Perspective.: The elimination from the natural environment of variola virus, the virus that causes smallpox, at one time the most devastating worldwide pestilence, is one of the great medical and public health accomplishments of the past century.⁵ The elimination of smallpox from the natural environment was possible because of the lack of nonhuman reservoirs or human carriers of variola and the availability of rapid diagnostic techniques and an effective vaccine. Global eradication was certified by the WHO in 1980. Other human poxvirus diseases include monkeypox, vaccinia virus infection, molluscum contagiosum, orf, and paravaccinia virus infection. The poxviruses are the largest pathogenic viruses, consisting of complex, brick-shaped capsids and double-stranded DNA.

Principles of Disease.: Recently, the possibility that military and research stores of virus could become weaponized and used as tools of terrorism or war has mandated that health care professionals familiarize themselves with the manifestations of smallpox, the clinical manifestations of vaccine-related illness, and the risks and benefits of the vaccine. The CDC has established extensive web-based information and training materials in preparation for the possibility of an outbreak.

Clinical Features.: Smallpox is transmitted by infected droplets or close contact with a patient in any stage of illness. The most common manifestation in the unvaccinated host is variola major, which has a fatality rate of approximately 30%. The illness is characterized by a short prodrome of headache, backache, and fever. An ensuing enanthem progresses from small macules to papules and then vesicles during a few days. Lesions begin on the face and limbs and spread in a centrifugal pattern. These develop into 4- to 6-mm firm, deep-seated vesicles or pustules that umbilicate, crust, and then desquamate in the next several weeks (Fig. 130-3). All lesions are at the same stage of development. Modified, milder forms of smallpox can appear in previously vaccinated patients and, more rarely, in nonimmune hosts. There are also two more rare but almost uniformly fatal forms of smallpox: a fulminant, “hemorrhagic” form and “flat type” smallpox, characterized by plaquelike lesions.³⁶

Diagnostic Strategies.: Major criteria for diagnosis include a prodrome of 1 to 4 days with fever (temperature higher than 38.3° C) and symptoms and signs such as headache and vomiting. Minor criteria include a centrifugal distribution of the rash, lesions on the palms and soles, a toxic appearance, and a rash that develops during several days. Routine laboratory tests are not helpful in the diagnosis. In the prodromal phase, there may be a relative granulocytopenia, but the white blood cell count usually is elevated in the eruptive phase. Laboratory diagnosis can be established by antibody testing, cell culture, or electron microscopy.

Differential Considerations.: Smallpox has been confused with other papulovesicular eruptions, including varicella (chickenpox), measles, erythema multiforme, molluscum contagiosum, generalized vaccinia virus infection, and monkeypox. The lesions of chickenpox generally are at different stages of development and healing and often spare the palms and soles.

Management.: The CDC guidelines classify suspected cases of smallpox into categories of high, moderate, and low risk. Cases with high or moderate risk should prompt appropriate isolation and consultation with an infectious disease specialist or local health care authority. Quarantine, contact tracing, and immunization efforts are a priority for public health officials, and prompt involvement of the appropriate agencies will be crucial to containment efforts in the event of an outbreak.

Immunization with vaccinia virus was the cornerstone of smallpox containment and eradication efforts. Vaccinia virus immunization has been associated with morbidity and death in vaccinated persons and their close contacts. The decision to vaccinate must balance the risk of smallpox infection against the risk of vaccine-related injury. Pre-event vaccination is contraindicated in several groups of patients, including those who are pregnant, are breast-feeding, have significant immunosuppression, or have eczema. Close household contacts of persons at risk for serious side effects from vaccine should not be vaccinated. There are no absolute contraindications to vaccination for persons who have been exposed to smallpox.

Perspective.: The origin of the vaccinia virus is not well established, but it is the poxvirus that is used to produce the smallpox vaccine. Although primary infection (through live virus vaccination) or secondary infection (from virus shed from an immunized patient) with vaccinia virus is usually well tolerated, severe local reactions from immunization as well as disseminated severe manifestations of primary or secondary infection have been well described. The normal reaction to vaccinia vaccine is a localized inflammatory reaction with scar formation. Viremia is possible, but manifestations are of a mild viral illness. In immunocompromised hosts, such as some young infants or persons with aberrant cell-mediated immunity, a syndrome of multiplying and aggressive necrotic skin lesions called progressive vaccinia can lead to death.

