29 - Nutrition

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 32 - Infectious Diseases: Viral & Rickettsial

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32

Infectious Diseases: Viral & Rickettsial

Wayne X. Shandera MD

Hoonmo Koo MD

Viral Diseases

This section discusses viral diseases caused by herpesviruses, those preventable by vaccines, and others causing distinct syndromes. Rickettsial illnesses and Kawasaki disease are also included. Disorders caused by hepatotropic viruses (see Chapter 15), papillomaviruses (see Chapters 6 and 17), and HIV (see Chapters 17 and 31) are dealt with elsewhere.

Clinical Diagnosis

Some viral illnesses present with typical syndromes (measles, mumps, and chickenpox). In others, the clinical picture suggests any of a number of viruses. For example, aseptic meningitis can be caused by the mumps virus, lymphocytic choriomeningitis virus, and several enteroviruses, among others. Symptoms of respiratory disease with many viruses are indistinguishable. Some viral diseases have a characteristic rash, although in most cases, the rash associated with viral syndromes is not pathognomonic.

Identification of a virus is useful for confirmation of atypical cases, help with outbreak investigation, elucidation of confusing syndromes, and increasingly to support the need for specific antiviral therapy. The frequency with which certain pathogens cause certain diseases allows for educated guesses, eg, respiratory syncytial virus (RSV) for bronchiolitis or parainfluenza virus for croup. Instances in which rapid diagnosis assists in patient management are noted.

Laboratory Diagnosis

Several techniques are used for diagnosis, including stain (the nonspecific Tzanck smear for herpesviruses), cell culture (coxsackievirus in suckling mice), immunologic detection (seroconversion with arboviruses, rabies virus on skin biopsy, detection of secretory immunoglobulin A [IgA]), or molecular techniques such as polymerase chain reaction (PCR) (for herpes simplex virus [HSV]) or antigen assays (for cytomegalovirus [CMV]). Isolation of virus from a normally sterile site (cerebrospinal fluid, lung) or from a lesion (vesicles) in an immunocompetent individual is diagnostically significant. Isolation from nonsterile sites (nasopharynx, stool) may represent a carrier state, and seroconversion and pathologic change are needed to establish a diagnosis.

A. Microscopic Methods

Microscopic techniques are used to examine cells, body fluids, or biopsy material in search of virus or cytopathic changes specific for one virus or a group of viruses (eg, multinucleated giant cells at the base of herpes lesions, rotavirus structures on electron micrographs of diarrheal stools).

Immunofluorescent methods, often with monoclonal antibodies, can rapidly identify some antigens (rabies, varicella, herpes simplex, RSV) in desquamated or scraped cells.

B. Immunologic Studies of Sera

Specific antibodies to viruses rise during the course of illness, though the rise and persistence of titer depend on both the virus and the host response. A fourfold or greater rise in antibody titer during illness is considered evidence of disease.

Single determinations are seldom helpful, and laboratories require paired sera (acute and convalescent, typically 2–3 weeks apart). Antigenic detection is used for certain viruses (hepatitis B surface antigen [HBsAg], CMV, HIV), with viral presence detected independently of disease duration or host response. As more is learned of the natural history of HSV-1 and HSV-2 infections, these viruses are increasingly managed clinically with support from serologic data. Quantification of viral antigen titer is useful in the management of HIV disease and is becoming a standard of care for other chronic viral infections (eg, hepatitis B and C virus [HBV, HCV]).

C. Molecular Techniques

Molecular technology has provided techniques such as PCR and nucleic acid probes that have proved useful in the identification of new pathogens (eg, HCV and

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Kaposi's sarcoma herpesvirus) as well as for the management of patients in whom quantification of viral activity, as with immunologic techniques, assists in following the course of clinical illness or the response to therapy. Results vary among laboratories.

Treatment

The armamentarium of antiviral therapy has expanded greatly with the advent of the HIV outbreak (Table 31-5), though for many viruses there remains no definitive antiviral therapy.

The mainstay of controlling viral diseases is vaccination. Currently available live vaccines include those against measles, mumps, rubella, poliovirus (Sabin vaccine), yellow fever, and varicella. The inactivated vaccines protect against the agents implicated in poliovirus (Salk vaccine), hepatitis A, hepatitis B, influenza A and B, rabies, RSV, and Japanese B encephalitis. Passive immunoprophylaxis remains important in prevention of hepatitis A and B, RSV infection and, among the immunosuppressed, varicella. There is now a trend favoring the combination of vaccines, with the sacrifice in immunogenicity compensated for by the increased compliance with vaccinations by the vaccinated patient and their families.

Fletcher MA et al: Vaccines administered simultaneously: directions for new combination vaccines based on an historical review of the literature. Int J Infect Dis 2004;8:328.

Human Herpesviruses

Herpesviruses cause a wide spectrum of human disease. Eight identified human herpesviruses (HHV) include HSV (type 1), HSV (type 2), varicella-zoster virus (VZV) (type 3), Epstein-Barr infectious mononucleosis virus (type 4), and CMV (type 5). A sixth type (HHV-6) has been identified as a causative agent of roseola (exanthema subitum), and a seventh (HHV-7) is serologically associated with several syndromes. Another herpesvirus (HHV-8) is linked with Kaposi's sarcoma (see Chapter 31).

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 the immunodeficient. Herpesviruses can transform cells in tissue culture. Associations with malignancies include Epstein-Barr virus (EBV) with Burkitt's lymphoma and nasopharyngeal carcinoma and HHV-8 with primary effusion lymphoma and Kaposi's sarcoma.

1. Herpesviruses 1 & 2

Essentials of Diagnosis

  • Spectrum of illness from stomatitis and urogenital lesions to facial nerve paralysis (Bell's palsy) and encephalitis.

  • Variable intervals between exposure and clinical disease, since HSV causes both primary (which may be subclinical) and reactivation disease.

  • Successful management with acyclovir or related acyclic compounds (valacyclovir, famciclovir).

General Considerations

Herpesviruses 1 and 2 affect primarily the oral and genital areas, respectively. Seroprevalence to both viruses increases with age; seroprevalence to HSV-2 increases with sexual activity. Disease is typically a manifestation of reactivation, and the triggers for clinical reactivation are not well understood. Although HSV-1 is increasingly recognized as causing primary urogenital infections (> 65–70% in series from Israel and the United States), genital recurrences are much more frequent with HSV-2. Following the first year after infection, HSV-1 recurrences are rare, while HSV-2 reactivations gradually decrease.

Clinical Findings

A. Mucocutaneous Disease

HSV-1 mucocutaneous disease largely involves the mouth and oral cavity (“herpes labialis”). HSV-2 is the most common cause of genital ulcers in the developing world. Digital lesions (whitlows) are an occupational hazard in medicine, nursing, and dentistry.

Vesicles form moist ulcers after several days and epithelialize over 1–2 weeks if left 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), or other undetermined factors.

HSV-2 lesions largely involve the genital tract. Virus remains latent in presacral ganglia. Typical lesions are multiple, painful, small, grouped, and vesicular. A manifestation of primary infection, predominantly in women, may be aseptic meningitis. Asymptomatic HSV-2 occurs frequently in the CNS. Urinary retention and chronic neuropathic pelvic pain may occur. Risk factors for HSV transmission include black race, female gender, a history of sexually transmitted infections (STIs), an increased number of partners, contact with commercial sex workers, lower socioeconomic status, young age of onset of sexual activity, and total duration of sexual activity.

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Asymptomatic shedding of either HSV-1 or HSV-2 is common, especially following primary infection or symptomatic recurrences, and appears to be responsible for transmission. HSV-2 increases the risk of HIV acquisition, and in advanced HIV infection, HSV reactivates more frequently.

Diagnosis is usually made clinically, but viral cultures of vesicular fluid or direct fluorescent antibody staining of scraped lesions remain the standard of diagnosis. HSV can be identified using PCR, and its presence correlates with clinical reactivation. The presence of intranuclear inclusion bodies and multinucleated giant cells on a Tzanck preparation or Calcofluor stain is supportive of a diagnosis of herpetic viral infection.

In STI, perinatal, and HIV clinics, type-specific serologies are useful for counseling HIV-infected individuals, pregnant women, and those with an uncertain clinical history, high-risk behavior, or increased number of sexual partners.

B. Ocular Disease

HSV can cause keratitis, blepharitis, and keratoconjunctivitis. Keratitis is usually unilateral, is suggested by impaired visual acuity, and is diagnosed by branching (dendritic) ulcers that stain with fluorescein. It may be difficult to differentiate HSV conjunctivitis clinically from adenoviral conjunctivitis in the acute stage. Recurrences are frequent.

C. Neonatal and Congenital Infection

Both herpesviruses can infect the fetus and induce congenital malformations (organomegaly, bleeding, and CNS abnormalities. Neonatal transmission during delivery is more common than intrauterine infection. Maternal infection during the third trimester is associated with the highest risk of neonatal transmission; about 70% of these infections are asymptomatic or unrecognized. Invasive fetal monitoring and vacuum or forceps delivery can facilitate the risk of transmitting herpes.

D. Encephalitis and Recurrent Meningitis

Herpes simplex encephalitis presents with nonspecific symptoms: a flu-like prodrome, followed by headache, fever, behavioral and speech disturbances, and seizures that may be focal or generalized. There is a propensity to involve the temporal lobe, with mass effect on imaging studies and temporal lobe seizure foci on electroencephalograms (EEGs). Cerebrospinal fluid pleocytosis is common, with roughly equal numbers of red cells. MRI scanning is often a useful adjunct showing increased signal in the temporal and frontal lobes.

HSV DNA PCR of the cerebrospinal fluid is a rapid, sensitive, and specific tool for early diagnosis. Cerebrospinal fluid findings of antibodies to HSV can confirm the diagnosis. Viral cultures show temperature dependence, with lower rates of recovery in the summer. Untreated disease and presentation with coma carry a high mortality rate, with many survivors suffering neurologic sequelae. HSV-1 predominantly causes herpes simplex encephalitis. However, HSV-1 and HSV-2 are both associated with benign recurrent lymphocytic (Mollaret's) meningitis.

E. Disseminated Infection

Disseminated HSV infection occurs in the setting of immunosuppression, either primary or iatrogenic, including corticosteroid usage, or rarely with pregnancy. Skin lesions are a particular complication in patients with atopic eczema (eczema herpeticum). In disseminated disease, skin lesions are not always present.

F. Bell's Palsy

An association between HSV-1 and Bell's palsy is established.

G. Esophagitis

Esophagitis from HSV-1 in AIDS and other immunocompromised patients is diagnosed by endoscopic biopsy and cultures. CMV esophagitis is distinguished by the size and depth of the lesion (smaller and deeper for HSV). HSV-1 is also postulated to activate mononuclear cells in the pathogenesis of achalasia.

H. Erythema Multiforme

Herpes simplex viruses remain, with drugs, the leading association with erythema multiforme and with the more severe, mucosally involved Stevens-Johnson syndrome.

I. Other

Recent studies suggest an association between HSV-1 and atrial myxoma.

Treatment & Prevention

Drugs that inhibit replication of HSV-1 and HSV-2 include trifluridine (for keratitis), acyclovir and related compounds (for urogenital, encephalitic, or disseminated disease), and foscarnet (for resistant strains in immunocompromised persons) (Table 32-1).

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
Amantadine 100 mg orally twice daily (100 mg/d in elderly) for 10 days Influenza A, not avian flu Yes/No Yes Confusion, gastrointestinal symptoms
Cidofovir 5 mg/kg intravenously weekly for 2 weeks, then every other week CMV Yes/NA NA Neutropenia, renal failure, ocular hypotonia
Entecavir 0.5 mg orally daily, increase to 1 mg orally daily in lamivudine-resistant patients HBV Yes/NA NA Lactic acidosis, rare exacerbation of HBV infection
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 Local reactions
Interferon α-2b 3-5 million IU subcutaneously 3 times weekly to daily. Intralesionally: 1 million IU per 0.1 mL in up to 5 warts three times weekly for 3 weeks HBV, HCV, HPV Yes/Yes 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
Lamivudine (3TC) 12 mg/kg/d HIV-1, ?HIV-2, HBV Yes/NA Yes Skin rash, headache, insomnia
Oseltamivir 75 mg twice daily for 5 days beginning 48 hours after onset of symptoms Influenza A and B Yes/NA NA Few
Penciclovir Topical, 1′ cream every 2 hours for 4 days HSV No/No No Local reactions
Palivizumab 15 mg/kg intramuscularly every month in RSV season RSV No/No No Upper respiratory infection symptoms
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 orally twice daily Influenza A Yes/No Yes Same as amantadine, but less severe
Trifluridine Topical, 1′ drops every 2 hours to 9 drops/d HSV keratitis 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
1Agents used exclusively in the management of HIV infection and AIDS are found in Chapter 31.
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.

A. Mucocutaneous Disease

While treatment is often not necessary in immunocompetent patients, it can ameliorate and shorten the duration of symptoms if initiated early. Immunocompromised patients are treated with oral or topical acyclic derivatives, with intravenous acyclovir reserved for severe or recalcitrant disease. Lesions heal faster with topical penciclovir than with topical acyclovir. Oral agents are generally superior to topical ones and include (for primary infection) acyclovir, 200 mg five times a day for 10 days, valacyclovir, 1 g twice daily for 7–10 days, or famciclovir, 250 mg three times daily for 7–10 days. Reactivation disease is treated with half the dose of the oral agents used against primary infection.

Acyclovir-resistant isolates associated with mucocutaneous lesions in the HIV-positive population are treated with foscarnet (phosphonoformic acid), 40–60

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mg/kg intravenously every 8 hours, adjusting for renal function. The acyclic nucleotide analog cidofovir is used against HSV and CMV in rare cases of infection resistant to both acyclovir and foscarnet.

Acyclovir and related compounds are effective in secondary prevention. Patients with recurrent genital infections may be placed on maintenance acyclovir at a dosage of 400 mg twice a day. Prophylaxis for herpes labialis and mucocutaneous HSV infections may be especially useful for patients exposed to ultraviolet radiation such as during skiing or sailing trips when topical sun-blocking agents cannot be used or for wrestlers at risk for herpes gladiatorum. Famciclovir (250 mg twice daily or 500 mg once daily) and valacyclovir (500 mg to 1 g—if the lower dose results in breakthrough lesions—once daily) are more costly alternatives for preventing recurrent disease. Studies with valacyclovir show a reduction in subclinical shedding and in the risk of transmission among HSV-2 discordant heterosexual partners. The advantages of these two agents include higher

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serum levels and less frequent administration. AIDS patients with a history of mucocutaneous disease should receive lifelong suppressive therapy. Acyclovir resistance occurs often among immunodeficient persons. Counseling, barrier protection or, in the future, microbicides, are useful to decrease the rate of transmission among sexual partners of infected persons.

HIV-infected individuals should be assayed for HSV-2 serologies and counseled if seropositive. In addition, among HIV-infected persons, the use of highly active antiretroviral therapy (HAART) is associated with fewer days of HSV-1 or -2 lesions.

B. Keratitis

Ophthalmic trifluridine, vidarabine, and acyclovir given as drops for 10 days (without corticosteroids) are the available alternatives. Long-term (greater than 1 year) treatment with acyclovir at a dosage of 800 mg/d orally decreases recurrence rates.

C. Neonatal Disease

Acyclovir intravenously is effective for disseminated lesions in neonatal disease. The dosage is 20 mg/kg intravenously every 8 hours for 14–21 days. The use of maternal antenatal suppressive therapy with acyclovir (typically, 800 mg/day) beginning at 36 weeks gestation decreases rates of HSV detection, asymptomatic shedding, and recurrence at delivery or need for cesarean section. However, cesarean section is recommended for pregnant women with active genital lesions or typical prodromal symptoms.

D. Encephalitis

Because of the need for rapid treatment and the difficulties associated with brain biopsy, patients with suspected HSV encephalitis are given intravenous acyclovir (10 mg/kg every 8 hours for 10 days or more, adjusting for renal impairment), starting upon suspicion of diagnosis, and stopping if another diagnosis is established. If the PCR is negative and clinical suspicion remains high in the absence of a biopsy, treatment should be continued for 10 days because of the relatively nontoxic nature of acyclovir. Long-term neurologic sequelae are common.

E. Disseminated Disease

Disseminated disease responds best to parenteral acyclovir (see the preceding paragraph for dosages) when treatment is initiated early.

F. Bell's Palsy

The efficacy of treating Bell's palsy with acyclovir or corticosteroids is not fully established although a number of studies suggest that a combination of acyclovir or valacyclovir and prednisone, if given in the first 3 days of disease, is associated with improved rates of recovery.

G. Esophagitis

Patients with esophagitis should receive either intravenous acyclovir at a dosage of 5–10 mg/kg every 8 hours or oral acyclovir, 400 mg five times daily. AIDS patients are maintained on acyclovir at a dosage of 400 mg three to five times daily.

H. Erythema Multiforme

Acyclovir may decrease the recurrence rate of HSV-associated erythema multiforme.

Prevention

Besides antiviral suppressive therapy, prevention also requires use of barrier precautions during sexual activity. Preventing spread to hospital staff and other patients from cases with mucocutaneous, disseminated, or genital disease requires isolation and the use of handwashing and gloving-gowning precautions. Staff with active lesions (eg, whitlows) should not have contact with patients. Asymptomatic transmission occurs, especially with HSV-2. A glycoprotein vaccine, preliminarily effective among female HSV-2 seronegative women, is under investigation.

Brown ZA et al: Genital herpes complicating pregnancy. Obstet Gynecol 2005;106:845.

Corey L et al; Valacyclovir HSV Transmission Study Group: Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11.

Holland NJ et al: Recent developments in Bell's palsy. BMJ 2004;329:553.

Roberts CM et al: Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis 2003;30:797.

Sheffield JS et al: Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol 2003;102:1396.

Tyler KL: Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes 2004;11(Suppl 2):57A.

Whitley R: Neonatal herpes simplex virus infection. Curr Opin Infect Dis 2004;17:243.

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

Essentials of Diagnosis

  • 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) is HHV-3. Disease manifestations are either chickenpox (varicella) or shingles (herpes zoster). Chickenpox is highly contagious and is

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generally a disease of childhood, with spread by inhalation of infective droplets or contact with lesions after an incubation of 10–20 days (average, 14–15 days).

The incidence and severity of herpes zoster (“shingles”) increases with age (although cases are reported among infants and children) 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. The annual incidence of zoster in the United States is at least 1 million cases, which is expected to increase as the population ages. Other persons at risk include those who are immunosuppressed (eg, patients receiving cancer treatment, patients with AIDS, and organ transplant recipients) and occasionally infants after intrauterine infection.

Clinical Findings

A. Varicella

1. Symptoms and signs

(Table 32-2.) Fever and malaise are mild in children and more marked in adults. Vesicular lesions, quickly rupturing to form small ulcers, may appear first in the oropharynx. The pruritic rash begins prominently on the face, scalp, and trunk, and later involves the extremities. Maculopapules change in a few hours to vesicles that become pustular and eventually form crusts. New lesions may erupt for 1–5 days, so that different stages of the eruption are usually present simultaneously, unlike smallpox in which all lesions tend to evolve simultaneously. The crusts slough in 7–14 days. The vesicles and pustules are superficial and elliptical, with slightly serrated borders.

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). Widespread dissemination can occur in the immunosuppressed, sometimes in the absence of cutaneous lesions. CNS complications, in particular cerebellar ataxia, vasculopathy, and encephalitis, occur rarely.

2. Laboratory findings

Diagnosis is usually made clinically, with confirmation by direct immunofluorescent antibody (DFA) 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 is often present.

B. Herpes Zoster

Herpes zoster (“shingles”) usually occurs among adults, but cases are reported among infants and children. Pain is often severe and may precede the appearance of rash. Lesions follow any nerve root distribution, with thoracic and lumbar roots being the most common; cervical or trigeminal involvement is typical. In most cases, a single unilateral dermatome is involved. The occurrence of zoster does not correlate with progression to AIDS in HIV-infected patients, but recurrent and in particular multidermatomal zoster indicates a poorer prognosis in established AIDS.

Skin lesions resemble those of chickenpox, developing as maculopapules and evolving into vesicles and pustules. Lesions on the tip of the nose indicate involvement of the nasociliary nerve, a branch of the ophthalmic division of the trigeminal nerve, which also serves the cornea. Facial palsy, lesions of the external ear with or without tympanic membrane involvement, vertigo and tinnitus, and deafness signify geniculate ganglion involvement (Ramsay Hunt syndrome). In either, treatment is indicated (see below).

Complications

A. Varicella

Interstitial pneumonia is more common in adults (especially smokers, HIV-infected patients, and pregnant women) than in children and may result in acute respiratory distress syndrome (ARDS). After healing, numerous densely calcified lesions are seen throughout the lung fields on chest radiographs. Ischemic strokes have been recognized in the wake of acute varicella and may be due to an associated vasculitis. Hepatitis is suggested by aminotransferase elevations and occurs in a small percentage of patients with varicella-zoster infection. Encephalitis is infrequent (1:1000) and is characterized by ataxia and nystagmus and may be life-threatening. Cerebellar ataxia occurs among younger people at a lower frequency than encephalitis (1:4000).

Secondary bacterial infections, particularly with group A β-hemolytic streptococci and Staphylococcus aureus, are common. Cellulitis, erysipelas, epiglottitis, osteomyelitis, scarlet fever and, rarely, meningitis are observed. Pitted scars are frequent sequelae.

Reye's 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). The many manifestations of VZV infection that occur in HIV infection include multifocal encephalitis, ventriculitis, myeloradiculitis, and arteritis.

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 a mother develops varicella within 5 days after delivery, the newborn is at risk for disseminated disease and should receive varicella-zoster immune globulin (VZIG). (See below for dosage.)

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

Disease Prodromal Signs and Symptoms Nature of Eruption Other Diagnostic Features Laboratory Tests
Eczema herpeticum None. Vesiculopustular lesions in area of eczema.   Herpes simplex virus isolated in cell culture. Multinucleate giant cells in smear of lesion.
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.
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).
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.
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, below. Koplik's spots on buccal mucosa. White blood count low. Virus isolation in cell culture. Antibody tests by hemagglutination inhibition or neutralization.
Atypical measles Same as measles. Maculopapular centripetal rash, becoming confluent. History of measles vaccination. Measles antibody present in past, with titer rise during illness.
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).
Erythema infectiosum (parvovirus B19) None. Usually in epidemics. Red, flushed cheeks; circumoral pallor; maculopapules on extremities. “Slapped face” appearance. White blood count normal.
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.
Typhus 3-4 days of fever, chills, severe headaches. Maculopapules, petechiae, initial distribution centrifugal (trunk to extremities). Endemic area, lice. Complement fixation.
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.
Ehrlichiosis Headache, malaise. Rash in one-third, similar to Rocky Mountain spotted fever. Pancytopenia, elevated liver function tests. Polymerase chain reaction, immunofluorescent antibody.
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.
Meningococcemia Hours of fever, vomiting. Maculopapules, petechiae, purpura. Meningeal signs, toxicity, shock. Cultures of blood, cerebrospinal fluid. High white blood count.
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.
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.
1http://www.bt.cdc.gov/agent/smallpox/response-plan/ .
EBV = Epstein-Barr virus; HHV = human herpesvirus.

