal from an infected person becomes infected with virus. In 8 to 10 days the virus spreads to tissues like salivary gland from the gut of the mosquito. Dengue may also get transmitted via infected blood products and through organ donation.

Vertical transmission from mother to child can also occur during pregnancy.5

WHO CLASSIFICATION

The WHO 2009 classification divides dengue fever into two groups: uncomplicated and severe, though the 1997 WHO classification is still widely used. 6 The 1997 classification divide dengue into undifferentiated fever, dengue fever and dengue hemorrhagic fever. Four main characteristic manifestation of dengue illness are i) continuous high fever lasting 2-7 days, ii) hemorrhagic tendency as shown by a positive tourniquet test, petechiae or epistaxis, iii) thrombocytopenia, iv) evidence of plasma leakage manifested by haemocencentration, pleural effusion and ascites etc.

DENGUE IN STATE OF ASSAM AND CAPITAL CITY OF GUWAHATI

Dengue arbovirus has recently emerged as a major public health concern with increased morbidity in Assam. 7 Entomological survey carried out in different time periods reveals the prevalence of potential dengue vectors in this region. 8A comprehensive entomological survey conducted during 2004-2005 in the seven states of northeast region of India revealed that the region is rich in known dengue vectors, viz. Aedes aegypti and Aedes albopictus. 9 It was in 2010 that for the first time 237 dengue cases and 2 deaths confirmed to be due to dengue were recorded in Assam state (Table 1). In the following years except in 2011, there was manifold increase in 1058 (5 deaths) and 4526 (2 deaths) confirmed cases in 2012 and 2013. 10 For each year, of the total confirmed cases, majority (69%-91%) were recorded in Guwahati, the capital city of Assam, during the post-monsoon months in September to December.

Guwahati is the largest and fast growing metropolis and gateway of northeast India. Over the past decade there

36

Table 2: Clinical Characteristics of Dengue positive Hospitalized patients in Guwahati city

Table 3: Districtwise distribution of dengue cases in Asam

Clinical & Laboratory Parameters

Districts

Dengue-positive cases

Kamrup

39

Barpeta

2

Sivasagar

2

Nagaon

1

Baksa

4

Dibrugarh

1

Jorhat

1

Hojai

1

Cachar

2

Karbi angling

1

Nalbari

4

Morigaon

3

Others*

7

INFECTION

Fever

% of patient 100

Headache

88.23

Myalgia

82.35

Arthralgia

54.41

Nausea/Vomiting

63.23

Abdominal Pain

11.76

Hepatomegaly

5.88

Skin Rash

30.88

Eyeball Pain

36.76

Conjunctival Injection

69.11

Palatal Petechiae

2.94

Diarrhea

33.82

Ns1ag

85.29

Igm

19.11

Igg

5.88

Leukopenia (<4000/cumm)

54.09

Thrombocytopenia (<50000/Cumm)

23.88

Hemorrhagic Manifestations

17.64

Icterus

00.00

Ascites

00.00

has been increase urbanization, deforestation, massive developmental activities, rapid population movement and increased air connectivity between Guwahati and other by metropolitan cities resulting in increased receptivity for mosquito breeding and possible importation and spread of dengue virus through human host in the region.

The disease is currently spreading to semi- urban areas of other districts of Assam supported by serological evidence for circulating dengue virus serotypes. 9 Given the reported regional abundance of disease vectors and case incidence in city areas, Ae. Aegypti is held the most probable mosquito vector transmitting dengue virus,11 and recently has been incriminated for circulating dengue virus 2 serotype. With the available data for prevalence of disease vectors and case incidence, there is a strong possibility of local transmission happening evidence by listing of cases without any travel history.10

CLINICAL PROFILE OF DENGUE IN GUWAHATI, ASSAM

The clinical manifestation of dengue and a complete medical history for early diagnosis are important for promote supportive therapy. The sign and symptoms of dengue being nonspecific, the physician must maintain a high index of suspicion if a clinical diagnosis of dengue is to be made. 12 The state of Assam has experienced an increased number of reported fever cases of unknown origin in recent years. The doctors rarely consider dengue as a differential diagnosis of an acute febrile illness. The confirmed dengue cases were consistent with classical

*others mentioned above are those patients who visited to endemic area but residing outside Assam.

descriptions like fever, headache, eye pain and vomiting.

Fever was the most common clinical feature in almost all cases. The other most common presenting features were headache, eye pain and myalgia. However abdominal pain, diarrhea was observed in few numbers of cases. 13 The proportion of cases with headache, rash, eye pain and vomiting was significantly higher. Bleeding tendency was observed in minimum number of patients.13 (Table 2) A comprehensive picture of dengue epidemic that occurred in Assam state in 2016 is given in Table 3.

Although dengue cases were presented to our hospital from 12 districts of Assam, clearly Kamrup was the worst affected, and it alone shared 63.93% of the dengue cases.

Figure 1 shows the distribution of the percentage of the dengue cases in various age groups in either sex. It clearly reveals that the highest number of cases belonged to the age group 20-50 yrs. and males clearly outnumbered the females.

As the outbreak of dengue mainly occurred in the months of August to September of 2016, Figure 2 shows the monthly distribution of the cases.

This graph shows month wise no. of dengue cases presented to our hospital in 2015 & 2016 (Figure 3).

ASSOCIATED PROBLEM

Dengue may occasionally affect several other body systems. This may be either in isolation or along with the classic dengue symptoms. A decreased level of consciousness occurs in 0.5-6% of severe cases. This may be caused by infection of the brain by the virus or indirectly due to impairment of vital organs, for example the liver and other neurological disorders have been reported in context of dengue, such as transverse myelitis and Guillian Barre syndrome. Infection of heart and acute liver failure are among the rare complications of dengue. 5

Figure 2: Month wise distribution of the NS1- and/or IgM-positive dengue cases—Jan. to

groups in either sex. It clearly reveals that the highest number of cases belonged to the October 2016. age group 20-50 yrs. and males clearly outnumbered the females.

16

37

50

45

14

40

12

35 30

10

male

8

25

no. of cases in year 2016

20

female in various

Figure 1 shows the distribution of the percentage of the dengue cases 15age groups in6 either sex. It clearly reveals that the highest number of cases belonged to 10 the age group 20-50 yrs. and males clearly outnumbered the females.

5 4 Fig. 1: Age and sex gradation according to IgM and/or NS1% positivity.

no. of cases in year 2015

0

2

Fig. 3: Comparison of monthwise distribution of cases in 2015 & 2016.

CHAPTER 8

As the outbreak of dengue mainly occurred in the months of August to September of 0 2016, Figure 20-10 shows11--20 the monthly of the cases.61--70 71--80 21--30 distribution 31--40 41--50 51--60

Figure Age and sexsex gradation according to IgMtoand/or NS1% NS1% positivity. This graph shows month wise no. of dengue cases presented to our hospital in 2015 & Fig.1:1: Age and gradation according IgM and/or 2016.

positivity

As the outbreak of dengue the months of August to September of Table 4: Laboratory finding of dengue positive Hospitalized no. ofmainly casesoccurred in yearin2016 2016, Figure 2 shows the monthly distribution of the cases. patients in Guwahati city ASSOCIATED PROBLEM

30 25 20 15

no. of cases in yearno.2016 of cases in year 2016

10 5 0

30 25

Alanine transaminase, > 40 U/L

20 15 10

Characteristics Dengue may occasionally affect several other body systems. This may be either in isolation or along with the classic<dengue A 3decreased level of consciousness occurs Thrombocytopenia, 1.5 Xsymptoms.

105/mm in 0.5-6% of severe cases. This may be caused by infection of the brain by the virus or indirectly 3 cells/mm dueLeucopenia, to impairment of <4000 vital organs, for example the liver and other neurological disorders have been reported in context of dengue, such as transverse myelitis and Guillian Barre syndrome.

Aspartate transaminase, > 40 U/L Infection of heart and acute liver failure are among the rare complications of dengue. 5 LABORATORY FINDING

TREATMENT OF DENGUE VIRUS INFECTION

2: Month wise distribution of the NS1- and/or IgM-positive Figure 2:Fig. Month 5 wise distribution of the NS1- and/or IgM-positive dengue cases—Jan. toAs per record (State Health Director Assam) which includes government hospital and No specific treatment is available. The management dengue cases—Jan. to October 2016 October 2016. 0 private hospital of Guwahati, Assam (reported cases) a significant higher percentage of patients no. of cases in year 2016

LABORATORY FINDING (TABLE 4)

As per record (State Health Director Assam) which includes government hospital and private hospital of Guwahati, Assam (reported cases) a significant higher percentage of patients showed lower platelet counts. The percentage value of alanine transaminase and aspartate transaminase was significantly higher. Leucopenia was observedin few numbers of cases. Studies suggested that liver injury is a common finding in dengue infections and it is mediated by direct infection of hepatocytes and kupffer cells.14 Recently studies suggested the use of markers such as Aspartate transaminase and Alanine transaminase as parameters to evaluate severity in patients with dengue fever.15 Since grossly elevated liver enzymes are known to be an early warning sign for severe disease along with bleeding vigorous follow up in such patients is warranted.14

DIAGNOSIS OF DENGUE VIRUS INFECTION

Diagnosis of dengue virus infection is routinely done by demonstration of anti-Dengue virus (DV) IgM antibodies or by NS-1 antigen in patients serum depending upon day of illness using ELISA kits (prepared by National Institute of Virology Pune) and commercial kits.16 Reverse transcriptase PCR (RTPCR) are being increasingly used in diagnosis of DV infection. A single tube nested PCR for detection and serotyping of DV was developed and used for detection of an infection by two viruses.17 DV isolation in tissue culture cells and its sequencing is also being done.

of dengue virus infection is essentially supportive

showed lower platelet counts. The percentage value of alanine transaminase and aspartate and symptomatic. is contraindicated.

Thereof cases. transaminase was significantly NSAID higher. Leucopenia was observedin few numbers

are Indian studies which have contributed in terms of better management of dengue hemorrhagic fever/ 6 Dengue shock syndrome. A rapid response to platelet and fresh frozen plasma transfusion is reported in a study. 18Hippophaerhamnoides (Seabuckthorn SBT) leaf extract has been shown to have a significant anti-dengue activity.19

CONCLUSION

With the continued phenomenon of urbanization and prevailing climatic conditions of high humidity, extended 5 monsoon and increasing distribution range of Ae aegypti it is projected the dengue will emerge as a major public health problem in capital city of Guwahati, Assam and northeast India. Since there is no vaccine available in northeast, Mosquito control is the most effective approach to the prevention of dengue transmission.

Measure should be taken to control the aforementioned causes to prevent disease spread and reduce epidemic flare up. Need is to organize health education programme about dengue disease to increase community knowledge and sensitize the community to participate in integrated vector control programmes. Dengue is one of the major public health problems which can be controlled with active participation of the community.

REFERENCES

1.

Sarkar JK, Chatterjee SN, Chakravarty SK, Hemorrhagic fever in Calcutta some epidemiological observation. Indian Journal of Medical Reserve 1964: 52:651-9.

2.

KimuraR, Hotta S, Studies on dengue fever (IV) on

7

38 3.

inoculation of dengue virus into mice. Nippon Igaku 1944; 3379:629-33.

12. Gubler D, Dengue and Dengue Hemorrhagic fever. Clinical Microbiology Review 1998; 11:480-496.

Sabin AB, Schlensinger MC, Production of immunity to dengue with virus modified by propagation in mice. Science 1945; 101:640-2.

13. Dutta P, Khan SA et al. Demographic and clinical features of patients with dengue in Northeastern Region of India: A Retrospective cross-Sectional study during 2009-2011.

Journal of Virology and Microbiology 2012, Article ID 786298, 11

4. Kabra SK, Verma IC, Arora NK et al. Dengue hemorrhagic fever in children in Delhi. Bull world Health Organ 1992; 70:105-8.

INFECTION

5.

Vaddadi Srinivas, Vaddadi Radha Srinivas, Dengue fever: A review article Journal of Evolution of Medical and Dental Science 2015; 4:5048-5058.

6. WHO Dengue Guidelines for diagnosis, treatment, prevention and control in sub-Saharan Africa and 13 countries in South America. Geneva World Health Organization 2009 7.

Dev V,Khaund K, Tewari GG, Dengue vectors in urban and suburban Assam, India entomological observations. WHO South-East Asia Journal of Public Health 2014; 3:51-59.

8.

Dutta P, Khan SA, SarmaC, et al. Distribution of potential Dengue vectors in Major Township along the national highway and trunk road Northeast India. Southeast Asian Journal of Tropical Medicine and Public Health 1998; 29:173176.

9.

Dutta P, Mahanta J, Potential vectors of Dengue and the profile of Dengue in the Northeastern Region of India: An Epidemiological Perspectives. WHO Dengue Bulletin 2006; 30:234-242.

10. Dev V, Mahanta N, Baruah BK, Dengue and emerging arboviral infection in Assam, Northeast India. Tropical Biomedicine 2015; 32:796-799.

11. Dev V, Khaund K, Tewari GG, Dengue vectors in urban and suburban Assam, India entomological observations. WHO South-East Asia Journal of Public Health 2014; 3:51-59.

14. Murgue B, Deparis X, Chungue E et al. Dengue: An Evaluation of Dengue severity in French Polynesis Based on an Analysis of 403 laboratory confirmed case. Tropical Medicine and International Health 1999; 4:765-773.

15. De Scuza L J, Nogueira RMR et al. The impact of Dengue on liver Function as elevated by Aminotransferase levels.

Brazilian Journal of Infectious Disease 2007; 11:407-410.

16. ChakravatibA, Kumar A, Malik S, Detection of dengue infection by combining the use of an NSI antigen based assay with antibody detection. Southeast Asian Journal of tropical Medicine Public Health 2011; 42:297-302.

17. Mishra B, Sharma M et al. Utility of multiplex reverse transcriptase polymerase chain reaction for diagnosis and serotype characterization of dengue and chikunguniya viruses in clinical samples. Diagnosis Microbial Infection 2011; 71:118-25.

18. Choudhury R, Khetan D, Sinha S, et al. Transfussion support to dengue patients in a hospital based blood transfusion service in north India. Transfuse Apher Science 2006; 35:23944.

19. Jain M, Gunju L, Katiyal A, et al. Effect of Hippophaerhamnoides leaf extract against dengue virus infection in human blood derived macrophages.

Phytomedicine 2008; 15:793-9.

C H A P T E R

9

Leptospirosis in Current Status

INTRODUCTION

India has taken giant strides in the field of medical science and we have cutting-edge technology available for the management of several ailments. But this advantage is restricted to non-communicable diseases; the same cannot be said about their communicable counterparts, which are posing a mammoth burden on our healthcare system.

Compounding this problem is the re-emergence of longforgotten diseases due to a conflux of environmental, socio-economic, and demographic factors like population pyramiding, poor sanitary infrastructure, deforestation, global warming and changing migration dynamics. One such disease which was sporadic till the eighties but subsequently became endemic in many Indian states and also caused major epidemics is leptospirosis.

CAUSATIVE ORGANISM

Leptospirosis is an acute anthropo-zoonotic disease of global importance. It is caused by the spirochete Leptospirosis interrogans complex which has 26 serogroups and over 250 pathogenic serovars. Even if most cases recover with mild infection, fulminant multiorgan dysfunction can occur in some cases. The causative pathogen belong to the class of spirochetes Leptospira which mainly consists of the species Leptospira interrogans and Leptospira biflexa.

EPIDEMIOLOGY

Leptospirosis, primarily a disease of animals, affects almost all mammalian species (wild, domestic, and farm animals): thus poses a significant veterinary burden.

Rodents are the most important reservoir. Leptospires can persist in the host urogenital tract for years by establishing a symbiotic relationship. Soil salinity and alkaline pH favour survival of leptospires for several months and waterlogging favours dissemination of disease. Infection in humans occurs through contact of abraded skin and /or intact mucus membrane (especially conjunctiva and gut) with the urine, blood or tissue from infected animal, or with contaminated environment. Leptospirosis is more common in the 20-45 years age –group with male preponderance due to greater occupational exposure to infected animals and contaminated environment. Other high-risk groups are agriculture workers, sewer cleaners, livestock handlers, healthcare /veterinary professionals, military troops, sugarcane workers and those engaged in water-sports. According to the Modified Faine’s Criteria (2004) search for epidemiological factors like rainfall, contact with contaminated environment and animal contact improves the diagnostic yield.

Shobha Manish Itolikar GLOBAL BURDEN

Leptospirosis occurs worldwide but is most common in tropical and subtropical areas which record high rainfall.

Sporadic cases may be reported throughout the year.

Incidences range from approximately 0.1–10 per 100 000 per year; it might reach over 50 per 10000 during outbreaks. Most cases have been reported from India, Indonesia, Thailand, Maldives and Sri Lanka. Epidemics in South-East Asia have been reported in the past in Jakarta (2003), Mumbai (2005) and Sri Lanka (2008).

INDIAN SITUATION

The endemic states are Gujarat, Maharashtra, Kerala, Tamil Nadu and Andaman-Nicobar Islands. Epidemic situations have arisen after natural calamities like flash floods (Mumbai 2005), cyclone (Orissa 1999) or due to spontaneous outbreaks like in Gujarat (2011).

More recently, after the massive Chennai floods (2015), contrary to what was expected there was no significant spike in the number of case or deaths (1204 cases in 2015 compared to 3616 cases in 2011); attributable largely to the preparedness of authorities in the form of aggressive surveillance, prompt treatment, and initiation of chemoprophylaxis in exposed groups. Awareness and attitude of the healthcare provider is an important factor in controlling the magnitude of infection.

PATHOGENESIS

Weil’s disease is the term employed for cases exhibiting a triad of bleeding, jaundice and renal failure, first described by a physician by the same name. Leptospira glycoprotein components or toxins could directly induce tissue damage by rapid induction of the inflammatory cytokine TNF-α.

Host immunity also influences the disease outcome.

In resistant hosts with mild symptoms, inflammatory responses occur rapidly to eradicate organisms and tissue damage is prevented. In those with inadequate immune response, inflammatory responses are delayed, leading to severe bacteremia. Such prolonged and massive immune response results in severe organ damage. After tissue invasion, the bacteria damage the microvascular endothelial linings leading to capillary leakage and severe hemorrhaging. Such damage results in injury to the proximal tubules (leading to renal interstitial nephritis), hepatocellular damage leading to jaundice, coagulopathy, liver failure and aseptic meningitis in the immune phase.

CLINICAL FEATURES

The incubation period ranges between 2-10 days. 8590% of patients experience a self-limiting episode of influenza-like illness (anicteric leptospirosis). The

INFECTION

40

typical course consists of an acute septicaemic phase followed by the immune phase as shown in Figure 1. In the small proportion developing severe icteric leptospirosis or Weil’s disease,, two phases are seen i.e. the leptospiremic phase characterized by remittent fever, headache, myalgia, vomiting, conjunctival suffusion and/ or hepatosplenomegaly and an immune phase which coincides with the appearance of antibodies and is characterized by the onset of organ dysfunctions in the form of hepatocellular jaundice, acute interstitial nephritis, vascular collapse secondary to bleeding or myocarditis, acute lung injury or aseptic meningitis. Rarely encountered complications are cardiac arrhythmias, pericarditis, congestive heart failure, necrotising pancreatitis and uveitis.

Pulmonary haemorrhage, occurring as a consequence of vascular endothelial damage is almost always the cause of death.

DIAGNOSIS

anemia, mild to moderate anemia, and thrombocytopenia. Weil’s disease is suggested by elevated levels of blood urea nitrogen and serum creatinine in conjunction with mixed hyperbilirubinemia with transaminase elevation (<200 U/L). Urinalysis may show abnormalities of sediments (leukocytes, erythrocytes, hyaline and granular casts). Elevation of the noncardiac isoform of creatine kinase may indicate skeletal muscle damage. On chest radiography, alveolar infiltrates predominate corresponding with hemoptysis but not purulent sputum. Other findings include diffuse interstitial infiltrate patterns suggesting acute respiratory distress syndrome and small nodular infiltrates and pleural-based densities representing hemorrhage. CSF shows elevated proteins, normal glucose and polymorph predominance (in early stages) and mononuclear cells (in the late stages).

SPECIFIC TESTS FOR LEPTOSPIROSIS

The various diagnostic approaches are depicted in Figure 2 with a brief description as follows:

Leptospirosis should be suspected in any patient presenting with an abrupt onset of fever, chills, conjunctival suffusion, headache, myalgia and jaundice. A high index of suspicion prompting elicitation of a detailed exposure history is critical and guides confirmatory testing.

1.

Culture ( Blood, Urine, CSF): Isolation of leptospires on culture gives definite proof of infection. It also helps in identifying the serovar. But it can be timeconsuming, relatively insensitive, hence not useful for early diagnosis

Common hematologic abnormalities noted are leukocytosis (typical in severe disease), leukopenia, hemolytic

2.

Microscopy: Dark-field microscopy : This is useful for observing leptospires in culture, particularly when they are present in large numbers, and for observing agglutination in MAT. But this process demands good expertise to avoid false positive results due to fibrin threads.

3.

Immunologic Methods:

a.

Microscopic agglutination test (MAT)

Pros: Gold standard serologic test with a high specificity

Useful for epidemiologic surveillance

4-7 d

2-10 d

Incubation period

Septicaemic phase Abrupt onset of fever, headache, muscle pain, nausea;

Bacteria enter body through cuts or mucosal surfaces; bacterial flagellae aid tissue penetration

leptospires isolated from blood, CSF, and most tissues; Mostly anicteric, 5-10% have jaundice

1-3 d

0-30 +d

Immune phase

Interphase Fever and other symptoms resolve temporarily prior to onset of immune phase

Recurring fever and CNS involvement (meningitis) primarily humoral response; antileptospiral antibodies lead to clearance of the organism from most tissues except kidney tubules; leptospires may continue to shed in the urine for long periods

Courtsey : Dr. Richard A. Collins, Hong Kong

Fig. 1: Typical course of Leptospirosis Laboratory Diagnosis of Leptospirosis

Culture

Microscopy

Dark Field Microscopy

Isolation

Immunoflourescence Microscopy Silver impregnation Techniques

Immunologic

Microscopic Agglutination Test (MAT) Slide Agglutination Tests (SAT) ELISA

Fig. 2: Approach to laboratory diagnosis of Leptospirosis

Molecular

Polymerase Chain Reaction (PCR)

Cons: MAT-detectable antibodies usually do not develop before seven days of illness.

Paired serum samples are needed often, which delays the diagnosis.

Less sensitive than MSAT and ELISA

b.

Macroscopic Slide agglutination Test (MSAT)

Pros: More sensitive as initial screening test.

Simple, easy to perform

Cons: Less specific than MAT

c.

IgM ELISA:

Pros: Simple, sensitive rapid test

Cons: Poor specificity

Not useful in early diagnosis

Cannot detect re-infection due to persistence of antibodies

4.

Molecular diagnosis: Polymerase Chain Reaction

Pros: PCR can rapidly confirm the diagnosis in the early phase of the disease before antibodies are detectable.

Cons: It requires special equipment and skilled personnel.