Management.: Therapy for this syndrome with vaccinia immune globulin (VIG) and antiviral medications such as cidofovir and ribavirin has been advocated.³⁷

Perspective.: Edward Jenner, in his An Inquiry into the Causes and Effects of the Variolae Vaccinae in 1798, observed that on inoculation into humans, the pustular material from the lesions of cowpox protected them from infection with smallpox.¹ Cowpox virus is similar to vaccinia virus and is found mostly in Europe, countries of the former Soviet Union, and Central Asia. It has natural reservoirs in wild animals but can also cause infection in domesticated animals, including cattle and cats.

Clinical Features.: In the immunocompetent human host, the disease is limited to a vesiculopustular, scabbing eruption that is often localized and can be accompanied by an influenza-like syndrome. In immunocompromised hosts and person with eczematous eruptions, the disease is more aggressive and sometimes fatal. There appears to be an increase of cowpox cases in Europe that is thought to be due to waning smallpox immunity and increased exposure to the disease from wild animal reservoirs.³⁸

Clinical Features.: The disease of monkeypox is clinically similar to that of smallpox. Most cases have occurred in west and central Africa, with a case fatality rate of 1 to 10% and higher death rates among children. An outbreak of 72 cases in the Midwest United States in spring 2003 was traced to contact with prairie dogs housed with Gambian giant rats that were imported from Ghana.³⁹ No deaths were associated with this outbreak. There seems to be an increase in monkeypox cases that could be attributable to decreased cross-immunity from the cessation of smallpox vaccination as well as to increased human exposure to rainforest wildlife from hunting “bush meat.” Monkeypox has also been seen as a potential biowarfare agent, but the greater threat for global spread of the disease comes from the illegal international trade of exotic animals.⁴⁰

Perspective.: Other viruses within the Poxviridae family that cause disease in humans include the parapoxviruses (paravaccinia virus and bovine pustular stomatitis virus) and the molluscum contagiosum and tanapox viruses.

Clinical Features.: The milker’s node virus, or paravaccinia virus, produces vesicular lesions on the udders or teats in cattle and is transmitted to humans by direct contact. Milker’s nodules, which develop on the fingers or hands, are small, watery, painless nodules occasionally associated with lymphadenopathy. The lesions generally resolve completely within 3 to 8 weeks.

Bovine pustular stomatitis, ecthyma contagiosum, and orf viruses cause papillomatous lesions on the mucous membranes and corneas of sheep. Single lesions generally develop in infected persons at the site of an abrasion.

Molluscum contagiosum is a generally benign human disease characterized by multiple small, painless, pearly, umbilicated nodules. They appear on epithelial surfaces, commonly in anogenital regions, and may be spread through close contact or autoinoculation. In immunocompetent persons, the lesions may clear rapidly or persist for up to 18 months. The infection often is seen in patients with HIV infection, in whom the lesions often are not restricted to the genital area and may increase in size and number.⁴¹ Curettage or other forms of local ablation may be helpful in such recalcitrant cases.

Principles of Disease.: At least eight human herpesviruses are known. Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are the agents of herpes genitalis, labialis, and encephalitis. Varicella-zoster virus (VZV) is the etiologic agent of chickenpox and herpes zoster. Epstein-Barr virus (EBV) is the agent of infectious mononucleosis and also is associated with nasopharyngeal carcinoma, Burkitt’s lymphoma, and other lymphoproliferative syndromes. Cytomegalovirus (CMV) is associated with heterophil-negative infectious mononucleosis and invasive disease in immunocompromised patients. Human herpesvirus 6 (HHV-6) is associated with roseola infantum.⁴² The role of human herpesvirus 7 (HHV-7) has not been completely elucidated. Human herpesvirus 8 (HHV-8) is associated with Kaposi’s sarcoma,⁴³ body cavity–based lymphomas, and multicentric Castleman’s disease. In addition, a closely related monkey virus, herpesvirus simiae or herpes B virus, has been shown to cause fatal encephalitis in humans.