VZV is a major etiologic agent of Bell's palsy in patients lacking antibodies to HSV.

VZV is the major virus associated with acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN), both of which occur with increased frequency among AIDS patients. Another AIDS-associated manifestation with VZV is immune restitution disease, among patients who have recently started HAART.

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B. Herpes Zoster

In immunosuppressed and HIV-infected patients, herpes zoster may produce skin lesions beyond the dermatome, visceral lesions, and encephalitis. Postherpetic neuralgia occurs in 60–70% of zoster patients over age 60 years. The pain can be prolonged and debilitating. Risk factors for postherpetic neuralgia include age, female sex prodrome, and severity of rash or pain. There may also be an immunogenetic determinant to the development of postherpetic neuralgia.

Prevention

Patients with active varicella or zoster are separated from seronegative patients. Respiratory isolation is needed in varicella pneumonia. Health care workers should be screened for varicella and vaccinated if seronegative. They should stay away from work when active vesicles are present, typically from the tenth day after onset through the twenty-first day. VZIG is effective in preventing chickenpox in

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exposed susceptible—particularly immunosuppressed—individuals. These include (1) susceptible persons receiving immunosuppressive therapy; (2) persons with congenital cellular immunodeficiency; (3) persons with an acquired immunodeficiency, including AIDS; (4) susceptible and exposed persons, in particular pregnant females; (5) newborns; and (6) premature infants of low birth weight.

A. Varicella

A live attenuated vaccine, administered as one dose, or two doses 3 months apart, is safe and currently recommended for all children between 12 and 18 months of age who have not had chickenpox. Patients with impaired cellular immunity should not be immunized, although the vaccine appears to be safe and effective when given to asymptomatic or mildly symptomatic HIV-infected children or to patients with chronic kidney disease. Susceptible, nonimmunocompromised household contacts with no prior history of varicella should also be vaccinated. Under such conditions, the vaccine is 85% effective in preventing illness and 95% effective in preventing serious disease. Vaccine effectiveness decreases significantly within a year after administration and is lower when vaccination occurs at age 15 months or younger, although breakthrough cases are usually mild. Vaccination during early pregnancy (weeks 13–20), however, is associated with congenital malformations. Children receiving the vaccine should not take aspirin for at least 6 weeks, because of the possibility of hepatic encephalopathy (Reye's syndrome). Rashes occur after vaccination in up to 5% of healthy children and 50% of leukemic children. Concomitant administration with other childhood vaccinations, including the measles-mumps-rubella, Haemophilus influenza, or hepatitis B virus vaccines, appears to be safe with no significant loss of immunogenicity. Adults should receive a second dose of the vaccine, typically 1–3 months after the first dose.

Universal childhood vaccination in the United States has been very successful in reducing the incidence, mortality rate, and health care expenditures secondary to varicella. Preliminary results of quadrivalent measles, mumps, rubella, and varicella vaccine are favorable and may eventually replace separate vaccinations. There is a concern that varicella vaccination will increase reactivation of herpes zoster as a result of lack of reexposures in adults to varicella, which boosts their immunity to latent VZV, but this has not occurred thus far. The incidence of herpes zoster has not changed significantly between 1992 and 2002.

If given within 4 days of exposure to an active varicella case, VZIG is effective in preventing chickenpox in exposed susceptible—particularly immunosuppressed—individuals. It is given by intramuscular injection in a dosage of 12.5 units/kg up to a maximum of 625 units, with a repeat 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). Because VZIG appears to bind the varicella vaccine, the two should not be given concomitantly.

B. Zoster

A recent trial investigating a new live attenuated herpes zoster vaccine among adults age 60 years and older, designed to boost their cell-mediated immunity to VZV, demonstrated dramatic decreases in incidence of herpes zoster and postherpetic neuralgia. Future studies are awaited.

Treatment

A. General Measures

Patients should be isolated until primary crusts have disappeared and kept at bed rest until afebrile. Hospitalized patients with VZV infections should be isolated, and caregivers should wear gowns, gloves, and masks when in contact with them. The skin is kept clean. Pruritus can be relieved with antihistamines, calamine lotion, and colloidal oatmeal baths. As an antipyretic, acetaminophen is used. Gabapentin is used for postherpetic neuralgia.

B. Antiviral Therapy

For the infrequent varicella infection for which antiviral therapy is indicated, the mainstay of therapy is acyclovir; its analogs (the prodrug valacyclovir and the related drug famciclovir) are approved only for immunocompetent individuals. These agents reduce the severity and shorten the duration of chickenpox and zoster in adults and in children. These antiviral agents, however, do not prevent the development of postherpetic neuralgia.

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. Acyclovir-resistant varicella has been observed in AIDS patients receiving long-term acyclovir therapy. Foscarnet may be used for acyclovir-resistant virus, although resistance to foscarnet is also recognized. Acyclovir is useful but not fully effective for retinal disease in AIDS (ARN, PORN [above]).

C. Treatment of Complications

The most troublesome issue with VZV infection is postherpetic neuralgia, especially in older patients. Initial treatment with antivirals and corticosteroids does not clearly reduce the incidence or severity of postherpetic neuralgia. Once established, pain may respond to tricyclic antidepressants, lidocaine patches, gabapentin, or analgesics. Secondary bacterial infections of lesions are treated with antibiotics providing coverage for staphylococci.

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.

Zoster resolves in 2–6 weeks. Antibodies persist longer and at higher levels than with primary varicella.

Johnson RW et al: Management of herpes zoster (shingles) and postherpetic neuralgia. Expert Opin Pharmacother 2004;5:551.

Jumaan AO et al: Incidence of herpes zoster, before and after varicella-vaccination-associated decreases in the incidence of varicella, 1992–2002. J Infect Dis 2005;191:2002.

Klassen TP et al: Acyclovir for treating varicella in otherwise healthy children and adolescents. Cochrane Database Syst Rev 2004;(2):CD002980.

Nguyen HQ et al: Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med 2005;352:450.

Oxman MN et al; Shingles Prevention Study Group: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271.

Shinefield H et al; Dose Selection Study Group for Proquod: Dose-response study of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Ped Infect Dis J 2005;24:670.

Sorensen HT et al: The risk and prognosis of cancer after hospitalisation for herpes zoster: a population-based follow-up study. Br J Cancer 2004;91:1275.

Zhou F et al: Impact of varicella vaccination on health care utilization. JAMA 2005;294:797.

3. Epstein-Barr Virus & Infectious Mononucleosis

Essentials of Diagnosis

  • 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.

  • Possible complications: hepatitis, myocarditis, neuropathy, encephalitis, airway obstruction secondary to lymph node enlargement, anti-i hemolytic anemia, thrombocytopenia.

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General Considerations

Infectious mononucleosis is usually due to the EBV (HHV-4, found as two variants, EBV-1 and EBV-2, with multiple strains present in disease). It is universal in distribution and may be seen at any age but usually occurs in the United States in persons between the ages of 10 and 35 years, sporadically or in epidemic distribution. In the developing world, acute infections occur at much younger ages and tend to be less symptomatic. Rare cases occur in the elderly, usually without the full complex of symptoms. Its mode of transmission is probably by saliva. Saliva may remain infectious during convalescence for 6 months or longer from symptom onset. The incubation period probably lasts several weeks.

Clinical Findings

A. Symptoms and Signs

The protean manifestations reflect the pathogenesis of infection with viruses disseminating in the oral cavity, peripheral blood lymphocytes, and cell-free plasma. Symptoms typically include fever, sore throat, fatigue and toxic symptoms (malaise, anorexia, and myalgia) in the early phase of the illness. Physical findings include lymphadenopathy (discrete, nonsuppurative, slightly painful, especially along the posterior cervical chain) and splenomegaly (in up to 50% of patients). A maculopapular or occasionally petechial rash occurs in less than 15% of patients unless ampicillin has been given (when rash is seen in > 90%). Exudative pharyngitis, tonsillitis, or gingivitis may occur and soft palatal petechiae may be noted.

Other manifestations include hepatitis, nervous system involvement (mononeuropathies and occasionally aseptic meningitis, encephalitis, or Guillain-Barré syndrome), renal failure (interstitial nephritis), pulmonary involvement (dyspnea and cough, and in severe forms, “pseudocroup”), and myocarditis. Airway obstruction from lymph node enlargement is an indication for hospitalization or close observation.

B. Laboratory Findings

Initially, EBV infection is associated with granulocytopenia followed within 1 week by a lymphocytic leukocytosis. Many lymphocytes are atypical; specifically, they are larger than normal mature lymphocytes, stain more darkly, and show vacuolated, foamy cytoplasm and dark chromatin in the nucleus. Hemolytic anemia, usually secondary to anti-i antibodies, is occasionally encountered, as is thrombocytopenia (at times marked).

Heterophil (sheep cell agglutination) antibody tests and the correlated mononucleosis spot (Monospot) test usually become positive within 4 weeks after onset of illness. Titer rises in antibodies directed at several EBV antigens can be detected. 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 to EBV nuclear antigen (EBNA) appear at 3–4 weeks after onset and also persist. A false-positive rapid plasma reagin (RPR) occurs in 10%. PCR for EBV DNA is useful in immunocompromised patients in the differential diagnosis of CNS processes and perhaps in monitoring disease. Hepatic aminotransferases and bilirubin are commonly elevated. In aseptic meningitis, the cerebrospinal fluid may show increased opening pressure, lymphocytosis with abnormal morphology, and increased protein concentration.

Differential Diagnosis

CMV infection, toxoplasmosis, acute HIV infection, 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; false-positive heterophil antibody tests can occur with CMV and toxoplasmosis. With acute HIV infection, a rash is sometimes seen but lymphocytic atypia is much less common. Mycoplasmal infection may also present as pharyngitis, though lower respiratory symptoms usually predominate. A hypersensitivity syndrome induced by carbamazepine 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 for the lymphadenopathy of mononucleosis.

Complications

Secondary bacterial pharyngitis can occur and is often streptococcal. Splenic rupture is a rare but dramatic complication, and a history of preceding trauma can be elicited in 50% of the cases. Fulminant hepatitis with massive necrosis is a reported complication. Pericarditis and myocarditis are also infrequent complications, although nonspecific electrocardiographic changes are seen in about 5% of all EBV-infected patients. Neurologic involvement—including transverse myelitis, encephalitis, and Guillain-Barré syndrome—is infrequent.

Treatment

A. General Measures

Given that over 95% of patients recover without specific antiviral therapy, treatment is largely symptomatic. Acyclovir decreases viral shedding but does not have verified clinical benefit. Efforts to sensitize the virus to nucleoside analogs have yet to be proved beneficial. Symptomatic relief can be achieved with acetaminophen or other nonsteroidal anti-inflammatory drugs and warm saline throat irrigations or gargles three or four times daily. Corticosteroid therapy, although widespread, is not recommended in uncomplicated cases; its use is reserved for impending airway

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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 cases without complications, 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.

4. Other Epstein-Barr Virus Syndromes

EBV viral antigens have been found in over 90% of patients with African Burkitt's lymphoma or nasopharyngeal carcinoma (among whom quantified EBV DNA can be used to follow disease). A causative role for EBV has been postulated with both neoplasms. Chronic EBV infection is associated with aberrant cellular immunity (a low frequency of EBV-specific CD8 cells), an X-linked lymphoproliferative syndrome (Duncan's disease), and a fatal T cell lymphoproliferative disorder in children. EBV-induced lymphoproliferation gives rise to B cell lymphomas among immunodeficient patients, such as the HIV-infected individuals (HIV-infected patients, even on HAART, show higher EBV DNA loads than HIV-noninfected patients) or after transplantation (“posttransplant lymphoproliferative disorder”). Immunologically privileged areas such as the CNS are particularly susceptible. The prophylactic use of EBV-specific cytotoxic T cell lymphocytes may prevent the development of EBV-associated lymphoproliferative disease. Rituximab is useful before viral burdens become excessive.

EBV has also been associated with leiomyomas in children with AIDS and with nasal T cell lymphomas. There is no persuasive evidence that chronic fatigue syndrome is caused by EBV infection. Oral hairy leukoplakia (associated with EBV) is discussed in Chapter 8.

EBV is also implicated in the pathogenesis of a proportion of Hodgkin's disease (a subset with diminished cellular immunity) as well as a variety of solid neoplasms, including oral tumors, and of systemic lupus erythematosus, pediatric multiple sclerosis, encephalitis, rheumatoid arthritis, drug-induced hypersensitivity reactions, and Sézary's and Sjögren's syndromes.

Carpentier L et al: Epstein-Barr virus (EBV) early-antigen serologic testing in conjunction with peripheral blood EBV DNA load as a marker for risk of post transplantation lymphoproliferative disease. J Infect Dis 2003;188:1853.

Fafi-Kremer S et al: Long-term shedding of infectious Epstein-Barr virus after infectious mononucleosis. J Infect Dis 2005;191:985.

Hjalgrim H et al: Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 2003;349:1324.

Lin JC et al: Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004;350:2461.

Macsween KF et al: Epstein-Barr virus—recent advances. Lancet Infect Dis 2003;3:131.

Sitki-Green DL et al: Biology of Epstein-Barr virus during infectious mononucleosis. J Infect Dis 2004;189:483.

Thompson MP et al: Epstein-Barr virus and cancer. Clin Cancer Res 2004;10:803.

5. Cytomegalovirus Disease

Most CMV infections are asymptomatic, with the virus remaining latent. It can be isolated from a variety of tissues under nonpathogenic conditions including up to 25% of salivary glands and 10% of uterine cervices. The cells of latency include vascular endothelial cells, monocytes, macrophages, polymorphonuclear neutrophils, and renal and pulmonary epithelial cells. Seroprevalence increases with age and with the number of sexual partners. Detectable antibody is present in the serum of most homosexual men. Transmission is sexual, congenital, through breast-feeding, blood products or transplantation, and person-to-person (eg, day care centers). Serious disease occurs primarily in immunocompromised persons, especially those with AIDS and transplant recipients.

Clinical Findings

A. Classification

There are three recognizable clinical syndromes.

1. Perinatal disease and CMV inclusion disease

Congenital CMV infection is the most common congenital infection in developed countries, affecting about 1% of all neonates. About 10% of infected newborns born to mothers with primary CMV infection during pregnancy will be symptomatic with CMV inclusion disease. It is characterized by jaundice, hepatosplenomegaly, thrombocytopenia, purpura, microcephaly, periventricular CNS calcifications, mental retardation, and motor disability. Hearing loss develops in greater than 50% of infants who are symptomatic at birth. Most patients with congenital CMV infection are asymptomatic, but neurologic deficits

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may ensue later in life. Perinatal infection acquired through breast-feeding or blood products typically has a benign clinical course.

2. Disease in immunocompetent hosts

a. Acute acquired CMV infection

Akin to EBV-associated infectious mononucleosis, this syndrome is characterized by fever, malaise, myalgias and arthralgias (but rarely exudative pharyngitis or cervical lymphadenopathy), splenomegaly, atypical lymphocytes, and abnormal liver function tests. The mean duration of symptoms is 7–8 weeks. Typically, leukopenia is followed by leukocytosis. Heterophil antibody is absent. Transmission occurs by sexual contact, in breast milk, via respiratory droplets among nursery or day care center attendants, and by transfusions of blood. Complications include mucosal gastrointestinal damage, encephalitis, Guillain-Barré syndrome, pericarditis, and myocarditis.

b. Other associations with CMV

Other clinical syndromes that are reported to be associated with CMV and whose role in pathogenesis requires further elucidation include inflammatory bowel disease, atherosclerosis and myocardial infarction, and breast cancer (the last of these is associated with a higher risk of late CMV disease in life).

3. Disease in immunocompromised hosts

Tissue and bone marrow transplant patients are mainly at risk in the first 100 days after allograft transplantation and in particular when graft-versus-host disease or CMV seropositivity is present. HIV-infected patients may show numerous manifestations, described below, and these occur most prominently when the CD4 count is < 100 cell/mcL or when the HIV viral load is > 10,000 copies/mcL. CMV is itself immunosuppressive and promotes other infections such as Pneumocystis and Aspergillus pneumonia. It may contribute to transplanted organ dysfunction, in particular, hepatitis, which can mimic organ rejection. The so-called “CMV syndrome” in renal transplant patients is a mononucleosis-like syndrome among new transplant recipients.

a. CMV retinitis

Retinitis occurs in AIDS patients with CD4 counts less than 50 cells/mcL and on occasion among the immunocompetent (among whom the rate of retinal detachment is lower). Ophthalmologic documentation of neovascular, proliferative lesions (“pizza-pie” retinopathy) is required for diagnosis. With HAART, the frequency of retinitis is reduced, CD4 counts are less predictive, and active disease may be reversible. Immune restoration with HAART is associated with CMV vitreitis and CMV-associated cystoid macular edema. Infants with CMV retinitis tend to have more macular than peripheral disease. CMV retinitis may also develop in persons who have undergone heart transplantation; it is usually asymptomatic.

b. Gastrointestinal and hepatobiliary CMV

Serious gastrointestinal CMV disease occurs in AIDS (usually with CD4 counts < 100 cells/mcL) and after organ transplantation, cancer chemotherapy, or corticosteroid therapy. Esophagitis presents with odynophagia; 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. CMV has been identified—often with other pathogens such as Cryptosporidium—in up to 15% of patients with AIDS cholangiopathy. Diagnosis is made by mucosal biopsy showing characteristic CMV histopathologic findings of intranuclear (“owl's eye”) and intracytoplasmic inclusions.

c. Pulmonary CMV

CMV pneumonitis—characterized by cough, dyspnea, relatively little sputum production, and chest radiograph findings consistent with interstitial pneumonia—occurs in transplant recipients with a mortality rate up to 60–80%, and less commonly in AIDS patients. In AIDS patients, the significant morbidity and mortality appear to be diminished by the use of antiretroviral therapy. High-titer CMV immunoglobulin may be effective in preventing CMV pneumonia in seronegative recipients.

d. Neurologic CMV

Neurologic syndromes associated with CMV include polyradiculopathy, transverse myelitis, ventriculoencephalitis, and focal encephalitis. The encephalitis has a subacute onset in patients with advanced AIDS and is usually associated with disseminated CMV infection. CMV can be isolated in the cerebrospinal fluid in cases of transverse myelitis or disseminated disease.

B. Laboratory Findings

Virus isolation should be combined with pathologic findings to distinguish viral shedding from tissue invasion. Cultures alone are of little use in diagnosing AIDS-related CMV infections, but when positive have been associated with a risk of progressive retinitis. Tissue confirmation is especially useful in establishing a diagnosis of CMV pneumonitis and CMV gastrointestinal or neurologic disease.

The acute mononucleosis-like syndrome is associated with lymphocytosis, often 2 weeks after the fever, but absolute leukopenia may also be noted. Serologic tests are useful primarily in seroepidemiologic studies and occasionally in confirming acute infection (with IgM) in nonimmunosuppressed patients. Antigen detection in blood components, urine, or cerebrospinal fluid by virus technology (including the PCR technique) should be interpreted in the context of clinical and pathologic findings but is increasingly being used to guide both treatment and prevention. Among transplant recipients, PCR appears to be more useful than CMV antigenemia in predicting clinical disease.

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.

Prevention

No vaccine is currently available. Strategies for prevention in transplant recipients include use of leukocyte-depleted

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blood products, antiviral agents, and CMV immune globulin. The risk for CMV disease is proportionate to the intensity of immunosuppression, which depends in part on the organ being transplanted. PCR and antigen assays increase the ability to detect CMV disease prior to clinical expression. Oral ganciclovir is being replaced by oral valganciclovir in prevention because of its greater bioavailability. The optimal method of monitoring and preventing CMV disease among transplant patients remains to be elucidated. HAART is effective in preventing CMV infections in HIV-infected patients.

The virus is so ubiquitous that it is not recommended that children with known CMV infection be withdrawn from day care centers or that health care workers restrict their patient contact beyond intensifying handwashing. Screening programs are not recommended for women of childbearing age and breast-feeding should not be restricted.

Treatment

First-line therapy against CMV infections is ganciclovir, 5 mg/kg intravenously every 12 hours for 14–21 days. Due to potential toxicities, foscarnet (loading with 90 mg/kg intravenously, followed by 60 mg/kg every 8 hours over weeks) and cidofovir (5 mg/kg intravenously every week for 2 weeks) are usually reserved for CMV infections that are resistant to ganciclovir. A daily maintenance regimen using both ganciclovir (3.75 mg/kg intravenously) and foscarnet (60 mg/kg intravenously), each over 1 hour, has been shown to be safe and effective in inhibiting CMV replication. Cidofovir is given only every 2 weeks, 375 mg intravenously, for maintenance. Oral valganciclovir (900 mg daily) is replacing oral ganciclovir for maintenance and for prophylactic therapy among persons who have undergone solid organ or bone marrow transplantation. Transplant recipients do not benefit from combined foscarnet and ganciclovir preemptive therapy. Dosage adjustments of all medications are needed for renal impairment. Adoptive immunotherapy with polyclonal CMV-specific T cells is a new modality of therapy for infections in the allogeneic bone marrow transplant population that may obviate the need for antivirals in the future.

In pregnant women with primary CMV infection, passive immunization with hyperimmune globulin appears preliminarily to be efficacious in both treatment and prevention of fetal infection, but controlled clinical trials are needed for confirmation.

A sustained-release ganciclovir implant controls disease in the implanted eye (but not elsewhere) more effectively than intravenous ganciclovir. Again, the role of HAART in reducing the need for CMV antivirals is primary. Fomivirsen is an intravitreal agent active against CMV strains that are resistant to ganciclovir, foscarnet, and cidofovir. Adjuvant filgrastim may be useful in managing the neutropenia associated with ganciclovir and its analogues.

Erice A et al: Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) burden, CMV end-organ disease, and survival in subjects with advanced HIV infection (AIDS Clinical Trials Group Protocol 360). Clin Infect Dis 2003;37:567.

