Chuong 32

1350

CMDT 2013

32 cc

Viral & Rickettsial Infections Wayne X. Shandera, MD Ingrid L. Roig, MD

Viral Diseases

HUMAN HERPESVIRUSES Herpesviruses cause a wide spectrum of human disease. Eight identified human herpesviruses (HHV) include herpes simplex virus (HSV) (type 1), HSV (type 2), varicella zoster virus (VZV) (type 3), Epstein–Barr (EBV) infectious mononucleosis virus (type 4), and cytomegalovirus (CMV) (type 5). A sixth type (HHV-6) is identified as a causative agent of roseola (exanthema subitum), and a seventh (HHV-7) is serologically associated with several syndromes. Finally, human herpesvirus 8 (HHV-8) is linked with Kaposi sarcoma (see Chapter 31) and primary effusion lymphoma.

Subclinical primary infection with the herpesviruses is more common than clinically manifest illness. Each persists in a latent state for the remainder of the person’s life. With HSV and VZV, virus remains latent in sensory ganglia. Upon reactivation, lesions appear in the distal sensory nerve distribution. As a result of disease, drug, or radiation-induced immunosuppression, virus reactivation may lead to widespread lesions in affected organs such as the viscera or the central nervous system (CNS). Severe or fatal illness may occur in infants and immunodeficient persons. Herpesviruses can induce cell transformation, hence the association with certain malignancies, such as Burkitt lymphoma and nasopharyngeal carcinoma (with EBV) or primary effusion lymphoma and Kaposi sarcoma (with (HHV-8).

1. Herpesviruses 1 & 2 ``

E sse n t i a l s o f d i a g n o s i s

Spectrum of illness from stomatitis and urogenital lesions to facial nerve paralysis (Bell palsy) and encephalitis. `` Variable intervals between exposure and clinical disease, since HSV causes both primary (often subclinical) and reactivation disease. `` Successful management with acyclovir, valacyclovir, or famciclovir. ``

``General Considerations Herpesviruses 1 and 2 affect primarily the oral and genital areas, respectively. Risk factors for HSV transmission include black race, female gender, a history of sexually transmitted infections, an increased number of partners, contact with commercial sex workers, lower socioeconomic status, young age at onset of sexual activity, and total duration of sexual activity. Therefore, seroprevalence of both viruses increases with age, and the seroprevalence of HSV-2 increases with sexual activity. Currently, 16% of the population in the United States is seropositive for HSV-2; of these, only 10–25% have recognized disease. Asymptomatic shedding of either virus is common, especially following primary infection or symptomatic recurrences, and may be responsible for transmission. Asymptomatic HSV-2– infected individuals shed the virus less frequently than those with symptomatic infection. Disease is typically a manifestation of reactivation. Total and subclinical shedding of HSV-2 virus decrease after the first year of initial infection, although viral shedding continues for years thereafter. Higher than expected rates of HSV-2 lesions occur among women in the postpartum period and also among women who have sex with women.

Although HSV-2 is the most common cause of genital ulcers in the developed world, HSV-1 is increasingly recognized as causing primary urogenital infections. Genital recurrences are much more frequent with HSV-2 and gradually decrease over time, whereas HSV-1 recurrences are rare after the first year. HSV-2 seropositivity increases the risk of HIV acquisition (it is threefold higher among persons who are HSV-seropositive than among those who are HSV-2 seronegative), and reactivates more frequently in advanced HIV infection. HIV replication is increased by interaction with HSV proteins. Suppression of HSV-2 decreases HIV-1 plasma levels and genital tract shedding of HIV, which can contribute to a reduction in sexual transmission of HIV-1.

``Clinical Findings A. Symptoms and Signs 1. Mucocutaneous disease—HSV-1 mucocutaneous disease largely involves the mouth and oral cavity (“herpes

Viral & Rickettsial Infections

CMDT 2013

1351

malformations (organomegaly, bleeding, and CNS abnormalities). Maternal infection during the third trimester is associated with the highest risk of neonatal transmission, but about 70% of these infections are asymptomatic or unrecognized. Neonatal transmission during delivery, however, is more common than intrauterine infection.

Invasive fetal monitoring and vacuum or forceps delivery can increase the risk of herpesvirus transmission.

s Figure 32–1. Herpetic whitlow. (Used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine.

McGraw-Hill, 2009.) labialis” or “gingivostomatitis;” the latter largely in children). Digital lesions (whitlows) (Figure 32–1) are an occupational hazard in medicine and dentistry. Contact sports (eg, wrestling) are associated with outbreaks of skin infections (“herpes gladiatorum”). Asymptomatic shedding of HSV-1 is frequent, with most infected individuals shedding virus at least once a month.

Vesicles form moist ulcers after several days and epithelialize over 1–2 weeks if untreated. Primary infection is usually more severe than recurrences but may be asymptomatic. Recurrences often involve fewer lesions, tend to be labial, heal faster, and are induced by stress, fever, infection, sunlight, chemotherapy (eg, fludarabine, azathioprine) or other undetermined factors. A specific apolipoprotein E polymorphism correlates with the presence of oral herpetic disease but not with reactivation.

HSV-2 lesions largely involve the genital tract, with the virus remaining latent in the presacral ganglia. Lesions arising on the external genitalia are multiple, painful, small, grouped, and vesicular. Occasionally, lesions arise in the perianal region or on the buttocks and upper thighs.

Dysuria, cervicitis, and urinary retention may occur in women. Most HSV-2 infected persons in the United States are unaware that they are infected.

Proctitis and sacral lesions in HIV-infected persons with CD4 cytopenia may present with extensive, ulcerating, weeping lesions. Large ulcerations and atypical lesions suggest drug-resistant isolates (see below).

2. Ocular disease—HSV can cause keratitis, blepharitis, and keratoconjunctivitis. Keratitis is usually unilateral and is often associated with impaired visual acuity. Lesions limited to the epithelium usually heal without affecting vision, whereas stromal involvement can cause uveitis, scarring, and eventually blindness. Recurrences of ocular disease are frequent. HSV is the second most common cause, after VZV, of acute retinal necrosis.

3. Neonatal and congenital infection—Both ­herpesviruses can infect the fetus and induce congenital

4. Central nervous system disease—Herpes simplex encephalitis is predominantly caused by HSV-1 and presents with nonspecific symptoms: a flu-like prodrome, followed by headache, fever, behavioral and speech disturbances, and focal or generalized seizures. The temporal lobe is often involved. Untreated disease and presentation with coma carry a high mortality rate, with many survivors suffering neurologic sequelae. Herpes encephalitis does not occur disproportionately among immunosuppressed persons and a subset of pediatric herpes encephalitis is associated with toll-like receptor 3 deficiencies or abnormalities.

Both HSV-1 and HSV-2 are increasingly recognized as a cause of mild, nonspecific neurologic symptoms and are also associated with benign recurrent lymphocytic (Mollaret) meningitis. Primary HSV-2 infection in women often presents as aseptic meningitis. Recurrent meningitis from HSV-2 occurs in both younger and older individuals.

HSV-1 infection may enhance the development of Alzheimer disease by promoting tau phosphorylation.

5. Disseminated infection—Disseminated HSV infection occurs in the setting of immunosuppression, either primary or iatrogenic, or rarely with pregnancy. In disseminated disease, skin lesions are not always present.

Disseminated skin lesions are a particular complication in patients with atopic eczema (eczema herpeticum) and burns. Pneumonia can occur in both immunocompetent and immunosuppressed persons.

6. Bell palsy—An association between HSV-1 and Bell palsy is established.

7. Esophagitis and proctitis—HSV-1 can cause esophagitis in immunocompromised patients, particularly those with AIDS. The lesions are smaller and deeper than those observed in patients with CMV esophagitis or with other herpesvirus known to cause esophagitis in immunocompromised hosts. HSV-1 is also postulated to activate mononuclear cells in the pathogenesis of achalasia. Proctitis often occurs mainly in men who have sex with men.

8. Erythema multiforme—Herpes simplex viruses remain, along with certain drugs, a leading cause of erythema multiforme and of the more severe Stevens–Johnson syndrome.

9. Other—HSV is the cause of approximately 1% of cases of acute liver failure, particularly in pregnant women and immunosuppressed patients. When it occurs, the mortality of fulminant hepatitis is nearly 75%. An HSV lower respiratory tract infection of unknown clinical significance is common in mechanically ventilated patients. Evidence suggests that this finding is an indicator of a poor clinical

1352

CMDT 2013

Chapter 32

condition rather than the cause. HSV-1 pneumonia is associated with high morbidity in patients with solid tumors.

HSV-1 is reported to be a cause of perinephric abscess, febrile neutropenia, chronic urticaria, and esophagitis and enteritis in systemic lupus erythematosus. HSV is also associated with Helicobacter pylori–negative upper gastrointestinal tract ulcers. An association between HSV-1 and endocardial inflammation in the pathogenesis of atrial myxoma is postulated.

B. Laboratory Findings 1. Mucocutaneous disease—Diagnosis is usually made clinically, but viral cultures of vesicular fluid or direct fluorescent antibody staining of scraped lesions remain the standard of diagnosis. Intranuclear inclusion bodies and multinucleated giant cells on a Tzanck preparation or Calcofluor stain are indicative of herpetic infection.

Polymerase chain reaction (PCR) is a more sensitive diagnostic assay. A DNA microarray test for simultaneous detection of HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, and adenovirus in immunocompromised patients is found to be sensitive, specific, cost-effective, and time saving. Typespecific serologies are useful for counseling HIV-infected individuals; pregnant women; sexual partners of persons infected with HSV; and those with an uncertain clinical history, high-risk behavior, or increased number of sexual partners.

2. Ocular disease—Herpes keratitis is diagnosed by branching (dendritic) ulcers that stain with fluorescein.

The extent of epithelial injury in herpes keratitis correlates well with PCR positivity.

3. Encephalitis and recurrent meningitis—Cerebrospinal fluid pleocytosis is common, with a similar increase in the number of red cells. HSV DNA PCR of the cerebrospinal fluid is a rapid, sensitive, and specific tool for early diagnosis. Antibodies to HSV in cerebrospinal fluid can confirm the diagnosis but appear late in the course of the disease. Viral culture shows a sensitivity of only 10%.

MRI scanning is often a useful adjunct showing increased signal in the temporal and frontal lobes. Temporal lobe seizure foci may be shown on electroencephalograms (EEGs).

4. Esophagitis and proctitis—Esophagitis is diagnosed by endoscopic biopsy and cultures. Proctitis may be diagnosed by rectal swab for PCR or culture, or both, although complicated cases may require biopsy.

5. Pneumonia—Pneumonia is diagnosed by clinical, pathologic, and radiographic findings. The CT findings include diffuse or multifocal areas of ground-glass attenuation or consolidative changes or both and are best confirmed using high-resolution CT techniques.

``Treatment & Prophylaxis Drugs that inhibit replication of HSV-1 and HSV-2 include trifluridine and vidarabine (both for keratitis), acyclovir and related compounds, foscarnet, and cidofovir (Table 32–1).

A. Mucocutaneous Disease While treatment is often not necessary in immunocompetent patients, it can ameliorate and shorten the duration of symptoms if initiated early. Oral therapy for 7–10 days is the preferred treatment for primary genital infection and includes acyclovir (200 mg five times a day or 400 mg three times a day), valacyclovir (1 g twice daily), or famciclovir (250 mg three times daily). Primary herpes labialis is most often treated with oral acyclovir (same doses and duration as for genital infection). Intravenous acyclovir (5–10 mg/kg every 8 hours for 7–14 days) should be considered in immunosuppressed patients. Topical 1% hydrocortisone cream in combination with 5% acyclovir cream is also safe and effective in the treatment of recurrent herpes simplex labialis.

For recurrent genital disease, acyclovir (800 mg orally three times daily for 2–5 days), valacyclovir (500 mg orally twice daily for 3 days or 1 g once a day for 5 days), or famciclovir (1 g orally twice daily for 1 day or 500 mg initial dose followed by 250 mg twice daily for 2 days) are all acceptable alternatives. Patient-initiated therapy with a short course (1–2 day regimens) of antiviral agents at first symptoms of recurrence or prodrome is a frequently used approach. For the treatment of recurrences of herpes labialis, lesions heal faster with topical penciclovir than with topical acyclovir. Docosanol cream offers modest benefit.

Atypical isolates, large ulcerations, new lesions, or poor response to therapy suggest acyclovir resistance, which often occurs in immunodeficient patients. Alternatives include high dose acyclovir (4–5 g), which is effective in treating proctitis in the HIV-positive population, or foscarnet (40–60 mg/kg intravenously every 8 hours), adjusting the dose interval in patients with kidney dysfunction. Cidofovir is used in rare cases of infection resistant to both acyclovir and foscarnet.

Patients with frequent recurrent genital infections may be given secondary prophylaxis with acyclovir, 400 mg twice a day; valacyclovir, 500–1000 mg once daily; or famciclovir, 250 mg twice a day. For herpes labialis, valacyclovir, 500 mg daily, is the best option. Sunscreen may be useful for recurrences associated with sunlight exposure.

Advantages of suppressive therapy include a significant reduction in acquisition of disease among the HSV-2 discordant heterosexual partners and a likely reduced transmission in persons with multiple partners, including men who have sex with men and patients with recent HSV-2 infection. AIDS patients with a history of mucocutaneous disease should continue receiving suppressive therapy unless a sustained improvement of immune status occurs.

Among the HIV-infected, the use of highly active antiretroviral therapy (HAART) is associated with a shortened duration of HSV-1 or -2 lesions. The CAPRISA study 004 trial recently showed that although topical tenofovir 1% gel was associated with a significant decrease in HSV-2 acquisition, there was no impact in the shedding rates among coinfected adults.

B. Keratitis For the treatment of acute epithelial keratitis, topical antiviral agents (ophthalmic trifluridine, vidarabine,

Viral & Rickettsial Infections

1353

CMDT 2013

Table 32–1. Agents for viral infections.1 Drug

Dosing

Spectrum

Renal Clearance/ Hemodialysis

CNS/CSF Penetration

Toxicities

Acyclovir

200–800 mg orally five times daily; 250–500 mg/m2 intravenously every 8 hours for 7 days

HSV, VZV

Yes/Yes

Yes

Neurotoxic reactions, reversible renal dysfunction, local reactions

Adefovir

10 mg daily orally

HBV

Yes/Yes

NA

Gastrointestinal symptoms, transaminitis, lactic acidosis, nephrotoxicity, rebound hepatitis.

Amantadine

200 mg daily orally, once daily in the elderly

Influenza A (not H1N1)

Yes/Yes

Yes

Confusion

Boceprevir

800 mg three times daily

HCV

NA/NA

NA

Flu like illness, fatigue, nausea, dysgeusia, anemia.

Cidofovir

5 mg/kg intravenously weekly for 2 weeks, then every other week

CMV

Yes/NA

NA

Neutropenia, renal failure, ocular hypotonia

Emtricitabine

200 mg daily orally

HBV, HIV

Yes/Yes

Some

Lactic acidosis, rebound hepatitis.

Entecavir

0.5 mg orally daily, increase to 1 mg orally daily in lamivudine-resistant patients

HBV

Yes/Some

NA

Lactic acidosis, rebound hepatitis.

Famciclovir

500 mg orally three times daily for 7 days for acute VZV; 250 mg three times daily for 7–10 days for genital or cutaneous HSV-1/HSV-2 infection; 125 mg twice daily for 5 days for recurrences (500 mg twice daily for 7 days if HIV-infected)

HSV, VZV

Yes/NA

NA

NA

Fomivirsen

165 mcg by intravitreal injection once weekly for 3 weeks, then every other week

CMV

NA

NA

Ocular inflammation, retinal detachment

Foscarnet

20 mg/kg intravenous bolus, then 120 mg/kg intravenously every 8 hours for 2 weeks; maintain with 60 mg/kg/d intravenously for 5 days each week

CMV, HSV resistant to acyclovir, VZV, HIV-1

Yes/Yes

Variable

Nephrotoxicity, genital ulcerations, calcium disturbances

Ganciclovir

5 mg/kg intravenous bolus every 12 hours for 14–21 days; maintain with 3.75 mg/kg/d intravenously for 5 days each week

CMV

Yes/Yes

Yes

Neutropenia, thrombocytopenia, CNS side effects

Idoxuridine

Topical, 0.1% every 1–2 hours for 3–5 days

HSV keratitis

NA

NA

Local reactions

Interferon α-2b

3–5 million international units subcutaneously three times weekly to daily.

Intralesionally: 1 million international units per 0.1 mL in up to five warts three times weekly for 3 weeks

HBV, HCV, HPV

Yes/Yes

NA

Influenza-like syndrome, myelosuppression, neurotoxicity

Interferon α-n3

0.05 mL/wart biweekly up to 8 weeks

HPV

NA/NA

NA

Local reactions

3 mU intravenously three times per week

HCV

NA/NA

NA

Influenza-like syndrome, myelosuppression, neurotoxicity (continued )

1354

CMDT 2013

Chapter 32

Table 32–1. Agents for viral infections.1 (continued) Drug

1

Dosing

Spectrum

Renal Clearance/ Hemodialysis

CNS/CSF Penetration

Toxicities

Lamivudine (3TC)

150 mg orally twice daily or 300 mg once daily

HIV, HBV

Yes/NA

Yes

Skin rash, headache, insomnia, rebound hepatitis

Oseltamivir

75 mg orally twice daily for 5 days beginning 48 hours after onset of symptoms

Influenza A and B

Yes/No

NA

Few

Palivizumab

15 mg/kg intramuscularly every month in RSV season

RSV

No/No

No

Upper respiratory infection symptoms

Penciclovir

Topical 1% cream every 2 hours for 4 days

HSV

No/No

No

Local reactions

Peramivir2

Intravenous, 600 mg daily for 5–10 days

Influenza (H1N1)

Yes/NA

NA

Nausea, vomiting, diarrhea, neutropenia

Ribavirin

Aerosol: 1.1 g/d as 20 mg/mL dilution over 12–18 hours for 3–7 days (See text for Lassa fever doses.)

RSV, severe influenza A or B, Lassa fever

Yes/No

Yes

Wheezing

Rimantadine

100 mg twice daily orally, once daily in the elderly

Influenza A (not H1N1)

No/No

Yes

Confusion

Telaprevir

750 mg three times daily

HCV

NA/NA

NA

Anemia, neutropenia, rash including StevensJohnson syndrome

Telbivudine

600 mg once daily orally

HBV

Yes/Yes

NA

Myositis, fatigue, headache, diarrhea, cough, nausea, dizziness, rash, arthralgias, neutropenia; lactic acidosis and rebound hepatitis

Tenofovir

300 mg once daily orally

HBV, HIV

Yes/Some

Some

Rash, neutropenia, lactic acidosis, renal failure (Fanconi syndrome), rebound hepatitis

Trifluridine

Topical, 1% drops every 2 hours to 9 drops/d

HSV keratitis

NA

NA

Local reactions

Valacyclovir

1 g orally three times daily for 7 days for acute VZV; 1 g twice daily for primary genital HSV-1/HSV-2 infection with 500 mg three times daily for recurrences

VZV, HSV

Yes/Poorly

NA

Thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome in AIDS

Valganciclovir

900 mg orally twice daily for 3 weeks; 900 mg daily as maintenance

CMV

Yes/Yes

Yes

See ganciclovir

Vidarabine

15 mg/kg/d intravenously for 10 days

HSV, VZV

Yes/Yes

Yes

Teratogenic, megaloblastosis, neurotoxicity

Zanamivir

2–5 mg inhalations twice daily for 5 days

Influenza A and B

Yes/NA

NA

Few

Agents used exclusively in the management of HIV infection and AIDS are found in Chapter 31.

Available through the Centers for Disease Control and Prevention Emergency Use Authorization.

CNS, central nervous system; CSF, cerebrospinal fluid; HSV, herpes simplex virus; VZV, varicella-zoster virus; HBV, hepatitis B virus; CMV, cytomegalovirus; HPV, human papillomavirus; HCV, hepatitis C virus; RSV, respiratory syncytial virus.

2

Viral & Rickettsial Infections acyclovir, and ganciclovir) are all nearly equivalent in efficacy and are recommended. Combination of topical antiviral agents with interferon or debridement (or both) hastens healing. Intravenous acyclovir is used for acute retinal necrosis. Oral famciclovir is a reasonable alternative, especially in patients unable to tolerate intravenous therapy and when acyclovir resistance is present.

The usage of topical corticosteroids may exacerbate the infection, although systemic corticosteroids may help with selected cases of stromal infection. Long-term treatment (> 1 year) with acyclovir at a dosage of 800 mg/d orally decreases recurrence rates of keratitis, conjunctivitis or blepharitis due to HSV.

C. Neonatal Disease Intravenous acyclovir (20 mg/kg every 8 hours for 14–21 days) is effective for the treatment of disseminated lesions in neonatal disease. Counseling with serologic screening should be offered to pregnant mothers. The use of maternal antenatal suppressive therapy with acyclovir (typically, 400 mg three times daily) beginning at 36 weeks gestation decreases the presence of detectable HSV, the rates of recurrence at delivery, and the need for cesarean section. Cesarean section is recommended for pregnant women with active genital lesions or typical prodromal symptoms.

D. Encephalitis and CNS Meningitis Because of the need for rapid treatment to decrease mortality and neurologic sequelae, intravenous acyclovir (10 mg/ kg every 8 hours for 10 days or more, adjusting for kidney dysfunction) should be started in those patients with suspected HSV encephalitis, stopping only if another diagnosis is established. If the PCR of cerebrospinal fluid is negative but clinical suspicion remains high, treatment should be continued for 10 days because the false-negative rate for PCR can be as high as 25% (especially in children) and acyclovir is relatively nontoxic. Long-term neurologic sequelae are common and late pediatric relapse is recognized. Acyclovir resistance in a case of herpes simplex encephalitis is reported. Aseptic meningitis may also require a course of intravenous acyclovir or valacyclovir.

E. Disseminated Disease Disseminated disease responds best to parenteral acyclovir when treatment is initiated early.

F. Bell Palsy Prednisolone, 25 mg orally twice daily for 10 days started within 72 h of onset, significantly increases the rate of recovery. Data on antiherpes antiviral agents are equivocal; according to one study, valacyclovir (but not acyclovir), 1 g orally daily for 5 days, plus corticosteroid therapy may be beneficial if started within 7 days of symptom onset. In patients with severe or complete facial paralysis, such antiviral therapy is often administered but without a firm proof of efficacy.

CMDT 2013

1355

G. Esophagitis and Proctitis Patients with esophagitis should receive either intravenous acyclovir (5–10 mg/kg every 8 hours) or oral acyclovir (400 mg five times daily). Maintenance therapy for AIDS patients is also with acyclovir (400 mg three to five times daily). Proctitis is treated with similar dosages and usually responds within 5 days.

H. Erythema Multiforme Suppressive therapy with oral acyclovir (400 mg twice a day for 6 months) decreases the recurrence rate of HSVassociated erythema multiforme. Valacyclovir (500 mg twice a day) may be effective in cases unresponsive to acyclovir.

``Prevention Besides antiviral suppressive therapy, prevention also requires counseling and the use of condom barrier precautions during sexual activity. Disclosure of partner status is associated with about a 50% reduction in the HSV-2 acquisition. Arguments favoring partner testing include confirming exposure, assistance with management, reducing the risk of transmission, and aiding in public health strategies. Male circumcision is associated with a lower incidence of acquiring HSV-2 infection.

Preventing spread to hospital staff and other patients from cases with mucocutaneous, disseminated, or genital disease requires isolation and the usage of hand-washing and gloving–gowning precautions. Staff with active lesions (eg, whitlows) should not have contact with patients.

Asymptomatic transmission occurs, especially with HSV-2.

Initial success with a glycoprotein vaccine did not persist with studies on a larger scale where the vaccine was found to be ineffective. Current vaccine trials focus on HSV-2 peptides, plasmid expressing peptides (DNA vaccine), viral vectors, and attenuated/replication-defective versions of HSV-2.

Barnabas RV et al; NIAID HIV Vaccine Trials Network. Impact of herpes simplex virus type 2 on HIV-1 acquisition and progression in an HIV vaccine trial (the Step study). J Acquir Immune Defic Syndr. 2011 Jul 1;57(3):238–44. [PMID: 21860356] Cohen J. Immunology: painful failure of promising herpes vaccine. Science. 2010 Oct 15;330(6002):304. [PMID: 20947733] Phipps W et al. Persistent genital herpes simplex virus-2 shedding years following the first clinical episode. J Infect Dis. 2011 Jan 15;203(2):180–7. [PMID: 21288817] Tan DH et al. No impact of oral tenofovir disoproxil fumarate on herpes simplex virus shedding in HIV-infected adults. AIDS. 2011 Jan 14;25(2):207–10. [PMID: 21150556] Tronstein E et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011 Apr 13;305(14):1441–9. [PMID: 21486697] Workwoski KA et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1–110.

Erratum in: MMWR Recomm Rep. 2011 Jan 14;60(1):18.

[PMID: 21160459]

1356

CMDT 2013

Chapter 32

2. Varicella (Chickenpox) & Herpes Zoster (Shingles)

E sse n t i a l s o f d i a g n o s i s

``

Exposure 14–21 days before onset.

Fever and malaise just before or with eruption. `` Rash: pruritic, centrifugal, papular, changing to vesicular (“dewdrops on a rose petal”), pustular, and finally crusting. `` ``

``General Considerations Varicella zoster virus (VZV), or HHV-3, disease manifestations include chickenpox (varicella) and shingles (herpes zoster). Chickenpox generally presents during childhood; has an incubation period of 10–20 days (average 2 weeks); and is highly contagious, spreading by inhalation of infective droplets or contact with lesions.

The incidence and severity of herpes zoster (“shingles”), which affects up to 25% of persons during their lifetime, increases with age due to an age-related decline in immunity against VZV. More than half of all patients in whom herpes zoster develops are older than 60 years, and the incidence of herpes zoster reaches 10 cases per 1000 patient-years by age 80 (by which time 50% are infected with VZV). The annual incidence in the United States of 1 million cases is increasing as the population ages. Populations at increased risk for varicella-zoster– related diseases include immunosuppressed persons and persons receiving biologic agents (tumor necrosis factor inhibitors).

``Clinical Findings A. Varicella 1. Symptoms and signs—Fever and malaise are mild in children and more marked in adults. The pruritic rash begins prominently on the face, scalp, and trunk, and later involves the extremities (Table 32–2). Maculopapules

Table 32–2. Diagnostic features of some acute exanthems.

Disease

Prodromal Signs and Symptoms

Other Diagnostic Features

Nature of Eruption

Laboratory Tests

Atypical measles

Same as measles.

Maculopapular centripetal rash, becoming confluent.

History of measles vaccination.

Measles antibody present in past, with titer rise during illness.

Chikungunya fever

2–4 (sometimes 1–12) days, fever, headaches, abdominal complaints, myalgias, arthralgias.

Maculopapular, centrally distributed, pruritus, can be bullous with sloughing in children, occasional facial edema and petechiae.

History of mosquito bites, epidemiologic factors.

ELISA-based immunoglobulin M or IgG (fourfold increase in titers); PCR and cultures are infrequently available.

Eczema herpeticum

None.

Vesiculopustular lesions in area of eczema.

Herpes simplex virus isolated in cell culture. Multinucleate giant cells in smear of lesion.

Ehrlichiosis

Headache, malaise.

Rash in one-third, similar to Rocky Mountain spotted fever.

Pancytopenia, elevated liver function tests.

Polymerase chain reaction, immunofluorescent antibody.

Enterovirus infections

1–2 days of fever, malaise.

Maculopapular rash resembling rubella, rarely papulovesicular or petechial.

Aseptic meningitis.

Virus isolation from stool or cerebrospinal fluid; complement fixation titer rise.

Erythema infectiosum (parvovirus B19)

None. Usually in epidemics.

Red, flushed cheeks; circumoral pallor; maculopapules on extremities.

“Slapped face” appearance.

White blood count normal.

Exanthema subitum (HHV-6, 7; roseola)

3–4 days of high fever.

As fever falls by crisis, pink maculopapules appear on chest and trunk; fade in 1–3 days.

White blood count low.

(continued )

Viral & Rickettsial Infections

CMDT 2013

1357

Table 32–2. Diagnostic features of some acute exanthems. (continued) Disease

Prodromal Signs and Symptoms

Other Diagnostic Features

Nature of Eruption

Laboratory Tests

Infectious mononucleosis (EBV)

Fever, adenopathy, sore throat.

Maculopapular rash resembling rubella, rarely papulovesicular.

Splenomegaly, tonsillar exudate.

Atypical lymphocytes in blood smears; heterophil agglutination (Monospot test).

Kawasaki disease

Fever, adenopathy, conjunctivitis.

Cracked lips, strawberry tongue, maculopapular polymorphous rash, peeling skin on fingers and toes.

Edema of extremities.

Angiitis of coronary arteries.

Thrombocytosis, electrocardiographic changes.

Measles (rubeola)

3–4 days of fever, coryza, conjunctivitis, and cough.

Maculopapular, brick-red; begins on head and neck; spreads downward and outward, in 5–6 days rash brownish, desquamating.

See Atypical Measles, above.

Koplik spots on buccal mucosa.

White blood count low. Virus isolation in cell culture. Antibody tests by hemagglutination inhibition or neutralization.

Meningococcemia

Hours of fever, vomiting.

Maculopapules, petechiae, purpura.

Meningeal signs, toxicity, shock.

Cultures of blood, cerebrospinal fluid. High white blood count.

Rocky Mountain spotted fever

3–4 days of fever, vomiting.

Maculopapules, petechiae, initial distribution centripetal (extremities to trunk, including palms).

History of tick bite.

Indirect fluorescent antibody; complement fixation.

Rubella

Little or no prodrome.

Maculopapular, pink; begins on head and neck, spreads downward, fades in 3 days. No desquamation.

Lymphadenopathy, postauricular or occipital.

White blood count normal or low. Serologic tests for immunity and definitive diagnosis (hemagglutination inhibition).

Scarlet fever

One-half to 2 days of malaise, sore throat, fever, vomiting.

Generalized, punctate, red; prominent on neck, in axillae, groin, skin folds; circumoral pallor; fine desquamation involves hands and feet.

Strawberry tongue, exudative tonsillitis.

Group A β-hemolytic streptococci in cultures from throat; antistreptolysin O titer rise.

Smallpox (based on prior experience)

Fever, malaise, prostration.

Maculopapules to vesicles to pustules to scars (lesions develop at the same pace).

Centrifugal rash; fulminant sepsis in small percentage of patients, gastrointestinal and skin hemorrhages.

Contact CDC1 for suspicious rash; EM and gel diffusion assays.

Typhus

3–4 days of fever, chills, severe headaches.

Maculopapules, petechiae, initial distribution centrifugal (trunk to extremities).

Endemic area, lice.

Complement fixation.

Varicella (chickenpox)

0–1 day of fever, anorexia, headache.

Rapid evolution of macules to papules, vesicles, crusts; all stages simultaneously present; lesions superficial, distribution centripetal.

Lesions on scalp and mucous membranes.

Specialized complement fixation and virus neutralization in cell culture.

Fluorescent antibody test of smear of lesions.

1 http://www.bt.cdc.gov/agent/smallpox/response-plan/.

EBV, Epstein–Barr virus; EM, electron microscopy; HHV, human herpesvirus.

change in a few hours to vesicles that become pustular and eventually form crusts (Figures 32–2 and 32–3). New lesions may erupt for 1–5 days, so that different stages of the eruption are usually present simultaneously. The crusts slough in 7–14 days. The vesicles and pustules are superficial and elliptical, with slightly serrated borders. Pitted scars are frequent. Although the disease is often mild,

c­ omplications such as secondary bacterial infection, pneumonitis, and encephalitis occur in about 1% of cases and often lead to hospitalization.

After the primary infection, the virus remains dormant in cranial nerves sensory ganglia and spinal dorsal root ganglia. Latent VZV will reactivate as herpes zoster in about 10–30% of persons (see below). Varicella is more

1358

CMDT 2013

Chapter 32 severe in older patients and immunocompromised persons. In the latter, atypical presentations, including widespread dissemination in the absence of skin lesions, are often described.

There is a small increased risk of Guillain-Barré syndrome for at least 2 months after an acute herpes zoster attack.

2. Laboratory findings—Diagnosis is usually made clinically, with confirmation by direct immunofluorescent antibody staining or PCR of scrapings from lesions.

Multinucleated giant cells are usually apparent on a Tzanck smear or Calcofluor stain of material from the vesicle bases. Leukopenia and subclinical transaminase elevation are often present and thrombocytopenia occasionally occurs.

A varicella skin test and interferon-gamma enzymelinked immunospot (ELISPOT) can screen for VZV susceptibility.

B. Herpes Zoster

s Figure 32–2. Primary varicella (chickenpox) skin lesions. (Public Health Image Library, CDC.)

Herpes zoster (“shingles”) usually occurs among adults, but cases are reported among infants and children. Skin lesions resemble those of chickenpox. Pain is often severe and commonly precedes the appearance of rash. Lesions follow a dermatomal distribution, with thoracic and lumbar roots being the most common. In most cases, a single unilateral dermatome is involved, but occasionally, neighboring and distant areas are involved. Lesions on the tip of the nose, inner corner of the eye, and root and side of the nose (Hutchinson sign) indicate involvement of the trigeminal nerve (herpes zoster ophthalmicus). Facial palsy, lesions of the external ear with or without tympanic membrane involvement, vertigo and tinnitus, or deafness signify geniculate ganglion involvement (Ramsay Hunt syndrome or herpes zoster oticus). Shingles is a particularly common and serious complication among patients with multiple myeloma who receive bortezomib therapy, and it also occurs among patients with systemic lupus erythematosus receiving corticosteroids and immunomodulators. Contact with patients who have varicella does not appear to be a risk factor for zoster.

``Complications A. Varicella

s Figure 32–3. Chickenpox (varicella) with classic “dew drop on rose petal” appearance. (Courtesy of Richard P. Usatine, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

Secondary bacterial skin superinfections, particularly with group A β-hemolytic streptococci and Staphylococcus aureus, are the most common complications in children.

Cellulitis, erysipelas, and scarlet fever are described. Bullous impetigo and necrotizing fasciitis are less often seen. Other associations with varicella include epiglottitis, necrotizing pneumonia, osteomyelitis, septic arthritis, epidural abscess, meningitis, endocarditis, and purpura fulminans. Toxic shock syndrome can also develop.

Interstitial VZV pneumonia is more common in adults (especially smokers, HIV-infected patients, and pregnant women) and may result in acute respiratory distress syndrome (ARDS). After healing, numerous densely calcified lesions are seen throughout the lung fields on chest radiographs.

Viral & Rickettsial Infections Historically, neurologic complications developed in about 1 in 2000 children. Currently, cerebellar ataxia occurs at a frequency of 1:4000 in the young. A limited course and complete recovery are the rule. Encephalitis is similarly infrequent, occurs mostly in adults, and is characterized by delirium, seizures, and focal neurologic signs.

Both mortality and long-term neurologic sequelae rates are about 10%. Ischemic strokes in the wake of acute VZV infection present a mean of 4 months after rashes and may be due to an associated vasculitis. Multifocal encephalitis, ventriculitis, myeloradiculitis, arterial aneurysm formation, and arteritis are also described in immunosuppressed, especially HIV-infected, patients.

Purpura fulminans is an extremely rare complication of varicella secondary to protein S deficiency resulting in diffuse intravascular coagulation and severe skin defects. VZV reactivation on rare occasions causes a hemophagocytic lymphohistiocytosis syndrome in severely immunocompromised patients.

Clinical hepatitis is uncommon and mostly presents in the immunosuppressed patient but can be fulminant and fatal. Reye syndrome (fatty liver with encephalopathy) also complicates varicella (and other viral infections, especially influenza B), usually in childhood, and is associated with aspirin therapy (see Influenza, below).

When contracted during the first or second trimesters of pregnancy, varicella carries a very small risk of congenital malformations, including cicatricial lesions of an extremity, growth retardation, microphthalmia, cataracts, chorioretinitis, deafness, and cerebrocortical atrophy. If varicella develops around the time of delivery, the newborn is at risk for disseminated disease.

B. Herpes Zoster Postherpetic neuralgia occurs in 60–70% of patients who have herpes zoster and are older than 60 years. The pain can be prolonged and debilitating. Risk factors for postherpetic neuralgia include advanced age, female sex, the presence of a prodrome, and severity of rash or pain but not family history.

Other complications include the following: (1) bacterial skin superinfections; (2) herpes zoster ophthalmicus, which occurs with involvement of the trigeminal nerve and is a sight-threatening complication (especially when it involves the cornea or the iris), and is a marker for stroke over the ensuing year (Hutchinson sign is a marker of ocular involvement in the HIV-positive population); (3) rarely, unilateral ophthalmoplegia; (4) involvement of the geniculate ganglion of cranial nerve VII as well as cranial nerves V, VIII, IX, and X; (5) aseptic meningitis; (6) peripheral motor neuropathy; (7) transverse myelitis; (8) encephalitis; (9) acute cerebellitis; (10) stroke; (11) vasculopathy; (12) acute retinal necrosis; and (13) progressive outer retinal necrosis (largely among HIV infected persons). VZV is a major cause of Bell palsy in patients who are HSV seronegative. Diagnosis of neurologic complications requires the detection of VZV DNA or anti-VZV IgG in cerebrospinal fluid or the detection of VZV DNA in tissue. Zoster sine herpete (pain without rash) can also be associated with most of the above complications. Associations between

CMDT 2013

1359

recent attacks of zoster and the development of multiple sclerosis and Guillain-BarrĂŠ syndrome are recognized.

``Treatment A. General Measures In general, patients with varicella should be isolated until primary crusts have disappeared and kept at bed rest until afebrile. The skin is kept clean. Pruritus can be relieved with antihistamines, calamine lotion, and colloidal oatmeal baths.

As an antipyretic, acetaminophen is used. Fingernails can be closely cropped to avoid skin excoriation and infection.

B. Antiviral Therapy Acyclovir, 20 mg/kg (up to 800 mg per dose) orally four times daily for 5 days, should be given within the first 24 hours after the onset of varicella rash and should be considered for patients older than 12 years, secondary household contacts (disease tends to be more severe disease in secondary cases), patients with chronic cutaneous and cardiopulmonary diseases, and children receiving longterm therapy with salicylates (to decrease the risk of Reye syndrome). Experience with valacyclovir and famciclovir in these settings is scant.

In immunocompromised patients, in pregnant women during the third trimester, and in patients with extracutaneous disease (encephalitis, pneumonitis), antiviral therapy with high-dose acyclovir (30 mg/kg/d in three divided doses intravenously for at least 7 days) should be started once the diagnosis is suspected. Corticosteroids may be useful in the presence of pneumonia. Prolonged prophylactic acyclovir is important for thorough suppression of VZV reactivation in profoundly immunosuppressed patients.

For uncomplicated herpes zoster, acyclovir (800 mg orally five times daily) or valacyclovir (1 g orally three times daily) for 7 days is recommended. Therapy should start within the first 72 hours of the onset of the lesions.

Intravenous acyclovir is used for extradermatomal complications of zoster, although acyclovir is not fully effective in retinal disease. A topical antiviral, sorivudine, appears to be a safe and well-tolerated adjuvant therapy to valacyclovir for treatment of acute herpes zoster. Foscarnet may be used for acyclovir-resistant VZV infections seen in immunosuppressed patients. The Ramsay Hunt syndrome is more resistant to antiviral therapy.

C. Treatment of Complications Once established, postherpetic neuralgia may respond to gabapentin or lidocaine patches (FDA approved drugs for neuropathic pain). Tricyclic antidepressants, opioids, and capsaicin cream are also widely used and effective. The epidural injection of corticosteroids and local anesthetics appears to modestly reduce herpetic pain at 1 month but is not effective for prevention of long-term postherpetic neuralgia. Secondary bacterial infections are treated with antibiotics providing coverage for staphylococci. The use of antiviral agents for postherpetic neuralgia is under further study.

1360

CMDT 2013

Chapter 32

``Prognosis The total duration of varicella from onset of symptoms to disappearance of crusts rarely exceeds 2 weeks. Fatalities are rare except in immunosuppressed patients.

Herpes zoster resolves in 2–6 weeks. Antibodies persist longer and at higher levels than with primary varicella. Eye involvement with herpes zoster necessitates periodic future examinations.

``Prevention Health care workers should be screened for varicella and vaccinated if seronegative. Patients with active varicella or herpes zoster are promptly separated from seronegative patients. For those with varicella, airborne and contact isolation is recommended, whereas for those with zoster, contact precautions are sufficient. For immunosuppressed patients with zoster, precautions should be the same as if the patient had varicella. Exposed serosusceptible patients should be placed in isolation and exposed serosusceptible employees should stay away from work between days 10 and 21 after exposure. Health care workers with zoster should receive antiviral agents during the first 72 hours of disease and withdraw from work until lesions are crusted.