Conventional PCR may give false-positive results in the presence contaminants and false-negative results due to the presence of inhibitors

DIFFERENTIAL DIAGNOSIS

When fever and severe myalgia predominate, influenza is often considered; other important possibilities include malaria, rickettsial diseases, arboviral infections (e.g., dengue and chikungunya), typhoid fever, Hantavirus infection (hemorrhagic fever with renal syndrome or Hantavirus cardiopulmonary syndrome), and viral hepatitis.

for hypovolemic shock. Timely initiation of dialysis and lung-protective ventilation are associated with a favourable outcome. Chemoprophylaxis with oral doxycycline (200 mg weekly) throughout the period of exposure is recommended in high risk individuals.

IMMUNISATION

Immunization by means of vaccines seems to provide a certain degree of protection. Vaccines are, in principle, suspensions of killed leptospires of particular serovars only. Hence protection is largely serovar-specific.

CONCLUSION

It is ironic that despite the progress we have made on other fronts, we are losing our fight against infectious diseases. The constant threat of a leptospirosis epidemic looms large whenever there is heavy flooding.

Adherence to recommended guidelines, as well as urgent implementation of appropriate surveillance and control measures is the need of the hour.

REFERENCES

1.

Sambasiva RR, Naveen G, Bhalla P and Agarwal SK. Leptospirosis in India and rest of the world. Braz J Infect Dis 2003; 7:178–193.

2.

Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, Lovett MA et al. Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis 2003; 3:43–489.

3.

Shivakumar S. Leptospirosis: Current Scenario in India.

Medicine Update Edition 18, Chapter 106, Publisher : The Association of Physicians of India, 2008: 799-809.

4.

John TJ. The prevention and control of Human leptospirosis.

J Post Grad Med 2005; 57:205-209.

5.

Shivakumar S. Indian Guidelines for the Diagnosis and Management of Human Leptospirosis. Medicine Update 2013. Publisher : The Association of Physicians of India.

Available at < www.apiindia.org/medicine_update_2013/ chap07.pdf>

6. Shivakumar S, Shareek PS. Diagnosis of leptospirosis utilizing modified Faine’s criteria. JAPI 2004; 52:678-79.

7.

Leptospirosis Fact Sheet. Available at http://www.searo. who.int/about/administration_structure/cds/zoonoses/ leptospirosis. Accessed on 23rd October 2016

8.

Bhatia M, Umapathy B L, Navaneeth B V. Evaluation of diagnostic utility of modified Faine’s criteria in leptospirosis- experience from a tertiary care hospital. Natl J Integr Res Med 2015; 6:20-26.

TREATMENT

Leptospires are susceptible to all clinically useful antibiotics expect chloramphenicol and rifampicin. Oral therapy with penicillin, doxycycline and azithromycin is recommended in mild cases. In severe cases, in addition to treatment with intravenous penicillin or ceftriaxone, specific therapy should be directed towards correction of organ dysfunction i.e. dialysis for renal injury, lung protective ventilation for ARDS, and fluid resuscitation

41

9. National Guidelines for Diagnosis, Case Management, Prevention and Control of Leptospirosis (2015). Available at www.ncdc.gov.in

CHAPTER 9

C H A P T E R

10

Management of Kala-Azar – from Bench to Bedside

INTRODUCTION

Leishmaniasis, a vector-borne neglected tropical disease, caused by an obligate intracellular protozoan. The only proven vector of human disease is sandfly. Visceral leishmaniasis (VL; also known as kala-azar), the severest form of leishmaniasis is caused by the Leishmania donovani complex: L. donovani, is the causative organism of VL in the Indian subcontinent and Africa; L. infantum (L. chagasi) which causes VL in the Mediterranean basin, Central and South America.

EPIDEMIOLOGY

More than 90% of global VL cases occur in just six countries: India, Bangladesh, Sudan, South Sudan, Brazil and Ethiopia. It is endemic in 54 districts of Bihar, Jharkhand, Uttar Pradesh and West Bengal.The state of Bihar accounts for most of the cases. With the implementation of The Kala-azar elimination program in India, there has been a dramatic reduction in new cases and deaths due to VL. In India as per report of 2014, more than 70% of endemic blocks have achieved elimination i.e. the incidence rate was below 1/10 000 population. As compared to 2011 the number of cases have reduced by 72% and the number of deaths by 86%.There was a decreasing trend also in the number of PKDL (post kalaazar deenal leishmaniasis) cases.

CLINICAL FEATURES

The incubation period is approximately to be 2–3 months but may be up to 1 year or more, and the onset of the disease is usually gradual. The common symptoms are fever with chills and rigor, malaise, weight loss, anorexia and discomfort in the left hypochondrium. The common clinical signs are splenomegaly which is usually palpable by 2 weeks and may become huge as the illness progresses, moderate hepatomegaly, and there is wasting and pallor of mucous membranes . Blackish discoloration of the skin of the face, hands, feet and abdomen (the vernacular name, kala-azar, means black fever or deadly fever). Signs of malnutrition (edema, skin and hair changes) develop as the disease progresses. Anemia can be severe and may lead to congestive heart failure. Thrombocytopenia can lead to epistaxis, retinal hemorrhages, and gastrointestinal bleeding. Intercurrent infections are common. VL is usually fatal if left untreated.

In the Indian subcontinent 5–15% patients (highest in Bangladesh) with VL develop a chronic form of dermal leishmaniasis characterized by hypopigmented macules, papules and/or indurated nodules which is called PKDL. PKDL occur 6 months to 3 years after the cure of VL and

Shyam Sundar, Jaya Chakravarty spontaneous resolution is rare in India. Approximately.

5-6% of cases of PKDL cases occur without the preceding history of Kalaazar.

Initially, HIV-VL coinfection was reported from the Mediterranean countries, but the number of cases is increasing in sub-Saharan Africa especially in Ethiopia, Brazil and Indian subcontinent. HIV infection increases the risk of developing VL by 100–2,320 times in areas of endemicity, reduces the likelihood of a therapeutic response, and greatly increases the probability of relapse.

VL promotes the clinical progression of HIV.

DIAGNOSIS

Parasite Detection

The visualization of the amastigote form of the parasite by microscopic examination of aspirates from bone marrow or spleen is the gold standard for the diagnosis of VL. Although the specificity is high, the sensitivity of microscopy varies, being higher for spleen (93–99%) than for bone marrow (53–86%). However, splenic aspiration can be complicated by life threatening haemorrhage and bone marrow aspiration is painful and both procedures requires technical expertise. The national vector borne disease control program of India recommends parasite detection only in those with a past history of kala-azar or if antibody based rapid diagnostic tests are negative.

MOLECULAR DIAGNOSIS

The detection of parasite DNA by PCR in blood or bone marrow aspirates is substantially more sensitive than microscopic examination, although its use is currently restricted to referral hospitals and research centres.

Serological Tests

Serological tests is the preferred mode of diagnosis.

The direct agglutination test (DAT) and the rK39based immunochromatographic test (ICT) are two serological tests that have been specifically developed for field use. DAT needs multiple pipetting, has a long incubation time, cost of antigen is high and there is limited production facility of quality controlled antigen.

Therefore immunochromatographic strip tests (ICTs) based on rK39 is preferred in the national program are it is easy to perform in the periphery, rapid, cheap and yields reproducible results. rK39 is a 39-amino acid repeat that is part of a kinesin-related protein in Leishmania chagasi and is conserved within the L. donovani complex. A metaanalysis that included 13 validation studies of the rK39 ICT showed sensitivity and specificity estimates of 93.9 % (95 % CI, 87.7–97.1) and 95.3 % (95 % CI, 88.8–98.1), respectively.

The major drawbacks of antibody based tests are : serum antibody levels remain detectable up to several years after cure, therefore, VL relapse cannot be diagnosed by antibody detection. Secondly, up to 32% healthy individuals living in endemic areas with no history of VL are positive for anti-leishmanial antibodies owing to asymptomatic infections. Thus antibody-based tests must always be used in combination with a standardized clinical case definition for visceral leishmaniasis.

All patients with above symptoms should be screened with rK39 based Rapid Diagnostic Test (RDT) and if found positive should be treated with an effective drug.

In cases with past history of Kala-azar or in those with high suspicion of Kala-azar but with negative RDT test result, confirmation of Kala-azar can be done by examination of bone marrow/spleen aspirate for LD bodies.

In the national program a probable case of PKDL is a patient from a KA-endemic area with multiple hypopigmented macules,papules, plaques or nodules, who are RDT positive.

While a confirmed case of PKDL is a patient from a KAendemic area with multiple hypopigmented macules, papules, plaques or nodules, who is parasite positive in slit-skin smear (SSS) or biopsy.

ANTILEISHMANIAL DRUGS

Pentavalent Antimonials (SBV)

Sodium stibogluconate (100mg of SbV /ml) and meglumine antimoniate at the dose of 20 mg/kg body weight for 28 -30 days has been the standard treatment for VL in most parts of the world. However, it is no longer used in India due to its ineffectiveness in Bihar and adjoining Nepal where the cure rate is <50% due to growing resistance.

Another drawback of this drug is its toxicity which is more in patients with HIV.

Amphotericin B (AMB)

AmB is a polyene antibiotic was recommended for the treatment of antimony resistant VL in Bihar, India. It has excellent cure rates (~ 100%) at doses of 0.75- 1.0 mg/ kg for 15 days but therapy is prolonged and needs close monitoring due to its adverse effects. Infusion reactions are the commonest but, nephrotoxicity, hypokalemia ,hypersensitivity reaction, bone marrow toxicity and myocarditis are some of its serious side effects .

Lipid formulations of AmB are rapidly concentrated into reticuloendothelial tissues, decreasing the amount of free drugs available and leading to less toxicity . Thus a large dose of the drug can be given over a short period.

Liposomal amphotericin B (AmBisome_; Gilead Sciences; L-AmB), is the only US Food and Drug Administration approved lipid formulation.

MILTEFOSINE

Miltefosine is an alkyl phospholipid (hexadecylphosphocholine) and the first oral antileishmanial agent. It is registered for use in India since 2002 for the treatment of VL. The recommended dose in children between 2-11 years is 2.5mg/kg for 28 days , for children 12 years and above 50mg for those <25kg and 50 mg twice daily for those >25 kg for 28 days. Cure rate is 94% in India. Although it had an oral advantage there are many drawback : long duration of therapy , adverse events like vomiting, diarrhea, elevation of liver enzymes and nephrotoxicity and teratogenicity due to which women of child-bearing potential have to observe contraception for the duration of treatment and for an additional three months. Its long half life also makes it vulnerable to the rapid development of drug resistance which is evident from a study done after a decade of its use in India which observed a decline in its efficacy and doubling of relapse rate.

PAROMOMYCIN (PM, AMINOSIDINE)

It is an aminoglycoside-aminocyclitol antibiotic approved by the Indian government in 2006 for the treatment of VL. It has excellent cure rate of 95% in the Indian subcontinent at the dose of 11 mg base/kg intramuscular injection daily for 21 days. The dose in other endemic region has not been established.

Pain at the injection site is the commonest adverse event (55%), reversible ototoxicity occurs in 2% of patients,6% patients developed reversible rise in hepatic transaminases. Renal toxicity is rare. There is no data regarding its use in pregnancy. The main advantage of the drug is its low cost.

MULTIDRUG THERAPY

With the growing resistance to antileishmanials, multidrug therapy was thought to have certain advantage : i) increased activity through use of drugs with synergistic or additive activity acting at different sites ii) shorter duration of therapy iii) lower dose requirement of individual drugs thereby decreasing toxicity and cost, and iv ) preventing the emergence of drug resistance.

In a phase III study combination of single injection of

43

CHAPTER 10

A â&#x20AC;&#x2DC;suspectâ&#x20AC;&#x2122; case: history of fever of more than 2 weeks and enlarged spleen and liver not responding to anti malaria in a patient from an endemic area. Pancytopenia and hypergammaglobinemia resulting in reversal of albumin globulin ratio is common.

The cost of L AmB was prohibitive however, a preferential pricing agreement with WHO (agreement between Gilead and WHO of 14 March 2007) reduced the price of L-AmB for endemic regions of developing countries to $18 per 50 mg vial . Encouraged by this preferential pricing and the low dose of L AmB required to cure VL in India, a study to compare a single dose of 10 mg/kg of body weight L-AmB to the conventional amphotericin B deoxycholate administered in 15 infusions of 1 mg/kg, given every other day during a 29-day hospitalization was conducted. Cure rate at 6 months were excellent in both the groups. The preferential pricing, along with a single day of hospitalization, makes a single infusion of the liposomal preparation an excellent option and has been recommended as the preferred treatment for this region.

INFECTION

44

5 mg/kg L AmB and 7-day 50 mg oral miltefosine or single injection of 5 mg/kg L AmB plus 10-day 11 mg/ kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin showed excellent cure rates (>97% in all arms) in India. The combination of miltefosine and paromomycin has been adopted by the national program.

TREATMENT GUIDELINES

The rationale for VL elimination in the Indian subcontinent are as follows: the disease in this area is anthroponotic, with humans being the only reservoir and Phlebotomous argentipes sandflies the only known vector; new and more effective drugs and a rapid diagnostic test, the rk39 immunochromatographic test, are available that can be used in the field; there is strong political commitment and inter-country collaboration; and the disease is endemic in only a limited number of districts.

•

The national strategy for elimination of Kala-azar is a multipronged approach which is in line with WHO Regional Strategic Framework for elimination of Kalaazar from the South-East Asia Region (2011-2015) and includes:

Within the Indian National Programme, assuming availability of drugs, appropriate training of health personnel, infrastructure and indication, the following drugs are used in order of preference at all levels: Single Dose 10mg/kgbw Liposomal Amphotericin B (LAMB)

• Combination regimens Paromomycin) •

(e.g.

Miltefosine

&

Amphotericin B emulsion

• Miltefosine •

I.

II. Integrated Vector Surveillance III. Supervision, evaluation

Amphotericin B deoxycholate in multiple doses

IV. For PKDL, miltefosine for 12 weeks or liposomal V. amphotericin B: 5mg/kg per day by infusion two times per week for 3 weeks for a total dose of 30mg/kg or Amphotericin B 60 -- 80 doses over 4 months or are the VI. recommended regimens.

Liposomal AmB is the drug of choice for HIV-VL co infection. A dose of 3 -- 5 mg/kg/day or intermittently for 10 doses (days 1 -- 5, 10, 17, 24, 31 and 38) up to a total dose of 40 mg/kg is recommended but relapse is common.

Antiretroviral therapy should be initiated and secondary prophylaxis should be given till the CD4 counts are > 200/ μL to prevent relapse.

VL ELIMINATION PROGRAMME

The National Health Policy (2002) set the goal of Kala-azar elimination in India by the year 2010 and later revised in 12th Five Year Plan document to 2015. The Kala-azar elimination programme has the objective of reducing the annual incidence of Kala-azar to less than 1 case per 10,000 population at block PHC level. In 2014, the Pentalateral MoU signed between Bangladesh, Nepal, Bhutan, and Thailand which also included India as a signatory, the target date for elimination was revised to 2017 or earlier by WHO South East Asia Region at Dhaka.

Early diagnosis & complete case management Management

monitoring,

and

surveillance

Vector and

Strengthening capacity of human resource in health Advocacy, communication and social mobilization for behavioral impact and inter-sectoral convergence Programme management .

REFERENCES

1.

Control of the Leishmaniasis. Report of a meeting of the WHO Expert Committee on the Control of Leishmaniases; 22 -- 26 March 2010; Geneva. Available from: http:// whqlibdoc.who. int/trs/ WHO_TRS_949_eng.pdf

2.

Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 2010; 362:504-12.

3.

Sundar S, Sinha PK, Rai M, Verma DK, Nawin K, Alam S, et al.Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial.

Lancet 2011; 5:477-86.

4.

Sundar S, Chakravarty J. An update on pharmacotherapy for leishmaniasis. Expert Opin Pharmacother 2015; 16:237-52.

5.

National vector bourne disease program. http://nvbdcp. gov.in/kal13.html.

Viral Hemorrhagic Fever

C H A P T E R

11

INTRODUCTION

Viral hemorrhagic fevers (VHFs) refer to a group of illnesses that are caused by several distinct families of viruses. In general, the term “viral hemorrhagic fever” is used to describe a severe multisystem syndrome (multiple organ systems in the body are affected). Characteristically, the overall vascular system is damaged, and the body’s ability to regulate itself is impaired. These symptoms are often accompanied by hemorrhage (bleeding). While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, lifethreatening diseases.

ETIOLOGY

A wide range of viruses can cause viral hemorrhagic fever (VHF) and hence are designated as hemorrhagic fever viruses.

•

The family Arenaviridae include the viruses responsible for Lassa fever and Argentine, Bolivian, Brazilian and Venezuelan hemorrhagic fevers.

•

The family Bunyaviridae include the members of the Hantavirus genus that cause hemorrhagic fever with renal syndrome (HFRS), the CrimeanCongo hemorrhagic fever (CCHF) virus from the Nairovirus genus, and the Rift Valley fever (RVF) virus from the Phlebovirus genus.

•

The family Filoviridae includes Ebola virus and Marburg virus. Finally, the family Flaviviridae includes dengue, yellow fever, and two viruses in the tick-borne encephalitis group that cause VHF: Omsk hemorrhagic fever virus and Kyasanur Forest disease virus.

COMMON CHARACTERISTICS

•

They are all RNA viruses, and all are covered, or enveloped, in a fatty (lipid) coating.

•

Their survival is dependent on an animal or insect host, called the natural reservoir.

•

The viruses are geographically restricted to the areas where their host species live.

•

Humans are not the natural reservoir for any of these viruses.

•

Humans are infected when they come into contact with infected hosts. However, with some viruses, after the accidental transmission from the host, humans can transmit the virus to one another.

Debasis Chakrabarti

•

Human cases or outbreaks of hemorrhagic fevers caused by these viruses occur sporadically and irregularly. The occurrence of outbreaks cannot be easily predicted.

With a few noteworthy exceptions, there is no cure or established drug treatment for VHFs. General characteristics of these viral families can be found in this table below.

TRANSMISSIONS

Viruses causing hemorrhagic fever are initially transmitted to humans when the activities of infected reservoir hosts or vectors and humans overlap. Some viruses that cause hemorrhagic fever can spread from one person to another, once an initial person has become infected. Ebola, Marburg, Lassa and Crimean-Congo hemorrhagic fever viruses are examples. This type of secondary transmission of the virus can occur directly, through close contact with infected people or their body fluids. It can also occur indirectly, through contact with objects contaminated with infected body fluids. For example, contaminated syringes and needles have played an important role in spreading infection in outbreaks of Ebola hemorrhagic fever and Lassa fever.

PATHOPHYSIOLOGY

The primary defect in patients with viral hemorrhagic fever (VHF) is that of increased vascular permeability due to multiple cytokines activations. Hemorrhagic fever viruses have an affinity for the vascular system, leading initially to signs such as flushing, conjunctival injection, and petechial hemorrhages, usually associated with fever and myalgias. Later, frank mucous membrane hemorrhage may occur, with accompanying hypotension, shock, and circulatory collapse.

Inadequate or delayed immune response to these novel viral antigens may lead to one hand rapid development of overwhelming viremia and other hand pronounced macrophage activation with extensive damage of affected organs. Hemorrhagic complications are multifactorial and are related to hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes.

Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, CCHF, and yellow fever. Renal failure with oliguria is a prominent feature of HFRS seen in Hantavirus infection and may be seen in other VHFs as intravascular volume depletion becomes more pronounced. Bleeding complications are

46

Table 1: Viruses causing Hemorrhagic Fever Diseases

Incubation Period (Days)

Case Infection ratio

Case Fertility Rate

Natural Distribution

Lassa Fever

5-16

Commonly mild infection

15%

West Africa

Rodent

All ages Both sexes

Argentine HF

7-14

>1/2 infections result in Disease

15-30%

South America

Rodent

All ages Both sex

Bolivian HF

9-15

>1/2 infections result in Disease

15-30%

South America

Rodent

Countryside:Men. Village: All age both sexes

Venezuelans HF

7-14

>1/2 infections result in Disease

15-30%

South America

Rodent

All ages both sexes

Bunia viridae i. Phlebo virus

Rift valley Fever

2-5

1:100

50%

Sub-Saharan Africa, Madagaskar, Egypt

Mosquito

All age both sex, Men more exposed, Liver disease Predisposed

ii. Nairo virus

CrimeanCongo HF

3-22

â&#x2030;Ľ1:5

15-30%

Europe, Asia, Africa

Tick

All age both sex, Men more exposed

iii. Hanta virus

HF with renal syndrome

9-35

Hantan > 1:1.25 Puumala 1:20

Hantan 5-15% Puumala <1%

Worldwide depending on rodent reservoir

Rodent

Adult male more prone

Hanta virus Pulmonary syndrome

7-28

Very high

40-50%

Americas

Rodent

Adult male more prone

Filoviridae Filovirus

Marburg and Ebola virus

3-16

High

25-90%

Sub Saharan Africa

Unknown

All ages both sex, Child less exposed

Flavivirus

Yellow fever

3-6

1:2 â&#x20AC;&#x201C; 1:20

20%

Africa, South America

Mosquito

All ages both sexes adult more exposed, preexisting flaviirus immunity may cross protect

New Arena virus

Luzo virus (Discovered in 2008)

2 weeks

Very high

Highly fatal

Lusaka (Zambia), Johannesburg (South Africa)

Rodent, Bat

All ages both sexes

New Flavi virus

Alkhumra Few weeks hemorrhagic fever

Very high

25%

Saudi Arabia

Sheep, Goat, Rodent.

Mosquito

Al ages both sexes

Virus

INFECTION

Arenaviridae: Arena virus

Usual Target Population Source of Human Infection

New

particularly prominent with Ebola, Marburg, CCHF, and the South American arena viruses.

•

Avoid intramuscular injections and the use of aspirin or other anticoagulants.

COMMON CLINICAL FEATURES

•

Minimize invasive procedures because of the risk associated with viral transmission from sharp objects

Although clinical features vary somewhat for the various hemorrhagic fever viruses, the clinical presentations overlap substantially. All of the agents cause a febrile prodrome associated with varying degrees of prostration; other notable features include the following.

•

All staff entering the room should wear gloves and gowns

•

Persons coming within 3 feet of the patient should wear face shields or surgical masks with eye

•

Severe exudative pharyngitis is a characteristic early feature of Lassa fever.

protection (including side shields); use HEPA filter masks if patients have prominent respiratory, GI, or hemorrhagic symptoms.

•

Several agents cause meningoencephalitis in addition to VHF (eg, Rift Valley fever, Kyasanur Forest disease, Omsk hemorrhagic fever viruses).

If large amounts of blood or other body fluids are present in the environment, use leg and shoe coverings.

•

Jaundice may be a prominent feature in some infections (eg, Ebola and Marburg hemorrhagic fevers, Lassa fever, Rift Valley fever, yellow fever).

Before exiting the room, discard all used protective barriers and clean shoes with a hospital disinfectant or solution of household bleach.

•

If possible, use an anteroom for putting on and removing protective barriers and for storing supplies.