Griffiths P: Cytomegalovirus infection of the central nervous system. Herpes 2004;11(Suppl 2):95A.

Kuo IC et al: Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004;138:338.

Nigro G et al; Congenital Cytomegalovirus Collaborating Group: Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350.

Peggs KS et al: Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 2003;362:1375.

Whitley RJ: Congenital cytomegalovirus infection: epidemiology and treatment. Adv Exp Med Biol 2004;549:155.

Wreghitt TG et al: Cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 2003;37:1603.

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 the most common cause of infantile febrile seizures. Reactivation of HHV-6 in adults is associated with immunocompromised states such as HIV and lymphoma. It is associated with graft rejection and bone marrow suppression in transplant patients and with encephalitis and pneumonitis in AIDS patients. Possible roles of HHV-6 in the evolution of multiple sclerosis and progressive multifocal leukoencephalopathy remain unproven.

Two variants (A and B) of HHV-6 have been identified. HHV-6B is the predominant strain found in both normal and immunocompromised persons. In vitro data suggest susceptibility to ganciclovir and foscarnet but not acyclovir. HHV-7 is a T cell lymphotropic virus that is associated with roseola (serologically), seizures and, rarely, encephalitis. Infection with HHV-7 appears to be synergistic with CMV in renal transplant recipients. The membrane glycoprotein CD4 is involved in HHV-7 recognition, and an antagonistic interaction between HHV-7 and HIV is established.

HHV-8 is associated with Kaposi's sarcoma in AIDS patients. It has also been implicated in multicentric Castleman's disease and primary effusion lymphoma (body cavity lymphoma). See Chapter 31 for pathogenesis and management.

Caserta MT et al: Human herpesvirus 6. Clin Infect Dis 2001;33:829.

De Bolle L et al: Update on human herpesvirus 6 biology, clinical features, and therapy. Clin Microbiol Rev 2005;18:217.

Dewhurst S: Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system. Herpes 2004;11(Suppl 2):105A.

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Major Vaccine-Preventable Viral Infections

1. Measles

Essentials of Diagnosis

  • Exposure 10–14 days before onset in an unvaccinated patient.

  • Prodrome of fever, coryza, cough, conjunctivitis, malaise, irritability, photophobia, Koplik's 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 an acute systemic paramyxoviral infection transmitted by inhalation of infective droplets. It is a major worldwide cause of pediatric morbidity and mortality, with nearly 800,000 estimated deaths annually. 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. The largest recent outbreak in the Americas was in São Paulo, Brazil, in 1997, with over 42,000 cases among largely unvaccinated young adults. This and other sporadic recent outbreaks of the disease in adults, adolescents, and unvaccinated preschool children in dense urban areas emphasize the need for specific recommendations concerning prevention (see below).

In the United States, with largely imported cases and few geographically dispersed cases whose isolates fail to show a recurrent strain, measles is no longer considered endemic.

Clinical Findings

A. Symptoms and Signs

(Table 32-2.) Fever is often as high as 40–40.6°C. It persists through the prodrome and early rash (about 5–7 days). 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 the 2–4 days before the onset of the rash and peak on the first day of the rash.

Koplik's spots are pathognomonic of measles. They appear about 2 days before the rash and last 1–4 days as tiny “table salt crystals” most often in the buccal mucosa opposite the second molars and vaginal mucous membranes. Other findings include pharyngeal erythema, a yellowish exudate on the tonsils, coating of the tongue in the center with a red tip and margins, moderate generalized lymphadenopathy and, in occasional cases, splenomegaly.

The rash usually appears first 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 may coalesce to form a nearly uniform erythema on some body 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 then it fades in the same manner it appeared. Hyperpigmentation remains in fair-skinned individuals and severe cases. Slight desquamation may follow.

Atypical measles is a syndrome occurring in adults who received inactivated measles vaccine (available 1963–1968) or who received live measles vaccine before age 12 months and as a result developed hypersensitivity rather than protective immunity. When persons are infected later with wild measles virus, a potentially fatal illness may develop, with high fever; unusual rashes (papular, hemorrhagic), most prominent on the extremities, without Koplik's spots; headache; arthralgias; hepatitis; and a high rate of pneumonitis, occasionally with pleural effusions; followed by the appearance of extremely high measles antibody titers.

Measles may occur in HIV-infected individuals in an uncharacteristic fashion, with higher rates of pneumonitis and higher mortality. Vaccine failure rates, both primary and secondary, are higher in HIV-infected children. The frequent difficulty in establishing a diagnosis suggests that measles may be more prevalent in epidemics than heretofore recognized.

Measles during pregnancy is not known to cause congenital abnormalities of the fetus. However, it is associated with spontaneous abortion and premature delivery. Measles in the offspring of mothers with measles ranges from mild to severe; therefore, it is recommended that infants born to such mothers be passively immunized with immunoglobulin at birth.

B. Laboratory Findings

Leukopenia is usually present unless secondary bacterial complications exist. A lymphocyte count under 2000/mcL is a poor prognostic sign. Proteinuria is often observed. Although technically difficult, virus can be cultured from nasopharyngeal washings and from blood. 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.

Differential Diagnosis

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

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Complications

A. Central Nervous System

Postinfectious encephalomyelitis occurs in approximately 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 a variety of 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 rate (10–20%), and 33% of survivors are left with neurologic morbidity.

A similar form, “inclusion body encephalitis,” is also reported to occur after measles vaccination but is associated with isolation of the measles virus.

Subacute sclerosing panencephalitis (SSPE) is a very late CNS complication, the measles virus acting 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.

An acute progressive encephalitis (subacute measles encephalitis), characterized by seizures, neurologic deficits, and often progressive stupor and death, can occur among immunosuppressed patients. Measles virus opportunistically invades the CNS. Treatment is supportive, withholding immunosuppressive chemotherapy 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. 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 (eg, tuberculin) skin tests.

E. Gastroenteritis

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

F. Other Complications

Ocular complications such as conjunctivitis and keratitis are common.

Prevention

In the United States, it is recommended that children receive their first vaccine dose at 12–15 months and a second at age 4–6 years prior to entry into school (see Table 30-4).

Students beyond high school and medical staff starting employment must have the above vaccination schedule documented or must have serologic evidence of immunity if they were born after 1956. For individuals born before 1957, herd immunity can be assumed. Health care workers should be screened and vaccinated if necessary regardless of date of birth.

Outbreak control in the United States is similar. If outbreaks are occurring in preschool children 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 born after 1956 who do not have documentation of immunity as defined above. Susceptible personnel who have been exposed should be isolated from patient contact between the fifth and the twenty-first day after exposure regardless of whether they have been vaccinated or have received immune globulin. If measles develop in these persons, they should be isolated from patient contact until 7 days after the rash develops.

When susceptible individuals are exposed to measles, the live virus vaccine can prevent disease if given within 5 days of exposure. This is rarely feasible within a household. Later, 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 the second vaccine dose is an important aspect of achieving control of measles in the community-at-large.

Pregnant women and immunosuppressed persons should not receive this vaccine. There are two exceptions: asymptomatic HIV-infected patients, who have not shown adverse effects from measles vaccination, and HIV-infected children, in whom exposure to vaccines improves survival after measles (and among whom HAART therapy is associated with an improved vaccine response). Immune globulin should be considered for postexposure prophylaxis in any high-risk person exposed to measles. This group includes children with malignant disease and patients with AIDS, who are more likely to develop severe disease or fatal measles. To be effective, immune globulin should be administered within 6 days after an exposure.

Severe allergic reactions to the measles, mumps, and rubella (MMR) vaccine are rare, though fever and rash appear to occur slightly more often among female recipients. Future vaccines for a variety of infectious agents may utilize measles vectors, thereby augmenting immunity to measles.

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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 beneficial effects of which include maintenance of gastrointestinal and respiratory epithelial mucosa and perhaps immune enhancement), reduces pediatric morbidity rates although high-dose vitamin A exposure increases the severity and risk of antibiotic failure in nonmeasles pneumonia.

B. Treatment of Complications

Secondary bacterial infections are treated with appropriate antimicrobial drugs. Pneumonia is managed with antibacterial antibiotics when clinical signs suggest sepsis or significant pulmonary findings. Postmeasles encephalitis, including SSPE, can be managed only symptomatically.

Prognosis

During the past 13 years in the United States, the case-fatality rate stayed around 3 per 1000 reported measles cases; the mortality rate may be as high as 10% in developing nations. Deaths in the United States are due principally to encephalitis (15% mortality rate) and secondary bacterial pneumonia. Deaths in the developing world are mainly related to diarrhea and protein-losing enteropathy. Higher case-fatality rates in developing countries are related to young age at infection, crowding, and underlying immune deficiency, among other factors.

D'Souza RM et al: Vitamin A for preventing secondary infections in children with measles—a systematic review. J Trop Pediatr 2002;48:72.

Elliman D et al: Measles. Curr Opin Infect Dis 2005;18:229.

Ni J et al: Vitamin A for non-measles pneumonia in children. Cochrane Database Syst Rev 2005;(3):CD003700.

Ota MO et al: Emerging diseases: measles. J Neurovirol 2005;11:447.

Tangy F et al: Live attenuated measles vaccine as a potential multivalent pediatric vaccination vector. Viral Immunol 2005;18:317.

Wood DL: American Academy of Pediatrics Committee on Community Health Services; American Academy of Pediatrics Committee on Practice and Ambulatory Medicine: increasing immunization coverage. Pediatrics 2003;112:993.

2. Mumps

Essentials of Diagnosis

  • Exposure 14–21 days before onset.

  • Painful, swollen salivary glands, usually parotid.

  • Frequent involvement of other tissues, including testes, pancreas, and meninges, in unvaccinated individuals.

General Considerations

Mumps is a paramyxoviral disease spread by respiratory droplets that usually produces inflammation of the salivary glands and, less commonly, orchitis, aseptic meningitis, encephalomyelitis, pancreatitis, and oophoritis. Most patients are children, and 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 but may last a week. Up to one-third of affected individuals have subclinical infection.

Clinical Findings

A. Symptoms and Signs

Parotid tenderness and overlying facial edema are the most common physical findings. Usually, one parotid gland enlarges a couple of days before the other, but unilateral parotitis alone occurs in 25% of patients. Swelling and tenderness of the submaxillary and sublingual glands are variable. The orifice of Stensen's duct may be red and swollen. Trismus may result from the parotitis. The parotid glands return to normal size within a week. Involvement of other salivary glands in conjunction with the parotids occurs in 10% of cases.

Fever and malaise are variable and are often minimal in young children. High fever usually accompanies meningitis or orchitis. Neck stiffness, headache, and lethargy suggest meningitis. Testicular swelling and tenderness (unilateral in 75% of cases) denote orchitis, which is the most common extrasalivary gland manifestation of mumps in adults. Orchitis, which develops typically 7–10 days after the onset of parotitis, occurs in about 25–40% of postpubertal men, but sterility is rare. 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), but the diagnosis may be difficult to make.

B. Laboratory Findings

Mild leukopenia with relative lymphocytosis may be present. Serum amylase is commonly elevated with or without pancreatitis because of salivary gland involvement. Lymphocytic pleocytosis (and normal to low glucose) of the cerebrospinal fluid is present in meningitis, which may be asymptomatic. Mild renal function abnormalities are the presenting finding in up to 60% of patients. The diagnosis of mumps is confirmed by isolating the virus from saliva, cerebrospinal fluid, or urine or demonstrating a fourfold rise in

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complement-fixing antibodies to mumps virus in paired sera.

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 use for dry mouth, and Sjögren's syndrome. Parotitis may also 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, coxsackieviruses, 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 than inflammation of the salivary glands. These usually follow the parotitis but may precede it or occur without salivary gland involvement and include meningitis (30%), orchitis (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 develops from eighth nerve neuritis and recent surveillance from Japan suggests it occurs in about 0.3% of patients.

Prevention

Mumps live virus vaccine is safe and highly effective. It is recommended for routine immunization for children over age 1 year, either alone or in combination with other virus vaccines (eg, in MMR vaccine or as a quadrivalent vaccine with varicella). A second dose is recommended for children prior to starting school. 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. Mumps vaccine markedly decreased the incidence of mumps in the United States and in the United Kingdom. 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.

Treatment

A. General Measures

The patient should be isolated until swelling subsides and kept at bed rest during the febrile period. Treatment is symptomatic as needed. Topical application of warm or cold compresses may relieve parotid discomfort.

B. Management of Complications

1. Meningitis

The treatment of aseptic meningitis is purely symptomatic. The management of encephalitis requires attention to cerebral edema, the airway, and vital functions.

2. Orchitis

The scrotum should be supported using a suspensory or toweling “bridge” and ice bags applied. Incision of the tunica may be necessary in severe cases. Codeine or meperidine may be given as necessary for pain. Pain can also be relieved by injection of 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) to reduce the inflammatory reaction is not firmly established.

3. Pancreatitis

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

Prognosis

The entire course of mumps rarely exceeds 2 weeks. Fatalities (usually from encephalitis) are rare.

Davidkin I et al: Etiology of mumps-like illnesses in children and adolescents vaccinated for measles, mumps, and rubella. J Infect Dis 2005;191:719.

Harling R et al: The effectiveness of the mumps component of the MMR vaccine: a case control study Vaccine 2005;23:4070.

Kawashima Y et al: Epidemiological study of mumps deafness in Japan. Auris Nasus Larynx 2005;32:125.

Shinefield H et al: Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J 2005;24:665.

3. Poliomyelitis

Essentials of Diagnosis

  • 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 excess leukocytes, with lymphocytic predominance; count is rarely more than 500/mcL.

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General Considerations

Poliomyelitis virus, an enterovirus, is present in throat washings and stools (where it can be excreted for several weeks after infection). Infection is most commonly acquired by the fecal-oral route. Since the introduction of an effective vaccine, poliomyelitis has become a rare disease in developed areas of the world, and globally, between 1988 and 2001, the number of cases decreased by 99%. The global poliomyelitis eradication initiative was launched in 1988 and has led to elimination of wild poliovirus from the Western hemisphere. The Pacific Rim, Europe, and most of Central Asia also appear to be polio free. However, at the end of 2004, six countries had endemic polio (Afghanistan, Egypt, India, Niger, Nigeria, and Pakistan), and transmission was reestablished in six countries (Burkina Faso, Central African Republic, Chad, Côte d'Ivoire, Mali, and Sudan). An imported vaccine-associated case occurred in the United States in 2005.

Three antigenically distinct types of poliomyelitis virus are recognized, with little cross-immunity between them. Disease with type 2 (of the three types) in particular is on the verge of extinction. Infectivity is maximal during the first week.

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)

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 can be 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 enteroviruses.

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 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. Alterations in blood pressure and heart rate may occur. 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 fewer than 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 vaccine-related 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) and tick paralysis may initially resemble poliomyelitis. In Guillain-Barré 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 Guillain-Barré syndrome. The cerebrospinal fluid usually has a 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.

Prevention

Given the epidemiologic distribution of poliomyelitis and the continued concern about vaccine-associated

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disease with the oral live vaccine, recommendations for prevention were modified. Currently in the United States, the inactive (Salk) parenteral vaccination is used for all four doses (at ages 2 months, 4 months, and 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, 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). These adults should be given inactivated poliomyelitis vaccine (Salk) as should immunodeficient or immunosuppressed individuals and members of their households.

In the developing world, the interval between oral polio vaccine doses should probably be longer than 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. Ancillary useful control measures in polio-endemic 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 outbreak responses as well as intensified immunization activities in countries recently affected by armed conflicts. Recent outbreaks of vaccine-derived poliomyelitis occurred in Hispaniola (both Haiti and the Dominican Republic) with type 1 isolates and Madagascar with type 2 isolates. Both followed the administration of oral vaccine (Sabin). These incidents serve as a reminder of the need to maintain high levels of immunization coverage even in the absence of overt disease. The risks associated with oral vaccination and the importance of continued surveillance for disease are continuing public health concerns.

Recent success has been reported with a monovalent type 1 oral vaccine in India and Egypt.

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. Cranial nerve involvement must be vigilantly sought. Comfortable but rotating positions should be maintained in a “polio bed”: firm mattress, footboard, sponge rubber pads or rolls, sandbags, and light splints. Fecal impaction and urinary retention (especially with paraplegia) are managed appropriately. In cases of respiratory weakness or paralysis, intensive care is needed.

Prognosis

During the febrile period, paralysis may develop or progress. Mild weakness of small muscles is more likely to regress than is severe weakness of large muscles. Bulbar poliomyelitis carries a mortality rate of up to 50%. New muscle weakness may develop and progress slowly years after recovery from acute paralytic poliomyelitis. This entity, postpoliomyelitis syndrome, presents with signs of chronic and new denervation, is not infectious in origin, and is associated with increasing dysfunction of surviving motor neurons. Series that report increased incidences of multiple sclerosis or other motor neuron diseases among poliomyelitis survivors need to be evaluated in the context of what is known about the postpoliomyelitis syndrome. Although bulbar poliomyelitis causes the greatest threat to life, it is rarely responsible for permanent damage among surviving patients.

Alexander LN et al: Vaccine policy changes and epidemiology of poliomyelitis in the United States. JAMA 2004;292:1696.

Centers for Disease Control and Prevention (CDC): Brief report: Conclusions and recommendations of the Advisory Committee on Poliomyelitis Eradication—Geneva, Switzerland, October 2005. MMWR Morb Mortal Wkly Rep 2005;54:1186.

Centers for Disease Control and Prevention (CDC): Progress toward interruption of wild poliovirus transmission—worldwide, January 2004-March 2005. MMWR Morb Mortal Wkly Rep 2005;54:408.

Duintjer Tebbens RJ et al: A dynamic model of poliomyelitis outbreaks: learning from the past to help inform the future. Am J Epidemiol 2005;162:358.

Nielsen NM et al: Long-term mortality after poliomyelitis. Epidemiology 2003;14:355.

Philip DM: Polio eradication, cessation of vaccination and re-emergence of disease. Nat Rev Microbiol 2004;2:473.

Silver JK et al: What internists need to know about postpolio syndrome. Cleve Clin J Med 2002;69:704.

4. Rubella

Essentials of Diagnosis

  • 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 lymphadenopathy 5–10 days before rash.

  • Fine maculopapular rash of 3 days duration; face to trunk to extremities.

  • Leukopenia, thrombocytopenia.

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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. 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, echovirus infections, and coxsackievirus infections, though arthritis is more prominent in rubella. Definitive diagnosis can be made only by isolating the virus or serologically.

In the United States, rubella is no longer endemic and congenital rubella syndrome is on the verge of elimination. Surveillance of female military recruits suggests, however, that serologic protection against rubella as well as measles and mumps are inadequate.

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 continues to occur in parts of the developing world at rates equivalent to those reported from the industrialized world during the prevaccine era. More than 100,000 cases occur annually in the developing world. Recent outbreaks occurred in Italy and Brazil, with Recife, Brazil reporting 49 cases of congenital rubella syndrome between 1998 and 2001. The majority of recent cases of congenital rubella syndrome in the United States occurred among immigrants; between 2001 and 2004 only four cases were reported to the Centers for Disease Control and Prevention (CDC) (three among immigrants).

Clinical Findings (Table 32-2)

A. Symptoms and Signs

Age is the most important determinant of the severity of rubella. Postnatally acquired rubella is usually innocuous, whereas fetal rubella can be devastating. 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. 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. Virus isolation and serologic tests of immunity (rubella virus hemagglutination inhibition and fluorescent antibody tests) are available. Definitive diagnosis is based on a fourfold or greater rise in antibody titers.

Complications

A. Exposure during Pregnancy

Rubella antibodies are sought at the beginning of pregnancy, since fetal infection during the first trimester leads to congenital rubella in at least 80% of fetuses.

When a pregnant woman is exposed to a possible case of rubella, an immediate hemagglutination-inhibiting rubella antibody level should be obtained. There is no reason for concern with positive tests since these indicate immunity. If no antibodies are found, clinical observation and serologic follow-up are essential although 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 risk to the fetus is highest for maternal infection in the first trimester but continues into the second trimester.

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, microphthalmia, glaucoma, hearing deficits, psychomotor retardation, congenital heart defects, organomegaly, and maculopapular rash. In general, the younger the fetus when infected, the more severe the illness. Viral excretion in the throat and urine persists for many months despite high antibody levels. The diagnosis is confirmed by isolation of the virus. A specific test for IgM rubella antibody is useful for diagnosis in the newborn. 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, and mild hepatitis.

Prevention

Live attenuated rubella virus vaccine should be given to all infants and to susceptible girls before 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

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women are immune to rubella.) Postpartum administration to susceptible female hospital employees is recommended, though many hospitals fail to comply. It is recommended that women not become pregnant for at least 1 month 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. The association between chronic arthropathies and rubella vaccination is controversial. MMR may be given in conjunction with diphtheria-pertussis-tetanus (DPT) 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.

Treatment

Acetaminophen provides symptomatic relief. Encephalitis and non-life-threatening thrombocytopenia 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.

Centers for Disease Control and Prevention (CDC): Elimination of rubella and congenital rubella syndrome—United States, 1969–2004. MMWR Morb Mortal Wkly Rep 2005;54:279.

Centers for Disease Control and Prevention (CDC): Global Measles and Rubella Laboratory Network, January 2004-June 2005. MMWR Morb Mortal Wkly Rep 2005;54:1100.

Haas DM et al: Rubella, rubeola, and mumps in pregnant women: susceptibilities and strategies for testing and vaccinating. Obstet Gynecol 2005;106:295.

Lanzieri TM et al: Incidence, clinical features and estimated costs of congenital rubella syndrome after a large rubella outbreak in Recife, Brazil, 1999–2000. Pediatr Infect Dis J 2004;23:1116.

Sheridan E: Congenital rubella syndrome: a risk in immigrant populations. Lancet 2002;359:675.

Other Neurotropic Viruses

1. Rabies

Essentials of Diagnosis

  • 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. Globally, an estimated 30,000–70,000 deaths occur annually from rabies, and as a cause of disability, it is roughly equivalent in its public health impact to trachoma or onchocerciasis. In the United States domestically acquired rabies cases are rare but probably underreported; eight human cases were reported in 2004. Raccoons, skunks, bats, and foxes are common wildlife reservoirs. Biting species that cause rabies in the United States are geographically determined and include raccoons in the East, including New England; skunks in the Midwest, Southwest, and in California; coyotes in Texas; and foxes in the Southwest and in Alaska. The contribution of bats (particularly the eastern pipistrelle bat and the silver-haired bat) to the rabid wild animal population is increasing, and bats are distributed throughout the United States. As a result, most cases in the United States since 1990 until late 2005 (34 of 47 total) are associated with bat rabies virus variants. Greater than 90% of human cases acquired in developing countries, where rabid dogs are the major reservoirs of the rabies virus, are due to infected dog bites. Dogs and cats are rarely infected in the United States because of successful rabies vaccination campaigns. Rodents and lagomorphs (eg, rabbits) are unlikely to spread rabies because they cannot survive the disease long enough to transmit it, although woodchucks and groundhogs can become infected and transmit the virus. 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. Most recently, the rabies virus was transmitted to three persons who underwent solid organ transplant and one person who received a vascular segment from an infected donor with unrecognized rabies.