Postexposure prophylaxis should be evaluated (see below).

A. Varicella 1. Vaccination—Universal childhood vaccination against varicella is effective. The varicella vaccine (Varilrix) is safe and over 98.1% effective when given after 13 months of age.

A single antigen live attenuated vaccine (VARIVAX) or a quadrivalent measles, mumps, rubella, and varicella vaccine (ProQuad) are available. The first dose should be administered at 12–15 months of age and the second at 4–6 years.

Aspirin should be avoided for at least 6 weeks because of the risk of Reye syndrome. This vaccine is safe, well tolerated, but the quadrivalent vaccine is associated with a small risk of febrile seizures 5–12 days after vaccination among infants aged 12–23 months. Rashes, when secondary to the varicella vaccine, appear 15–42 days after vaccination. Rare cases of zoster among children who received the varicella vaccine are attributable to delayed vaccination (after age 5), severe asthma, and developmental disorders. Such complications appear to occur less often among American children of African ancestry.

For serosusceptible individuals older than 13 years, two doses of varicella vaccine (single antigen) administered 4–8 weeks apart is recommended. For those who received a single dose in the past, a catch-up second dose is advised, especially in the epidemic setting (where it is effective when it can be given during the first 5 days postexposure).

Household contacts of immunocompromised patients should adhere to these recommendations. Susceptible pregnant women need to receive the first dose of vaccine before discharge after delivery and the second dose 4–8 weeks later. The quadrivalent vaccine MMRV can be used for the second doses of MMR and varicella in patients aged 15 months to 12 years and for the first dose in patients aged 48 months or older. (Before this age, the MMR and varicella vaccination can safely be given separately.)

The vaccine, administered 3 months apart, should also be considered for HIV-infected adolescents and adults with CD4 T lymphocyte counts ≥ 200 cells/mcL. The vaccine may also be given to patients with impaired humoral immunity, to patients receiving corticosteroids, and to patients with juvenile rheumatoid arthritis who receive methotrexate. Patients receiving high doses of corticosteroids for over 2 weeks may be vaccinated a month after discontinuation of the therapy. Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and who have not undergone chemotherapy for at least 3 months may be vaccinated. Kidney and liver transplant patients should be vaccinated if they are susceptible to varicella.

The incidence of varicella in the United States has been reduced between 67% and 87% as a consequence of the varicella vaccine.

2. Postexposure—Postexposure vaccination is recommended for unvaccinated persons without other evidence of immunity. Varicella-zoster immune globulin (VZIG) (in short supply with production stopped in 2004) or VariZIG (a lyophilized product available under expanded access since December 2007) should be considered for susceptible exposed patients who cannot receive the vaccine, including immunosuppressed patients, neonates from mothers with varicella around the time of delivery, exposed premature infants born from serosusceptible mothers at > 28 weeks of gestation, neonates born at < 28 weeks of gestation regardless of maternal serostatus, and pregnant women. No controlled studies have evaluated the use of acyclovir in this setting. VZIG is given by intramuscular injection in a dosage of 12.5 units/kg up to a maximum of 625 units, with a repeat identical dose in 3 weeks if a high-risk patient remains exposed. VZIG has no place in therapy of established disease.

Further information may be obtained by calling the Centers for Disease Control and Prevention’s Immunization Information Hotline (800-232-2522).

B. Herpes Zoster A live attenuated VZV vaccine (ZOSTAVAX, 19,400 plaque forming units [pfu] of Oka/Merck strain) consists of varicella virus at a concentration at least 14 times that found in VARIVAX (1350 pfu). This vaccine should be offered to persons 60 years and older but cannot be used in children in place of varicella vaccine; if the vaccine is accidentally given to a child, the event should be reported to the CDC. In adults, the vaccine reduces the incidence of postherpetic neuralgia and herpes zoster by 67% and 51%, respectively.

Before administration of zoster vaccine, patients do not need to be asked about their history of varicella (chickenpox) or have serologic tests to determine varicella immunity because the vaccine is safe, tolerated, and immunogenic in persons with a history of herpes zoster. A second dose of the zoster vaccine is not recommended because it does not boost VZV specific immunity beyond the levels achieved by the first dose. The attenuated VZV vaccine is safe and modestly immunogenic among HIV-infected persons with a CD4 count of at least 300 cells/mcL.

Viral & Rickettsial Infections In 2009, the manufacturer advised against concurrent administration with 23-valent pneumococcal polysaccharide vaccine based on a study showing lower VZV titers; however, a subsequent larger study showed equal effectiveness among persons who received the vaccine at the same time when compared to those who received the vaccines 4 weeks apart. Consequently, the CDC continues to recommend the administration of both vaccines at the same visit.

If a varicella vaccine is mistakenly administered to an adult instead of a zoster vaccine, the dose should be considered invalid and the patient should be administered a dose of zoster vaccine at the same visit. Prophylaxis with acyclovir, 800 mg orally twice daily, can be considered in patients at high risk for VZV reactivation (eg, allogeneic hematopoietic cell transplant patients).

Kang JH et al. Increased risk of multiple sclerosis following herpes zoster: a nationwide, population-based study. J Infect Dis. 2011 Jul 15;204(2):188–92. [PMID: 21653524] Lu PJ et al. Herpes zoster vaccination among adults age 60 years and older, in the U.S., 2008. Am J Prev Med. 2011 Feb;40(2): e1–6. [PMID: 21238856] Oxman MN. Zoster vaccine: current status and future prospects.

Clin Infect Dis. 2010 Jul 15;51(2):197–213. [PMID: 20550454] Pahud BA et al. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J Infect Dis. 2011 Feb 1;203(3):316–23. [PMID: 21177308] Tseng HF et al. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011 Jan 12; 305(2):160–6. [PMID: 21224457] Vermeulen JN et al. Safety, tolerability, and immunogenicity after 1 and 2 doses of zoster vaccine in healthy adults ≥ 60 years of age. Vaccine. 2012 Jan 20;30(5):904–10. [PMID: 22154769]

3. Epstein–Barr Virus & Infectious Mononucleosis ``

E sse n t i a l s o f d i a g n o s i s

CMDT 2013

1361

persisting for the lifetime of the host. Infectious mononucleosis is a common manifestation of EBV and may occur at any age. In the United States, EBV infection usually develops in persons between the ages of 10 and 35 years, sporadically or epidemically. In the developing world, infectious mononucleosis occurs at younger ages and tends to be less symptomatic. Rare cases in the elderly occur usually without the full symptomatology. EBV is largely transmitted by saliva but can also be recovered from genital secretions. Saliva may remain infectious during convalescence, for 6 months or longer after symptom onset. The incubation period lasts several weeks (30–50 days).

``Clinical Findings A. Symptoms and Signs The protean manifestations of infectious mononucleosis reflect the dissemination of the virus in the oral cavity and through peripheral blood lymphocytes and cell-free plasma.

Fever, sore throat, fatigue, malaise, anorexia, and myalgia typically occur in the early phase of the illness. Physical findings include lymphadenopathy (discrete, nonsuppurative, slightly painful, especially along the posterior cervical chain), transient bilateral upper lid edema (Hoagland sign), and splenomegaly (in up to 50% of patients). A maculopapular or occasionally petechial rash occurs in < 15% of patients unless ampicillin is given (in which case rash is seen in > 90%). Conjuctival hemorrhage (Figure 32–4), exudative pharyngitis, uvular edema, tonsillitis, or gingivitis may occur and soft palatal petechiae may be noted.

Other manifestations include hepatitis, cholestasis, gastritis, nervous system involvement in 1–5% (mononeuropathies and occasionally aseptic meningitis, encephalitis, cerebellitis, peripheral and optic neuritis, transverse myelitis, or Guillain-Barré syndrome), kidney disease (mostly interstitial nephritis), pneumonia, pleural involvement, and myocarditis. Vaginal ulcers are rare but may be present.

Airway obstruction from lymph node enlargement, pericarditis, life-threatening thrombocytopenia, severe CNS

Malaise, fever, and sore throat, sometimes with exudates. `` Palatal petechiae, lymphadenopathy, splenomegaly, and, occasionally, a maculopapular rash. `` Positive heterophil agglutination test (Monospot). `` Atypical large lymphocytes in blood smear; ­lymphocytosis. `` Complications: hepatitis, myocarditis, neuropathy, encephalitis, airway obstruction secondary to lymph node enlargement, hemolytic anemia, thrombocytopenia. ``

``General Considerations Epstein-Barr virus (EBV, or human herpes virus-4 [HHV-4]) is one of the most ubiquitous human viruses, infecting > 95% of the adult population worldwide and

s Figure 32–4. Conjunctival hemorrhage of the eye due to infectious mononucleosis. (Courtesy of Dr. Thomas F. Sellers, Emory University, Public Health Image Library, CDC.)

1362

CMDT 2013

Chapter 32

complications, and massive splenomegaly are all considered indications for hospitalization or close observation.

Mesenteric adenitis may mimic an acute abdomen.

B. Laboratory Findings In infectious mononucleosis an initial phase of granulocytopenia is followed within 1 week by lymphocytic leukocytosis (> 50% of all leukocytes) with atypical lymphocytes (larger than normal mature lymphocytes, staining more darkly, and showing vacuolated, foamy cytoplasm and dark nuclear chromatin) comprising > 10% of the leukocyte count. Hemolytic anemia, with anti-i antibodies, occurs occasionally as does thrombocytopenia (at times marked).

The diagnosis of infectious mononucleosis is commonly made on the basis of characteristic manifestations and serologic evidence of infection (the heterophil sheep cell agglutination [HA] antibody tests or the correlated mononucleosis spot test [Monospot]). These tests usually become positive within 4 weeks after onset of illness and are specific but often not sensitive in early illness. Heterophil antibodies may be absent in young children and in as many as 20% adults. During acute illness, there is a rise and fall in immunoglobulin M (IgM) antibody to EB virus capsid antigen (VCA) and a rise in IgG antibody to VCA, which persists for life. Antibodies (IgG) to EBV nuclear antigen (EBNA) appear after 4 weeks of onset and also persist.

Absence of IgG and IgM VCA or the presence of IgG EBNA should make one reconsider the diagnosis of acute EBV infection.

PCR for EBV DNA is useful in the evaluation of malignancies associated with EBV. For instance, detection of EBV DNA in cerebrospinal fluid shows a sensitivity of 90% and specificity of nearly 100% for the diagnosis of primary CNS lymphoma in patients with AIDS, and monitoring of quantitative EBV DNA levels (a “viral load”) in blood may be useful in early detection of posttransplant lymphoproliferative disorder in high-risk patients. PCR analysis may also be helpful in monitoring disease and treatment response in primary CNS lymphoma and posttransplant lymphoproliferative disorder patients. Antibodies against ZEBRA (a replication protein) are produced in early infection and assays for these antibodies are commercially available.

``Differential Diagnosis CMV infection, toxoplasmosis, acute HIV infection, secondary syphilis, HHV-6, rubella, and drug hypersensitivity reactions may be indistinguishable from infectious mononucleosis due to EBV, but exudative pharyngitis is usually absent and the heterophil antibody tests are negative. With acute HIV infection, rash and mucocutaneous ulceration are common but atypical lymphocytosis is much less common. Heterophil-negative infectious mononucleosis with nonsignificant lymphocytosis (especially if rash or mucocutaneous ulcers are present) should prompt investigation for acute HIV infection. Heterophil-negative infectious mononucleosis with atypical lymphocytosis can be caused by CMV, toxoplasmosis and, on occasion,

EBV itself. Mycoplasma infection may also present as pharyngitis, though lower respiratory symptoms usually predominate. A hypersensitivity syndrome induced by carbamazepine or phenytoin may mimic infectious mononucleosis.

The differential diagnosis of acute exudative pharyngitis includes diphtheria, gonococcal and streptococcal infections, and infections with adenovirus and herpes simplex.

Head and neck soft tissue infections (pharyngeal and tonsillar abscesses) may occasionally be mistaken as the lymphadenopathy of mononucleosis.

``Complications Secondary bacterial pharyngitis can occur and is often streptococcal. Splenic rupture (0.5–1%) is a rare but dramatic complication, and a history of preceding trauma can be elicited in 50% of the cases. Acalculous cholecystitis, fulminant hepatitis with massive necrosis, pericarditis and myocarditis are also infrequent complications. Neurologic involvement—including transverse myelitis, encephalitis, and Guillain-Barré syndrome—is infrequent.

``Treatment A. General Measures Over 95% of patients with acute EBV-associated infectious mononucleosis recover without specific antiviral therapy.

Treatment is symptomatic with acetaminophen or other nonsteroidal anti-inflammatory drugs and warm saline throat irrigations or gargles three or four times daily.

Acyclovir decreases viral shedding but shows no clinical benefit. Corticosteroid therapy, although widespread, is not recommended in uncomplicated cases; its use is reserved for impending airway obstruction from enlarged lymph nodes, hemolytic anemia, and severe thrombocytopenia. The value of corticosteroid therapy in impending splenic rupture, pericarditis, myocarditis, and nervous system involvement is less well defined. If a throat culture grows β-hemolytic streptococci, a 10-day course of penicillin or erythromycin is indicated. Ampicillin and amoxicillin are avoided because of the frequent association with rash.

B. Treatment of Complications Hepatitis, myocarditis, and encephalitis are treated symptomatically. Rupture of the spleen requires splenectomy and is most often caused by deep palpation of the spleen or vigorous activity. Patients should avoid contact or collision sports for at least 4 weeks to decrease the risk of splenic rupture (even if splenomegaly is not detected by physical examination which can be insensitive).

``Prognosis In uncomplicated cases, fever disappears in 10 days and lymphadenopathy and splenomegaly in 4 weeks. The debility sometimes lingers for 2–3 months.

Death is uncommon and is usually due to splenic rupture, hypersplenic phenomena (severe hemolytic anemia, thrombocytopenic purpura), or encephalitis.

Viral & Rickettsial Infections

4. Other Epstein–Barr Virus Syndromes EBV viral antigens are found in > 90% of patients with endemic (African) Burkitt lymphoma and nasopharyngeal carcinoma (among whom quantified EBV DNA can be used to follow disease). Risk factors for Burkitt lymphoma include a history of malaria (which may decrease resistance to EBV infection) while risk factors for nasopharyngeal carcinoma include long-term heavy cigarette smoking and seropositive EBV serologies (VCA and deoxyribonuclease [DNase]).

VCA-IgA in peripheral blood is a sensitive and specific predictor for nasopharyngeal carcinoma in endemic areas.

Chronic EBV infection is associated with aberrant cellular immunity (a low frequency of EBV-specific CD8 cells), an X-linked lymphoproliferative syndrome (Duncan disease), lymphomatoid granulomatosis, and a fatal T cell lymphoproliferative disorder in children.

EBV is an important cause of hemophagocytic lymphohistiocytosis among immunodeficient patients, B-cell lymphomas (such as primary CNS lymphoma in HIV-infected individuals), and posttransplant lymphoproliferative disorder. In fact, over 70% of posttransplant lymphoproliferative states are associated with EBV. EBV-naïve patients who receive a donor organ from an EBV-infected donor are at the highest-risk for the development of posttransplant lymphoproliferative disorder. Decreasing the iatrogenic immunosuppression, given to reduce graft rejection, is the initial step in managing such patients, while rituximab (CD20 monoclonal antibody) is effective in treating some cases. The efficacy of rituximab therapy can be often assessed by monitoring levels of EBV DNA load in the blood and, if indicated, CNS. Infusion of EBV-specific cytotoxic T cell lymphocytes (adoptive cell therapy) is also used but with a less established role.

Age is a major determinant of the type of tumor associated with EBV. T and NK cell lymphoma caused by chronic active EBV infections are more frequent in childhood while peripheral T cell lymphomas and diffuse large B cell lymphomas are more common in the elderly due to waning immunity. EBV is also associated with leiomyomas in children with AIDS and with nasal T cell lymphomas.

EBV is often implicated in the pathogenesis of a host of disorders from Hodgkin disease and gastric carcinoma to CNS demyelination, multiple sclerosis, Graves disease, histiocytic necrotizing lymphadenitis (Kikuchi-Fugimoto disease), chronic obstructive pulmonary disease (COPD), rheumatic diseases, and dental disorders (pulpitis and apical periodontitis). EBV was previously linked with the chronic fatigue syndrome but there is no persuasive evidence for an association, nor does there appear to be an association between chronic fatigue syndrome and xenotropic murine leukemia virus-related virus. Oral hairy leukoplakia and its association with EBV are discussed in Chapter 8.

``When to Admit • Acute meningitis, encephalitis, or acute Guillain-Barré syndrome.

• Severe thrombocytopenia.

• Potential splenic rupture.

• • • •

CMDT 2013

1363

Airway obstruction from severe adenitis.

Significant hemolysis.

Pericarditis.

Abdominal findings mimicking an acute abdomen.

Akahori H et al. Graves’ disease associated with infectious mononucleosis due to primary Epstein-Barr virus infection: report of 3 cases. Intern Med. 2010;49(23):2599–603. [PMID: 21139299] Hisamatsu A et al. Gastritis associated with Epstein-Barr virus infection. Intern Med. 2010;49(19):2101–5. [PMID: 20930436] Lucas RM et al. Epstein-Barr virus and multiple sclerosis. J Neurol Neurosurg Psychiatry. 2011 Oct;82(10):1142–8.

[PMID: 21836034] Luzurriaga K et al. Infectious mononucleosis. N Engl J Med. 2010 May 27;362(21):1993–2000. [PMID: 20505178] Parker A et al; Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients– BCSH and BTS Guidelines. Br J Haematol. 2010 Jun; 149(5):675–92. [PMID: 20408847] Sárdy M et al. Genital ulcers associated with Epstein-Barr virus infection (ulcus vulvae acutum). Acta Derm Venereol. 2011 Jan;91(1):55–9. [PMID: 21031278]

5. Cytomegalovirus Disease ``

E sse n t i a l s o f d i a g n o s i s

Mononucleosis-like syndrome.

Frequent pathogen seen in transplant populations. `` Diverse clinical syndromes in HIV (retinitis, esophagitis, pneumonia, encephalitis). `` Major pathogen to consider in neonates in the differential of maternally transmitted agents. `` ``

``General Considerations Most CMV infections are asymptomatic. After primary infection, the virus remains latent in most body cells.

Seroprevalence in adults of Western developed countries is about 60–80% but is higher in developing countries. CMV seroprevalence increases with age, number of sexual partners, history of prior sexually transmitted infections, and low socioeconomic status. The virus can be isolated from a variety of tissues under nonpathogenic conditions.

Transmission occurs through sexual contact, breastfeeding, blood products, or transplantation; it may also occur person-to-person (eg, day care centers) or be congenital. Serious disease occurs primarily in immunocompromised persons.

There are three recognizable clinical syndromes: (1) perinatal disease and CMV inclusion disease; (2) diseases in immunocompetent persons; and (3) diseases in immunocompromised persons. Congenital CMV infection is the most common congenital infection in developed countries (between 0.2% and 2% of all live births, with higher rates in

1364

CMDT 2013

Chapter 32

underdeveloped areas and among lower socioeconomic groups). Transmission is much higher from mothers with primary disease than those with reactivation (40% vs 0.2–1.8%). About 10% of infected newborns will be symptomatic with CMV inclusion disease. In immunocompetent persons, acute CMV infection is the most common cause of the mononucleosis-like syndrome with negative heterophil antibodies. CMV appears to play a role in critically ill immunocompetent adults wherein it is reactivated and associated with prolonged hospitalization and death.

Other syndromes associated with CMV and whose role in pathogenesis requires further elucidation include inflammatory bowel disease, atherosclerosis, cognitive decline, and breast cancer. In immunocompromised persons, tissue and bone marrow transplant patients are mainly at risk for a year after allograft transplantation (but especially during the first 100 days afterward) and in particular when graft-versus-host disease or CMV seropositivity, or both, are present in the donor and recipient. Depending on the serostatus of the donor and recipient, disease may present as primary infection or reactivation. The risk of CMV disease is proportionate to the intensity of immunosuppression. CMV itself is immunosuppressive. CMV may contribute to transplanted organ dysfunction, which often mimics organ rejection. CMV disease in HIV-infected patients (retinitis, serious gastrointestinal disease) occurs most prominently when the CD4 count is < 50 cells/mcL. HAART reduces the frequency of retinitis and may reverse active disease. CMV retinitis may also develop after solid organ or bone marrow transplantation. CMV retinitis associated with intravitreal delivery of corticosteroids (injections or implants) or systemic anti-tumor necrosis factor antibodies is also described. Occasionally, CMV retinitis presents in immunocompetent persons. Serious gastrointestinal CMV disease also occurs after organ transplantation, cancer chemotherapy, or corticosteroid therapy. CMV may exist alongside other pathogens, such as Cryptosporidium, in up to 15% of patients with AIDS cholangiopathy. CMV pneumonitis occurs in transplant recipients (mainly bone marrow and lung) with a mortality rate up to 60–80%, and less often in AIDS patients.

CMV pneumonitis in hematologic malignancies (eg, lymphoma) is increasingly reported. Neurologic CMV in patients with advanced AIDS is usually associated with disseminated CMV infection.

``Clinical Findings A. Symptoms and Signs 1. Perinatal disease and CMV inclusion disease— CMV inclusion disease in infected newborns is characterized by jaundice, hepatosplenomegaly, thrombocytopenia, purpura, microcephaly, periventricular CNS calcifications, mental retardation, and motor disability. Hearing loss develops in > 50% of infants who are symptomatic at birth.

Most infected neonates are asymptomatic, but neurologic deficits may ensue later in life, including hearing loss in 15% and mental retardation in 10–20%. Perinatal infection acquired through breastfeeding or blood products typically shows a benign clinical course.

2. Disease in immunocompetent persons—Acute acquired CMV infection is characterized by fever, malaise, myalgias, arthralgias, and splenomegaly. Exudative pharyngitis or cervical lymphadenopathies are uncommon, but cutaneous rashes (including the typical maculopapular rash after exposure to ampicillin) are common. The mean duration of symptoms is 7–8 weeks. Complications include mucosal gastrointestinal damage, encephalitis, severe hepatitis, thrombocytopenia (on occasion, refractory), the Guillain-Barré syndrome, pericarditis, and myocarditis. The risk of Guillain-Barre syndrome developing after primary CMV infection is estimated to be 0.6–2.2 cases per 1000 primary infection, similar to that seen with Campylo­ bac­ter jejuni infection. The mononucleosis-like syndrome due to CMV can also occur postsplenectomy, often years later and associated with a protracted fever, marked lymphocytosis, and impaired anti-CMV IgM response.

3. Disease in immunocompromised persons—Distinguishing between CMV infection (with evidence of CMV replication) and CMV disease (evidence for systemic symptoms or organ invasion) is important. In addition to patients infected with HIV, those who have undergone transplantation (solid organ or hematopoietic stem cell) show a wide spectrum of disease including gastrointestinal (including acute cholecystitis), renal, and CNS disease, as outlined above. CMV viral loads correlate with prognosis after transplantation.

A. CMV retinitis—A funduscopic examination reveals neovascular, proliferative lesions (“pizza-pie” retinopathy). Immune restoration with HAART is associated with CMV vitritis and cystoid macular edema. Infants with CMV retinitis tend to have more macular than peripheral disease.

B. Gastrointestinal and hepatobiliary CMV— Esophagitis presents with odynophagia. Gastritis can occasionally cause bleeding, and small bowel disease may mimic inflammatory bowel disease or may present as ulceration or perforation. Colonic CMV disease causes diarrhea, hematochezia, abdominal pain, fever, and weight loss and may mimic inflammatory bowel disease. CMV hepatitis commonly complicates liver transplantation and appears to be increased in those with hepatitis B or hepatitis C viral infection.

C. Respiratory CMV—CMV pneumonitis is characterized by cough, dyspnea, and relatively little sputum ­production.

D. Neurologic CMV—Neurologic syndromes associated with CMV include polyradiculopathy, transverse myelitis, ventriculoencephalitis (suspected with ependymitis), and focal encephalitis. These manifestations are more prominent in patients with advanced AIDS in whom the encephalitis has a subacute onset.

B. Laboratory Findings 1. Mothers and newborns—Pregnant women should be tested for IgM CMV antibodies every 3 months if an assay during the first trimester is seropositive. Congenital

Viral & Rickettsial Infections CMV disease is confirmed by presence of the virus in amniotic fluid or an IgM assay from fetal blood.

Amniocentesis is less reliable before 21 weeks of gestation (due to inadequate fetal urinary development and release into the amniotic fluid), but amniocentesis is attendant with greater risk when performed after 21 weeks of gestation. PCR assays of dried blood samples from newborns and micro- enzyme-linked immunosorbent assay (ELISA) on urine, saliva or blood specimens obtained during the first 3 weeks of life are used to diagnose congenital CMV infection.

2. Immunocompetent persons—The acute mononucleosislike syndrome is characterized by initial leukopenia; within 1 week, it is followed by absolute lymphocytosis with atypical lymphocytes. Abnormal liver function tests are common in the first 2 weeks of the disease (often 2 weeks after the fever). Detection of CMV specific IgM or a fourfold increase of specific IgG levels support the diagnosis of acute infection.

3. Immunocompromised persons—CMV retinitis is diagnosed on the basis of the characteristic ophthalmoscopic findings. In HIV-infected patients, negative CMV serologies lower the possibility of the diagnosis but do not eliminate it. Cultures alone are of little use in diagnosing AIDS-related CMV infections, since viral shedding of CMV is common. PCR analysis should be used to diagnose CNS infection since cultures are insensitive.

Detection of pp65 antigen in blood and determination of quantitative CMV antigenemia (“viral load”) by PCR are increasingly used in posttransplant patients for guidance on both treatment and prevention and should be interpreted in the context of clinical and pathologic findings, although full standardization of CMV viral loads is under development.

The PCR is sensitive in predicting clinical disease.

Quantitative PCR of bronchoalveolar lavage fluid seems to be useful for diagnosing CMV pneumonia.

Rapid shell-vial cultures for detection of early CMV antigens with fluorescent antibodies have largely replaced the conventional tube culture (for detection of cytopathic changes) since the time to positivity is greatly reduced (24–48 hours compared to weeks). Shell-vial cultures are more useful on bronchoalveolar lavage fluid than in routine blood monitoring.

A variety of false-positive immunologic assays occur in the setting of acute CMV infections, including positive rheumatoid factor, direct Coombs test, cryoglobulins, and speckled antinuclear antibody.

In gastrointestinal disease, CMV antigenemia is more specific than sensitive.

C. Imaging The chest radiographic findings of CMV pneumonitis are consistent with interstitial pneumonia.

D. Biopsy Tissue confirmation is especially useful in diagnosing CMV pneumonitis and CMV gastrointestinal disease; the

CMDT 2013

1365

diagnosis of colonic CMV disease is made by mucosal biopsy showing characteristic CMV histopathologic findings of intranuclear (“owl’s eye”) and intracytoplasmic inclusions.

``Treatment Sight-threatening CMV retinitis (lesions close to the fovea or optic nerve head) is treated with ganciclovir induction therapy (5 mg/kg intravenously every 12 hours for 14–21 days) followed by maintenance therapy at lower doses (5 mg/kg intravenously daily). Sustained-release ganciclovir intraocular implants (always accompanied by systemic valganciclovir) are another option. In less severe retinal disease, valganciclovir (900 mg orally twice daily for 14–21 days followed by 900 mg/d maintenance) is preferred. Due to potential toxicities, foscarnet, cidofovir, and fomivirsen are usually reserved for CMV infections that are resistant to ganciclovir. Combinations of ganciclovir and foscarnet are shown to be safe and effective in treating clinically resistant CMV retinitis. The role of HAART in reducing the need for CMV antiviral agents is essential. Other forms of CMV disease in AIDS are managed initially with intravenous ganciclovir and subsequently with oral valganciclovir; alternative agents (listed above) are used when resistance evolves.

The treatment of other systemic CMV infection (colitis, encephalitis, pneumonia) involves the use of the main antiviral agents used in CMV retinitis. The length of therapy depends on the state of immunosuppression, and secondary prophylaxis is typically maintained until immune restoration is present for at least 6 months. Prolonged prophylaxis may be necessary in other immunosuppressed patients, such as those receiving tumor necrosis factor (TNF) inhibitors.

For non-severe, posttransplant CMV disease, oral valganciclovir (900 mg twice daily) or intravenous ganciclovir (5 mg/kg every 12 hours) are the recommended first-line agents. Valganciclovir has been shown to be noninferior to intravenous ganciclovir-based therapy in solid organ transplant patients and is associated with less clinical resistance than ganciclovir. For severe CMV disease, intravenous ganciclovir remains the treatment of choice. Dosage adjustments of all medications are needed for kidney dysfunction. Reduction of immunosuppression should be attempted when possible (especially for muromonab, azathioprine, or mycophenolate mofetil). Treatment should be continued for at least 2 weeks until viral eradication is achieved. Two consecutive negative samples of CMV quantitative analysis testing or antigenemia based assay ensure viral clearance. Other agents that may be useful in resistant CMV infections include leflunomide, sirolimus-based therapy, and artesunate. Adoptive immunotherapy is also under study.

In pregnant women with primary CMV infection, passive immunization with hyperimmune globulin appears preliminarily to be effective in both treatment and prevention of fetal infection, but controlled clinical trials are lacking. While CMV immunoglobulin is also used in the

1366

CMDT 2013

Chapter 32

treatment of CMV pneumonia in stem cell transplant recipients, its efficacy is not completely established.

``Prevention A CMV glycoprotein B with MF59 adjuvant vaccine is currently under development. Phase 2 studies show vaccine efficacy of 50% in preventing congenital disease as well as increased antibody titers compared to placebo in seronegative and seropositive transplant recipients and in a population of CMV infected women.

HAART is effective in preventing CMV infections in HIV-infected patients. Use of leukocyte-depleted blood products effectively reduces the incidence of CMV disease in patients who have undergone transplantation.

Prophylactic and preemptive strategies (eg, antiviral agents only when antigen detection or PCR assays show evidence of active CMV replication) are effective in preventing disease in the early transplantation period but are associated with a risk of a late-onset form of the disease after the prophylaxis is discontinued. The appropriate management of transplant patients is based on the serostatus of the donor and the recipient. All effective anti-CMV agents can serve as prophylactic agents for CMV-seropositive transplants or for CMV-seronegative recipients of CMV-positive organ transplants. A recent meta-analysis shows that valganciclovir prophylaxis at a lower dose (450 mg orally twice daily vs 900 mg orally twice daily) is equally effective in solid organ transplant patients with less risk of leukopenia and rejection. CMV immune globulin may also be useful in reducing the incidence of bronchiolitis obliterans in the bone marrow transplant population and is used in some centers as part of the prophylaxis in kidney, liver, and lung transplantation patients. CMV immune globulin as prophylaxis is not recommended in hematopoietic stem cell transplant recipients.

Withdrawal of infected children from day care centers, reduction of patient contact by health care workers, screening for women of childbearing age, or restrictions to breastfeeding are not recommended because the virus is ubiquitous.

``When to Refer • Neonatal infections consistent with CMV inclusion disease.

• AIDS patients with retinitis, esophagitis, colitis, hepatobiliary disease, or encephalitis.

• Organ and hematopoietic stem cell transplants with suspected reactivation CMV.

``When to Admit • Risk of colonic perforation.

• Evaluation of unexplained, advancing encephalopathy.

• Biopsy of tissues in the differential diagnosis of transplant rejection vs infection.

• Initiation of treatment with intravenous anti-CMV agents.

Cannon MJ et al. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010 Jul;20(4):202–13. [PMID: 20564615] Griffiths PD et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011 Apr 9;377(9773):1256–63.

[PMID: 21481708] Kalil AC et al. Effectiveness of valganciclovir 900 mg versus 450 mg for cytomegalovirus prophylaxis in transplantation: direct and indirect treatment comparison meta-analysis. Clin Infect Dis. 2011 Feb 1;52(3):313–21. [PMID: 21189424] Kotton CN et al; Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010 Apr 15;89(7):779–95. [PMID: 20224515] Orlikowski D et al. Guillain-Barré syndrome following primary cytomegalovirus infection: a prospective cohort study. Clin Infect Dis. 2011 Apr 1;52(7):837–44. [PMID: 21427390] Sabbaj S et al. Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. J Infect Dis. 2011 Jun 1;203(11): 1534–41. [PMID: 21592981]

6. Human Herpesviruses 6, 7, & 8 HHV-6 is a B cell lymphotropic virus that is the principal cause of exanthema subitum (roseola infantum, sixth disease). Primary HHV-6 infection occurs most commonly in children under 2 years of age and is a major cause of infantile febrile seizures. HHV-6 is also associated with encephalitis (symptoms may include insomnia, seizures, and hallucinations) and with acute liver failure. Primary infection in immunocompetent adults is rare and can produce a mononucleosis-like illness. Reactivation of HHV-6 in immunocompetent adults is rare and can present as encephalitis.

Imaging studies in HHV-6 encephalitis typically show lesions in the hippocampus, amygdala, and limbic structures.

Infection during pregnancy and congenital transmission is recognized. Most cases of reactivation, however, occur in immunocompromised persons. Reactivation is associated with graft rejection, graft-versus-host disease, and bone marrow suppression in transplant patients and with encephalitis and pneumonitis in AIDS patients and in recipients of hematopoietic cell transplants. HHV-6 is on occasion also associated with drug-induced hypersensitivity syndromes that may evolve into diabetes mellitus.

The roles of HHV-6 in multiple sclerosis, chronic fatigue syndrome, certain malignancies, myocarditis and progressive multifocal leukoencephalopathy remain unproven.

HHV-6 may cause fulminant hepatic failure and acute decompensation of chronic liver disease in children.

Purpura fulminans is reported rarely with HHV-6 infection. Recent studies suggest that HHV-6 can cause corneal inflammation.

Two variants (A and B) of HHV-6 have been identified.

HHV-6B is the predominant strain found in both normal and immunocompromised persons. Ganciclovir, cidofovir, and foscarnet (but not acyclovir) appear to be clinically active against HHV-6.

HHV-7 is a T cell lymphotropic virus that is associated with roseola (serologically), seizures and, rarely, encephalitis. Pregnant women are often infected. Infection with

Viral & Rickettsial Infections HHV-7 is synergistic with CMV in kidney transplant recipients. The membrane glycoprotein CD4 is involved in HHV-7 recognition, but a clinical interaction between HHV-7 and HIV is not established.

HHV-8 is associated with Kaposi sarcoma, multicentric Castleman disease, and primary effusion (body cavity) lymphoma. HHV-8 infection is endemic in Africa; transmission seems to be primarily horizontal in childhood from intrafamilial contacts and continues through adulthood possibly by nonsexual routes. An association between HHV-8 and the development of systemic lupus erythematosus is under study. See Chapter 31 for pathogenesis and management.

Butler LM et al. Human herpesvirus 8 infection in children and adults in a population-based study in rural Uganda. J Infect Dis. 2011 Mar 1;203(5):625–34. [PMID: 21273188] Ogata M. Human herpesvirus 6 in hematological malignancies. J Clin Exp Hematop. 2009 Nov;49(2):57–67. [PMID: 19907110] Okuno T et al. Role of human herpes virus 6 in corneal inflammation alone or with human herpesviruses. Cornea. 2011 Feb;30(2):204–7. [PMID: 20847652] Sun Y et al. Prevalence of human herpesvirus 8 infection in systemic lupus erythematosus. Virol J. 2011 May 9;8:210.

[PMID: 21549013]

MAJOR VACCINE-PREVENTABLE VIRAL INFECTIONS1 1. Measles ``

E sse n t i a l s o f d i a g n o s i s

Exposure 10–14 days before onset in an unvaccinated patient. `` Prodrome of fever, coryza, cough, conjunctivitis, malaise, irritability, photophobia, Koplik spots. `` Rash: brick-red, irregular, maculopapular; onset 3–4 days after onset of prodrome; begins on the face and proceeds “downward and outward,” affecting the palms and soles last. `` Leukopenia. ``

``General Considerations Measles is a reportable acute systemic paramyxoviral infection transmitted by inhalation of infective droplets. It is a major worldwide cause of pediatric morbidity and mortality, although vaccination programs successfully reduced this number from nearly 750,000 deaths in 2000 to an estimated 164,000 in 2008. The case numbers increased in 2011 with over 28,000 cases reported in Europe (high risk groups include the Roma, travelers, immigrants, and Orthodox Jews) with the largest number from France. The 1

A general guide for vaccine preventable diseases is available at www.who.int/vaccines-documents/

CMDT 2013

1367

214 US measles cases as of October 2011 included 73 (34%) importations (France and India were the leading source countries).

Illness confers permanent immunity. It is highly contagious and communicability is greatest during the preeruptive and catarrhal stages but continues as long as the rash remains. Despite high community vaccination coverage, rising rates of intentional undervaccination lead to sporadic outbreaks among clusters of intentionally undervaccinated children and can undermine measles elimination programs. Therefore, laboratory testing and confirmation of suspected measles infection is especially important in countries that report the elimination of measles. Sporadic outbreaks of the disease in adults, adolescents, and unvaccinated preschool children in dense urban areas, and sporting event participants emphasize the need for specific recommendations concerning prevention (see below).

In the United States, measles was declared eliminated in 2000. The few reported cases since then are largely imported and geographically dispersed, and the associated isolates fail to show a recurrent strain. Immigrants and refugees can show serosusceptibility rates to measles in excess of 35%.

``Clinical Findings A. Symptoms and Signs Fever is often as high as 40–40.6 °C. It persists through the prodrome and early rash (about 5–7 days) (Table 32–2).

Malaise may be marked. Coryza (nasal obstruction, sneezing, and sore throat) resembles that seen with upper respiratory infections. Cough is persistent and nonproductive.

Conjunctivitis manifests as redness, swelling, photophobia, and discharge. These symptoms intensify over 2–4 days before onset of the rash and peak on the first day of the rash.

Koplik spots (small, irregular, and red with whitish center on the mucous membranes) are pathognomonic of measles. They appear about 2 days before the rash and last 1–4 days as tiny “table salt crystals” in the buccal mucosa opposite the molars and vaginal membranes. The rash usually appears on the face and behind the ears 4 days after the onset of symptoms. The initial lesions are pinhead-sized papules that coalesce to form a brick-red, irregular, blotchy maculopapular rash. In severe cases, the rash coalesces to form a nearly uniform erythema in some areas. The rash next appears on the trunk, followed by the extremities, including the palms (25–50% of those infected) and soles.

The rash lasts for 3–7 days and fades in the same manner it appeared. Hyperpigmentation remains in fair-skinned individuals and severe cases. Slight desquamation may follow.

Other findings in measles include pharyngeal erythema, tonsillar yellowish exudate, coating of the tongue in the center with a red tip and margins, moderate generalized lymphadenopathy and, at times, splenomegaly.

Atypical measles is a syndrome occurring in adults who received inactivated measles vaccine (1963–1968) or who received live measles vaccine before age 12 months and as a result developed hypersensitivity rather than protective immunity. Infection later in life with wild measles

1368

CMDT 2013

Chapter 32

virus can lead to a potentially fatal illness with high fever; unusual rashes (papular, hemorrhagic), most prominent on the extremities, without Koplik spots; headache; arthralgias; hepatitis; a high rate of pneumonitis, and sometimes pleural effusions. Atypical measles cases show unusually high hemagglutinin-inhibition titers. Measles may be distinctive in HIV-infected individuals, with higher rates of pneumonitis, higher mortality, prolonged viral shedding, and higher vaccine failure rates. Measles during pregnancy is not known to cause congenital abnormalities of the fetus. It is, however, associated with spontaneous abortion and premature delivery and can cause severe disease in the mother. Although measles does not always develop in the offspring of mothers with the disease, it can be severe when it does. It is recommended that infants born to such mothers be passively immunized with immunoglobulin at birth.

The virologic clearance of measles can take months.

B. Laboratory Findings Leukopenia is usually present unless secondary bacterial complications exist. A lymphocyte count under 2000/mcL is a poor prognostic sign. Thrombocytopenia is common.

Proteinuria is often observed. Although technically difficult, virus can be cultured from nasopharyngeal washings and from blood. Detection of IgM measles antibodies with ELISA or a fourfold rise in serum hemagglutination inhibition antibody supports the diagnosis. Fluorescent antibody staining of respiratory or urinary epithelial cells can also confirm the diagnosis.