Principles of Disease.: A localized primary lesion, latency, and a tendency for local recurrence characterize infections with HSV-1 and HSV-2 (herpesvirus hominis). The primary lesion with HSV-1 may be mild and inapparent; the first outbreak may occur during childhood. Reactivation of latent HSV-1 infection usually results in herpes labialis (cold sores, fever blisters). Neurologic involvement is not uncommon with HSV-1. Although such involvement usually occurs in association with a primary infection, neurologic signs may appear after a recrudescence and may be manifested as encephalitis. Although it is uncommon, HSV-1 encephalitis is one of the most common causes of encephalitis in the United States, with estimates of several hundred to several thousand cases occurring yearly. HSV-2 most commonly is associated with genital herpes, although either HSV-1 or HSV-2 may infect any mucous membrane, depending on the route of inoculation. HSV-2 is commonly associated with aseptic meningitis rather than with meningoencephalitis. The incubation period for primary herpes infection is 2 to 12 days.⁴⁴

On contact with abraded skin or mucous membranes, HSV replicates locally in epithelial cells, which lyse and cause a local inflammatory response. Thin-walled vesicles on an erythematous base are the characteristic lesions of superficial HSV infection. Multinucleated giant cells with ballooning degeneration and intranuclear inclusions may be seen on a Tzanck preparation of a smear of material obtained from the base of these vesicles. After primary infection, HSV can become latent within sensory nerve ganglia. Emotional stress, sunlight, fever, or local trauma can trigger reactivation of the virus. HSV encephalitis usually involves the temporal lobes, resulting in a necrotizing, hemorrhagic encephalitis.

Clinical Features.: Primary HSV-1 often is asymptomatic but may appear as pharyngitis and gingivostomatitis in children younger than 5 years. Associated with fever, pharyngeal edema, erythema, cervical adenopathy, and multiple small vesicles that ulcerate and multiply, the disease generally lasts 10 to 14 days. Recurrences develop in 60 to 90% of people after primary infection but generally are milder than the primary infection. Vesicles generally recur on the vermilion border, usually are small, and crust within 48 hours.

Herpes simplex infections of the eye most often are caused by HSV-1. Primary infections are manifested as follicular conjunctivitis, blepharitis, or corneal epithelial opacities, which usually heal completely within 2 to 3 weeks. Recurrences may result in keratitis. Branching dendritic ulcers, detectable with fluorescein staining, are diagnostic and may result in diminished visual acuity. Deep stromal involvement may result in corneal scarring.

Primary herpetic finger infections (i.e., herpetic whitlow) generally are caused by HSV-1 among medical or dental personnel and by HSV-2 among the general population. The lesions are associated with intense pain and itching but generally resolve in 2 to 3 weeks. Recurrent whitlow with severe local neuralgia may occur.

Primary genital herpes generally is seen in the sexually active population and is caused by HSV-2 in 70 to 95% of cases. The lesions usually involve the shaft or glans of the penis in men and the vulva, perineum, buttocks, cervix, and vagina in women. Primary perianal and anal herpes can be seen in persons who have had receptive anal intercourse. Primary infection may be associated with fever, malaise, anorexia, and inguinal adenopathy. Vaginal discharge is common, and urethral involvement can result in urinary retention. Herpetic sacral radiculomyelitis is uncommon but is associated with urinary retention, myalgias, and obstipation. The lesions of primary genital herpes can last for several weeks before completely clearing. Recurrences of genital herpes generally are shorter and milder than the primary episodes and may be preceded by a prodrome of tenderness, itching, or tingling. Healing of recurrent lesions generally is complete in 6 to 10 days. Minimally symptomatic lesions are often overlooked as recurrent episodes by the patient. Over time, symptomatic recurrences can be expected to diminish in frequency, intensity, and duration, but persons who have diminished immunity, such as those infected with HIV, may suffer with prolonged, frequent, or atypical recurrences.