The incubation period may range from 10 days to many years but is usually 3–7 weeks. The interval is dependent in part on 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 is almost uniformly fatal, with only six documented surviving cases to date. Five received either preexposure or postexposure prophylaxis. Recently, a teenager survived with only naturally acquired immunity, but received intense antiviral treatment. The most common clinical problem confronting the physician is the management of a patient bitten by an animal (see Prevention).

Clinical Findings

A. Symptoms and Signs

There is usually a history of animal bite, though bat bites may not be recognized. The prodromal syndrome

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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. About 10 days later, the CNS stage begins, which may be either encephalitic (“furious”) or paralytic (“dumb”). The encephalitic form produces the classic rabies manifestations of delirium alternating with periods of calm, when attempts at drinking cause extremely painful laryngeal spasms (hydrophobia). 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 despite intensive support.

B. Laboratory Findings

Biting animals that appear well should be quarantined under observation 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; the diagnosis is made by the direct fluorescent antibody technique or immunohistochemistry testing. 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%.

Reverse transcriptase PCR, nucleic acid sequence-based amplification, and viral isolation from the cerebrospinal fluid or saliva are being advocated as definitive diagnostic assays. Antibodies can be detected in the serum and the cerebrospinal fluid. Pathologic specimens often demonstrate round or oval eosinophilic inclusion bodies (Negri bodies) in the cytoplasm of neuronal cells, although their presence is neither sensitive nor specific. MRI signs include nonenhancing, ill-defined, mild hyperintense changes in the brainstem, hypothalamus, and multiple deep and subcortical white and gray matter zones and potential enhancement along the nerve course from the site of bites.

Prevention

Because rabies is almost always fatal, prevention is the only reasonable approach, and all exposures must be evaluated individually. Immunization of household dogs and cats and active immunization of persons with significant animal exposure (eg, veterinarians) are important. The most important common decisions, however, concern animal bites.

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.

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

Therapy is indicated when the disease is seriously under consideration. 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 endemicity 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 rabies immune globulin (20 IU/kg). 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. If immune globulin (human) is not available, equine rabies antiserum (20–40 IU/kg) can be used if available (it was last produced in 2001) after appropriate tests for horse serum sensitivity. An inactivated human diploid cell rabies vaccine (HDCV) is given as five injections of 1 mL intramuscularly (in the deltoid rather than the gluteal muscle) on days 0, 3, 7, 14, and 28 after exposure.

Several cell culture vaccines are available and are preferable to embryonated tissue vaccine (eg, duck embryo vaccine; DEV) because of better antigenic response and fewer systemic reactions. HDCV availability and cost limit its use in the developing world.

Rabies immune globulin and rabies vaccine (HDCV) should never be given in the same syringe or at the same site. Allergic reactions to the vaccine are rare, though local reactions (pruritus, erythema, tenderness) occur in about 25% and mild systemic reactions (headaches, myalgias, nausea) in about 20% of recipients. The vaccine is commercially available or can be obtained through health departments. For patients who previously received preexposure or postexposure vaccine, rabies immune globulin should not be given; vaccine, 1 mL in the deltoid, should be given twice (on days 0 and 3).

In other countries, the less costly inactivated DEV or mouse brain vaccine may be available, but the method of administration is more complex, the rate of allergic reactions—including ascending paralysis—is higher, and the efficacy is lower.

Exposure to rabies still requires postexposure vaccination, even if preexposure vaccination was received, but the need for immune globulin is eliminated (rabies immune globulin is in short supply worldwide).

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Neither the passive nor the active form or 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 HDCV intramuscularly (1 mL on days 0, 7, and 21 or 28) or intradermally (0.1 mL on days 0, 7, and 28, over the deltoid) is recommended for persons at high risk of exposure: veterinarians (who should have rabies antibody titers checked every 2 years and be boosted with 1 mL intramuscularly or 0.1 mL intradermally if seronegative); animal handlers; laboratory workers; Peace Corps workers; and travelers to remote areas in endemic countries in Africa, Asia, and Latin America. An intradermal route is available for preexposure prophylaxis only. Immunosuppressive illnesses and agents including corticosteroids as well as antimalarials—in particular chloroquine—may diminish the antibody response.

Treatment

This very severe illness with an almost universally fatal outcome requires intensive care with attention to the airway, maintenance of oxygenation, and control of seizures. Universal precautions are essential. Other modalities of therapy that may be beneficial include a combination of rabies vaccine, rabies immune globulin, monoclonal antibodies (investigational), ribavirin, interferon-α, amantadine, and ketamine. Corticosteroids are of no use.

Prognosis

If postexposure prophylaxis is given expediently, before clinical signs develop, it is nearly 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.

CDC National Center for Infectious Diseases—Rabies http://www.cdc.gov/ncidod/dvrd/rabies

Coleman PG et al: Estimating the public health impact of rabies. Emerg Infect Dis 2004;10:140.

Hankins DG et al: Overview, prevention, and treatment of rabies. Mayo Clin Proc 2004;79:671.

Jerrard DA: The use of rabies immune globulin by emergency physicians. J Emerg Med 2004;27:15.

Krebs JW et al: Rabies surveillance in the United States during 2004. J Am Vet Med Assoc 2005;227:1912.

Rupprecht CE et al: Prophylaxis against rabies. N Engl J Med 2004;351:2626.

Srinivasan A et al; Rabies in Transplant Recipients Investigation Team: Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med 2005;352:1103.

Willoughby RE Jr et al: Survival after treatment of rabies with induction of coma. N Engl J Med 2005;353:2508.

2. Arbovirus Encephalitides

Essentials of Diagnosis

  • Fever, malaise, stiff neck, sore throat, and nausea and vomiting, progressing to stupor, coma, and convulsions.

  • Signs of an upper motor neuron lesion (exaggerated deep tendon reflexes, absent superficial reflexes, pathologic reflexes, and spastic paralysis).

  • Cerebrospinal fluid protein and opening pressure often increased, with lymphocytic pleocytosis.

General Considerations

The arboviruses are arthropod-borne pathogens that produce clinical manifestations in humans. The mosquito-borne pathogens include three alphaviruses (causing Western, Eastern, and Venezuelan equine encephalitis), five flaviviruses (causing West Nile fever, St. Louis encephalitis, Japanese B encephalitis, dengue, and yellow fever), bunyaviruses (the California serogroup of viruses [in particular, California encephalitis caused by the Lacrosse agent]), and some causes of viral hemorrhagic fever (Rift Valley fever). The tick-borne causes of encephalitis include the flavivirus Powassan (northeastern United States and Canada) and tick-borne encephalitides of Europe. Pathogens associated with viral hemorrhagic fever are discussed below, and only those viruses causing primarily encephalitis in the United States will be discussed here.

Infection with West Nile virus was first identified in the United States in the New York City area in 1999. The virus spread rapidly, with initial cases reported along the Atlantic seaboard. Current cases are reported throughout the continental United States. Earlier outbreaks occurred in France in the early 1960s and in Romania in 1996.

Along with West Nile fever, the leading causes of arbovirus encephalitis in the United States are St. Louis encephalitis and California encephalitis. Pathogen-specific reservoirs (typically small mammals or birds) are responsible for maintaining the encephalitis-producing viruses in nature. Birds are the main reservoir for West Nile virus and substantial avian mortality accompanies West Nile fever outbreaks, a fact that is used to monitor disease patterns. Outbreaks tend to occur in late summer and early fall.

Transplacental transmission is documented for the viruses that cause Western and Venezuelan equine encephalitis and West Nile fever. The virus that causes West Nile fever is also transmissible via blood donation, organ transplantation, breast-feeding, and laboratory and possibly aerosol exposures. The human incubation period is 2–14 days. The proportion of patients in whom the disease develops after acquiring

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the virus is unknown. Estimates were reported from serologic surveillance from the New York epidemic; fever developed in 1 of 5 infected patients and severe neurologic disease developed in 1 of 150.

Clinical Findings

A. Symptoms and Signs

The symptoms of arboviral encephalitis include fever, malaise, sore throat, headache, gastrointestinal upset, lethargy, and stupor progressing to coma. Stiff neck and mental status changes are the most common neurologic signs. Seizures are present in 5% of patients and flaccid paralysis is seen in 10%. Other signs include tremors, convulsions, cranial nerve palsies, paralysis of extremities, and pathologic reflexes. About 50% of patients in the United States with West Nile virus infection with symptoms severe enough to warrant hospitalization had significant muscle weakness. This weakness can cause diagnostic confusion with the Guillain-Barré syndrome and may evolve into a poliomyelitis-like syndrome. Rash is reported in fewer than one-third of cases.

Among cases of encephalitis reported in 2003 in the United States, 70% were reported as West Nile fever (milder disease) and about 30% were reported as West Nile meningitis or encephalitis. Age older than 70 years seems to be the main risk factor for severe meningoencephalitis and death. The role of immunosuppression as a risk factor remains uncertain. The outcome of encephalitis is also age-dependent with residual damage principally in older patients. St. Louis encephalitis occurs among adults; Western and Venezuelan encephalitides occur primarily among children while the Eastern encephalitis is a disease of both children and the elderly. The disease manifestations associated with West Nile fever are strongly age-dependent with the acute febrile syndrome and mild neurologic symptoms more common in the young, aseptic meningitis and poliomyelitis-like syndromes in the middle aged, and frank encephalopathy in the elderly.

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—including West Nile fever—depends on serologic tests. For West Nile virus, an IgM capture enzyme-linked immunosorbent assay (ELISA) can be done on either serum or cerebrospinal fluid and is almost always positive by the time the disease is clinically evident. The virus is also detectable in urine and blood using PCR but only during limited intervals, thus limiting PCR as a diagnostic assay. There is cross-reaction among the different flaviviruses, so a plaque reduction assay may be needed to definitively distinguish between West Nile fever and St. Louis encephalitis. Serum IgM may be positive for many months after acute infection, so an increase in antibody titer between acute and convalescent samples is necessary to confirm acute infection when cerebrospinal fluid samples are unavailable. 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 (Table 32-2) 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's 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. Late sequelae are mental deterioration, parkinsonism, and epilepsy.

Prevention

No human arbovirus vaccine is currently available (two equine encephalitis vaccines are available). Mosquito control (repellents, protective clothing, and insecticides) is effective in prevention. Because the virus that causes West Nile fever is transmissible via both organ donation and blood transfusion, all potential blood donors should be screened for neurologic symptoms and all donated blood should be assayed with nucleic acid amplification tests for West Nile virus during periods of maximum transmission (summer and fall for the continental United States). Laboratory precautions are indicated for handling all 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 protection against the West Nile pathogen (since both agents are related flaviviruses) in certain settings such as among laboratory workers.

Treatment

Although specific antiviral therapy is not available for most causative entities, vigorous supportive measures

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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 was useful in West Nile encephalitis has now been substantiated. Other therapeutic options such as interferon-α and immunoglobulin are not proven to be effective.

Prognosis

The prognosis is always guarded, especially at the extremes of age. Sequelae may become apparent late in the course of what appears to be a successful recovery. The prognosis is generally better for Western equine than for Eastern equine or St. Louis encephalitis. St. Louis encephalitis is reportedly associated with a postinfectious encephalomyelitis. As of 2002, the case fatality rate for recognized cases of arboviral encephalitis was 5%. Many infections result in seroconversion only and do not result in clinical illness.

Centers for Disease Control and Prevention (CDC): West Nile virus activity—United States, January 1-December 1, 2005. MMWR Morb Mortal Wkly Rep 2005;54:1253.

Gea-Banacloche J et al: West Nile virus: pathogenesis and therapeutic options. Ann Intern Med 2004;140:545.

Hayes EB et al: Epidemiology and ecology of West Nile virus. Emerg Infect Dis 2005;11:1167.

Hayes EB et al: Virology, pathology, and clinical manifestations of West Nile virus disease. Emerg Infect Dis 2005;11:1174.

Mackenzie JS et al: Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 2004;10(12 Suppl):S98.

Watson JT et al: Clinical characteristics and functional outcomes of West Nile fever. Ann Intern Med 2004;141:360.

Yamshchikov G et al: The suitability of yellow fever and Japanese encephalitis vaccines for immunization against West Nile virus. Vaccine 2005;23:4785.

3. Lymphocytic Choriomeningitis

Essentials of Diagnosis

  • “Influenza-like” prodrome of fever, chills, malaise, and cough, followed by meningitis with associated stiff neck.

  • Aseptic meningitis with positive Kernig's sign, 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

Lymphocytic choriomeningitis is an arenaviral infection of the CNS (related to the pathogen causing Argentinian hemorrhagic fever, discussed below). The main reservoir of infection is the infected house mouse, though other reservoirs include guinea pigs, monkeys, dogs, swine, and even pet hamsters. The virus is shed by the infected animal via nasal secretions, urine, and feces, with transmission to humans probably through exposure to animal droppings via contaminated food and dust. Human cases of lymphocytic choriomeningitis are most common in autumn. The virus is not spread person to person, though vertical transmission occurs and lymphocytic choriomeningitis is a potential fetal teratogen. Rare cases related to solid organ transplantation are reported. The incubation period is 8–13 days to the appearance of systemic manifestations and 15–21 days to the appearance of meningeal symptoms. CD4 cells may be involved in pathogenesis. Lymphocytic choriomeningitis is considered a model of cell-mediated immunity in vaccine development.

Outbreaks occur among persons with rodent exposure. Complications of clinical disease are rare.

This disease is principally confined to the eastern seaboard and northeastern states of the United States, and serologic evidence of infection is increased among women, the elderly, and members of lower socioeconomic groups.

Clinical Findings

A. Symptoms and Signs

Symptoms are biphasic. The prodromal illness is characterized by fever, chills, headache, myalgia, cough, and vomiting, occasionally with lymphadenopathy and maculopapular rash. Signs of pneumonia are occasionally present during the prodromal phase. After 3–5 days, the fever subsides and recurs in 2–4 days with the meningeal phase, characterized by headache, nausea and vomiting, and lethargy. During the meningeal phase, there may be neck and back stiffness with a positive Kernig's sign. Obstructive hydrocephalus is a rare complication. Arthralgias can develop late.

Chorioretinitis also appears to be a sequela of lymphocytic choriomeningitis. Lymphocytic choriomeningitis is an underrecognized neuroteratogen.

B. Laboratory Findings

Leukocytosis or leukopenia and thrombocytopenia may be present. Cerebrospinal fluid lymphocytic pleocytosis (total count is often 500–3000/mcL) may occur, with a slight increase in protein and normal to low glucose in at least 25%. Complement-fixing antibodies appear during or after the second week. The virus may be recovered from the blood and cerebrospinal fluid by mouse inoculation. A PCR technique for the detection of lymphocytic choriomeningitis virus in the cerebrospinal fluid is described.

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Differential Diagnosis

The influenza-like prodrome and latent period help 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.

Prevention

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

Treatment

Treatment is supportive as for encephalitis or aseptic meningitis. The membrane protein α-dystroglycan interacts with lymphocytic choriomeningitis and Lassa fever virus (both arenaviruses), and this interaction provides a potential avenue for future interventions.

Prognosis

Fatalities are rare. The illness usually lasts 1–2 weeks, though convalescence may be prolonged.

Barton LL et al: Lymphocytic choriomeningitis virus: emerging fetal teratogen. Am J Obstet Gynecol 2002;187:1715.

Centers for Disease Control and Prevention (CDC): Lymphocytic choriomeningitis virus infection in organ transplant recipients—Massachusetts, Rhode Island, 2005. MMWR Morb Mortal Wkly Rep 2005;54:537.

Riera L et al: Serological study of the lymphochoriomeningitis virus (LCMV) in an inner city of Argentina. J Med Virol 2005;76:285.

Sevilla N et al: Infection of dendritic cells by lymphocytic choriomeningitis virus. Curr Top Microbiol Immunol 2003;276:125.

4. Prion Disease

Several neurologic diseases are caused by communicable pathogens with slow replicative capacity and long latent intervals in the host. Such pathogens are called proteinaceous infectious particles, or “prions,” and are resistant to most procedures that modify nucleic acid. The transmissible pathogens induce conversion of a normal brain protein (PrPC) to an abnormal isoform (PrPSc), a process that appears to be both genetically determined and in need of the infectious organism. The accumulated abnormal isoform proteins are associated with disease, though the pathogenesis of spongiform changes and the accumulation in some cases of amyloid plaque are poorly understood. There is evidence of lymphoreticular involvement (spleen, lymph nodes, tonsils), but the significance of this is unclear. A variety of animal diseases exhibit these properties, including visna and scrapie in sheep and goats, chronic wasting disease of mule deer and elk, and transmissible encephalopathy of mink. The pathogens or related pathogens that cause human disease are discussed here.

Kuru and Creutzfeldt-Jakob disease are transmissible in brain or eye tissue to primates, including humans. After an incubation period measured in years, disease ensues, characterized by an inexorably progressive neurologic decline. Kuru—once prevalent in central New Guinea but no longer seen since abandonment of cannibalism—was characterized by cerebellar ataxia, tremors, dysarthria, and emotional lability.

The four forms of Creutzfeldt-Jakob disease (CJD) are sporadic (80–85%), familial (15%), iatrogenic (< 1%), and variant (vCJD), described below. Sporadic, familial, and iatrogenic are classified as classic CJD (cCJD). There are no definitive risk factors for cCJD, which occurs worldwide with an incidence of 1 per million, although data show that butchers and medical office staff may be at increased occupational risk. Classic CJD usually presents in the sixth or seventh decade with dementia progressive over several months, myoclonic fasciculations, ataxia, and somnolence. The characteristic electroencephalographic pattern shows paroxysms with high voltages and slow waves. MRI typically shows bilateral areas of increased signal intensity, predominantly in the caudate and putamen. Assays of the cerebrospinal fluid for 14–3-3 protein and neuron-specific enolase may help with the diagnosis. Familial cases are inherited in an autosomal dominant pattern with variable penetrance. Iatrogenic cases have occurred in patients who receive tissue, such as cadaveric growth hormone and dural grafts from the CNS of patients with CJD.

There is no specific treatment, and the only known means of prevention is avoidance of contamination by affected brain tissue, electrodes, or neurosurgical tools or by transplants of cornea, dura, or cadaveric growth hormone from infected donors. 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 solution. Predictors for survival are younger age at onset of illness, female sex, a particular codon heterozygosity of the prion protein (129), the presence in the cerebrospinal fluid of protein 14–3-3, and the 2a prion protein type.

New vCJD was originally described in an outbreak from Great Britain that spread to involve several countries in Western Europe. Rare cases in the United States and Canada are reported among former UK residents. Compared with patients who have cCJD, patients with vCJD are younger, the duration of disease is longer, the clinical symptoms are unique (psychiatric and sensory symptoms and cerebellar signs are more common), and the MRI characteristically demonstrates hyperintensity of the posterior thalamus (“pulvinar sign”). All patients with vCJD have been homozygous for methionine at codon 129. vCJD probably results from ingestion of beefsteak contaminated with neural tissue (brain, spinal cord) from livestock infected with bovine spongiform encephalopathy (BSE) (“mad cow disease”). Most cases of BSE to date are reported from Europe, particularly Great Britain. Over the past 12 years two cases of BSE occurred

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in Canada and two were recently reported from Texas and Washington State. BSE is a product of livestock contaminated by ingesting material rendered from infected ruminants (deer, cattle, bison, sheep, and goats). Such feeding practices are now forbidden in many countries including the United States and Canada. There is no animal-to-animal spread of BSE and milk and its derived products are not infected. The risk for vCJD associated with the ingestion of beef products in the United States and Canada is deemed very small. Nonetheless, the US Food and Drug Administration (FDA) is currently embarking on a set of restrictive measures that will prevent the use of potentially infected beef and other ruminant offal in food and cosmetic products. A case of vCJD attributed to blood transfusion was reported from the United Kingdom. Patients with vCJD studied to date show a unique PrP phenotype.

Another animal disease that causes slow neurologic deterioration is chronic wasting disease of elk. It is caused by a prion that is distinctive from the causative pathogen of BSE. Thus far, there is no evidence of transmission of chronic wasting disease to humans.

Other prion diseases include fatal familial insomnia (rarely sporadic) and Gerstmann-Sträussler-Scheinker disease (with dementia and spastic paraparesis).

Aguzzi A et al: Progress and problems in the biology, diagnostics, and therapeutics of prion diseases. J Clin Invest 2004;114:153.

CDC National Center for Infectious Diseases—Variant Creutzfeldt-Jakob Disease http://www.cdc.gov/ncidod/dvrd/vcjd

Demaerel P et al: Accuracy of diffusion-weighted MR imaging in the diagnosis of sporadic Creutzfeldt-Jakob disease. J Neurol 2003;250:222.

Glatzel M et al: Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease. N Engl J Med 2003;349:1812.

Llewelyn CA et al: Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004;363:417.

Pocchiari M et al: Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Brain 2004;127:2348.

Wadsworth JDF et al: Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science 2004;306:1793.

5. Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder with a propensity for affliction of immunosuppressed adults with impaired cell-mediated immunity, especially AIDS patients. Recently, natalizumab, a monoclonal antibody, against 4 integrins, with potential therapeutic roles in multiple sclerosis and inflammatory bowel disease, was withdrawn from the market after case reports of progressive multifocal leukoencephalopathy in patients receiving this medication.

The cause of all progressive multifocal leukoencephalopathy is reactivation of JC virus (JCV), a widespread papovavirus that initially infects children, leading to latent infection in the kidneys and lymphoid organs. JCV targets myelinating oligodendrocytes of the CNS. PCR of the cerebrospinal fluid for JCV is used for diagnosis in patients with compatible clinical and radiologic findings. HAART for HIV infection is effective when CD4 counts improve to > 100 cells/mcL in improving survival as well as the clinical and radiographic features associated with this disease, although a small number of cases appear to worsen with immune restoration. Other agents used include cidofovir, not routinely recommended, and topotecan, which appears to be of some benefit.

Berenguer J et al: Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047.

Cinque P et al: The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol 2003;9(Suppl 1):73.