IgM assays can be falsely negative the first few days of infection and falsely positive in the presence of rheumatoid factor or with acute rubella, erythrovirus (parvovirus) B19, or HHV-6 infection. White reverse transcriptase-PCR techniques, typically available in research settings, can help establish a diagnosis; the persistence of the virus for months after an acute infection can lead to false positive results.

occur after measles vaccination in patients with inadequate cellular immunity but is associated with isolation of the measles virus.

Subacute sclerosing panencephalitis (SSPE) is a very late CNS complication (5–15 years after infection; the measles virus acts as a “slow virus” to produce degenerative CNS disease years after the initial infection. SSPE is rare (1:100,000 cases of measles) and occurs more often when measles develops early in life among males who live in rural environments. SSPE very rarely develops in adults.

Measles virus can opportunistically invade the CNS. An acute progressive encephalitis (subacute measles encephalitis), characterized by seizures, neurologic deficits, and often progressive stupor and death, can occur among immunosuppressed patients. Treatment is supportive, withholding immunosuppressive chemo­ therapy when feasible. Interferon and ribavirin are variably successful.

B. Respiratory Tract Disease Early in the course of the disease, bronchopneumonia or bronchiolitis due to the measles virus may occur in up to 5% of patients and result in serious respiratory difficulties. Bronchiectasis may occur in up to a quarter of non­ vaccinated children. Pneumonia occurring with or without an evanescent rash is seen in atypical measles.

C. Secondary Bacterial Infections Immediately following measles, secondary bacterial infection, particularly cervical adenitis, otitis media (the most common complication), and pneumonia, occurs in about 15% of patients.

D. Immune Reactivity Measles produces temporary anergy to cell-mediated skin tests.

``Differential Diagnosis

E. Gastroenteritis

Measles is usually diagnosed clinically but may be mistaken for other exanthematous infections (see Table 32–2).

Frequent difficulty in establishing a diagnosis suggests that measles may be more prevalent than is recognized.

Diarrhea and protein-losing enteropathy (prodromal rectal Koplik spots may be seen) are significant complications among malnourished children.

``Complications

Other complications include conjunctivitis, keratitis, and otosclerosis.

A. Central Nervous System Postinfectious encephalomyelitis occurs in about 0.05–0.1% of cases. Higher rates of encephalitis occur in adolescents and adults than in school-aged children. Its onset is usually 3–7 days after the rash. Vomiting, convulsions, coma, and diverse, severe neurologic symptoms and signs may develop.

Treatment is symptomatic and supportive. Virus is usually not found in the CNS, though demyelination is prominent.

There is an appreciable mortality (10–20%) and morbidity (33% of survivors are left with neurologic deficit).

A similar form, “inclusion body encephalitis,” occurs months after exposure. This complication is reported to

F. Other Complications

``Treatment A. General Measures The patient should be isolated for the week following onset of rash and kept at bed rest until afebrile. Treatment is symptomatic including antipyretics and fluids as needed.

Vitamin A, 200,000 units/d orally for 2 days (the benefit being maintenance of gastrointestinal and respiratory epithelial mucosa), reduces pediatric morbidity (diarrhea, night blindness, xerophthalmia) and measles-associated mortality for infants between 6 months and 5 years of age,

Viral & Rickettsial Infections although high-dose vitamin A exposure increases the severity and risk of antibiotic failure in non-measles pneumonia. Measles virus is susceptible to ribavirin in vitro and has been used in selected severe cases of pneumonitis (35 mg/kg/d intravenously in three divided doses for 2 days, followed by 20 mg/kg/d intravenously in three divided doses for 5 days).

B. Treatment of Complications Secondary bacterial infections, including pneumonia, are treated with appropriate antibacterial antibiotics. Post­ measles encephalitis, including SSPE, can be managed only symptomatically.

Repeated studies fail to show an association between vaccination and autism. The prevalence of asthma-like diseases in childhood appears to be reduced among vaccinated children. Some data implicate the measles virus in the pathogenesis of rheumatoid arthritis.

``Prognosis Between 1999 and 2005, measles mortality rate was reduced an estimated 60%. In the last decade, the case-fatality rate in the United States stayed around 3 per 1000 reported cases, with deaths principally due to encephalitis (15% mortality rate) and secondary bacterial pneumonia. Deaths in the developing world are mainly related to diarrhea and protein-losing enteropathy.

``Prevention In the United States, children receive their first vaccine dose at 12–15 months and a second at age 4–6 years prior to entry into school. Combination measles-mumps-­ rubella-varicella vaccines (MMRV) can be used in place of the traditional measles, mumps, and rubella (MMR) vaccine. Recent outbreak data suggest that the efficacy of the vaccine persists longer if the first vaccination is given at a later age (eg, 15 months). The evidence is not convincing that routine anthelmintic treatment affects the immune response to childhood vaccination.

American students beyond high school and medical staff starting employment require documentation of the above vaccination schedule or must show serologic evidence of immunity if they were born after 1956. For individuals born before 1957, herd immunity is assumed.

Health care workers, immigrants, and refugees should be screened and vaccinated if necessary regardless of date of birth. International travelers (if immunocompetent and born after 1956) to the developing world and teachers should receive booster doses of vaccination.

At 6 months of age, more than 99% of infants of vaccinated women and 95% of infants of naturally immune women lose maternal antibodies. Therefore, in outbreaks that include infants under 1 year of age, initial vaccination may be given at 6 months, with repeat at 15 months. When outbreaks take place in day care centers, K–12 institutions, or colleges and universities, revaccination is probably indicated for all, in particular for students and their siblings

CMDT 2013

1369

born after 1956 who do not have documentation of immunity as defined above. Susceptible personnel who were exposed should be isolated from patient contact between the fifth and the twenty-first day after exposure regardless of whether they were vaccinated or given immune globulin.

If measles develops in these persons, they should be isolated from patient contact until 7 days after the rash develops.

When susceptible individuals are exposed to measles, live virus vaccine can prevent disease if given within 5 days of exposure. In addition, immune globulin (0.25 mL/kg [0.11 mL/lb] body weight) can be injected intramuscularly for prevention or modification of clinical illness if given within 6 days after exposure. This must be followed by active immunization with live measles vaccine 3 months later. Vaccination of all immunocompetent persons born after 1956 who travel to the developing world is important. In the developing world, the use of a second vaccine dose is an important aspect of achieving control of measles in the community.

Pregnant women and immunosuppressed persons should not receive this vaccine. Exception to this contraindication is asymptomatic HIV-infected patients, including children, who have not shown adverse effects from measles vaccination. In asymptomatic HIV-infected children, vaccination improves survival after measles, and HAART therapy is associated with an improved vaccine response.

Repeat vaccination may be necessary in HIV-infected children after immune restoration. Immune globulin should be administered within 6 days of exposure for postexposure prophylaxis in any high-risk person exposed to measles. Such high-risk persons include children with malignancy and patients with AIDS who are at risk for developing severe or fatal disease.

Severe allergic reactions including anaphylaxis to the MMR vaccine are rare, though fever and rash appear to occur slightly more often among female recipients.

Quadrivalent MMRV vaccine is associated with an increased risk of seizures that appears to be age-related; the risk is highest when MMRV is given to infants under 15 months of age. An aerosolized measles vaccine remains under study.

Future vaccines for a variety of infectious agents may utilize measles vectors, thereby augmenting immunity to measles.

Rare cases of post-immunization encephalitis represent a form of acute disseminated encephalomyelitis (which can occur after many other vaccines including rabies, DPT, smallpox, and hepatitis B virus vaccinations).

``When to Refer • Any suspect cases should be reported to public health authorities.

• HIV infection.

• Pregnancy.

``When to Admit • Meningitis, encephalitis, or myelitis.

• Severe pneumonia.

• Diarrhea that significantly compromises fluid or electrolyte status.

1370

CMDT 2013

Chapter 32

Leuridan E et al. Early waning of maternal measles antibodies in era of measles elimination: longitudinal study. BMJ. 2010 May 18;340:c1626. [PMID: 20483946] Mayo-Wilson E et al. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ. 2011 Aug 25;343: d5094. [PMID: 21868478] Moss WJ et al. Biological feasibility of measles eradication. J Infect Dis. 2011;204(1):S47–53. [PMID: 21666201] Omer SB et al. Vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases. N Engl J Med. 2009 May 7;360(19):1981–8. [PMID: 19420367] Sever AE et al. Measles elimination in the Americas: a comparison between countries with a one-dose and two-dose routine vaccination schedule. J Infect Dis. 2011 Sep;204(Suppl 2): S748–55. [PMID: 21954277] Webb EL et al. Effect of single-dose anthelmintic treatment during pregnancy on an infant’s response to immunization and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial. Lancet. 2011 Jan 1;377(9759):52–62. [PMID: 21176950]

2. Mumps ``

s Figure 32–5. Mumps. (Public Health Image Library, CDC.)

E sse n t i a l s o f d i a g n o s i s

Exposure 14–21 days before onset.

Painful, swollen salivary glands, usually parotid. `` Frequent involvement of testes, pancreas, and meninges in unvaccinated individuals. `` ``

``General Considerations Mumps is a paramyxoviral disease spread by respiratory droplets. Children are the age group most affected, al­though in some outbreaks, patients are in the late second or early third decades of life. Mumps can spread rapidly in congregate settings, such as colleges and schools. The incidence is highest in spring. The incubation period is 14–21 days (average, 18 days). Infectivity occurs via saliva and urine and precedes the symptoms by about 1 day and is maximal for 3 days, although it may last a week. Up to onethird of affected individuals have subclinical infection. In 2006, an outbreak of mumps in the United States occurred and involved over 6000 persons; 85% of these cases were reported from eight Midwestern states. More recent mumps outbreak involved 1521 cases at a summer camp in New York (2009) and 134 cases among mostly undervaccinated boys in Ontario (2010). In recent seroprevalence studies of mumps antibody, the highest rates were seen in US-born Americans of African and Hispanic (Mexican-born) ancestry, reflecting perhaps immunity associated with natural infection.

``Clinical Findings A. Symptoms and Signs Mumps is more serious in adults than in children. Parotid tenderness and overlying facial edema (Figure 32–5) are

the most common physical findings and typically develop within 48 hours of the prodromal symptoms. Usually, one parotid gland enlarges before the other, but unilateral parotitis alone occurs in 25% of patients. The orifice of Stensen duct may be red and swollen. Trismus may result from parotitis. The parotid glands return to normal within a week. Involvement of other salivary glands (submaxillary and sublingual) occurs in 10% of cases.

Fever and malaise are variable but often minimal in young children. High fever accompanies meningitis or orchitis. Neck stiffness, headache, and lethargy suggest meningitis. Testicular swelling and tenderness (unilateral in 75% of cases) denote orchitis; the testes are the most common extrasalivary site of disease in adults. Orchitis develops 7–10 days after the onset of parotitis in about 25–40% of postpubertal men, but sterility is rare. Acute hormonal disturbances are prevalent, including decreased levels of testosterone and inhibin B with low or normal levels of gonadotropins in up to 35% cases with mumps orchitis. Upper abdominal pain, nausea, and vomiting suggest pancreatitis. Mumps is the leading cause of pancreatitis in children. Lower abdominal pain and ovarian enlargement suggest oophoritis (which occurs in 5% of postpubertal women, usually unilateral); it is a difficult diagnosis to establish.

B. Laboratory Findings Mild leukopenia with relative lymphocytosis may be present.

Serum amylasemia usually reflects salivary gland involvement rather than pancreatitis. Lymphocytic pleocytosis and hypoglychorrhachia of the cerebrospinal fluid in meningitis may be asymptomatic. Mild kidney function abnormalities are found in up to 60% of patients.

Characteristic clinical picture is usually sufficient for diagnosis. An elevated serum IgM is considered diagnostic

Viral & Rickettsial Infections and a repeat test 2–3 weeks after the onset of symptoms is recommended if the first assay is negative due to a delay in IgM rise, especially in vaccinated persons. A fourfold rise in complement-fixing antibodies to mumps virus in paired serum IgG also confirms infection. Confirmatory diagnosis of mumps is also made by isolating the virus preferably from a swab of the duct of the parotid or other affected salivary gland. The virus can also be isolated from cerebrospinal fluid early in the course of aseptic meningitis.

Isolation from urine is no longer advised. Nucleic acid amplification techniques are more sensitive than viral cultures but their availability is limited.

``Differential Diagnosis Swelling of the parotid gland may be due to calculi in the parotid ducts, tumors, or cysts, or to a reaction to iodides.

Other causes include starch ingestion, sarcoidosis, cirrhosis, diabetes, bulimia, pilocarpine usage, and Sjögren syndrome. Parotitis may be produced by pyogenic organisms (eg, S aureus, gram-negative organisms), particularly in debilitated individuals with poor oral intake, drug reaction (phenothiazines, propylthiouracil), and other viruses (influenza A, parainfluenza, EBV infection, coxsackie­ viruses, adenoviruses, HHV-6). Swelling of the parotid gland must be differentiated from inflammation of the lymph nodes located more posteriorly and inferiorly than the parotid gland.

``Complications Other manifestations of the disease are less common and usually follow parotitis but may precede it or occur without salivary gland involvement. Such manifestations include meningitis (30%), orchitis (which on rare occasion leads to priapism or testicular infarction), pancreatitis (usually mild), oophoritis, thyroiditis, neuritis, hepatitis, myocarditis, thrombocytopenia, migratory arthralgias (noted infrequently among adults and rarely in children), and nephritis. Mumps has also been associated with cases of endocardial fibroelastosis.

Rare neurologic complications include encephalitis, Guillain-Barré syndrome, cerebellar ataxia, facial palsy, and transverse myelitis. Encephalitis is associated with cerebral edema, serious neurologic manifestations, and sometimes death. Deafness from eighth nerve neuritis develops in about 0.1%; it is typically unilateral, severe, and permanent.

``Treatment A. General Measures The patient should be isolated until swelling subsides (about 9 days from onset) and kept on bed rest while febrile. Treatment is symptomatic. Topical compresses may relieve parotid discomfort. Some clinicians advocate intravenous immunoglobulin (IVIG) for complicated disease (eg, thrombocytopenia) although its definitive role is unproven.

CMDT 2013

1371

B. Management of Complications 1. Aseptic meningitis—The treatment is symptomatic.

The management of encephalitis requires attention to cerebral edema, the airway, and vital functions.

2. Epididymo-orchitis—The scrotum should be supported with a suspensor or toweling “bridge” and ice bags applied. Incision of the tunica may be necessary in severe cases. Pain can be relieved with opioids, or by injecting the spermatic cord at the external inguinal ring with 10–20 mL of 1% procaine solution. The merit of hydrocortisone sodium succinate (100 mg intravenously, followed by 20 mg orally every 6 hours for 2 or 3 days) in reducing inflammation is not firmly established.

Interferon alfa-2b may be useful in preventing testicular atrophy.

3. Pancreatitis—Symptomatic treatment should be provided, with emphasis on parenteral hydration.

``Prognosis The entire course of mumps rarely exceeds 2 weeks. Rare fatalities are usually due to encephalitis.

``Prevention Mumps live virus vaccine is safe and effective (there is some variability among vaccines, the Jeryl Lynn strain being highly effective, the Urabe intermediate, the Rubini less so) with long lasting immunity. It is recommended for routine immunization for children over age 1 year, either alone or in combination with other virus vaccines (eg, in the MMR vaccine or as a quadrivalent vaccine with varicella). A second dose is recommended for children (ages 4–6 years) before starting school.

(In recent outbreaks from Canada and Scotland, cases disproportionately included those who received only one dose of the vaccine.) Two doses of the vaccine should also be considered for high-risk individuals (eg, health care workers) born before 1957 and without evidence of immunity. There are no known cases of longterm sequelae associated with mumps vaccination and the currently used mumps strain (Jeryl Lynn) shows the lowest associated incidence of post vaccine aseptic meningitis (from 1 in 150,000 to 1 in 1.8 million). This vaccine is less effective in epidemic settings. Reactions are reviewed in the measles section. It should not be given to pregnant women or to immunocompromised individuals, though the vaccine has been given to asymptomatic HIV-infected individuals without adverse sequelae, especially when the individuals are taking HAART. In the developed world, persons in whom mumps develops are less likely to have received a second vaccine dose. The mumps skin tests are less reliable than serum neutralization titers in determining immunity.

``When to Refer Any suspect cases should be reported to public health authorities.

1372

CMDT 2013

Chapter 32

``When to Admit • Trismus.

• Meningitis, encephalitis.

• Severe abdominal pain or vomiting suggesting ­pancreatitis.

• Severe testicular pain.

• Priapism.

• Severe thrombocytopenia.

• Myocarditis.

Centers for Disease Control and Prevention (CDC). Update: mumps outbreak—New York and New Jersey, June 2009–­ January 2010. MMWR Morb Mortal Wkly Rep. 2010 Feb 12; 59(5):125–9. [PMID: 20150887] Deeks SL et al. An assessment of mumps vaccine effectiveness by dose during an outbreak in Canada. CMAJ. 2011 Jun 14;183(9):1014–20. [PMID: 21576295] Kutty PK et al. Seroprevalence of antibody to mumps virus in the US population, 1999–2004. J Infect Dis. 2010 Sep 1; 202(5): 667–74. [PMID: 20662720] Smith PJ et al. The association between intentional delay of vaccine administration and timely childhood vaccination coverage. Public Health Rep. 2010 Jul–Aug;125(4):534–41. [PMID: 20597453]

3. Poliomyelitis ``

E sse n t i a l s o f d i a g n o s i s

Incubation period 9–12 days from exposure.

Muscle weakness, headache, stiff neck, fever, nausea and vomiting, sore throat. `` Lower motor neuron lesion (flaccid paralysis) with decreased deep tendon reflexes and muscle wasting. `` Cerebrospinal fluid shows lymphocytic pleocytosis but rarely > 500/mcL. `` ``

``General Considerations Poliomyelitis virus, an enterovirus, is present in throat washings and stools (excretion may last for weeks after infection). It is highly contagious through fecal–oral route, especially during the first week of infection. By 2005, because of global vaccination efforts, indigenous transmission of wild poliovirus (WPV) types 1 and 3 were eliminated from all but four countries (Afghanistan, India, Nigeria, and Pakistan) and no cases of WPV type 2 were reported since 1999, although a case was reported in 2011 of a woman with combined variable immunodeficiency who acquired type 2 poliomyelitis in Minnesota nearly 12 years after her child was given the oral vaccination. As of October 2011, a total of 467 cases of WPV infection were reported (down from 350,000 in 1988) from 11 countries with 47% of cases in endemic countries of Afghanistan,

India, Nigeria, and Pakistan, with reactivation of the ­outbreak in the Democratic Republic of the Congo and Chad, and new outbreaks in the Central African Republic, China, Mali, Kenya, Guinea, Cote d’Ivoire, and Nigeria.

India is down to a single case this year. The largest number of cases is being reported currently from Pakistan, Chad, and the Democratic Republic of the Congo. The last major outbreak in the Western Hemisphere occurred in Hispaniola (Haiti and the Dominican Republic) from 2000 to 2001. An ongoing outbreak of type 2 VDPV in Nigeria is reportedly the largest to date and is unique in occurring in the presence of extensive transmission of indigenous type 1 and 3 WPV.

``Clinical Findings A. Symptoms and Signs At least 95% of infections are asymptomatic, but in those who become ill, manifestations include abortive poliomyelitis (minor illness), nonparalytic poliomyelitis, and paralytic poliomyelitis.

1. Abortive poliomyelitis (minor illness)—Such minor illness occurs in 4–8% of infections and the symptoms are fever, headache, vomiting, diarrhea, constipation, and sore throat lasting 2–3 days. This entity is suspected clinically only during an epidemic.

2. Nonparalytic poliomyelitis—In addition to the above symptoms, signs of meningeal irritation and muscle spasm occur in the absence of frank paralysis. This disease is indistinguishable from aseptic meningitis caused by other viruses.

3. Paralytic poliomyelitis—Paralytic poliomyelitis represents 0.1% of all poliomyelitis cases (the incidence is higher when infections are acquired later in life). Paralysis may occur at any time during the febrile period. Tremors, muscle weakness, constipation, and ileus may appear.

Paralytic poliomyelitis is divided into two forms, which may coexist: (1) spinal poliomyelitis, with involvement of the muscles innervated by the spinal nerves, and (2) bulbar poliomyelitis, with weakness of the muscles supplied by the cranial nerves (especially nerves IX and X) and of the respiratory and vasomotor centers.

In spinal poliomyelitis, paralysis of the shoulder girdle often precedes intercostal and diaphragmatic paralysis, which leads to diminished chest expansion and decreased vital capacity. The paralysis occurs over 2–3 days, is flaccid, has an asymmetric distribution, and affects the proximal muscles of the lower extremities more frequently. Sensory loss is very rare.

In bulbar poliomyelitis, symptoms include diplopia (uncommonly), facial weakness, dysphagia, dysphonia, nasal voice, weakness of the sternocleidomastoid and trapezius muscles, difficulty in chewing, inability to swallow or expel saliva, and regurgitation of fluids through the nose. The most life-threatening aspect of bulbar poliomyelitis is respiratory paralysis. Lethargy or coma may be due to hypoxia, most often from hypoventilation. Vasomotor disturbances in blood pressure and heart rate may occur.

Viral & Rickettsial Infections Convulsions are rare. Bulbar poliomyelitis is more common in adults.

B. Laboratory Findings The peripheral white blood cell count may be normal or mildly elevated. Cerebrospinal fluid pressure and protein are normal or slightly increased. Glucose is not decreased.

White blood cells usually number < 500/mcL and are principally lymphocytes after the first 24 hours. Cerebrospinal fluid is normal in 5% of patients. The virus may be recovered from throat washings (early) and stools (early and late). Neutralizing and complement-fixing antibodies appear during the first or second week of illness. Serologic testing cannot distinguish between wild-type and vaccinerelated virus infections.

``Differential Diagnosis Nonparalytic poliomyelitis is similar to other forms of enteroviral meningitis; the distinction is made serologically. Acute flaccid paralysis is the term used in the developing world for the variety of neurologic illnesses that both include and mimic poliomyelitis. Acute flaccid paralysis due to poliomyelitis is distinguished by the greater frequency of fever and asymmetric neurologic signs. Acute inflammatory polyneuritis (Guillain-Barré syndrome), Japanese B virus encephalitis, West Nile virus infection, and tick paralysis may resemble poliomyelitis. In GuillainBarré syndrome (see Chapter 24), the weakness is more symmetric and ascending in most cases, but the Miller Fisher variant is quite similar to bulbar polio. Paresthesias are uncommon in poliomyelitis but common in GuillainBarré syndrome. The cerebrospinal fluid usually has high protein content but normal cell count in Guillain-Barré syndrome.

``Complications Urinary tract infection, atelectasis, pneumonia, myocarditis, paralytic ileus, gastric dilation, and pulmonary edema may occur. Respiratory failure may be a result of paralysis of respiratory muscles, airway obstruction from involvement of cranial nerve nuclei, or lesions of the respiratory center.

``Treatment In the acute phase of paralytic poliomyelitis patients should be hospitalized. Strict bed rest in the first few days of illness reduces the rate of paralysis. Comfortable but rotating positions should be maintained in a “polio bed”: firm mattress, footboard, sponge rubber pads or rolls, sandbags, and light splints. Intensive physiotherapy may help recover some motor function with paralysis. Fecal impaction and urinary retention (especially with paraplegia) are managed appropriately. In cases of respiratory weakness or paralysis, intensive care is needed. Attention to psychological disorders in long-standing disease is also important. The antiviral pleconaril shows no clear benefit in cases of polio meningoencephalitis.

CMDT 2013

1373

``Prognosis During the febrile period, paralysis may develop or progress. Mild weakness of small muscles is more likely to regress than severe weakness of large muscles. Bulbar poliomyelitis carries a mortality rate of up to 50%. Longterm sequelae include pain, weakness, fatigue, and obesity, factors often worsened by age and comorbidities.

When new muscle weakness and pain develop and progress slowly years after recovery from acute paralytic poliomyelitis, the entity is called postpoliomyelitis syndrome. This syndrome presents with signs of chronic and new denervation, is associated with increasing dysfunction of surviving motor neurons, and is not infectious in origin; patients do not shed the virus. Immune modulators, such as prednisone, interferon, and IVIG, do not show any clear benefits in the treatment of post poliomyelitis syndrome.

``Prevention Given the epidemiologic distribution of poliomyelitis and the continued concern about vaccine-associated disease (estimated in 1:750,000 recipients) with the trivalent oral live poliovirus vaccine (OPV), the inactive (Salk) parenteral vaccination is currently used in the United States for all four recommended doses (at ages 2 months, 4 months, 6–18 months, and at 4–6 years). Inactivated vaccine is also routinely used elsewhere in the developed world. Oral vaccines are limited to usage for outbreak control, travel to endemic areas within the ensuing month, and protection of children whose parents do not comply with the recommended number of immunizations. The advantages of oral vaccination are the ease of administration, low cost, effective local gastrointestinal and circulating immunity, and herd immunity.

Routine immunization of adults in the United States is no longer recommended because of the low incidence of the disease. Exceptions include adults not vaccinated within the prior decade who are exposed to poliomyelitis or who plan to travel to endemic areas (mentioned above). Vacci­ nation should also be considered for adults engaged in high-risk activities (eg, laboratory workers handling stools).

Such adults should be given inactivated poliomyelitis vaccine (Salk) as should immunodeficient or immunosuppressed individuals and members of their households.

In the developing world, three doses of OPV seem sufficient for adequate immunization and the interval between doses should probably be > 1 month (because of interference from enteric pathogens). Intramuscular injections should be routinely avoided during the month following oral poliomyelitis vaccination to prevent provocation paralysis. Clinical studies suggest that rotavirus and OPV can be given concomitantly. Ancillary useful control measures (“supplementary immunization activities”) in polioendemic countries include national immunization days (mass campaigns in which all children are vaccinated twice, 4–6 weeks apart, regardless of vaccine history); cross-border vaccination activities; surveillance for acute flaccid paralysis, an indicator for poliomyelitis; and aggressive

1374

CMDT 2013

Chapter 32

outbreak responses as well as intensified immunization activities in countries impacted by armed conflicts.

VDPV cases with the oral Sabin vaccination are due to mutations leading to neurovirulence. Such cases serve as a reminder of the need to maintain high levels of immunization coverage even in the absence of overt disease. An immunogenic monovalent type 1 oral vaccine (several times more effective than the trivalent oral vaccine) is successfully used in India, Egypt, and Nigeria. Cost and administrative considerations along with a need for effective herd immunity remain major reasons the oral Sabin is still administered.

There is no epidemiologic evidence to implicate poliomyelitis vaccination as a cause for recurrent worsening wheezing or eczema in childhood.

``When to Refer • Neurologic compromise.

• Any suspicious cases should be referred to public health authorities.

DeVries AS et al. Vaccine-derived poliomyelitis 12 years after infection in Minnesota. N Engl J Med. 2011 Jun 16;364(24): 2316–23. [PMID: 21675890] Gonzalez H et al. Management of postpolio syndrome. Lancet Neurol. 2010 Jun;9(6):634–42. [PMID: 20494327] Heinsbroek E et al. The global introduction of inactivated polio vaccine can circumvent the oral polio vaccine paradox.

Vaccine. 2010 May 14;28(22):3778–83. [PMID: 20362626] Steele AD et al. Comparison of 2 different regimens for reactogenicity, safety, and immunogenicity of the live attenuated oral rotavirus vaccine RIX4414 coadministered with oral polio vaccine in South African infants. J Infect Dis. 2010 Sep 1;202(Suppl):S93–100. [PMID: 20684724]

4. Rubella ``

E sse n t i a l s o f d i a g n o s i s

Exposure 14–21 days before onset.

Arthralgia, particularly in young women. `` No prodrome in children, mild prodrome in adults; mild symptoms (fever, malaise, coryza) coinciding with eruption. `` Posterior cervical and postauricular lympha­ denopathy 5–10 days before rash. `` Fine maculopapular rash of 3 days duration; face to trunk to extremities. `` Leukopenia, thrombocytopenia. `` ``

``General Considerations Rubella is a systemic disease caused by a togavirus transmitted by inhalation of infective droplets. It is only moderately communicable. One attack usually confers permanent immunity but reinfection is possible, albeit rarely. The incubation period is 14–21 days (average, 16 days). The

disease is transmissible from 1 week before the rash appears until 15 days afterward.

The clinical picture of rubella is difficult to distinguish from other viral illnesses such as infectious mononucleosis, measles, echovirus infections, and coxsackievirus infections; however, arthritis is more prominent in rubella.

Surveillance of female military recruits suggests that serologic protection against rubella, measles, and mumps are inadequate. The rubella case load decreased from 670,894 cases in 2000 to 121,344 cases in 2009 with reports of disease from 167 nations. Rubella containing vaccine is available in 130 nations. In the United States, rubella is not endemic since 2001.

The principal importance of rubella lies in its devastating effects on the fetus in utero, producing teratogenic effects and a continuing congenital infection (congenital rubella syndrome). The control of rubella is so successful that the number of cases worldwide of reported congenital rubella syndrome in 2008 was only 165 with over one-third of these from the Eastern Mediterranean region. In the United States, congenital rubella syndrome is eliminated since 2004. Two reported cases of congenital rubella syndrome between 2005 and 2007 were imported from Nigeria and Cote d’Ivoire.

``Clinical Findings A. Symptoms and Signs While fetal rubella can be devastating, postnatally acquired rubella is usually innocuous with up to 50% cases asymptomatic. In the postnatally acquired infection, fever and malaise, usually mild, accompanied by tender suboccipital adenitis, may precede the eruption by 1 week. Mild coryza may be present. Polyarticular arthritis occurs in about 25% of adult cases and involves the fingers, wrists, and knees.

Rarely does chronic arthritis develop. The polyarthritis usually subsides within 7 days but may persist for weeks.

Early posterior cervical and postauricular lymphadenopathy is very common. Erythema of the palate and throat, sometimes patchy, may be noted.

A fine, pink maculopapular rash appears on the face, trunk, and extremities in rapid progression (2–3 days) and fades quickly, usually lasting 1 day in each area (Table 32–2).

Rubella without rash may be at least as common as the exanthematous disease. Diagnosis, when suspected because of disease in the community, requires serologic confirmation.

B. Laboratory Findings Leukopenia may be present early and may be followed by an increase in plasma cells. The definitive diagnosis of acute rubella infection is based on elevated IgM anti­ body, fourfold or greater rise in IgG antibody titers, or isolation of the virus. False-positive IgM antibodies, however, are associated with Epstein-Barr virus, cytomegal­ ovirus, erythrovirus (parvovirus), and rheumatoid factor.

Detection of antibodies against rubella in other body fluids, such as urine and saliva, are promising diagnostic aids. An interferon-gamma-ELISPOT can provide valuable additional information in seronegative individuals. PCR techniques are also available.

Viral & Rickettsial Infections

CMDT 2013

1375

``Complications

``Prevention

A. Exposure During Pregnancy

Live attenuated rubella virus vaccine should be given to all infants and a second dose should be given to children of school age. It is important that girls in particular are immune to rubella prior to the menarche. When women are immunized, they should not be pregnant, and the absence of antibodies should be established. (In the United States, about 80% of 20-year-old women are immune to rubella.) Postpartum administration to susceptible female hospital employees is recommended. It is recommended that women not become pregnant for at least 3 months after vaccine administration. Nonetheless, there are no reports of congenital rubella syndrome after rubella immunization, and inadvertent immunization of a pregnant woman is not considered an indication for therapeutic abortion. Arthritis is more marked after rubella vaccination than in native disease and appears to be immunologically mediated. A flare of juvenile rheumatoid arthritis after rubella vaccination is reported. The association between chronic arthropathies and rubella vaccination is controversial. Anaphylactoid reactions following vaccination are rare, and a self-limited thrombotic thrombo­ cytopenic purpura is a reported but very rare (2.6 per 100,000 doses) complication. The immune response to rubella vaccination is mediated by several polymorphisms in vitamin A receptor and innate immunity genes.

MMR may be given in conjunction with DPT or varicella boosters as adequate serologic responses are documented. The administration of two or more doses appears to overcome an immunogenetic risk for vaccine failure in some vaccinees. Immunogenicity is similar with intramuscular and intracutaneous infection, for MMR and varicella vaccinations. Children with biliary atresia in particular show impaired responses to MMR and varicella vaccinations. Preliminary data suggests that the vaccination of transplant (solid organ, bone marrow, and stem cell) patients on immunosuppressive therapy may be safe.

When a pregnant woman is exposed to a possible case of rubella, an immediate hemagglutination-inhibiting rubella antibody level should be obtained to document immunity, since fetal infection during the first trimester leads to congenital rubella in at least 80% of fetuses.

Positive tests for IgG antibodies alone indicate past infection or vaccination. High-avidity anti-rubella IgG assays may distinguish past infection from vaccination. If no antibodies are found, clinical observation and serologic follow-up are essential. An isolated IgM-positive test needs to be interpreted with caution because it does not necessarily imply acute infection. Confirmation of rubella in the expectant mother raises the question of therapeutic abortion, an alternative to be considered in light of personal, religious, legal, and other factors.

The immune status of the mother needs to be evaluated because titers fall to seronegativity in about 10% by 12 years after vaccination.

B. Congenital Rubella An infant acquiring the infection in utero may be normal at birth but probably—50% in a series of nearly 70 pregnant women with rubella in Mexico—will have a wide variety of manifestations, including early-onset cataracts and glaucoma, microphthalmia, hearing deficits, psychomotor retardation, congenital heart defects (patent ductus arteriosus, branch pulmonary artery stenosis), organomegaly, and maculopapular rash. In general, the younger the fetus when infected, the more severe the illness. Deafness is the primary complication in the second trimester. Viral excretion in the throat and urine persists for many months despite high antibody levels. A specific test for IgM rubella antibody is useful for diagnosis in the newborn. A confirmatory diagnosis is made by isolation of the virus or PCR detection of viral RNA in tissues. Treatment is directed toward the many anomalies.

C. Postinfectious Encephalopathy In 1:6000 cases, postinfectious encephalopathy develops 1–6 days after the rash; the virus cannot always be isolated.

The mortality rate is 20%, but residual deficits are rare among the recovered. The mechanism is unknown.

Other unusual complications of rubella include hemorrhagic manifestations due to thrombocytopenia and vascular damage, duodenal stenosis, and mild hepatitis.

``Treatment Acetaminophen provides symptomatic relief for acute rubella. Encephalitis and non–life-threatening thrombo­ cytopenia should be treated symptomatically.

``Prognosis Rubella is a mild illness and rarely lasts more than 3–4 days.

Congenital rubella, on the other hand, has a high mortality rate, and the associated congenital defects are largely ­permanent.

``When to Refer • • • •

Pregnancy.

Meningitis/encephalitis.

Significant vaccination reactions.

Any suspect cases should be reported to public health authorities.

Abernathy ES et al. Status of global virologic surveillance for rubella viruses. J Infect Dis. 2011 Jul;204(Suppl 1):S524–32.

[PMID: 21666209] Klein NP et al; Vaccine Safety Datalink. Measles-mumps-rubellavaricella combination vaccine and the risk of febrile seizures.

Pediatrics. 2010 Jul;126(1):e1–8. [PMID: 20587679] Ovsyannikova IG et al. Polymorphisms in the vitamin A receptor and innate immunity genes influence the antibody response to rubella vaccination. J Infect Dis. 2010 Jan 15;201(2):207–13.

[PMID: 20001730] Strebel PM et al. Global use of rubella vaccines, 1980–2009. J Infect Dis. 2011 Sep 1;204(Suppl 2):S579–84. [PMID: 21954250]

1376

CMDT 2013

Chapter 32

OTHER NEUROTROPIC VIRUSES 1. Rabies ``

E sse n t i a l s o f d i a g n o s i s

History of animal bite.

Paresthesia, hydrophobia, rage alternating with calm. `` Convulsions, paralysis, thick tenacious saliva. `` ``

``General Considerations Rabies is a viral (rhabdovirus) encephalitis transmitted by infected saliva that gains entry into the body by an animal bite or an open wound. Worldwide, 17.4 million cases of animal bites are reported every year, and more than 50,000 deaths are attributed to rabies. Most of these cases occur in rural areas of Africa and Asia, with India accounting for 36% of the global deaths. In developing countries, more than 90% of human cases are secondary to bites from infected dogs. Rabies among travelers to rabies-endemic areas is usually associated with animal injuries (including dogs in North Africa and India, cats in the Middle East, and non-human primates in sub-Saharan Africa and Asia), with most travelassociated cases occurring within 10 days of arrival. In the United States, domestically acquired rabies cases are rare (approximately 92% of cases are associated with wildlife) but probably underreported. In 2010, 6154 cases of animal rabies and 2 cases of bat-associated human rabies were reported in the United States. Wildlife reservoirs, each species having its own rabies variant(s), follow a unique geographic distribution in the United States: raccoons in the East Coast; skunks in the Midwest, Southwest, and California; and foxes in the Southwest and in Alaska. Hawaii is the only rabies-free state to date. Bats were the third most reported rabid animal after raccoons and skunks during 2010. Coyotes are also common reservoirs. Rodents and lagomorphs (eg, rabbits) are unlikely to spread rabies because they cannot survive the disease long enough to transmit it (woodchucks and groundhogs are exceptions). Wildlife epizootics present a constant public health threat in addition to the danger of reintroducing rabies to domestic animals. Vaccination is the key to rabies in small animals and rabies transmission to human beings.

The virus gains entry into the salivary glands of dogs 5–7 days before their death from rabies, thus limiting their period of infectivity. Less common routes of transmission include contamination of mucous membranes with saliva or brain tissue, aerosol transmission, and corneal transplantation. Transmission through solid organ and vascular segment transplantation from donors with unrecognized infection is also reported.

The incubation period may range from 10 days to many years but is usually 3–7 weeks depending in part on the distance of the wound from the CNS. The virus travels in the nerves to the brain, multiplies there, and then migrates along the efferent nerves to the salivary glands. Rabies virus infection forms cytoplasmic inclusion bodies similar to

Negri bodies. These Negri body-like structures are thought to be the sites of viral transcription and replication.

``Clinical Findings A. Symptoms and Signs While there is usually a history of animal bite, bat bites may not be recognized. The prodromal syndrome consists of pain at the site of the bite in association with fever, malaise, headache, nausea, and vomiting. The skin is sensitive to changes of temperature, especially air currents (aerophobia). Percussion myoedema can be present and persist throughout the disease. The CNS stage begins about 10 days after the prodome and may be either encephalitic (“furious”) or paralytic (“dumb”). The encephalitic form (about 80% of the cases) produces the classic rabies manifestations of delirium alternating with periods of calm, extremely painful laryngeal spasms on attempting drinking (hydrophobia), autonomic stimulation (hypersalivation), and seizures. In the less common paralytic form, an acute ascending paralysis resembling Guillain-Barré syndrome predominates with relative sparing of higher cortical functions initially. Both forms progress relentlessly to coma, autonomic nervous system dysfunction, and death.

B. Laboratory Findings Biting animals that appear well should be quarantined and observed for 10 days. Sick or dead animals should be tested for rabies. A wild animal, if captured, should be sacrificed and the head shipped on ice to the nearest laboratory qualified to examine the brain for evidence of rabies virus.

When the animal cannot be examined, raccoons, skunks, bats, and foxes should be presumed to be rabid.

Direct fluorescent antibody testing of skin biopsy material from the posterior neck (where hair follicles are highly innervated) has a sensitivity of 60–80%.

Quantitative reverse transcriptase-PCR, nucleic acid sequence-based amplification, direct rapid immuno­ histochemical test and viral isolation from the cerebrospinal fluid or saliva are advocated as definitive diagnostic assays.

Antibodies can be detected in the serum and the cerebro­ spinal fluid. Pathologic specimens often demonstrate round or oval eosinophilic inclusion bodies (Negri bodies) in the cytoplasm of neuronal cells, but the finding is neither sensitive nor specific. MRI signs are diffuse and nonspecific.

``Treatment & Prognosis Management requires intensive care with attention to the airway, maintenance of oxygenation, and control of seizures. Universal precautions are essential. The induction of coma by ketamine, midazolam, and supplemental barbiturates along with the use of amantadine and ribavirin (the Milwaukee protocol) was reportedly helpful in one case but has failed to reproduce success in subsequent cases.

Corticosteroids are of no use.

If postexposure prophylaxis (discussed below) is given expediently, before clinical signs develop, it is nearly

Viral & Rickettsial Infections 100% successful in prevention of disease. Once the symptoms have appeared, death almost inevitably occurs after 7 days, usually from respiratory failure. Most deaths occur in persons with unrecognized disease who do not seek medical care or in individuals who do not receive postexposure prophylaxis. Up to date, there are only seven cases of rabies that survived to hospital discharge after clinical symptoms started, only one of them did not receive the postexposure prophylaxis (index Milwaukee protocol case) and survived with naturally acquired immunity. Since 2004, the Milwaukee protocol has been applied to 26 additional patients with only one surviving to hospital discharge. The very rare cases in which patients recover without intensive care are referred to as “abortive rabies.”