•

A maculopapular rash may be noted early in the clinical course in some forms of VHF (notably in Ebola and Marburg hemorrhagic fevers)

•

•

INVESTIGATIONS

There may be leucopenia, thrombocytopenia with elevated hepatic enzymes, raised prothombin time, activated partial thromboplastin time and fibrin degradation product in patients with hemorrhages and hepatopathy.

Specific viral diagnosis can be made using serologic tests, including enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction. Difficult cases may require tissue cultures. During the 2000-2001 Ebola outbreak in Uganda, reverse transcriptase-PCR (RT-PCR) emerged as a very effective means for detecting Ebola virus in patient serum, plasma, and whole blood. Report all suspected cases of viral hemorrhagic fever (VHF) immediately to local and state public health departments and to the CDC. Because of the need for specialized microbiologic containment and handling of these viruses, initiate contact with the Centers for Disease Control and Prevention (CDC; Atlanta, GA) as soon as possible and prior to transport of specimens for virus-specific diagnosis. Specific state and federal statutes govern the shipment of highly infectious disease agents.

TREATMENT

Fluid resuscitation and supportive care are the mainstays of emergency department therapy.

Intravenous crystalloids, oxygen, and cardiac monitoring are the most appropriate initial steps in the treatment of patients in whom viral hemorrhagic fever (VHF) is suggested. Other measures include the following: •

Administer blood and blood products as clinically indicated.

No specific antiviral therapy is available for Ebola or Marburg virus infection. The use of convalescent serum (ie, sera from patients who have survived infection) is suggested as a possible therapy.

Lassa fever and HFRS due to Hantavirus infection have been treated effectively with intravenous and oral ribavirin. Because of this, ribavirin has been recommended as a potential treatment for other arena viruses and bunya viruses. Treatment is most effective when given early in the clinical course. Ribavirin also is recommended for post exposure prophylaxis. Other potential antiviral therapies against Lassa fever include novel benzimidazole compounds such as ST-193 and other related heterocyclic compounds.

Recently proposed guidelines for the use of ribavirin for post exposure prophylaxis recommend the use of oral ribavirin exclusively for definitive, high-risk exposures, such as contaminated needle stick injury, mucous membrane or no intact skin exposure with contaminated blood or body fluids, participation in emergency resuscitative procedures (eg, intubation, suctioning), or prolonged close contact in an enclosed space with infected patients without appropriate personal protective equipment.

PREVENSION

1.

Because many of the hosts that carry hemorrhagic fever viruses are rodents, disease prevention effort include:

a.

Controlling of rodent populations

CHAPTER 11

Prevent nonessential staff and visitors from entering the room

Bleeding manifestations occur in variable proportions of patients (eg, in about 30% of patients with Ebola or Marburg hemorrhagic fever and in only about 1% of patients with Rift Valley fever).

•

Infection control measures include the following: •

•

47

48

b.

Discouraging rodents from entering and living in homes or workplaces.

c.

Encouraging safe cleanup of rodent nest and droppings.

INFECTION

2. Vaccines:

Yellow fever vaccine is readily available and is both safe and effective. A bivalent vaccine is being developed from the preexisting 17D yellow fever vaccine that would express not only yellow fever glycoprotein’s but also Lassa glycoprotein’s, theoretically stimulating a protective immune response against both viruses.

A recent study evaluating the safety and efficacy of a tetravalent dengue vaccine demonstrated full seroconversion against all WHO dengue serotypes in flavivirus-naive adults.

Argentine HF (Junín) vaccine is also effective and may protect against Bolivian HF as well.

Rift Valley fever and Hantan (HFRS) vaccines are also available.

Although there is no approved vaccine for either Ebola or Marburg virus, significant progress has been made in developing an effective experimental vaccine using a vesicular stomatitis virus-based vaccine.

Other efforts to create a viable (and marketable) Ebola vaccine have led to the development of an experimental bivalent vaccine that confers protection against both rabies and Ebola virus.

COMPLICATION

Complications from viral hemorrhagic fever (VHF) infection include retinitis, orchitis, encephalitis, hepatitis, transverse myelitis, and uveitis.

In patients who recover from Lassa fever infection, deafness is the most common complication.

Renal insufficiency is associated with HFRS infection.

DENGUE HEMORRHAGIC FEVER

Introduction

Dengue virus, belong to a family Flaviviridae and have four serotypes (DEN 1, 2, 3, 4). They are transmitted mainly by Aedes aegypti and Aedes albopictus mosquito.

Among the four serotype DEN 2 is more virulent and most of DHF are due to infection of DEN 2.

Dengue is a mosquito borne viral disease, which has raised concern globally, due to alarming 30 fold increase in its incidence in last few decades. Almost 75% of global population exposed to dengue live in Asia-Pacific region.

In India first major epidemic of DHF was observed in 1996 involving Delhi, Lucknow, Kolkata and Chennai. In 2015 India also faced a major outbreak affected worstly in Delhi and Punjab followed by West Bengal and Gujarat having total mortality of 90000 with 180 deaths.

Transmission

Most Dengue epidemic occurs post monsoon, due to increase in vector population. However virus maintenance during inter epidemic period has been attributed to transoverian transmission of Dengue virus. Dengue virus primarily transmitted to human through an infected mosquito bite. Humans are the main amplifying host of the virus. After a blood meal virus infect the mosquito and stays in its gut for 8-12 days of extrinsic incubation period.

Virus again reenter the human body after subsequent bite. Aedes aegypti is one of the most efficient vector for arboviruses because it is highly anthrophilic, frequently bites several times before completing oogenesis, and thrives in close proximity to Humans.

Pathogenesis

Replication of the dengue virus occurs within mononuclear cells including skin dendritic cells, tissue macrophages, peripheral blood monocytes, and hepatocytes. At present, the host cell receptors involved in the viral entry are mostly unknown. Primary or first infection in nonimmune persons usually causes DF. Subsequent dengue infection by a different serotype causes more severe illness, such as DHF/DSS. The key manifestations of DHF/DSS are sudden onset of shock, capillary leakage, and hemorrhagic diathesis/thrombocytopenia occurring at the time of defervescence. Pathogenesis is not well-defined, but it is suggested that during secondary infection with a different serotype, cross-reactive nonneutralizing antibodies bind to DENV and facilitate uptake via Fc receptors, resulting in enhanced viral replication. The resultant higher viral antigen load leads to an exaggerated activation of cross-reactive dengue specific T cells. Biological mediators released by the activated T cells as well as virus-infected cells along with complement activation by viral proteins and immune complexes are implicated in increasing vascular permeability and coagulopathy.

This phenomenon is known as antibody-dependent enhancement.

Clinical features

This model for classifying dengue has been suggested by an expert group (Geneva, Switzerland, 2008) and is currently being tested in 18 countries by comparing its performance in practical settings to the existing WHO case classification (Table 2).

Diagnosis

The nonspecific nature of the illness mandates laboratory verification for diagnosis.

For confirmation of Dengue infection, Govt of India recommends use of ELISA- based virus specific antigen (NS1) for diagnosing the cases from the first day onwards and antibody detection test IgM capture ELISA (MACELISA) for diagnosing the cases after the fifth day of disease onset.

Govt of India introduced ELISA- based NS1 antigen in 2010 in addition to MAC- ELISA tests which can detect the case during ay 1 to day 5 of illness.

49

Table 2: Expert Group Classification for Dengue Criteria For Dengue Warning Signs

Criteria For Severe Dengue

Probable Dengue

Warning Signs*

Severe plasma leakage

Live in or travel to Dengue endemic area.

Abdominal pain or tenderness

Shock

Persistent vomiting

Fluid accumulation with severe respiratory distress.

Fever and 2 of the following criteria : Clinical fluid accumulation 1. Nausea, vomiting Mucosal bleeding 2. Rash

3. Aches and pains 5. Leucopenia 6. Any warning signs 7. Liver: AST/ALT> 1000

Liver enlargement > 2cm Laboratory: Increase in HCT with rapid decrease in platelet count.

Severe organ involvement.

CNS: Impaired consciousness Heart and other organs

(*requiring strict observation and medical intervention)

Laboratory confirmed Dengue (important when no signs of plasma leak)

Treatment

The management of dengue virus infection is essentially supportive and symptomatic. No specific treatment is available. However, there are Indian studies which have contributed in terms of better management of DHF/DSS. A rapid response to platelet and fresh frozen plasma (FFP) transfusion is reported in a study. Anti-D has been used in children with DHF and severe refractory thrombocytopenia. In experimental study pre-feeding mice with trivalent chromium picolinate (CrP) in drinking water could abolish the adverse effects of DV infection on most of the hematological parameters. Hippophae rhamnoides (Sea buckthorn, SBT) leaf extract has been shown to have a significant anti-dengue activity.

5.

Feldmann H, Geisbert TW. Ebola hemorrhagic fever. Lancet 2011; 377:849-62 [Abstract]

6.

WHO. Ebola hemorrhagic fever: fact sheet. Revised Dec 2011.

7.

WHO. Revised recommendations for yellow fever vaccination for international travelers, 2011.Wkly Epidemiol Rec 2011; 86:401-11.

8.

Mallhi TH, Khan AH, Adnan AS, et al. Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study. BMC Infect Dis 2015 (published online Sep 30)

9.

Jessie K, Fong MY, Devi S, Lam SK, Wong KT. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J Infect Dis 2004; 189:1411–1418.[PubMed]

REFERENCES

10. World Health Organization. Comprehensive guidelines for prevention and control of Dengue and Dengue Hemorrhagic fever. Preface. World Health Organization Regional office for south East Asia.2011.

2.

Banerjee K, Gupta NP, Goverdhan MK. Viral infections in laboratory personnel. Indian J Med Res 1979; 69:363-73

11. World Health Organization. Global strategy for Dengue prevention and control 2012-2020. Geneva: WHO; 2012.

3.

CDC. Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order. 2011 Oct 12[Full text]

4.

Cleri DJ, Ricketti AJ, Porwancher RB, et al. Viral hemorrhagic fevers: current status of endemic disease and strategies for control. Infect Dis Clin North Am 2006; 20:359-93

12. Shah I, Deshpande G C and Tardeja P N. Outbreak of dengue in Mumbai and Predictive markers for dengue shock syndrome; J Trop Pediatr 2004; 50:301–305.

1. Centers for Disease Control (CDC). Management of patients with suspected viral hemorrhagic fever. MMWR Morb Mortal Wkly Rep. 1988; 37:1–16

CHAPTER 11

4. Tourniquet test positive

Lethargy, Restlessness

Severe bleeding as evaluated by clinician.

Swine Flu

C H A P T E R

12

Bala Vinoth, D Suresh Kumar

pulmonary diseases,

INTRODUCTION

Influenza (the “flu”) is a seasonal respiratory illness caused by influenza viruses. Influenza is usually a mild and selflimited respiratory illness, but it has the potential to cause significant morbidity & mortality as it spreads widely in the community. In the last few years, we are experiencing a new strain of Influenza A virus called Swine origin of influenza virus (A/2009/H1N1). A highly contagious form of human influenza virus related to a virus formerly isolated from infected swine. The respiratory infection popularly known as swine flu is caused by this influenza virus first recognized in March 2009 and it speeded quickly across other countries within short span of time and resulted in recent big pandemic. This 2009 pandemic influenza A (H1N1) virus is continued to co-circulate following years along with seasonal influenza A and cased significant mortality among young people.

•

Persons with hemodynamically significant cardiac disease ( both congenital & acquired)

•

Persons who have immunosuppressive disorders or who are receiving immunosuppressive therapy & HIV-infected persons

•

Persons with sickle cell anemia and other hemoglobinopathies

•

Persons with diseases that requiring long-term aspirin therapy,

•

Persons with chronic renal dysfunction

•

Persons with cancer

•

Persons with chronic metabolic disease, such as diabetes mellitus

EPIDEMIOLOGY

•

Persons with neuromuscular disorders, seizure disorders, or cognitive dysfunction that may compromise the handling of respiratory secretions

•

Residents of any age of nursing homes or other long-term care institutions

The latest pandemic of swine flu was first noted in Mexico in March 2009, the outbreak rapidly spread worldwide affected nearly 195 countries and finally declared ended in August 2010. In India the swine flu outbreak killed 981 people in 2009 and 1763 in 2010.

The mortality decreased in 2011 to 75. However during subsequent years the mortality gradually increased to 405 lives in 2012 and 699 lives in 2013. In 2015, the outbreak became widespread throughout India. The states of Gujarat and Rajasthan were the worst affected. H1N1 influenza A 2009 pandemic strain is now responsible for periodic seasonal outbreaks of influenza in India.

The average incubation period is 1-3 days (maximum of 7 days) and the main mode of transmission is through contact with large-particle respiratory droplets by sneezing and coughing. Other body fluids (eg, diarrheal stool) and fomites also play a role in transmission. Viral shedding begins the day prior to symptom onset and often to persist for five to seven days or even longer in children and in immunocompromised individuals.

RISK GROUPS

ETIOLOGICAL AGENT

The influenza virus is a RNA virus belonging to the family Orthomyxoviridae with three main genera – Influenza A, B and C. Influenza A is further sub-typed into 16 distinct H types and 9 distinct N types based on the hemagglutinin and neuraminidase antigens on the surface of the virus as shown in the Figure 1.

Every year new strains of influenza virus emerge as its Lipid bilayer Hemagglutinin (H)

Matrix protein

The risk factors for influenza complications are seen in •

Infants & children aged < 5 years and adults aged> 65 years

•

Obese individuals

•

Pregnant ladies

•

Persons with asthma or COPD & other chronic

Neuraminidase (N)

Fig. 1: Structure of Influenza virus

RNA and Protein

51

Table 1: Clinical features of Swine Influenza Common clinical features

Extra pulmonary manifestations

Complications

Fever

CVS: Chest pain, Hypotension

Pulmonary: Progressive viral pneumonia, secondary bacterial pneumonia, ARDS

Sore throat

CNS: seizures, lethargy, altered mental status, weakness or paralysis

Extra- Pulmonary: CNS: Encephalitis, encephalopathy, GBS, ADEM

Rhinorrhea

Others: decreased urine output, cyanosis, dehydration

CVS: Myocarditis, pericarditis

Myalgia, arthralgia Headache Vomiting, diarrhea

Table 2: Diagnostic tests for Swine Flu Nonspecific findings:

Specific findings

CBC: Leucopenia, thrombocytopenia, Anemia

RT- PCR: Highly sensitive * very high specific, usually recommended test for clinical diagnosis faster turnaround time (nasopharyngeal or throat swab in sick patient lower respiratory samples)

LFT: Raised liver enzymes, & elevated bilirubin

Viral culture: Moderately sensitive, highest specificity, usually recommended for public health surveillance , not useful in clinical situations due to long turnaround time

Others: Increased CPK & LDH

Rapid antigen test: The sensitivity widely varies and negative test will not rule out influenza. Not recommended nowadays.

X-ray: Bilateral infiltrates (lower lobe predominance) & features of ARDS CT chest: Patchy consolidation or ground glass opacities

Table 3: Antiviral agents against Influenza Oseltamivir (NA inhibitor)

Zanamavir (Na inhibitor)

Amantadine & Rimantadine (M2 inhibitor)

Swine Influenza

Susceptible

Susceptible

Resistant

Seasonal H1N1

Mostly susceptible

Mostly susceptible

Mostly resistant

Seasonal H3N2

Susceptible

Susceptible

Resistant

Influenza B

Susceptible

Susceptible

Resistant

genes undergo point mutations leading to an ‘antigenic drift’. This process helps the virus to evade host defense mechanism. The influenza A virus is different when compared to other two influenza viruses by having a segmented genome with eight single stranded RNA segments. When the host cell is infected with more than one influenza virus, these genes have the opportunity to get reassorted and produce a very different strain altogether. This process is called ‘antigenic shift’ is mainly responsible for pandemics strains of influenza viruses.

The current swine origin influenza A virus 2009 train has undergone triple reassortment and contains genes from the avian, swine and human viruses.

other seasonal influenza virus, the A/2009/H1N1 virus also binds to the 2, 3-linked sialic acid receptors that are present in the lower respiratory tract and cause diffuse alveolar damage. This finding may partially explain the predilection of this new virus to cause pneumonia in healthy individuals. After the initial illness, the host usually mounts a protective mmune response which involves a rise in antibody titers as well as T cell activation. The production of interferon in the respiratory mucosa is associated with a fall in virus shedding. Specific histopathologic findings in the lungs included edema, hyaline membranes , fibrin , hemorrhage , inflammation , type II pneumocyte hyperplasia and organizing fibrosis..

PATHOGENESIS

CLINICAL MANIFESTATIONS CASE DEFINITIONS

Virus-containing droplet particles may settle on nasopharyngeal, tracheobronchial,conjunctival, or other respiratory mucosal epithelial cells. In contrast to the

Probable case of Influenza: (Influenza-like illness (ILI)) is defined as fever (temperature of 100ºF [37.8ºC] or greater)

CHAPTER 12

Others: renal failure, rhabdomyolysis, ryes syndrome, hemophagocytosis, multi-organ failure syndrome

ALTERNATIVE & NEWER REGIMENS

52

Peramivir 600 mg (FDA approved for single dose intravenous). It has got longer duration and may be considered for severe disease). Commonest adverse effect of peramivir is rash.

Zanamivir 600 mg IV q12h for at least 5 days (Investigational) can be considered for patients with inability to take oseltamivir orally and contraindications to inhaled zanamivir or who have progressive disease despite at least 5 days of therapy, or suspected or confirmed oseltamivir resistance.

INFECTION

OTHER SUPPORTIVE CARE

Fig. 2 Clinical algorithm for the management of suspected Swine flu with cough or sore throat in the absence of a known cause other than influenza (Table 1).

A confirmed case of pandemic H1N1 influenza A is defined as an individual with an ILI with laboratory-confirmed H1N1 influenza A virus detection by real-time reverse transcriptase polymerase chain reaction (rRT-PCR) or culture (Table 2).

DIAGNOSIS MANAGEMENT

Common anti-viral agents used to treat influenza viruses are neuraminidase inhibitors and M protein inhibitors, their activity against common influenza viruses are shown in Table-3

INDICATIONS FOR TREATMENT

•

Illness requiring hospitalization

•

Progressive, severe, or complicated regardless of previous health status

•

Extremes of age

•

Pregnant women and women up to two weeks postpartum

•

Individuals with high risk medical conditions .and those who were obese

illness,

PRIMARY REGIMENS FOR ADULTS

•

Oseltamivir 75 mg po bid x 5 days OR Zanamivir 2 inhalations (5 mg each) bid x 5 days

•

Oseltamavir can cause diarrhoea, nausea, vomiting and abnormal behaviour. Zanamavir can cause bronchospasm.

Supportive management including IV fluids, antipyretics, and oxygen support for hypoxic patients and Low tidal volume ventilation for mechanically ventilated patients may be necessary. It is recommended that patients with pandemic H1N1 influenza A, who developed pneumonia be treated empirically for community-acquired pneumonia (CAP) given the risk of secondary bacterial pneumonia. Adjunctive approaches have been evaluated including extracorporeal membrane oxygenation, N-acetyl cysteine, and glucocorticoids, but further studies are required to clearly know their role.

Clinical algorithm to manage swine flu is shown in Figure 2 below.

PREVENTION

Measures to prevent swine flu spread include use of face mask (triple layer surgical mask), frequent hand wash and adherence to cough etiquettes by the patient. Contact surfaces should be disinfected with sodium hypochlorite or household bleach 5%. Adult patients need to be isolated till their symptoms had subsided. In children the isolation period is little longer due to prolonged excretion of viruses.

ANTIVIRAL PROPHYLAXIS

The post exposure antiviral prophylaxis could be considered for adults and children who had close contact with a confirmed or suspected case and also fell into one of the following categories: •

Adults who are at high risk for complications of influenza

•

Pregnant women and women who are up to two weeks postpartum

•

Children who are <5 years of age or who are at high risk of complications of influenza

•

Healthcare workers and emergency medical personnel

DOSE & REGIMENS

Oseltamivir 75 mg po once daily for 10 days..

Zanamivir inhaled powder, 10 mg, once daily.

VACCINATION

The CDC\) recommended that H1N1 influenza vaccine be given to all patients from six months of age and older.

Priority is given to health care personnel and the above mentioned high risk groups.

Inactivated influenza vaccine (IIV), recombinant influenza vaccine (RIV) and live attenuated influenza vaccine (LAIV) are all what are available. IIV is the most common used.

The selection of vaccine subunits is based on the strain prevalence during the previous year influenza activity.

Efficacy is 70 to 80 %. It takes 2 to 3 weeks for the immunity to develop. Immunogenicity is retained if pandemic and seasonal influenza vaccines are coadministered..

1.

Centers for Disease Control and Prevention (CDC). Update: novel influenza A (H1N1) virus infections - worldwide, May 6, 2009. MMWR Morb Mortal Wkly Rep 2009; 58:453.

2.

World Health Organization. World now at the start of 2009 influenza pandemic. http://www.who.int/mediacentre/ news/statements/2009/h1n1_pandemic_phase6_20090611/ en/index.html

3.

Clinical management of Human infection with pandemic H1 N1 2009: Revised Guidance

4.

Pandemic Influenza A H1N1 Clinical management protocol & Infection control guidelines, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India.

5.

Harper SA et al. Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America.

Clin Infect Dis 2009; 48:1003-32.

53

CHAPTER 12

The small excess risk of Guillain-Barré syndrome and narcolepsy is observed with the use of vaccine. Other neurologic syndromes, such as transverse myelitis and opsoclonus myoclonus syndrome has also been reported.

It is generally well tolerated and there is no safety concern for the pregnant woman.

REFERENCES

C H A P T E R

13

Clinical Presentation and Systemic Manifestations of Zika Virus

The rise in the spread of Zika virus has been accompanied by a rise in cases of microcephaly and Guillain-Barré syndrome. In 1947, A STUDY OF YELLOW FEVER YIELDED THE FIRST ISOLATION OF A NEW virus, from the blood of a sentinel rhesus macaque that has been placed in the Zika Forest of Uganda. Zika virus remained in relative obscurity for nearly 70 years; then, within the span of just 1 year, Zika virus was introduced in to Brazil from the Pacific Islands and spread rapidly throughout the Americas. It became the first major infectious disease linked to human birth defects to be discovered in more than half a century and created such global alarm that the World Health Organization (WHO) would declare a Public Health Emergency of International Concern.

THE HISTORY OF ZIKA VIRUS

Zika virus is flavivirus, in the family Flaviviridae. In 1947 scientists identify a new virus in a rhesus monkey in the Zika forest of Uganda - named as the Zika virus. In 1948 the virus is then recovered from the mosquito Aedes africanus, caught in the Zika forest. In 1952 the first human cases of Zika are detected in Uganda and the United Republic of Tanzania. In 1964 a researcher in Uganda is infected with Zika while working on the virus confirming that Zika virus causes human disease. In 1960s - 1980s human cases are confirmed through blood tests.

No deaths or hospitalizations are reported, but studies consistently show widespread human exposure to the virus.

Rajib Ratna Chaudhary

Easter Island, the Cook Islands, and New Caledonia.

Thousands of suspected infections are investigated in French Polynesia and results reveal possible associations between Zika virus and congenital malformations and severe neurological and autoimmune complications.