Neonatal herpes infection occurs in 8 to 60 in 100,000 births, depending on the population of patients studied, and is caused by the transmission of the virus at the time of delivery. Most babies with neonatal herpes infection are born to asymptomatic mothers, but there appears to be a much higher risk of transmission by a mother who experiences the first genital herpes infection during pregnancy. It is estimated that 50 to 80% of infants with neonatal herpes are born to mothers who acquire genital herpes infection near term. This might indicate that women with long-standing infection transmit antibody to the fetus that decreases disease manifestation after exposure to virus during birth.⁴⁵ The use of invasive monitoring and premature delivery also are associated with an increased risk of infection.⁴⁶ Infection may be manifested after several days to weeks with vesicles or conjunctivitis; neurologic involvement, with seizures, cranial nerve palsies, lethargy, and coma, is common. Untreated disseminated or CNS disease is fatal in more than 70% of patients.

Encephalitis caused by HSV is uncommon, but it is the most common acute, nonepidemic encephalitis in the United States. Cases do not have a seasonal distribution. Other than in the neonate, HSV-1 is the usual pathogen. The clinical disease begins acutely, with fever and focal neurologic signs, often localized to the temporal lobe. The patient may complain of a bad odor not perceived by anyone else (temporal lobe hallucination). Common clinical manifestations include headache, meningeal signs, lethargy, confusion, stupor, and coma. The mortality rate among untreated patients with CNS disease approaches 80%, and less than 10% of patients are left with no neurologic sequelae. Treatment with acyclovir appears to reduce mortality and to decrease the neurologic sequelae more effectively than treatment with vidarabine.

Diagnostic Strategies.: CSF findings are nonspecific, with a moderate mononuclear pleocytosis. Results of culture of the CSF generally are negative for HSV. Localization of the encephalitis within the temporal lobes by electroencephalography, magnetic resonance imaging (MRI), or computed tomography (CT) scan increases the likelihood of a diagnosis of HSV encephalitis. The diagnosis of HSV encephalitis can be made reliably only with a biopsy of the lesion and subsequent isolation or detection of the virus by culture, direct fluorescent antibody tests, or polymerase chain reaction (PCR) assay.

Differential Considerations.: The superficial lesions of HSV infection are indistinguishable from those of VZV infection. Pharyngitis and gingivostomatitis in children can mimic streptococcal or diphtheritic pharyngitis, herpangina, aphthous stomatitis, Stevens-Johnson syndrome, Vincent’s angina, or infectious mononucleosis. Primary genital herpes can mimic the appearance of chancroid, syphilis, candidiasis, or Behçet’s syndrome. In the neonate, in the absence of vesicles, congenital HSV infection can mimic disease caused by rubella, CMV, or Toxoplasma organisms. Encephalitis caused by HSV may be clinically indistinguishable from other viral encephalitides, tuberculous and fungal meningitis, brain abscesses, brain tumors, and cerebrovascular accidents.

Management.: Oral acyclovir (400 mg three times daily), oral valacyclovir (1 g twice daily), or intravenous acyclovir (5 mg/kg three times daily) is recommended for treatment of primary genital herpes or mucocutaneous herpes in the immunocompromised host, although some authorities use higher dosages in these patients despite no clear evidence.⁴⁷ Because of the safety and efficacy of oral acyclovir, there is little indication for use of acyclovir ointment. In people with severe or frequent recurrences, acyclovir, ranging in doses from 200 mg five times daily to 800 mg once daily, can be used as an effective suppressive regimen. Both famciclovir and valacyclovir also are approved for suppressive therapy and daily dosing of the affected partner in an HSV-discordant couple; a 500-mg dose of valacyclovir yielded about a 50% reduction in transmission to the unaffected partner in a recent study.⁴⁵

In the immunocompromised host, acyclovir is effective for both treatment and prophylaxis of recurrent mucocutaneous herpes. Foscarnet has been shown to be effective for the treatment of mucocutaneous herpes that is resistant to acyclovir. Intravenous acyclovir, 10 mg/kg every 8 hours, is the treatment of choice for HSV encephalitis in adults and children. Vidarabine, 30 mg/kg/day intravenously, also is effective in neonatal encephalitis but is rarely used.