``Prevention Immunization of household dogs and cats and active immunization of persons with significant animal exposure (eg, veterinarians) are important. The most important decisions, however, concern animal bites. Animals that are frequent sources of infection to travelers are dogs, cats, and non-human primates.

In the developing world, education, surveillance, and animal (particularly dog) vaccination programs are preferred over mass destruction of dogs, which is followed typically by invasion of susceptible feral animals into urban areas. In some Western European countries, campaigns of oral vaccination of wild animals led to the elimination of rabies in wildlife.

A. Local Treatment of Animal Bites and Scratches Thorough cleansing, debridement, and repeated flushing of wounds with soap and water are important. Rabies immune globulin or antiserum should be given as stated below. Wounds caused by animal bites should not be sutured.

B. Postexposure Immunization The decision to treat should be based on the circumstances of the bite, including the extent and location of the wound, the biting animal, the history of prior vaccination, and the local epidemiology of rabies. Any contact or suspect contact with a bat is usually deemed a sufficient indication to warrant prophylaxis. Consultation with state and local health departments is recommended. Postexposure treatment including both immune globulin and vaccination should be administered as promptly as possible when indicated.

The optimal form of passive immunization is human rabies immune globulin (HRIG; 20 international units/kg), administered once. As much as possible of the full dose should be infiltrated around the wound, with any remaining injected intramuscularly at a site distant from the wound. Finger spaces can be safely injected without development of a compartment syndrome. If HRIG is not available, equine rabies antiserum (40 international units/kg) can be used if available after appropriate tests for horse serum

CMDT 2013

1377

sensitivity. All of the rabies immunoglobulin should be injected at the wound site as much as possible and the remainder injected intramuscularly at a distant site from the vaccine administration.

Two vaccines are licensed and available for use in humans in the United States: a human diploid cell vaccine and a purified chick embryo cell vaccine. The current vaccines may be given as four injections of 1 mL intramuscularly in the deltoid or, in small children, into the anterolateral thigh muscles on days 0, 3, 7, and 14 after exposure. (The fifth dose at 28 days after exposure is no longer recommended except among immunosuppressed patients.) The vaccine should not be given in the gluteal area due to suboptimal response. An alternative vaccination strategy that only takes 1 week, with injections on days 0, 3, and 7 after exposure with a verocell vaccine is under study in Thailand.

Rabies vaccines and HRIG should never be given in the same syringe or at the same site. Allergic reactions to the vaccine are rare, although local reactions (pruritus, erythema, tenderness) occur in about 25% and mild systemic reactions (headaches, myalgias, nausea) in about 20% of recipients. Adverse reactions to HRIG seem to be more frequent in women and rare in young children. The vaccine is commercially available or can be obtained through health departments.

Globally diverse anti-rabies vaccines are used. After Pasteur’s research in the 19th century with increasingly virulent strains, the first licensed vaccine (1911) was inactivated and grown on bovine brain tissue. Subsequent vaccines were grown using duck or chick embryo cells but remained allergenic. Increasingly purified vaccines are now grown on verocells, and a sixth-generation verocell rabies vaccine is under development. In some countries, the full spectrum of vaccines, from human diploid rabies to chromatographically purified rabies vaccine are available, whereas in others, the gamut is smaller and intradermal application of smaller vaccine doses at multiple sites and at different times is commonly practiced in an attempt to lower costs, and is deemed safe and effective by the World Health Organization.

In patients with history of past vaccination, the need for HRIG is eliminated (RIG is in short supply worldwide) but postexposure vaccination is still required. The vaccine should be given 1 mL in the deltoid twice (on days 0 and 3). Neither the passive nor the active form of postexposure prophylaxis is associated with fetal abnormalities and thus pregnancy is not considered a contraindication to vaccination.

C. Preexposure Immunization Preexposure prophylaxis with three injections of human diploid cell vaccine intramuscularly (1 mL on days 0, 7, and 21 or 28) is recommended for persons at high risk for exposure: veterinarians (who should have rabies antibody titers checked every 2 years and be boosted with 1 mL intramuscularly); animal handlers; laboratory workers; Peace Corps workers; and travelers with stays over 1 month to remote areas in endemic countries in Africa, Asia, and Latin America. An intradermal route is also available (0.1 mL on days 0, 7, and 21 over the deltoid) but not in the

1378

CMDT 2013

Chapter 32

United States. Immunosuppressive illnesses and agents including corticosteroids as well as antimalarials—in particular chloroquine—may diminish the antibody response. A single dose booster at 10 years after initial immunization increases the level of antibody titers.

``When to Refer Suspicion of rabies requires contact with public health personnel to initiate appropriate passive and active prophylaxis and observation of suspect cases.

``When to Admit • Respiratory, neuromuscular, or CNS dysfunction consistent with rabies.

• Patients with suspect rabies require initiation of therapy until the disease is ruled out in suspect animals, and this requires coordination of care based on likelihood of patient compliance, availability of inpatient and outpatient facilities, and response of local public health teams.

Aramburo A et al. Failure of the Milwaukee protocol in a child with rabies. Clin Infect Dis. 2011 Sep;53(6):572–4. [PMID: 21865193] Blanton JD et al. Rabies surveillance in the United States during 2010. J Am Vet Med Assoc. 2011 Sep 15;239(6):773–83. [PMID: 21916759] Centers for Disease Control and Prevention (CDC). Human rabies from exposure to a vampire bat in Mexico—Louisiana, 2010. MMWR Morb Mortal Wkly Rep. 2011 Aug 12;60(31): 1050–2. [PMID: 21832976] Centers for Disease Control and Prevention (CDC). Human rabies—Wisconsin, 2010. MMWR Morb Mortal Wkly Rep. 2011 Sep2;60(34):1164–6. [PMID: 21881547]

2. Arbovirus Encephalitides

``

E sse n t i a l s o f d i a g n o s i s

Fever, malaise, stiff neck, sore throat, and vomiting, progressing to stupor, coma, and convulsions. `` Upper motor neuron lesion signs: exaggerated deep tendon reflexes, absent superficial reflexes, and spastic paralysis. `` Cerebrospinal fluid opening pressure and protein are often increased, with lymphocytic pleocytosis. ``

``General Considerations The arboviruses are arthropod-borne pathogens that produce clinical manifestations in humans. The mosquitoborne pathogens that cause encephalitis include three

togaviruses (causing Western, Eastern, and Venezuelan equine encephalitis), five flaviviruses (causing West Nile fever, St. Louis encephalitis, Japanese B encephalitis, ­dengue, and Murray Valley encephalitis), and bunyaviruses (the California serogroup of viruses, including the Lacrosse agent of California encephalitis). The tick-borne causes of encephalitis include the flavivirus of the Powassan encephalitis (northeastern United States and Canada) and tickborne encephalitis virus of Europe; and the Colorado tick fever reovirus. Tick-borne encephalitis virus, Colorado tick fever, and the arboviruses associated with viral hemorrhagic fever (including dengue) are discussed below, and only those viruses causing primarily encephalitis in the United States will be discussed here, although West Nile agent is being reported in many other areas, especially western Europe with recent cases from Greece, Portugal, and Hungary.

The reported total number of cases in the United States for all but the West Nile virus is low. The 2010 tally of reported patients includes 68 with the La Crosse agent of California encephalitis (22 alone in North Carolina), 10 with Eastern equine encephalitis (4 in Florida), and 8 each with Powassan encephalitis and St Louis encephalitis (5 in Texas and Arkansas). There are no reported patients with Western equine encephalitis since 1999.

Infection with West Nile virus was first identified in the United States in the New York City area in 1999. The virus spread rapidly, and current cases are reported throughout the continental United States. The homeless appear to be at particularly increased risk for infection. In the United States during 2011, 690 cases of West Nile virus disease were reported from all 50 states and the District of Columbia. Among these, there were 216 (31.3%) cases of neuroinvasive disease (0.07 per 100,000), with an increased incidence in the elderly. There were 43 deaths. Among blood donors testing seropositive, an additional 130 presumptively infected patients were identified.

Pathogen-specific reservoirs (typically small mammals or birds) are responsible for maintaining the encephalitisproducing viruses in nature. For the Eastern equine encephalitis virus, cotton rats and house sparrows were recently shown to serve as amplifying reservoirs. Birds are the main reservoir for West Nile virus and substantial avian mortality accompanies West Nile fever outbreaks (chicken surveillance is a recommended and possible mode of disease surveillance). The mosquito species associated with transmission is different in the Western vs Eastern United States (Culex tarsalis vs Culex pipiens) and consequently the terrain associated with high prevalence areas differs (open grasslands vs urban areas).

Outbreaks tend to occur in late summer and early fall and climatic factors, including elevated mean temperatures and rainfall, are shown to correlate with increased West Nile infection. Only dengue and Venezuelan equine encephalitis viruses produce viremias high enough to allow continued transmission to other mosquitoes and ticks.

Human to human transmission of the other arboviruses is usually related to blood (including granulocyte) transfusion or organ transplantation (although most infected donors give a history of clinically significant disease). West

Viral & Rickettsial Infections Nile virus perinatal, transplacental, breastfeeding (rarely), laboratory, and possibly aerosol transmission can also occur. Rare case reports of West Nile virus infection follow solid organ transplant. It is estimated that fever develops in 1 of 5 patients infected with West Nile virus, while severe neurologic disease presents in 1 of 150. St. Louis encephalitis and Powassan encephalitis occur among adults; Western equine encephalitis, Venezuelan equine encephalitis, and California encephalitis occur primarily among children, while West Nile fever and Eastern equine encephalitis are diseases of both children and adults.

``Clinical Findings A. Symptoms and Signs The human incubation period for arboviral encephalitides is 2–14 days. Symptoms include fever, malaise, sore throat, headache, gastrointestinal upset, lethargy, and stupor progressing to coma. Using blood donor surveys, it is estimated that only about 26% of infections are symptomatic (women and the highly viremic are more symptomatic). A nonpruritic maculopapular rash is variably present. Stiff neck and mental status changes are the most common neurologic signs. About 50% of hospitalized patients with West Nile virus infection in the United States have significant muscle weakness that may be initially confused with the Guillain-Barré syndrome. Acute flaccid (poliomyelitislike) paralysis is seen in 10% of West Nile virus neuroinvasive disease and less commonly with the other arboviruses.

Other signs include tremors, seizures, cranial nerve palsies, and pathologic reflexes. Myocarditis, pancreatitis, and hearing loss are also reported. The disease manifestations associated with West Nile virus infection are strongly agedependent: the acute febrile syndrome and mild neurologic symptoms (but on occasion meningitis) are more common in the young, aseptic meningitis and poliomyelitis-like syndromes are seen in the middle aged, and frank encephalopathy is seen more often in the elderly. All forms of disease tend to be severe in immunocompromised persons in whom neuroinvasive manifestations and associated high mortality are more apt to develop.

B. Laboratory Findings The peripheral white blood cell count is variable.

Cerebrospinal fluid protein is elevated; cerebrospinal fluid glucose is normal; there is usually a lymphocytic pleocytosis; and polymorphonuclear cells may predominate early. The diagnosis of arboviral encephalitides depends on serologic tests. Antibodies to arboviruses persist for life and the presence of IgG in the absence of a rising titer of IgM may indicate past exposure rather than acute infection. Individuals with chronic symptoms after West Nile virus infection may show persistent renal infection for up to 6 years with West Nile virus RNA present in urine. Documentation of a fourfold increase in acute/convalescence titers IgG or the presence of IgM antibodies is confirmatory. For West Nile virus, an IgM capture ELISA in serum or cerebrospinal fluid is almost always positive

CMDT 2013

1379

by the time the disease is clinically evident, and the presence of IgM in cerebrospinal fluid indicates neuroinvasive disease. These tests are available commercially but also through local or state health departments. Cross-reactivity exists among the different flaviviruses, so a plaque reduction assay may be needed to definitively distinguish between West Nile fever and St. Louis encephalitis. PCR assays (also available through the CDC) are less sensitive than serologic tests for the diagnosis of acute infections but are the preferred method for screening blood products and may be particularly useful in immunocompromised patients with abnormal antibody responses. CT scans of the brain usually show no acute disease, but MRI may reveal leptomeningeal, basal ganglia, thalamic, or periventricular enhancement.

``Differential Diagnosis Mild forms of encephalitis must be differentiated from aseptic meningitis, lymphocytic choriomeningitis, and nonparalytic poliomyelitis.

Severe forms of arbovirus encephalitides are to be differentiated from other causes of viral encephalitis (HSV, mumps virus, poliovirus or other enteroviruses, HIV), encephalitis accompanying exanthematous diseases of childhood (measles, varicella, infectious mononucleosis, rubella), encephalitis following vaccination (a demyelinating type following rabies, measles, pertussis), toxic encephalitis (from drugs, poisons, or bacterial toxins such as Shigella dysenteriae type 1), Reye syndrome, and severe forms of stroke, brain tumors, brain abscess, autoimmune processes such as lupus cerebritis, and intoxications. In the California Encephalitis Project, the cause for most cases of encephalitis was not identified.

``Complications Bronchial pneumonia, urinary retention and infection, prolonged weakness, and decubitus ulcers may occur. St. Louis encephalitis is reportedly associated with a postinfectious encephalomyelitis. A chronic syndrome consisting of myalgias, arthralgias, and difficulty with concentration and memory is reported in over half the symptomatic cases.

``Treatment Although specific antiviral therapy is not available for most causative entities, vigorous supportive measures can be helpful. Such measures include reduction of intracranial pressure (mannitol) and monitoring of intraventricular pressure. The efficacy of corticosteroids in these infections is not established. Preliminary evidence that ribavirin is useful in West Nile virus encephalitis is not substantiated.

Other therapeutic options such as IVIG or interferon-α await confirmation of effectiveness. A recent case report suggests that prophylaxis with West Nile virus hyper­ immune plasma and gamma globulin may prevent neuroinvasion.

1380

CMDT 2013

Chapter 32

``Prognosis Although most infections are mild or asymptomatic, the prognosis is always guarded, especially at the extremes of age. Homozygosity for a 32bp deletion in the gene coding for the chemokine receptor CCR5, associated with complete loss of function, predisposes to symptomatic West Nile virus infection. People with this mutation are resistant to acquiring HIV infection. Between January and October 2011, the case fatality rate for West Nile virus disease in the United States was 6.2% (43 of 690). Age older than 50 years is the most important risk factor for severe disease and death. Other risk factors for mortality include black race, chronic kidney disease, hepatitis C virus infection, and immunosuppression. Recovery of persons with severe neurologic compromise may take months. Sequelae of West Nile virus infection include a poliomyelitis-like syndrome, cognitive complaints, movement disorders, epilepsy, and depression; and they may become apparent late in the course of what appears to be a successful recovery.

The long-term prognosis is generally better for Western equine than for Eastern equine or St. Louis encephalitis.

`` Prevention No human vaccine is currently available for the arboviruses prevalent in North America, although yellow fever virusbased chimeric vaccines and recombinant vaccines are under development for West Nile virus. Mosquito control (repellents, protective clothing, and insecticides) is effective in prevention. Since 2003, all blood donations in the United States are screened with nucleic acid amplification tests for West Nile virus. Laboratory precautions are indicated for handling all these pathogens, in particular the West Nile virus.

A vaccine against Japanese B encephalitis is recommended for travelers to rural areas of East Asia, though the risk of disease acquisition among the exposed is estimated at only 1:1,000,000. This vaccination appears to provide some protection against West Nile virus (both agents are related flaviviruses).

Cook RL et al. Demographic and clinical factors associated with persistent symptoms after West Nile virus infection.

Am J Trop Med Hyg. 2010 Nov;83(5):1133–6. [PMID: 21036852] Lindsey NP et al; Centers for Disease Control and Prevention (CDC). Surveillance for human West Nile virus disease– United States, 1999–2008. MMWR Surveill Summ. 2010 Apr 2;59(2):1–17. [PMID: 20360671] Morelli MC et al. Absence of neuroinvasive disease in a liver transplant recipient who acquired West Nile virus (WNV) infection from the organ donor and who received WNV antibodies prophylactically. Clin Infect Dis. 2010 Aug 15;51(4): e34–7. [PMID: 20597692] United States Geological Survey. Disease maps 2010: West Nile virus. http://diseasemaps.usgs.gov/wnv_us_human.html Zeller H et al. West Nile virus: the need to strengthen preparedness in Europe. Euro Surveill. 2010 Aug 26;15(34):19647.

[PMID: 20807490]

Zou S et al. West Nile fever characteristics among viremic persons identified through blood donor screening. J Infect Dis. 2010 Nov 1;202(9):1354–61. [PMID: 20874087]

3. Lymphocytic Choriomeningitis ``

E sse n t i a l s o f d i a g n o s i s

“Influenza-like” prodrome of fever, chills, and cough, followed by a meningeal phase. `` Aseptic meningitis with stiff neck, headache, ­nausea, vomiting, and lethargy. `` Cerebrospinal fluid: slight increase of protein, lymphocytic pleocytosis (500–3000/mcL); low glucose in 25% of patients. `` Complement-fixing antibodies within 2 weeks. ``

``General Considerations The lymphocytic choriomeningitis virus is an arenavirus (related to the pathogen causing Lassa fever, discussed below) that primarily infects the CNS. Its main reservoir is the house mouse (Mus musculus). Other rodents (such as rats, guinea pigs, and even pet hamsters), monkeys, dogs, and swine are also potential reservoirs. Lymphocytic choriomeningitis virus is shed by the infected animal via nasal secretions, urine, and feces; transmission to humans probably occurs through aerosolized particles, direct contact, or animal bites. The disease in humans is underdiagnosed and occurs most often in autumn. The lymphocytic choriomeningitis virus is typically not spread person to person, although vertical transmission is reported, and it is considered as an underrecognized teratogen. Rare cases related to solid organ transplantation and autopsies of infected individuals are also reported. Outbreaks are uncommon, and usually occur in laboratory settings among those workers with significant rodent exposure. Complications of clinical disease are rare.

The ubiquitous nature of its reservoir and the wide distribution of the reported cases suggest a widespread geographic risk for lymphocytic choriomeningitis virus infection. Serologic surveys in the southern and eastern United States suggest past infection in approximately 3–5% of those tested, although more recent data from upstate New York showed < 1% seroprevalence. The risk of infection can be reduced by limiting contact with pet rodents and rodent trappings.

``Clinical Findings A. Symptoms and Signs The incubation period is 8–13 days to the appearance of systemic manifestations and 15–21 days to the appearance of meningeal symptoms. Symptoms are biphasic, with a prodromal illness characterized by fever, chills, headache, myalgia, cough, and vomiting, occasionally with lymphadenopathy

Viral & Rickettsial Infections and maculopapular rash. After 3–5 days the fever subsides only to return after 2–4 days alongside the meningeal phase, characterized by headache, nausea and vomiting, lethargy, and variably present meningeal signs. Arthralgias can develop late in the course. Transverse myelitis, deafness, Guillain-Barré syndrome and transient and permanent hydrocephalus are reported. As stated above, lymphocytic choriomeni­ngitis virus is a well known, albeit underrecognized, cause of congenital infection frequently complicated with obstructive hydrocephalus and chorioretinitis, leading to an infant mortality of up to 30%. Occasionally, a syndrome resembling the viral hemorrhagic fevers (see below) is described in transplant recipients of infected organs and in patients with lymphoma.

B. Laboratory Findings Leukocytosis or leukopenia and thrombocytopenia may be initially present. During the meningeal phase, cerebrospinal fluid analysis frequently shows lymphocytic pleocytosis (total count is often 500–3000/mcL) alongside a slight increase in protein, while a low to normal glucose is seen in at least 25%. The virus may be recovered from the blood and cerebrospinal fluid by mouse inoculation. Complementfixing antibodies appear during or after the second week.

Detection of specific IgM by ELISA is becoming widely used. Detection of lymphocytic choriomeningitis virus by PCR is available in research settings.

``Differential Diagnosis The influenza-like prodrome and latent period may distinguish this from other aseptic meningitides, and bacterial and granulomatous meningitis. A history of exposure to mice or other potential vectors is an important diagnostic clue.

``Treatment Treatment is supportive. In the survivor of a transplantassociated outbreak, ribavirin (which is effective against other arenaviruses) was used successfully along with decreasing immunosuppression.

``Prognosis Fatalities are rare. The illness usually lasts 1–2 weeks, though convalescence may be prolonged. Congenital infection is more severe with about 30% mortality rate among infected infants, and more than 90% of survivors suffering long-term neurologic abnormalities.

``Prevention Pregnant women should be advised of the dangers to their unborn children inherent in exposure to rodents.

Folk S et al. Lymphocytic choriomeningitis with severe manifestations, Missouri, USA. Emerg Infect Dis. 2011 Oct;17(10): 1973–4. [PMID: 22000392] Razonable RR. Rare, unusual, and less common viruses after organ transplantation. Curr Opin Organ Transplant. 2011 Dec;16(6):580–7. [PMID: 22001713]

CMDT 2013

1381

4. Prion Diseases ``

E sse n t i a l s o f d i a g n o s i s

Rare in humans.

Cognitive decline. `` Myoclonic fasciculations, ataxia, visual disturbances, pyramidal and extrapyramidal symptoms. `` Variant form presents in younger people with prominent psychiatric or sensory symptoms. `` Specific EEG patterns. `` ``

``General Considerations Transmissible spongiform encephalopathies is a group of fatal neurodegenerative diseases affecting humans and animals. They are caused by infectious proteins called prions for proteinaceous infectious particles. These agents show slow replicative capacity and long latent intervals in the host. They induce the conformational change of a normal brain protein (prion protein; PrP[C]) into an abnormal isoform (PrP[Sc]) that accumulates and causes neuronal vacuolation (spongiosis), reactive proliferation of astrocytes and microglia and, in some cases, the deposition of beta-amyloid oligomeric plaques (PrP[C]).

Prion disease can be hereditary, sporadic, and trans­ missible in humans. Hereditary disorders are caused by germ line mutations in the PrP[C] gene causing familial Creutzfeldt–Jakob disease (fCJD), Gerstmann-SträusslerScheinker syndrome (GSS), and fatal familial insomnia.

Variations at PrP codons sites, in particular codon 129 but also codons 114, 178, 180, and 232, determine host susceptibility to prion disease and the different phenotypes of the disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common of the human prion diseases, accounting for approximately 85% of cases; it has no known cause, although a spontaneous misfolding of PrP[C] as well as somatic mutations of PrP[C] or undetectable horizontal transmission are postulated as possible explanations.

Transmissible prion disease is only described for kuru and Creutzfeldt-Jakob disease in its iatrogenic (iCJD) and ­variant (vCJD) form. Iatrogenic transmission of CJD is associated with prion contaminated human corneas, dura mater grafts, growth hormone, gonadotropins, stereotactic electroencephalography, electrodes, and neurosurgical instruments. Kuru, once prevalent in central New Guinea, is now rare, a decline in prevalence that started after the abandonment of cannibalism in the late 1950s (a protective allele of the PrP gene is now identified at codon 127).

More than 200 cases of vCJD (bovine spongiform encephalopathy [BSE] or “mad cow disease”) were reported in the United Kingdom since the first documented cases there in the mid-1990s. It is far less common in North America, with only 3 cases reported in the United States (the last 1 in 2006) and 19 in Canada. Of the US reported cases, none acquired the disease locally (2 of them acquired

1382

CMDT 2013

Chapter 32

the infection in the United Kingdom and 1 in Saudi Arabia). This disease is characterized by its bovine-to-­ human transmission through ingestion of meat from cattle infected with BSE. There is no animal-to-animal spread of BSE, and milk and its derived products are not considered to be infected. Reports of secondary transmission of vCJD due to blood transfusions from asymptomatic donors are reported in the United Kingdom. Although iCJD and vCJD are not associated with a known PrP gene mutation, a polymorphism in codon 129 is prevalent and seems to determine susceptibility and expression of clinical disease. The overall annual incidence of prion disease worldwide is approximately one in 1 million people per year. In the United States, among 2441 cases reported through August 19, 2011 to the US National Prion Disease Pathology Surveillance Center, 2068 (85%) were sporadic, 356 (15%) familial, 5 (0.2%) iatrogenic, and 3 (0.1) vCJD.

``Clinical Findings A. Symptoms and Signs Both sCJD and fCJD usually present in the sixth or seventh decade of life, whereas the iCJD form tends to occur in a much younger population. Clinical features of these three forms of disease usually involve mental deterioration (dementia, behavioral changes, loss of cortical function) progressive over several months, as well as myoclonus, extrapyramidal (hypokinesia) and cerebellar manifestations (ataxia, dysarthria). Finally, coma ensues, usually associated with an akinetic state and less commonly ­decerebrate/decorticate posturing. Like iCJD, vCJD usually affects younger patients (averaging ~28 years), but the duration of disease is longer (about 1 year). The degree of organ involvement is often extensive, and the clinical symptoms are unique, mainly characterized by prominent psychiatric and sensory symptoms. Kuru presents with an early stage of tremors, ataxia, and postural instability followed by a sedentary stage characterized by involuntary movements (myoclonus, fasciculations, and choreoathetosis) and a final stage of dementia. GSS, a rare inherited autosomal dominant (rarely sporadic) disorder that occurs in kindred is rapidly fatal. It typically causes a disruption of the circadian sleep-activity pattern leading to insomnia, hallucinations, behavioral changes, motor disturbance and, rarely, dementia. Fatal familial insomnia is the only prion disease associated with endocrine disorders and dysautonomia.

B. Laboratory Findings CJD should be considered as a diagnosis in the proper clinical scenario, in the absence of alternative diagnoses after routine investigations. Abnormalities in cerebro­ spinal fluid are subtle and rarely helpful. The detection of 14-3-3 protein in the cerebrospinal fluid is helpful for the diagnosis of sCJD but not in vCJD and fCJD. Its sensitivity and specificity are widely variable among different studies. Cerebrospinal fluid detection of other proteins like tau, neuron-specific enolase, and S100 protein are reported in smaller studies but do not as yet show clinical utility. More recently, a new blood-based assay and a PCR

in cerebrospinal fluid showed some promising results and are currently under evaluation for clinical use.

In CJD, EEG typically shows a pattern of paroxysms with high voltages and slow waves, while MRI is characteristic for bilateral areas of increased signal intensity, predominantly in the caudate and putamen. In contrast, vCJD shows a diffusely abnormal but nondiagnostic EEG. MRI characteristically reveals hyperintensity of the posterior thalamus (“pulvinar sign”). Positron emission tomography can help distinguish GSS disease. The differentiation and definitive diagnosis of these neurodegenerative diseases are ultimately established by neuropathologic confirmation.

``Treatment & Prevention There is no specific treatment for CJD. Once symptoms appear, the infection invariably leads to death. Flupirtine (an analgesic drug) is sometimes useful in slowing the associated cognitive decline but does not affect survival.

Iatrogenic CJD can be prevented by limiting patient exposure to potentially infectious sources as mentioned above. Disinfection of equipment requires autoclaving at 15 psi for 1 hour, and disinfection of contaminated surfaces requires 5% hypochlorite or 0.1 N sodium hydroxide solutions. Prevention of vCJD relies on surveillance of potentially infected livestock. The American Red Cross does not accept blood donations from persons with a family history of CJD or with a history of dural grafts or pituitary-derived growth hormone injections.

An international referral and database for CJD is available at: http://www.cjdsurveillance.com/index.html.

Atarashi R et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med. 2011 Feb;17(2):175–8. [PMID: 21278748] Colby DW et al. Prions. Cold Spring Harb Perspect Biol. 2011 Jan 1;31(1):a006833. [PMID: 21421910] Edgeworth JA et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet. 2011 Feb 5;377(9764):487–93. [PMID: 21295339] Norrby E. Prions and protein-folding diseases. J Inter Med. 2011 Jul;270(1):1–14. [PMID: 21481020] Puopolo M et al. Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possible biases.

Transfusion. 2011 Jul;51(7):1556–66. [PMID: 21214582]

5. Progressive Multifocal Leukoencephalopathy (PML) PML is a rare demyelinating CNS disorder caused by the reactivation of the JC virus (John Cunningham virus or JCV). This polyomavirus usually causes its primary infection during childhood with > 60% of adults typically being seropositive. The virus remains latent in the kidneys, lymphoid tissues, epithelial cells, peripheral blood leukocytes, bone marrow, and possibly brain until the time reactivation occurs and symptoms become evident (see below). This reactivation is usually seen in adults with impaired cell-mediated immunity, especially AIDS patients (5–10% of whom develop PML), as well as those with idiopathic CD4 lymphopenia syndrome. It is also

Viral & Rickettsial Infections reported among those with lymphoproliferative and myeloproliferative disorders; granulomatous, inflammatory, and rheumatic diseases (systemic lupus erythematosus and rheumatoid arthritis in particular); as well as in those who have undergone solid and hematopoietic cell transplantation; and occasionally in those who have other medical states, including cirrhosis and renal failure.

Monoclonal antibody-associated PML is described with the use of natalizumab, rituximab, infliximab, and efalizumab (withdrawn from the market in April 2009).

Natalizumab, a monoclonal antibody used in the treatment of multiple sclerosis, is associated with the risk of PML developing in 1.35 cases per 1000 patients treated for more than a year and 1.78 per 1000 for patients treatment > 2 years. Although an immune reconstitution inflammatory state may follow cessation of monoclonal antibody therapy, the JCV presence and the residual neurologic deficits may not clear for years after therapy is stopped. The risk of developing PML associated with rituximab is at least 1 in 25,000 exposed patients with cases reported in various autoimmune conditions (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis). The mean interval between the use of the drug to the diagnosis of PML is 5.5 months. Only one case of infliximabassociated PML is reported. Smoking is reportedly associated with an increased risk of PML.

``Clinical Findings A. Symptoms and Signs JCV causes lytic infection of oligodendrocytes in the white matter and symptoms presenting subacutely reflect the div­ erse areas of CNS involvement. Symptoms include altered mental status, aphasia, ataxia, hemiparesis or hemiplegia and visual field disturbances. Seizures occur in about 18%.

Involvement of cranial nerves and cervical spine is rare.

``B. Laboratory Findings PCR for JCV in cerebrospinal fluid is used for diagnosis in patients with compatible clinical and radiologic findings. A quantitative PCR is more sensitive. Persistent JC viremia and increasing urinary JCV DNA may be predictive of PML. MRIs of the brain show multifocal areas of white matter demyelination without mass effect or contrast enhancement.

``Treatment & Prevention Limiting the immunosuppression state represents the mainstay of therapy for PML. Treatment of HIV with HAART reduces the incidence of PML, improves the clinical symptoms and reverses some of the radiographic abnormalities as well as improves the 1-year mortality rate, regardless of baseline CD4 count. Immune restoration, however, can induce worsening of the clinical picture in a small number of cases. Immune reconstitution syndromes do not alter mortality but are associated with a form of PML called non-determined leukoencephalopathy associated with a distinct chemokine polymorphism. Significant

CMDT 2013

1383

neurologic sequelae to PML infections are the rule and the deficits associated with monoclonal associated PML may persist for years.

Decreasing immunosuppression in non-AIDS patients with PML (eg, transplant patients) is also typically beneficial. Cidofovir may be beneficial in non-AIDS related cases while corticosteroids may be useful with immune reconstitution. Because the JCV infects cells through serotonin receptors, the use of risperidone and mirtazapine are recommended by some clinicians but the success of these agents remains anecdotal. Future reports will assess the role of small inhibitory RNAs. Plasma exchange, which theoretically reduces the plasma level of agents associated with PML, is used by some for the management of natalizumabassociated PML. Aly L et al. Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome. Brain. 2011 Sep; 134(Pt 9):2687–702. [PMID: 21908874] Bosch X et al. Monoclonal antibody therapy-associated neurological disorders. Nat Rev Neurol. 2011 Mar;7(3):165–72.

[PMID: 21263460] Clifford DB et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol.

2011 Sep;68(9):1156–64. [PMID: 21555606] Weissert R. Progressive multifocal leukoencephalopathy. J Neuroimmunol. 2011 Feb;231(1–2):73–7. [PMID: 20937530] White MK et al. Pathogenesis of progressive multifocal leukoencephalopathy—revisited. J Infect Dis. 2011 Mar 1;203(5): 578–86. [PMID: 21227915]

6. Human T Cell Lymphotropic Virus (HTLV) HTLV-1 and -2 are retroviruses that infect CD4 and CD8 T cells respectively, where they persist as a lifelong latent infection. HTLV-1 currently infects approximately 20 million individuals worldwide. It is endemic to many regions in the world including southern Japan, the Caribbean, central and south Africa, South America, Eastern Europe, and Oceania. The Caribbean basin and Southwestern Japan show the highest prevalence of infection (4–37%). Con­ versely, HTLV-2 is mainly found in native populations of South (1–58%), Central (8–10%) and North America (2–13%) as well as African pygmy tribes.

In the United States, studies done in blood donors show a seroprevalence of HTLV-1 of 0.01% and HTLV-2 of 0.02%. The virus is transmitted horizontally (sex), vertically (intrauterine, peripartum, and breastfeeding), and parenterally (injection drug use and blood transfusion).

Hence, a higher prevalence is seen among injection drug users.

``Clinical Findings A. Symptoms and Signs HTLV-1 infection is associated with HTLV-1 adult T cell lymphoma/leukemia (ATL) and HTLV-1 associated ­myelopathy/tropical spastic paraparesis (HAM/TSP). In contrast, HTLV-2 is significantly less pathogenic, with few reported cases of HAM/TSP as well as other neurologic

1384

CMDT 2013

Chapter 32

manifestations. The causative association of HTLV-1 with ATL, attributed to the virally encoded oncoprotein tax, is well established. The lifetime risk of developing ATL among seropositive persons is estimated to be 3% in women and 7% in men, with an incubation period of at least 15 years. The mean age of diagnosis of ATL is 40–50 years in Central and South America and 60 years in Japan.

ATL clinical syndromes may be classified as chronic, acute (leukemic), smoldering, or lymphomatous. A primary cutaneous tumor is also described and shows a worse prognosis compared with the smoldering type. Clinical features of ATL include diffuse lymphadenopathy, maculopapular skin lesions that may evolve into erythroderma, organomegaly, lytic bone lesions, and hypercalcemia.

Opportunistic infections, such as Pneumocystis jiroveci pneumonia and cryptococcal meningitis, are common.

HAM/TSP, associated with both HTLV-1 and HTLV-2, develops in 0.3–4% of seropositive individuals and is more common in women. A chronic inflammation of the spinal cord leads to progressive motor weakness and symmetric spastic paraparesis, nociceptive low back pain, and para­ plegia with hyperreflexia. Bladder and sexual disorders (eg, dyspareunia), sensory disturbances, erectile dysfunction, and constipation are also common. A progressive cognitive impairment is seen with HAM/TSP in children.

Both viruses can also induce motor abnormalities, such as leg weakness, impaired tandem walk, and vibration sense, without overt HTLV-associated myelopathy.

An HTLV-1 provirus load in peripheral blood mononuclear cells and cerebrospinal fluid cells, and an HTLV-1 mRNA load are proposed as markers of HAM risk and progression.

HTLV positivity is associated with erythrocytosis, lymphocytosis (HTLV-2) and with thrombocytosis (HTLV-1).

HTLV-1 seropositivity is associated with an increased risk of tuberculosis and Strongyloides stercoralis hyperin­ fection. Crusted scabies and infective dermatitis are also associated. Inflammatory states associated with HTLV-1 infection include arthropathy, polymyositis, uveitis, Sjögren syndrome, vasculitis, cryoglobulinemia, infiltrative pneumonitis, and ichthyosis. An increased risk for bronchioloalveolvar carcinoma in the presence of HTLV-1 is recently reported.

HTLV-2 is no longer considered to be associated with hairy cell leukemia. HTLV-2 appears to cause a myelopathy that is milder and slower to progress than HAM. All-cause and cancer mortality is higher among HTLV-2 seropositive patients.

HTLV-1/HIV coinfection is associated both with higher CD4 counts and a higher risk of HAM.

B. Laboratory Findings The peripheral smear can show atypical lymphoid cells with basophilic cytoplasm and convoluted nuclei (flower cells) but the diagnostic standard is evidence of clonal integration of the proviral DNA genome into tumor cell. The identification of HTLV-1 antibodies supports the diagnosis.

``Treatment & Prevention Management of ATL consists mainly of chemotherapy, with allogeneic stem cell transplantation and the use of

monoclonal antibodies (anti-CCR4 and anti-CD25). A new chemotherapy regimen in Japan using eight different agents shows a higher response rate than traditional biweekly CHOP (40% vs 25%). Therapy using interferon-α combined with zidovudine is effective in the smoldering type.

HAM is treated with a variety of immune-modulating agents (including corticosteroids) without consistent results. Combination of antiretrovirals does not show benefit. Interferon-α may be of some efficacy. Small uncontrolled studies showed that plasmapheresis appears to result in some improvement in gait and sensory disturbance among PML patients.

Screening of the blood supply for HTLV-1 is required in the United States. There is significant cross-reactivity between HTLV-1 and HTLV-2 by serologic studies, but PCR can distinguish the two. Better assays to screen organ donors for HTLV-1 and -2 infections are needed.

Bittencourt AL et al. Cutaneous manifestations associated with HTLV-1 infection. Int J Dermatol. 2010 Oct;49(10):1099–110.

[PMID: 20883400] Matsuoka M et al. Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy. Oncogene. 2011 Mar 24;30(12):1379–89. [PMID: 21119600] Nomori H et al. Risk of bronchioloalveolar carcinoma in patients with human T-cell lymphotropic virus type 1 (HTLV-I): case-control study results. Ann Thorac Cardiovasc Surg. 2011 Feb;17(1):19–23. [PMID: 21587123]

OTHER SYSTEMIC VIRAL DISEASES 1. Hemorrhagic Fevers This diverse group of illnesses results from infection with one of several single-stranded RNA viruses (members of the families Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae). Flaviviruses, such as the pathogens causing dengue and yellow fever (both with occasional hemorrhagic complications), are discussed in separate sections.

Lassa fever (an Old World arenavirus) is rodent associated and transmission usually occurs through aerosolized particles (from rodents or infected individuals). Trans­ mission through direct contact with infected biologic fluids or tissues is also documented and food-borne trans­ mission, while considered, is not definitively proven.

Similar modes of transmission are assumed for Junin virus and other members of the New World Arenaviridae (Machupo virus, Sabia virus, Guanarito virus, Whitewater Arroyo virus). Bats (fruit bats for Ebola) are the suspected reservoir for Ebola and Marburg viruses (Filoviridae) but their vectors are unknown. A subtype of Ebola (Bundibugyo) is reported in Uganda (earlier Ebola outbreaks occurred in Democratic Republic of Congo, Sudan, and one case in Côte d’Ivoire). Cases of Marburg hemorrhagic fever are reported in travelers exploring caves and mines inhabited by bats in endemic areas of sub-Saharan Africa. The bunyaviruses include the Crimean-Congo hemorrhagic fever (transmitted by infected animal

Viral & Rickettsial Infections e­ xposure or tick bite), the Rift Valley fever (transmitted by exposure to infected animal products or bite of an infected mosquito or flea), and the hantaviruses (associated with rodent exposure and discussed separately below). The geographic distribution of Crimean-Congo hemorrhagic fever, like that of its tick vector, is widespread with cases reported in Asia, the Middle East, and Eastern Europe. In 2002, Turkey experienced the largest reported outbreak with over 2500 cases. Hospital-associated transmission of Crimean-Congo hemorrhagic fever is well documented in Iran. Rift Valley fever causes outbreaks in sub-Saharan and Northern Africa, including a recent 2007 outbreak with 155 deaths in Kenya following heavy rainfalls and associated with three different lineages of the virus. Rift Valley cases are also confirmed outside the African continent, in Saudi Arabia, and Yemen.

A new bunyavirus, a phlebovirus, associated with fever and thrombocytopenia, was identified in 2010 in Central and Northeastern China and is named for its symptoms: the severe fever with thrombocytopenia syndrome. Its differential diagnosis includes anaplasmosis, hemorrhagic fever with renal syndrome, or leptospirosis. The current candidate vector is a tick of the Ixodidae family. A mortality of 12% was noted among the first 171 patients.

CMDT 2013

1385

noted), anemia, increased hematocrit, elevated liver function tests, and findings consistent with disseminated intravascular coagulation (although less prominently in Lassa fever). Urinalysis can reveal proteinuria and hematuria.