In 20 March 2014 during the outbreak of Zika virus in French Polynesia, 2 mothers and their newborns are found to have Zika virus infection within 4 days of birth.

The infants’ infections appear to have been acquired by transplacental transmission or during delivery. In 31 March 2014 during the same outbreak of Zika virus in French Polynesia 1,505 asymptomatic blood donors are reported to be positive for Zika by PCR. These findings alert authorities that Zika virus can be passed on through blood transfusion. In 29 March 2015 Brazil notifies WHO of an illness characterized by skin rash in northeastern states.

In 17 July 2015 Brazil reports neurological disorders associated with a history of infection, primarily from the north-eastern state of Bahia. Among these reports, 49 cases were confirmed as Guillain–Barré syndrome. Of these cases, all but 2 had a prior history of infection with Zika, chikungunya or dengue.

In 2007 first large Zika outbreak in humans in the Pacific Island of Yap in the Federated States of Micronesia. Prior to this, no outbreaks and only 14 cases of human Zika virus disease had been documented anywhere in the world. An estimated 73% of Yap residents are infected with Zika virus.

Brazil reports an unusual increase in the number of cases of microcephaly among newborns. On 17 November 2015 WHO issue an epidemiological alert asking countries to report increases of congenital microcephaly and other central nervous system malformations. Brazil reports the detection of Zika virus in amniotic fluid samples from 2 pregnant women, whose foetuses were confirmed by ultrasound examinations to have microcephaly. In 28 November 2015 Brazil detects Zika virus genome in the blood and tissue samples of a baby with microcephaly and other congenital anomalies; the baby died within 5 minutes of birth. Brazil reports 3 deaths among 2 adults and a newborn associated with Zika infection. On 1 December 2015 WHO issue an alert on the association of Zika virus infection with neurological syndrome and congenital malformations in the Americas.

IN 2008 a US scientist conducting field work in Senegal falls ill with Zika infection. On his return home to Colorado he infects his wife in what is the first documented case of sexual transmission of a disease usually transmitted by insects. In 2012 researchers identify 2 distinct lineages of the virus, African and Asian. In 2013 – 2014 outbreaks occur in 4 other groups of Pacific islands: French Polynesia,

In 5 January 2016 researchers report the first diagnoses of intrauterine transmission of the Zika virus in 2 pregnant women in Brazil whose fetuses were diagnosed with microcephaly, including severe brain abnormalities, by ultrasound. Although tests of blood samples from both women are negative, Zika virus is detected in amniotic fluid.

The disease is mapped as it moves from Uganda to western Africa and Asia in the first half of the 20th century. In 1969 – 1983 Zika virus is detected in mosquitoes found in equatorial Asia, including India, Indonesia, Malaysia and Pakistan.

55

CHAPTER 13

Fig. 1: Elecron micrograph of the virus. Virus particles (digitally colored purple) are 40 nm in diameter, with an outer envelope and a dense inner core In 7 January 2016 Ophthalmologists in Brazil report severe ocular malformations in 3 infants born with microcephaly.

In 12 January 2016 in collaboration with health officials in Brazil, the United States Centers for Disease Control and Prevention release laboratory findings of 4 microcephaly cases in Brazil (2 newborns who died in the first 24 hours of life and 2 miscarriages) which indicate the presence of Zika virus RNA by PCR and by immunohistochemistry of brain tissue samples of the 2 newborns. In addition, placenta of the 2 fetuses miscarried during the first 12 weeks of pregnancy test positive by PCR. Clinical and epidemiological investigations in Brazil confirm that all 4 women presented fever and rash during their pregnancy.

The findings are considered the strongest evidence to date of an association between Zika infection and microcephaly.

In 19 January 2016 El Salvador reports an unusual increase of Guillain–Barré syndrome.

In 22 January 2016 Brazil reports that 1,708 cases of Guillain–Barré syndrome have been registered by hospitals between January and November 2015. Most states reporting cases are experiencing simultaneous outbreaks of Zika, chikungunya, and dengue. In 27 January 2016 French Polynesia reports retrospective data on its Zika outbreak, which coincided with a dengue outbreak. During the outbreak, 42 cases of Guillain– Barré syndrome were diagnosed - a 20-fold increase over previous years. All 42 cases tested positive for Zika and dengue. The investigation concluded that successive dengue and Zika virus infections might be a predisposing factor for developing Guillain–Barré syndrome.

In 2 February 2016 the United States reports a case of sexual transmission of Zika infection in Texas. Venezuela

Fig. 2: Zika Virus Transmission Cycle reports an increase in cases of Guillain–Barré syndrome (GBS) since the second week of January 2016. By end January 2016, 252 GBS cases, associated in time and place with Zika, are reported.

In 4 February 2016 Brazilian health officials confirm a case of Zika virus infection transmitted by transfused blood from an infected donor. In 7 February 2016 Suriname reports an increase in Guillain–Barré syndrome, beginning in 2015, with 10 cases of Guillain–Barré syndrome positive for Zika. In 10 February 2016 a case report describes severe fetal brain injury associated with Zika virus infection in a woman who became pregnant in Brazil in February 2015.

No virus or pathological changes were found in any other organs, suggesting that the virus is strongly neurotropic, which means it preferentially attacks the nervous system.

Honduras reports at least 37 Guillain–Barré syndrome cases in 2016.

The report brings the number of countries detecting an increase in GBS associated with Zika virus circulation to 8: French Polynesia, Brazil, El Salvador, the French territory of Martinique, Colombia, Suriname, Venezuela, and Honduras.

In 3 March 2016 a case report published online in the Lancet describes a 15-year-old Zika-positive girl in Guadeloupe who developed acute myelitis (inflammation of the spinal cord), which caused severe back pain, numbness, and bladder dysfunction. This association suggests that Zika virus preferentially affects the nervous system. In 4 March 2016 a study in Brazil of 88 pregnant women

INFECTION

56

Fig. 5: Symptoms of Zika Virus Fig. 3: Transplacental Transmission

ZIKA virus

Fig. 4: Transmission from Mother to Foetus found that 72 women tested positive for Zika virus in their blood and/or urine. Abnormalities of the fetus were detected by ultrasound in 12 Zika-positive women.

These findings add to the growing body of evidence linking Zika virus infection to fetal abnormalities. In 10 March 2016 the United States reports 2 GBS cases with confirmed Zika virus infection. The first case, an elderly man with a recent history of travel to El Salvador, died from sudden subarachnoid haemorrhage caused by a ruptured aneurysm. The second case, a male resident of Haiti in his 30s, was diagnosed after he travelled to the US for treatment. He recovered fully after 5 days of treatment in hospital.

ZIKA VIRUS TRANSMISSION

Mosquito – Borne Transmission

Zika virus exists in a sylvatic transmission cycle involving nonhuman primates and forest-dwelling species of aedes mosquitoes. Figure 1 shows the electron micrograph of the virus. In Asia, a sylvatic transmission cycle has not yet been identified. In urban and suburban environments, Zika virus is transmitted in a human-mosquito-human transmission cycle (Figure 2). Two species in the stegomyia subgenus of aedeses - A. aegypti and, to a lesser extent, A. albopictus – have been linked with nearly all known Zika virus out-breaks. A. aegypti is thought to have high vectorial capacity (i.e, the overall ability of a vector species to transmit a pathogen in a given location and at a specific time) because it feeds primarily on humans, often bites multiple humans in a single blood meal, has an almost imperceptible bite, and lives in close association with human habitation.

Fig. 6: Rash on an arm due to ZIKA Nonmosquito Transmission

Substantial evidence now indicates that Zika virus can be transmitted from the mother to the foetus during pregnancy and peripartum transmission of Zika have been reported among mother-infant pairs (Figures 3 and 4).

Sexual transmission to partners of returning male travelers who acquired Zika virus infection abroad has been reported. Replicative viral particles, as well as viral RNA – often in high copy numbers – have been detected up to 62 days after the onset of symptoms. Male-tomale transmission repoted from Texas in January 2016.

Transmission of Zika virus thrugh blood transfusion has been reported. Transmission of Zika virus occurred after a monkey bite in Indonesia. Transmission through on breast milk has not been documented, although the

57

breast milk of a woman who became symptomatic with Zika virus infection on the day of the delivery contained infective Zika viral particles in high titer.

CLINICAL PRESENTATION

The incubation period for Zika virus is unknown, but if it is similar to that of other mosquito borne flaviviruses, it is expected to be generally less than one week (average 3 to 10 days).

The most common symptoms of Zika virus disease are fatigue, chills, loss of appetite, or sweating , rash which is maculopapular and pruritic (90% of patients), fever when present, is generally short-term and low-grade (65%), arthritis or arthralgia (65%), non-purulent conjunctivitis (55%), myalgia (48%), headache (45%), retro-orbital pain (39%), oedema (19%), and vomiting (10%). Other symptoms include haematospermia, transient dull and metallic hearing, swelling of hands and ankles, and subcutaneous bleeding (Figures 5 and 6).

SYSTEMIC MANIFESTATION

Neurologic Complications

A temporal and geographic relationship has been observed between Guillain-Barre’ syndrome and Zika virus outbreaks in the Pacific and the Americas. A casecontrol study in French Polynesia revealed a strong association (odds ratio, >34) between Guillain-Barre’ syndrome and previous Zika virus infection; the findings from elecrophysiological studies were compatible with the acute motor axonal neuropathy subtype of Guillain-Barre’ syndrome. Meningoencephalitis and acute myelitis complicating Zika virus infection also have been reported. Brazilian scientists said they had discovered a new neurologic disorder associated with Zika virus infections in adults, an autoimmune syndrome called acute disseminated encephamyelitis. Resembling multiple sclerosis and found mostly in childern, acute disseminated encephamyelitis attacks nerve fibers in the brain and spinal cord.

ADVERSE FOETAL OUTCOMES

The findings of Zika virus RNA in amniotic fluid of foetuses with microcephaly and in the brain tissue of

foetuses and infants with microcephaly, as well as the high rates of microcephaly among infants born to mothers with proven antecedent acute Zika virus infection, provide strong evidence linking microcephaly to maternal Zika virus infection. The greatest risk of microcephaly is in the first trimester.

In addition to microcephaly , an absent corpus callosum, hydranencephaly, cerebral calcifications, ventricular dilatation, brain atrophy, and abnormal gyration, hydrops foetalis, anhydramnios, and intrauterine growth retardation have been found.

OCULAR MANIFESTATION

The most common ocular abnormalities were focal pigment mottling, chorioretinal atrophy, and optic nerve abnormalities (hypoplasia and severe cupping of the optic disk). Other ocular manifestations include foveal reflex loss, macular neuroretinal atrophy, lens subluxation, and iris coloboma (Figure 7).

REFERENCES

1.

Deckard DT, Chung WM, Brooks JT, et al, Male-to-male transmission of Zika virus – Texas, January 2016. MMWR Morb Mortal Wkly Rep 2016; 65:372-374.

2.

Hughes S, “Zika virus now linked to autoimmune neurologic condition, “Published April 12, 2016.

3.

Goodman B. CDC: “ Zika virus definitely causes microcephaly. “ Published April 13, 2016

4.

Centers for Disease Control and Prevention. Zika Virus 2015. http://www.cdc.gov/zika/index.html.

5.

World Health Organization. Zika virus infection e Brazil and Colombia.21 Oct 2015. http://www.who.int/csr/don/21october-2015-zika/en/.

6.

Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS,et al. Zika virus outbreak on Yap island, Federated States of Micronesia. N Engl J Med 2009; 360:2536e43.

7.

Dupont-Rouzeyrol M, O’Connor O, Calvez E, Daures M, John M, Grangeon JP, et al. Co-infection with Zika and dengue viruses in 2patients, New Caledonia, 2014. Emerg Infect Dis 2015; 21:381e2.

8.

Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastere S, Valour F, et al. Zika virus infection complicated by Guillain-

CHAPTER 13

Panel - A Panel - B Panel - C Fig. 7: Slit-Lamp Photographs of The Patient’s Eyes. Conjunctival hyperaemia in the right eye (Panel – A) and left eye (Panel – B) 8 days after the onset of systemic symptoms. Panel – C , are keratic precipitates and grade 2+ inflammatory cells in the anterior chamber of the left eye 16 days after the onset of Zika virus infection`

Barre syndrome e case report, French Polynesia, December 2013. Euro Surveill 2014; 19. Pii 20720.

58 9.

European Centre for Disease Prevention and Control. Rapid risk assessment: microcephaly in brazil potentially linked to the Zika virus epidemic. 24 Nov 2015. http://ecdc.europa. eu/en/publications/ Publications/zika-microcephaly-Brazilrapid-risk-assessment-Nov-2015.pdf.

INFECTION

10. World Health Organization. Zika virus infection e suriname.

13 Nov 2015. http://www.who.int/csr/don/13-november2015-zika/en/.

11. European Centre for Disease Prevention and Control.

Zika virus infection: factsheet for health professionals.

2015. http://ecdc.europa.eu/en/ healthtopics/zika_virus_ infection/factsheet-health-professionals/Pages/ factsheet_ health_professionals.aspx.

12. Foy BD, Kobylinski KC, Chilson Foy JL, Blitvich BJ, Travassos da Rosa A, Haddow AD, et al. Probable nonevector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis 2011;17:880e2.

13. World Health Organization and Pan American Health Organization. Zika Virus (ZIKV) surveillance in the Americas: interim guidance for laboratory detection and diagnosis. 2015. Available at: http://www.paho.org/ hq/ index.php?option¼com_topics&view¼article&id¼427&Ite mid¼ 41484&lang¼en.

14. Epidemiological Alert Neurologocal syndrome, congenital malformations, and ZIKA virus infection. Implications for public health in the Americas: 1 December 2015

C H A P T E R

14

Typhoid Fever: An Index of Sanitation in India K Nagesh

due to water borne diseases is nearly 50% of that due to acute myocardial infarction!

INTRODUCTION

Typhoid fever remains an important and persistent public health problem in India. Most of the developed countries have virtually eliminated typhoid fever by providing safe drinking water and good sanitation (Figure 1). Globally nearly 26 million cases are reported annually killing around 2 lakh people. Asia contributes 62% of the global burden. A recently conducted epidemiological survey in five Asian countries shows the highest prevalence of typhoid fever cases in India1 (Table 1).

WHY HIGH PREVALENCE IN INDIA?

•

•

•

Poor sanitation: More than 50% of the Indians do not have access to toilets, that means nearly 65 crore people defecate and urinate in the open field every day. (Figure 2) Unsafe drinking water: Only 18% of the rural mass has access to treated water, one third have piped water supply and 50% of the piped water supply is also untreated.

Lack of health education: The print media & electronic media are not giving much importance in India to health education, so also the educational curriculum in India. In addition, poverty, illiteracy, ignorance, malnutrition has compounded the issue. It is very astonishing to know that annually 38 million people in India suffer from water borne diseases leading to 7.8 lakh death. The mortality

•

The prevalence of typhoid fever in India can be viewed as an index of sanitation in this country.

TERMINOLOGIES

Typhoid fever- is the bacterial infection caused by Salmonella enterica serovar typhi.

Enteric fever- comprises both Typhoid and Paratyphoid (A, B, C) fevers.

Table 1: Epidemiological survey in five Asian countries1 Site

Incidence of Typhoid fever

China

Urban and Rural

15.3 cases per 100 000 per year in people aged 5-60 years old

Vietnam

Urban

24.2 cases per 100 000 per year in people aged 6-18 years old

Indonesia

Urban Slum

81.7 cases per 100 000 per year (all ages)

Pakistan

Urban Slum

451.7 cases per 100 000 per year in children aged 2-15 years

India

Urban Slum

493.5 cases per 100 000 per year (all ages)

Fig. 1: Global scenario in 21st century

60

Fig. 3: Source and route of transmission of Enteric Fever

INFECTION

CLINICAL FEATURES

Fig.2: Open air defecation in India India is supposed to be the world’s largest open air toilet!

Suspected case: Fever > 380C for 3 days plus at least 3 of the following 1.

Toxic look

2.

Bronchitic chest

3.

Abdominal discomfort

4.

Relative bradycardia

5.

Palpable recessive spleen

Probable case: A suspected case + a positive serological test Confirmed case: A suspected case + a positive culture Chronic carrier: Excretion of S.typhi in stools or urine for longer than 1 year after the onset of acute Typhoid fever.

SOURCE AND SPREAD OF INFECTION

Typhoid fever has no other reservoir apart from the human beings. It is essentially a “faeco-oral route” of transmission. Faeces or urine from case or carrier need to be transmitted to the mouth of the healthy person through contaminated food, water, soil, flies, fingers etc. (Figure 3) S.typhi can survive in the ice and ice creams for days and in dirty water for months.

TODAY’S CHALLENGES IN TYPHOID FEVER

• Widespread resistance to Chloramphenicol, Ampicillin, Co-trimoxazole (MDR) since the last two decades.

•

Decreased susceptibility to fluoroquinolones.

•

Lack of availability of equipped bacteriological laboratories in the rural and suburban areas where majority of the enteric fever cases are being treated.

•

Need to use newer and more expensive antibiotics, which may be unaffordable by the rural mass.

•

The popular WIDAL test is becoming unreliable.

•

Vaccination is less immunogenic in children who constitute the maximum burnt of the disease.

•

The cost of hospitalization in severe and complicated cases, in addition, the work loss, the income loss, may all only leads to maintain the “poverty cycle”.

Enteric fever being one of the common acute febrile illness we come across in our day to day practice, the clinical features of which may be indistinguishable from other acute febrile illnesses in tropical countries like that of malaria, dengue, leptospirosis, typhus etc.

UNIQUE FEATURES OF TYPHOID FEVER

•

Step ladder pattern of fever (Figure 4)

•

Relative bradycardia

•

Diffuse abdominal pain

• Constipation/diarrhoea •

Muttering delirium

•

Rose spots (Figure 5)

•

Coated tongue

Atypically Typhoid fever can manifest as only fever, severe headache mimicking meningitis, arthralgias, jaundice, GB syndrome, pancreatitis, osteomyelitis, acalculus cholecystitis etc.

FINDINGS NOT SUGGESTIVE OF TYPHOID

•

Sudden onset of high fever

•

High fever ushered by rigors

•

Presence of herpes simplex (fever blisters)

•

Presence of coryza

RED FLAG SYMPTOMS (TABLE 2)

The appearance of any of the red flag symptoms/signs should alert the treating physician about the impending complications2.

LAB DIAGNOSIS

Routine tests: A complete blood count may reveal low to normal total leucocyte count and platelets. Liver function test may reveal slightly elevated SGOT and SGPT. •

A febrile toxic looking patient with a low count should raise the suspicion of typhoid fever.

BLOOD CULTURE

Still the gold standard to confirm the diagnosis but it is positive only in two third of the cases, it is time consuming, not available in the peripheral centers, however antibiotic sensitivity can only be known by culture and sensitivity.

Bone marrow, stool, urine, duodenal aspirate, rose spots can also be cultured.

Table 2: Red flag symptoms2 in Enteric fever Involvement

61

Symptoms

Central nervous Headache, vomiting, seizures, altered states of consciousness, papilledema, and focal neurological deficits Chest pain, palpitations, new murmur or change in characteristics of a previous murmur, cardiac arrhythmias

Respiratory system

Chills, cough (with or without sputum), pleuritic pain, coarse crackles, and bronchial breathing

Musculoskeletal Local tenderness, rigidity, and pain system giving rise to a loss of functionality in the affected limb; acute swelling and pain in joints with or without an effusion Gastrointestinal system

Jaundice, nausea, vomiting and abdominal pain

Genitourinary system

Dysuria, frequency and suprapubic or pelvic discomfort

negative predictive value3. Typhidot rapid cards are also commercially available which are based on lateral immunochromatography, which serves as an effective diagnostic tool in resource limited setups and in handling the epidemics.

•

Fig. 5: Rose spots 2-3 mm pink papules, on the trunk & chest, fade on pressure, disappears in 3-4days and seen in only 30% of the cases

SEROLOGICAL TESTS

Widal Test: Though considered as a benchmark diagnostic test for typhoid fever for more than a century, is of little help in the treatment of typhoid fever because of delay in elevation of ‘O’ and ‘H’ titres. There is a wide inter lab difference, may be false positive in various non typhoidal fevers and due to anamnestic reactions, negative in 30% of the culture positive cases, a fourfold rise in titre over a span of one week is needed to be confirmatory.

•

A single WIDAL test in endemic areas should be viewed against the background titres of the population in question.

Typhidot tests are slowly replacing and should replace the unreliable Widal test.

Though PCR is more sensitive and specific, its routine use in clinical practice in India is far from reality, however IDL Tubex test, IgM Dipstick test are quite useful in practice. Newer tests in pipeline include salivary IgM test, molecular immunology based tests and nano technology based tests4.

MANAGEMENT

90% of the enteric fever patients can be managed on outpatient basis, hospitalization maybe needed in severe and complicated cases5. Supportive cares like tepid sponging, antipyretics like paracetemol, good oral hydration and soft diet should constitute important supportive treatment in all cases.

ANTIBIOTICS

Done by a rapid dot enzyme immunoassay (EIA), detects the antibody against the 50kD antigen (OMP) of S.typhi, as early as day two of fever. It is simple, rapid, more sensitive (95%), more specific (75%), superior and reliable than WIDAL test3,9.

Early administration of appropriate antibiotics is the key point in the treatment of typhoid fever. Before 1990 chloramphenicol was the drug of choice followed by ampicillin and co-trimoxazole. With the development of plasmid mediated wide spread resistance to these drugs (MDR) and the marrow toxicity of chloramphenicol has forced to keep them back into the shelf6,8.

Currently Fluoroquinolones, azithromycin and third generationcephalosporins are widely used (Table 3).

Typhidot-M: is a modified improved version of Typhidot, detects only IgM, highly specific and sensitive with high

Is the drug of choice in all severe and complicated enteric

TYPHIDOT TEST

CEFTRIAXONE

CHAPTER 14

Fig. 4: Step- ladder Pattern of Fever Fever increases a little each day, rarely seen now because of extensive use of antipyretics and early initiation of antibiotics.

Cardiovascular system

62

Table 3: Recommended antibiotic treatment for typhoid fever (adapted from WHO5and Bhutta7) Optimal treatment

Susceptibility

Drug

Alternative effective treatment

Daily dose (mg/kg)

Course (days)

Drug

Daily dose (mg/kg)

Course (days)

Fluoroquinolone (such as ofloxacin or ciprofloxacin)

15

5-7*

Chloramphenicol

50-75

14-21

Amoxicillin

75-100

14

TMP-SMX

8-40

14

Multidrug resistance

Fluoroquinolone or

15

5-7

Azithromycin

8-10

7

Cefixime

15-20

7-14

Cefixime

15-20

7-14

Quinolone resistance†

Azithromycin or

8-10

7

Cefixime

Ceftiaxone

75

10-14

20

7-14

Chloramphenicol

100

14-21

Ampicillin

100

14

TMP-SMX

8/40

14

Ceftriaxone or

60

10-14

Cefotaxime

80

Uncomplicated typhoid fever

INFECTION

Fully sensitive

Severe typhoid fever requiring parenteral treatment Fully sensitive

Fluoroquinolone (such as ofloxacin)

15

Multidrug resistant

Fluoroquinolone

Quinolone resistant

Ceftriaxone or

60

Cefotaxime

80

10-14

15

10-14 10-14

Fluoroquinolone

20

14

*Three day courses also effective, particularly so in epidemic containment. †Optimum treatment for quinolone resistant typhoid fever has not been determined. Azithromycin, third generation cephalosporins, or a 10-14 day course of high dose fluoroquinolone is effective. Combinations of these are now being evaluated.