Langer-Gould A et al: Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375.

Tyler KL: The uninvited guest: JC virus infection of neurons in PML. Neurology 2003;61:734.

6. Human T Cell Lymphotropic Virus (HTLV)

Retroviruses include both the lympholytic HIV agents and the lymphotropic oncoviruses, human T cell leukemia viruses types 1 and 2 (HTLV-1 and -2). The isolation of HTLV-1 from a young man with T cell lymphoma established an association of the virus with adult T cell lymphoma/leukemia (ATL)—an association that has been confirmed from endemic areas throughout the world, including the Caribbean, southern Japan, sub-Saharan Africa (where over 10% of the population of Gabon and Cameroon are seropositive), Latin America (an ancient HTLV-1 provirus has been detected in an Andean mummy), Eastern Europe, and the southeastern United States (where seroprevalence is most common among injection drug users). The viruses are transmitted horizontally, vertically, and parenterally (injection drug use and blood transfusion).

The lifetime risk of developing ATL among seropositive persons is estimated to be 3% among women and 7% among men, with an incubation period of at least 15 years.

ATL clinical syndromes may be classified as chronic, smoldering, lymphomatous, or leukemic. Common clinical features of ATL include diffuse lymphadenopathy, maculopapular skin lesions that may evolve into erythroderma, organomegaly, lytic bone lesions, and hypercalcemia. Increased amounts of seborrheic dermatitis, eczema, and lower extremity hyperreflexia

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are also seen. A bronchiolitis associated with HTLV may mimic that of diffuse panbronchiolitis although the response of the latter to antibiotics, typically macrolide, can differentiate the two.

ATL patients show a predisposition toward opportunistic infections such as Pneumocystis jiroveci pneumonia and cryptococcal meningitis. A large percentage of patients are infected with Strongyloides stercoralis. Diagnosis is supported by identification of HTLV-1 antibodies. Confirmatory evidence for clonal integration of the proviral DNA genome into tumor cells is the current diagnostic standard.

HTLV-1 also causes HTLV-associated myelopathy (HAM; tropical spastic paraparesis). It is characterized by progressive motor weakness, especially of the lower extremities, with spastic paraparesis or paraplegia with hyperreflexia. Sensory disturbances, peripheral neuropathy, and urinary incontinence may also be seen. Much of the pathology appears to be a product of HTLV-1-induced cytokine production and associated inflammation. The disease may resemble multiple sclerosis but does not remit. Cutaneous manifestations of HAM include xerosis, cutaneous candidiasis, and palmar erythema. Cranial nerve abnormalities are rare, and cognitive function is usually preserved. HAM develops in less than 1% of HTLV-1 seropositive individuals. Studies among seropositive blood donors suggest there is a spectrum of illness of HTLV-1-associated neurologic disease, which includes myopathy and neuropathy.

HTLV-2 was initially implicated in hairy cell leukemia, but this association has not been confirmed. HTLV-2 seropositivity is common in some American populations, especially injection drug users. The virus infects primarily CD8 cells, whereas HTLV-1 infects primarily CD4 cells. HTLV-2 appears to also cause a form of myelopathy that is milder and slower to progress. Coinfection with HTLV-2 and HIV appears to be associated with increased risk of peripheral neuropathy.

A viral load assay is under development that shows that viremia with HTLV-1 is higher than with HTLV-2 and that transfusion-acquired infections are associated with greater viremia than sexually acquired infections.

Management of ATL is similar to that for non-Hodgkin's lymphoma and includes combination chemotherapy and radiation of particular sites (weight-bearing bony lesions, paraspinal masses, intracerebral lesions). HTLV-associated myelopathy is treated with a variety of immune-modulating agents without consistent results. Antiretrovirals have not shown clear benefit for ATL- or HTLV-associated myelopathy, although in vitro sensitivity to several antiretrovirals is recognized. Interferon-α may be of some efficacy.

Screening of the blood supply for HTLV-1 is required in the United States, since transfusion is a recognized mode of transmission along with sexual contact and vertical transfer. There is significant cross-reactivity between HTLV-1 and HTLV-2 by serologic studies, but PCR can distinguish the two.

Kashiwagi K et al: A decrease in mother-to-child transmission of human T lymphotropic virus type I (HTLV-I) in Okinawa, Japan. Am J Trop Med Hyg 2004;70:158.

Mahieux R et al: HTLV-1 and associated adult T-cell leukemia/lymphoma. Rev Clin Exp Hematol 2003;7:336.

Murphy EL et al: Higher human T lymphotropic virus (HTLV) provirus load is associated with HTLV-I versus HTLV-II, with HTLV-II subtype A versus B, and with male sex and a history of blood transfusion. J Infect Dis 2004;190:504.

Orland JR et al: HTLV Outcomes Study. Prevalence and clinical features of HTLV neurologic disease in the HTLV Outcomes Study. Neurology 2003;61:1588.

Saito M et al: Decreased human T lymphotropic virus type I (HTLV-I) provirus load and alteration in T cell phenotype after interferon-alpha therapy for HTLV-I-associated myelopathy/tropical spastic paraparesis. J Infect Dis 2004;189:29.

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 West Nile pathogen, are discussed above under arboviruses; dengue and yellow fever, both with occasional hemorrhagic complications, are discussed in the following sections alongside the immunologic responses to them. 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. Headache, myalgia, gastrointestinal symptoms, and symptoms of upper respiratory tract infection dominate the clinical picture and hepatitis is common. Laboratory features usually include thrombocytopenia, leukopenia, (although with Lassa fever leukocytosis is noted), anemia, and often elevated liver function tests as well as findings consistent with disseminated intravascular coagulation (except in Lassa fever).

The late phase is more specific and is characterized by organ failure, persistent leukopenia, altered mental status, and hemorrhage. The case-fatality rate ranges from 5% to 30% and may be as high as 90% in Ebola fever. There is no evidence of chronic infection among survivors.

Modes of transmission are similarly diverse. Dengue and yellow fever are due to flaviviruses transmitted by mosquitoes, while Omsk hemorrhagic fever and Kyasanur Forest disease are due to tick-borne flaviviruses. Lassa fever is rodent associated, as are Junin hemorrhagic fever and other diseases due to New World Arenaviridae. Ebola fever and Marburg fever are due to filoviruses with unknown vectors. The bunyaviruses include the tick-borne Crimean-Congo hemorrhagic fever and the mosquito-borne Rift Valley fever (a major outbreak in Saudi Arabia in 2000–2001 involved over 800 persons), while infections due to the

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hantaviruses (discussed separately below) are associated with rodent exposure.

The Nipah virus in Malaysia is a zoonotic paramyxovirus that does not cause hemorrhagic fever but instead causes a primarily encephalitic infection. Most cases are associated with a history of contact with pigs. Flying foxes appear to be the natural host.

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. Diagnosis may be made by growing the virus from blood obtained early in the disease, by reverse transcriptase PCR, or by demonstration of a significant specific fourfold or greater rise in antibody titer. These tests are generally available only through the CDC. 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%.

The pathophysiology of these infections includes infection of a wide variety of cell types, but in particular lymphoid tissues, tissues involved in the coagulation cascade, and the immune system. Many of the symptoms are due to the effect of inflammatory mediators such as cytokines and chemokines. Adrenal dysfunction is a common sequela and a cause for the development of the late-stage shock associated with viral hemorrhagic fevers.

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

Certain arenaviruses (the Lassa pathogen, Junin virus in its viscerotropic phase, Machupo virus) and bunyaviruses (provisionally, the Congo-Crimean Hemorrhagic Fever and Rift Valley Fever pathogens) respond to ribavrin 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 (see Chapter 37). The filoviruses and the flaviviruses do not respond to ribavirin. Vaccines are needed for these pathogens. The successful yellow fever vaccine is discussed below. A live attenuated Junin vaccine is undergoing trials. A formalin-inactivated vaccine against the Rift Valley Fever pathogen is in use and a live-attenuated vaccine is under development. Therapeutic interventions that target the hematologic system are either ineffective or only marginally effective. Future studies will target combining antivirals with immune mediators.

Bray M: Pathogenesis of viral hemorrhagic fever. Curr Opin Immunol 2005;17:399.

Feldmann H et al: Therapy and prophylaxis of Ebola virus infections. Curr Opin Investig Drugs 2005;6:823.

Ferguson NE et al: Bioterrorism web site resources for infectious disease clinicians and epidemiologists. Clin Infect Dis 2003; 36:1458.

Geisbert TW et al: Exotic emerging viral diseases: progress and challenges. Nat Med 2004;10(12 Suppl):S110.

Jones SM et al: Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med 2005;11:786.

Mardani M et al: The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran. Clin Infect Dis 2003;36:1613.

2. Dengue

Essentials of Diagnosis

  • Exposure 7–10 days before onset.

  • Sudden onset of high fever, chills, severe myalgias, headache, sore throat, prostration, 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 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. 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%. Transmission occurred in the United States in southern Texas and nearby Mexican border towns in 1986 and 1999. In 2001, a large outbreak in Hawaii was traced to a traveler returning from French Polynesia. Severe epidemics of dengue hemorrhagic fever (serotype 3) occurred over the past 20 years in East Africa, Sri Lanka, and Latin America.

Clinical Findings

A. Symptoms and Signs

Dengue fever is usually a nonspecific, self-limited biphasic febrile illness, but its presentation may range from asymptomatic to severe hemorrhagic fever and fatal shock (dengue shock syndrome). Infection is asymptomatic in 80% of infants and children. 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

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by sore throat, prostration, and malaise. There may be conjunctival redness and flushing or blotching of the skin. Initially, the skin appears flushed, 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. Hepatitis frequently complicates dengue fever.

Dengue hemorrhagic fever usually affects children living in endemic areas and is most likely to occur in secondary 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 hemorrhagic fever subset of patients include restlessness, epistaxis, and abdominal pain.

Some dengue virus envelope glycoproteins are homologous with segments of clotting factors, including plasminogen, and thus the hemorrhagic fever may represent an autoimmune reaction. A subset of patients progresses to dengue shock syndrome in which acute fever, hemorrhagic manifestations, and marked capillary leak are prominent, the latter manifesting as pleural effusions, ascites, and a tendency to develop shock.

Before the rash of dengue appears, the infection is difficult to distinguish from malaria, yellow fever, or influenza; the rash makes dengue far more likely. Continuous abdominal pain with vomiting, a decrease in the level of consciousness, and hypothermia should raise concern about dengue shock syndrome.

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 function abnormalities are nearly universal. The nonspecific nature of the illness mandates laboratory verification for diagnosis, usually with IgM and IgG ELISAs. Virus may be recovered from the blood during the acute phase, and several PCR protocols are being developed. Immunohistochemistry for antigen detection in tissue samples can also be used.

Complications

Usual complications include depression, chronic fatigue, pneumonia, bone marrow failure, hepatitis, iritis, orchitis, and oophoritis. Neurologic complications such as encephalitis and transverse myelitis are less often reported. Dengue hemorrhagic fever or shock with concomitant bacterial infection is associated with advanced age, higher fever, gastrointestinal bleeding, renal impairment, and altered consciousness.

Prevention

Available prophylactic measures include control of mosquitoes by screening and insect repellents, particularly during early morning and late afternoon exposures. A screening program at an airport for persons with fever facilitated the diagnosis of dengue and the implementation of public health measures in Taipei, Taiwan.

A variety of vaccines, involving attenuated or genetically modified virus, are under study including combinations of attenuated dengue strains.

Treatment

Treatment entails the appropriate use of volume support (with Ringer's lactate the preferred agent in moderately severe shock), blood products, and pressor agents, and acetaminophen rather than nonsteroidal anti-inflammatory 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. Monitoring platelet counts does not usefully predict clinically significant bleeding. Monitoring for hemoconcentration, however, may help in anticipating the complications of dengue hemorrhagic fever or shock syndrome.

Prognosis

Fatalities are rare but do occur, especially during epidemic outbreaks, with occasional patients dying from fulminant hepatitis. Convalescence for most patients is slow.

Centers for Disease Control and Prevention (CDC): Travel-associated dengue infections—United States, 2001–2004. MMWR Morb Mortal Wkly Rep 2005;54:556.

Lee IK: Clinical characteristics and risk factors for concurrent bacteremia in adults with dengue hemorrhagic fever. Am J Trop Med Hyg 2005;72:221.

Shu PY: Fever screening at airports and imported dengue. Emerg Infect Dis 2005;11:460.

Stephenson JR: Understanding dengue pathogenesis: implications for vaccine design. Bull World Health Organ 2005;83:308.

Wills BA et al: Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005;353:877.

3. Hantaviruses

Hantaviruses are rodent-borne enveloped RNA bunyaviruses with several distinct serotypes. These differ in rodent hosts, geographic distribution, and degree of pathogenicity for humans. They cause two major clinical syndromes: hemorrhagic fever (discussed above) and the hantavirus pulmonary syndrome. Aerosols of virus-contaminated rodent urine and perhaps feces are thought to be the main vehicle for transmission to humans. The ubiquity of hantaviruses is becoming recognized, with descriptions of infections from North and South America and additional infections from Europe and Asia. The Hantaan serotype viruses cause severe hemorrhagic fever with renal syndrome and are found primarily in Korea, China, and eastern Russia. The Seoul viruses produce a

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less severe form and are found primarily in Korea and China. The Puumala and Dobrava viruses are found in Scandinavia and Europe and are associated with a milder form of the syndrome, nephropathia epidemica, which usually presents with fever, headache, gastrointestinal symptoms, and impaired renal function.

The Sin Nombre (Muerto Canyon, Four Corners) virus is one of the viruses responsible for the hantavirus pulmonary syndrome, most cases of which have been seen in the southwestern United States. Approximately 300 cases have been reported from 31 states since 1993. Outbreaks are currently being reported from Central and South America. Hantavirus pulmonary syndrome begins as a nonspecific febrile illness followed by a severe increase in pulmonary vascular permeability, leading to respiratory failure, and rapid progression to a shock-like state. Hematologic features include thrombocytopenia, hemoconcentration, and leukocytosis, with abnormal lymphocytes and immature myeloid cells in the peripheral smear. Clinical similarities, including a propensity toward renal involvement exist between the New World hantaviruses and their Old World counterparts.

Diagnosis can be made serologically, with most patients having both IgM and IgG antibodies at the time of presentation; by immunohistochemical staining; or by PCR amplification of viral tissue DNA. Because infection is thought to occur by inhalation of rodent wastes, prevention is aimed toward eradication of rodents in houses and avoidance of exposure to rodent excreta in rural settings.

No treatment has been established as definitely effective for hantavirus pulmonary syndrome. Intravenous ribavirin has been used with some success in hemorrhagic fever with renal syndrome, and studies are currently ongoing for its use in hantavirus pulmonary syndrome.

Boroja M et al: Radiographic findings in 20 patients with hantavirus pulmonary syndrome correlated with clinical outcome. AJR Am J Roentgenol 2002;178:159.

Hujakka H et al: Diagnostic rapid tests for acute hantavirus infections: specific tests for Hantaan, Dobrava and Puumala viruses versus a hantavirus combination test. J Virol Methods 2003;108:117.

Olsson G et al: Human hantavirus infections, Sweden. Emerg Infect Dis 2003;9:1395.

Peters CJ et al: Hantavirus pulmonary syndrome: the new American hemorrhagic fever. Clin Infect Dis 2002;34:1224.

4. Yellow Fever

Essentials of Diagnosis

  • 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.

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. Epidemics have extended far into the temperate zone during warm seasons. The role of yellow fever in preventing economic development in tropical areas is devastating.

The mosquito transmits the infection by first biting an individual having the disease and then biting a susceptible individual after the virus has multiplied within the mosquito's body. 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% of those infected with yellow fever. 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's 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. Proteinuria is present, sometimes as high as 5–6 g/L, and disappears completely with recovery. Abnormal liver function tests are seen, and prothrombin time may be elevated. Serologic diagnosis is primarily by measurement of IgM by a capture ELISA. Other serologic tests include hemagglutination-inhibition and neutralization. PCR protocols are becoming more widely available.

Differential Diagnosis

It may be difficult to distinguish yellow fever from hepatitis, malaria, leptospirosis, louse-borne relapsing

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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.

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. Vaccine-induced reactions, including viscerotropic and hepatotropic diseases that resemble yellow fever, are reported (particularly among elderly patients). Mass campaigns with the vaccine were carried out without significant complications in Cote d'Ivoire. 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, with forest rodents serving as a reservoir. Discrete enzootic foci of transmission appear to be more important than wandering epizootic foci as formerly thought. (See Chapter 30.)

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, and anuria are unfavorable signs. Convalescence is prolonged, including 1–2 weeks of asthenia. Infection confers lifelong immunity.

Gubler DJ: The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle? Comp Immunol Microbiol Infect Dis 2004;27:319.

Khromaava AY et al: Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 2005;23:3256.

Pugachev KV et al: New developments in flavivirus vaccines with special attention to yellow fever. Curr Opin Infect Dis 2005;18:387.

Tattevin P et al: Yellow fever vaccine is safe and effective in HIV-infected patients. AIDS 2004;18:825.

Weir E at al: Yellow fever: readily prevented but difficult to treat. CMAJ 2004;170:1909.

5. Tick-Borne Encephalitis

Essentials of Diagnosis

  • Flaviviral encephalitis found in Eastern, Central, and occasionally Northern Europe.

  • 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) is a flaviviral infection caused by TBE virus that is endemic in Russia and in eastern and central Europe. In parts of Europe and the Baltic, attack rates exceed 100 cases per 100,0000 population and 10,000 to 12,000 cases are estimated to occur annually. TBE occurs predominantly in the late spring through fall. It is usually a consequence of exposure to infected ticks, although unpasteurized cow's, sheep's, and goat's milk are recognized forms of transmission. 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 persulcatus and Ixodes ricinus.

Clinical Findings

A. Symptoms and Signs

Although the majority of cases are subclinical and many resemble a flu-like syndrome, symptomatic and severe disease occurs in all age groups. There are two variants, a Western and an Eastern subtype. Disease with the Western subtype occurs mainly in the fall and is most severe among the elderly, whereas disease with the Eastern subtype is associated with more severe disease among children.

Western subtype disease is biphasic; after a 2–10 day asymptomatic interval, a febrile period of 2–7 days is followed by neurologic symptoms. Eastern subtype disease is progressive without an asymptomatic interval. The leading neurologic symptom is a febrile headache, the clinical presentation accounting for up to 50% of Eastern subtype TBE cases. Aseptic meningitis is a significant clinical manifestation of disease. A greater degree of encephalitic symptoms presents in some patients, and a myelitis with severe extremity pain develops 5–10 days after the fever remits in a small percentage of patients. Mortality is usually a consequence of brain edema or bulbar involvement.

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B. Diagnosis

Diagnosis is established clinically. Abnormal cerebrospinal fluid findings include a pleocytosis that may persist for up to 4 months. Leukocytosis and neutrophilia are common. PCR of infected tissue, such as brain, may be useful. Neuroimaging studies show hyperintense lesions in the thalamus, brainstem, and basal ganglia.

Complications

The main sequela of disease is paresis, which occurs in up to 10% of Western and up to 25% of Eastern subtype disease. Among those with encephalitis, about 25% recover within 2 months. In the remaining 40%, either protracted, cognitive dysfunction or persistent spinal nerve paralysis with or without other postencephalitic symptoms develops. 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 may occur 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, and other flaviviral infections.

Therapy

Therapy is largely supportive. Some clinicians believe corticosteroids or other nonsteroidal anti-inflammatory drugs may be useful, although no controlled clinical trials exist.

Prevention

Prevention is based on vaccination. Although a vaccine has not been approved in the United States, a variety of vaccines are in current use, with the most popular and most effective being a formaldehyde-inactivated whole virus vaccine from Austria. Alternative effective vaccines have been developed in Germany and Russia. The initial vaccination schedule requires 1 year with boosters every 3 years. Other prevention recommendations include avoidance of tick exposure, pasteurization of milk, and passive immunization with immunoglobulin within 4 days of exposure (disease exacerbation from exposure to immunoglobulin is not substantiated).

Charrel RN: Tick-borne virus diseases of human interest in Europe. Clin Microbiol Infect 2004;10:1040.

Kunze U et al: Tick-borne encephalitis in childhood—consensus 2004. Wien Med Wochenschr 2004;154:242.

Rendi-Wagner P et al: Persistence of protective immunity following vaccination against tick-borne encephalitis—longer than expected? Vaccine 2004;22:2743.

6. Colorado Tick Fever

Essentials of Diagnosis

  • Onset 1–19 days (average, 4 days) following tick bite.

  • Fever, chills, myalgia, headache, prostration.

  • Leukopenia.

  • Second attack of fever after remission lasting 2–3 days.

General Considerations

Colorado tick fever is an acute coltivirus infection transmitted by Dermacentor andersoni bites. 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.

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 symptoms. Physical findings are limited to an occasional faint rash. The acute symptoms resolve within a week. The 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.

B. Laboratory Findings

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. Viremia may be demonstrated by inoculation of blood into mice or by fluorescent antibody staining of the patient's red cells (with adsorbed virus). Complement-fixing antibodies do not appear until the third week of disease but are the most frequently used tool to document an infection. A reverse transcriptase PCR assay may be used to detect viremia.

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Complications

Aseptic meningitis (particularly in children), encephalitis, and hemorrhagic fever occur rarely. Malaise may ensue, but fatalities are very rare.

Treatment

No specific treatment is available. Ribavirin has shown efficacy in an animal model. Antipyretics are used, although aspirin should be avoided. Codeine or hydrocodone may be given for pain. Tick-avoidance measures may be effective in preventing the disease.

Prognosis

The disease is usually self-limited and benign.

Bratton RL et al: Tick-borne disease. Am Fam Physician 2005;71:2323.

Klasco R: Colorado tick fever. Med Clin North Am 2002;86:435.

Common Viral Respiratory Infections

Infections of the respiratory tract are perhaps the most common human ailments. Specific associations of some groups of viruses with certain disease syndromes are established. In young infants and in the elderly, or in persons with impaired respiratory tract reserve, bacterial superinfection increases morbidity and mortality. Croup, epiglottitis, and the common cold are discussed in Chapter 8.

Leder K et al: Respiratory tract infections in travelers: a review of the GeoSentinel surveillance network. Clin Infect Dis 2003;36:399.

Muether PS: Variant effect of first- and second-generation antihistamines as clues to their mechanism of action on the sneeze reflex in the common cold. Clin Infect Dis 2001;33:1483.