Special care should be taken for handling clinical specimens of suspected cases. Laboratory personnel should be warned about the diagnostic suspicion and the CDC must be contacted for guidance (Special Pathogens Branch, 404-639-1115). Diagnosis may be made by growing the virus from blood obtained early in the disease, antigen detection (by ELISA), nucleic acid amplification (PCR techniques), or by demonstration of a significant specific fourfold or greater rise in antibody titer. Detection of Ebola virus antigen in oral fluid samples by ELISA and RT-PCR may be possible; sample collection in this manner will be useful since certain ethnic customs prohibit blood collection. These tests are generally available only through the CDC.

``Differential Diagnosis The differential diagnosis for hemorrhagic fever includes meningococcemia or other septicemias, Rocky Mountain spotted fever, dengue, typhoid fever, and malaria. The likelihood of acquiring hemorrhagic fevers among travelers is low.

``Clinical Findings

``Treatment

A. Symptoms and Signs

Patients should be placed in private rooms with standard contact and droplet precautions. Barrier precautions to prevent contamination of skin or mucous membranes should also be adopted by the caring personnel. Airborne precautions should be considered in patients with significant pulmonary involvement or undergoing procedures that stimulate cough.

Certain arenaviruses (the Lassa pathogen, Junin virus in its viscerotropic phase, Machupo virus) and bunyaviruses (the Congo-Crimean hemorrhagic fever and Rift Valley fever pathogens) respond to oral ribavirin if it is started promptly: 30 mg/kg as loading dose, followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for 3 days. The efficacy for postexposure ribavirin in the management of Lassa fever, other arenaviruses, or hospitalâ&#x20AC;&#x201C;­ associated Crimean-Congo hemorrhagic fever remains anecdotal. However, if ribavirin is used, it should be given in a high loading dose (35 mg/kg orally followed by 15 mg/ kg three times daily for 10 days) and only for high-risk settings (eg, needle stick injury, mucous membrane contamination, emergency resuscitative contact, or prolonged intimate exposure during transport).

The filoviruses and the flaviviruses do not respond to ribavirin. Live attenuated vaccines are available for Junin hemorrhagic fever and the Rift Valley fever, and they are under study for the Crimean-Congo hemorrhagic fever, Ebola, and Marburg viruses. In addition, recombinant vaccines are under development for most of these pathogens (including the Lassa fever virus but not the Junin hemorrhagic fever virus). Therapeutic interventions that target the hematologic system are either ineffective or only marginally effective.

The incubation period can be as short as 2 days for the Rift Valley fever or as long as 21 days for Lassa fever. The clinical symptoms in the early phase of a viral hemorrhagic fever are very similar, irrespective of the causative virus, and resemble a flu-like illness or gastroenteritis. Hepatitis is common.

The late phase is more specific and is characterized by organ failure, persistent leukopenia, altered mental status, and hemorrhage. Exanthemas and mucosal lesions can occur. The range of pathology described with CrimeanCongo hemorrhagic fever continues to grow and include cardiac failure, bilateral alveolar hemorrhages, and retinal hemorrhages. Rift Valley fever is reportedly associated with encephalitis and also retinitis. Adrenal dysfunction is a common sequela of this class of infections and a cause for the development of the late-stage shock associated with these infections. The case-fatality rate ranges from 5% to 30% and may be as high as 90% in Ebola fever. The convalescence period can be long and complicated. There is no evidence of chronic infection among survivors. Risk factors for complications in patients with CrimeanCongo hemorrhagic fever include advanced age, thrombocytopenia, prolonged clotting factor parameters, and hepatitis; risk factors for mortality include altered sensorium and prolonged international normalized ratio.

B. Laboratory Findings Laboratory features usually include thrombocytopenia, leukopenia, (although with Lassa fever leukocytosis is

1386

CMDT 2013

Chapter 32

``When to Admit • Persons with symptoms compatible with those of any hemorrhagic fever and who have traveled from a possible endemic area should be isolated for diagnosis and symptomatic treatment.

• Isolation is particularly important because diseases due to some of these agents, such as Ebola virus, are highly transmissible and carry a mortality rate of 50–90%.

Bausch DG. Ebola virus as a foodborne pathogen? Cause for consideration, but not panic. J Infect Dis. 2011 Jul 15;204(2): 179–81. [PMID: 21571727] Bausch DG et al. Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever. Clin Infect Dis. 2010 Dec 15;51(12):1435–41.

[PMID: 21058912] Feldmann H et al. Ebola haemorrhagic fever. Lancet. 2011 Mar 5;377(9768):849–62. [PMID: 21084112] Ikegami T et al. Rift valley fever vaccines. Vaccine. 2009 Nov 5;27(Suppl 4):D69–72. [PMID: 19837291] Soares-Weiser K et al. Ribavirin for Crimean-Congo hemorrhagic fever: systematic review and meta-analysis. BMC Infect Dis. 2010 Jul 13;10:207. [PMID: 20626907] Yu XJ et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med. 2011 Apr 21;364(16): 1523–32. [PMID: 21410387]

2. Dengue ``

E sse n t i a l s o f d i a g n o s i s

Exposure 7–10 days before onset.

Sudden onset of high fever, chills, severe myalgias and arthralgias, headache, sore throat, and depression. `` Biphasic fever curve: initial phase, 3–7 days; remission, few hours to 2 days; second phase, 1–2 days. `` Biphasic rash: evanescent, then maculopapular, scarlatiniform, morbilliform, or petechial changes from extremities to torso. `` Leukopenia and thrombocytopenia in the hemorrhagic form. `` ``

``General Considerations Dengue is due to a flavivirus transmitted by the bite of the Aedes mosquito. It may be caused by one of four serotypes widely distributed globally between the tropics of Capricorn and Cancer. An estimated 50–100 million cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever occur each year with numbers growing in both dengue fever and dengue hemorrhagic fever as a consequence of climatic factors, travel, and urbanization. It is thus the most common and important vector-borne disease of humans, with 2.5 billion living in dengue-infected regions and major intermittent outbreaks including over 7000 in 2010 in Nepal. The incubation period is 3–15 days

(usually 7–10 days). When the virus is introduced into susceptible populations, usually by viremic travelers, epidemic attack rates range from 50% to 70%. Dengue is endemic in the lower Rio Grande Valley and adjacent border towns, with 40% of Brownsville, Texas residents showing serologic evidence of past infection and the virus being detected in mosquito larvae among 30% of households.

The seroprevalence of Haitians by age 3 is over 53%.

Severe epidemics of dengue hemorrhagic fever (serotype 3) occurred over the past 20 years in East Africa, Sri Lanka, and Latin America. Dengue is the second most common cause of fever (after malaria) in travelers returning from developing countries. In one US series based on CDC reports, the highest proportion of laboratory-confirmed and probable cases were among travelers returning from the Dominican Republic (121 cases, 20% of total), Mexico (55 cases, 9% of total) and India (43 cases, 7% of total). In general, the more advanced forms of disease (hemorrhagic fever and shock) occur less often in the Americas than in Asia. Since the 1980s, locally acquired cases of dengue are reported from Texas-Mexico border, and Key West, Florida. Health care–associated transmission (needlestick, mucocutaneous exposure or transplant related) and vertical transmission occur rarely.

``Clinical Findings A. Symptoms and Signs A history of travel to a dengue-endemic area within 14 days of symptom onset is helpful in establishing a diagnosis of dengue. Dengue infection may range from asymptomatic to severe hemorrhagic fever to fatal shock (dengue shock syndrome). Dengue fever is usually a nonspecific, self-limited biphasic febrile illness. More than half of infected children are asymptomatic. The illness is more severe and begins more suddenly in adults. After an incubation period of 4–5 days, there is a sudden onset of high fever, chills, and “break bone” aching of the head, back, and extremities accompanied by sore throat, prostration, and malaise. There may be conjunctival redness. Initially, the skin appears flushed or blotched, but 3–4 days after the lysis of the fever, a maculopapular rash, which spares palms and soles, appears in over 50% of cases. As the rash fades, localized clusters of petechiae on the extensor surface of the limbs become apparent. Up to 25% may manifest signs of cardiac involvement. Hepatitis frequently complicates dengue fever with acute fulminant hepatitis in up to 5%.

Dengue hemorrhagic fever usually affects children living in endemic areas and is most likely to occur in secondary infections and in infections with serotype 2. A few days into the illness, signs of hemorrhage such as ecchymoses, gastrointestinal bleeding, and epistaxis appear.

Symptoms found more often among the dengue hemorrhagic fever subset of patients include restlessness, epistaxis, and abdominal pain. Gastroenterologic complications, including hemorrhage, tenderness, and ascites, are more common with dengue hemorrhagic fever and often require intensive care observation.

Viral & Rickettsial Infections A subset of patients (more often girls than boys) often with secondary infection, may progress to dengue shock syndrome in which acute fever, hemorrhagic manifestations, and marked capillary leak are prominent; the latter manifests as pleural effusions and ascites, and there is a tendency for shock to develop. In infants, even primary infection can lead to dengue shock syndrome. While the infection is difficult to distinguish from malaria, yellow fever, or influenza, the rash makes dengue far more likely. Continuous abdominal pain with vomiting, bleeding, a decrease in the level of consciousness, rash, conjunctival congestion, and hypothermia should raise concern about dengue shock syndrome.

Acute kidney injury in dengue largely occurs with dengue shock syndrome and shows a high mortality. While acute severe hepatitis can occur with dengue, concomitant other hepatotropic agents are usually responsible.

Distinguishing between dengue and other causes of febrile illness in endemic areas is difficult. Fevers due to dengue are more often associated with neutropenia and thrombocytopenia and with myalgias, arthralgias/arthritis, and lethargy among adults.

B. Laboratory Findings Leukopenia is characteristic, and elevated transaminases are found frequently in dengue fever. Thrombocytopenia, increased fibrinolysis, and hemoconcentration occur more often in the hemorrhagic form of the disease. Liver biochemical test abnormalities are nearly universal. Thrombo­ cytopenia, plasma leakage, and acute hepatitis are identified as predictors of severe manifestations of dengue and higher mortality. The nonspecific nature of the illness mandates laboratory verification for diagnosis, usually with IgM and IgG ELISAs after the febrile phase. Virus may be recovered from the blood during the acute phase. PCR or detection of the specific viral protein NS1 by ELISA may be diagnostic during the first few days of infection and may be appropriate for febrile travelers. Immunohistochemistry for antigen detection in tissue samples can also be used. Because the erythrocyte sedimentation rate is normal in most cases, elevation may help with the differential. Chest radiographs in dengue hemorrhagic fever show infiltrates and effusions, which follow the course of laboratory abnormalities.

``Complications Usual complications include pneumonia, bone marrow failure, hepatitis, iritis, retinal hemorrhages and maculopathy, orchitis, and oophoritis. Depression and chronic fati­ gue, occurring more often in older women, are also reported.

Neurologic complications (such as encephalitis, GuillainBarré syndrome, phrenic neuropathy, subdural hematoma, and transverse myelitis) are less common, although encephalitic complications are increasingly recognized. Aplastic anemia and hemophagocytosis syndrome are very rare complications. Dengue is rarely associated with stroke in patients with focal neurologic deficit and encephalopathy.

Maternal infection poses a risk for premature birth and hemorrhage in both the mother and the infant if infection occurs near term.

CMDT 2013

1387

Bacterial superinfection occurs more commonly with advanced age, higher fever, gastrointestinal bleeding, kidney disease, and altered consciousness.

``Treatment Treatment entails the appropriate use of volume support (with Ringer lactate in moderately severe shock and colloids in more severe cases), blood products, and pressor agents, and acetaminophen rather than nonsteroidal antiinflammatory drugs for analgesia. Activities are gradually restored during prolonged convalescences. Endoscopic therapy is useful in evaluating and managing gastrointestinal hemorrhage, although injection therapy with sclerosing agents is not beneficial in most dengue hemorrhagic states.

Platelet counts do not usefully predict clinically significant bleeding. Platelet transfusions, however, should be considered for severe thrombocytopenia (< 10,000/mcL) or when there is evidence of bleeding. Monitoring vital signs and blood volume may help in anticipating the complications of dengue hemorrhagic fever or shock syndrome.

The efficacy of corticosteroids in the management of dengue is not proven. There is anecdotal evidence for the efficacy of intravenous anti-D globulin in the management of dengue hemorrhagic fever.

``Prognosis Fatalities are rare but do occur (and more often among girls and the very young), especially during epidemic outbreaks, with occasional patients dying of fulminant hepatitis. Renal failure in dengue shock syndrome portends an especially poor prognosis. Convalescence for most patients is slow.

``Prevention Available prophylactic measures include control of mosquitoes by screening and insect repellents, particularly during early morning and late afternoon exposures. Testing of blood supplies is increasingly necessary especially in endemic areas as dengue spreads.

Two tetravalent live attenuated reverse DNA-based and genetically modified chimeric dengue virus vaccines (one of which uses a yellow fever viral backbone) remain under study and are undergoing clinical trials.

Anders KL et al. Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. Am J Trop Med Hyg. 2011 Jan; 84(1):127–34. [PMID: 21212214] Centers for Disease Control and Prevention (CDC). Travelassociated Dengue surveillance—United States, 2006–2008.

MMWR Morb Mortal Wkly Rep. 2010 Jun 18;59(23):715–9.

[PMID: 20559202] Durbin AP et al. Dengue vaccine candidates in development.

Curr Top Microbiol Immunol. 2010;338:129–43. [PMID: 19802583] Durbin AP et al. Heterotypic dengue infection with live attenuated monotypic dengue virus vaccines: implications for

1388

CMDT 2013

Chapter 32

vaccination of populations in areas where dengue is endemic.

J Infect Dis. 2011 Feb 1;203(3):327–34. [PMID: 21208923] Mohammed HP et al. Travel-associated dengue infections in the United States, 1996 to 2005. J Travel Med. 2010 Jan–Feb; 17(1):8–14. [PMID: 20074096] Thomas SJ. The necessity and quandaries of dengue vaccine development. J Infect Dis. 2011 Feb 1;203(3):299–303. [PMID: 21208919]

3. Hantaviruses ``

E sse n t i a l s o f d i a g n o s i s

Transmitted by rodents and cause two clinical syndromes. `` Hemorrhagic fever with renal syndrome (HFRS): mild to severe illness. `` Hantavirus pulmonary syndrome (HPS): 40% ­mortality rate. `` Ribavirin is used with some success in HFRS. ``

``General Considerations Hantaviruses are enveloped RNA bunyaviruses naturally hosted in rodents, moles, and shrews. Currently, over 21 hantavirus strains are known to cause human disease.

These differ in rodent hosts, geographic distribution, and degree of pathogenicity. Two major clinical syndromes are described: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Each year, over 150,000 cases of these two syndromes occur globally, with HPS being far less common. While they share many clinical features, evidence over the past decade suggest that a specific strain is no longer associated with a specific syndrome, but different degrees of overlap are seen between both syndromes.

Usually seen in the southwestern United States, Sin Nombre virus (Muerto Canyon, Four Corners) is the most common hantavirus infection in the United States and is the main North American virus responsible for HPS. Although retrospective diagnostics show that the disease occurred decades earlier, it was not until 1993 when the first outbreak was recognized in the United States. Through 2011, 580 cases were reported in 34 states. Other strains native to North America known to cause HPS include Bayou, Black Creek Canal, New York, and Monongahela viruses. Outbreaks of HPS associated with other hantavirus types are also reported in Central and South America.

Hantaviruses are ubiquitous, with infections described in North and South America (New World hantaviruses) as well as Europe, Africa, and Asia (Old World hantaviruses).

The Hantaan viruses cause severe hemorrhagic fever with renal syndrome and are found primarily in Korea, China, and eastern Russia. The Seoul viruses produce a less severe form of disease and are found primarily in Korea and China. Cases of domestically acquired Seoul hantavirus

were recently described in the United States. The Puumala and Dobrava viruses are found in Scandinavia and Europe and are associated with a usually milder form of the syndrome, termed “nephropathia epidemica,” which presents with fever, headache, gastrointestinal symptoms, and impaired kidney function.

Aerosols of virus-contaminated rodent urine and feces are thought to be the main vehicle for transmission to humans. Human to human transmission is rare and confined to one hantavirus, the Andes virus. Occupation is the main risk factor for transmission of all hantavirus, with animal trappers, forestry workers, laboratory personnel, farmers, and military personnel considered to be at highest risk. Climate change appears to be impacting the incidence of hantavirus infection mainly through effects on reservoir ecology.

``Clinical Findings A. Symptoms and Signs ascular leakage is the hallmark of the disease for both V syndromes, with lungs being the main target on HPS and the kidneys on HFRS. HPS is a more severe disease than HFRS, with a mortality rate of about 40%. The clinical course of HPS is divided into a febrile prodrome, a cardiopulmonary stage, oliguric and diuretic phase followed by convalescence. A 14- to 17-day incubation period is followed by a prodromal phase, typically lasting 3–6 days, that is associated with myalgia, malaise, a fever of abrupt onset, gastrointestinal disturbance, headache, and chills. An ensuing cardiopulmonary phase is characterized by the acute onset of pulmonary edema. In this stage, cough is generally present, gastrointestinal manifestations may dominate the clinical presentations, and in severe cases, significant myocardial depression occurs. Acute kidney injury and myositis may occur. Sequelae include neuropsychological impairments in some HPS survivors.

HFRS manifests as mild, moderate, or severe illness depending on the causative strain, with a mortality rate of up to 12%. A 2- to 3-week incubation period is followed by a protracted clinical course, typically consisting of five distinct phases: febrile period, hypotension, oliguria, diuresis, and convalescence phase. Various degrees of renal involvement are usually seen, occasionally with frank hemorrhage. Pulmonary edema is not typically seen but when present usually occurs in the final stages of disease (oliguric and diuretic phase). Encephalitis and pituitary involvement are rare findings with hantavirus infection, although a few cases are reported with Puumala virus.

B. Laboratory Findings Laboratory features include hemoconcentration and elevation in lactate dehydrogenase, serum lactate, and hepatocellular enzymes. Early thrombocytopenia and leukocytosis (as high as 90,000 cells/mcL in HPS) are seen in both HFRS and HPS. In HPS, immunoblasts (activated lymphocytes with plasmacytoid features) can be seen in blood, lungs, kidneys, bone marrow, liver, and spleen. The severity of

Viral & Rickettsial Infections “nephropathia epidemica” correlates with plasma interleukin-6 levels.

The viremia of human hantavirus infections is shortterm, and therefore, viral RNA cannot be readily detected in the blood or urine of patients. An indirect fluorescent assay and enzyme immunoassay are available for detection of specific IgM or low-avidity IgG virus-specific antibodies. A plaque reduction neutralization test is considered the gold standard serologic assay and distinguishes between the different hantavirus species, although cross reaction between Old World and New World viruses exist. This test needs to be performed in a laboratory with appropriate biosafety (level 3).

CMDT 2013

1389

4. Yellow Fever ``

E sse n t i a l s o f d i a g n o s i s

Endemic area exposure (tropical South and Central America, Africa, but not Asia). `` Sudden onset of severe headache, aching in legs, and tachycardia. `` Brief (1 day) remission, followed by bradycardia, hypotension, jaundice, hemorrhagic tendency. `` Proteinuria, leukopenia, bilirubinemia, bilirubinuria. `` Rare and potentially fatal reactions to vaccination. ``

``Differential Diagnosis The differential diagnosis of the acute febrile syndrome seen with HFRS or early HPS includes scrub typhus, leptospirosis, and dengue. HPS requires differentiation from other respiratory infections caused by such pathogens as Legionella, Chlamydia, and Mycoplasma. Coxsackievirus infections should also be considered in the differential diagnosis.

``Treatment Treatment is mainly supportive. Cardiorespiratory support with vasopressors and sometimes extracorporeal membrane oxygenation are frequently needed in severe cases.

Intravenous ribavirin is used in HFRS (Hantaan virus) with some success in decreasing the severity of the kidney injury. Its effectiveness in HPS, however, is not established.

The evidence for the use of corticosteroids in the treatment of severe HFRS and HPS is mostly anecdotal.

``Prognosis The outcome is highly variable depending on severity of disease. In Sin Nombre virus infections, the persistence of elevated IgG titers correlates with a favorable outcome.

``Prevention Because infection is thought to occur by inhalation of rodent wastes, prevention is aimed at eradication of rodents in houses and avoidance of exposure to rodent excreta in rural settings, including forest service facilities.

Vaccine development is underway.

Macneil A et al. Hantavirus pulmonary syndrome. Virus Res. 2011 Dec;162(1–2):138–47. [PMID: 21945215] Rasmuson J et al. Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus. Eur J Clin Microbiol Infect Dis. 2011 May;30(5):685–90. [PMID: 21234633] Roig IL et al. Severe pulmonary involvement in a case attributed to domestically acquired Seoul hantavirus in the United States. Clin Infect Dis. 2012 Jan;54(1):91–4. [PMID: 22042876]

``General Considerations Yellow fever is a zoonotic flavivirus infection transmitted

by Aedes and jungle mosquitoes. It occurs in an urban and jungle cycle in Africa and in a jungle cycle in South America (where genetic studies suggest it arose through the slave trade 300–400 years ago). Epidemics have extended far into the temperate zone during warm seasons.

Infection is transmitted by an infected mosquito bite.

The incubation period in humans is 3–6 days. Adults and children are equally susceptible, though attack rates are highest among adult males because of their work habits.

Between 5% and 50% of infections are asymptomatic.

``Clinical Findings A. Symptoms and Signs 1. Mild form—Symptoms are malaise, headache, fever, retroorbital pain, nausea, vomiting, and photophobia.

Relative bradycardia, conjunctival injection, and facial flushing may be present.

2. Severe form—Severe illness develops in about 15%.

Initial symptoms are similar to the mild form, but a brief fever remission lasting hours to a few days is followed by a “period of intoxication” manifested by fever and relative bradycardia (Faget sign), hypotension, jaundice, hemorrhage (gastrointestinal, nasal, oral), and delirium that may progress to coma.

B. Laboratory Findings Leukopenia occurs, although it may not be present at the onset. Kidney disease with proteinuria is present, sometimes as high as 5–6 g/L, and usually disappears completely with recovery. Levels of liver enzymes and bilirubin can be remarkably abnormal with the levels of aspartate aminotransferase (AST) usually doubling those of alanine aminotransferase (ALT). Prothrombin time may be elevated as well. Serologic diagnosis is made by using capture ELISA to measure IgM during the acute and convalescent phases. Viral culture is used in epidemic settings.

Rapid test involving PCR and monoclonal antibodies assays against circulating viral antigens are becoming available.

1390

CMDT 2013

Chapter 32

``Differential Diagnosis It may be difficult to distinguish yellow fever from hepatitis, malaria, leptospirosis, louse-borne relapsing fever, dengue, and other hemorrhagic fevers on clinical evidence alone.

Albuminuria is a constant feature in yellow fever patients and its presence helps differentiate yellow fever from other viral hepatitides. Serologic confirmation is often needed.

``Treatment No specific antiviral therapy is available. Treatment is directed toward symptomatic relief and management of complications. If not in an endemic area, the patient should be isolated from mosquitoes to prevent transmission, since blood in the acute phase is potentially infectious.

``Prognosis The mortality rate of the severe form is 20–50%, with death occurring most commonly between the sixth and the tenth days. In survivors, the temperature returns to normal by the seventh or eighth day. The prognosis in any individual case is guarded at the onset, since sudden changes for the worse are common. Intractable hiccups, copious black vomitus, melena, anuria, jaundice, and elevated AST are unfavorable signs. Convalescence is prolonged, including 1–2 weeks of asthenia. Infection confers lifelong immunity to those who recover.

``Prevention Transmission is prevented through mosquito control. Live virus vaccine is highly effective and should be provided for immunocompetent persons over 9 months of age living in or traveling to endemic areas. Revaccination is recommended every 10 years for persons with continued exposure. Vaccine-induced reactions—including neurotropic (encephalitis-like syndrome) and viscerotropic (resembling yellow fever; with one space-time cluster of viscerotropic disease among five patients with four deaths reported from Ica, Peru in 2007) diseases—are reported particularly among patients aged 60 years or older, patients with immune dysfunction or with multiple sclerosis (whose rate of exacerbation in increased 1–5 weeks after vaccination).

The aged should probably not be vaccinated and those with immune dysfunction or multiple sclerosis should not be vaccinated, although HIV-infected persons with high CD4 counts safely receive the vaccine with an adverse event rate of about 3%. The safety of the vaccine in pregnant patients is not verified, and pregnant women should, if possible, defer travel to endemic areas (see Chapter 30). Eradication is difficult because of the sylvatic cycle (mainly maintained by non-human primates). Transmission from mother to infant during breastfeeding is documented.

An inactivated, alum-adjuvant vaccine is under development and in phase I studies appears to be safer than the live vaccine and is immunogenic.

The yellow fever virus vaccine shows genetic homology to a melanoma antigen, and in one retrospective study, patients who were given the vaccine showed a reduced risk of melanoma after 10 years.

Farez MF et al. Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis. Arch Neurol. 2011 Oct;68(10):1267–71. [PMID: 21670384] Kay A et al. Yellow fever vaccine seroconversion in travelers. Am J Trop Med Hyg. 2011 Oct;85(4):748–9. [PMID: 21976582] Monath TP et al. An inactivated cell-culture vaccine against yellow fever. N Engl J Med. 2011 Apr 7;364(14):1326–33.

[PMID: 21470010] Staples JE et al; Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).

MMWR Recomm Rep. 2010 Jul 30;59(RR-7):1–27. [PMID: 20671663] Whittembury A et al. Viscerotropic disease following yellow fever vaccination in Peru. Vaccine. 2009 Oct 9;27(43):5974–81.

[PMID: 19679215]

5. Tick-Borne Encephalitis ``

E sse n t i a l s o f d i a g n o s i s

Flaviviral encephalitis found in Eastern, Central, and occasionally Northern Europe and Asia. `` Transmitted via ticks or ingestion of unpasteurized milk. `` Long-term neurologic sequelae occur in 2–25% of cases. `` Therapy is largely supportive. `` Prevention is based on avoiding tick exposure, pasteurization of milk, and vaccination. ``

``General Considerations Tick-borne encephalitis (TBE), flaviviral infection caused

by TBE virus is the most common arbovirus infection transmitted by ticks in Europe. This infection is endemic in Russia and in eastern and central Europe, but cases are also well recognized in Western Europe and Japan. A toll-like receptor 3 mutation appears to be a risk factor for TBE. An estimated 10,000 to 12,000 cases occur each year in parts of Europe and the Baltic, with annual increases thought to be a function of increased recognition, climatic changes, and personal or social habits. TBE is endemic in parts of China as well, but information regarding its epidemiology is limited. TBE occurs predominantly in the late spring through fall. It is usually a consequence of exposure to infected ticks, although unpasteurized milk from viremic livestock is also a recognized form of transmission. Surges in cases over the last 20 years are thought to be a consequence of agricultural policies that alter land cover, host prevalence, climatic factors, and human behavior (including pesticide usage). The incubation period is 7–14 days for tick-borne exposures but only 3–4 days for milk ingestion. The principal reservoirs for TBE virus are small rodents; humans are an accidental host. The vectors for most cases are Ixodes ricinus (most of Europe, including Turkey, Iran, and the Caucasus) and Ixodes persulcatus (in the belt from Eastern Europe to China and Japan).

Viral & Rickettsial Infections Related viruses found in Eastern and mid-Western North America are the Powassan agent and the deer tick virus. Increasing prevalence of deer ticks in North America is thought to be responsible for the increased (but still small) number of North American cases of these two serologically indistinguishable viruses.

``Clinical Findings A. Symptoms and Signs Most cases are subclinical and many resemble a flu-like syndrome. There are two variants of clinical presentation: the Western subtype occurs mainly in the fall and is most severe among the elderly, and the Eastern subtype is more severe among children.

Western subtype disease is biphasic in which after 2–10 days of fever (usually with malaise, headache, and myalgias), a 1–21 day symptom-free interval leads to a second phase with resumed fevers followed by neurologic symptoms. Eastern subtype disease is progressive without an asymptomatic interval. The neurologic manifestations range from febrile headache (accounting for up to 50% of Eastern subtype cases) to aseptic meningitis and encephalitis with or without myelitis (preferentially of the cervical anterior horn) and spinal paralysis (usually flaccid). A myeloradiculitic form can also develop but is less common.

Double infection with Borrelia burgdorferi (the agent of Lyme disease; transmitted by the same tick vector) may result in a more severe disease. Homozygosity for a 32bp deletion in the gene coding for the chemokine receptor CCR5, producing its complete loss of function, predisposes to severe disease. Mortality in TBE is usually a consequence of brain edema or bulbar involvement.

B. Diagnosis Leukocytosis and neutrophilia are common. Abnormal cerebrospinal fluid findings include a pleocytosis that may persist for up to 4 months. Neuroimaging shows hyperintense lesions in the thalamus, brainstem, and basal ganglia. TBE virus IgM and IgG are detected by ELISA techniques when neurologic symptoms occur. Cross-reactivity with other flaviviruses or a vaccinated state (see below) may require confirmation by detection of TBE virus–specific antibodies in cerebrospinal fluid. RT-PCR of blood (at earlier stages of the disease) or cerebrospinal fluid can sometimes, if available, assist with the diagnosis. TBE virus can be differentiated from serologically indistinguishable viruses (Powassan agent and deer tick virus) by plaque-reduction neutralization tests.

``Complications The main sequela of disease is paresis, which occurs in up to 10% of Western and up to 25% of Eastern subtype disease. Other causes of long-term morbidity include protracted cognitive dysfunction and persistent spinal nerve paralysis. The postencephalitic syndrome, characterized by headache, difficulties concentrating, balance disorders, dysphasia, hearing defects, and chronic fatigue, occurs with both subtypes. A progressive motor neuron disease and

CMDT 2013

1391

partial continuous epilepsy are complications seen with the Eastern subtype.

``Differential Diagnosis The differential diagnosis includes other causes of aseptic meningitis such as enteroviral infections, herpes simplex encephalitis, and a variety of tick-borne pathogens including tularemia, the rickettsial diseases, babesiosis, Lyme disease, poliomyelitis (no longer reported from Eastern Europe) and other flaviviral infections.

``Treatment Therapy is largely supportive. Some clinicians believe corticosteroids may be useful, although no controlled clinical trials exist.

``Prevention There are two inactivated TBE virus vaccines for adults and two vaccines for children licensed in Europe. Their effectiveness is about 99% when properly administered. The initial vaccination schedule requires 1 year with boosters every 3–5 years. There are decreased antibody titers and booster response in recipients of TBE vaccines who are over 50 years of age, indicating the need for a modified immunization strategy in older patients. Neuritis and neuropathies of peripheral nerves (plexus neuropathy—paresis of lower limb muscles, polyradiculopathy) are recognized complications of TBE vaccination. Rare cases of olfactory dysfunction are also reported. Other prevention recommendations include avoidance of tick exposure and pasteurization of milk.

Andersson CR et al. Vaccine failures after active immunisation against tick-borne encephalitis. Vaccine. 2010 Apr 1;28(16): 2827–31. [PMID: 20167301] Centers for Disease Control and Prevention (CDC). Tick-borne encephalitis among U.S. travelers to Europe and Asia—2000– 2009. MMWR Morb Mortal Wkly Rep. 2010 Mar 26;59(11): 335–8. [PMID: 20339345] Kindberg E et al. A functional Toll-like receptor 3 gene (TLR3) may be a risk factor for tick-borne encephalitis virus (TBEV) infection. J Infect Dis. 2011 Feb 15;203(4):523–8. [PMID: 21216866] Weinberger B et al. Decreased antibody titers and booster respo­ nses in tick-borne encephalitis vaccinees aged 50–90 years.

Vaccine. 2010 Apr 30;28(20):3511–5. [PMID: 20332047]

6. Colorado Tick Fever ``

E sse n t i a l s o f d i a g n o s i s

Onset 1–19 days (average, 4 days) following tick bite. `` Fever, chills, myalgia, headache, prostration. `` Leukopenia, thrombocytopenia. `` Second attack of fever after remission lasting 2–3 days. ``

1392

CMDT 2013

Chapter 32

``General Considerations

``Prevention

Colorado tick fever is a reportable acute reovirus infection transmitted by Dermacentor andersoni tick bite. The disease is limited to the western United States and Canada and is most prevalent during the tick season (March to November). There is a discrete history of tick bite or exposure in 90% of cases. The virus infects the marrow erythrocyte precursors, leading to viremia lasting the life span of the infected red cells. Blood transfusions can be a vehicle of transmission.

The essence of prevention is vector (tick) control, particularly from March to November.

``Clinical Findings A. Symptoms and Signs The incubation period is 3–6 days. The onset is usually abrupt with fever (to 38.9–40.6 °C), sometimes with chills.

Severe myalgia, headache, photophobia, anorexia, nausea and vomiting, and generalized weakness are prominent.

Physical findings are limited to an occasional faint rash.

The acute symptoms resolve within a week. Remission is followed in 50% of cases by recurrent fever and a full recrudescence lasting 2–4 days. In an occasional case, there may be three bouts of fever.

The differential diagnosis includes influenza, Rocky Mountain spotted fever, numerous other viral infections and, in the right setting, relapsing fevers.

Brackney MM et al. Epidemiology of Colorado tick fever in Montana, Utah, and Wyoming, 1995–2003. Vector Borne Zoonotic Dis. 2010 May;10(4):381–5. [PMID: 19725767]

7. Chikungunya Fever Chikungunya (“that which bends up” in Bantu) is a flaviviral infection transmitted to humans by Aedes aegypti and Aedes albopictus (the “Asian tiger mosquito”) and is considered a classic “arthrogenic” virus. The virus is indigenous to tropical Africa and Asia with recent outbreaks reported from areas that adjoin the Indian Ocean, Southeast Asia and its neighboring islands (2005–2007), South India (2005) a major outbreak in Reunión Island, but also from Europe including an outbreak in Italy (2007) . The attack rates are often as high as 50%. The endemicity of A aegypti in the Americas and the introduction of A albopictus into Europe and the New World raise the concerns of a global extension of the epidemic. The Rh-negative population appears to be immune. There are reports of cases of Chikungunya coinfection with yellow fever, malaria, and dengue fever.

``Clinical Findings

B. Laboratory Findings

A. Symptoms and Signs

Leukopenia (2000–3000/mcL) with a shift to the left and atypical lymphocytes occurs, reaching a nadir 5–6 days after the onset of illness. Thrombocytopenia may occur. Viremia may be demonstrated by inoculation of blood into mice or by fluorescent antibody staining of the patient’s red cells (with adsorbed virus). An RT-PCR assay may be used to detect early viremia. Detection of IgM by capture ELISA or plaque reduction neutralization is possible after 2 weeks from symptom onset and is the most frequently used diagnostic tool.

After an incubation period of 1–12 days (average 2–4), there is an abrupt onset of fever; headache; intestinal complaints; myalgias; and arthralgias/arthritis affecting small, large, and axial joints. The simultaneous involvement of more than 10 joints and the presence of tenosynovitis (especially in the wrist) are characteristic. The stooped posture of patients gives the disease its name. Joint symptoms persist for 4 months in 33% and linger for years in about 10%. A centrally distributed pruritic maculopapular rash is reported in 50% of the patients, but it can be bullous with sloughing in children. Mucosal disease occurs in about 15%. Facial edema and localized petechiae are reported. Neurologic complications, including encephalitis, myelopathy, peripheral neuropathy, myeloneuropathy, and myopathy, are usually associated with a good outcome. Rare cases of mother-to-child transmission at birth are reported. The virus has no observable effect on the outcome of pregnancy.

In infants, primary manifestations of disease include fever, lethargy, acrocyanosis, and erythema evolving into vesiculobullous lesions. Hemorrhagic fever–like presentations are exceptional. Coinfection with other respiratory viruses, in particular dengue, is common. Death is rare and usually related to underlying comorbidities.

``Complications Aseptic meningitis (particularly in children), encephalitis, and hemorrhagic fever occur rarely. Malaise may last weeks to months. Fatalities are very rare. There is one reported case of spontaneous abortion and multiple congenital anomalies associated with Colorado tick fever infection during pregnancy.

``Treatment No specific treatment is available. Ribavirin has shown efficacy in an animal model. Antipyretics are used, although salicylates should be avoided due to potential bleeding with the thrombocytopenia seen in patients with Colorado tick fever. Tick avoidance is the best prevention.

``Prognosis The disease is usually self-limited and benign.

B. Laboratory Findings Diagnosis is made epidemiologically and clinically. Mild leukopenia occurs as does thrombocytopenia, which is seldom severe. Elevated inflammatory markers do not correlate well with the severity of arthritis. Radiographs of affected joints are normal.

Viral & Rickettsial Infections Serologic confirmation requires elevated IgM titers or fourfold increase in convalescent IgG levels using an ELISA. RT-PCR and culture techniques (viral isolation in insect or mammalian cell lines or by inoculation of mosquitoes or mice) are seldom available. Suspected cases in the United States should be promptly reported to public health authorities including the CDC Arboviral Diseases Branch, 970-221-6400. The differential includes other tropical febrile diseases, such as malaria, leishmaniasis, or dengue.

``Treatment & Prevention Treatment is largely supportive with nonsteroidal anti-­ inflammatory drugs. Chloroquine may be useful for managing refractory arthritis. No vaccine is available, and prevention relies on avoidance of the mosquito vectors.

Vertical transmission is documented, but teratogenicity is not established. Prophylaxis with specific Chikungunya immuno­globulins may be useful for exposed neonates or immunosuppressed persons. Establishing the immuno­ pathologic profile of acute versus chronic cases is an ongoing area of investigation.

Powers AM. Chikungunya. Clin Lab Med. 2010 Mar;30(1):209–19.

[PMID: 20513548] Roques P et al. Chikungunya fever: focus on peripheral markers of pathogenesis. J Infect Dis. 2011 Jan 15;203(2):141–3.

[PMID: 21288810]

COMMON VIRAL RESPIRATORY INFECTIONS 1. Respiratory Syncytial Virus (RSV) & Other Paramyxoviruses ``

E sse n t i a l s o f d i a g n o s i s

RSV is a major cause of morbidity and mortality at the extremes of age. `` Care for patients with RSV infections is largely supportive. `` A monoclonal antibody against RSV, palivizumab, is good but expensive prophylaxis among patients with certain at-risk cardiopulmonary conditions. `` No active vaccination for RSV is available to date. ``

``General Considerations Respiratory syncytial virus (RSV) is a paramyxovirus that causes annual outbreaks during the wintertime with usual onset of pulmonary symptoms between mid October and early January in the United States (excluding Florida).

There are two major subtypes, A and B. RSV is the leading cause of hospitalization in US children, with annual hospitalization rates of 17 per 1000 children under 6 months and 3 per 1000 children under 5 years of age. Risk factors for infection in children include prematurity, low birth weight, younger age (especially younger than 6 months), bronchopulmonary dysplasia, congenital heart disease, later

CMDT 2013

1393

birth order, and day care exposure. RSV infection in children is associated with persistence of airway reactivity later in life.

RSV also causes upper and lower respiratory tract infection in adults with increased severity in the elderly, persons with severe combined immunodeficiency, and following lung or bone marrow transplantation (because CD8 T cells are not available for viral clearance). Recurrent infections occur throughout life. The virus enters through contact with mucosal surfaces. The average incubation period is 5 days.

In immunocompromised patients, such as bone marrow transplant recipients, serious pneumonia can occur and outbreaks with a high mortality rate (> 70%) are reported.

Other paramyxoviruses important in human disease include human metapneumovirus, parainfluenza virus, and Nipah virus.

Human metapneumovirus is less common and less pathogenic than RSV and is mainly a seasonal virus circulating during late winter to early spring. It is divided into subgroups A and B. Clinical presentations include mild upper respiratory tract infections to severe lower respiratory tract infections (eg, bronchiolitis, croup, and pneumonia) among slightly older children and lower respiratory tract (sometimes severe) infections among immunocompromised and elderly adults. In lung transplant recipients, human metapneumovirus is a common cause of respiratory illness and is thought to increase the risk of acute and chronic graft rejection.

Human parainfluenza viruses (HPIVs) are commonly seen in children and are the most common cause of laryngotracheitis (croup). Four different serotypes are described, and they differ in their clinical presentations as well as epidemiology. HPIV-1 and HPIV-2 are responsible for croup. HPIV-3 is associated with bronchiolitis and pneumonia. HPIV-4 is a less frequently reported pathogen.

Reinfections are common throughout life. HPIVs can also cause severe disease in the elderly, immunocompromised persons, and those with chronic illnesses.