Table 4: Comparison of Vi-PS and Ty21a vaccines Vaccine Name

How given

Number of doses necessary

Time between doses

Minimum age for vaccination

Booster needed every….

Ty21a (Live attenuated Vaccine)

1 capsule by month

4

2 days

6 years

5 years

Injection

1

N/A

2 years

2 years

ViCPS (Killed Vaccine)

fever, where there is fluoroquinolone resistance, it should be used with a dosage of 60-75mg/kg/day, IV for 7 to 14 days. It is better to slightly overdose than underdose when trying to adjust the dose bearing in mind the strength available in the market. It is safe in pregnancy and children.

dose as compared to their non-enteric indications.

•

Azithromycin is the preferred alternative agent in uncomplicated cases.

•

Fluoroquinolones may be used in infections resistant to all other recommended antibiotics.

•

Carbanopems are potential second line drugs.

There are no clear cut guidelines to use monotherapy/ combination therapy, but the available data shows that there is no difference in time taken for defervescence after single/multiple drug groups. Combination therapy may be considered only when monotherapy fails. Avoid fixed drug combinations as they lack dosage flexibility.

•

The “Right drug-Right dose-Right duration” is crucial;

•

Antibiotics should be continued for minimum of 5 days after defervescence.

IAP RECOMMENDATIONS

•

It is in no way different from typhoid fever in epidemiology, pathogenesis, pathology, clinical features, diagnosis and treatment

•

Milder in severity

•

Fewer in complications

•

Better in prognosis

SINGLE VERSUS MULTIPLE DRUG REGIMENS4

•

•

6

Third generation cephalosporins are recommended in all cases of typhoid fever as the first line of treatment. Oral, in uncomplicated cases and parenteral, in severe and complicated cases.

Oral cephalosporins need to be given in the higher

PARATYPHOID FEVERS (A, B, C)

•

Paratyphoid C is not reported in India

PREVENTION OF ENTERIC FEVER

Deserves a serious consideration in India. Supply of safe drinking water, improvement of basic sanitation, promotion of personal hygiene and food hygiene, health education using mass media and incorporating health education in primary and secondary education. Simple advices like boiling the water, washing the hand before handling/eating the food and after using the toilets are very cost effective in preventing not only typhoid fever but also other water borne diseases 5,10.

REFERENCES

1.

John Wain, Rene S Hendriksen, Matthew L Mikoleit, Karen H Keddy, R Leon Ochiai, Typhoid Fever, Lancet 2015; 385:1136–45.

2.

Huang DB, DuPont HL. Problem pathogens: extraintestinal complications of Salmonella enterica serotype Typhi infection. Lancet Infect Dis 2005; 5:341-8.

3.

Sushma Krishna, Seemanthini Desai, Anjana V. K.1, Paranthaaman R. G.,Typhidot (IgM) as a reliable and rapid diagnostic test for typhoid fever, Annals of Tropical Medicine and Public Health, http://www.atmph.org on Friday, January 15, 2016, IP: 75.101.163.131

4.

Rajesh Upadhyay, Milind Y Nadkar, A Muruganathan, Mangesh Tiwaskar, Deepak Amarapurkar, et al, API Recommendations for the Management of Typhoid Fever, JAPI 2015; 63:77-96.

5.

WHO Guidelines for the Management of Enteric fever 2011.

Available at http://apps.who.int/medicinedocs/documents/ s20994en/s20994en.pdf.

6.

Kundu R, Ganguly N, Ghosh TK, Yewale VN, Shah RC,et al, IAP Task Force Report:Diagnosis of enteric fever in children. Indian Pediatric 2006; 43:884-7.

7.

Zulfiqar A Bhutta, Current concepts in the diagnosis and treatment of typhoid fever, BMJ 2006;333:78–82

8.

T. Butler, Treatment of typhoid fever in the 21st century: promises and Shortcomings, Clin Microbiol Infect 2011; 17:959–963.

9.

Kiranyadav, Suresh Kumar Yadav and Geetha Parihar, A comparative study of Typhoid and widal test for rapid Diagnosis of Typhoid Fever, Int. J.CurrMicrobiol App Sci 2015; 4:34-38.

“Wash it-peel it-boil it” or “forget it”

VACCINATION

Two routinely used vaccines (Table 4) are less immunogenic in young children and also they do not induce a long term immunity, hence IAP recommends a Vi-PS conjugate vaccine10 at less than one year of age which also gives a long time immunity. WHO recommends targeted vaccinations to travellers to endemic areas and people living in endemic areas whose personal hygiene is unreliable.

CONCLUSIONS

India has got the highest prevalence of typhoid fever in the world which should be viewed as an index of poor sanitation in this country. Hence emphasis should be on prevention, by improving basic sanitation and the supply of safe drinking water and health education should be geared up at all levels. The early initiation of treatment with the “Right drug-Right dose-Right duration” is crucial. WIDAL test is of little help in the treatment of the enteric fever which should be replaced by much simple, rapid and reliable typhidot test. Lastly the diagnostics in India do not meet the daily challenges of physicians in differentiating the causes of fever, there is a need to

63

10. NicholasA.Feasey, Melita A.Gordon, Salmonella Infections, Manson’s text book of Tropical diseases 2015; 23:337-343.

CHAPTER 14

•

develop a ‘fever stick’ which can rule in or rule out the common infections like malaria, typhoid, typhus, dengue, leptospirosis etc.

C H A P T E R

15

Typhoid Fever – Recent Management

INTRODUCTION

Sometimes even the simplest problem throws the toughest challenge. A young girl aged 17 years was suffering from fever with headache for 3 weeks. Despite treatment by several physicians with recent well known antibiotics she continued to suffer from high fever all the same. Many other investigations were done which did not suggest otherwise. Incidentally, her blood culture and drug sensitivity test was not done because of expenses and feasibility problems. Meanwhile, a senior erudite Professor of Medicine examined her and empirically prescribed her Azithromycin at a dose of 1 gm per day.

She was cured with total alleviation of symptoms in 4 days.

So, even in 2016, that is, 132 years after the isolation of the bacterium by the German Scientist Gaffky, it is sad to say that typhoid fever is still an enigma. Every year throughout the world there are still around 15 million cases of typhoid out of which some 600,000 succumb to death. Interestingly, more than 80% of all cases of typhoid fever belong to Asia and Africa. However, it is not uncommon in western countries either, like in the UK about 1 out of 1, 00,000 populations suffer from typhoid every year.

Added to these problems, the treatment of typhoid fever has been even more challenging because of the emerging trends of resistant strains. Microbial resistance regarding Salmonella Typhi is basically of two types, viz., Quinolone Resistant Salmonella Typhi (QRST), and multidrug resistant (MDR) type. There is also a strain which is known as DCS (decreased ciprofloxacin susceptibility) strain of S. typhi causing typhoid fever.

A study on knowledge, attitude and practice of general practitioners (GP) regarding treatment of typhoid fever by Paul et al in January, 2016 has shown that the antibiotics used by GPs for treatment of typhoid are : Azithromycin (42%), Fluoroquinolones (32%), Cefixime(16%), Amoxycillin (6%) and Choramphenicol (4%). A combination of antibiotics is preferred by 38% of GPs and the preferred combinations of antibiotics are Cefixime + Azithromycin (26%) and Ciprofloxacin + Azithromycin (12%). Parenteral antibiotic is preferred in most cases when the patient is unable to consume orally usually due to excessive vomiting.

Thus, a new plan and expanded thinking is now required regarding present and future management of typhoid fever.

Uttam Kumar Paul

CLINICAL MANIFESTATIONS

In the first week of typhoid fever, the features are non specific with headache (80%), malaise and a rising remittent fever. Patient may have constipation (16%) or diarrhoea (28%). Constipation is more common in cases of adults whereas, diarrhoea is more prominent in cases of children. Rose spots is a faint, salmon-colored, blanching, maculo-papular rash located primarily on the trunk and chest, evident in 30% of patients at the end of the first week and resolves after 2–5 days (difficult to detect in dark skinned person). Patients can have two or three crops of lesions, and Salmonella can be cultured from punch biopsies of these lesions.

During the second week of the disease, the patient looks more toxic with sustained temperature, abdominal distension and splenomegaly may be found. In the third week, development of continuous high fever and a delirious confusional state with pronounced abdominal distension, ileus, or diarrhoea may occur, with liquid, foul green–yellow stools. The patient is likely to become obtunded and hypotensive and crackles may develop over the lung bases. Death may occur at this stage from overwhelming toxemia, myocarditis, intestinal hemorrhage or perforation.

The diagnosis of typhoid fever is usually made on clinical grounds. The symptoms sometimes mimic other common illnesses, such as malaria, sepsis with other bacterial pathogens, tuberculosis, brucellosis, tularemia, leptospirosis and rickettsial disease. Viral infections such as dengue, acute hepatitis and infectious mononucleosis are also included in the differential diagnosis.

Positive blood culture confirms diagnosis of typhoid fever.

In 15 -25% of cases, leucopenia and neutropenia can be detected. Leukocytosis is more common among children, during the first 10 days of illness and in cases complicated by intestinal perforation or secondary infection.

Blood cultures are the standard diagnostic method, and the results can be positive in 60 – 80 % of patients, provided that a large volume of blood (typically 15 ml for adults) is cultured. Culture of the infectious agent may also be obtained from stool, urine, bone marrow or bile.

Bone marrow is the most sensitive source (80-95 %), but is not practical.

Widal test is commonly used. A fourfold or greater increase in titer (when paired acute and convalescent samples are compared) is considered positive. However, seropositivity (8 – 14%) amongst healthy blood donors

65 Onset of clinical symptoms of typhoid fever like Fever, headache , myalgia , constipation….

Secondary Bacteremia

Ingestion

Widespread dissemination

Intestine

Blood Stream

Enterocytes lining the terminal ileum

CHAPTER 15

Peyer patches re- exposed to S. typhi via bile

Peyer patch and resident macrophages Liver and and

Spleen

Bone Marrow

Mesenteric Lymph node

S. typhi is disseminated throughout the body and colonize the organs of Reticulo endothelial system , where they may replicate within macrophage

Blood Stream

Usually asymptomatic and blood culture results are frequently negative

Primary Bacteremia

Fig 1: Pathogenesis of typhoid fever Fig 1: Pathogenesis of typhoid fever antibodies appear on days 6-8 and H antibodies on days 10-12 after the onset of the disease

Detection of typhoid antigen Titration of antibody against S. typhi

Isolation of organism

Laboratory diagnosis of typhoid fever Fig. 2: Laboratory Diagnosis was found in a study performed in Central India. Hence clinical utility is controversial, with divergent views on the test’s utility in various areas of endemicity. Usually, O

Recent advances include the IDL Tubex® which detects IgM antibodies, Typhidot®, a dot enzyme immuneassay, Typhidot-M® and typhoid IgM dipstick assay for the sero-diagnosis of typhoid fever. However, most of the GPs do not prefer to use these modalities in their day to day practice.

SUPPORTIVE MANAGEMENT

With early diagnosis, majority of the patients with typhoid fever can be managed at home with oral antibiotics and antipyretics. Proper nutrition and hydration should be maintained.

EMERGING RESISTANCE

Emergence of extended spectrum cephalosporinase producing strains of S. typhi have been reported from Bangladesh, Egypt, India, Kuwait, Iraq, Pakistan, Philippines and the UAE. Confirmed cases reported from

66

Empirical treatment

INFECTION

Fully susceptible

Multidrug resistant

Quinolone resistant

• Ceftriaxone • Azithromycin • Optimal treatment Ciprofloxacin , Azithromycin • Alternative treatment - Amoxicillin , Chloramphenicol , Trimethoprimsulfamethoxazole •Optimal treatment Ceftriaxone , Azithromycin •Alternative treatment Ciprofloxacin •Optimal treatmentCeftriaxone , Azithromycin •Alternative treatment High dose ciprofloxacin

Fig. 3: Antibiotic therapy for enteric fever in adults India (blaCTS-M-15) and Philippines (blaSHV-12). The first case of AmpC producing S. typhi was isolated from an Indian child in 2009.

ANTIMICROBIALS WITH PROMISING EFFECT AGAINST S. TYPHI

The treatment of enteric fever is given in Table 1. Fourth generation fluoroquinolones have good effect against S. typhi but presence of drug related toxicity limits its use

Table 1 : Treatment of Enteric fever OPD Cases

Indoor Cases

Oral Cefixime 20 mg/kg/ day for 14 days

Inj Ceftriaxone 100 mg/ kg/day and shift to oral Cefixime once fever resolves

Azithromycin 10-20 mg/ kg/day for 7-10 days

Second line • Ofloxacin 15 mg/kg/ day in 2 divided doses for 10 to 14 days.

• Chloramphenicol 50-75 mg/kg/day orally for 14 days • TMP-SMX 8 mg/kg/ day orally for 14 days

(Gatifloxacin was banned by the Indian Government in 2011). Carbapenems and Tigecycline show good in- vitro activity against S. typhi.

TREATMENT OF CARRIERS

An individual is considered to be a chronic carrier if he or she is asymptomatic and continues to have positive stool or rectal swab cultures for S. typhi a year following recovery from acute illness and can be treated for 4-6 weeks with an appropriate antibiotic. Treatment with oral amoxicillin, TMP-SMX, ciprofloxacin, or norfloxacin is effective. However, in cases of biliary or kidney stones, eradication often requires both antibiotic therapy and surgical correction.

CONCLUSIONS

Lack of reliable rapid diagnostic test create a problem in confirmation of diagnosis of typhoid fever. Emergence of antimicrobial resistant strains of typhoid bacilli creates a great challenge for a treating physician. However, safe drinking water supply, proper sanitation, early diagnosis and treatment and effective vaccination will help to control typhoid fever (Table 2).

REFERENCES

1.

Paul UK, Barik KL, Sinharay K, Banik S, Bandopadyopadhyay A. Knowledge, Attitude and Practice

Table 2: Vaccines for Typhoid Fever Vaccine

Age (years)

Route

Dosage

Revaccination (years)

Vi CPS

2

subcutaneous

0.5 ml, single dose

2

Ty21 a, live

6

oral

1 capsule given on days 1,3, 5, and 7 days

5

of General Practitioners Regarding Typhoid Fever. Int J Sci Stud 2016; 3:83-86.

2.

Upadhyay R, Nadkar MY, Murganathan A, Tiwaskar M, Amarapukur D, Banka NH, et al. API recommendations for the management of typhoid fever. J Assoc Phys India 2015; 63:77-96.

John Wain, Rene S Hendriksen, Matthew L Mikoleit, Karen H Keddy, R Leon Ochiai. Typhoid Fever. The Lancet 2015; 385:1136-45.

4.

Vinay Pandit, Ashwini Kumar ; Study of Clinical Profile and Antibiotic Sensitivity in Paratyphoid Fever Cases Admitted at Teaching Hospital in South India; J Family Med Prim Care 2012; 1:118â&#x20AC;&#x201C;121.

National Treatment Guidelines for Antimicrobial Use in Infectious Diseases; National Centre for diseases control Directorate General of Health Services Ministry of Health & Family Welfare Government of India (version 1.0 [2016]); Pages 34-35

6.

Harrisonâ&#x20AC;&#x2122;s Principles of Internal Medicine; 19th Edn,2015.

Chapter 190, pgs 1049- 1053.

7.

Nelson Textbook of Pediatrics, 20th Edn, 2016. Vol 1; chapter 198, pgs 1388-1393.

8.

Guidelines for the diagnosis, management, and prevention of typhoid fever.[2010] Ministry of Health; Fiji Islands and WHO.

67

CHAPTER 15

3.

5.

C H A P T E R

16

Atypical Presentation of Typhoid Fever: A Case Report

ABSTRACT

Typhoid fever is a common public health problem. All cases may not have typical presentation with fever, toxaemia and constipation in the first week and complications in the form of intestinal haemorrhage and intestinal perforation in the third week. Unusual presentations of typhoid fever include jaundice, abdominal lymphadenopathy, acalculous cholecystitis, splenic and liver abscess, myocarditis and pneumonitis. We report a case of typhoid fever in a 22 year old male who presented with fever, frank jaundice and thrombocytopenia. Early diagnosis and prompt treatment is the key to successful outcome.

INTRODUCTION

Typhoid fever is an important public health problem caused by Salmonella typhi and Salmonella paratyphi.

The most common method of spread is by ingestion of contaminated food and water.1,2 The ailment is quite common in developing countries like south-east Asia, China, Africa, south and central America. It has become of rare occurance in developed countries due to improvement in safe water supply and proper disposal of excreta. It is an acute systemic ailment caused by bacterial invasion of Peyer’s patches in the ileum leading to bacteremia and multiplication of bacteria in the phagocytic cells of liver, spleen, and lymph nodes. Various organs can be involved in the course of typhoid fever resulting in wide spectrum of presentations from simple fever to involvement of multiple organs, leading to multi-organ failure.

Fever, toxaemia and constipation in the first week, leading to abdominal discomfort, rose spots on trunk, splenomegaly, diarrhoea and vomiting in the second week and further leading to complications in the form of intestinal haemorrhage and intestinal perforation in the third week are the typical features of typhoid fever.

However, all patients of typhoid fever do not have typical features and atypical presentations are not uncommon.

Atypical presentations include fever with – • Abdominal lymphadenopathy • Acute acalculus cholecystitis • Splenic abscess • Liver abscess • Jaundice • Pancreatitis • Pneumonitis

J Bhagwan, A Bansal, S Bansal

• Meningitis • Pancarditis/myocarditis • Orchitis • Osteomyelitis • Parotitis Complications of typhoid fever usually occur in 3rd or 4th week of illness, mostly in inadequately treated patients.

Commonest complications are intestinal haemorrhage and perforation due to necrosis in the Peyer’s patches of intestine requiring prompt medical or surgical intervention.3 These are life threatening emergencies and carry a high mortality rate of upto 10%.4 Involvement of liver is uncommon and is caused either by hematogenous seedling or contagious spread from reticuloendothelial system. Clinically, it manifests as hepatomegaly and abnormal liver function tests. Jaundice is usually seen during the course of typhoid hepatitis.

Myocarditis in typhoid fever is an underdiagnosed condition. There is inflammation of intramural vessels alongwith lymphocytic-macrophage infiltration of stroma leading to granuloma formation and necrosis of cardiac myocytes. Clinical features include chest pain, shortness of breath, fatigue, reduced functional capacity and new onset arrhythmias. The presentation with congestive heart failure and pulmonary edema in young patients especially when it is concurrent with typhoid infection, should arouse suspicion of myocarditis. The common ECG abnormalities are PR prolongation, QTc prolongation, ST segment depression, T wave inversion and sinus bradycardia. Cardiac enzymes may be elevated.

CASE REPORT

A 22 year old boy came to our hospital with history of fever for the last one week and jaundice for the last 3 days. He was febrile (temp 101F), icteric with hepatosplenomegaly. Laboratory investigations revealed Hb 12.2gm%, TLC 3800/cumm (N70, L25, M3, E2), platelets 40,000/cumm, ESR 12mm, total bilirubin 7.4mg% (direct 6.4mg%), ALT 234, AST 190, ALP 230, total proteins 5.8gm/dl, serum albumin 3.0gm/dl. Peripheral smear showed normocytic normochromic picture with thrombocytopenia. Serum electrolytes, prothrombin time and renal function tests were normal. Dengue IgM and leptospira IgM were negative. Ultrasound abdomen revealed hepatosplenomegaly without any free fluid in the abdomen. Widal test was highly positive (Salmonella

typhi H positive upto 1:320 dilutions). Blood culture grew Salmonella typhi organisms after 2 days of incubation.

Patient developed petechial spots all over the body and the platelet count dropped to 28,000/cumm on the 2nd day of admission. He was treated with parenteral ceftriaxone, ofloxacin and IV fluids. The patient became afebrile after 3 days, jaundice started improving and petechial rash disappeared. Total bilirubin came down to 2.4mg/dl on the 7th day of admission. Platelets increased to 92,000/ cumm. He was discharged after 10 days on oral cefixime and ofloxacin.

Typical presentation of typhoid fever has changed over the years. Atypical presentations can delay the clinical suspicion, diagnosis and treatment. Our patient also had atypical presentation in the form of fever, jaundice and thrombocytopenia. Initially, we considered the possibility of malaria, dengue, leptospirosis and viral hepatitis.

Typhoid fever is also associated with abnormal liver function tests but frank jaundice and thrombocytopenia at presentation is rare. Rasoolinejad et al reported only 2 patients (1.86%) having frank jaundice out of a total of 107 cases of typhoid fever.5 However, Dutta TK et al, did not report any case of jaundice out of 32 cases of typhoid fever.6 Khosla reported liver involvement in 4.8% cases of typhoid fever.7 Typhoid hepatitis has a higher relapse rate.7 Incidence of intestinal haemorrhage, intestinal perforation and overall mortality is higher in jaundiced typhoid patients.8 Pohan et al, in a study involving 119 patients of typhoid fever, reported thrombocytopenia (platelets between 10,000 to 50,000/cumm) in 2.6% patients.9 Prevalence of atypical presentation is high in MDRTF (Multi Drug Resistant Typhoid Fever).10 Zaki et al, observed that MDRTF can mimic endemic ailments like malaria, viral hepatitis, meningitis and bronchopneumonia.10

69

Clinical presentations of typhoid fever vary from case to case. Fever with jaundice and thrombocytopenia is usually seen in malaria, dengue and leptospirosis.

However, differential diagnosis of typhoid fever must be kept in mind in a febrile patient with jaundice, especially in tropics as early diagnosis is crucial for a favourable outcome. This case report is aimed to sensitize the physicians that typhoid infection can present with fever, frank jaundice and thrombocytopenia.

REFERENCES

1.

Bhan MK, Bahl R, Bhatnagar S; Typhoid and paratyphoid fever. Lancet 2005; 366:749-62.

2. Bhutta ZA, Current concepts in the diagnosis and treatment of typhoid fever. BMJ 2006; 333:78-82.

3. Crump JA, Mintz ED; Global trends in typhoid and paratyphoid Fever. Clin Infect Dis 2010; 50:241-6.

4. Public Health Operational Guidelines for Typhoid and Paratyphoid (Enteric Fever), Health Protection Agency (Feb 2012) 5. Rasoolinejad M, Esmailpoor Bazaz NT, Mogbel Alhosein B. Salmonella hepatitis (analysis of hepatic involvement in 107 patients with typhoid fever). Acta Med Iranica 2003; 161-163.