Several vaccines against HSV have reached differing phases of development and testing, but none has shown enough promise to become clinically available.⁴⁸ Research in this area is ongoing.

Disposition.: Patients with cutaneous HSV infections generally can be managed easily. The diagnosis often carries with it a great deal of stigma that should be addressed. Assurance of the generally benign nature of the infection is helpful. Counseling should include cautions about the transmissibility of the virus, even during asymptomatic periods. Women of childbearing age should discuss management of HSV infection during pregnancy and delivery with their obstetricians. It is clear that shedding of HSV occurs when there is no clinical outbreak in persons with a history of recurrent lesions and that persons who have never had recognizable lesions but who have antibody to HSV can also shed virus. With the advent of dependable commercialized serologic tests for HSV-1 and HSV-2, it is hoped that clinicians will be better able to identify persons with asymptomatic infection and to provide counseling on ways to decrease transmission. There are no clear current guidelines for how to decrease such transmission, but the routine use of condoms and suppressive therapy with antiviral medications are reasonable until more research in the field is conducted.

Encephalitis caused by HSV constitutes a treatable medical emergency. Prompt recognition and institution of appropriate therapy in the emergency department (ED) before a definitive diagnosis has been made may decrease the high mortality rate and neurologic sequelae associated with this disease. When HSV encephalitis is suspected, empirical initiation of intravenous acyclovir is indicated in the ED. This approach has minimal toxicity and demonstrable efficacy.

Principles of Disease.: VZV, or human (alpha) herpesvirus 3, is the agent of both chickenpox and herpes zoster, or shingles.

Clinical Features.: Chickenpox is an acute, generalized viral disease characterized by sudden onset of fever, malaise, and a skin eruption that initially is maculopapular and then becomes vesiculated for several days before a granular scab is left (Fig. 130-4). Lesions occur in crops, with several stages present at the same time. Lesions can appear anywhere on the skin and mucous membranes. There may be few lesions and mild, inapparent infections. Most cases occur in children younger than 9 years; adults with the disease may have high fevers and severe constitutional symptoms. Children with acute leukemia are at increased risk for disseminated disease, which carries a case fatality rate of greater than 5%. Neonates in whom varicella develops before 10 days of age and mothers who contract the disease in the perinatal period are at increased risk for generalized infection. Fatal disease in adults, although uncommon, usually is associated with pneumonic involvement. In children, fatal disease usually is associated with septic complications and encephalitis.

Herpes zoster is due to reactivation of VZV that has been latent in a dorsal root ganglion after an episode of chickenpox; it occurs predominantly in older adults and those with an immunocompromised state, such as HIV infection.⁴⁹ There are about 1 million cases in the United States annually.⁵⁰ The rash is often preceded by tingling or hypesthesia; multiple vesicles on an erythematous base appear in crops along nerve pathways supplied by sensory nerves of a single dorsal root ganglion or an associated group of dorsal root ganglia. The distribution usually is unilateral and dermatomal (Fig. 130-5). The lesions often are extremely painful. Postherpetic neuralgia, which is defined as continued pain for 6 months after lesions have healed, is more likely to occur in elders with larger and more painful rashes. It can last for months or years and is refractory to treatment. Ophthalmic infection, which can occur without other cutaneous lesions, can lead to corneal ulceration. Two relatively rare but often cited facial zoster infections are Hutchinson’s sign, which is the appearance of a blister on the tip of the nose with herpes ophthalmicus, and Ramsey Hunt syndrome, which is characterized by localized pain, facial weakness, and a rash of the face or ear canal that can be subtle.⁵¹

Diagnostic Strategies.: Both chickenpox and herpes zoster are often easily diagnosed on physical examination, and laboratory tests generally are not required. Multinucleated giant cells may be seen on Tzanck preparations of material from the base of a lesion but will not allow differentiation of HSV from VZV lesions. Submission of scrapings for a direct fluorescent antigen test is cost-effective and allows differentiation of VZV from HSV infection.