Nipah virus, is a highly virulent paramyxovirus first described in 1999. Cases are concentrated mainly in Southeast Asia (Malaysia, Singapore, Bangladesh and India). Fruit bats are identified as the natural host of the virus. Direct pig-human, cow-human, human-human, and nosocomial transmission are reported. Nipah virus causes acute encephalitis with a high fatality rate (67–92%), although respiratory symptoms are also described. Cranial nerves palsies, encephalopathy, and dystonia are among neurologic sequelae (15–32%) seen on infected individuals. Relapses occurring weeks and months after initial infection are described (3.4–7.5%).

Bocavirus infections are discussed under Erythrovirus (parvovirus) infections below.

``Clinical Findings A. Symptoms and Signs In RSV bronchiolitis, proliferation and necrosis of bronchiolar epithelium develop, producing obstruction from

1394

CMDT 2013

Chapter 32

sloughed epithelium and increased mucus secretion. Signs include low-grade fever, tachypnea, and wheezes. Apnea is a common presenting symptom. Hyperinflated lungs, decreased gas exchange, and increased work of breathing are present. In children, RSV is globally the most common cause of acute lower respiratory infection and also a common cause of acute and recurrent otitis media. In patients with Down syndrome, RSV develops at a later age and is associated with more protracted hospitalizations.

B. Laboratory Findings A rapid diagnosis of RSV infection is made by viral antigen identification of nasal washings using an ELISA or immunofluorescent assay. Culture of nasopharyngeal or lower respiratory tract secretions remain the standard of diagnosis, although PCR is increasingly used. Coinfection with bacteria is relatively uncommon in industrialized countries. Coinfection with B pertussis and other viruses occurs in a subset of patients hospitalized for RSV infection. Detection of parainfluenza virus usually requires culture, but tests for rapid detection of viral antigens with immunofluorescence or ELISA, and PCR techniques are also available. Human metapneumovirus is best diagnosed

by PCR. ELISA (serum and cerebrospinal fluid) and PCR (urine, respiratory secretions but not blood) are both used for Nipah virus infection diagnosis.

``Treatment & Prevention Treatment of RSV consists of supportive care, including hydration, humidification of inspired air, and ventilatory support as needed. Neither bronchodilating agents nor corticosteroids have demonstrated efficacy in bronchiolitis although individual patients with significant bronchospasm or history of asthma might respond to them.

The use of nebulized or intravenous ribavirin can be considered in high-risk patients, such as those with a history of bone marrow transplantation, although it is of limited benefit. Pregnant women, including hospital staff, should avoid ribavirin exposure. Therapy with surfactant lacks evidence to make recommendations on its use. In the United States, RSV immunoglobulin G is no longer available and has been replaced with palivizumab, a monoclonal RSV antibody. Prophylactic administration of palivizumab (15 mg/kg intramuscularly monthly during the season of high transmission) is recommended for infants with highrisk factors, such as chronic lung disease of prematurity and congenital heart disease. Future studies may entail the use of small inhibitory RNA molecules and of new monoclonal antibodies under development, such as motavizumab (awaiting FDA approval).

No RSV vaccine is licensed to date; a past formalin-­ inactivated RSV vaccine was complicated with adverse outcomes and was discontinued. A phase-1 study of a live attenuated RSV given with the parainfluenza virus type 3 vaccine is promising with good seroresponse and safety profile. Other vaccine attempts have included live attenuated vaccines (which failed to show significant clinical protection or immunogenicity), protein subunit vaccines, and live viral vector vaccines (all with limited data). The

use of RNA interference therapy in lung transplant patients may have some beneficial effects.

Prevention in hospitals entails rapid diagnosis, handwashing, contact isolation, and perhaps passive immunization. The use of conjugated pneumococcal vaccination appears to decrease the incidence of concomitant pneumonia associated with viral infections in children in some countries.

Therapeutic modalities for human metapneumovirus and parainfluenza virus infections under investigation include intravenous ribavirin administration. During the initial Nipah virus outbreak, ribavirin was used empirically, although its efficacy remains questionable. Human­ ized monoclonal antibodies used in animal models show promising results.

Bernstein DI et al; MI-CP149 Investigators. Phase 1 study of the safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in seronegative children. Pediatr Infect Dis J. 2012 Feb;31(2):109–14.

[PMID: 21926667] Centers for Disease Control and Prevention (CDC). Respiratory syncytial virus—United States, July 2007–June 2011. MMWR Morb Mortal Wkly Rep. 2011 Sep 9;60(35):1203–6. [PMID: 21900874] Kroll JL et al. Human metapneumovirus. Semin Respir Crit Care Med. 2011 Aug;32(4):447–53. [PMID: 21858749] Ksiazek TG et al. A review of Nipah and Hendra viruses with an historical aside. Virus Res. 2011 Dec;162(1–2):173–83. [PMID: 21963678] Shadman KA et al. A review of palivizumab and emerging therapies for respiratory syncytial virus. Expert Opin Biol Ther.

2011 Nov;11(11):1455–67. [PMID: 21831008] Zamora MR et al. RNA interference therapy in lung trans­­ plant patients infected with respiratory syncytial virus. Am J Respir Crit Care Med. 2011 Feb 15;183(4):531–8. [PMID: 20851929]

2. Seasonal Influenza ``

E sse n t i a l s o f d i a g n o s i s

Cases usually in epidemic pattern.

Abrupt onset with fever, chills, malaise, cough, coryza, and myalgias. `` Aching, fever, and prostration out of proportion to catarrhal symptoms. `` Leukopenia. `` ``

``General Considerations Influenza (an orthomyxovirus) is a highly contagious disease transmitted by the respiratory route. Transmission occurs primarily by droplet nuclei rather than fomites or direct contact. There are three types of influenza viruses.

While type A can infect a variety of mammals (humans, swine, horses, etc) and birds, types B and C almost exclusively infect humans. Type A viruses are further divided into subtypes based on the hemagglutinin (H) and the

Viral & Rickettsial Infections neuraminidase (N) expressed in their surface. There are 16 subtypes of hemagglutinin and 9 subtypes of neuraminidase. Annual epidemics usually appear in the fall or winter (although sporadic cases occur as summer outbreaks in northern areas such as Alaska or the southern hemisphere).

Epidemics affect 10–20% of the global population on average each year and are typically the result of frequent minor antigenic variations of the virus, or antigenic drift, which are more common in influenza A virus. On the other hand, pandemics—associated with higher mortality—appear at longer and varying intervals (decades) as a consequence of a major genetic reassortment of the virus (antigenic shift) or the mutation of an animal virus that adapts to the human (as with the pandemic virus of 1918 with H1N1 properties).

Currently, the main circulating seasonal influenza viruses are the human-origin A (H3N2) subtype (seasonal H1N1 is no longer widely prevalent), as well as two lineages of type B. A highly pathogenic avian (H5N1) subtype that caused occasional human infections in Asia, Africa (Egypt), and Europe over the last decade is of continued global concern. The novel swine-origin influenza A (pandemic H1N1) virus, which emerged in Mexico in March of 2009 and quickly spread through North America, is of particular concern for pregnant women and immunosuppressed persons. Infections due to avian-origin and the 2009 H1N1 viruses are covered in the next sections.

``Clinical Findings A. Symptoms and Signs Seasonal influenza viruses of antigenic types A and B produce clinically indistinguishable infections, whereas type C usually causes a minor illness. The incubation period is 1–4 days. In unvaccinated persons, uncomplicated influenza often begins abruptly. Symptoms include fever, chills, malaise, myalgias, substernal soreness, headache, nasal stuffiness, and occasionally nausea. Fever lasts 1–7 days (usually 3–5). Coryza, nonproductive cough, and sore throat are present. Elderly patients may present with only lassitude and confusion, often without fever or respiratory symptoms. Signs include mild pharyngeal injection, flushed face, and conjunctival redness. Moderate enlargement of the cervical lymph nodes may be observed. The presence of fever (> to 38.2°C) and cough during influenza season is highly predictive of influenza infection in those older than 4 years of age.

B. Laboratory Findings Leukopenia is common, but leukocytosis can occur.

Proteinuria may be present. The virus may be isolated from throat swabs or nasal washings by inoculation of embryonated eggs or cell cultures. Rapid immunofluorescence assays and enzyme immunoassays for detection of influenza antigens from nasal or throat swabs are becoming widely available. The sensitivity of such assays is suboptimal (60–80%) and only a few can distinguish between influenza A and B. More sensitive nucleic acid (PCR) techniques are increasingly accessible. Complement-fixing and

CMDT 2013

1395

hemagglutination-inhibiting antibodies appear during the second week. Microarrays may be used in the future to monitor the spread of pathogenic viral variants.

``Complications Influenza causes necrosis of the respiratory epithelium, which predisposes to secondary bacterial infections. In turn, bacterial enzymes (eg, proteases, trypsin-like compounds, and streptokinase) activate influenza viruses. Frequent complications are acute sinusitis, otitis media, purulent bronchitis, and pneumonia. Children under 5 years of age, pregnant women, residents of nursing homes and longterm–care facilities, the elderly (aged 65 years or older), children and teens under 19 years of age who are receiving long-term aspirin therapy, and persons with underlying medical conditions (pulmonary, renal, cardiovascular, hepatic, hematologic, neurologic and neurodevelopmental conditions and immune-deficient conditions such as HIV) are at high risk for complications. Persons who are morbidly obese (body mass index > 40), American Indians, and Alaskan natives are also at high risk for complications.

Primary influenza pneumonia may occur, particularly in young children with cardiovascular disease and pregnant women, and is associated with a high mortality.

Secondary bacterial pneumonia due to pneumococci, staphylococci, or Haemophilus spp is common. Pericarditis and myocarditis occur rarely. There is an association of acute myocardial infarction with preceding respiratory infection, including influenza; a UK study showed that influenza vaccination is associated with a lower rate of acute myocardial infarction. Rhabdomyolysis is a rare late complication of influenza.

Reye syndrome (fatty liver with encephalopathy) is a rare and severe complication of influenza (usually B type) and other viral diseases (eg, varicella), particularly in young children. It consists of rapidly progressive hepatic failure and encephalopathy, and there is a 30% mortality rate. The pathogenesis is unknown, but the syndrome is associated with aspirin use in the management of viral infections. Hypoglycemia, elevation of serum aminotransferases and blood ammonia, prolonged prothrombin time, and change in mental status all occur within 2–3 weeks after onset of the viral infection. Histologically, the periphery of liver lobules shows striking fatty infiltration and glycogen depletion. Treatment is supportive and directed toward the management of cerebral edema. Other encephalopathic complications of influenza are uncommon and include an acute necrotizing encephalopathy associated with disseminated intravascular coagulation and cytokine storm, with worsening when treated with certain nonsteroidal anti-inflammatory drugs (diclofenac and mefenamic acid), and an acute encephalopathy associated with febrile seizures and the use of theophylline. Influenza infections are an infrequent trigger of Guillain-Barré ­syndrome.

``Treatment Many patients with influenza prefer to rest in bed.

Analgesics and a cough mixture may be used. Treatment should be considered for those with a suggestive clinical

1396

CMDT 2013

Chapter 32

presentation or with laboratory confirmed influenza and at high risk for developing complications (nursing home residents; patients with chronic pulmonary, cardiovascular, kidney, or liver disease; those with diabetes mellitus, active malignancy, immunosuppression, or impairment for managing respiratory secretions), or living with persons at significant risk for them. Maximum benefit is expected with the earliest initiation of therapy.

Although the benefit of antiviral therapy after 48 hours of illness is reduced, it should be considered if the patient is hospitalized.

The neuraminidase inhibitors, either inhaled zanamivir, 10 mg (2 inhalations) twice daily for 5 days, or oral oseltamivir, 75 mg twice daily for 5 days, are equally effective in the treatment of susceptible strains of influenza. Clinical trials show a reduction in the duration of symptoms as well as secondary complications, such as otitis, sinusitis, or pneumonia, but not in the rate of hospitalizations or mortality when using these agents. When administered early, antiviral medications (neuraminidase inhibitors) are most effective. Since high levels of resistance to the adamantanes (amantadine and rimantadine) persist among 2009 influenza A (H1N1) and A (H3N2) viruses and these agents are not effective against influenza B viruses, adamantanes are generally not recommended for treatment. Resistance to neuraminidase inhibitors (oseltamivir and zanamivir) can occur with prolonged use in immunocompromised patients or in avian (H5N1)-infected patients. High rates (approximately 25%) of oseltamivir resistance in influenza A (H1N1) viruses were reported in surveillance data from several areas in Europe and Africa between 2007 and 2009 associated with a genetic mutation (H275Y) in the neuraminidase protein.

With the advent of the pandemic H1N1 strain (below) circulating levels of seasonal H1N1 were so low that resistance to oseltamivir was not a significant problem. Oseltamivirresistant pandemic H1N1 isolates are reported with the same H275Y mutation that shows zanamivir sensitivity.

Since December 2010, there is no evidence that significant neuraminidase resistance is occurring among pandemic H1N1 isolates and resistance among current seasonal influenza A (H1N1), influenza A (H3N2), and influenza B isolates is rare. The association of oseltamivir resistance with possible pneumonia is reported but requires further study.

Zanamivir is relatively contraindicated among persons with asthma because of the risk of bronchospasm and is not formulated for use in mechanically ventilated patients.

Transient neuropsychiatric events, occasionally resulting in self-injury and death, have been reported post marketing for both neuraminidase inhibitors. Patients receiving these drugs should be closely monitored for any unusual behavior, and healthcare professionals should be notified immediately if such signs occur. Laninamivir is a long-acting neuraminidase inhibitor used for the treatment of seasonal influenza, including infection caused by oseltamivir-resistant virus. It remains under phase III clinical trials in America but is licensed in Japan. Ribavirin (unlabeled usage, 1.1 g/d, diluted to 20 mg/ mL, delivered as small particle aerosol with oxygen over 12–18 hours a day for 3–7 days [see Table 32–1]) may be effective in severely ill patients with influenza A or B. In vivo studies often do not mimic efficacy in vitro.

The neuraminidase inhibitor, peramivir, is indicated for intravenous use in patients with 2009 H1N1 (available through the CDC’s Emergency Use Authorization).

Antibacterial antibiotics should be reserved for treatment of bacterial complications. Acetaminophen or ibuprofen rather than aspirin should be used for fever in children.

``Prognosis The duration of the uncomplicated illness is 1–7 days, and the prognosis is excellent in healthy, nonelderly adults.

Purulent bronchitis and bronchiectasis may result in chronic pulmonary disease and fibrosis that persist throughout life. Most fatalities are due to bacterial pneumonia although exacerbations of other diseases processes, in particular cardiac diseases, occur which contributed to the overall increase in fatalities. Influenza pneumonia has a high mortality rate among pregnant women and persons with a history of rheumatic heart disease. Current mortality is low except in debilitated individuals.

If the fever recurs or persists for more than 4 days with productive cough and white cell count over 10,000/mcL, secondary bacterial infection should be suspected. Pneumococcal pneumonia is the most common secondary infection, and staphylococcal pneumonia is the most serious.

``Prevention Annual administration of influenza vaccine is the most effective measure for preventing influenza and its complications. Vaccines available for use in the United States are the FDA-approved trivalent inactivated influenza vaccine (TIV) and the trivalent live attenuated influenza vaccine (LAIV). They both contain antigens from 1 strain each of pandemic influenza A (H1N1), influenza A (H3N2), and influenza B. All persons 6 months of age are greater are recommended to receive annual influenza vaccination.

The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists’ Committee recommend influenza vaccination for all women who will be pregnant through the influenza season (October through May in the United States) and vaccination early in the season regardless of gestational age. No study to date has shown any adverse consequence of inactivated influenza vaccine in pregnant women or their offspring. The FDA has approved Fluzone High-Dose, a TIV containing four-times more hemagglutinin than standard TIV, for persons age 65 or older as well as Fluzone intra­ dermal trivalent vaccine (15 mcg hemagglutinin per strain) which is now commercially available. The intradermal vaccine is equally immunogenic and safe but more expensive than the traditional intramuscular vaccine.

The LAIV is available for use in healthy individuals between 2 and 49 years of age; it should not be given to adult women who are pregnant. For children, LAIV shows superior efficacy over TIV. The seasonal influenza vaccines can reduce influenza hospitalizations by an estimated 61%.

Viral & Rickettsial Infections All of these vaccines are contraindicated in persons with well-substantiated hypersensitivity to chicken eggs or other components of the vaccine (skin testing can be performed by an allergist), in persons with a history of Guillain-Barré syndrome, or in persons with an acute febrile illness until symptomatic improvement. Concom­ itant warfarin or corticosteroid therapy is not a contraindication to influenza vaccination. Side effects are infrequent and include tenderness, redness, or induration at the intramuscular site of the TIV and mild upper respiratory symptoms for the LAIV. Chemoprophylaxis is considered for individuals when vaccination is contraindicated and in those exposed to an infected patient within 2 weeks after vaccination with TIV. It is not necessary and is contraindicated with the LAIV, since this vaccine confers more rapid protection. Other circumstances that warrant consideration of chemoprophylaxis include outbreaks in long-term–care facilities, persons living with or in close contact with high-risk individuals, persons with immune deficiencies who might not respond to vaccination, unvaccinated staff during response to an outbreak in a closed institutional setting with residents at high risk, and first responders to epidemic situations.

Chemoprophylaxis against influenza A and B is traditionally accomplished with a single daily dose of the neuraminidase inhibitors oseltamivir (75 mg/d, oral) or zanamivir (10 mg/d, inhaled). These agents reduce the attack rate among unvaccinated individuals if begun within 48 hours after exposure. The CDC recommends chemoprophylaxis for 7 days after exposure. For outbreak control in long-term–care facilities and hospitals, a minimum of 2 weeks is recommended, including in vaccinated person, and until 1 week after identification of the last known case.

Zanamivir should not be given as chemoprophylaxis to asthmatic persons, nursing home residents, or children under 5 years of age. Hand hygiene and surgical facemasks appear to prevent household transmission of influenza virus isolates when implemented within 36 hours of recognition of symptoms in an index patient. Such nonpharmaceutical interventions assist in mitigating the spread of pandemic and interpandemic influenza to nonvaccinated persons. Vaccination remains the mainstay of prevention.

``When to Admit • • • •

Limited availability of supporting services.

Pneumonia or decreased oxygen saturation.

Changes in mental status.

Consider with pregnancy.

American College of Obstetricians and Gynecologists Committee on Obstetric Practice. ACOG Committee Opinion No. 468: Influenza vaccination during pregnancy. Obstet Gynecol.

2010 Oct;116(4):1006–7. [PMID: 20859176] Centers for Disease Control and Prevention (CDC). FluView: a weekly influenza surveillance report. http://www.cdc.gov/flu/ weekly Centers for Disease Control and Prevention (CDC). Licensure of a high-dose inactivated influenza vaccine for persons aged

CMDT 2013

1397

≥ 65 years (Fluzone High-Dose) and guidance for use-United States, 2010. MMWR Morb Mortal Wkly Rep. 2010 Apr 30; 59(16):485–6. [PMID: 20431524] Fiore AE et al; Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010 Aug 6;59(RR–8):1–62. [PMID: 20689501] Talbot HK et al. Effectiveness of seasonal vaccine in preventing confirmed influenza-associated hospitalizations in community dwelling older adults. J Infect Dis. 2011 Feb 15; 203(4):500–8. [PMID: 21220776] Thorlund K et al. Systematic review of influenza resistance to the neuraminidase inhibitors. BMC Infect Dis. 2011 May 19;11:134. [PMID: 21592407]

3. Avian Influenza (H5N1) ``

E sse n t i a l s o f d i a g n o s i s

Cases to date in humans, mostly from Southeast Asia and Egypt. `` Clinically indistinguishable from influenza. `` Epidemiologic factors assist in diagnosis. `` Rapid antigen assays are the means of confirming diagnosis. ``

``General Considerations The normal hosts for avian influenza viruses are aquatic waterfowl. Although avian influenza was first recognized in Italy in 1878, the current outbreak of highly pathogenic influenza A subtype (H5N1) in poultry was recognized in 1997 in Hong Kong and was followed by the first documented human cases. A massive slaughter of poultry was attempted to contain the disease. Outbreaks of H5N1 influenza in poultry emerged in 2003 and now involve more than 65 countries of East and Southeast Asia, Eurasia, Western and Eastern Europe, Northern Africa, and Haiti.

The 562 confirmed human cases as of October 2011 include 332 deaths (79% of cases and 78% of deaths are reported from 3 countries, Egypt, Indonesia, and Vietnam) (details maintained and updated by Global Outbreak Alert and Response Network, World Health Organization).

Although highly contagious among birds, the transmission of this H5N1 strain from human to human is inefficient and not sustained. Evidence from cluster outbreaks suggests that host genetic susceptibility limits human to human transmission. The result is only rare cases of person-to-person infection. Occasional transmission to other mammals, including domestic cats and dogs, is also documented.

Cases of influenza H7N7, transmitted from poultry to persons, especially poultry handlers and their contacts in the Netherlands occurred in 2003.

Rare cases of influenza H9N2, another poultry pathogen, are reported from Bangladesh and human to human transmission of this pathogen is not documented.

1398

CMDT 2013

Chapter 32

Most human cases occur after exposure to infected poultry or surfaces contaminated with poultry droppings.

Because infection in humans is associated with a mortality rate > 50% (over 80% [91 of 113] for Indonesian cases) and the avian H5N1 subtype continues to spread among birds (with many parts of Southeast Asia now considered endemic for the virus), there is worldwide concern that the virus may undergo genetic reassortment or mutation (as with the 1918 strain) and develop greater human to human transmissibility with the potential to produce a global ­pandemic.

``Clinical Findings A. Symptoms and Signs Distinguishing avian influenza from regular influenza is difficult. History of exposure to dead or ill poultry in the prior 10 days, recent travel to Southeast Asia or Egypt, or contact with known cases should be investigated. The symptoms and signs include predominantly respiratory symptoms (cough and dyspnea), but a variety of other systems may be involved, producing headaches and gastrointestinal complaints in particular. Subclinical disease is relatively rare. With cytokines responsible for much of the pathology, prolonged febrile states and generalized malaise are common. Children are preferentially impacted.

Respiratory failure is the usual cause of death.

B. Laboratory Findings Current commercial rapid antigen tests are not optimally sensitive or specific for detection of H5N1 influenza but are still first-line diagnostic tests because of their widespread availability. Diagnostic yield can be improved by early collection of samples. More sensitive RT-PCR assays are available through many hospitals and state health departments. An initial negative result in the right clinical setting warrants retesting. Throat or lower respiratory swabs may provide higher yield of detection than nasal swabs. When highly pathogenic strains (eg, H5N1) are suspected, extreme care in the handling of these samples must be observed during preliminary testing. Positive samples must then be forwarded to the appropriate public health authorities for further investigations (eg, culture) in laboratories with the adequate level of biosafety (level 3).

``Treatment Resistance of avian H5N1 influenza strains to amantadine and rimantadine is present in most geographic areas.

The current first-line recommendation is to use the neuraminidase inhibitor oseltamivir, 75 mg orally twice daily for 5 days administered within 48 hours from onset of illness. Overall oseltamivir, by modeling, is associated with a 49% reduction in mortality from H5N1 infections.

A higher dose (150 mg twice daily), longer duration (7–10 days), and possible combination therapy with amantadine or rimantadine (in countries where A [H5N1] viruses are likely to be susceptible to adamantanes) may be considered in patients with pneumonia or progressive

disease. Evidence of resistance to oseltamivir is reported.

Although inhaled zanamivir is proven effective in treating seasonal influenza, no data of its efficacy against H5N1 strains are available. Therapy should still be considered for patients when severe avian influenza disease persists after several days of onset. Parenteral treatment with unapproved (but under study) parenteral peramivir or zanamivir preparations may be considered.

``Prevention Postexposure prophylaxis with 75 mg of oseltamivir orally once daily for 7–10 days should be given to household contacts of documented cases. Personnel exposed to patients should be monitored for symptoms. Careful surveillance for human cases and prudent stockpiling of medications with establishment of an infrastructure for dissemination are essential modalities of control.

Nonpharmacologic means of control include masks, social distancing, quarantine, travel limitations, and infrastructure development, particularly for emergency departments.

A human vaccine against H5N1 influenza is licensed (but not marketed) in the United States with the government stockpiling supplies in the event of need. This vaccine does not contain adjuvant and as a result, its immunogenicity is only modest. A vaccine with oil-in-water emulsionbased adjuvant is available in Europe. Several other vaccine candidates are undergoing clinical trials. A major concern with H5N1 vaccinology is the evolution of the virus in vaccinated poultry, especially in the endemic nations of Egypt and Indonesia, and the need to maintain current surveillance and update vaccine development should avian influenza become more pathogenic in humans. Seasonal and H5N1 vaccines are given together safely in preliminary studies. Prevention of exposure to avian influenza strains also includes hygienic practices during handling of poultry products, including hand-washing and prevention of crosscontamination, as well as thorough cooking of poultry products (to 70°C). There is no risk of acquiring avian influenza through the consumption of poultry products, although there is a risk associated with handling feathers or birds from endemic areas, and the US government bans the importation of poultry from infected areas.

Adisasmito W et al. Effectiveness of antiviral treatment in human influenza A (H5N1) infections: analysis of a Global Patient Registry. J Infect Dis. 2010 Oct 15;202(8):1154–60.

[PMID: 20831384] Aditama TY et al. Risk factors for cluster outbreaks of avian influenza A H5N1 infection, Indonesia. Clin Infect Dis. 2011 Dec;53(12):1237–44. [PMID: 22016499] Couch RB et al. Has oseltamivir been shown to be effective for treatment of H5N1 influenza? J Infect Dis. 2010 Oct 15; 202(8):1149–51. [PMID: 20831386] Reece PA. Treatment options for H5N1: lessons learned from the H1N1 pandemic. Postgrad Med. 2010 Sep;122(5):134–41.

[PMID: 20861597] Uyeki TM. Human infection with highly pathogenic avian influenza A (H5N1) virus: review of clinical issues. Clin Infect Dis. 2009 Jul 15;49(2):279–90. [PMID: 19522652]

Viral & Rickettsial Infections

4. 2009 Pandemic H1N1 Influenza (“A(H1N1)pdm09”) ``

E sse n t i a l s o f d i a g n o s i s

Influenza-like illness with consistent epidemiologic background. `` Respiratory swab allows local screen and more specific analysis by state public health laboratories. ``

``General Considerations An outbreak of swine-origin (H1N1) influenza virus (formerly Swine-Origin Influenza Virus [S-OIV] or H1N1/A/ California/04/2009, currently “A(H1N1)pdm09”) emerged in Mexico City in March 2009. After initially spreading in the United States and Canada, the virus spread globally with cases reported from over 40 nations by mid-2009. The World Health Organization declared a pandemic on June 11, 2009 which lasted until August 10, 2010. This was the first pandemic since 1968 with circulation outside the usual influenza season in the Northern Hemisphere. The 2009 H1N1 influenza virus has replaced seasonal A (H1N1) and will presumably continue to spread for years to come, akin to the seasonal influenza virus. This virus originates from triple-reassortment North American swine, human and avian virus lineages and Eurasian swine virus lineages.

``Clinical Findings

CMDT 2013

1399

case fatality rate is < 0.5% with 90% of deaths in those under 65 years of age and higher mortality recognized among men and patients with liver disease or a cancer diagnosis within the last year.

B. Laboratory Findings Laboratory findings may include normal to low leukocyte counts with lymphocytopenia and elevated aminotransferases. Elevated alkaline phosphatase, creatine kinase, creatinine, thrombocytopenia and metabolic acidosis suggest poor prognosis. A nasopharyngeal swab, nasal aspirate, combined nasopharyngeal swab with oropharyngeal swab, or material from a bronchoalveolar lavage can be tested for 2009 H1N1. Test material can be kept at 4°C up to 4 days (not frozen) and shipped with an ice pack. Chest radiographic findings are most commonly unremarkable or may show exacerbation of bibasilar markings, but rarely show lobal infiltrates. The CDC or many state public health laboratories can then perform a real-time PCR or viral culture.

Local laboratories can perform rapid influenza antigen enzyme or direct immunofluorescent assays to distinguish influenza viruses types A and B, but the results of these assays should be interpreted with caution due to a limited sensitivity (11–70%) and inability to differentiate between seasonal and the 2009 H1N1 influenza viruses.

Pathologic findings in pandemic H1N1 influenza show a particular propensity toward diffuse alveolar damage, akin to the damage seen in patients with avian influenza.

This explains the increased risk of the development of ARDS with pandemic H1N1.

A. Symptoms and Signs

``Treatment

This pandemic strain of H1N1 causes a broad range of clinical symptoms ranging from typical symptoms (fever, malaise, myalgias, cough, sore throat, rhinorrhea, shortness of breath) commonly accompanied by gastrointestinal manifestations (especially diarrhea) to fulminant viral pneumonia. The principal clinical syndrome leading to hospitalization and ICU admission is diffuse viral pneumonitis with severe hypoxemia and sometimes shock and renal failure. Neurol­ ogic complications, including seizures and encephalopathy, and cardiac dysfunction, including myocarditis and pulmonary thromboemboli, have occurred. Cases with pandemic H1N1 associated hemophagocytic syndrome are reported.

Most patients with mild disease make full recovery, but 9–31% of hospitalized cases require ICU admission, where the mortality ranges between 14% and 46%. The disease has an incubation period of 1.5 to 7 days.

Attack rates are highest in children and young adults, particularly Hispanics, blacks, and native Americans, with relative sparing of adults older than 60 years of age presumably due to previous exposure with related strains (conferring some degree of cross-protection).

High-risk groups include patients with severe obesity, immunosuppression, or neurologic disorders, and especially pregnant and postpartum women. Infection during pregnancy may be associated with severe illness, sepsis, pneumothorax and respiratory failure, spontaneous abortion, preterm labor, and fetal distress. Overall

The virus is usually resistant to the adamantanes (amantadine or rimantadine). See the seasonal influenza section for side effects and concerns with these medications.

Treatment entails using neuraminidase inhibitors (oseltamivir or zanamivir; dosages are available in Table 32–1) as early as possible (within 96 hours of onset of symptoms). Early therapy with oseltamivir may reduce duration of hospitalization and progression to severe disease requiring ICU admission or resulting in death. Intravenous formulations of zanamivir and peramivir are available for emergency use in severely ill patients. Oseltamivir-resistant virus is recognized (one cluster of resistant cases is reported from a hospital hematology-oncology ward in North Carolina) and such virus remains sensitive to zanamivir.

Person to person transmission with oseltamivir-resistant pandemic H1N1 is documented.

The efficacy of intravenous peramivir is similar to that of oseltamivir but is reduced by a factor of 80 in oseltamivir-resistant 2009 H1N1 viral infection. In such patients, intravenous zanamivir is preferred. While a case of multidrug-resistant pandemic H1N1 virus with resistance to oseltamivir, zanamivir, and peramivir is reported, this particular isolate is less pathogenic in animal studies than standard H1N1 strains. The use of high frequency oscillatory ventilation and extracorporeal membrane oxygenation can improve oxygenation but the impact on mortality in unknown. Corticosteroids for an associated ARDS are

1400

CMDT 2013

Chapter 32

not useful and may increase the mortality with one exception. The use of corticosteroids are associated with a lower rate of mechanical ventilation if they are used in high doses (1 mg/kg prednisone equivalence orally at the time of diagnosis), in patients with a history of hematologic stem cell transplantation.

Updated advice is available at http://www.cdc.gov/ h1n1flu/recommendations.htm.

``Prevention The 2011–2012 seasonal influenza vaccines (discussed above) include the A/California/7/2009 (H1N1)–like viral strain and confer protection against 2009 H1N1 influenza.

It is especially important that vaccination includes pregnant and unvaccinated postpartum women, household and caregiver contacts of children under 6 months of age, health care and emergency service personnel, healthy persons between 6 months and 24 years of age, and adults 24–64 with underlying medical complications that predispose to influenza (as listed above).

In other areas of the world, monovalent H1N1 vaccines are used. With respect to such pandemic H1N1 vaccines, postmarketing surveillance in China (where 10 different suppliers are used) fails to show any adverse effects or risk for Guillain-Barré syndrome with the vaccine. In another analysis with a monovalent pandemic H1N1 vaccine, the response in elderly patients with asthma was insufficient at the usual 15 mcg; in this group, it is recommended that the dose be increased to 30 mcg (given twice, 30 days apart).

In general, persons with 2009 H1N1 influenza infection should be considered potentially infectious from 1 day before to about 7 days following illness onset. Children and immunosuppressed persons exhibit prolonged viral shedding and may be infectious longer. Any hospital patient in whom the infection is suspected should be isolated in individual rooms with standard and contact precautions plus eye protection.

The World Health Organization guidelines recommend surgical masks for all patient care with the exception of N95 masks for aerosol generating procedures (eg, bronchoscopy, elective intubation, suctioning, administering nebulized medications). For such procedures, an airborne infection isolation room can be used, with air exhausted directly outside or recirculated after filtration by a high efficiency particulate air (HEPA) filter. Strict adherence to hand hygiene with soap and water or an alcohol-based hand sanitizer and immediate removal of gloves and other equipment after contact with respiratory secretions is essential. Precautions should be maintained until 7 days from symptom onset or until the resolution of symptoms, whichever is longer. Postexposure prophylaxis should be considered for close contacts of patients (confirmed, probable, or suspected) who are at high risk for complications of influenza (see section on seasonal influenza) as well as for healthcare personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with novel (H1N1) influenza virus infection (confirmed, probable, or suspected) during that person’s infectious period. Despite incomplete data about the safety of neuraminidase inhibitors, the CDC

recommends considering postexposure prophylaxis as well in this population.

The MMWR and World Health Organization website (http://www.who.int/csr/disease/swineflu/en/) provide updates about this pandemic.

Brun-Buisson C et al; REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2011 May 1;183(9):1200–6. [PMID: 21471082] Centers for Disease Control and Prevention (CDC). Update: influenza A(H3N2)v transmission and guidelines—five states, 2011. MMWR Morb Mort Wkly Rep. 2012 Jan 6;60(51–52): 1741–4. [PMID: 22217624] Chen LF et al. Cluster of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infections on a hospital ward among immunocompromised patients—North Carolina, 2009. J Infect Dis. 2011 Mar 15;203(6):838–46. [PMID: 21343149] Cunha BA et al. Swine influenza (H1N1) pneumonia in hospitalized adults: chest film findings. Heart Lung. 2011 May–Jun; 40(3):253–6. [PMID: 21545936] Ellington SR et al. Pandemic 2009 influenza A (H1N1) in 71 critically ill pregnant women in California. Am J Obstet Gynecol. 2011 Jun;204(6 Suppl 1):S21–30. [PMID: 21514554] Liang XF et al. Safety of influenza A (H1N1) vaccine in postmarketing surveillance in China. N Engl J Med. 2011 Feb 17; 364(7):638–47. [PMID: 21288090]

5. Severe Acute Respiratory Syndrome (SARS) ``

E sse n t i a l s o f d i a g n o s i s

Mild, moderate, or severe respiratory illness.

Travel to endemic area within 10 days before symptom onset, including mainland China, Hong Kong, Singapore, Taiwan, Vietnam, and Toronto. `` Persistent fever; dry cough, dyspnea in most. `` Diagnosis confirmed by antibody testing or isolation of virus. `` No specific treatment; mortality as high as 10% in clinically diagnosed cases. `` ``

``General Considerations SARS is a respiratory syndrome caused by an apparently unique coronavirus, transmitted through direct or indirect contact of mucous membranes with infectious respiratory droplets. The virus is shed in stools but the role of fecal–oral transmission is unknown. The natural reservoir appears to be the horseshoe bat (which eats and drops fruits ingested by civets, the earlier presumed reservoir and a likely amplifying host).

The earliest cases were traced to a health care worker in Guangdong Province in China in late 2002, with rapid spread thereafter throughout Asia and Canada, considered a consequence of spread through travel. The 2003 outbreak involved 8098 probable cases from 29 countries, with

Viral & Rickettsial Infections 774 fatalities. Nine additional cases associated with a research laboratory were reported in China in 2004 with no further cases reported since then.

``Clinical Findings A. Symptoms and Signs SARS is an atypical pneumonia that affects persons in all age groups. Severity ranges from asymptomatic disease to severe respiratory illness. Many subclinical cases probably go undiagnosed. Seasonality, as with influenza, is not established. The incubation period is 2–7 days, and it can be spread to contacts of affected patients for 10 days. The mean time from onset of clinical symptoms to hospital admission is 3–5 days. In all clinical cases, persistent fever is present; chills or rigor (or both), cough, shortness of breath, rales, and rhonchi are the rule. Headache, myalgias, and sore throat are common with watery diarrhea occurring in a subset of patients. Elderly patients may report malaise and delirium, without the typical febrile response.

B. Laboratory Findings and Imaging Leukopenia (particularly lymphopenia) and low-grade disseminated intravascular coagulation are common. Modest elevations of ALT and creatine kinase are frequently seen.

Arterial oxygen saturation < 95% with associated nonspecific pulmonary infiltrates is evident in 80% of affected individuals. A high-resolution CT scan is abnormal in 67% of patients with initially normal chest radiographs.

Serum serologies, including enzyme immunoassays and fluorescent antibody assays, are available through public health departments at the state level, although seroconversion may not occur until 3 weeks after the onset of symptoms. The detection rates for the virus using conventional RT-PCR are generally low in the first week of illness.

Urine, nasopharyngeal aspirate, and stool specimens are positive in 42%, 68%, and 97%, respectively, on day 14 of illness. Although viral isolation is possible, it is a technically laborious and time-consuming procedure.

``Complications ARDS, with extensive bilateral consolidation, occurs in about 16% patients, and about 20–30% of patients require intubation and mechanical ventilation.

``Treatment Severe cases require intensive supportive management.

Different agents including, lopinavir/ritonavir, ribavirin, interferon, IVIG, and systemic corticosteroids were used during the 2003 epidemic, but the treatment efficacy of these agents remains inconclusive. In vitro studies with ribavirin show no activity against the virus, and a retrospective analysis of the epidemic in Toronto suggests worse outcomes in patients who received the drug.

``Prognosis The overall mortality rate of identified cases is about 14%.

Poor prognostic factors include advanced age (mortality

CMDT 2013

1401

rate > 50% in those over 65 years of age compared to < 1% for those under 2 years of age), chronic hepatitis B infection treated with lamivudine, high initial or high peak lactate dehydrogenase concentration, high neutrophil count on presentation, diabetes mellitus, acute kidney disease, and low counts of CD4 and CD8 on presentation.

``Prevention Health care workers engaged in procedures that involve contact with respiratory droplets are at risk. Isolation of high-risk patients is essential, and simple hygienic measures may help reduce transmission.

Control measures include quarantining in the home for high-risk exposed persons and the use of facemasks for preventing hospital-acquired infections. The validity of using such masks in the community remains unsubstantiated. Continual reporting of suspected cases is crucial, as is awareness of restrictions on international travel. The most cautious modalities include monitoring for 10 days after the last potential exposure and confinement of recovering patients for a similar interval.

Barnard DL et al. Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy. Future Virol. 2011 May;6(5):615–31. [PMID: 21765859] Cleri DJ et al. Severe acute respiratory syndrome (SARS). Infect Dis Clin North Am. 2010 Mar; 24(1):175–202. [PMID: 20171552] Raboud J et al. Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation in Toronto, Canada. PLoS One. 2010 May 19;5(5):e10717. [PMID: 20502660]

ADENOVIRUS INFECTIONS ``General Considerations About a half of the existing adenoviruses (there are over 52 serotypes described to date and divided into 7 subgroups A–G) produce a variety of clinical syndromes. Adenoviruses show a worldwide distribution and occur throughout the year. These infections are usually self-limited or clinically inapparent and most common among infants, young children, and military recruits. However, these infections may cause significant morbidity and mortality in immunocompromised persons, such as HIV-infected persons and COPD patients, as well as in patients who have undergone solid organ and hematopoietic stem cell transplantation or cardiac surgery or in those who have received cancer chemotherapy.

A few cases of donor-transmitted adenoviral infection are reported in the past years. Adenoviruses, although a common cause of human disease, also receive particular recognition through their role as vectors in gene therapy.

``Clinical Findings A. Symptoms and Signs The incubation period is 4–9 days. Clinical syndromes of adenovirus infection, often overlapping, include the following. The common cold (see Chapter 8) is characterized by rhinitis, pharyngitis, and mild malaise without fever.

1402

CMDT 2013

Chapter 32

Nonstreptococcal exudative pharyngitis is characterized by fever lasting 2–12 days and accompanied by malaise and myalgia. Conjunctivitis is often present. Lower respiratory tract infection may occur, including bronchiolitis, suggested by cough and rales, or pneumonia (types 3, 4, and 7 commonly cause acute respiratory disease and atypical pneumonia). Adenovirus type 14 is increasingly reported as a cause of severe and sometimes fatal pneumonia in those with chronic lung disease, but it is also seen in healthy young adults and military recruit outbreaks.