6. Dutta TK, Beeresha, Ghotekar LH. Atypical manifestations of typhoid fever. J Postgrad Med 2001; 47:248.

7. Khosla SN. Typhoid hepatitis. Postgrad Med J 1990; 66:9235.

8. Ahmed A, Ahmed B. Jaundice in typhoid patients: Differentiation from other common causes of fever and jaundice in the tropics. Ann Afr Med 2010; 9:135-140.

9. Pohan HT. Clinical and laboratory manifestations of typhoid fever at Persahabatan Hospital, Jakarta. Acta Med Indones 2004; 36:78-83.

10. Zaki SA, Karande S. Multidrug-resistant typhoid fever: a review. J Infect Dev Ctries 2011; 5:324-337.

CHAPTER 16

DISCUSSION

CONCLUSION

C H A P T E R

17

Current Management: Filariasis Manoranjan Behera, Sidhartha Das, Jayanta K Panda

INTRODUCTION

Infections with human filarial nematodes affect 170 million people world wide out of which more than 150 million people are from the tropics. Eight filarial species infect humans; of the, four-Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus, and Loa loa are responsible for most serious filarial infections.

Lymphatic filariasis (LF) is a major cause of clinical morbidity, disfigurement and disability in endemic areas, leading to significant economic and psychosocial impact.

It is the worldâ&#x20AC;&#x2122;s second leading cause of permanent longterm disability (after mental illness) and thought to be only next to malaria among the tropical debilitating diseases.

LF is caused by nematodes that inhabit the lymphatic and subcutaneous tissue, transmitted by mosquito vectors and humans are definitive hosts. Three filarial species cause LF: Wuchereria bancrofti, Brugia malayi and Brugia timori. W.bancrofti is responsible for almost 90% of the disease burden in the tropical countries while the remainder is largely due to B.malayi. Approximately 120 million people in 83 endemic countries worldwide are estimated to be infected with filarial parasites. Estimates suggest that more than 40 million infected individuals are seriously incapacitated and disfigured by this neglected tropical disease. Overall, nearly two-thirds of individuals infected with LF are in Asia. It is still a public health problem in India and is endemic in 17 states and 6 union territories. India accounts for 40% of the world disease burden. About 31 million people are estimated to be the carriers of microfilaria and over 23 million suffer from filarial disease manifestations in India. A study from India has estimated that more than $ 840 million is lost each year due to treatment costs and missed working days. Another study from India reported that patients with chronic filariasis lose around 29 days of work per year due to complications of infection.

PATHOGENESIS

The pathogenesis depends on various factors like host immune response to adult worms, super added bacterial infection and agent factors like endosymbiotic bacteria Wolbachia. When the adult worm dies either with drugs or naturally at the end of their life spans, an inflammatory reaction including granulomas, macrophages and eosinophils develops. At this time release of Wolbachia add to the inflammatory response.

The filarial degeneration products and Wolbachia results in an increase in Th1, Th2 and Th17 numbers leading to

the release of inflammatory cytokines like TNF, IL-1β, and IL-6. These contribute to lympahangiectasia which has already started during the period when adult worms were alive and lymphangiogenesis through vascular endothelial growth factors (VEGF-A, VEGF-C, VEGFR-3).

These deformed lymphatic vessels are less efficient in transporting lymph from periphery especially legs leading to stasis of lymph which predisposes to secondary bacterial infections, specially streptococci leading to acute dermato-lymphangio-adenitis (ADLA) which leads to lymphedema if not properly managed. Recurrent attacks of ADLA results in irreversible skin and dermal changes of elephantiasis.

DISEASE SPECTRUM OF LYMPHATIC FILARIASIS

The disease profile of LF ranges from the initial phase of asymptomatic microfilaremia to later stages of acute and chronic clinical manifestation. Estimates suggest that only about one-third of infected individuals in endemic areas will develop clinical manifestations and rest are asymptomatic (sub clinical). Proper understanding and the clinical manifestations will help in managing the cases.

Asymptomatic Microfilaremia

Infected patients who have a down regulated immune system towards filarial antigens demonstrate high levels of microfilariae in their blood without any overt clinical manifestations. Even at this stage there is hidden damage to their lymphatics like dilation and tortuosity which are demonstrable by ultrasound (US) examination and lymphangio- scintigraphy (LSG). These abnormalities are usually irreversible, even after treatment.

ACUTE MANIFESTATIONS

Acute Dermato- Lymphangio- Adenitis (ADLA)

Attacks of ADLA are characterised by localized pain and tenderness, lymphadenitis and/or lymphangitis and / or cellulitis and local warmth, with (mostly 97% cases) or without systemic manifestations of fever, nausea and vomiting. Secondary infections due to bacteria like Group A streptococcus are responsible for these acute episodes and lesions favouring entry of bacteria can be demonstrated in the affected limbs. If attacks of ADLA are not properly treated or prevented, recurrent attacks are responsible for persistence and progression of lymphedema leading to elephantiasis.

Acute Filarial Lymphangitis

It is caused by spontaneous or drug induced (Diethy

carbamazine-DEC) destruction of adult worms. Small tender nodules develop at the site of death of worm either in the scrotum or along the lymphatics. The inflammation is retrograde progressing from the lymph node to the periphery with the lymphatics standing out as inflammed tender cords. There is no fever, toxaemia or evidence of secondary bacterial infection.

Acute Epididymo - Orchitis and Funiculitis

Tropical Pulmonary Eosinophilia

This is caused by an immune hyperresponsiveness to microfilariae trapped in the lungs and is characterised by nocturnal cough, dyspnea, marked peripheral blood eosinophilia (>3000 cell/cumm), diffuse reticulonodular infiltrates in radiological examination of chest and primary restrictive defects with mild obstruction in pulmonary function test (PFT).

Filarial Fever

Filarial fever is characterised by acute, self limited episodes of fever, often in the absence of lymphangitis or lymphadenopathy.

CHRONIC MANIFESTATIONS

Lymphedema and Elephantiasis

One of the most common chronic manifestations of LF is lymphedema of the extremities which on progression leads to elephantiasis. Even though lower limbs are frequently affected, upper limbs, male genitalia and breasts in females may also be affected rarely. Recurrent ADLA is responsible for the progression of lymphedema to elephantiasis.

Genitourinary Lesions

Hydrocele is a common chronic manifestation of bancroftian filariasis. Other genitourinary manifestations are chylocele, chylohematocele, lymphocele, hematuria, chyluria and proteinuria.

DIAGNOSIS

A diagnosis of LF should be considered in any patient with an appropriate exposure history who presents with characteristic signs and symptoms or unexplained eosinophilia. Definitive diagnosis can be made by detection of circulating filarial antigen (For W.bancrofti infection only), demonstration of microfilariae or filarial DNA in the blood or of adult worms in the lymphatics.

Rarely, microfilariae and/or adult worms are identified incidentally in tissue biopsies or cytological specimens.

Circulating Antigen detection

Circulating filarial antigen (CFA) assays have been developed for diagnosis of W.bancrofti infections but are not yet available for Brugian filariasis. This is regarded as

Microfilarial detection

Microfilariae can be detected in blood, urine or hydrocele fluid through direct microscopy. Examination of blood smears for microfilariae should be performed in all individuals in whom the diagnosis of filariasis is suspected, if CFA tests are not available or Brugian filariasis is a consideration based on exposure history. The timing of the blood collection is critical and should be based on the periodicity (between 10 pm and 2 am) of the microfilariae in the endemic region involved. Concentration technique (e.g. Nueclepore filtration and knott’s concentration) are more sensitive as they facilitate examination of larger quantities of blood. DEC provocation test is used to facilitate day time detection of microfilariae.

Imaging Studies

In cases of suspected LF, examination of the scrotum, lymph nodes, or the breasts (in females) by means of high frequency ultrasound in conjuction with Doppler techniques may result in the identification of motile adult worms within dilated lymphatics. Live adult worms have a distinctive pattern of continuous motion within the lymphatic vessels described as “filarial dance sign”.

Radionuclide lymphoscintigraphy is a useful tool for assesing the extent of lympatic damage in both overt and subclinical microfilaremic persons.

DNA based Diagnosis

DNA - based techniques like polymerase chain reaction (PCR), though not as sensitive as CFA assays, are more specific. PCR amplification of the glutathione peroxidase gene helps in diagnosis of LF and restriction fragment length polymorphism (RFLP) enables differentiation of species.

71

CHAPTER 17

Inflammation of structures in the scrotal sac may result in acute epididymo-orchitis or funiculitis in bancroftian filariasis. This is manifested by severe pain, tenderness and swelling of scrotum, usually with fever and rigor.

The testes, epididymis or the spermatic cord may become swollen and extremely tender like ADLA. These attacks are also precipitated by bacterial infections.

“gold standard” by World Health Organisation (WHO) for diagnosis of LF. These tests detect antigens released by adult filarial worms and may be positive in cryptic (amicrofilaremic) infection. In addition antigen level remains stable during the day and night, so these tests can be performed at any time. Two CFA tests are commercially available for specific detection of W.bancrofti: an Og4C3 monoclonal antibody - based enzyme - linked immunosorbent assay (ELISA) which gives a quantitative result that correlate with adult worm burden and a rapid format immuno chromatographic technique (ICT), which gives only qualitative results. In comparision with microfilarial detection in blood, CFA has been found to be 94% to 100% sensitive and 90% to 100% specific. False positive W.bancrofti antigen test results are common in patients with large numbers of circulating loa loa microfilariae. In addition, a negative test exclude filarial infection as a cause of chronic pathology since filarial antigens eventually become indetectable in treated or “burned out” infection, even in the settings of lymphatic damage. Although the quantitative Og4C3 ELISA may be of some use in following patients after treatment since antigen levels typically decline with treatment, it remains unclear whether a persistently positive antigen tests should prompt additional therapy.

INFECTION

72

Antifilarial antibody test

Serological tests for filarial antibodies that detect elevated levels of IgG and IgG4 are available. The majority of these assays are based on crude antigen mixtures; therefore, they donâ&#x20AC;&#x2122;t differentiate between the various types of filarial infections and often cross react with antigens from other helminths. Further more, since these tests canâ&#x20AC;&#x2122;t distinguish between active infection and past infection or exposure, they are useful primarily in detecting infection in travellers from non endemic areas and have little predictive value in long-term residents of endemic areas.

Although a negative test can help exclude recent infection, patients with chronic manifestations of lymphatic filariasis can become antibody negative over time.

Several assays based on recombinant antigen appears to have enhanced specificity. These include two rapid IgG4 antibody detection tests: BRUGIA rapid, which is specific for Brugia antigen BmR1 and PanLF Rapid, which combines Brugia Rapid with a test for BmSXP that detects infection with both Brugia species and W.bancrofti. An IgG4 assay specific for the recombinant antigen Wb123 appears to be a sensitive and specific marker of early infection with W.bancrofti and is in development as a rapid diagnostic test.

Treatment

The approach to treatment of LF requires an understanding of antimicrobial agent mechanisms as well as attention to the possibility of coinfection. The clinical approach is described below, followed by a discussion of data related to individual antimicrobial agents.

Clinical Approach to Therapy

Orally administered diethyl carbamazine (DEC) remains the drug of choice for treatment of active LF (defined by microfilaremia, antigen positivity or adult worms on ultrasound). It is contraindicated in patients coinfected with onchocerciasis and must be used with caution in patients with loiasis, since severe adverse events can occur in individuals with high microfilarial loads.

Monoinfection

Patients with LF (in the absence of onchocerciasis or loiasis) should receive treatment with DEC (6 mg/kg daily for12 days), regardless of whether clinical symptoms or microfilaremia are present. Asymptomatic patients who have microfilaremia have some degree of subclinical disease (hematuria, proteinuria, lymphatic damage) also need early treatment to prevent further lymphatic damage. Reversal of early lymphatic damage has been observed following DEC treatment. Evidences suggest that addition of doxycycline (200 mg/day for four to six weeks) also reduces pathology in mild to moderate disease. Treatment is generally warranted even in the setting of advanced disease who have evidence of active infection or to kill any remaining adult parasites although clinical improvement may be limited.

Concomitant infection

DEC is contraindicated in patients coinfected with onchocerciasis and/or patients with loiasis who have high

microfilarial loads due to possibility of severe adverse events.

Onchocerciasis

DEC is contraindicated in these patients due to potential for severe adverse events related to killing of microfilariae in the eye and /or skin. Therefore, ivermectin (150 mcg/kg single dose) should be administered to clear O. volvulus microfilariae in the skin and eye prior to standard treatment of LF with DEC (preferably one month). Alternatively, doxycycline (200 mg orally once daily for 4 to 6 weeks) followed by ivermectin (150 mcg/kg orally single dose) can be used to treat both infection, although the relative efficacy of this regimen compared with standard therapy for the treatment of LF is not known.

Loiasis

For patients with LF who are coinfected with loa loa but have less than 2500 loa loa mf/mL of blood, DEC therapy using the standard regimen for loiasis (8 to 10 mg/kg/ day for 21 days) should be administered. For patients with higher levels of loa loa microfilaremia, doxycycline (200mg orally, once daily for 4 - 6 weeks) or albendazole (200 to 400 mg twice daily for 21 days in who can not take doxycycline) are the drugs having no effect on loa loa microfilariae, are the treatment of choices for LF. Heavy loa loa microfilaremia (>8000 mf/mL) can be treated initially with apharesis to remove the microfilariae and with glucocorticoids (40-60 mg of prednisone/day) followed by doses of DEC (0.5 mg/kg/day). If antifilarial treatment has no adverse effects, the prednisone dose can be rapidly tapered and the dose of DEC gradually increased to 8-10 mg/kg per day.

Antimicrobial Agents

Selection of therapy for treatment of LF requires an understanding of the macrofilaricidal and microfilaricidal activity of therapeutic agents. The epidemiology of other filarial diseases is also important; in regions where loiasis and onchocerciasis may coexist with LF, additional consideration is important for minimizing the likelihood of adverse effects.

Diethyl carbamazine

DEC, is a potent microfilaricidal and macrofilaricidal agent with activity against W. bancrofti, B. malayi and B. timori. Estimates suggest that DEC kills approximately 50% of adult worms and its effect on adult worms in turn decreases the microfilarial burden. It significantly lowers microfilariae levels even in single annual doses of 6 mg/kg body weight which makes it a perfect antimicrobial agent in the campaign to eliminate LF transmission through mass drug administration (MDA). It is also treatment of choice with loa loa coinfection. Direct adverse effects of DEC are rare; most of the side effects like rash, fever, headache, anorexia, nausea, cough, myalgia and arthralgia are likely attributable to the host response following death of microfilariae (systemic immune reactions) and damage to adult worms (local reaction). These adverse effects lasts for 24 to 48 hours and management is symptomatic (antipyretics and/or anti inflammatory agents). Since

post DEC reactions are more severe in onchocerciasis and loiasis, evaluation for these coinfections should be persuaded prior to administering DEC. DEC should be avoided in pregnancy. It is not excreted in breast milk and is considered safe during lactation.

Ivermectin

Albendazole

Albendazole has no microfilaricidal activity but leads to slow decline in microfilaremia due to macrofilaricidal activity against the adult worms (400mg twice daily orally for 14 to 21 days). Consequently, side effects due to rapid killing of microfilariae are not seen and albendazole can be used in patients with concomitant loiasis and onchocerciasis. A single dose of albendazole 400 mg greatly acclerates the microfilaricidal action of DEC. Therefore, the strategy of combining single annual dose of DEC 6 mg/kg body weight with albedazole 400 mg is appropriate for eliminating LF in India. Studies have showed enhanced suppression of microfilaremia with albendazole and ivermectin as compared to ivermectin alone. Severe scrotal reaction might be induced by death of adult worms inside the scrotal lymphatics.

Doxycycline

A promising alternative approach to attack worm directly is to focus treatment against Wolbachia that is present in microfilariae and adult worms of W. bancrofti and both Brugia species. By destroying Wolbachia it reduces the plasma levels of VEGFs, thus reduce lymphatic dilation.

It has both microfilaricidal and macrofilaricidal activity. It has been shown that, doxycline in a dose of 200 mg/day for 8 weeks (even 4 to 6 week) result in a sustained decrease in blood microfilariae level as does DEC / albendozole used daily for 7 days. Addition of albendazole may enhance macrofilarial clearance by doxycycline. There is also convincing evidence that doxycycline treatment alone or in combination with DEC (3 weeks doxycycline) reduce clinical pathology including lymph vessel dilation and hydrocele in affected individuals. It is most effective when combined with DEC-albendazole or ivermectin with the added advantage of doxycycline pretreatment markedly

73

The treatment of LF involves not only antifilarial drug therapy but it also encompasses the management of asymptomatic carriers, treatment and prevention of ADLA, management of lymphedema/elephantiasis and patient counselling/education.

Asymptomatic carriers

DEC is the drug of choice for treatment of asymptomatic carriers at a dose of 6 mg/kg/day in divided doses for 12 days, preferably combined with single dose of albendazole or ivermectin. Prior treatment with doxycycline 200mg/ day for 6 weeks before DEC-albendazole administration gives better results with less adverse drug reactions.

Acute Dermato-Lymphangio-Adenitis

Early, aggressive management and prevention of episodes of ADLA is the key to prevent the progression towards elephantiasis. Bedrest and symptomatic treatment with simple drugs like paracetamol are enough in mild cases.

Any local precipitating factors like injury and bacterial or fungal infection should be treated with local antibiotics or antifungal ointments. Moderate or severe attacks of ADLA require rest, proper hydration, oral or parenteral antibiotics depending on the general condition of the patient, together with antipyretics / analgesic drug and cold compresses to alleviate pain. The preferred commonly used antibiotics are penicillin, tetracycline, ampicillin, amoxicillin or cotrimozalole in adequate doses and duration till the infection subsides. Culture and sensitivity examination of swabs from the entry lesions may help in selecting the appropriate antibiotic in severe cases. Systemic antifungal therapy is rarely required since the fungal infections of the skin act as only entry points for the bacteria and fungi themselves do not cause ADLA.

Prevention of Acute Dermato-Lymphangio-Adenitis

Presently there is a simple, practicable, effective, cheap and sustainable method available for prevention of recurrent attacks of ADLA. Recent studies have revealed that this can be achieved by proper “local hygiene” of the affected limbs; need to be carried out regularly. Foot-care aimed at prevention of secondary bacterial or fungal infections have become the mainstay for disability alleviation or prevention in Global Programme for Elimination of Lymphatic Filariasis (GPELF). Patients, community health workers and also providers of “home care” should be trained in this foot-hygiene programme (Table 1).

In patients with advanced stages of lymphedema, proper local care of the limb is not always possible due to deep skin folds or warty projections. If such patients have recurrent ADLA attacks, long-term antibiotic therapy using oral penicillin or long acting benzathine penicillin 1.2 MU, deep IM every 3 weeks is indicated. Recent evidences have shown that antifilarial drugs like DEC have no role either in the treatment or prevention of the acute ADLA attacks occuring in case of lymphedema which are caused by bacterial infections. In endemic areas, regular foot care

CHAPTER 17

Ivermectin has microfilaricidal activity but does not have significant macrofilaricidal activity. Therefore, the reduction in microfilaremia is not sustained without repeat dosing. The clinical benefits of ivermectin are uncertain as it lacks activity against adult worms, which play important role in pathogenesis of lymphangitis and lymphedema. It may have some role in reducing fertility of worms. It is as effective as DEC in reducing microfilaremia due to Bancroftian filariasis. A single dose has been shown to reduce microfilaremia by approximately 90 percent even one year after treatment. It is the drug of choice for onchocerciasis and should be used as part of the regimen to patients with concomitant LF and onchocerciasis but is contraindicated in patients with loiasis and high levels of loa loa microfilariae in the blood due to risk of post treatment encephalopathy. It is contraindicated during pregnancy and lactation. Adverse effects are similar to DEC but slower due to slower clearance of parasitaemia.

reducing the adverse events following DEC-albendazole administration. Doxycycline is contraindicated in pregnancy, lactation and children less than 8 years of age.

INFECTION

74

Table 1: Prevention of Acute Dermato- Lymphangio-Adenitis

Table 2: Treatment and prevention of Lymphedema

•

Washing of the affected area, especially the webs of toes and deep skin folds, with soap and water twice a day

•

•

Thorough gentle drying after washing

Regular manual light massage of the limb with an emolient with a gentle upward milking pattern to stimulate the lymph vessels and to promote flow of lymph towards larger patent vessels

•

Massage with simple emolients like coconut oil

•

•

Applying antibiotic ointments to any local infection / injury

Using crepe bandage, elasto crepe bandage or tailor made stocking while ambulant, ideally after manual massage

•

Treatment of any local fungal infection with local antifungal ointments

•

Intermittent pneumatic compression of the affected limb using single or multicell jackets

•

Nails to be kept clean and trimmed

•

Heat therapy using either wet heat or hot ovens

•

Elevation of affected limb at night / during rest

•

•

Gentle exercise of affected limb regularly

Interferential therapy using medium frequency currents helps in relieving painful muscle spasms

•

Regular use of proper foot wear

•

Limb elevation in night after removing the compression bandage

•

Regular exercise of the affected limb

•

Surgical procedures: see text.

should be encouraged from early childhood age, as LF is first acquired mostly in childhood leading to irreversible lymphatic damage.

Treatment and prevention of Lymphedema

Once lymphedema is established there is no permanent cure and treatment with DEC does not seem to reverse the existing lymphatic damage. All the measures mentioned in Table 1 for preventing ADLA, play important role in decreasing lymphedema progression. The following treatment modalities offer relief and help to prevent further progression of the lymphedema are described in Table 2. Oral and tropical benzopyrones and flavonoids are suggested for the treatment of lymphedema. These drugs are thought to reduce high protein oedema by stimulating macrophages to remove the proteins from the tissues when administered for long periods. Further randomised controlled trials are required to establish this fact. Chyluria may be associated with secondary nutritional deficiency. In such cases, low fat, high-protein diet supplemented with medium-chain triglycerides can be helpful Surgery is usually the last option for treating lymphedema / elephantiasis but the long term benefit is still unclear.

There are various surgical options available to offer relief of lymphedema, like lymph nodo-venous shunts, omentoplasty, and lymphatico-venous anastomosis to enhance lymphatic drainage in limb. Excisional surgery of the affected skin and subcutaneous tissue, closed by skin flap or graft is usually complicated by lymphorrhoea, haemorrhage and lymphangitis.

Hydrocele and lymphedema of external genitalia require surgical management when response to medical therapy is incomplete.

Global Programme to Eliminate Lymphatic Filariasis (GPELF)

The World Health assembly called for LF to be eliminated as a public health problem in 1997. Whose response included the launch of GPELF in 2000. An important tool for elimination is MDA with albendezole combined with either ivermectin or DEC, for which the minimum effective coverage of the total population is considered to be 65%

and has been targeted for elimination by 2020. India is a part to the GPELF and through its National Filaria Control Programme (NFCP) has started a campaign of MDA of single annual dose of DEC or DEC - Albendazole to interrupt transmission of the disease.