1. Respiratory Syncytial Virus & Other Paramyxoviruses

RSV is a paramyxovirus that causes annual outbreaks of pneumonia, bronchiolitis, and tracheobronchitis, with the majority of cases occurring in the very young. Premature infants with bronchopulmonary dysplasia are at highest risk. Other risk factors in children include male gender, age less than 6 months, and day care exposure. Incomplete immunity commonly leads to reinfection manifested typically as an upper respiratory tract infection and tracheobronchitis in older children or adults. Serious pulmonary RSV infections have been described in elderly and immunocompromised adults. Outbreaks with a high mortality rate in bone marrow transplant and pediatric liver transplant patients are reported.

Annual epidemics occur in winter and spring. The average incubation period is 5 days. Inoculation may occur through the nose or the eyes. RSV is an increasingly recognized as contributing to recurrent otitis media in children and upper respiratory tract infections. Among hematologic adult cancer patients with upper respiratory tract infections, the isolation of RSV is a significant marker for progression to pneumonia.

Other paramyxoviruses important in human disease include human metapneumovirus and parainfluenza viruses. Human metapneumovirus is less common and less pathogenic than RSV. Like RSV, it appears to cause bronchiolitis; croup; exacerbation of pneumonia; and pneumonia during the winter and spring among infants, with highest rates in the 3–24 month age range; and lower respiratory tract infections among elderly adults. Parainfluenza viruses that most commonly cause disease are types 1, 2, and 3. They tend to cause respiratory tract infections in the very young, the elderly, the immunocompromised, and those with chronic illnesses.

In RSV bronchiolitis, proliferation and necrosis of bronchiolar epithelium develop, producing obstruction from sloughed epithelium and increased mucus secretion. Signs include low-grade fever, tachypnea, and wheezes. Hyperinflated lungs, decreased gas exchange, and increased work of breathing are present. Otitis media is a frequent complication often with concomitant Streptococcus pneumoniae infection.

RSV is the only respiratory pathogen that produces its most serious illness at a time when specific maternal antibody is generally present. Most mothers report a recent infection. This—combined with the observation that infants who received a particular past live RSV vaccine had more severe disease—suggests an immune-mediated component to the disease. The complexity of the relationship between immunity and RSV is shown by the fact that among adults, low levels of RSV-specific nasal IgA are a risk factor for infection, and among infants, antibody levels appear to be lower during episodes of RSV reinfection. RSV infections are not thought to be a strong predictor for the later development of asthma.

Rapid diagnosis may be made by viral antigen identification of nasal washings using an ELISA or immunofluorescent assay. Culture of nasopharyngeal secretions remains the standard of diagnosis, although the usefulness of PCR methods for diagnosis is increasingly appreciated. Human metapneumovirus is diagnosed only using PCR.

Treatment of RSV consists of hydration, humidification of inspired air, and ventilatory support as needed. Although bronchodilating agents and ribavirin are widely used, evidence supporting their effectiveness in populations not at high risk is lacking. The effectiveness of corticosteroid therapy is also controversial. Pregnant women should avoid ribavirin exposure—and indeed, patients with upper RSV infections probably do not need ribavirin. Hyperimmune RSV immunoglobulin G (1500 mg/kg) is no longer available in the United States. RSV immune globulin is now replaced with palivizumab, a monoclonal RSV antibody, given safely at 15 mg/kg. The FDA recommends

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the administration of palivizumab prophylactically (parenterally at 15 mg/kg monthly during the season of high transmission) to infants with high-risk factors, such as congenital heart disease. Infants with acute RSV bronchiolitis may not always show severe prognostic criteria for RSV respiratory tract disease.

The search for an effective RSV vaccine, originally disheartened by early formalin-inactivated vaccine candidates which enhanced RSV disease, is encouraged now by studies showing that a live-attenuated vaccine is well tolerated and shows protection in challenge studies. Because nosocomial RSV infections disseminate rapidly, prevention in hospitals entails rapid diagnosis, handwashing, contact isolation, and perhaps passive immunization. Therapeutic modalities for human metapneumovirus and parainfluenzavirus infections are under investigation, including trials of ribavirin.

Bader MS et al: Viral infections in the elderly. The challenges of managing herpes zoster, influenza, and RSV. Postgrad Med 2005;118:45,51.

Bentur L et al: Dexamethasone inhalations in RSV bronchiolitis: a double-blind, placebo-controlled study. Acta Paediatr 2005;94:1866.

Ebbert JO et al: Respiratory syncytial virus pneumonitis in immunocompromised adults: clinical features and outcome. Respiration 2005;72:263.

Englund J: In search of a vaccine for respiratory syncytial virus: the saga continues. J Infect Dis 2005;191:1036.

Prais D et al: Impact of palivizumab on admission to the ICU for respiratory syncytial virus bronchiolitis: a national survey. Chest 2005;128:2765.

Williams JV et al: Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350:443.

2. Influenza

Essentials of Diagnosis

  • 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. In contrast to RSV and rhinoviruses, transmission occurs by droplet nuclei rather than fomites or large particle aerosols. Epidemics and pandemics appear at varying intervals, usually in the fall or winter (although sporadic cases occur as do summer outbreaks in northern areas such as Alaska) affecting 10–20% of the global population on average each year. Antigenic types A and B produce clinically indistinguishable infections, whereas type C is usually a minor illness. Annual influenza epidemics are the result of frequent and significant antigenic variation of the virus, or antigenic drift, which is more common in influenza A virus. Pandemics—associated with higher mortality—typically are associated with type A infections in which significant genetic recombination of the virus (antigenic shift) has taken place. The incubation period is 1–4 days.

Avian influenza is discussed in the next section.

Clinical Findings

A. Symptoms and Signs

Typical 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.

B. Laboratory Findings

Leukopenia is common. Proteinuria may be present. The virus may be isolated from throat washings by inoculation of embryonated eggs or cell cultures. Rapid laboratory tests for influenza antigens from nasal or throat swabs are becoming widely available. Complement-fixing and hemagglutination-inhibiting antibodies appear during the second week.

Complications

Influenza causes necrosis of the respiratory epithelium, which predisposes to secondary bacterial infections. Bacterial enzymes in turn (eg, proteases, trypsin-like compounds, streptokinase, and plasminogen) activate influenza viruses. Frequent complications are acute sinusitis, otitis media, purulent bronchitis, and pneumonia. The elderly and the chronically ill, including HIV-infected individuals, are at high risk for complications. Rhabdomyolysis is a rare late complication.

Pneumonia is commonly due to bacterial infection with pneumococci or, less often, staphylococci or Haemophilus. Primary viral pneumonia (caused by the influenza virus itself) may occur, particularly in patients with cardiovascular disease and pregnant women and has a high mortality. Pericarditis, myocarditis, toxic shock syndrome, and thrombophlebitis sometimes occur.

Reye's 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

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hepatic failure and encephalopathy, and there is a 30% fatality rate. The pathogenesis is unknown, but the syndrome is associated with aspirin use in a variety 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.

Prevention

Trivalent influenza virus vaccine provides partial immunity (about 85% efficacy) for a few months to 1 year. The vaccine's antigenic configuration changes yearly and is based on prevalent strains of the preceding year. Vaccination in October or November each year is recommended for persons over 50 years of age (a substantial portion of the older population suffers from at least one chronic medical condition), children (over 6 months of age) and teenagers receiving long-term aspirin therapy, nursing home residents, patients with chronic lung or heart disease or other debilitating illnesses (including pregnant women during the second and third trimesters), health care workers, service personnel, and contacts of < 2-year-old children. The breadth of these recommendations includes much of the adult population.

The vaccine is contraindicated in persons with well-substantiated hypersensitivity to chicken eggs (based on dietary history) or other components of the vaccine (skin testing can be performed by an allergist), persons with Guillain-Barré syndrome, an acute febrile illness, or thrombocytopenia. Concomitant warfarin or corticosteroid therapy is not a contraindication. Side effects are infrequent and include tenderness, redness, or induration at the site of the injection and, rarely, myalgias, fever, or the oculorespiratory syndrome (conjunctivitis, facial edema, and respiratory symptoms within 2–48 hours of vaccination).

Adequate immunity is achieved about 2 weeks after vaccination. In healthy subjects, the antibody level remains sufficiently high throughout the season. Levels wane quickly, however, in elderly nursing home patients. Therefore, the time of administration of the vaccine should be based on surveillance data. The vaccination effectively reduces both morbidity (preventing 35–60% of hospital admissions in the elderly) and mortality (preventing 35–80% of hospital deaths). A new live-attenuated, nasally administered, vaccine is now licensed for use in the United States, while a nasally administered inactivated vaccine is under development.

HIV-infected persons can be safely vaccinated, and concerns about activating replication of the HIV virus by the immunogen appear to be exaggerated and may be less severe than the increase in HIV viral load associated with a full influenza infection. Vaccination is less effective when CD4 counts are less than 100/mcL. False-positive assays for HIV, HTLV-1, and HCV antibodies have been reported in the wake of influenza vaccination.

Chemoprophylaxis can be accomplished with either amantadine or rimantadine or the newer neuraminidase inhibitors, zanamivir and oseltamivir. Amantadine (200 mg/d orally in two divided doses—or 100 mg/d in the elderly, who are susceptible to CNS side effects) and rimantadine (200 mg/d in two divided doses) are ineffective against influenza B and many avian strains. Oseltamivir (75 mg/d) and zanamivir (10 mg inhaled daily) are effective against influenza A and B. All the above medications will reduce the attack rate among unvaccinated individuals if begun within 48 hours after exposure, although a nursing home outbreak in 2004 documented the presence of amantadine resistance in 12 of 16 residents assayed.

Treatment

Many patients with influenza prefer to rest in bed. Analgesics and a cough mixture may be used. Amantadine or rimantadine, in the same doses as are used for prophylaxis, appreciably decrease the duration of symptoms and signs. Rimantadine is preferred in patients with renal failure. Resistance to amantadine and rimantadine develops in > 50% of children, typically after 3–5 days of exposure, and this resistance is reported in a majority of the influenza isolates from the 2005–2006 season. The clinical significance of resistance to antiviral agents is controversial. Ribavirin (1.1 g/d, diluted to 20 mg/mL and delivered as particulate aerosol with oxygen over 12–18 hours a day for 3–7 days [see Table 32-1]) helps severely ill patients with influenza A or B. The new neuraminidase inhibitors, either inhaled zanamivir (two 5-mg inhalations twice daily for 5 days) or oral oseltamivir (75 mg twice daily for 5 days), are equally helpful in the treatment of influenza but are more costly. Clinical trials have shown a reduction in the duration of symptoms, but not in the rate of hospitalizations or mortality when using these agents. All agents are most effective when given within 48 hours after symptom onset and are shown to be effective mainly in high-risk patients over age 12 years.

Antibacterial antibiotics should be reserved for treatment of bacterial complications. Acetaminophen 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. Influenza pneumonia has a high mortality rate among pregnant women and persons with a history of rheumatic heart disease. In recent epidemics, the mortality rate has been low except in debilitated individuals.

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If the fever 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 such infection, and staphylococcal pneumonia is the most serious.

Armstrong BG et al: Effect of influenza vaccination on excess deaths occurring during periods of high circulation of influenza: cohort study in elderly people. BMJ 2004;329:660.

Fagan HB et al: What is the best agent for influenza infection? Am Fam Physician 2004;70:1331.

Schilling M et al: Emergence and transmission of amantadine-resistant influenza A in a nursing home. J Am Geriatr Soc 2004;52:2069.

Schmidt AC: Antiviral therapy for influenza: a clinical and economic comparative review. Drugs 2004;64:2031.

Thompson WW et al: Influenza-associated hospitalizations in the United States. JAMA 2004;292:1333.

3. Avian Influenza

Essentials of Diagnosis

  • Rare cases to date in humans, mostly from Southeast Asia.

  • 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 birds and occasionally pigs. Recently, a highly pathogenic influenza A subtype (H5N1) was found in poultry in East and Southeast Asian countries. In 1997, an outbreak of H5N1 influenza occurred in poultry in Hong Kong, resulting in the first recognized human cases. A massive slaughter of poultry was attempted to contain the disease. New outbreaks of H5N1 influenza in poultry emerged, however, in 2003 and continue to spread to different nations. At least 20 countries reported poultry outbreaks as of early 2006, largely in Asia but also recently in Nigeria, Greece, Turkey, and Italy. There are, as of July 26, 2006, 232 confirmed human cases with 134 deaths (from Azerbaijan, Cambodia, China, Djibouti, Egypt, Iraq, Indonesia, Thailand, Turkey, and Vietnam).

Although the H5N1 strain of avian influenza is highly contagious from one bird to another, the transmission from human to human is relatively inefficient and not sustained. The result is only rare cases of person-to-person infection. 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 greater than 50% (most patients die of respiratory failure), there exists considerable concern that H5N1 strains might widely disseminate and initiate a pandemic. 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 earlier collection of samples. More sensitive tests such as reverse-transcription PCR are of limited availability. Throat or lower respiratory swabs may provide higher yield of detection than nasal swabs for H5N1 strains. Epidemiologic risk factors (travel to Southeast Asia, contact with known cases) should guide testing strategies.

Most Asian H5N1 influenza strains are resistant to amantadine and rimantadine, but this is not an inherent property of all H5N1 strains. Sensitivity to rimantadine and amantadine can also be possibly reacquired through genetic reassortment. The current recommendations for the neuraminidase inhibitors oseltamivir and zanamivir include administration within 48 hours from onset of illness. These medications should still be considered for patients with severe avian influenza disease even after several days of onset. Recent evidence of resistance to oseltamivir is reported.

The worldwide concern that the avian H5N1 subtype of influenza may transform by genetic reassortment and mutation, developing greater human-human transmissibility, is the basis for fear of a global avian influenza pandemic. The risk of these events appears more realistic as avian influenza continues to spread among birds, with many parts of Southeast Asia now considered endemic for the virus. Careful surveillance of new human cases and continued development of a commercially available vaccine are important aspects of influenza control. Only partial protection can be achieved using conventional tricomponent inactivated influenza vaccines because of major differences in the major components, particularly the hemagglutinin.

Prevention of exposure to avian influenza strains also includes hygienic practices during handling of poultry products, including handwashing and prevention of cross-contamination, as well as thorough cooking of poultry products (to 70°C). Nonetheless, the risk of acquiring avian influenza through the consumption of poultry products is very small.

Beigel JH et al; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza (H5N1) in humans. N Engl J Med 2005;353:1374.

CDC Key Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus. http://www.cdc.gov/flu/avian/gen-info/facts.htm

Ungchusak K et al: Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med 2005;352:333.

World Health Organization: Avian influenza frequently asked questions. http://www.who.int/csr/disease/avian_influenza/avian_faqs/en/print.html

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Yuen KY et al: Human infection by avian influenza A H5N1. Hong Kong J 2005;11:189.

4. Severe Acute Respiratory Syndrome (SARS)

Essentials of Diagnosis

  • 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 of varying severity but capable of causing death in as many as 10% of clinically established cases. It is caused by an apparently unique coronavirus. The earliest cases were traced to a health care worker in Guangdong Province in China in late 2002, with rapid spread thereafter to Hong Kong, Singapore, Vietnam, Taiwan, and Toronto. The primary mode of transmission appears to be through direct or indirect contact of mucous membranes (eyes, nose, or mouth) with infectious respiratory droplets or fomites. The use of aerosol-generating procedures (endotracheal intubation, bronchoscopy, nebulization treatments) in hospitals may amplify the transmission of the SARS coronavirus. 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).

The variable distribution of cases throughout Asia and Canada is considered a consequence of spread through travel. The virus is sufficiently virulent that it may be transmitted and acquired by patients during brief stops in airports. As a result, sporadic confirmed and suspected cases have appeared throughout the United States. As of September 2003, about 8098 cases were reported to the World Health Organization from about 30 countries, with 774 fatalities to that date.

Clinical Findings

A. Symptoms and Signs

SARS is considered an atypical pneumonia that affects persons in all age groups. The CDC recognizes asymptomatic or mild cases, moderate disease, and severe respiratory illness. 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 and/or rigor, cough, shortness of breath, rales, and rhonchi are the rule. Many patients report headache, myalgias, and sore throat as well. A watery diarrhea occurs in some patients late in the course of the illness. Elderly patients may report malaise and delirium, without the typical febrile response. No single symptom or sign is diagnostic or highly suggestive, and the history and physical examination of a patient in whom SARS in suspected are to be interpreted in this context.

B. Laboratory Findings and Imaging

Leukopenia and especially lymphopenia are observed commonly. A low-grade disseminated intravascular coagulation (thrombocytopenia, prolonged activated thromboplastin time, and elevated D-dimer level) is present in many patients. Other abnormalities include modest elevations of alanine aminotransferase and creatine kinase. Arterial oxygen saturation is less than 95% in 80% of affected individuals, and pulmonary infiltrates are noted in all. The roentgenographic pattern is not specific, and severe cases may progress to ARDS, with extensive bilateral consolidation. A high-resolution CT scan is abnormal (ground-glass opacifications or focal consolidation) 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 reverse transcriptase-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

To date, the principal complications are confined to the lung. As with any viral pneumonia, pulmonary decompensation is the most feared problem. About 20–30% of patients experience refractory hypoxemia requiring intubation and mechanical ventilation. Sequelae of intensive care include infection with nosocomial pathogens, tension pneumothorax from ventilation at high peak pressures, and noncardiogenic pulmonary edema.

Treatment

The benefit of ribavirin in the treatment of SARS is controversial. There is only one randomized study in which the drug was used at a low dose (400–600 mg/d) and was shown to be ineffective. Other nonrandomized studies used higher doses (4 g/d) and showed

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some benefit but a very high rate of side effects, mainly hemolysis. The limited data suggest that doses of 2 g/d may be effective and not produce adverse reactions. The use of high-dose pulse methylprednisolone during the clinical progression phase (with development of radiologic evidence of pneumonia and hypoxemia) is associated with a more favorable clinical improvement. The role of corticosteroids, alone or in combination with ribavirin, is also controversial. The synthetic form of interferon, alfacon-1, in combination with corticosteroids may be beneficial in reducing disease-associated hypoxemia and in promoting a more rapid resolution of radiographic abnormalities. Reports from one center in Hong Kong suggest that the addition of lopinavir/ritonavir as initial therapy is associated with an overall lower mortality. Recovery in severe cases requires intensive support.

Prognosis

The overall mortality rate of identified cases is about 14%. Mortality is age-related, ranging from less than 1% in persons under 24 years of age to greater than 50% in persons over 65 years of age. Poor prognostic factors include advanced age, chronic hepatitis B infection treated with lamivudine, high initial or high peak lactate dehydrogenase concentration, high neutrophil count on presentation, diabetes mellitus, and low counts of CD4 and CD8 on presentation. Many subclinical cases probably go undiagnosed. Seasonality, as with influenza, is not established. Although the overall case incidence diminishes in areas in which appropriate preventive measures are taken, sporadic outbreaks, including one near Toronto, were reported through summer 2003.

Prevention

Because the known modalities of transmission for the SARS agent include intubation, suctioning, and nebulization, health care workers engaged in procedures that involve these activities are at high risk for acquiring the virus. Transmission may occur shortly after the development of symptoms and perhaps before the appearance of fever, cough, and dyspnea. Thus, an increased level of suspicion is critical, and isolation of high-risk patients is essential. For health care workers exposed to presumptive cases of SARS, simple hygienic measures such as handwashing after touching patients, use of appropriate and well-fitted face masks, and early introduction of infection control measures, including quarantine, may help reduce transmission.

Measures enacted for air travelers have included screening for fever and compatible symptoms and quarantining in the home for high-risk exposed persons. 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. Use of face masks, adopted by many in endemic areas, is not harmful but its efficacy is not substantiated.

Chau T et al: Value of initial chest radiographs for predicting clinical outcomes in patients with severe acute respiratory syndrome. Am J Med 2004;117:249.

Cheng VC et al: Medical treatment of viral pneumonia including SARS in immunocompetent adults. J Infect 2004;29:262.

Jiang S et al: SARS vaccine development. Emerg Infect Dis 2005;11:1016.

Leung GM et al: The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann Intern Med 2004;141:662.

Li W et al: Bats are natural reservoirs of SARS-like coronaviruses. Science 2005;310:676.

Perlman S et al: Immunopathogenesis of coronavirus infections: implications for SARS. Nat Rev Immunol 2005;5:917.

Adenovirus Infections

Adenoviruses (there are over at least 51 serotypes) produce a variety of clinical syndromes. These infections are usually self-limited or clinically inapparent and most common among infants, young children, and military recruits. Adenoviruses, however, may cause significant morbidity and mortality in immunocompromised persons, such as HIV-infected persons and liver, renal, and stem cell transplant patients (risk factors for severe infection include immunosuppressive therapy, graft-versus-host disease and lymphocytopenia). The incubation period is 4–9 days. Adenoviruses, although a common cause of human disease, also receive particular recognition through their role in gene therapy.

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. 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 (type 3 and type 7 commonly cause acute respiratory disease and pneumonia). Pharyngoconjunctival fever is manifested by fever and malaise, conjunctivitis (often unilateral), and mild pharyngitis. Epidemic keratoconjunctivitis (transmissible person to person) occurs in adults and is manifested by unilateral 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. 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), leading to intussusception, and are rarely associated with encephalitis, acute flaccid paralysis,

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and pericarditis. In a recent review of viruses causing dilated cardiomyopathy, adenoviruses were the most common isolates, found in 12% of samples. Severity of systemic adenoviral disease correlates with the concentration of lactate dehydrogenase and with oxygen saturation on admission.

Hepatitis (type 5 adenovirus) tends to develop in infected liver transplant recipients, whereas pneumonia or hemorrhagic cystitis (types 11 and 34) tend to develop in bone marrow and renal transplant recipients.

A rapid diagnostic direct fluorescence assay may assist with directing appropriate therapy and a rapid-cycle PCR is currently available.

Treatment is symptomatic. Ribavirin and cidofovir are used in immunocompromised individuals with occasional success, although the use of cidofovir, especially in the immunocompromised, is attendant with significant renal toxicity. Immunosuppression should be reduced if possible. Adoptive immunotherapy with transfusion of adenovirus-specific T cells is currently being investigated.

Vaccines are not available for general use. Live oral vaccines containing attenuated type 4 and type 7 are used in military personnel.

Bowles NE et al: Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003;42:466.

Faix DJ et al: Evaluation of a rapid quantitative diagnostic test for adenovirus type 4. Clin Infect Dis 2004;38:391.

Guarner J et al: Intestinal intussusception associated with adenovirus infection in Mexican children. Am J Clin Pathol 2003;120:845.

Leen AM et al: Adenovirus as an emerging pathogen in immunocompromised patients. Br J Haematol 2005;128:135.