Pharyngoconjunctival fever is manifested by fever and malaise, conjunctivitis (often unilateral), mild pharyngitis, and cervical adenitis. Epidemic keratoconjunctivitis (transmissible person to person) occurs in adults and is manifested by bilateral conjunctival redness, pain, tearing, and an enlarged preauricular lymph node (multiple types may be involved in a single outbreak). Keratitis may lead to subepithelial opacities (especially with types 8, 19, or 37).

Acute hemorrhagic cystitis is a disorder of children often associated with adenovirus type 11 and 21. Sexually transmitted genitourinary ulcers and urethritis may be caused by types 2, 8, and 37 in particular. Adenoviruses also cause acute gastroenteritis (types 40 and 41), mesenteric adenitis, acute appendicitis, and intussusception. Rarely, they are associated with encephalitis, acute flaccid paralysis, and pericarditis. Adenovirus is commonly identified in endo­ myocardial tissue of patients with myocarditis and dilated cardiomyopathy. Risk factors associated with severity of infection include youth, chronic underlying infections, recent transplantation, and serotypes 5 or 21.

Hepatitis (type 5 adenovirus), pneumonia, and hemorrhagic cystitis (types 11 and 34) tend to develop in infected liver, lung, or kidney transplant recipients, respectively.

Syndromes that may develop in hematopoietic stem cell transplant patients include hepatitis, pneumonia, hemorrhagic cystitis, tubulointerstitial nephritis, colitis, and encephalitis.

B. Laboratory Findings Antigen detection assays including direct fluorescence assay or enzyme immunoassay are rapid and show sensitivity of 40–60% compared with viral culture (considered the standard). Samples with negative rapid assays require PCR assays or viral cultures for diagnosis. Quantitative real-time rapidcycle PCR is useful in distinguishing disease from colonization, especially in hematologic cell transplant patients.

``Treatment Treatment is symptomatic. Ribavirin and cidofovir are used in immunocompromised individuals with occasional success, although cidofovir is attendant with significant renal toxicity and reduced immunosuppression is often required. Adoptive immunotherapy with transfusion of adenovirus-specific T cells is currently being investigated.

IVIG is used in immunocompromised patients, but data are still limited. Typing of isolates is useful epidemiologically and in distinguishing transmission from endogenous reactivation. Complications of adenovirus pneumonia in children include bronchiolitis obliterans.

Vaccines are not available for general use. Live oral vaccines containing attenuated type 4 and type 7 were used in military personnel, but they have been discontinued.

Castelli JB et al. Fatal adenoviral necrotizing bronchiolitis case in a post-cardiac surgery intensive care unit. Braz J Infect Dis. 2011 Jun;15(3):285–7. [PMID: 21670932] Kozlowski T et al. Donor-transmitted adenovirus infection causing kidney allograft nephritis and graft loss. Transpl Infect Dis. 2011 Apr;13(2):168–73. [PMID: 20854282] Vento TJ et al. Pneumonia in military trainees: a comparison study based on adenovirus serotype 14 infection. J Infect Dis. 2011 May 15;203(10):1388–95. [PMID: 21502080]

OTHER EXANTHEMATOUS VIRAL INFECTIONS 1. Erythrovirus (Parvovirus) Infections Erythrovirus, formerly parvovirus B19, infects human erythroid precursor cells. It is quite widespread (by age 15 years about 50% of children have detectable IgG) and its transmission occurs through respiratory secretions and saliva, through the placenta (vertical transmission with 30–50% of pregnant women nonimmune), and through administration of blood products. The incubation period is 4–14 days. Chronic forms of the infection can occur.

Bocavirus, another erythrovirus (parvovirus), is a cause of winter acute respiratory disease in children and adults.

``Clinical Findings A. Symptoms and Signs Erythrovirus (parvovirus B19) causes several syndromes and manifests differently in various populations.

1. Children—In children, an exanthematous illness (“fifth disease,” erythema infectiosum) is characterized by a fiery red “slapped cheek” appearance, circumoral pallor, and a subsequent lacy, maculopapular, evanescent rash on the trunk and limbs. Malaise, headache, and pruritus (especially on the palms and soles) occur. Systemic symptoms and fever are mostly abated by the time of rash appearance.

2. Immunocompromised patients—In immunosuppressed patients, including those with HIV infection or transplanted organs, or with hematologic conditions such as sickle cell disease, transient aplastic crisis and pure red blood cell aplasia may occur. Bone marrow aspirates reveal absence of mature erythroid precursors and characteristic giant pronormoblasts.

3. Adults—A limited nonerosive symmetric polyarthritis that mimics lupus erythematosus and rheumatoid arthritis, which may in some cases be a type II mixed cryoglobulinemia, can develop in middle-aged persons (especially women) but can also occur in children. Rashes, especially facial, are less common in adults.

Chloroquine and its derivatives exacerbate erythrovirus (parvovirus)-associated anemia and are linked with significantly lower hematocrit in hospital admissions in malaria

Viral & Rickettsial Infections endemic areas. Rare reported presentations include myocarditis with infarction, constrictive pericarditis, chronic dilated cardiomyopathy, hepatitis, pneumonitis, neutropenia, thrombocytopenia, a lupus-like syndrome, glomerulopathy, CNS vasculitis, and a chronic fatigue syndrome. A subclinical infection is documented among patients with sickle cell disease. Other CNS manifestations of erythrovirus (parvovirus) include encephalitis, meningitis, stroke (usually in sickle cell anemia patients with aplastic crises), and peripheral neuropathy (brachial plexitis and carpal tunnel syndrome) with occasional chronic residua.

The symptoms of erythrovirus (parvovirus) infection can mimic those of autoimmune states such as lupus, systemic sclerosis, antiphospholipid syndrome, or vasculitis.

The molecular mimicry of erythrovirus (parvovirus) to human cytokeratin and transcription factors engaged in hematopoiesis is the basis for theories that implicate erythrovirus (parvovirus) in the pathogenesis of these autoimmune states.

In pregnancy, premature labor, hydrops fetalis, and fetal loss are reported sequelae. Pregnant women with a recent exposure or with suggestive symptoms should be tested for the disease and carefully monitored if results are positive.

B. Laboratory Findings The diagnosis is clinical (Table 32–2) but may be confirmed by an elevated titer of IgM anti-erythrovirus (parvovirus) anti-bodies in serum or with PCR in serum or bone marrow. Autoimmune antibodies (antiphospholipid and anti-neutrophil cytoplasmic antibodies) can be present and are thought to be a consequence of molecular mimicry.

``Complications Uncommon complications include the CNS diseases listed above, chronic hemolytic anemia, thrombotic thrombocytopenic purpuric syndrome, acute postinfectious glomerulonephritis, and hepatitis.

``Treatment Treatment in healthy persons is symptomatic (nonsteroidal anti-inflammatory drugs are used to treat arthralgias, and transfusions are used to treat transient aplastic crises). In immunosuppressed patients, IVIG can aid in the reduction of anemia. IVIG does not reduce the complications associated with encephalitis related to erythrovirus (parvovirus).

Intrauterine blood transfusion can be considered in severe fetal anemia.

``Prevention & Prognosis Several nosocomial outbreaks are documented. In these cases, standard containment guidelines, including handwashing after patient exposure and avoiding contact with pregnant women are paramount.

The prognosis is generally excellent in immuno­ competent individuals. In immunosuppressed patients,

CMDT 2013

1403

persistent anemia may require prolonged transfusion dependence. Remission of erythrovirus (parvovirus) infection in AIDS patients may occur with HAART, though the immune restoration syndrome is also reported.

Bock CT et al. Human parvovirus B19-associated myocarditis. N Engl J Med. 2010 Apr 1;362(13):1248–9. [PMID: 20357294] Bönsch C et al. Chloroquine and its derivatives exacerbate B19Vassociated anemia by promoting viral replication. PLoS Negl Trop Dis. 2010 Apr 27;4(4):e669. [PMID: 20436917] Brown KE. The expanding range of parvoviruses which infect humans. Rev Med Virol. 2010 Jul;20(4):231–44. [PMID: 20586082] Lamont RF et al. Parvovirus B19 infection in human pregnancy.

BJOG. 2011 Jan;118(2):175–86. [PMID: 21040396]

2. Poxvirus Infections Among the nine poxviruses causing disease in humans, the following are the most clinically important: variola/­ vaccinia, molluscum contagiosum, orf and paravaccinia, and monkeypox.

1. Variola/vaccinia—Smallpox (variola) was a highly contagious disease associated with high mortality and disabling sequelae. Its manifestations include severe headache, acute onset of fever, prostration and a rash characterized by the uniform progression from macules to papules to firm, deep-seated vesicles or pustules. The synchronous progression in smallpox readily differentiates lesions from those of varicella (see also Chapter 6).

Complications of smallpox include bacterial superinfections (cellulitis and pneumonia), encephalitis, and keratitis with corneal ulcerations (risk factor for blindness).

Effective vaccination led to its global elimination by 1979 and routine vaccination stopped in 1985. Despite the recommendation of destroying remaining samples of this virus, significant concern exists for the potential misuse of these repositories in military or terrorist activities.

Smallpox should be considered, in concordance with the CDC’s Smallpox Response Plan (www.bt.cdc.gov/ agent/smallpox/response-plan/index.asp), in any patient with fever and a characteristic rash (see above) for which other etiologies—such as herpes infections, erythema multiforme, drug reactions (eczema herpeticum may be differentiated from suspect smallpox by appropriate serologic stains), or other infections—are unlikely. Rare cases of vaccine-related disease from contact with a smallpox vaccinee, (including sexually transmission) are reported.

Two cases of vaccinia infection after contact with oral rabies animal baits (which uses the vaccinia vector) are reported. Patients with suspected infection should be placed in airborne and contact isolation and the official agency contacted (CDC Emergency Preparedness and Response Branch; 770-488-7100). Original smallpox vaccine was crudely manufactured with a significant side-effect profile, including eczema vaccinatum and acute vaccinia syndrome (fatigue, headaches, myalgias, and fever). Subsequent smallpox vaccines had similar ­side-effect profiles, but myocarditis and pericarditis also developed in

1404

CMDT 2013

Chapter 32

some patients. The most recent vaccine, ACAM2000 (Acambis, Inc) shows similar safety profiles and is currently used by the US military and stockpiled in the event of biologic warfare.

Contraindications to vaccination include immunosuppression, eczema or other dermatitis in the vaccinee or household contacts, allergy to any component of the vaccine, infants younger than 1 year and pregnant or breastfeeding women. According to current recommendation, it is unnecessary for anyone not handling the smallpox vaccine to be vaccinated.

Inoculation of the vaccine in inappropriate sites (eg, eyes) is unfortunately common. Asymptomatic vaccinia viremia can be detected up to 21 days post vaccination and no blood donation should occur during this interval.

Cidofovir may be considered for treatment of poxviral conditions and intravenous human vaccinia immunoglobulin may be useful for vaccinia.

2. Molluscum contagiosum—Molluscum contagiosum may be transmitted sexually or by other close contact. It is manifested by pearly, raised, umbilicated skin nodules sparing the palms and soles. Keratoconjunctivitis can occur. There may be an association with atopic dermatitis or eczema. Marked and persistent lesions in AIDS patients respond readily to combination antiretroviral therapy.

Treatment options include destructive therapies (curettage, cryotherapy, cantharidin, and keratolytics, among others), immunomodulators (imiquimod, cimetidine, and Candida antigen), and antiviral agents (cidofovir). No treatment is uniformly effective and multiple courses of therapy are often needed.

Cryptococcal skin lesions can mimic molluscum ­contagiosum.

3. Orf and paravaccinia—Orf (contagious pustular dermatitis, or ecthyma contagiosa) and paravaccinia (milker’s nodules) are occupational diseases acquired by contact with sheep and cattle, respectively. Orf also occurs among children with ruminant exposures. Orf anecdotally responds to imiquimod.

4. Monkeypox—First identified in 1970, monkeypox is enzootic in the rain forests of equatorial Africa and presents in humans as a syndrome similar to smallpox. The incubation period is about 12 days, and limited person-toperson spread occurs. African mortality rates vary from 3% to 11% depending on the immune status of the patient.

Secondary attack rates appear to be about 10%. The first community-acquired outbreak in the United States of monkeypox occurred in 2003 in Wisconsin and other states of the upper Midwest. The source appeared to be imported Gambian giant rats via consequent exposure of prairie dogs. Other susceptible animals include nonhuman primates, rabbits, and rodents. Confusion with smallpox and varicella occurs; however, both lymphadenopathy (seen in up to 90% of unvaccinated persons) and a febrile prodrome are prominent features in monkeypox infection.

Distinguishing characteristics of the monkeypox rash are its deep seated and well-circumscribed nature, it appears at the same stage of development (unlike varicella but like

smallpox), and is centrifugal (including the palms and soles). Suspected cases should be placed on standard, contact and droplet precautions; and local and state public health officials, and the CDC should be notified for assistance with confirmation of the diagnosis (electron microscopy, viral culture, ELISA, PCR). Cidofovir is effective against monkeypox, and IVIG can be used in selected cases.

Other general precautions that should be taken are avoidance of contact with prairie dogs and Gambian giant rats (whose illness is manifested by alopecia, rash, and ocular or nasal discharge), appropriate care and isolation of those exposed within 3 prior weeks to such animals, and veterinary examination and investigation of suspect animals through health departments. Vaccinia immunization is effective against monkeypox and is recommended, if no contraindication exists (outlined above), for those involved in the investigation of the outbreak and for healthcare workers caring for those infected with monkeypox. Post exposure vaccination is also advised for documented contacts of infected persons or animals. US federal agencies currently prohibit the importation of African rodents.

Centers for Disease Control and Prevention (CDC). Updated interim CDC guidance for use of smallpox vaccine, cidofovir, and vaccinia immune globulin (VIG) for prevention and treatment in the setting of an outbreak of monkeypox infections. http://www.cdc.gov/ncidod/monkeypox/treatment­ guidelines.htm Centers for Disease Control and Prevention (CDC). Vaccinia virus infection after sexual contact with a military smallpox vaccinee—Washington, 2010. MMWR Morb Mortal Wkly Rep. 2010 Jul 2;59(25):773–5. [PMID: 20592687] Essbauer S et al. Zoonotic poxviruses. Vet Microbiol. 2010 Jan 27;140(3–4):229–36. [PMID: 19828265] MacNeil A et al. Monkeypox or varicella? Lessons from an outbreak rash investigation in the Republic of the Congo. Am J Trop Med Hyg. 2009 Apr;80(4):503–7. [PMID: 19346366] Nalca A et al. ACAM2000: the new smallpox vaccine for United States Strategic National Stockpile. Drug Des Devel Ther.

2010 May 25;4:71–9. [PMID: 20531961]

VIRUSES & GASTROENTERITIS Viruses are responsible for at least 30–40% of cases of infectious diarrhea in the United States. These agents include rotaviruses; caliciviruses, including noroviruses such as Norwalk virus; astroviruses; enteric adenoviruses; and, less often, toroviruses, coronaviruses, picornaviruses (including the Aichi virus), and pestiviruses. Rotaviruses and noroviruses are responsible for most of nonbacterial cases of gastroenteritis.

Rotaviruses are the leading worldwide cause of dehydrating gastroenteritis in young children and are associated with significant morbidity and mortality (at least 500,000 children under 5 years of age annually from rotavirus infection). Children aged 6 months to 2 years are the most affected, although adults are affected occasionally as well. By age 5, virtually every child has been infected with this pathogen. The diverse set of rotaviruses

Viral & Rickettsial Infections (classified by ­glycoproteins and protease-sensitive proteins [G-type and P-type antigens] which segregate independently) results in a constellation of phenotypes although only about four of these are responsible for over 90% of disease. Rotavirus infections follow an endemic pattern, especially in the tropics, although they peak during the winter in temperate regions. The virus is transmitted by fecal-oral route and can be shed in feces for up to 3 weeks in severe infections. In outbreak settings (eg, daycare centers), the virus is ubiquitously found in the environment, and secondary attack rates are between 16% and 30% (including household contacts). The disease is usually mild and self-limiting. A 2- to 3-day prodrome of fever and vomiting is followed by nonbloody diarrhea (up to 10–20 bowel movements per day) lasting for 1–4 days. The method of choice for diagnosis is PCR of the stool. It is thought that rarely systemic disease occurs. Treatment is largely symptomatic, with fluid and electrolyte replacement. A trial with nitazoxanide was attendant with moderate success among a small cohort of patients with gastroenteritis from Egypt with efficacy in both the rotavirus and norovirus subgroups. The enkephalinase inhibitor racecadotril (also known as acetorphan, given 1.5 mg/kg every 8 hours orally) is available in many countries (but not the United States), and in a meta-analysis appears to be clinically effective in reducing diarrheal symptoms. Local intestinal immunity gives protection against successive infection.

Two oral rotavirus vaccines are available in the United States: pentavalent human-bovine reassortment rotavirus vaccine (PRV, RotaTeq; to be given at 2, 4, and 6 months of age) and attenuated human rotavirus vaccine (HRV, Rotarix; to be given at 2 and 4 months of age). Contrain­ dications include allergy to any of the vaccine ingredients, previous allergic reaction to the vaccine, and immunodeficiency. The risk of intussusception, which is far lower with this than earlier rotavirus preparations, is small (1:51,000 to 1:68,000 vaccinated infants) and is considered significantly lower than the risk associated with untreated rotavirus gastroenteritis.

Noroviruses, such as Norwalk virus (one of a variety of small round viruses divided into 3 genogroups and at least 25 genotypes), are the major cause of epidemic gastroenteritis. They are responsible for a significant percentage of childhood hospitalizations for gastroenteritis in the developing world (15% in surveys from India, 31% from Peru).

They appear to evolve by antigenic drift (similar to influenza). While 90% of young adults show serologic evidence of past infection, no long-lasting protective immunity develops and reinfections are common. In the United States, noroviruses are responsible for over 90% of reported nonbacterial gastroenteritis outbreaks during cold weather intervals (hence the colloquial name “gastric flu”). Outbreak environments include restaurants, longterm care facilities, hospitals, schools, daycare centers, vacation destinations (including cruise ships), and Middle Eastern military bases deployed abroad. Persons at particular risk are the young, the elderly, the institutionalized, and the immunosuppressed. Although transmission is usually fecal–oral, airborne and waterborne transmission

CMDT 2013

1405

are also documented. A short incubation period (24–48 hours), a short symptomatic illness (12–60 hours, but up to 5 days in hospital-associated cases and in children under 11 years of age), a high frequency (> 50%) of vomiting, and absence of bacterial pathogens in stool samples are highly predictive of norovirus gastroenteritis. RT-PCR of stool samples is used for epidemiologic purposes.

Treatment is largely symptomatic.

Outbreak control for both rotavirus and norovirus infections include strict adherence to general hygienic measures. Despite the promise of alcohol-based sanitizers for the control of pathogen transmission, such cleansers may be relatively ineffective against the noroviruses compared with antibacterial soap and water, reinforcing the need for new hygienic agents against this prevalent group of viruses. Cohorting of sick patients, contact precautions for symptomatic hospitalized patients, exclusion from work of symptomatic staff until symptom resolution (or 48–72 h after this for norovirus disease), and proper decontamination procedures are crucial.

The reports of efficacy with nitazoxanide or raceca­ dotril in acute gastroenteritis suggest that new avenues of therapy may become more widely available in the future.

Vaccine developments are attendant with the complications associated with the rapid evolution (“antigenic drift”) of noroviruses and the probable need for annual strain selection to match circulating variants.

Desselberger U et al. Immune responses to rotavirus infection and vaccination and associated correlates of protection. J Infect Dis. 2011 Jan 15;203(2):188–95. [PMID: 21288818] Glass RI et al. Norovirus gastroenteritis. N Engl J Med. 2009 Oct 29;361(18):1776–85. [PMID: 19864676] Lehert P et al. Racecadotril for childhood gastroenteritis: an individual patient data meta-analysis. Dig Liver Dis. 2011 Sep;43(9):707–13. [PMID: 21514257] Liu P et al. Effectiveness of liquid soap and hand sanitizer against Norwalk virus on contaminated hands. Appl Environ Microbiol. 2010 Jan;76(2):394–9. [PMID: 19933337] Patel MM et al. Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil. N Engl J Med. 2011 Jun 16;364(24):2283–92. [PMID: 21675888] Ward RL. Rotarix: a rotavirus vaccine for the world. Clin Infect Dis. 2009 Jan 15;48(2):222–8. [PMID: 19072246]

ENTEROVIRUSES THAT PRODUCE SEVERAL SYNDROMES The most famous enterovirus, the poliomyelitis virus, is discussed above under Vaccine Preventable Diseases. Other clinically relevant enteroviral infections are discussed in this section.

1. Coxsackievirus Infections Coxsackievirus infections cause several clinical syndromes.

As with other enteroviruses, infections are most common during the summer. Two groups, A and B, are defined either serologically or by mouse bioassay. There are more than 50 serotypes.

1406

CMDT 2013

Chapter 32

``Clinical Findings A. Symptoms and Signs The clinical syndromes associated with coxsackievirus infection are summer grippe; herpangina; epidemic pleurodynia; aseptic meningitis and other neurologic syndromes; acute nonspecific pericarditis; myocarditis; hand, foot, and mouth disease; epidemic conjunctivitis; and other syndromes.

1. Summer grippe (A and B)—A febrile illness, principally of children, summer grippe usually lasts 1–4 days.

Minor symptoms of upper respiratory tract infection are often present.

2. Herpangina (A2–6, 10: B3)—There is sudden onset of fever, which may be as high as 40.6 °C, sometimes with febrile convulsions. Other symptoms are headache, myalgia, and vomiting. The sore throat is characterized early by petechiae or papules on the soft palate that ulcerate in about 3 days and then heal. An outbreak in Taiwan with A2 was associated with herpangina and coincided with an enterovirus 71 (below) outbreak, characterized by hand, foot, and mouth disease. Treatment is symptomatic.

3. Epidemic pleurodynia (Bornholm disease) (B1–5)— Pleuritic pain is prominent. Tenderness, hyperesthesia, and muscle swelling are present over the area of diaphragmatic attachment. Other findings include headache, sore throat, malaise, nausea, and fever. Orchitis and aseptic meningitis occur in < 10% of patients. Most patients are ill for 4–6 days.

4. Aseptic meningitis (A and B) and other neurologic syndromes—Fever, headache, nausea, vomiting, stiff neck, drowsiness, and cerebrospinal fluid lymphocytosis without chemical abnormalities may occur, and pediatric clusters of group B (especially B5) meningitis are reported. Focal encephalitis and transverse myelitis are reported with coxsackievirus group A. Disseminated encephalitis occurs after group B infection, and acute flaccid paralysis is reported with both coxsackievirus group A and B. An outbreak of aseptic meningitis occurred in central China (Gansu Province) in 2008, with 85 cases reported of coxsackie A9 disease. Severe neonatal illnesses are reported with B1 infections, including encephalomyocarditis and neonatal deaths due to multiorgan failure.

5. Acute nonspecific pericarditis (B types)—Sudden onset of anterior chest pain, often worse with inspiration and in the supine position, is typical. Fever, myalgia, headache, and pericardial friction rub appear early and these symptoms are often transient. Evidence for pericardial effusion on imaging studies is often present, and the occasional patient has a paradoxical pulse. Electrocardiographic evidence of pericarditis is often present. Relapses may occur.

6. Myocarditis (B1–5)—Heart failure in the neonatal period secondary to in utero myocarditis and over 20% of adult cases of myocarditis and dilated cardiomyopathy are associated with group B (especially B3) infections.

7. Hand, foot, and mouth disease (A5, 10, 16)—This disease is sometimes epidemic and is characterized by stomatitis and a vesicular rash on hands and feet.

Enterovirus 71 is also a causative agent (see below).

8. Epidemic conjunctivitis—As with enterovirus 70 (see below), the A24 variant of coxsackievirus is associated with acute epidemic hemorrhagic conjunctivitis in tropical areas with outbreaks reported in the last few years in southern China, Pakistan, southern Sudan, and Uganda.

9. Other syndromes associated with coxsackievirus infections—These include rhabdomyolysis, fulminant neonatal hepatitis (occurs rarely), glomerulopathy (group B infections), type 1 diabetes mellitus (mainly group B infections), and thyroid disease (group B4), although definitive causality is not established. A pathogenic role in primary Sjögren syndrome and acute myocardial infarction has also been proposed for group B coxsackievirus infections. A recent report of confirmed infective endocarditis due to coxsackievirus B2 in a patient with a prosthetic cardiac device suggests that viral etiologies of culture-negative infective endocarditis should be considered.

B. Laboratory Findings Routine laboratory studies show no characteristic abnormalities. Neutralizing antibodies appear during convalescence. The virus may be isolated from throat washings or stools inoculated into suckling mice. Viral culture is expensive, labor demanding, and requires several days for results.

A PCR test for enterovirus RNA is available and, although it cannot identify the serotype, it appears to be useful, particularly in cases of meningitis.

``Treatment & Prognosis Treatment is symptomatic. With the exception of meningitis, myocarditis, pericarditis, perhaps diabetes, and rare illnesses such as pancreatitis or polio-like syndrome, the syndromes caused by coxsackieviruses are benign and self-limited. Two controlled trials showed a potential clinical benefit with pleconaril for patients with enteroviral meningitis although the compassionate use of this drug has stopped. There are anecdotal reports of success with IVIG in severe disease.

Blumental S et al. Enteroviral infection of a cardiac prosthetic device. Clin Infect Dis. 2011 Mar 15;52(6):710–6. [PMID: 2136772] Liapounova NA et al. Acute myocardial infarction spurred by myopericarditis in a young female patient: Coxsackie B2 to blame. Acta Cardiol. 2011 Feb;66(1):79–81. [PMID: 21446385]

2. Echovirus Infections Echoviruses are enteroviruses that produce several clinical syndromes, particularly in children. Infection is most common during summer. Among reported specimens, death ensues in about 3%. Males younger than 20 years are more commonly infected than other persons.

Viral & Rickettsial Infections Over 30 serotypes of echoviruses are recognized and the most common serotypes for disease are types 6, 9, 11, and 30.

Most can cause aseptic meningitis, which may be associated with a rubelliform rash. Types 30 and 13 (the latter also associated with meningitis) outbreaks are increasingly reported globally, including a Korean outbreak of the former in 2008, Finland in 2009, and five epidemics of the latter in the United States. An echovirus 4 outbreak of aseptic meningitis occurred in Australia in 2007. A type 18 outbreak in Taiwan in 2006 and another in Missouri in 2007 were associated with childcare. Transmission is primarily fecal–oral.

Hand-washing is an effective control measure in outbreaks of aseptic meningitis. Outbreaks related to fecal contamination of water sources, including drinking water and swimming and bathing pools, were reported in the past.

Besides meningitis, other conditions associated with echoviruses range from common respiratory diseases (bronchiolitis occurs often in children) and epidemic diarrhea to myocarditis, a hemorrhagic obstetric syndrome, keratoconjunctivitis, hepatitis with coagulopathy, leukocytoclastic vasculitis, and neonatal as well as adult cases of encephalitis and sepsis, interstitial pneumonitis, hemophagocytic syndromes (in children with cancer), sudden deafness, encephalitis, optic neuritis, uveitis, and septic shock. Echoviruses, and enteroviruses in general, are also a common cause of nonspecific exanthems.

Echovirus 1 (EV1) is an oncolytic virus that selectively targets and destroys malignant prostate and ovarian cancer cells in vivo and is being studied as a potential adjunctive therapy for the control of the peritoneal dissemination of gastric cancer.

As with other enterovirus infections, diagnosis is best established by correlation of clinical, epidemiologic, and laboratory evidence. Cytopathic effects are produced in tissue culture after recovery of virus from throat washings, blood, or cerebrospinal fluid. An enterovirus PCR of the cerebrospinal fluid can assist in the diagnosis and is associated with a shorter duration of hospitalization in febrile neonates. Fourfold or greater rises in antibody titer signify systemic infection.

Treatment is usually symptomatic, and the prognosis is excellent, though there are reports of mild paralysis after CNS infection. Pleconaril, investigational, appears to be of some use among meningitis patients with more severe disease in shortening the course of illness.

From a public health standpoint, clustered illnesses such as swimming in sewage-infested sea water in travelers suggest point-source exposure. Prevention of fecal–oral contamination and maintenance of pool hygiene through chlorination and pH control are important public health control measures.

Centers for Disease Control and Prevention (CDC). Nonpolio enterovirus and human parechovirus surveillance—United States, 2006–2008. MMWR Morb Mortal Wkly Rep. 2010 Dec 10;59(48):1577–80. [PMID: 21150865] Tsai HP et al. An echovirus 18-associated outbreak of aseptic meningitis in Taiwan: epidemiology and diagnostic and genetic aspects. J Med Microbiol. 2011 Sep;60(Pt 9):1360–5.

[PMID: 21546563]

CMDT 2013

1407

3. Enteroviruses 70, 71, & Related Agents Several distinct clinical syndromes are being described in association with enteroviruses. Enterovirus 70 (HEV-70), a ubiquitous agent first identified in 1969 and responsible for abrupt bilateral eye discharge and subconjunctival hemorrhage with occasional systemic symptoms, is most commonly associated with acute hemorrhagic conjunctivitis.

Enterovirus infection of the pancreas can trigger cell-mediated autoimmune destruction of beta-cells resulting in diabetes. Enterovirus myocarditis can be a serious infection in neonates, complicated by cardiac dysfunction and arrhythmias. Enterovirus 71 (HEV-71) almost always occurs in the Asia-Pacific region and is associated with hand, foot, and mouth disease (HFMD), herpangina as well as a form of epidemic encephalitis associated on occasion with pulmonary edema, and acute flaccid paralysis. An outbreak of HFMD in Fuyang China in 2008 was caused by a recombinant virus between HEV-71 and coxsackievirus A16.

Human enteroviruses are neurotropic and a potential role for these viruses in amyotropic lateral sclerosis is the subject of some investigation.

Mortality is especially high in enterovirus 71-associated brainstem encephalitis, which is often complicated by pulmonary edema, particularly when it occurs in children younger than 5 years. A complication is autonomic nervous system dysregulation, which may develop prior to the pulmonary edema. Because of lower herd immunity, HFMD tends to infect the very young (under age 5) in nonendemic areas. Disease is usually more severe and sequelae more common than with other enteroviruses. Some children with enterovirus-associated cardiopulmonary failure require the usage of extracorporeal life support which can improve the outcome. Recognized sequelae include central hypoventilation, dysphagia, and limb weakness.

Diagnosis of both entities is facilitated by the clinical and epidemiologic findings with the isolation of the suspect agent from conjunctival scraping for enterovirus 70 or vesicle swabs, body secretions, or cerebrospinal fluid for entero­ virus 71. Serologic methods, including enzyme immunoassays and complement fixation tests, are developed. These assays show good specificity but poor sensitivity (< 80%).

RT-PCR may increase the detection rate in enterovirus infections and is useful in the analysis of cerebrospinal fluid samples among patients with meningitis and of blood samples among infants with a sepsis-like illness.

Treatment of both entities remains largely symptomatic, though pleconaril (see above) may be of some use. The role of immunoglobulins is under investigation. Treatment of enterovirus 71 infections with corticosteroids or pyrazolones was associated with a worse prognosis in one study. The major complication associated with enterovirus 70 is the rare development of an acute neurologic illness with motor paralysis akin to poliomyelitis. Attention-deficit with hyperactivity occurs in about 20% with confirmed infection.

Household contacts, especially children under 6 months of age, are at particular risk for enterovirus 71 acquisition. A commercial disinfectant, Virkon S, at 1–2% application, appears to reduce infectivity titers. A stage-based supportive treatment for enterovirus 71 infections, recognizing the potential for late

1408

CMDT 2013

Chapter 32

onset CNS disease and cardiopulmonary failure is important.

A human vaccine is needed for enterovirus 71.

Enterovirus 72 (HEV-2) is another term for hepatitis A virus (see Chapter 16). Enterovirus EV-104A is related to rhinoviruses and associated with respiratory illness in reports from Italy and Switzerland.

Enterovirus 68 (HEV-68) is a unique enterovirus that shares epidemiologic characteristics with human rhinovirus and is typically associated with respiratory illness.

Several clusters are reported from the Philippines, Japan, Netherlands and the United States. The agent is implicated in a recent, fatal case of meningomyeloencephalitis.

Centers for Disease Control and Prevention (CDC). Clusters of acute respiratory illness associated with human enterovirus 68—Asia, Europe, and United States, 2008–2010. MMWR Morb Mortal Wkly Rep. 2011 Sep 30;60(38):1301–4. [PMID: 21956405] Kreuter JD et al. A fatal central nervous system enterovirus 68 infection. Arch Pathol Lab Med. 2011 Jun;135(6):793–6.

[PMID: 21631275]

Harvala H et al. Comparison of human parechovirus and enterovirus detection frequencies in cerebrospinal fluid samples collected over a 5-year period in Edinburgh: HPeV type 3 identified as the most common picornavirus type. J Med Virol. 2011 May;83(5):889–96. [PMID: 21412796] Sainato R et al. Severe human parechovirus sepsis beyond the neonatal period. J Clin Virol. 2011 May;51(1):73–4. [PMID: 21388870]

cc

RICKETTSIAL DISEASES

TYPHUS GROUP 1. Epidemic Louse-Borne Typhus ``

E sse n t i a l s o f d i a g n o s i s

Prodrome of headache, then chills and fever.

Severe, intractable headaches, prostration, persisting high fever. `` Macular rash appearing on the fourth to seventh days on the trunk and in the axillae, spreading to the rest of the body but sparing the face, palms, and soles. `` Diagnosis confirmed by specific antibodies using complement fixation, microagglutination, or immu­ nofluorescence. `` ``

4. Human Parechovirus Infection (HPeV) HPeV is a member of the Picornaviridae family. The pathogen mainly affects small children although disease can also occur in older adults. Cases are spread worldwide. There were 16 genotypes recognized worldwide by 2011. Clinical presentation is mainly driven by gastrointestinal and respiratory illness, although otitis, neonatal sepsis, flaccid paralysis, aseptic meningitis, and encephalitis are described in the literature.

The added screening with a human parechovirus-­ specific PCR provides a significant increase in determining the viral cause of neonatal sepsis or CNS symptoms in children younger than 5 years. Human parechoviruses are one of the leading causes of viral sepsis and meningitis in young children. HPeV1 is the most prevalent genotype found among stool and nasopharyngeal samples in children (under 2 years old), whereas HPeV6 affects older individuals (> 20 years old). HPeV3 is responsible for encephalitis, neonatal sepsis, and was recently reported in association with necrotizing enterocolitis and hepatitis. It is the most prevalent picornavirus type found in cerebrospinal fluid samples of CNS-related infections in very young children. Respiratory and gastrointestinal illnesses are seen with types HPeV4–HPeV6. Neonatal deaths are reported with HPeV3 and HPeV6. Treatment is largely supportive and rapid identification of the viral antigen by PCR in stools, respiratory samples, and cerebrospinal fluid may decrease use of unnecessary antibiotics and shorten hospital stay, although current PCR assays are not always sufficiently sensitive to exclude pachecoviruses. Reported complications of neonatal cerebral infections include learning disabilities, epilepsy, and cerebral palsy.

Chieochansin T et al. Molecular epidemiology, genome characterization, and recombination event of human parechovirus.

Virology. 2011 Dec 20;421(2):159–66. [PMID: 22018784]

``General Considerations Epidemic louse-borne typhus is caused by Rickettsia prowaze­ kii, an obligate parasite of the body louse Pediculus humanus corporis (Table 32–3). Transmission is favored by crowded, unsanitary living conditions, famine, war, or any circumstances that predispose to heavy infestation with lice. After biting a person infected with R prowazekii, the louse becomes infected by the organism, which persists in the louse gut and is excreted in its feces. When the same louse bites an uninfected individual, the feces gain entry into the bloodstream when the person scratches the itching wound. Dry, infectious louse feces may also enter via the respiratory tract. Cases can be acquired by travel to pockets of infection (eg, central and northeastern Africa, Central and South America). In the last few years, outbreaks have been reported from Peru, Burundi, and Russia. Because of aerosol transmissibility, R prowazekii is considered a possible bioterrorism agent.

R prowazekii can survive in lymphoid tissues after primary infection, and years later, produce recrudescence of disease (Brill-Zinsser disease) without exposure to infected lice. This phenomenon can serve as a point source for future outbreaks.

An extrahuman reservoir of R prowazekii in the United States is flying squirrels, Glaucomys volans. Transmission to humans can occur through their ectoparasites, usually causing atypical mild disease. A case of recrudescent (BrillZinsser) disease 11 years after the initial flying squirrel-­ associated disease was reported.

Viral & Rickettsial Infections

CMDT 2013

1409

Table 32–3. Rickettsial diseases.

Disease

Rickettsial Pathogen

Geographic Areas of Prevalence

Insect Vector

Mammalian Reservoir

Travel Association

Typhus group Epidemic (louse-borne) typhus

Rickettsia prowazekii

South America, Northeastern and Central Africa

Louse

Humans, flying squirrels

Rare

Endemic (murine) typhus

Rickettsia typhi

Worldwide; small foci (United States: southeastern gulf coast)

Flea

Rodents, opossums

Often

Orientia tsutsugamushi

Southeast Asia, Japan, Australia, Western Siberia

Mite1

Rodents

Often

Rocky Mountain spotted fever

Rickettsia rickettsii

Western Hemisphere; United States (especially midAtlantic coast region)

Tick1

Rodents, dogs, porcupines

Rare

California flea rickettsiosis

Rickettsia felis

Worldwide

Flea

Cats, opossums

Mediterranean spotted fever, Boutonneuse fever, Kenya tick typhus, South African tick fever, Indian tick typhus

Rickettsia conorii

Africa, India, Mediterranean regions

Tick1

Rodents, dogs

Often

Queensland tick typhus

Rickettsia australis

Eastern Australia

Tick1

Rodents, marsupials

Rare

Siberian Asian tick typhus

Rickettsia sibirica

Siberia, Mongolia

Tick1

Rodents

Rare Often

Scrub typhus group Scrub typhus Spotted fever group

1

African tick bite fever

Rickettsia africae

Rural sub-Saharan Africa, Eastern Caribbean

Tick

Cattle

Rickettsialpox

Rickettsia akari

United States, Korea, former USSR

Mite1

Mice

Ehrlichiosis and anaplasmosis, human Monocytic

Ehrlichia chaffeensis, Anaplasma equi, Ehrlichia canis

Southeastern United States

Tick1

Dogs

Granulocytic

Anaplasma phagocytophilum, Ehrlichia ewingii

Northeastern United States

Tick1

Rodents, deer, sheep

Q fever

Coxiella burnetii

Worldwide

None2

Cattle, sheep, goats

Other

1

Also serve as arthropod reservoirs by maintaining rickettsiae through transovarian transmission.

Human infection results from inhalation of dust.

2

``Clinical Findings A. Symptoms and Signs (Table 32–2). Prodromal malaise, cough, headache, backache, arthralgia, and chest pain begin after an incubation period of 10–14 days, followed by an abrupt onset of chills, high fever, and prostration, with flu-like symptoms progressing to delirium and stupor. The headache is severe and the fever is prolonged.

Other findings consist of conjunctivitis, mild vitritis, retinal lesions, optic neuritis, hearing loss from neuropathy of the eighth cranial nerve, flushed facies, rales at the lung bases, abdominal pain, myalgias, and often splenomegaly.

A macular rash (that may become confluent) appears first in the axillae and then over the trunk, spreading to the extremities but rarely involving the face, palms, or soles. In severely ill patients, the rash becomes hemorrhagic, and hypotension becomes marked. There may be acute kidney injury, stupor, seizures, and delirium. Improvement begins 13–16 days after onset with a rapid drop of fever and typically a spontaneous recovery.

B. Laboratory Findings The white blood cell count is variable. Thrombocytopenia, elevated liver enzymes, proteinuria and hematuria commonly

1410

CMDT 2013

Chapter 32

occur. Serum obtained 5–12 days after onset of symptoms usually shows specific antibodies for R prowazekii antigens as demonstrated by complement fixation, microagglutination, or immunofluorescence. In primary rickettsial infection, early antibodies are IgM; in recrudescence (Brill disease), early antibodies are predominantly IgG. A PCR test exists, but its availability is limited. R prowazekii is differentiated into 7 genotypes.