CONCLUSION

LF is still a public health problem in India harbouring 40% of world disease burden. The pathogenesis and clinical progression of filarial disease is likely influenced by a number of factors, including the host immune response to adult worms, release of endosymbiotic bacteria wolbachia and the number of secondary bacterial infection. Definitive diagnosis of LF can be made by detection of CFA, demonstration of microfilaria or filarial DNA in blood or of adult worm in lymphatics. Patients with LF (in absence of onchocerciasis or loiasis) should receive treatment with DEC. The addition of doxycycline is also appropriate. Patients with concomitant infection due to LF and onchocerciasis should undergo treatment of onchocerciasis first either with ivermectin alone followed by standard treatment for LF or alternatively doxycycline followed by ivermectin in proper dose and duration. The approach to patients with concomitant infection due to LF and loiasis depends upon the level of circulating loa loa microfilaremia. Treatment of ADLA comprises of bed rest, antipyretics / analgesics, local application of antibacterial / antifungal ointments and oral or parenteral appropriate antibiotics in proper dose and duration.

Prevention of recurrent attacks of ADLA can be achieved by maintaining proper local hygiene of the affected limbs following foot care programme judiciously. Lymphedema can be managed and its progression can be prevented by aggressive treatment of secondary infections, proper local hygiene and different manoeuvres to stimulate the lymph vessels and to promote flow of lymph towards larger patent vessels. Various surgical options are available to provide relief from advanced lymphedema / elephantiasis as a last resort. Hydrocele of the scrotum and lymphedema of external genitalia are amenable to surgery. The WHO’s

initiative of GPELF to eliminate this parasite infection through MDA is one of the most economical and effective disease control strategies undertaken so far in public health programmes.

REFERENCES

1.

Hoerauf A. Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis. Curr Opin Infect Dis 2008; 21:673-81.

2. Addis DG, Brady MA. Morbidity management in the Global Programme to Eliminate Lymphatic Filariasis: a review of the scientific literature. Filaria Journal 2007, 6:2.

4. Zachariah S. Filariasis and other related Infections. In: Munjal YP (Ed-in-Chief). API Text Book of Medicine, 10th Ed. The Assoc Physicians India: Mumbai; 2015.pp.1658-63.

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6. Ramaiah KD, Das PK, Michael E, et al. Economic burden of lymphatic filariasis in India. Parasitol Today 2000; 16:251-53.

7. Kumaraswami V. The clinical manifestations of lymphatic filariasis. In: Nutman TB (Ed). Lymphatic filariasis. London: Imperial College Press; 2000.pp. 103-25.

8. Suman TK, Shenoy RK, Kumaraswami V. Efficacy and sustainability of foot-care programme in preventing acute attacks of adeno lymphangitis in Brugian filariasis. Trop Med Int Health 2002; 7:763-6 9. Kilon AD. Diagnosis, treatment and prevention of lymphatic filariasis. www.uptodate.com (accessed on July 25, 2016) 10. WHO Global programme to eliminate lymphatic filariasis: progress report, 2013. Wkly Epidemiol Rec 2014; 89:409-18.

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3. Suman TK. Indian scenario of Elimination of Lymphatic Filoriasis. In: Muruganathan A. (Ed). Medicine update. The Assoc Physicians India: Mumbai; 2013.pp.6-9.

5. Nutman TB, Weller PF. Filarial and related infections.

In: Kasper DL, Fauci AS, Hauser SL (Eds). Harrisonâ&#x20AC;&#x2122;s Principles of Internal Medicine, 19th edition. Mc Graw Hill education: New York; 2015.pp.1417-22.

C H A P T E R

18

The four most important fungi producing invasive fungal infections (candida, cryptococcus, aspergillus and mucor) are commonly considered together. However, in reality, their clinical syndromes as well as the approach to their diagnosis and management are distinct from one another.

Yet, certain management principles, that are different from those applicable to bacterial infections, remain common to them.1 1.

Fungi generally produce disease only when the immune system of the host is compromised or mucosal or integumental barriers are disrupted.

The immune system also plays an important role in expression, progression and recovery of the disease.

2.

Fungal culture lacks sensitivity in some cases and specificity in others. Hence, diagnosis and its level of certainty, is often based on a combination of host factors, the particular clinical syndrome, radiological findings, non-culture based tests, histopathology and culture.

3.

Fungi are eukaryotic organisms. Unlike bacteria, they possess fewer unique metabolic pathways, distinct from their mammalian hosts that may be selectively inhibited by drugs. As a result, the antifungal agents have in general, lesser efficacy and greater toxicity.

4.

The use of antifungal combinations with different mechanisms of action, have an established place in certain invasive fungal infections (IFIs).

5.

Fungi have the property of forming biofilms on various implanted medical devices which has important implications for treatment.

6.

The use of adjunctive treatment in the overall management is important.

7.

The duration of treatment is relatively prolonged as compared to most bacterial infections.

8.

Transition to oral agents which are less toxic and expensive is attempted whenever possible.

9.

Prophylactic, preemptive and empirical strategies have been proposed for IFIs as these have predictable occurrence, diagnostic difficulties and serious consequences associated with delayed treatment.

The risk factors and clinical syndromes of IFIs are given

Invasive Fungal Infections Ayesha J Sunavala, Rajeev Soman

in Table 1. The diagnosis and management of IFIs is given in Table 2.

MANAGEMENT CHALLENGES IN THE INDIAN SETTING

Candidiasis

A vast spectrum of agents, (31 species) of candida has been reported from different parts of the country. The incidence of candidemia in India is 1-12 cases/1000 admissions. This is 20-30 times higher as compared to the developed world and may be attributed to sub-optimal hospital care practices, heavy patient load and high cost of disposables leading to suboptimal infection control practices.9 A study on ICU acquired candidemia in India found that candidemia was acquired significantly earlier after ICU admission, in patients who were considerably younger, predominantly non neutropenic and with lower APACHE scores than in other studies. Prior exposure to broadspectrum antibiotics and use of steroids in a large number of patients were thought to be responsible for this.10 In contrast to data from the developed world, the commonest species of candida in our country is C. tropicalis. Features unique to this species are its predisposition to septic shock and skin emboli and its shorter time to positivity of blood cultures. A study has shown that 82% of health care worker’s hands were colonised with yeast, of which 80% were C. tropicalis.

The emergence of MDR C. auris in India is a matter of concern, as this fungus was isolated from 19 of 27 ICUs.9, 10

The lower rate of blood culture positivity in candidemia (21%) as compared to 50% elsewhere, remains a diagnostic hurdle, leading to delay in initiation of treatment and poor outcomes. Prediction models and scores are complex and require local validation. Non culture based rapid diagnostic methods such as β-D-glucan, antigen assays and PCR assays have been introduced in the country.9

Cryptococcosis

With the advent of HAART, the incidence of cryptococcosis has reduced considerably in the developed world. However, Indian studies show a 42-fold increase in the incidence over the past 40 years. Cryptococcus is responsible for 4% of meningitis in the HIV infected population in Eastern India. It typically presents as a sub-acute to chronic meningitis with lymphocyte predominance in CSF. If specific tests like India Ink staining and CRAG levels are not done, these cases are

77

Table 1: Risk Factors & Clinical Syndrome of IFIs2, 3, 4, 5, 6, 7, 8 IFI

Predisposing Conditions

Clinical Syndrome

Candidiasis

1. Critically ill- ICU stay

1. Candidemia- sepsis, septic shock

2. Central venous catheter

2. Acute disseminated candidiasis-cutaneous manifestations

3. Broad spectrum antibiotics

3. Endovascular infection â&#x20AC;&#x201C; infective endocarditis, infection of implantable cardiac devices

4. Total parenteral nutrition 5. Hemodialysis 6. Pancreatitis

4. Osteomyelitis, arthritis

7. GI perforation, surgery

5. Endophthalmitis 6. Chronic disseminated candidiasis (hepatosplenic candidiasis)

9. Immunocompromised host Cryptococcosis

1. HIV

1. Chronic meningitis, cerebral cryptococcoma

2. Transplant recipients 3. Idiopathic CD4 lymphocytopenia Emerging Risk Factors: DM, ESRD, CLD, TB, SLE, malignancy, steroid use Aspergillosis

3. Other commonly involved sites: skin, eye, prostate

1. Prolonged/profound neutropenia

1. Pulmonary aspergillosis

2. Prolonged steroids, T-cell immunosuppressants

2. Acute rhinosinusitis

3. Hematopoietic & solid organ transplant recipients 4. Primary immunodeficiency states: CGD Emerging Risk Factors: COPD, liver cirrhosis critically ill, mechanical ventilation Mucormycosis

2. Pulmonary nodules, infiltrates, cavities, mediastinal adenopathy

3. Tracheobronchitis in lung transplant recipients, AIDS 4. Cerebral aspergillosis 5. Osteomyelitis 6. Cutaneous aspergillosis 7. Disseminated aspergillosis

Clinical Syndromes associated with specific risk factors 1. Poorly controlled DM ( type1 and type 2), DKA : rhinocerebral, sino-orbital, cutaneous 2. Hematological malignancy, HSCT, SOT recipient,: pulmonary, sino-orbital, cutaneous, disseminated, rhinocerebral 3. Penetrating trauma, burns: cutaneous, ocular 4. Chelation therapy with deferoxamine: disseminated, rhinocerebral, pulmonary, gastrointestinal, cutaneous 5. IV drug user: cerebral, endocarditis, cutaneous, disseminated 6. Malnutrition, premature infants: gastrointestinal, disseminated 7. Nosocomial acquisition/pseudo-outbreaks- linked to contaminated dressing, splints for IV cannulation etc.: cutaneous 8. Unknown etiology: isolated renal mucormycosis

*DM: diabetes mellitus, ESRD: end- stage renal disease, CLD: chronic liver disease, SLE: systemic lupus erythematosus, CGD: chronic granulomatous disease, COPD: chronic obstructive pulmonary disease, DKA: diabetic ketoacidosis, HSCT: hematopoietic stem cell transplant, SOT: solid organ transplant

often treated with empiric AKT leading to inordinate delays in diagnosis of this life threatening condition.

Latex agglutination â&#x20AC;&#x201C;based antigen tests have a good sensitivity but are still not widely available in India due to high cost, need for expertise, and maintenance of cold chain. Recently introduced lateral flow assay for CRAG is easy to perform, economical and has reagents which are stable at room temperature. This has major indications for preemptive management of cryptococcal meningitis

in patients with advance HIV infection in resource-poor environments.

Studies from India have identified that C. neoformans var grubii and C. gattii prevail all through the year in the environment with the highest prevalence in autumn months. There has been a rise in incidence of cryptococcosis in immunocompetent hosts in India with a reported association with pulmonary TB. 11

CHAPTER 18

8. Steroids

Table 2: Diagnosis & Management of IFIs.2, 3, 4, 5, 6, 7, 8 IFI

Diagnosis

Management

Candidiasis

1. Candida colonisation index 2. Scoring systems: Leon, Ostrosky Zeichner 3. Blood culturegold standard but sensitivity-50% 4. β-D-Glucan: pan-fungal marker with sensitivity & specificity of 80% for invasive candidiasis 5. MALDI-TOF- requires pure growth of an organism on artificial media 6. PNA FISH- performed directly on positive blood culture 7. T2Candida (PCR)–based assay -uses magnetic resonance detection to identify presence of candida in whole blood

Empiric Treatment: 1. Echinocandins: cidal drugs preferred for critically ill or recent azole exposure.

Recent data showing improved survival with echinocandins even in azole susceptible candidemia.

Poor penetration into eye, CNS, and urine.

2. Triazoles: static drugs Fluconazole- in less severely ill patients with no previous azole exposure.

3. Amphotericin B- option to echinocandins in resource limited settings.

Duration of treatment: 14 days of effective antifungal therapy following the first negative blood culture & resolution of illness Adjuvant treatment: 1. Source Control: removal of CVC in non neutropenic host 2. Metastatic infections: Ophthalmic evaluation and 2D echo to rule out metastatic infections.

Cryptococcosis CSF: 1. Lymphocytic pleocytosis with high protein and low-normal glucose 2. India Ink: sensitivity 80% in non-AIDS patients, 50% in patients with AIDS 3. CSF CRAG: sensitivity of 95% (Titre > 1:1024 suggestive of high burden with poor host response and likely failure) 4. CSF culture: less sensitive (around 70%), needs prolonged incubation (up to 21 days) 5. Serum CRAG: positive in meningeal & nonmeningeal infection, may be positive long before symptom onset. Positive S. CRAG should prompt LP to rule out meningeal disease.

Induction (2 weeks) 1. Amphotericin B + 5 Flucytosine 2. Amphotericin B + Fluconazole Consolidation (8 weeks):Fluconazole Maintenance (≥6 months): Fluconazole Duration: at least 1 yr on maintenance therapy + asymptomatic from cryptococcal infection + CD4 ≥100cell/µl for ≥3 months + suppressed HIV viral load in response to effective ART Therapeutic CSF drainage required during induction to lower raised intra cranial pressure.

HAART to be initiated only after induction treatment is over; generally between 2 to 10 weeks

Aspergillosis

Drug of choice: Voriconazole Alternative agents: 1. Amphotericin B 2. Echinocandins- not cidal for aspergillus and hence not primary therapy but may have a role in salvage therapy/ intolerance to amphotericin or if prior voriconazole prophylaxis was taken.

Combination treatment is used commonly in patients at the highest risk of poor outcome but is of unproven incremental value Duration of treatment: ≥ 3 months

INFECTION

78

EORTC-MSG criteria: Proven IPA: Positive aspergillus culture obtained from a sterile site/ positive culture from an unsterile site along with evidence of tissue invasion on histopathology.

Probable IPA: Positive non culture-based test like galactomannan in a susceptible host with compatible radiological features.

Possible IPA: Presence of compatible clinical and radiological features in a susceptible host.

Radiological features: dense consolidation, nodule surrounded by area of low attenuation (halo sign), nodular cavitation giving rise to the air-crescent sign Serum Aspergillus Galctomannan: sensitivity 70% in neutropenics, as low as 20% in nonneutropenic population.

BAL galactomannan: sensitivity >70% in all risk groups including patients on mold active prophylaxis

79

Table 2: Diagnosis & Management of IFIs.2, 3, 4, 5, 6, 7, 8 Diagnosis

Management

Mucormycosis

1. Direct microscopy: calcofluor stain 2. Culture: • Mucor is difficult to isolate from homogenized tissue, lab to be instructed to mince sample with sterile scissors to prevent damage to fungal hyphae.

3. Histopathology: to differentiate mucor from other molds, to document evidence of angio invasion Radiological features suggestive of pulmonary mucormycosis: 1. >10 nodular infiltrates 2. Reverse halo sign 3. Pleural effusion

Drug of choice: Polyenes Alternative treatment: Posaconazole only as salvage therapy • Requires 7-8 days to achieve therapeutic concentrations.

• Absorption maximized when taken with high fat food Adjuvant therapy: Deferasirox, hyperbaric oxygen, G CSF, IFN Ɣ Duration of treatment: Until near normalization of radiographic imaging, negative biopsy specimens, and cultures from the affected site and recovery from immunosuppression

Aspergillosis

Aspergillus is capable of surviving and thriving in all the diverse environmental conditions in India. The tropical climate allows greater dispersal of the hydrophobic spores. It produces a variety of infectious and allergic syndromes, the diagnosis of which requires invasive and hi-tech procedures.

Plain chest x-rays have limited diagnostic utility in IPA. Even CT radiological criteria for IPA are not as specific for the non-neutropenic host and closely resemble findings of pulmonary TB leading to diagnostic confusion and empiric anti-tubercular treatment (ATT). Rifampicin is an enzyme inducer which reduces the action of voriconazole by 95% when these drugs are used together. This interaction persists for up to 2 weeks even after the withdrawal of rifampicin thus reducing the efficacy of voriconazole.

Although, the availability of serum galactomannan levels has greatly revolutionalised the diagnosis of IPA in neutropenics, it has several limitations in our setting like cost and false positive results seen with the use of generic brands of certain antibiotics such as piperacillin tazobactam and in penicilliosis, an opportunistic endemic mycosis in northeast India.

Sino-orbital-cerebral aspergillosis is a condition reported almost exclusively from the Indian subcontinent and the Middle East. This occurs typically in males involved in agricultural work in moldy environments and presents as an indolent granulomatous condition with intracranial and cerebral extension. Most cases are due to A. flavus.12 Voriconazole, the recommended primary therapy for invasive aspergillosis must be used with adequate caution due to its narrow therapeutic window and interactions with other drugs, notably immunosuppressants like tacrolimus. It is metabolized by the hepatic CYP2C19 isozyme and polymorphisms in the CYP2C19 gene, influence the drug levels. Studies have shown a higher frequency of CYP2C19 poor-metabolizer genotype among Indians, thus increasing the potential for drug toxicity in this population. Therapeutic drug monitoring although

not widely available in our setting plays an important role in the management of this challenging condition.13, 14

Mucor

A review of several Indian studies has revealed a prevalence rate of 0.14 cases/1000 population of mucormycosis, which is 70 times the worldwide rate.

Uncontrolled diabetes is a strong risk factor; however in India this association is overwhelming. Data shows that 16-23% of patients were unaware of underlying DM and mucormycosis was in fact a diabetes-defining illness in these patients.9 As a result of poor access to healthcare and diagnostic facilities, most patients present with advanced orbital and intracranial extension.

There is a distinct entity of isolated renal mucormycosis seen in India and China. This typically affects young, immunocompetent individuals and has a fulminant course with high mortality.15, 16 Due to favourable weather conditions in our country, many species of mucor thrive in the environment. They may contaminate open soil injuries and lead to invasive disease.

SUMMARY

Invasive fungal infections are diseases of medical progress, closely following the evolution of various diagnostic and therapeutic strategies. Broad management principles include recognizing characteristic symptom complexes in high risk individuals, differentiating colonisation from invasion and timely initiation of appropriate antifungal agents. Individualized antifungal treatment based on host factors, organism, extent of disease as well as the incorporation of adjunctive methods such as source control, surgical debridement and immunomodulation are essential for optimal outcomes.

REFERENCES

1.

Soman R, Sunavala A. Principles of Management of Invasive Fungal Infections. In: Chakrabarti A, editor. Fungal

CHAPTER 18

IFI

Infections in Asia- The Eastern Frontier of Mycology. New Delhi: Elsevier 2013; 221–7.

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80 2.

Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62:e1.

3.

McCarty, Todd P. et al. Invasive Candidiasis. Infectious Disease Clinics 2016; 30:103-124.

4.

Maziarz, Eileen K. et al. Cryptococcosis. Infectious Disease Clinics 2016; 30:179-206.

5.

Perfect, JR, Dismukes, WE, Dromer, F et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis 2010; 50:291–322.

6.

Patterson, T.F., Thompson, G.R. 3rd, Denning, D.W. et al, Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63:e1–e60.

7.

Cadena, Jose et al. Invasive Aspergillosis. Infectious Disease Clinics 2016; 30:125-142.

8. Farmakiotis, Dimitrios et al. Mucormycosis. Infectious Disease Clinics 2016; 30:143-163.

9.

Chakrabarti A. Opportunistic Fungal Infections in Asia. In: Chakrabarti A, editor. The Eastern Frontier of Mycology.

New Delhi: Elsevier 2013; 11–21.

10. Chakrabarti A, Sood P, Rudramurthy S.M. et al. Intensive Care Med 2015; 41:285. doi:10.1007/s00134-014-3603-2.

11. Shivaprakash M, Rudramurthy H. Cryptococcosis in Asia.

In: Chakrabarti A, editor. The Eastern Frontier of Mycology.

New Delhi: Elsevier 2013; 120-134.

12. Panda, N. K., Balaji, P., Chakrabarti,A., Sharma, S. C. & Reddy, C. E. (2004). Paranasal sinus aspergillosis: its categorization to develop a treatment protocol. Mycoses 47; 277–283.

13. Chawla P, Nanday S, Dherai A et al. Correlation of CYP2C19 genotype with plasma voriconazole levels: a preliminary retrospective study in Indians. International Journal of Clinical Pharmacy 2015; 37:925-930.

14. Ashbee HR, Barnes RA, Johnson EM et al. Therapeutic drug monitoring (TDM) ofantifungal agents: guidelines from the British Society for Medical Mycology. JAC 2014; 69:1162-76.

15. Chakrabarti A, Das A, Sharma A et al. Ten years Experience in Zygomycosis at a tertiary care centre in India. J Infect 2001; 42:261-6.

16. Yu J, Li RY. Primary renal zygomycosis due to Rhizopus oryzae. Med Mycol 2006; 44:461-66.

C H A P T E R

19

Mucormycosis: A Challenge Not Limited to Diabetics

Mucormycosis is a devastating life threatening fungal infection caused by fungi of the order Mucorale and class of mucormycets; and is associated with high mortality of 40 -70%. Itâ&#x20AC;&#x2122;s ubiquitous in nature and abundant in our environment. It is highly concentrated near construction activities, decaying vegetables and organic material, soils etc. Mucoraleâ&#x20AC;&#x2122;s growth is favored in tropical countries as temperature and humidity supports sporulation.

Inhalations of spores infect humans. Seasonal variation in infection rates has been described in various parts of the worlds. India has more cases of mucormycosis in perimonsoon period and in autumn.1 Thus generally speaking this is a community-acquired infection in susceptible population. In the last decade cases of mucormycosis are also being increasingly recognized in hospital settings and nosocomial mucormycosis outbreaks been described. Recent outbreak involving 5 cases were described in Queens Marry hospital at Hong Kong in June-July 2015 due to contaminated linen.2 Adhesive tapes, wooden spatula are important source of nosocomial mucormycosis apart from contaminated air filters in the hospitals.

Risk factors

Mucorale spores germinate with available free iron, glucose and with acidic pH. Diabetic ketoacidosis creates an appropriate environment for spores lodged in patientâ&#x20AC;&#x2122;s paranasal sinuses and lung parenchyma during inhalation to germinate and produce clinical infection. Acidosis makes excess free iron available to fungus. Patients with qualitative neutrophil dysfunction &/or macrophage dysfunction (uncontrolled diabetes, steroids therapy) helps in tissue & vascular invasion by mucorale to produce devastating distant lesion with area of infarct. Patient can get cutaneous mucormycosis following subcutaneous inoculation of spores, minor trauma, penetrative injuries following road traffic accidents and even insect bite, tattooing can lead to infection. Intravenous drug users are also included in vulnerable populations and get brain abscess due to mucormycosis.

In India, diabetic patient outnumbers other risk factors for getting mucormycosis. Many of these diabetic patients were unaware about diabetic status and presented with mucormycosis. Other risk factors are hematological malignancy, solid organ transplant recipients, receiving immunosuppressants, victims of natural disaster like tsunami, tornado, Road traffic accident victims, iron over load states and desferioxamine therapy. Cases related to iron overload and chelation therapy is going

Ketan Patel, Swati Gohel, Atul Patel

down significantly in last decade. In recent years, many mucormycosis patients have been described as a breakthrough infection in patients receiving voriconazole or ecchinocandins. Exact association between voricanazole exposure and susceptibility for mucormycosis is not well understood. Animal model suggest that voriconazole may increase virulence of certain mucorale species by uncertain mechanism.

Sites of mucormycosis lesion are used to describe cases of mucormycosis. E.g. rhino-orbital-cerebral mucormycosis (ROC) involving paranasal sinuses, orbit with intracranial extension, pulmonary, cutaneous, gastrointestinal, disseminated and others like isolated renal in immunocompetent host, brain abscess, endocarditis in IV drug users etc.