Management.: Use of acyclovir for uncomplicated chickenpox in children is safe but only modestly effective. Parents of children with chickenpox should be cautioned not to give their children aspirin or aspirin-containing compounds because of the strong association between this practice and the development of Reye’s syndrome.⁵² Acetaminophen can be used as an antipyretic. Adults experience increased morbidity and mortality from chickenpox, so treatment of otherwise healthy adults with acyclovir, famciclovir, or valacyclovir frequently is indicated. Patients with pneumonitis or other severe illness should be treated with intravenous acyclovir. In immunocompromised patients, varicella-zoster immune globulin and intravenous acyclovir have been shown to decrease morbidity.

A live, attenuated vaccine that shows a high degree of protection for both normal children and children with leukemia was licensed in the United States in 1995. It is recommended for immunocompetent people older than 12 months. In those older than 12 years, two doses of vaccine are to be administered 4 to 8 weeks apart. It also is recommended for use as postexposure prophylaxis in the nonimmune host. The vaccine is most effective in preventing or attenuating illness in these circumstances if it is administered within the first 3 to 5 days after exposure.⁵³ The vaccine is a live attenuated virus and not recommended for use in immunocompromised patients.

Uncomplicated herpes zoster generally is treated with supportive measures, especially pain control, and antivirals (acyclovir, famciclovir, or valacyclovir). The currently recommended dosages are 800 mg five times a day for acyclovir, 500 mg three times a day for famciclovir, and 1 g three times a day for valacyclovir. Both famciclovir and valacyclovir are preferred to acyclovir because of increased compliance. In addition, there are data that valacyclovir 1.5 g twice a day yields equivalent therapeutic effect, and one might guess that compliance may be improved with dosing twice a day compared with three times a day, but this regimen is not currently approved for the treatment of herpes zoster.⁵⁴ There is good evidence that treatment with antivirals reduces the incidence and severity of postherpetic neuralgia, and treatment should be considered for those most at risk for this complication, such as those with large painful rashes and those 50 years of age or older.⁵⁴ Treatment with intravenous acyclovir should be considered for patients with disseminated disease and complicated zoster (involving more than one dermatome). Susceptible immunocompromised patients exposed to infected persons should receive varicella-zoster immune globulin within 72 hours to prevent or to modify clinical illness. Foscarnet is useful for treatment of infections due to acyclovir-resistant VZV in immunocompromised patients.

The use of corticosteroids to decrease the incidence of postherpetic neuralgia is controversial. A recent Cochrane review could not support the practice.⁵⁵ Nevertheless, the use of corticosteroids in conjunction with antivirals in persons who are at highest risk for postherpetic neuralgia and do not have contraindications to systemic steroid therapy is condoned by reliable sources. Herpes zoster is estimated to eventually occur in approximately 30% of the population; the introduction of an effective vaccine led to the recommendation that immunocompetent persons older than 60 years be vaccinated with one dose of varicella-zoster vaccine.

Disposition.: Chickenpox and herpes zoster are highly contagious. Although these diseases generally are benign, patients should avoid situations that put them in contact with steroid-treated or immunocompromised persons. The incubation period most commonly is 13 to 17 days, and the period of communicability may range from 5 days before to 5 days after the appearance of the vesicles. Susceptible persons should be considered potentially infectious from 10 to 21 days after exposure. Susceptible health care workers should not care for people with varicella or zoster. Health care workers without a well-documented history of chickenpox or herpes zoster should have antibody levels checked before they begin their employment to determine susceptibility to VZV, and they should strongly consider vaccination if they prove to be nonimmune.

Principles of Disease.: HHV-6 has been implicated as an agent of roseola infantum (exanthema subitum).