C. Imaging Radiographs of the chest may show patchy consolidation.

``Differential Diagnosis The prodromal symptoms and the early febrile stage lack enough specificity to permit diagnosis in nonepidemic situations. The rash is sufficiently distinctive for diagnosis, but it may be absent in up to 50% of cases or may be difficult to observe in dark-skinned persons. A variety of other acute febrile diseases should be considered, including typhoid fever, meningococcemia, and measles.

``Complications Pneumonia, thromboses, vasculitis with major vessel obstruction and gangrene, circulatory collapse, myocarditis, and uremia may occur.

``Treatment Treatment consists of either doxycycline (100 mg orally twice daily) or chloramphenicol (50–100 mg/kg/d in four divided doses, orally or intravenously) for 4–10 days.

Chloramphenicol is considered less effective than doxycycline, but it is still the drug of choice in pregnancy. In epidemic conditions, a single dose of doxycycline can be effective and is less costly.

``Prognosis The prognosis depends greatly on the patient’s age and immune status. In children under age 10 years, the disease is usually mild. The mortality rate is 10% in the second and third decades but in the past reached 60% in the sixth decade. Brill-Zinsser disease (recrudescent epidemic typhus) has a more gradual onset than primary R prowazekii infection, fever and rash are of shorter duration, and the disease is milder and rarely fatal.

``Prevention Prevention consists of louse control with insecticides, particularly by applying chemicals to clothing or treating it with heat, and frequent bathing. The control of typhus in Finland during World War II is attributed to sauna use.

A deloused and bathed typhus patient is not infectious.

The disease is not transmitted from person to person.

Patients are infectious for the lice during the febrile period and perhaps 2–3 days after the fever returns to normal.

Infected lice pass rickettsiae in their feces within 2–6 days after the blood meal and can be infectious earlier if

crushed. Rickettsiae remain viable in a dead louse for weeks.

No vaccine is currently available for the prevention of R prowazekii infection. Past vaccines with crude antigen or inactivated Rickettsia provided partial protection but were associated with undesirable toxic reactions and difficulties in standardization. Efforts to identify candidate antigens through DNA technology are underway.

Gross D et al. 100th anniversary of the death of Ricketts: Howard Taylor Ricketts (1871–1910). The namesake of the Rickettsiaceae family. Microbes Infect. 2011 Jan;13(1):10–3.

[PMID: 20888424] McQuiston JH et al. Brill-Zinsser disease in a patient following infection with sylvatic epidemic typhus associated with flying squirrels. Clin Infect Dis. 2010 Sep 15;51(6):712–5. [PMID: 20687836] Renvoisé A et al. Widespread use of real-time PCR for rickettsial diagnosis. FEMS Immunol Med Microbiol. 2012 Feb;64(1): 126–9. [PMID: 22092999]

2. Endemic Flea-Borne Typhus (Murine Typhus) Rickettsia typhi, a ubiquitous pathogen recognized on all continents, is transmitted from rat to rat through the rat flea (Table 32–3). Serosurveys of animals show high prevalence of antibodies to R typhi in opossums, followed by dogs and cats. Humans usually acquire the infection in an urban or suburban setting when bitten by an infected flea, which releases infected feces while sucking blood. Rare human cases in the developed world follow travel, usually to Southeast Asia and the Mediterranean area. In the United States cases are mainly reported from Texas and Southern California. Seroprevalence studies show antibody rates to R typhi of 10% among the homeless in Houston and up to 22% in Marseilles, France.

Endemic typhus resembles recrudescent epidemic typhus in that it has a gradual onset, less severe symptoms, and a shorter duration of illness than epidemic typhus (7–10 days versus 14–21 days). The presentation is nonspecific, including fever, headache, and chills. Maculopapular rash occurs in around 50% of cases; it is concentrated on the trunk and fades fairly rapidly. Peripheral facial paralysis and splenic infarction are reported to occur. Severe disease with mental confusion and signs of hepatic, cardiac, renal, and pulmonary involvement may develop. Postinfectious optic neuritis is rare and may occur weeks after successful treatment. Fatalities are uncommon but occur especially in the elderly. Jaundice, bradycardia, and the absence of a headache are correlated with a delayed defervescence (in both epidemic and endemic typhus).

The most common entity in the differential diagnosis is Rocky Mountain spotted fever, usually occurring after a rural exposure and with a different rash (centripetal versus centrifugal for epidemic or endemic typhus). Serologic confirmation may be necessary for differentiation, with complement-fixing or immunofluorescent antibodies detectable within 15 days after onset, with specific R typhi antigens.

A fourfold rise in serum antibody titers between the acute and the convalescence phase is diagnostic.

Viral & Rickettsial Infections Antibiotic treatment is the same as for epidemic typhus (see above). Ciprofloxacin (500–750 mg orally twice a day) and ampicillin (500 mg orally three times a day) are reportedly successful in pregnant women. Mortality is usually low with (1%) or without (4%) appropriate antibiotics.

Preventive measures are directed at control of rats and ectoparasites (rat fleas) with insecticides, rat poisons, and rat-proofing of buildings.

Abramowicz KF et al. Urban focus of Rickettsia typhi and Rickettsia felis in Los Angeles, California. Vector Borne Zoon­ otic Dis. 2011 Jul;11(7):979–84. [PMID: 21142968] Badiaga S et al. Murine typhus in the homeless. Comp Immunol Microbiol Infect Dis. 2012 Jan;35(1):39–43. [PMID: 22093517] Botelho-Nevers E et al. Host, pathogen and treatment-related prognostic factors in rickettsioses. Eur J Clin Microbiol Infect Dis. 2011 Oct;30(10):1139–50. [PMID: 21519943] Zhang J et al. Postinfectious optic neuropathy in endemic typhus. J Neuroophthalmol. 2011 Dec;31(4):342–3. [PMID: 21897295]

3. Scrub Typhus (Tsutsugamushi Fever)

CMDT 2013

1411

bite, a papule evolves into a flat black eschar, a finding which is usually helpful for diagnosis. The regional lymph nodes are commonly enlarged and tender, and sometimes a more generalized adenopathy occurs. Fever rises gradually and after 1 week, a macular rash appears primarily on the trunk area. This rash can be fleeting or last up to 1 week.

The patient may become obtunded. Gastrointestinal symptoms including nausea, vomiting, and diarrhea occur in nearly two-thirds of patients and correspond to the presence of superficial mucosal hemorrhage, multiple erosions, or ulcers in the gastrointestinal tract. Both acalculous cholecystitis and acute abdominal attacks are reported.

Severe complications, such as pneumonitis, myocarditis and cardiac failure, encephalitis or meningitis, acute abdominal pain, granulomatous hepatitis, disseminated intravascular coagulation, ARDS, hemophagocytosis, or acute kidney disease may develop during the second or third week. An attack confers prolonged immunity against homologous strains and transient immunity against heterologous strains. Heterologous strains produce mild disease if infection occurs within a year after the first episode.

B. Laboratory Findings ``

E sse n t i a l s o f d i a g n o s i s

Exposure to mites in endemic area of Southeast Asia, the western Pacific (including Korea), and Australia. `` Black eschar at site of the bite, with regional and generalized lymphadenopathy. `` High fever, headache, myalgia, and a short-lived macular rash. `` Frequent pneumonitis, encephalitis, and cardiac failure. ``

``General Considerations Scrub typhus is caused by Orientia tsutsugamushi, which is principally a parasite of rodents and is transmitted by larval trombiculid mites (chiggers). The disease is endemic in Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia and Queensland, Australia (Table 32–3), which form an area known as the “tsutsugamushi triangle”.

Transmission is often more common at higher altitudes.

The mites live on vegetation but complete their maturation cycle by biting humans who come in contact with infested vegetation. Therefore, the disease is more common in rural areas within these countries. Vertical transmission occurs, and blood transfusions may transmit the pathogen as well.

Rare occupational transmission via inhalation is documented among laboratory workers.

``Clinical Findings A. Symptoms and Signs After a 1- to 3-week incubation period, malaise, chills, severe headache and backache develop. At the site of the

Thrombocytopenia and elevation of liver enzymes, bilirubin, and creatinine are common. Serologic testing with immunofluorescence and immunoperoxidase assays or commercial dot-blot ELISA dipstick assays are convenient diagnostic aids, but a conclusive diagnosis requires documentation of a fourfold increase between acute and convalescence titers of antibodies. An indirect immunofluorescent assay is the mainstay of serologic diagnosis.

PCR (from the eschar or blood) may be the most sensitive diagnostic test but remains positive even after the initiation of treatment. Culture of the organism (by mouse inoculation) from blood obtained in the first few days of illness is another diagnostic modality but requires a specialized BioSafety Level 3 laboratory. Filter paper immunofluorescent assays are under development, and are as sensitive and specific as paired sera, and may be especially useful in field settings.

``Differential Diagnosis Leptospirosis, typhoid, dengue, malaria, Q fever, hemorrhagic fevers, and other rickettsial infections should be considered. The headache may mimic trigeminal neuralgia.

Scrub typhus is a recognized cause of obscure tropical fevers, especially in children.

``Treatment & Prognosis Without treatment, fever subsides spontaneously after 2 weeks, but the mortality rate may be 10–30%. Empiric treatment for 3 days with doxycycline, 100 mg orally twice daily, or with minocyline, 100 mg intravenously twice daily, or for 7 days with chloramphenicol, 25 mg/kg/d orally or intravenously in four divided doses, eliminates most deaths and relapses. Chloramphenicol- and tetracycline-resistant strains have been reported from Southeast Asia, where azithromycin or roxythromycin may become the drug of

1412

CMDT 2013

Chapter 32

choice for children, pregnant women, and patients with refractory disease. Rifampin reduces the duration of fever by 1 day when used with doxycycline.

Poor prognostic factors include requiring care in an ICU, high APACHE-II scores, age over 60 years, absence of an eschar (making the diagnosis difficult) and laboratory findings such as leukocytosis or hypoalbuminemia. HIV infection does not appear to influence the severity of scrub typhus.

``Prevention Repeated application of long-acting miticides can make endemic areas safe. Insect repellents on clothing and skin as well as protective clothing are effective preventive measures. For short exposure, chemoprophylaxis with doxycycline (200 mg weekly) can prevent the disease but permits infection. No effective vaccines are available.

Jayakrishnan MP et al. Rickettsial infection with hemophagocytosis. Trop Doct. 2011 Apr;41(2):111–2. [PMID: 21149571] Rajapakse S et al. Drug treatment of scrub typhus. Trop Doct.

2011 Jan;41(1):1–4. [PMID: 21172901] Shiao CC et al. Eschar: a clue to scrub typhus. CMAJ. 2011 Oct 18;183(15):E1152. [PMID: 21911554]

SPOTTED FEVERS 1. Rocky Mountain Spotted Fever ``

E sse n t i a l s o f d i a g n o s i s

Exposure to tick bite in an endemic area.

An influenza-like prodrome followed by chills, fever, severe headache, and myalgias; occasionally, delirium and coma. `` Red macular rash appears between the second and sixth days of fever, first on the wrists and ankles and then spreading centrally; it may become petechial. `` Serial serologic examinations by indirect fluorescent antibody confirm the diagnosis retrospectively. `` ``

Several hours of contact between the tick and the human host are required for transmission. The brown dog tick, Rhipicephalus sanguineus, is a vector in eastern Arizona.

Other hard ticks transmit the organism in the southern United States and in Central and South America and are responsible for transmitting it among rodents, dogs, porcupines, and other animals. There are 25 genotypes of R rickettsii in four different groups, and potential genomic-clinical correlations are underway.

In the United States, the estimated annual incidence of RMSF is increasing to as high as seven cases per million persons (primarily occurring from April through September), with a higher incidence among children and men. Better diagnostic capacity and improved surveillance are thought responsible for the changing epidemiology.

``Clinical Findings A. Symptoms and Signs RMSF can cause severe multiorgan dysfunction and fatality rates of up to 73% if left untreated, making it the most serious rickettsial disease. Two to 14 days (mean, 7 days) after the bite of an infectious tick, symptoms begin with the abrupt onset of high fevers, chills, headache, nausea and vomiting, myalgias, restlessness, insomnia, and irritability.

The characteristic rash (faint macules that progress to maculopapules and then petechiae) appears between days 2 and 6 of fever. It initially involves the wrists and ankles, spreading centrally to the arms, legs, and trunk over the next 2–3 days. Involvement of the palms and soles is characteristic. Facial flushing, conjunctival injection, and hard palatal lesions (Figure 32–6) may occur. In about 10% of cases, however, no rash or only a minimal rash is seen.

Cough and pneumonitis may develop and delirium, lethargy, seizures, stupor, and coma may also appear in more severe cases. Splenomegaly, hepatomegaly, jaundice, myocarditis (which may mimic an acute coronary syndrome), adrenal hemorrhage, or uremia are occasionally present.

``General Considerations Despite its name, most cases of Rocky Mountain spotted fever (RMSF) occur outside the Rocky Mountain area.

Passive surveillance data from 2002 to 2007 reported cases from 46 states and the District of Columbia. More than half (64%) of these cases were from only five states: North Carolina, Tennessee, Oklahoma, Missouri, and Arkansas.

RMSF is endemic in Central and Southern America, with well-documented cases in Mexico, Costa Rica, Panama, Colombia, Brazil, and Argentina. The causative agent, R rickettsii, is transmitted to humans by the bite of ticks, including the Rocky Mountain wood tick, D andersoni, in the western United States, and the American dog tick, Dermacentor variabilis, in the eastern United States.

s Figure 32–6. Hard palate lesion caused by Rocky Mountain spotted fever. (Public Health Image Library, CDC.)

Viral & Rickettsial Infections ARDS and necrotizing vasculitis, when present, are of greatest concern.

B. Laboratory Findings Thrombocytopenia, hyponatremia, elevated aminotransferases, and hyperbilirubinemia are common. Cerebrospinal fluid may show hypoglycorrhachia and mild pleocytosis.

Disseminated intravascular coagulation is observed in severe cases. Diagnosis during the acute phase of the illness can be made by immunohistologic (including PCR) demonstration of R rickettsiae in skin biopsy specimens (or cutaneous swabs of eschars or skin lesions), but this must be performed as soon as skin lesions become apparent and before antibiotics are started to achieve maximum sensitivity. Isolation of the organism using the shell-vial technique is available in some laboratories but is hazardous.

Serologic studies confirm the diagnosis, but most patients do not mount an antibody response until the second week of illness. The indirect fluorescent antibody test is most commonly used. No commercial PCR technique is validated for serologic use.

``Differential Diagnosis The diagnosis is challenging because early symptoms resemble those of many other infections. The classic triad of fever, rash, and tick bite is rarely recognized, with up to 40% of patients not recalling a tick bite. Moreover, the rash may be confused with that of measles, typhoid, and ehrlichiosis, or—most importantly—meningococcemia. Blood cultures and examination of cerebrospinal fluid establish the latter.

Some spotted fever rickettsioses may also mimic RMSF.

``Treatment & Prognosis Treatment with doxycycline at similar doses and duration as for epidemic typhus (see above) is recommended.

Similarly, chloramphenicol is the preferred alternative during pregnancy. Patients usually defervesce within 48–72 hours and therapy should be maintained for at least 3 days after defervescence occurs. Mild cases in low-risk individuals may be observed without treatment.

The reported mortality rate in the United States is about 3–5%, but it can be as high as 70% in the untreated elderly. Infection in very young children, the presence of atypical clinical features (absence of headache, no history of tick attachment, gastrointestinal symptoms) and underlying chronic diseases, as well as a delay in initiation of appropriate antibiotic therapy are also associated with increased mortality. The usual cause of death is pneumonitis with respiratory or cardiac failure. A fulminant form of RMSF can be seen in patients with glucose6-phosphate dehydrogenase deficiency. Sequelae, more common than formerly recognized, may include seizures, encephalopathy, peripheral neuropathy, paraparesis, bowel and bladder incontinence, cerebellar and vestibular dysfunction, hearing loss, and motor deficits.

These neurologic complications are more common in those patients who require hospitalization for more than 2 weeks.

CMDT 2013

1413

``Prevention Protective clothing, tick-repellent chemicals, and the removal of ticks at frequent intervals are helpful measures.

Prophylactic therapy after a tick bite is not currently ­recommended.

Bechah Y et al. Identification of rickettsial infections by using cutaneous swab specimens and PCR. Emerg Infect Dis. 2011 Jan;17(1):83–6. [PMID: 21192860] Moncayo AC et al. Absence of Rickettsia rickettsii and occurrence of other spotted fever group rickettsiae in ticks from Tennessee. Am J Trop Med Hyg. 2010 Sep;83(3):653–7.

[PMID: 20810834] Oppensaw JJ et al. Rocky Mountain spotted fever in the United States, 2000–2007: interpreting contemporary increase in incidence. Am J Trop Med Hyg. 2010 Jul;83(1):174–82.

[PMID: 20595498]

2. Rickettsialpox Rickettsialpox is an acute, self-limiting, febrile illness caused by Rickettsia akari, a parasite of mice, transmitted by the mite Liponyssoides sanguineus (Table 32–3).

Infections are reported globally. Seroprevalence studies done on injection drug users in inner Baltimore showed antibody positivity as high as 16%. Crowded conditions and mouse-infested housing allow transmission of the pathogen to humans. The primary lesion is a painless red papule that vesiculates and forms a black eschar followed by an incubation period of 7–12 days. Onset of symptoms is sudden, with chills, fever, headache, photophobia, and disseminated aches and pains. Two to 4 days later, a widespread papular eruption appears. The rash becomes vesicular and forms crusts that are shed in about 10 days. Early lesions may resemble those of chickenpox (typically vesicular versus papulovesicular in rickettsialpox). Pathologic findings include dermal edema, subepidermal vesicles, and at times a lymphocytic vasculitis.

Transient leukopenia and thrombocytopenia and acute hepatitis can occur. A fourfold rise in serum antibody titers to rickettsial antigen, detected by complement fixation or indirect fluorescent assays, is diagnostic. Conjugated anti­ rickettsial globulin can identify antigen in punch biopsies of skin lesions. PCR detection of rickettsial DNA in fresh tissue also appears of value. R akari can reportedly also be isolated from eschar biopsy specimens.

Treatment consists of oral doxycycline (200 mg/d) for 7 days. The disease is usually mild and self-limited without treatment, but occasionally severe symptoms may require hospitalization. Control requires the elimination of mice from human habitations and insecticide applications.

Bennett SG et al. Serologic evidence of a Rickettsia akari-like infection among wild-caught rodents in Orange County and humans in Los Angeles County, California. J Vector Ecol. 2007 Dec;32(2):198–201. [PMID: 18260508] Brouqui P. Arthropod-borne diseases associated with political and social disorder. Annu Rev Entomol. 2011;56:357–74.

[PMID: 20822446]

1414

CMDT 2013

Chapter 32

3. Tick Typhus (Rickettsial Fever) The term “tick typhus” denotes a variety of spotted rickettsial fevers, often named by their geographic location (eg, Mediterranean spotted fever, Queensland tick typhus, Oriental spotted fever, African tick bite fever, Siberian tick typhus, North Asian tick typhus), or by morphology (eg, boutonneuse fever). These illnesses are transmitted by tick vectors of the rickettsial organisms R africae, R australis, R conorii, R japonica, R massiliae, R parkeri, and R sibirica (Table 32–3). Dogs and wild animals, usually rodents and even reptiles, may serve as reservoirs. Travel is a risk factor for disease, particularly among elderly ecotourists. In a series of 280 international travelers with rickettsial disease, the most common cause was spotted fever rickettsiosis (231 cases, 82.5% of the total) followed by scrub typhus (16, 5.7%). The pathogens usually produce an eschar or black spot (tâche noire) at the site of the tick bite that may be useful in diagnosis, though spotless boutonneuse fever occurs. Symptoms include fever, headache, myalgias, and rash. Rarely, papulovesicular lesions may resemble rickettsialpox. Endothelial injury produces perivascular edema and dermal necrosis. Regional adenopathy, disseminated lesions, kidney disease, splenic rupture, and focal hepatic necrosis may occur. Neurologic manifestations, including encephalitis, internuclear ophthalmoplegia, coronary involvement, and the hemophagocytic syndrome, are rare. Diabetes, dehydration, and uremia were associated with mortality in one series.

The diagnosis is clinical, with serologic or PCR used for confirmation, and treatment should be started upon clinical suspicion since delayed therapy is the usual cause of increased morbidity. Oral treatment with doxycycline (200 mg/d), chlo­ ramphenicol (50–75 mg/kg/d in four divided doses), or ciprofloxacin (500 mg twice daily) for 7–10 days is indicated.

Ciprofloxacin is associated with a poor outcome and increases the severity of disease in Mediterranean spotted fever, so the other listed agents are preferred. The combination of erythromycin and rifampin is effective and safe in pregnancy. In one reported case, R africae infection was successfully treated with pristinamycin, a streptogramin marketed in Europe. Prevention entails protective clothing, repellents, and inspection for and removal of ticks.

Formerly classified as an endemic or murine typhus, the cat-flea typhus, caused by Rickettsia felis is now more properly classified as a spotted fever. The causative agent has been linked to the cat flea and opossum exposure. Most cases in the United States (southern Texas and California, and possibly Hawaii) occur in the spring and summer. Treatment is the same as for other rickettsial fevers.

A rickesttsial infection recognized as a cause of escharassociated illness was recognized in northern California and is referred to as the spotted fever group rickettsia 364D. Botelho-Nevers E et al. Analysis of risk factors for malignant Mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect. J Antimicrob Chemother.

2011 Aug;66(8):1821–30. [PMID: 21642652] Cascio A et al. Coronary involvement in Mediterranean spotted fever. New Microbiol. 2011 Oct;34(4):421–4. [PMID: 22143818]

Shapiro MR et al. Rickettsia 364D: a newly recognized cause of eschar-associated illness in California. Clin Infect Dis. 2010 Feb 15;50(4):541–8. [PMID: 20073993]

OTHER RICKETTSIAL & RICKETTSIAL-LIKE DISEASES 1. Ehrlichiosis & Anaplasmosis ``

E sse n t i a l s o f d i a g n o s i s

Infection of monocyte or granulocyte by tickborne gram-negative bacteria. `` Nine-day incubation period, with variable clinical illness, ranging from asymptomatic to persistent or life-threatening. `` Common symptoms are malaise, nausea, fever, and headaches. `` US cases are largely in elderly white men in the summer. `` Excellent response to therapy with tetracyclines. ``

``General Considerations Ehrlichiae and anaplasmae are small tick-borne gramnegative obligate intracellular bacteria that infect monocytes or granulocytes. Human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis (Table 32–3). Human granulocytic anaplasmosis is caused by Anasplasma phagocyto­ philium. Ehrlichia ewingii (infecting primarily dogs) can rarely cause human granulocytic ehrlichiosis similar to human granulocytic anaplasmosis. A third Ehrlichia species that infects humans appears to be related to Ehrlichia muris. An Ehrlichia-like organism, Neorickettsia sennetsu, is the etiologic agent of sennetsu fever, which is confined to western Japan.

Human monocytic ehrlichiosis is seen primarily in the South Central states (especially Arkansas, Missouri, and Oklahoma) of the United States, although cases are also recognized in Israel, Japan, Mexico, South America, and Europe.

Human granulocytic anaplasmosis is more frequent in the upper Midwestern United States; but infections in Europe and China are also well documented. Human infection with E ewingii is limited to Missouri, Oklahoma, and Tennessee and occurs mainly among the immunocompromised. In North America, the major vectors for these pathogens are the Lone Star tick (Amblyomma americanus for E chaffeensis and E ewingii), the western black-legged tick (Ixodes pacificus, for E chaffeensis), and Ixodes scapularis (the same vector for Lyme disease) and babesiosis for A phagocytophilium). Reported incidences of both human monocytic and granulocytic ehrlichiosis are increasing and both are now at about 3 per million, respectively, with higher rates in the summer among whites and among men.

The principal reservoirs for human monocytic ehrlichiosis and human granulocytic anaplasmosis are the

Viral & Rickettsial Infections white tail deer and the white footed mouse, respectively.

Other mammals are implicated as well. A nosocomial outbreak was reported from China. Perinatal transmission of human granulocytic anaplasmosis is also documented.

``Clinical Findings A. Symptoms and Signs Clinical disease of human monocytic ehrlichiosis ranges from mild to life threatening. Typically, after about a 9-day incubation period and a prodrome consisting of malaise, rigors, and nausea, worsening fever and headache develop.

A pleomorphic rash may occur. Presentation in immunosuppressed patients (including transplant patients) and the elderly tends to be more severe. Serious sequelae include acute respiratory failure and ARDS, encephalopathy, and acute kidney disease, which may mimic thrombotic thrombocytopenic purpura.

The symptoms of human granulocytic ehrlichiosis and E ewingii infection are similar to those seen with human monocytic ehrlichiosis. Rash, however, is infrequent in human granulocytic ehrlichiosis and should prompt the consideration of other infections (eg, Lyme disease).

Persistent fever and malaise are reported to occur for 2 or more years. Coinfection with Lyme disease or babesiosis may occur.

B. Laboratory Findings Diagnosis can be made by the history of tick exposure followed by a characteristic clinical presentation. Leukopenia, absolute lymphopenia, thrombocytopenia, and transaminitis occur often. Thrombocytopenia occurs more often than leukopenia in human granulocytic ehrlichiosis.

Examination of peripheral blood with Giemsa stain may reveal characteristic intraleukocytic vacuoles (morulae).

An indirect fluorescent antibody assay is available through the CDC and requires acute and convalescent sera. A PCR assay, if available, is a rapid diagnostic tool, especially for early disease.

``Treatment & Prevention Treatment for all forms of ehrlichiosis is with doxycycline, 100 mg twice daily (orally or intravenously) for at least 10 days or until 3 days of defervescence. Rifampin is an alternative in pregnant women and children. Treatment should not be withheld while awaiting confirmatory serology when suspicion is high. Lack of clinical improvement and defervescence 48 hours after doxycycline initiation suggests an alternate diagnosis. Tick control is the essence of prevention.

Dahlgren FS et al. Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000– 2007. Am J Trop Med Hyg. 2011 Jul;85(1):124–31. [PMID: 21734137] Ismail N et al. Human ehrlichiosis and anaplasmosis. Clin Lab Med. 2010 Mar;30(1):261–92. [PMID: 20513551] Pritt BS et al. Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. N Engl J Med. 2011 Aug 4;365(5):422–9. [PMID: 21812671]

CMDT 2013

1415

2. Q Fever ``

E sse n t i a l s o f d i a g n o s i s

Exposure to sheep, goats, cattle, or their products; some infections are laboratory acquired. `` An acute or chronic febrile illness with severe headache, cough, prostration, and abdominal pain. `` Extensive pneumonitis, hepatitis, or encephalopathy; less often, endocarditis, vascular infections, or chronic fatigue syndrome. `` A common cause of culture-negative endocarditis. ``

``General Considerations Q fever (for “query” in view of its formerly unknown cause), a reportable disease in the United States, is caused

by Coxiella burnetii, an organism previously classified as a rickettsia but now considered a proteobacteria. Unlike rickettsiae, C burnetii is usually transmitted to humans not by arthropods but by inhalation or ingestion. Coxiella infections occur globally, mostly in cattle, sheep, and goats, in which they cause mild or subclinical disease (Table 32–3).

In these animals, reactivation of the infection occurs during pregnancy and causes abortions or low birth weight offspring. Coxiella is resistant to heat and drying and remains infective in the environment for months.

Humans become infected by inhalation of aerosolized bacteria (in dust or droplets) from feces, urine, milk, or products of conception of infected animals. Ingestion and skin penetration are other recognized routes of transmission. Outbreaks associated with other mammals such as cats and dogs are also described. A major outbreak in Netherlands that began in 2007 was thought to be due to exposure to aborting ruminants. There is a known occupational risk for animal handlers, slaughterhouse workers, veterinarians, laboratory workers, and other workers exposed to animal products. Outbreaks in military personnel returning from Iraq and Afghanistan were described.

Transmission through aerosols is possible in that Coxiella can be pathogens of other organisms (free living amoebae) which are transmitted through air ducts.

Endocarditis, an uncommon but serious form of Coxiella infection, is linked to preexisting valvular conditions, immunocompromised states, urban residence, and raw milk ingestion. Horizontal spread from one human to another does not seem to occur even in the presence of florid pneumonitis, but maternal–fetal infection can occur.

``Clinical Findings A. Symptoms and Signs Asymptomatic infection is common. For the remaining cases, a febrile illness develops after an incubation period of 1–3 weeks, usually accompanied by headache, relative bradycardia, prostration, and muscle pains. The clinical course may be acute, chronic (duration ≥ 6 months), or

1416

CMDT 2013

Chapter 32

relapsing. Pneumonia and granulomatous hepatitis are the predominant manifestation in the acute form, whereas other less common manifestations include skin rashes (maculopapular or purpuric), fever of unknown origin, myocarditis, pericarditis, aseptic meningitis, encephalitis, hemolytic anemia, orchitis, acute kidney disease, spondylodiscitis, tenosynovitis, and regional (mediastinal) or diffuse lymphadenopathies. Cases of Q fever mimicking autoimmune and systemic inflammatory disease are reported. The most common presentation of chronic Q fever is culturenegative endocarditis, which occurs in < 1% of infected individuals. It is found mainly in the setting of preexisting valve disease. Vascular infections, particularly of the aorta (causing mycotic aneurysms), are the second most common form of Q fever and are associated with a high mortality (25%). Q fever chronic fatigue syndrome is thought by some experts to involve bacteremic shedding from bone marrow reservoirs and to be immunogenetically ­determined.

Reactivation of Q fever in pregnant women may cause spontaneous abortions, intrauterine growth retardation, intrauterine fetal death, premature delivery, and oligamnios.

B. Laboratory Findings Laboratory examination during the acute phase may show elevated liver function tests and occasional leukocytosis.

Patients with acute Q fever usually produce antibodies to C burnetii phase II antigen. A fourfold rise between acute and convalescent sera by indirect immunofluorescence is diagnostic. Realtime PCR for C burnetii DNA is helpful only in early diagnosis of Q fever with C burnetii DNA becoming undetectable in serum as serologic responses develop.

While chronic Q fever can be diagnosed on the basis of serologic tests done at 3- and 6-month intervals (with an IgG titer against phase I antigen of 1:1600 or greater), it is now recommended that clinical criteria be used for diagnosis of chronic disease. Diagnosis may be made at the time of valve replacement with PCR of tissue samples.

C burnetti may also be isolated from affected valves using the shell-vial technique. The organism is highly transmissible to laboratory workers and culture techniques require a biosafety level 3 setting.

C. Imaging Radiographs of the chest show patchy pulmonary infiltrates, often more prominent than the physical signs suggest.

``Differential Diagnosis Viral, mycoplasmal, and bacterial pneumonias, viral hepatitis, brucellosis, Legionnaire disease, Kawasaki disease, tuberculosis, psittacosis, and other animal-borne diseases must be considered. Q fever should be considered in cases of unexplained fevers with negative blood cultures in association with embolic or cardiac disease.

``Treatment & Prognosis For acute infection, treatment with doxycycline (100 mg orally twice daily) for 14 days or at least 3 full days after

defervescence is recommended. Even in untreated patients, the mortality rate is usually low, except when endocarditis develops.

For chronic infection, there is no agreement on the type and duration of antimicrobial therapy. Most experts recommend a combination oral therapy with doxycycline (100 mg twice a day) plus ciprofloxacin (typically 750 mg twice a day) or rifampin (300 mg twice a day) or hydroxychloroquine (200 mg three times a day) for approximately 2 years or more for the treatment of endocarditis. A study reported in 1999 of 35 patients with Q fever endocarditis showed favorable outcomes with oral doxycycline (100 mg twice a day) plus oral hydroxychloroquine (200 mg three times a day) for 18 months for native valves and 24 months for prosthetic valves. Serologic responses can be monitored during and after completion of therapy and treatment extended in the absence of favorable serologic response (considered a titer of 1:1600 or greater to phase I antigen).

The general variability of serologic data, however, limits their usefulness and providers usually rely on clinical criteria. Patients should be monitored for at least 5 years due to risk of relapse. Heart valve replacement may be necessary in refractory disease. Given the difficulty in treating endocarditis, transthoracic echocardiography is recommended for all patients with acute Q fever, and the same aforementioned therapy for 1 year should be offered in the presence of valvulopathy.

Because of the many and serious obstetric complications that occur among pregnant women in whom Q fever develops (listed above), a regimen of long-term trimethoprim-sulfamethoxasole (320/1600 mg orally for at least 5 weeks) should be given to all infected, pregnant women.

``Prevention Prevention is based on detection of the infection in livestock, reduction of contact with infected and, in particular, parturient animals or contaminated dust, special care when working with animal tissues, and effective pasteurization of milk. No vaccine is approved for use in the United States, although a whole-cell Q fever vaccine, with a 5-year efficacy of > 95%, is available in Australia for persons with high-risk exposures.

C burnetii is a category B bioterrorism agent. In the setting of a bioterrorist attack, postexposure prophylaxis with doxycycline (100 mg orally twice daily) for 5 days should be started 8–12 days after exposure. Pregnant women should take trimethoprim-sulfamethoxazole (160 mg/800 mg orally twice daily) for the duration of the pregnancy.

Million M et al. Long-term outcome of Q fever endocarditis: a 26-year personal survey. Lancet Infect Dis. 2010 Aug; 10(8):527–35. [PMID: 20637694] Raoult D. Q fever, free amoeba, and air conditioning. Clin Infect Dis. 2010 Oct 1;51(7):869–70. [PMID: 20809841] van der Hoek W et al. Follow-up of 686 patients with acute Q fever and detection of chronic infection. Clin Infect Dis. 2011 Jun 15;52(12):1431–6. [PMID: 21628483]

Viral & Rickettsial Infections cc

``

KAWASAKI Disease

E sse n t i a l s o f d i a g n o s i s

Fever, conjunctivitis, oral mucosal changes, rash, cervical lymphadenopathy, peripheral extremity changes. `` Elevated erythrocyte sedimentation rate and C-reactive protein levels. ``

``General Considerations Kawasaki disease is a worldwide multisystemic disease initially described by Tomisaku Kawasaki in 1967. It is also known as the “mucocutaneous lymph node syndrome.” It occurs mainly in children between the ages of 3 months and 5 years but can occur occasionally in adults as well.

Kawasaki disease occurs significantly more often in Asians or native Pacific Islanders than in whites. It is an acute, selflimiting, mucocutaneous vasculitis characterized by the infiltration of vessel walls with mononuclear cells and later

by IgA secreting plasma cells that can result in the destruction of the tunica media and aneurysm formation. Several infectious agents (New Haven coronavirus, parvovirus, bocavirus, CMV, Yersinia pseudotuberculosis, meningococcus), bacterial superantigens, and genetic polymorphisms (confirmed in whole genome analysis) in components of the immune system (interleukin 10 and 18) are currently implicated in its pathogenesis.

``Clinical Findings A clinical diagnosis of “complete” Kawasaki disease requires, in the absence of other processes, explaining the current illness of fever and four of the following criteria for at least 5 days: bilateral nonexudative conjunctivitis, mucous membrane changes of at least one type (injected pharynx, erythema, swelling and fissuring of the lips, strawberry tongue), peripheral extremity changes of at least one type (edema, desquamation, erythema of the palms and soles, induration of the hands and feet, Beau lines [transverse grooves of the nails]), a polymorphous rash, and cervical lymphadenopathy > 1.5 cm. An “incomplete” form is diagnosed when only two criteria are met. The classic syndrome is often preceded by nonspecific symptoms including irritability, vomiting, anorexia, cough, and diarrhea for up to 10 days.

Major complications include arteritis and aneurysms of the coronary vessels, occurring in about 25% of untreated patients, on occasion causing myocardial infarction. The pathogenesis of infarction is often thrombus formation, vasospasm, stenosis, or aneurysm rupture. Coronary complications are more common among patients older than 6 years or younger than 1 year of age. Noninvasive diagnosis of coronary complications can be made with magnetic resonance angiography or transthoracic echocardiography. Other factors associated with the development of coronary artery aneurysms are male sex, relentless fever (even after the

CMDT 2013

1417

administration of IVIG), high C-reactive protein, urticarial exanthems, anemia, hypoalbuminemia, hyponatremia, and thrombocytopenia. Pericardial effusions, myocarditis, and mitral regurgitation (usually mild) are also common.

Coronary artery fistulas occur in up to 5% of patients and diastolic dysfunction is also reported. Arteritis of extremity vessels, peripheral gangrene, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and the hemophagocytic syndrome are also reported. Cases of pancreatitis and bile duct stenosis due to underlying vasculitis are reported. Cerebrospinal fluid pleocytosis is found in onethird of cases and encephalitis is rarely reported. Other CNS complications include seizures, oculomotor palsies, and sensorineural hearing loss which, when sought, can be found in as many as 55% of cases. Rare case reports of atypical presentations (eg, retropharyngeal abscess) are described.

Differentiation from disseminated adenovirus infection is important and can be performed with rapid adenovirus assays.

``Treatment & Prevention Every patient with a clinical diagnosis of Kawasaki disease (complete or incomplete) should be treated. IVIG (2 g/kg over 10–12 hours) is given within the first 10 days of illness.

For those presenting later, but with persistent fever, ongoing systemic inflammation, or aneurysm formation, IVIG should be offered as well. Concomitant aspirin should be started at 80–100 mg/kg/d orally (divided into four doses and not exceeding 4 g/d) until the patient is afebrile for 48 hours and then reduced to 3–5 mg/kg/d until markers of acute inflammation normalize. Aspirin therapy is continued if coronary aneurysm develops. If fevers persist beyond 36 hours after the initial IVIG infusion, a second dose of IVIG at 2 g/kg should be given if no other source of fever is found. Rare cases of aseptic meningitis are reported with IVIG, and this complication may be hard to distinguish from the occasional CNS disease associated with Kawasaki syndrome itself although the time course and the cerebrospinal fluid differential (more polymorphonuclear with IVIG, more lymphocytic with Kawasaki syndrome) may help differentiate the two. Methylprednisolone (30 mg/kg/d intravenously if possible for a maximum of 3 days) followed by tapering dose of corticosteroids should follow if the disease persists after the second IVIG administration. Routine childhood vaccinations should be given and live vaccines (eg, MMR) should be delayed for at least 9 months only if IVIG was administered (because IVIG can block the immune response to live vaccines). If vaccine preventable disease endemicity requires urgent vaccination, it is prudent to revaccinate 11 months after the IVIG and first vaccination were given.

Further options for refractory cases include TNF blockers (infliximab or etanercept), cyclophosphamide, methotrexate, and plasmapheresis. Abciximab therapy may be associated with coronary vessel remodeling in large coronary artery aneurysms. An echocardiogram is essential in the acute phase of illness and 6–8 weeks after onset.

Anticoagulation with warfarin or low-molecular-weight heparin (the latter is preferable for children where dosage

1418

CMDT 2013

Chapter 32

adjustments are difficult using warfarin) is indicated along with aspirin, 81 mg orally daily, in patients with aneurysms > 8 mm in diameter. If myocardial infarction occurs, therapy with thrombolytics, percutaneous coronary intervention, coronary artery bypass grafts, and even cardiac transplantation should be considered. Manifestation of coronary artery aneurysms can occur as late as in the third or fourth decade of life. Data are equivocal on the development of accelerated atherosclerosis among those with a history of Kawasaki disease.

While secondary prevention of complications entails the modalities described above, primary prevention is difficult in the absence of a clear explanation for the disease.

``Prognosis ases that develop recurrent disease tend to more often C show cardiac complications. Patients with a parental history of Kawasaki disease show more recurrent disease and more cardiac complications. The long-term prognosis for adults with a history of Kawasaki disease but without coronary artery aneurysms is excellent. A heart-healthy lifestyle,

however, is essential. The prognosis of patients with a history of cardiac complications requires regular follow-up with risk stratification based on published guidelines and under cardiologic supervision. Children with Kawasaki disease appear to have an increased risk for subsequent allergic diseases.

``When to Refer All cases of Kawasaki disease merit referral to specialists.

Falcini F et al. Kawasaki syndrome: an intriguing disease with numerous unsolved dilemmas. Pediatr Rheumatol Online J. 2011 Jul 20;9:17. [PMID: 21774801] Gomard-Mennesson E et al. Kawasaki disease in adults: report of 10 cases. Medicine (Baltimore). 2010 May;89(3):149–58.

[PMID: 20453601] McCandless RT et al. Does abciximab promote coronary artery remodeling in patients with Kawasaki disease? Am J Cardiol.

2010 Jun 1;105(11):1625–8. [PMID: 20494673] Yeung RS. Kawasaki disease: update on pathogenesis. Curr Opin Rheumatol. 2010 Sep;22(5):551–60. [PMID: 20616737]