High index of suspicion is required for the diagnosis of mucormycosis, mainly due to non-specific clinical features and culture can be sterile in up to 50% of cases due to aseptate fungus being damaged during tissue handling in laboratory.

Clinical manifestations depend upon site of infection.

In a diabetic or organ transplant recipient patient with ROC, acute onset of facial pain, orbital pain with proptosis, fixed eye ball, black eschar over palate, black necrotic discharge from nose and rapid progression are sufficient clinical findings supporting clinical diagnosis of mucormycosis.

Organ involvement preference in mucormycosis is different in different vulnerable host, is described in Table 1.

Treatment principles include 1.

Reversal or control of precipitating cause like correction of diabetic ketoacidosis, minimization of immunosuppressions if possible etc

2.

Antifungal therapy: Amphotericin B, Posaconazole, Isavuconazole

3.

Surgical debridement/ excision of lesion

4.

Adjuvant therapy: Hyperbaric oxygen, Deferasirox, Caspofungin, statins

Early diagnosis and prompt treatment is critical in improving outcome in patients with mucormycosis.

Delay in institution of amphotericin B therapy by 1 week is associated with doubling mortality.3 Standard dose of Liposomal Amphotericin B (L AmB) 5mg/kg is drug of

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82

Table 1 Host/Site

ROC

Lungs

GI

Cutaneous

Disseminated

Other

Diabetes

++

+

+

-

-

-

Organ Tx/ steroids

++

++

+

+

+

+

HSCT

++

++

+

+

++

+

IV drug

-

-

-

+

+

Brain abscess, Endocarditis

Malnutrition

-

-

++

-

+

+

Trauma

-

-

-

++

+

+

choice for management of mucormycosis. Higher dosage up to 10mg/kg didn’t improve outcome but was associated with higher rate of renal toxicity (40%).4 Newer azole, Posaconazole and Isavuconazole has antimucor activity in vitro and vivo and are well tolerated.5 Recent introduction of extended release tablet formulation of posaconazole has better pharmacokinetics.

US FDA approves Isavuconazole for treatment of invasive mold infections and mucormycosis. Clinically relevant important benefit of isavuconazole over other newer azole is that it is not an inhibitor of hepatic cytochromal enzyme system, though it is a substrate and metabolized

by CYP 450 enzyme system. Thus it has fewer drug-drug interactions.

Combination antifungal therapy for mucormycosis is generally not recommended, though in vitro studies and animal experiments showed evidence of synergism between polyenes and echinocandins, and also few clinical studies & experts also supports combination of L AmB + ecchinocandins in treatment of mucormycosis.6 One recent presentation at ICAAC conference failed to show any benefit from combination therapy compared to amphotericin B monotherapy in hematological malignancy patient.7 In summary of antifungal treatment for mucormycosis: Standard dosage of L AmB 5mg/kg is firstline therapy. Oral posaconazole & Isavuconazole are acceptable salvage option for intolerant patients and can be use for longer duration if required.

Surgical debridement or resection of necrotic lesion improves outcome of patients with mucormycosis and should be performed in ROC, cutaneous, renal mucormycosis and selected cases of pulmonary mucormycosis.

Adjuvant treatment with hyperbaric oxygen (HBO) inhibits fungal growth and improves the rate of wound healing. HBO therapy may be beneficial in patients with diabetes who have sinusitis, or in cutaneous mucormycosis.

Iron chelator, deferasirox showed promising results in animal model but didn’t showed usefulness in a small human study.8 Case series from India showed acceptable response with deferasirox in diabetic patients with mucormycosis.9

Mortality with mucormycosis varies and it depends upon host factor and site of infection apart from species of mucorale causing infection. Patients with disseminated infections, pulmonary, CNS and deep-seated infections where surgical debridement or resection is not possible have higher mortality. Similarly patients with HSCT, hematological malignancies have higher mortality.10 Certain mucorale species like Cunninghamella is associated with a 2.78 fold-increase in the risk of death compared with more common Rhizopus species.11 Breakthrough mucormycosis in cancer patients receiving voriconazole has highest mortality of > 70%.12 Despite advancement in diagnosis of fungal infections and availability of newer antifungal agents, mortality of mucormycosis is still high. Clinicians shall be ready to face challenges of treating mucormycosis due to rising numbers of at risk population and cost of therapy.

REFERENCES

1.

Nithyanandam S, Jacob MS, Battu RR, Thomas RK, Correa MA, D’Souza O. Rhino-orbito-cerebral mucormycosis. A retrospective analysis of clinical features and treatment outcomes. Indian journal of ophthalmology 2003; 51:231-6.

2.

Cheng VC, Chen JH, Wong SC, et al. Hospital Outbreak of Pulmonary and Cutaneous Zygomycosis due to Contaminated Linen Items From Substandard Laundry.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016; 62:714-21.

3.

Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008; 47:503-9.

4.

Lanternier F, Poiree S, Elie C, et al. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. The Journal of antimicrobial chemotherapy 2015; 70:3116-23.

5.

Marty FM, Ostrosky-Zeichner L, Cornely OA, et al.

Isavuconazole treatment for mucormycosis: a singlearm open-label trial and case-control analysis. The Lancet Infectious diseases 2016; 16:828-37.

6.

Spellberg B, Ibrahim A, Roilides E, et al. Combination therapy for mucormycosis: why, what, and how? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2012; 54:S73-8.

7.

Kyvernitakis A TH, Jiang Y. initial use of combination

treatment does not impact early survival of 106 patients with hematologic malignancies and mucormycosis: a propensity score analysis. ICCAC. San Diego2015.

10. Spellberg B, Kontoyiannis DP, Fredricks D, et al. Risk factors for mortality in patients with mucormycosis.

Medical mycology 2012; 50:611-8.

8.

Spellberg B, Ibrahim AS, Chin-Hong PV, et al. The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial. The Journal of antimicrobial chemotherapy 2012; 67:715-22.

11. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2005; 41:634-53.

9.

Soman R, Gupta N, Shetty A, Rodrigues C. Deferasirox in mucormycosis: hopefully, not defeated. The Journal of antimicrobial chemotherapy 2012; 67:783-4.

83

12. Kontoyiannis DP, Lionakis MS, Lewis RE, et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillusactive antifungal therapy: a case-control observational study of 27 recent cases. The Journal of infectious diseases 2005; 191:1350-60.

CHAPTER 19

C H A P T E R

20

Management of Sexually Transmitted Infections (STI)

INTRODUCTION

Sexually Transmitted Infections (STI) are quite prevalent and one of the most common reasons or which patients seek medical advice (more so in Dermatology). Many patients, especially females, do not come forward for consultation and treatment in view of social stigma attached to STIâ&#x20AC;&#x2122;s. This leads to persistent disease and greater chances of spread of disease to sexual partner/ partners. In this era of HIV, it has been shown that there are higher chances of spread of the dreaded virus among patients with STI. Managing STI involves syndromic case management and treatment of partner/partners of the patient. Also, treating STI gives opportunity to spread awareness regarding HIV, hepatitis B and counselling regarding safe sexual practices. Physicians must be sensitive enough to consider STI in those who come with classical history and manage these patients at the first instance and also treat the partner/partners, if required.

In this chapter, syndromic case management will be discussed. HIV and hepatitis B management will not be discussed here.

SYNDROMIC CASE MANAGEMENT

Syndrome here is a group of symptoms and signs which are caused by more than one organism. Syndromic management leads to prompt identification of patients and helps in fast treatment without relying much on laboratory investigations. This is especially helpful in primary health care centres where laboratory services might not be accessible. Syndromic management involves correct identification of a syndrome based on history and examination and laboratory investigations (wherever required or accessible) and initiating early management of patient and partner/partners. Emphasis is on single dose treatment and Directly Observed Therapy (DOT) wherever feasible. Counselling regarding timely follow up, safe sexual practices, change in high risk behaviour and usage of condoms is done. All the attendees are screened for syphilis and HIV. For a patient presenting in a tertiary care centre or being referred from a primary health care set up due to non resolution of symptoms, investigations to find out etiological agent and co-morbidities is done.

Here, treatment beyond syndromic management is done. In this chapter, we are discussing only syndromic management. For management of individual STI, CDC guidelines can be followed.

History

History should preferably be taken in a language comprehensible by the patient. Patient might not

Nitin Sinha

forthrightly tell his/her symptoms. The physician must build up the confidence, be empathetic, ensure privacy and maintain confidentiality. If a couple approach together, it is advisable to assess them separately. The most common symptoms in STI in males and females are listed in Table 1. Also, history of other co-morbid conditions like diabetes, any urethral catheterization in the past, any past STI, drug allergies, ongoing pregnancy must be sought. Menstrual, contraceptive and obstetric history should also be sought. History regarding sexual behaviour is a must and should focus on recent change in partner, having multiple sexual partners, male having sex with male (MSM), type of sex (oral, vaginal, anal) and date of last intercourse. History of symptoms in partner/partners must be asked for. Occupational history (male/female sex worker, seamen, workers in hospitality industry, transport workers, migrant workers) is essential as is the history of blood transfusions, tattooing, injectable substance abuse.

Examination

Genital examination along with draining lymph node examination is a must. Swelling of testes or vulva must be observed. Both bimanual and Per Speculum examination is essential in females with discharge to rule out cervicitis.

Rectal examination especially, in MSM or in patients with history of anal sex should be carried out. In those with history of oral sex and oral symptoms, oral examination is

Table 1: Symptoms in STI Females

Males

Dysuria, frequency of urination

Dysuria, frequency of urination

Vaginal discharge

Genital ulceration

Genital ulceration

Urethral discharge

Abnormal growth or mass Abnormal growth or mass in genital area in genital area Inguinal lymphadenopathy

Acute scrotal swelling, pain

Lower abdominal pain

Inguinal lymphadenopathy

Dyspareunia

Genital itching, balanitis

Vulval Itching

Dyspareunia

Perianal pain

Perianal pain

Anal discharge

Anal discharge

Pharyngitis

Pharyngitis

essential. A gross head to toe examination should be done where indicated (suspecting disseminated gonococcal infection, history of rash, history of arthritis).

Management of Cervical Discharge Syndrome (Cervicitis)— N. gonorrhoeae, Chlamydia trachomatis, Trichomonas, Herpes simplex, Human Papilloma Virus (HPV) are the etiological agents implicated in cervicitis. PS examination in patient with discharge is a must to rule out cervicitis. PS may reveal either mucopurulent discharge through cervical os and inflamed cervix or sustained endocervical bleeding on gentle passage of cotton swab through the os. Laboratory investigation (if available) should include wet mount and Gram stain examination of discharge to find out the etiological agent. A leucocyte count >10 WBC per high power field is termed leucorrhoea and is suggestive of gonococcal and chlamydial infection of the cervix. Treatment of patient involves giving Tab. Cefixime 400 mg single dose along with Tab. Azithromycin 1 gm orally, single dose. There should be no douching. All partners of the patient in last 30 days need to be treated with the above regimen. Abstinence during course of therapy is a must. Follow up is done after one week to assess response and if symptoms persist, further evaluation and referral to higher centre is required.

Pregnant women are to be given same regimen as non pregnant women. If speculum examination is not available or if the patient does not give consent for it, then she needs to be treated for both vaginitis and cervicitis.

3.

Management of Urethral Discharge/ Burning Micturation in Males— N. gonorrhoeae, C. trachomatis, Trichomonas, Mycoplasma genitalium, Herpes Simplex Virus (HSV), enteric bacteria and Adenovirus are organism implicated in causing this symptom. History and examination of patient is a must. Examination might not reveal urethral discharge. At this juncture, urethral massage on ventral side of penis towards the meatus needs to be done. Apart from Gram stain and wet mount, number of neutrophils in the discharge needs to be ascertained. More than 5 neutrophils per oil immersion field (1000X) in the discharge smear or >10 neutrophils in the sediment of first void urine is suggestive of non-gonococcal urethritis. Treatment of patient comprises of Tab. Cefixime 400 mg orally, single dose along with Tab. Azithromycin 1 gm orally, single dose or Cap. Doxycycline 100 mg twice a day for 7 days. Review patient after seven days. If symptoms persist, treat for Trichomonas infection (as mentioned in treatment of vaginitis syndrome). If the symptoms still persist, then further evaluation is required at a higher centre. All sexual partners of the patient in last 60 days of onset of symptoms should be evaluated and treated for urethral discharge syndrome.

4.

Management of Painful Scrotal Swelling (PSS) in males-- N. gonorrhoeae and C. trachomatis are the most common organisms implicated. Tubercular

Laboratory Investigations

Use laboratory investigations, where available to find etiological agent. However, treatment should not be deferred for want of etiological diagnosis. Gram stain of discharge, wet mount, KOH mount are helpful. All patients must be screened for syphilis and HIV. So, Rapid Plasma Reagin (RPR) and referral to Integrated Counselling and Testing Centre (ICTC) for HIV testing must be done.

EVALUATION AND MANAGEMENT OF INDIVIDUAL SYNDROMES

After thorough history taking, examination and laboratory tests (where available/required) a syndromic diagnosis must be reached and further evaluation and treatment should be done according to the syndromic diagnosis reached.

1.

Management of Vaginal Discharge Syndrome (Vaginitis)— Most common organisms causing this are Trichomonas vaginalis (TV), Candida albicans, Gardnerella vaginalis, Mycoplasma, Ureaplasma and certain uncultivable anerobes. The alst four cause Bacterial Vaginosis (BV). A thorough history and examination is mandatory as mentioned above.

Examination must include PS examination prior to bimanual examination to rule out cervicitis. Colour of discharge might give clue to etiological agent.

For example, green frothy discharge is suggestive of Trichomoniasis, curdy white discharge is suggestive of Candidiasis. Laboratory investigation (if available) of discharge will reveal Trichomonas on wet mount, Candida on KOH mount and Clue cells on Gram’s Stain suggesting Bacterial Vaginosis. Treatment of patient (TV+BV) involves single dose of Secnidazole 2 gm orally or Tab. Tinidazole 500 mg orally, twice daily for 5 days or Tab. Metronidazole 400 mg twice a day for 7 days.

If suspecting Candida infection, give Fluconazole 150 mg orally, single dose or local Clotrimazole 500 mg vaginal pessary once. Douching is not recommended. For the partner, if symptomatic, give same treatment as the patient. However, if asymptomatic, and if the patient has BV or Candida, there is no need of treatment. However, if the patient does not improve after the therapy, then even asymptomatic partner needs treatment.

For TV, treat all partners of patient in last 30 days with the above protocol and patient and partner/ partners to maintain sexual abstinence during course of treatment. For pregnant patients, give only metronidazole and local clotrimazole. Follow up after 7 days of treatment is must to look for cure or for persistence of symptoms. If the symptoms persist, referral to higher centre is done for further investigations and treatment.

85

CHAPTER 20

2.

and filarial genital involvement form important differential. Also, trauma, hydrocoele, torsion should be ruled out. Laboratory investigation (if available) should include Gram staining of urethral smear or of sediment of first void urine. Treatment comprises of Tab. Cefixime 400 mg orally, single dose along with Tab. Azithromycin 1 gm orally, single dose. Supportive treatment in the form of scrotal support, T-bandage and analgesics is also essential. All the partners of the patient in the last 60 days from onset of symptoms need to be evaluated and treated. Sexual abstinence is advised during the course of treatment. Follow up is done after 7 days and if symptoms persist further evaluation is done.

INFECTION

86

5.

6.

Management of Inguinal Bubo-- Bubo is swelling in inguinal region which may be painful. There may be history of preceding ulcer but it is not evident at the time of presentation. C.trachomatis serovars (L1, L2, L3) which cause Lymphogranuloma Venereum (LGV) and Hemophilus ducreyi which cause Chancroid are etiological agents for bubo. Treatment comprises of Cap. Doxycycline 100 mg twice a day for 21 days along with Tab. Azithromycin 1 gm orally, single dose. Never drain a bubo as there are high chances of fistula formation, only aspirate if required. Sexual abstinence during course of treatment is advised.

All the partners of patient in last 90 days from onset of symptoms need to be treated as above. Follow up patient every week for three weeks and if there is no resolution of symptoms, evaluation further in a higher centre is advised.

Management of Genital Ulcer Disease Nonherpetic Syndrome-- Treponema pallidum, H. ducreyi, Klebsiella granulomatis and Chlamydia trachomatis are common etiological agents.

Klebsiella granulomatis causes Granuloma Inguinale. Examination gives clues to diagnosis.

Painless ulcer with firm lymph nodes suggests syphilis, painless ulcer without lymph nodes suggests Granuloma Inguinale, transient ulcer followed by painful enlarged lymph nodes (Bubos) is suggestive of LGV. Treatment comprises of Inj. Benzathaine Penicillin 2.4 million IU intramuscular, single dose along with Tab. Azithromycin 1 gm orally, single dose. For those allergic to penicillin, Cap. Doxycycline 100 mg twice a day for 15 days or Tab. Azithromycin 2 gm orally, single dose is given.

All the partners in last 3 months from onset of symptoms should be treated with above regimen.

Sexual abstinence is advised during course of treatment. Pregnant women must be treated on same lines as above but if pregnant fenale is allergic to penicillin, erythromycin should be used. Follow up is done after one week and if no resolution of symptoms, referral is done to higher centre. Further follow up is done at 3, 6, 12 and 24 months to rule

out syphilis by doing non-treponemal test (RPR/ VDRL).

7.

Management of Genital Ulcer Disease Herpetic Syndrome-- Caused by HSV. Examination shows presence of vesicles and multiple, painful ulcers.

For first episode give Tab. Acyclovir 400 mg three times a day for 7 days. For recurrences, give same regimen. Sexual abstinence is advised during course of treatment or till the lesions heal. Follow up is done after 7 days and if no relief, referral to higher centre is done. If the partner has no active lesion, he/she does not require treatment. Pregnant women should be treated with same regimen. If the pregnant lady has genital herpes and is in labour, Caesarean section should be performed. If there is a doubt regarding type of ulcer on examination, treat for both syndromes.

8.

Management of Lower Abdominal Pain (LAP) Syndrome-- N. gonorrhoeae, C. trachomatis, Gardnerella, Bacteroides, Mycoplasma, Gram positive cocci are the etiological agents implicated.

LAP can also occur due to endometritis, pelvic peritonitis, salpingitis, tubo-ovarian abscess. LAP syndrome consists to lower abdominal pain, fever, dysmenorrhoea, dyspareunia, dysuria, low back ache, vaginal discharge (number and intensity of symptoms varying). Cervical motion tenderness, uterine tenderness, adnexal tenderness on pelvic examination apart from raised body temperature, abnormal vaginal discharge, elevated ESR and CRP suggest LAP syndrome when no other disease as cause of lower abdominal pain is identifiable.

Investigations (where available) must include wet mount, Gram stain, complete blood counts, ESR, CRP, urine routine and microscopy. Pregnancy test must be done to rule out ectopic pregnancy.

In the absence of tubo-ovarian abscess, treatment comprises of Tab. Cefixime 400 mg orally, single dose along with Tab. Metronidazole 400 mg orally, twice daily for 14 days along with Cap. Doxycycline 100 mg twice a day, orally for 14 days.

Ibuprofen is prescribed for first 3-5 days to reduce pain and inflammation and Tab. Ranitidine is given to prevent gastritis. If the symptoms do not subside in 3 days or worsen, the referral to higher centre is done. Referral is also sought if there is suspicion of tubo-ovarian abscess at presentation or if the syndrome is due to surgical cause like appendicitis or peritonitis. Patient is followed after 3, 7 and 14 days of starting treatment. Male partners of patients in last 60 days from onset of symptoms should be examined and treated. Sexual abstinence is advised during course of therapy.

9.

Management of other STI’s—

A.

Anogenital warts: Caused by HPV. Manifest as single or multiple soft, painless, pink coloured “cauliflower” like growth which are present on genitalia, anus. Treatment of perianal and penile

B.

C.

Molluscum contagiosum: Caused by Pox virus.

The lesions are multiple, smooth, glistening, globular papules, with a cheesy material inside.

Lesions regress without treatment in 9-12 months.

Treatment comprises of opening of lesion by fine needle or scalpel and touching the inner walls with 25% phenol or 30% TCA. Pediculosis pubis: Caused by lice Phthirus pubis.

Lesions comprise of red papules with tiny central clot with local urticaria. Eczema and impetigo may be present. Treatment comprises of application of 1% permethrin cream and washing of after 10

minutes. Clothing and bed linen used by patient needs washing and drying. Retreatment is required after 7 days if lice/eggs are found on skin/hair junction. Sexual partner also needs treatment.

D. Scabies: Caused by mite Sarcoptes scabiei.

Symptoms are of severe itching specially at night.

Eczema and super added bacterial infections can occur. Diagnosis is made by demonstrating burrow over the skin. Treatment is by applying permethrin cream (5%) to all body parts below neck after a warm scrubbing bath and washing of the cream after 8-14 hours. Benzyl benzoate (25%) can also be used. Clothing and bed linen which have been used by patients need to washed and well dried.

All members of the family need treatment. Sexual partner needs to treated on same lines

CONCLUSION

STI need urgent treatment not only of patient but also of partner (where indicated). Syndromic approach is used to manage STI with laboratory evaluation not being a mandatory thing prior to initiation of treatment.

Counselling regarding safe sexual practices, condom use and HIV must be done at the first contact. Testing for syphilis and HIV to be done for all patients at first visit.

Need of the hour is to counsel population to shed the social stigma tag and approach the available health care at the earliest.

REFERENCES

1.

Centre for Disease Control and Prevention [Internet]. 2015 Sexually Transmitted Diseases Treatment Guidelines [cited 2016 Sep 10]. Available from: http://www.cdc.gov/std/ tg2015/

2.

National AIDS Control Organization [Internet]. Prevention, Management and Control of Reproductive Tract Infections and Sexually Transmitted Infections 2014 [cited 2016 Sep 10]. Available from: www.naco.gov.in/.../National%20 RTI%20STI%20technical%20guidelines%20Sep2014

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CHAPTER 20

warts comprises of chemical cauterization with 20% Podophyllin application over warts and weekly treatment till complete resolution of lesions.

Another agent used for chemical cauterization is Imiquimod (5%) cream which is applied over warts at bed time and washed in morning with application being done three times a week for 1216 weeks. Physical cauterization by cryotherapy, electrocautery or surgical excision is also modality available for treatment. For vaginal warts, apart from the above, Trichloracetic acid (TCA) (5075%) is also used for treatment. For cervical warts, podophyllin is contraindicated and cryotherapy is treatment of choice. Biopsy of cervical wart to rule out malignancy must be carried out. For urethral warts, 5-flurouracil applied weekly for 3 weeks may eradicate the lesions. For scrotal, vulval skin and pubic areas, TCA, cryotherapy or electro cautery are modalities of treatment. It is noteworthy that types of HPV causing genital infections are different from the types causing ano-genital cancers. HPV testing is not essential in partners of patients with warts. Also, asymptomatic partners do not require treatment. However, patients with warts are advised sexual abstinence. Patient and partner must be screened for other STIâ&#x20AC;&#x2122;s.