Peled N et al: Adenovirus infection in hospitalized immunocompetent children. Clin Pediatr 2004;43:223.

Other Exanthematous Viral Infections

1. Parvovirus Infections

Parvovirus B19 is quite widespread (by age 15 years about 50% of children have detectable IgG) and causes several syndromes. 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, but little fever. In immunosuppressed patients, including those with HIV infection, or posttransplantation, or with hematologic conditions such as sickle cell disease, transient aplastic crisis and pure red blood cell aplasia may occur. The pathophysiologic mechanism of red cell invasion is thought to be binding of the virus to the erythrocyte P antigen (globoside). Middle-aged persons (especially women) develop a limited symmetric polyarthritis that mimics lupus erythematosus and rheumatoid arthritis, preferentially involving the proximal interphalangeal joints of the hands and the wrists and knees. Arthralgias are uncommon in children. Rashes, especially facial, are uncommon in adults. In pregnancy, fetal loss and hydrops fetalis are reported sequelae. An association with Henoch-Schönlein purpura has also been noted. Rare reported presentations include myocarditis with infarction, constrictive pericarditis, a lupus-like syndrome, CNS vasculitis, and a chronic fatigue syndrome. Less accepted associations with parvovirus infection include hepatitis, myositis, rheumatoid arthritis (the arthralgias of parvovirus infection tend to be transient) and systemic lupus erythematosus. Subclinical infection is documented among patients with sickle cell disease.

The diagnosis is clinical (Table 32-2) but may be confirmed by an elevated titer of IgM anti-parvovirus antibodies in serum or with PCR. Scarlet fever is the most similar disorder. Arthritis with hypocomplementemia is a common complication in some outbreaks. Uncommon complications of infection include encephalitis, chronic hemolytic anemia, thrombotic thrombocytopenic purpuric syndrome, acute postinfectious glomerulonephritis, and hepatitis.

Treatment in healthy persons is symptomatic. Nonsteroidal anti-inflammatory drugs can be used to treat arthralgias and transfusions to treat transient aplastic crises. In immunosuppressed patients, intravenous immunoglobulin aids in the reduction of anemia.

Screening of donated blood could potentially prevent transfusion-related infection. Several nosocomial outbreaks have been documented, and hospital infection control personnel should administer standard containment guidelines, including handwashing after patient exposure and avoiding contact with pregnant women.

The prognosis is generally excellent in immunocompetent individuals. In immunosuppressed patients, persistent anemia may require prolonged transfusion dependence. Remission of parvovirus infection in AIDS patients may occur with HAART, though the immune restoration syndrome is also reported with parvovirus.

Gilberte NL et al: Seroprevalence of parvovirus B19 infection in daycare educators. Epidemiol Infect 2005;133:299.

Mishra B et al: Human parvovirus B19 in patients with aplastic anemia. Am J Hematol 2005;79:166.

Young NS et al: Parvovirus B19. N Engl J Med 2004;350:586.

2. Poxvirus Infections

Among the nine poxviruses causing disease in humans, the following are clinically important.

1. Variola/vaccinia: Smallpox was a highly contagious disease characterized by severe headache, fever, and prostration and accompanied by a centrifugal rash

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developing uniformly in order of progression from macules to papules to vesicles to pustules over 1–2 weeks. An international consensus among the scientific community in the 1990s resulted in a recommendation to destroy the virus since elimination of the disease was achieved. As long as this recommendation is not implemented, risk remains for unauthorized access to the remaining samples and potential misuse for military or terrorist purposes, resulting in exposure of large unvaccinated civilian populations.

In the wake of the recent international terrorism incidents, concern exists about the potential use of smallpox and other agents as biologic weapons.

Vaccination with vaccinia was historically crucial for smallpox eradication. Any form of immunosuppression is an absolute contraindication to smallpox vaccination. Eczema (or a history of it) in a patient or family member, other forms of dermatitis, and burns also contraindicate vaccination. Dilution of existing stores of vaccinia by fivefold to tenfold does not significantly reduce its effectiveness in stimulating an immune response and, of course, greatly increases availability. The current Department of Defense Smallpox Vaccination Program began on December 2002. Through April 2004, 615,000 persons were vaccinated. Potential side effects such as dermatologic, neurologic, and cardiac complications raise concerns among clinicians. Reported cardiac complications include myocarditis, cardiac arrhythmias, and pericarditis. A total of 67 cases of myopericarditis were reported between December 2002 and December 2003. Most of these cases presented with the prodromal symptoms of fever, myalgias, arthralgias, headache, and fatigue. The clinical, electrocardiographic, and biochemical presentation of smallpox vaccine-induced myopericarditis may mimic myocardial infarction.

Most physicians in practice today have not seen a case of clinical smallpox. The disseminated lesions of smallpox in the past were often confused with those of varicella, though the synchronous progression in smallpox readily distinguishes these lesions from those of varicella, wherein lesions of several stages are usually present simultaneously. (See also Chapter 6.)

A recent outbreak of a vaccinia virus (the Passatempo virus) was reported from Brazil. Exanthematous lesions were reported among both the dairy cattle and the cow milkers.

2. 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. Marked and persistent lesions in AIDS patients appear to respond readily to combination antiretroviral therapy. The many anecdotal agents reported to hasten resolution include cimetidine and CO2 laser therapy combined with natural interferon-β gel. Imiquimod cream (5%) appears to be effective in curing molluscum lesions.

3. Orf (contagious pustular dermatitis, or ecthyma contagiosa) and paravaccinia (milker's nodules) are occupational diseases acquired by contact with sheep and cattle, respectively.

4. Monkeypox, first identified in 1970, 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-to-person spread occurs. African mortality rates vary from 3% to 11% depending on the immune status of the patient. Secondary attack rates, which are hard to determine because of diagnostic confusion with varicella in older series, 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. Clinical findings included a prodrome of fever and chills, headaches, myalgias, and sweats. About one-third of patients reported a nonproductive cough. After 1–10 days, a papular rash appeared that progressed through stages of vesiculation, pustulation, umbilication, and crusting—and in some cases ulceration. The rash started on the head, trunk, and extremities, with occasional satellite lesions on the palms, soles, and extremities, and in some cases became generalized.

Susceptible animals include nonhuman primates, rabbits, and rodents. Contact with these species is the primary means of transmission to humans. 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 who are ill and those exposed within 3 prior weeks to such animals, and veterinary examination and investigation of suspect animals through health departments.

Primary prevention entails the use of vaccinia immunization, a procedure accompanied by a risk of dissemination in HIV-infected persons—a real concern considering the coincident areas of endemicity of HIV-1 and monkeypox.

The CDC recommends smallpox vaccination to individuals if their exposure to infected animals is sufficient and if the candidate vaccinee has no contraindications (outlined above). Cidofovir is under current study as an agent for treatment. Submission of specimens and case reporting can be conducted using the Association of Public Health Laboratories' Web site listed below.

Association of Public Health Laboratories: http://www.aphl.org/

CDC Bioterrorism Public Health Emergency Preparedness and Response—Smallpox: Laboratory Testing: http://www.bt.cdc.gov/agent/smallpox/lab-testing.

Leite A et al: Passatempo virus, a vaccinia virus strain, Brazil. Emerg Infect Dis 2005;11:1935.

Ligon BL: Monkeypox: a review of the history and emergence in the Western hemisphere. Semin Pediatr Infect Dis 2004;15:280.

Seward JF et al: Development and experience with an algorithm to evaluate suspected smallpox cases in the United States, 2002–2004. Clin Infect Dis 2004;39:1477.

Weiss MM et al: Rethinking smallpox. Clin Infect Dis 2004;39:1668.

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Viruses & Gastroenteritis

Viruses are responsible for at least 30–40% of cases of infectious diarrhea in the United States, and rotaviruses are a leading worldwide cause of dehydrating gastroenteritis in young children. The agents that can cause disease include groups A, B and C rotaviruses, caliciviruses such as Norwalk and Norwalk-like viruses (which cause epidemics of vomiting and diarrhea in contained environments), and other caliciviruses, astroviruses, enteric adenoviruses and, less often, toroviruses, coronaviruses, picobirnaviruses, and pestiviruses.

Rotaviruses (G1-G4 and G9 are the most common serotypes) are a major cause of diarrheal morbidity worldwide (nearly 600,000 die yearly, mainly due to dehydration), can also cause infections in adults exposed to infected infants, and are ubiquitous in the environment of an outbreak. (Secondary rates are between 16% and 30%.) Most rotavirus infections occur in children aged 6 months-2 years, and the incidence peaks during the winter. The disease is usually mild, and cases also occur among travelers, in epidemic fashion, and after waterborne exposure. The method of choice for diagnosis is PCR of the stool. Treatment is symptomatic, with fluid and electrolyte replacement. Local intestinal immunity gives protection against successive infection. Vaccine administration was discontinued because of a probable association with intussusception. New vaccines are under development (one was licensed recently in Mexico). Future administration of these vaccines may concentrate on the ages when the risk of intussusception is least likely (avoiding ages 3–9 months).

The Norwalk virus was first identified using electron microscopy on infectious stool infiltrate derived from an outbreak of gastroenteritis at a school in Norwalk, Ohio. This virus and the related Norwalk-like viruses are responsible for over 40% of cases of group-related and institutional outbreaks of diarrhea. There have been several recent reports of gastroenteritis outbreaks induced by Norwalk-like viruses on cruise ships.

Norwalk virus is also often responsible for military outbreaks. Although transmission is usually fecal-oral, airborne and waterborne (recently among snowmobilers in Wyoming) transmission is also documented. Infections appear to be more common during cold weather intervals. Reverse transcriptase-PCR of stool samples is used for epidemiologic purposes. Treatment is largely symptomatic. The presence of antibodies is not associated with protection against reinfection.

Bresee JS et al: Rotavirus in Asia: the value of surveillance for informing decisions about the introduction of new vaccines. J Infect Dis 2005;192(Suppl 1):S1.

Hutson AM et al: Norovirus disease: changing epidemiology and host susceptibility factors. Trends Microbiol 2004;12:279.

Kapikian AZ et al: A hexavalent human rotavirus-bovine rotavirus (UK) reassortant vaccine designed for use in developing countries and delivered in a schedule with the potential to eliminate the risk of intussusception. J Infect Dis 2005;192(Suppl 1):S22.

Ruiz-Palacios GM et al; Human Rotavirus Vaccine Study Group: Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006;354:11.

Walter JE et al: Astrovirus infection in children. Curr Opin Infect Dis 2003;16:247.

Ward RL: Rotavirus vaccines: is the second time the charm? Curr Opin Investig Drugs 2005;6:798.

Enteroviruses that Produce Several Syndromes

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.

Clinical Findings

A. Symptoms and Signs

The clinical syndromes associated with coxsackievirus infection may be described briefly as follows.

1. Summer grippe (A and B)

A febrile illness, principally of children, lasting 1–4 days. Minor symptoms and respiratory tract infection are often present.

2. Herpangina (A2–6, 10)

Sudden onset of fever, which may be as high as 40.6°C, sometimes with febrile convulsions; headache, myalgia, and vomiting; and sore throat, characterized early by petechiae or papules on the soft palate that become shallow ulcers in about 3 days and then heal. Treatment is symptomatic.

3. Epidemic pleurodynia (Bornholm disease) (B1–5)

Pleuritic pain is prominent, and 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 less than 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 meningitis are reported. Focal encephalitis, transverse myelitis, and acute flaccid paralysis are reported with coxsackievirus group A, and a disseminated encephalitis after group B infection.

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 paradoxic pulse. Electrocardiographic evidence of pericarditis is often present. Relapses may occur.

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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 possibly associated with group B infections. Upregulation of mast cells through inducing the innate immune system (Toll-like receptors) may be the means by which coxsackieviruses induce myocarditis.

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.

8. Hepatitis (B1)

Fulminant neonatal hepatitis with thrombocytopenia and coagulopathy occurs rarely.

9. Type 1 diabetes mellitus (B types)

An association purportedly exists between coxsackievirus B infections and subsequent development of type 1 diabetes mellitus, but results of different studies fail to definitively prove a causal association.

10. Glomerulopathy and tubular injury

Renal damage has been reported with several group B infections.

11. Sjögren's syndrome

Coxsackieviruses are theorized to initiate an autoimmune process in exocrine gland epithelial cells that results in Sjögren's syndrome

12. Epidemic conjunctivitis

As with enterovirus 70 (see below), the A24 variant of coxsackievirus is associated with acute epidemic hemorrhagic conjunctivitis.

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.

Treatment & Prognosis

Treatment is symptomatic. With the exception of myocarditis, pericarditis, perhaps diabetes, and rare illnesses such as pancreatitis or polio-like syndrome, the syndromes caused by coxsackieviruses are benign and self-limited. There are anecdotal reports of success with pleconaril as well as with intravenous immunoglobulin in severe disease.

Fairweather D et al: Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus-induced myocarditis. Rev Med Virol 2005;15:17.

Traintafyllopoulou A et al: Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome. Ann N Y Acad Sci 2005;1050:389.

2. Echovirus Infections

Echoviruses are enteroviruses that produce several clinical syndromes, particularly in children. Infection is most common during summer.

Over 30 serotypes have been demonstrated. Most cause aseptic meningitis, which may be associated with a rubelliform rash. Type 30 outbreaks have been reported from Canada (Saskatchewan), France, Germany, Italy, Japan, and Turkey. An increased number of type 13 cases, including five epidemics, occurred in the United States and cases are increasingly reported globally. Transmission is primarily fecal-oral. Handwashing 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.

Diseases associated with echoviruses range from common respiratory diseases and epidemic diarrhea (including type 22) 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, sudden deafness, encephalitis, optic neuritis, uveitis, and septic shock.

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. PCR of the cerebrospinal fluid may be diagnostic. 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. Trials are underway with pleconaril.

From a public health standpoint, the prevention of fecal-oral contamination and the maintenance of pool hygiene through chlorination and pH control are important.

Abzug MJ: Presentation, diagnosis, and management of enterovirus infections in neonates. Paediatr Drugs 2004;6:1.

Bernit E et al: Prospective investigation of a large outbreak of meningitis due to echovirus 30 during summer 2000 in Marseilles, France. Medicine (Baltimore) 2004;83:245.

Hauri AM et al: An outbreak of viral meningitis associated with a public swimming pond. Epidemiol Infect 2005;133:291.

Mullins JA et al: Emergence of echovirus type 13 as a prominent enterovirus. Clin Infect Dis 2004;38:70.

3. Enteroviruses 70 & 71

Several clinical syndromes are being described in association with newer enteroviruses. The most common of these are enterovirus 70, associated with acute hemorrhagic conjunctivitis, a ubiquitous agent first identified in 1969 and responsible for abrupt bilateral eye discharge and occasional systemic symptoms, but in most cases subconjunctival hemorrhage, and enterovirus 71, associated with hand, foot, and mouth disease as well as a form of epidemic encephalitis (genogroups B and C in the Western Pacific region) associated on occasion with pulmonary edema, and acute flaccid paralysis. Hand, foot, and mouth disease tends to infect the very young (under age 5) in nonendemic areas because of lower herd immunity. Sequelae include central hypoventilation, dysphagia,

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and limb weakness, all of which are minimized by stage-based treatment, dividing the illness into four classical stages (HFMD/herpangina, CNS disease, cardiopulmonary failure, and convalescence). Diagnosis of both entities is facilitated by the clinical and epidemiologic findings with the isolation of the suspect agent from either conjunctival scraping for enterovirus 70 or vesicle swabs, body secretions, or cerebrospinal fluid for enterovirus 71. An IgM capture ELISA is being developed for the latter agent.

Treatment of both entities remains largely symptomatic, though there are increasing reports of the successful use of pleconaril, an agent available in some countries but not the United States. The major complication associated with enterovirus 70 is the development in a small percentage of cases of an acute neurologic illness with motor paralysis akin to poliomyelitis. Household contacts, especially children under 6 months of age, are at particular risk for enterovirus 71 acquisition.

Enterovirus 72 is another term for hepatitis A virus (see Chapter 15).

Chang LY et al: Transmission and clinical features of enterovirus 71 infections in household contacts in Taiwan. JAMA 2004;291:222.

Kao SJ et al: Mechanism of fulminant pulmonary edema caused by enterovirus 71. Clin Infect Dis 2004;38:1784.

Palacios G et al: Enteroviruses as agents of emerging infectious diseases. J Neurovirol 2005;11:424.

Wang SY et al: Early and rapid detection of enterovirus 71 infection by an IgM-capture ELISA. J Virol Methods 2004;119:37.

Rickettsial Diseases

The rickettsioses are febrile exanthematous diseases caused by rickettsiae, small gram-negative obligate intracellular bacteria. In arthropods, rickettsiae grow in the gut lining, often without harming the host. Human infection results from either an arthropod bite or contamination with its feces. In humans, rickettsiae grow principally in endothelial cells of small blood vessels, producing vasculitis, cell necrosis, thrombosis of vessels, skin rashes, and organ dysfunctions. Rickettsiae are also capable of growing in human macrophages and hepatocytes.

Different rickettsiae and their vectors are endemic in different parts of the world, but two or more types may coexist in the same geographic area. New organisms are identified regularly. Travel-associated cases occur with selected species. A summary of epidemiologic features is given in Table 32-3. The clinical picture is variable but usually includes a prodromal stage followed by fever, rash, and prostration. Isolation of rickettsiae from the patient is difficult and potentially hazardous to laboratory workers. Diagnosis is usually based on clinical examination and epidemiologic evidence. Laboratory diagnosis relies on the development of specific antibodies detected by complement fixation (for diagnosis), immunofluorescence, or hemagglutination (for species identification) tests. Other newer means of isolation are the centrifugation shell-vial technique and PCR.

Prevention & Treatment

Preventive measures are directed at control of the vector and avoidance of exposure by use of repellents and protective clothing. A search of body surfaces should be conducted after potential exposure and the vector (louse, tick, or mite) gently removed. Many patients do not recall exposure to a vector.

Rickettsiae can be inhibited by tetracyclines or chloramphenicol. All early infections respond to treatment with these drugs. Dosage schedules are listed in the sections below.

Fournier PE et al: Gene sequence-based criteria for identification of new rickettsia isolates and description of Rickettsia heilongjiangensis sp. nov. J Clin Microbiol 2003;41:5456.

Jensenius M et al: Rickettsiosis and the international traveler. Clin Infect Dis 2004;39:1493.

Walker D et al: Pathogenic mechanisms of diseases caused by rickettsiae. Ann NY Acad Sci 2003;990:1. (Whole volume dedicated to rickettsial disease.)

Typhus Group

1. Epidemic Louse-Borne Typhus

Essentials of Diagnosis

  • 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 immunofluorescence.

General Considerations

Epidemic louse-borne typhus is due to infection with Rickettsia prowazekii, a parasite of the body louse. Transmission is favored by crowded, unsanitary living conditions, famine, war, or any circumstances that predispose to heavy infestation with lice. When the louse sucks the blood of a person infected with R prowazekii, the organism becomes established in the

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gut of the louse and grows there. When the louse is transmitted to another person (through contact or clothing) and has a blood meal, it defecates simultaneously, and the infected feces are rubbed into the itching bite wound. Dry, infectious louse feces may also enter the respiratory tract.

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, Central Africa Louse Humans, flying squirrels Rare
   Endemic (murine) typhus Rickettsia typhi Worldwide; small foci (United States: southeastern Gulf Coast) Flea Rodents Often
Scrub typhus group
   Scrub typhus Orientia tsutsugamushi Southeast Asia, Japan, Australia, Western Siberia Mite1 Rodents Often
Spotted fever group
   Rocky Mountain spotted fever Rickettsia rickettsii Western Hemisphere; United States (especially mid-Atlantic coast region) Tick1 Rodents, dogs 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
   African tick bite fever Rickettsia africae Rural sub-Saharan Africa Eastern Caribbean Tick1 Cattle Often
   Rickettsialpox Rickettsia akari United States, Korea, former USSR Mite1 Mice  
Other
   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  
1Also serve as arthropod reservoir by maintaining rickettsiae through transovarian transmission.
2Human infection results from inhalation of dust.

In a person who recovers from clinical or subclinical typhus infection, R prowazekii may survive in lymphoid tissues. Years later, there may be a recrudescence of disease (Brill-Zinsser disease) without exposure to infected lice, which can serve as a point source for future outbreaks.

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Mild and atypical cases of R prowazekii infection have rarely occurred in the United States after contact with flying squirrels or their ectoparasites or decades following exposure (eg, among concentration camp victims of World War II). Cases can be acquired by travel to pockets of infection (eg, central and northeastern Africa, Central and South America). Recent outbreaks were reported from Peru, Burundi, and Russia.

Clinical Findings

A. Symptoms and Signs

(Table 32-3.) 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, hearing loss from neuropathy of the eighth cranial nerve, flushed facies, rales at the lung bases, 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 renal insufficiency, stupor, and delirium. In spontaneous recovery, improvement begins 13–16 days after onset with a rapid drop of fever.

B. Laboratory Findings

The white blood cell count is variable. Thrombocytopenia, elevated liver enzymes, proteinuria and hematuria commonly 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's disease), early antibodies are predominantly IgG.

C. Imaging

Radiographs of the chest may show patchy consolidation.

Differential Diagnosis

The prodromal symptoms and the early febrile stage are not specific enough to permit diagnosis in nonepidemic situations. The rash is usually 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.

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.

Complications

Pneumonia, thromboses, vasculitis with major vessel obstruction and gangrene, circulatory collapse, myocarditis, and uremia may occur.

Prevention

Prevention consists of louse control with insecticides, particularly by applying chemicals to clothing or treating it with heat, and frequent bathing. 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.

Immunization with vaccines consisting of inactivated egg-grown R prowazekii gives some protection to laboratory personnel, physicians, or field workers who are exposed to the parasite. This vaccine is not currently commercially available in the United States or Canada. An improved cell culture vaccine is being developed.

Treatment

Treatment consists of either doxycycline (200 mg/d) or chloramphenicol (50–100 mg/kg/d in four divided doses) for 4–10 days.

Prognosis

The prognosis depends greatly on the patient's age and immunization 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. Effective vaccination can convert a potentially serious disease into a mild one.

Reynolds MG et al: Flying squirrel-associated typhus, United States. Emerg Infect Dis 2003;9:1341.

Woodward T et al: The history of epidemic typhus. Infect Dis Clin N Am 2004;18:127.

2. Endemic Flea-Borne Typhus (Murine Typhus)

Rickettsia typhi, a ubiquitous pathogen, is transmitted from rat to rat through the rat flea. 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. A recent surge in cases was reported from Hawaii.

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

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chills. The rash is maculopapular and concentrated on the trunk and fades fairly rapidly. Peripheral facial paralysis is reported to occur. Fatalities are uncommon but up to 4% may occur, especially in the elderly.

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 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.

Preventive measures are directed at control of rats and ectoparasites (rat fleas) with insecticides, rat poisons, and rat-proofing of buildings. Antibiotic treatment with doxycycline (100 mg twice daily for adults and children weighing > 45 kg, and 2 mg/kg twice daily for children weighing < 45 kg) or chloramphenicol (50–75 mg/kg/d in four divided doses) is indicated through 3 full days of defervescence. Ciprofloxacin (500–750 mg twice a day) may be an acceptable alternative.

Centers for Disease Control and Prevention (CDC): Murine typhus—Hawaii,2002. MMWR Morb Mortal Wkly Rep 2003;52:1224.

Chen MI et al: Epidemiological, clinical and laboratory characteristics of 19 serologically confirmed rickettsial disease in Singapore. Singapore Med J 2001;42:553.

Gikas A et al: Comparison of the effectiveness of five different antibiotic regimens on infection with Rickettsia typhi: therapeutic data from 87 cases. Am J Trop Med Hyg 2004;70:576.

3. Scrub Typhus (Tsutsugamushi Fever)

Essentials of Diagnosis

  • 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.

  • Conjunctivitis 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 transmitted by mites in the endemic areas listed above. The mites live on vegetation but complete their maturation cycle by biting humans who come in contact with infested vegetation. Vertical transmission occurs, and blood transfusions may transmit the pathogen. Serosurveys from Bangkok show prevalences over 20% for blood donors and nearly 60% for febrile malaria clinic patients. 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 bite, a papule evolves into a flat black eschar. The regional lymph nodes are enlarged and tender, and there may be generalized adenopathy. Fever rises gradually, and a macular rash appears primarily on the trunk after a week of fever and may be fleeting or may last a week. The patient may become obtunded. During the second or third week, pneumonitis, myocarditis and cardiac failure, encephalitis or meningitis, acute abdominal pain, granulomatous hepatitis, disseminated intravascular coagulation, or acute renal failure may develop. 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. 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

Blood obtained during the first few days of illness may permit isolation of the rickettsial organism by mouse inoculation. Fluorescein-labeled antirickettsial antibodies and indirect immunoperoxidase assays or commercial dot-blot ELISA dipstick assays are convenient means of establishing the diagnosis, though PCR may be the most sensitive test. A reticulonodular infiltrate is the most common finding on chest radiograph.

Differential Diagnosis

Leptospirosis, typhoid, dengue, malaria, and other rickettsial infections should be considered. Scrub typhus is a recognized cause of obscure tropical fevers, especially in children. When the rash is fleeting and the eschar is not evident, laboratory results are required for diagnosis, including a conventional indirect fluorescent assay or a more sensitive rapid immunochromatographic flow assay that is under development. Upper tract endoscopy may help with gastrointestinal lesions.

Prevention

Repeated application of long-acting miticides can make endemic areas safe. Insect repellents on clothing and skin provide some protection. For short exposure, chemoprophylaxis with doxycycline (200 mg weekly) can prevent the disease but permits infection. No effective vaccines are available.

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Treatment & Prognosis

Without treatment, fever subsides spontaneously after 2 weeks, but the mortality rate may be 10–30%. Treatment for 3 days with doxycycline, 100 mg twice daily, or for 7 days with chloramphenicol, 25 mg/kg/d 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 choice for children, pregnant women, and patients with refractory disease. Rifampin also appears to be effective. HIV infection does not appear to influence the severity of scrub typhus.

Aung-Thu et al: Gastrointestinal manifestations of septic patients with scrub typhus in Maharat Nakhon Ratchasima Hospital. Southeast Asian J Trop Med Public Health 2004;35:845.

Jiang J et al: Development of a quantitative real-time PCR assay specific for Orientia tsutsugamushi. Am J Trop Med Hyg 2004;70:351.

Sharma A et al: Investigation of an outbreak of scrub typhus in the Himalayan region of India. Jpn J Infect Dis 2005;58:208.

Silpapojakul K et al: Paediatric scrub typhus in Thailand: a study of 73 confirmed cases. Trans R Soc Trop Med Hyg 2004;98:354.

Spotted Fevers

1. Rocky Mountain Spotted Fever

Essentials of Diagnosis

  • Exposure to tick bite in an endemic area.

  • An influenza-like prodrome followed by chills, fever, severe headache, myalgias, restlessness, and prostration; 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 (IFA) confirm the diagnosis retrospectively.

General Considerations

Despite its name, most cases occur outside the Rocky Mountain area, with cases in the United States concentrated along the Middle and Southern Atlantic seaboard and in the central Mississippi valley. The causative agent, R rickettsii, is transmitted to humans by the bite of ticks, including the Rocky Mountain wood tick, Dermacentor andersoni, in the western United States, and by the bite of the American dog tick, Dermacentor variabilis, in the eastern United States. The brown dog tick, Rhipicephalus sanguineus, recently was identifed as 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. Most human cases occur in late spring and summer. In the United States, most cases occur in the eastern third of the country, with about 1000 cases reported per year, primarily from April through September, and with a higher incidence among children and men.

Clinical Findings

A. Symptoms and Signs

Two to 14 days (mean, 7 days) after the bite of an infectious tick, symptoms begin with fever, chills, headache, nausea and vomiting, myalgias, restlessness, insomnia, and irritability. Cough and pneumonitis may develop. Delirium, lethargy, seizures, stupor, and coma may appear. The face is flushed and the conjunctiva injected. The rash (faint macules that progress to maculopapules and then petechiae) appears between days 2 and 6 of fever, first on the wrists and ankles, spreading centrally to the arms, legs, and trunk for 2–3 days; involvement of the palms and soles is characteristic. About 10% of cases, however, occur without rash or with minimal rash. In some cases there is splenomegaly, hepatomegaly, jaundice, myocarditis, or uremia. ARDS and necrotizing vasculitis are of greatest concern. About 3–5% of cases reported in the United States in recent years were fatal. Advanced age, underlying chronic diseases, and delay of appropriate treatment are predictors of poor prognosis.

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 demonstration of R rickettsiae in skin biopsy specimens, but this must be performed as soon as skin lesions become apparent 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.

Differential Diagnosis

The diagnosis is challenging. Up to 40% of patients do not recall a tick bite, and initial diagnosis is made clinically. The early symptoms and signs of Rocky Mountain spotted fever resemble those of many other

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infections. 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.

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.

Treatment & Prognosis

Doxycycline (200 mg/d) either orally or intravenously is the drug of choice even in the pediatric population. Chloramphenicol (50 mg/kg/d in four divided doses) is reserved for pregnant women. Patients usually defervesce within 48–72 hours. Mild cases in low-risk individuals may be observed without treatment.

The mortality rate for Rocky Mountain spotted fever varies strikingly with age. In the untreated elderly, it may be 70%, but it is usually less than 20% in children. Other risk factors for a fatal outcome include advanced age, atypical clinical features (absence of headache, no history of tick attachment, gastrointestinal symptoms), and a delay in initiation of appropriate antibiotic therapy. The usual cause of death is pneumonitis with respiratory or cardiac failure. 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.

Demma LJ et al: Rocky Mountain spotted fever from an unexpected tick vector in Arizona. N Engl J Med 2005;353:587.

Paddock CD et al: Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis 2004;38:805.

Sexton DJ et al: Rocky mountain spotted fever. Med Clin North Am 2002;86:351.

2. Rickettsialpox

Rickettsia akari is a parasite of mice, transmitted by mites Liponyssoides sanguineus. Rickettsialpox occurs in humans when crowded conditions and mouse-infested housing allow transmission of the pathogen to humans. Pathologic findings include dermal edema, subepidermal vesicles, and at times a lymphocytic vasculitis. The incubation period is 7–12 days. Onset is sudden, with chills, fever, headache, photophobia, and disseminated aches and pains. The primary lesion is a painless red papule that vesiculates and forms a black eschar. Two to 4 days after onset of symptoms, a widespread papular eruption appears that 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).

Leukopenia and a rise in antibody titer to rickettsial antigen with complement fixation or indirect fluorescent assays using a conjugated antirickettsial globulin can identify antigen in punch biopsies of skin lesions.

Treatment includes 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 to suppress the mite vectors.

Koss T et al: Increased detection of rickettsialpox in a New York City hospital following the anthrax outbreak of 2001: use of immunohistochemistry for the rapid confirmation of cases in an era of bioterrorism. Arch Dermatol 2003;139:1545.

3. Tick Typhus (Rickettsial Fever)

The term “tick typhus” denotes a variety of spotted rickettsial fevers. They are often named by geography, eg, Mediterranean spotted fever, Queensland tick typhus, Oriental spotted fever, African tick bite fever, Siberian tick typhus, or by morphology, eg, boutonneuse fever. These illnesses are transmitted by tick vectors of the rickettsial organisms R conorii, R australis, R japonica, R africae, and R sibirica. Dogs and wild animals, usually rodents but even reptiles, may serve as reservoirs. The pathogens usually produce an eschar or black spot (tache 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, renal failure, and focal hepatic necrosis may occur. Diabetes, dehydration, and uremia were risk factors for mortality in one series. The disease occurs among travelers, the most common travel-associated rickettsiosis being African tick bite fever. Diagnosis is clinical, with serologic or PCR confirmation. Prevention entails protective clothing, repellents, and inspection for and removal of ticks. Treatment is with the following drugs given for 7–10 days: doxycycline (200 mg/d), chloramphenicol (50–75 mg/kg/d in four divided doses), or ciprofloxacin (500 mg twice daily). The combination of erythromycin and rifampin is effective and safe in pregnancy.

Another rickettsial infection, formerly classified as an endemic or murine typhus, is more properly classified as a spotted fever. The causative agent, R felis, is an organism that has been linked to the cat flea and opossum exposures. Most cases in the United States are reported from southern Texas and California and are treated as above.

de Sousa R et al: Mediterranean spotted fever in Portugal: risk factors for fatal outcome in 105 patients. Ann NY Acad Sci 2003;990:285.

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Graves S et al: Rickettsia honei: a spotted fever Rickettsia group on three continents. Ann NY Acad Sci 2004;990:62.

Lewin MR et al: Rickettsia sibirica infection in members of scientific expeditions to northern Asia. Lancet 2003;362:1201.

Other Rickettsial & Rickettsial-Like Diseases

1. Ehrlichiosis & Anaplasmosis

Essentials of Diagnosis

  • Infection of monocyte or granulocyte by tick-borne 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.

  • Excellent response to therapy with tetracyclines.

General Considerations & Clinical Findings

Ehrlichiosis and its analogous disease anaplasmosis present as two clinical entities involving either the monocyte or the granulocyte. Human monocytic ehrlichiosis (or when caused by its analog, anaplasma, anaplasmosis) is caused by Ehrlichia chaffeensis and by Ehrlichia canis. Human granulocytic ehrlichiosis (anaplasmosis) is caused by Anasplasma phagocytophilium and Ehrlichia ewingii. Another rickettsia-like organism, Neorickettsia sennetsu, is the etiologic agent of sennetsu fever, which appears to be confined to western Japan.

Ehrlichiae and anaplasmae are small tick-borne gram-negative obligate intracellular bacteria. The major nonhuman hosts include mice, dogs, and horses. These organisms grow as microcolonies in phagosomes of hematopoietic cells and form characteristic inclusions seen with Giemsa stain. Human monocytic ehrlichiosis (or its analog, anaplasmosis) is seen primarily in the Southeast, mid-Atlantic, and South Central states of the United States, though serologic evidence now documents a much more global endemicity (Israel, Japan, Mexico, Europe). Its major vector is the Lone Star tick (Amblyomma americanus). Reported incidences of both human monocytic and granulocytic ehrlichiosis are about 0.6 and 1.4 per million, respectively, with the highest attack rate in men over 60 years of age. Clinical disease 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. Infections among HIV-positive persons are more apt to be symptomatic. Disease is more severe among the elderly. Leukopenia, absolute lymphopenia, and thrombocytopenia occur often. Serious sequelae include acute respiratory failure and ARDS, encephalopathy, and acute renal failure, which may mimic thrombotic thrombocytopenic purpura. An indirect fluorescent antibody assay is available through the CDC and requires acute and convalescent sera. A PCR assay applied to whole blood samples is a rapid diagnostic tool, if available.

Human granulocytic ehrlichiosis (anaplasmosis) has an increasingly recognized ubiquitous geographic area of distribution with clinically consistent cases now reported from the United States (where it is tends to be present in the same geographic area as Borrelia burgdorferi, the causative agent of Lyme disease), Brazil, Israel, and Europe. The vectors are ticks of the Ixodes genus, and the reservoirs include woodrats, deer mice, chipmunks, deer, and perhaps horses. The incidence peaks in summer, but cases are seen year-round in warmer areas where ticks remain viable. The symptoms are similar to those seen with human monocytic ehrlichiosis. Persistent fever and malaise are reported to occur for 2 or more years. Coinfection with Lyme disease may occur, though patients with granulocytic ehrlichiosis appear to be older and sicker than those with acute Lyme disease.

Diagnosis & Treatment

Diagnosis is made by the history of tick exposure followed by a clinical illness with the characteristic symptoms and signs. Further laboratory evaluation is similar to that described for human monocytic ehrlichiosis.

Treatment for both forms of ehrlichiosis is with doxycycline, 200 mg orally or intravenously for at least 7 days or until 3 days of defervescence. Treatment should not be withheld while awaiting confirmatory serology when suspicion is high.

Demma LJ et al: Epidemiology of human ehrlichiosis and anaplasmosis in the United States, 2001–2002. Am J Trop Med Hyg 2005;73:400.

Dumler JS et al: Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combinations and designation of Ehrlichia equi and ‘HE agent’ as subjective synonyms of Ehrlichia phagocytophila. Int J Syst Evol Microbiol 2001;51:2145.

Stone JH et al: Human monocytic ehrlichiosis. JAMA 2004;292:2263.

Talbot TR et al: Ehrlichia chaffeensis infections among HIV-infected patients in a human monocytic ehrlichiosis-endemic area. Emerg Infect Dis 2003;98:1123.

2. Q Fever

Essentials of Diagnosis

  • Exposure to sheep, goats, cattle, or their products is common; some infections are laboratory acquired.

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  • An acute or chronic febrile illness with severe headache, cough, prostration, and abdominal pain.

  • Extensive pneumonitis, hepatitis, or encephalopathy; rarely, endocarditis or chronic fatigue syndrome.

General Considerations

Coxiella burnetii is unique among rickettsiae in that it is usually transmitted to humans not by arthropods but by inhalation or ingestion. It is distributed worldwide with few exceptions. Coxiella infections occur mostly in cattle, sheep, and goats, in which they cause mild or subclinical disease. Transmission by cows and goats is principally through the milk and placenta and by sheep through feces, placenta, and milk. Dry feces and milk, dust contaminated with them, and the tissues of these animals contain large numbers of infectious organisms that are spread by the airborne route. Inhalation of contaminated dust and of droplets from infected animal tissues is the main source of human infection. Outbreaks have been described in association with parturient cats. There is an occupational risk for animal handlers, slaughterhouse workers, veterinarians, and laboratory workers.

The route of acquisition appears to determine the main clinical syndrome. Endocarditis is an uncommon but serious form of Coxiella infection and has been linked with preexisting valvular conditions, immunocompromise, urban residence, and raw milk ingestion. Coxiella is resistant to heat and drying, perhaps because the organism forms endospore-like structures. Thus, it survives in dust, on the fleece of infected animals, or in inadequately pasteurized milk. 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

After an incubation period of 1–3 weeks, a febrile illness develops with headache, prostration, and muscle pains, often with a nonproductive cough. Pneumonia is the predominant manifestation of acute Q fever, although granulomatous hepatitis and CNS manifestations may occur. The most common manifestation of chronic Q fever is culture-negative endocarditis, which occurs in less than 1% of infected individuals. It is found mainly in the setting of preexisting valve disease. Uncommon manifestations of Coxiella infection include myocarditis, encephalitis, aortic aneurysm, hemolytic anemia, orchitis, acute renal failure, and mediastinal lymphadenopathy. The clinical course may be acute or may be chronic and relapsing. A Q fever chronic fatigue syndrome is thought by some experts to involve bacteremic shedding from bone marrow reservoirs and to be immunogenetically determined.

B. Laboratory Findings

Laboratory examination during the acute phase may show elevated liver function tests and occasionally leukocytosis. Patients with acute Q fever usually produce antibodies to C burnetii phase II antigen. A fourfold rise between acute and convalescent sera is diagnostic.

The diagnosis of Q fever endocarditis is made serologically. The IgG titer is usually 1:200 or greater and is directed against phase I antigen. Sometimes the diagnosis is not made until the time of valve replacement. Isolation of C burnetii from affected valves is possible using the shell-vial technique, but the organism is highly transmissible to laboratory workers. A nested PCR assay is most useful early in infection, typically during the first month.

C. Imaging

Radiographs of the chest show patchy pulmonary infiltrates, often more prominent than the physical signs would suggest.

Differential Diagnosis

Viral, mycoplasmal, and bacterial pneumonias, viral hepatitis, brucellosis, tuberculosis, psittacosis, and other animal-borne diseases must be considered. The history of exposure to animals or animal dusts or tissues (eg, in slaughterhouses) should lead to appropriate specific serologic tests. Unexplained fevers with negative blood cultures in association with embolic or cardiac disease should make one consider Q fever. Q fever is also one of the most common causes of culture-negative endocarditis.

Prevention

Prevention is based on detection of the infection in livestock, reduction of contact with infected animals or dusts contaminated by them, special care when working with animal tissues, and effective pasteurization of milk. A vaccine of formalin-inactivated phase 1 Coxiella is being developed for persons at high risk of infection and appears to be protective. A vaccine is available in some countries for persons with high-risk exposures.

Treatment & Prognosis

For acute infection, treatment with tetracycline (25 mg/kg/d in four divided doses) or doxycycline (100 mg twice daily) can suppress symptoms and shorten the clinical course but does not always eradicate the infection. The newer macrolides are an alternative. Treatment should continue through 3 full days of defervescence, which usually occurs within 72 hours. Even in untreated patients, the mortality rate is usually low, except when endocarditis develops (see below).

Although the optimal regimen for the treatment of endocarditis is not known, most experts recommend a

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combination of doxycycline (200 mg/d) plus hydroxychloroquine (600 mg/d), usually for at least 2 years. Serologic responses can be followed to determine cessation of therapy. Doxycycline levels correlate with declines in phase 1 antibody levels. Heart valve replacement may be necessary in refractory disease. Given the difficulty in treating endocarditis, the same combination therapy for 1 year is recommended for patients with acute disease and underlying valvular heart disease.

Arashima Y et al: Improvement of chronic nonspecific symptoms by long-term minocycline treatment in Japanese patients with Coxiella burnetii infection considered to have post-Q fever fatigue syndrome. Intern Med 2004;43:49.

Houpikian P et al: Blood culture-negative endocarditis in a reference center: etiologic diagnosis of 348 cases. Medicine (Baltimore) 2005;84:162.

Marmion BP et al: Long-term persistence of Coxiella burnetii after acute primary Q fever. QJM 2005;98:7.

Raoult D et al: Natural history and pathophysiology of Q fever. Lancet Infect Dis 2005;5:219.

Tissot-Dupont H et al: Wind in November, Q fever in December. Emerg Infect Dis 2004;10:1264.

Kawasaki Disease

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 under age 5 years but occasionally in adults, at times in epidemic fashion. The higher risk among Asian children may be explained by receptor polymorphisms. A leading current theory for Kawasaki disease is an aberrant reaction to common infectious agents among genetically susceptible persons. IgA plasma cell infiltration is noted in the visceral organs, lungs, and coronary arteries of patients with Kawasaki disease.

The disease is characterized by fever and four of the following 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's lines [transverse grooves of the nails]), a polymorphous rash, and cervical lymphadenopathy greater than 1.5 cm.

A major complication is arteritis of the coronary vessels, occurring in about 25% of untreated patients, on occasion causing myocardial infarction, and more common among patients over 6 years of age. Its frequency is reduced by the use of intravenous immune globulin to about 10%. Noninvasive diagnosis can be made with magnetic resonance angiography or transthoracic ultrasound. Factors associated with the development of coronary artery aneurysms are leukocytosis and elevated C-reactive protein. Pericardial effusions occur in 30% of cases. Myocarditis is common in the acute phase of the disease, and mitral regurgitation may be present in 30% of patients but is usually mild. Arteritis of extremity vessels, peripheral gangrene, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and the hemophagocytic syndrome are also reported. Cerebrospinal fluid pleocytosis is reported in one-third of cases. The cause of these complications is also unknown. Differentiation from disseminated adenovirus infection is important and may be facilitated in the future with rapid adenovirus assays.

Management is with intravenous immune globulin, 2 g/kg over 10 hours, with repeat dosing appearing to prevent cardiac complications. The use of plasmapheresis in up to 10% of patients who are unresponsive to immune globulin is controversial. Corticosteroids, which are also used by some in disease refractory to two or more episodes of intravenous immunoglobulin, appear to be associated with a hastened resolution of fever and inflammatory markers and a shortened duration of hospitalization. Their role in increasing the likelihood of the development of coronary aneurysms is controversial. Aspirin, traditionally recommended in a high dose, does not appear to lower the risk of the development of coronary abnormalities. Its use (80–100 mg/kg/d in divided doses with subsequent tapering) is recommended indefinitely for patients with persisting coronary abnormalities. Warfarin is indicated in addition for aneurysms larger than 8 mm in diameter. Regular follow-up by a cardiologist is recommended for patients with coronary artery disease or aneurysms. Success is reported with interventional catheter treatment, including stent implantation in patients with long-term cardiac complications. Rare patients with irreversible myocardial dysfunction have successfully undergone cardiac transplantation.

Bergner D et al: Kawasaki disease: what is the epidemiology telling us about the etiology? Int J Infect Dis 2005;9:185.

Burns JC et al: Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease. J Infect Dis 2005;192:344.

Hsieh KS et al: Treatment of acute Kawasaki disease: aspirin's role in the febrile stage revisited. Pediatrics 2004;114:e689.

Newburger JW et al: Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004;114:1708.

Seve P et al: Adult Kawasaki disease: report of two cases and literature review. Semin Arthritis Rheum 2005;34:785.

Weiss JE et al: Infliximab as a novel therapy for refractory Kawasaki disease. J Rheumatol 2004;31:808.