Clinical Features.: Roseola infantum is the most common exanthem of children younger than 2 years and occurs most often at approximately 1 year of age. The illness begins abruptly with the acute onset of fever, with temperature often as high as 41° C, lasting 3 to 5 days. A fine, evanescent, rose-colored maculopapular rash appears on the trunk after lysis of the fever and lasts 1 to 2 days. The rash may spread to the face and extremities. Most cases are self-limited, and despite the fever, the child usually remains active and alert. There is conflicting evidence on the frequency of HHV-6–associated febrile seizures.56,57 Although secondary cases occur after an incubation period of approximately 10 days, most cases of roseola occur without known exposure.

Differential Considerations.: The disease appears similar to other childhood exanthems. The child generally looks well despite the high fever.

Management.: Acetaminophen may reduce the fever. Routine supportive measures should be used if febrile seizures occur.

Principles of Disease.: Herpes B virus, or herpesvirus simiae, a close relative of human HSV, is enzootic in macaques and most commonly is associated with rhesus, cynomolgus, or African green monkeys. Like human HSV, herpes B virus produces mild disease in monkeys that is characterized by intermittent reactivation and shedding, particularly during times of stress, such as during handling. Among monkey handlers and those exposed to the animals’ saliva or tissues, monkey B virus is a serious occupational hazard and is associated with a high proportion of progressive mucocutaneous disease and fatal encephalitis in infected patients.⁶⁰ The first known case of fatal herpes B virus infection, from a mucosal splash exposure, occurred in 1998.

Clinical Features.: After a penetrating bite or scratch from an infected monkey, herpetiform vesicles may form at the site of the injury. Giant cells can be seen on a Tzanck preparation. An acute febrile illness with headache and lymphocytosis may follow as late as 3 weeks after the injury. An ascending myelitis ensues, leading to death from respiratory paralysis or encephalomyelitis within 3 weeks of onset of symptoms. The incidence of asymptomatic infection is unknown.

Differential Considerations.: The initial skin lesions appear similar to those of herpes simplex. In the context of any exposure to monkey tissues and the appearance of a herpetiform lesion, the diagnosis of herpes B virus infection must be considered because of its associated high mortality rate.

Management.: The most important step that can be taken to prevent B virus disease is thorough cleansing of exposed tissues. Current recommendations are that mucous membranes be flushed with sterile saline or water for 15 minutes and that areas of exposed skin be washed for 15 minutes with a detergent or a solution containing disinfectants (such as chlorhexidine or povidone-iodine). Affected tissue (except ocular or mucous membranes) can be initially washed with 0.25% hypochlorite (Dakin’s) solution before being washed with a detergent solution.

The decision to initiate postexposure prophylaxis is based on the severity of the exposure and the appropriateness of first aid measures. Postexposure prophylaxis does not need to be initiated if the exposed skin is intact or the exposure is to a nonmacque species of monkey. Valacyclovir, 1 g orally every 8 hours for 14 days, is recommended for postexposure prophylaxis.⁶⁰

Suspected B virus infection constitutes a medical emergency. Anecdotal reports have described successful prevention of disease progression with intravenous acyclovir. The apparent response of the infection to appropriate regimens emphasizes the need for early recognition and treatment. If CNS symptoms are present, ganciclovir is the drug of choice.

Principles of Disease.: Human papillomavirus (HPV) infections are common in all human populations and are the cause of a variety of cutaneous and mucous membrane lesions, including common warts, anogenital or venereal warts (condyloma acuminatum), and respiratory or laryngeal papillomas.

More than 70 types of HPVs have been identified. Laryngeal papillomas (most commonly caused by HPV types 6 and 11) and genital warts (most commonly caused by HPV types 16 and 18) can undergo malignant transformation.⁶¹ In addition, HPV has been implicated as a causative agent for oropharyngeal squamous cell carcinomas that have been traditionally attributed mainly to other causative agents, such as cigarettes. This observation has led to the prospect that vaccination against HPV might reverse the increasing incidence of oropharyngeal squamous cell carcinomas attributable to HPV infection.⁶² The association between HIV infection and more aggressive forms of HPV infection, including a greater likelihood for malignant transformation of lesions, has been shown.⁶³

Clinical Features.: Common warts generally are well-circumscribed, hyperkeratotic, painless papules occurring most commonly on the extremities and transmitted by close personal contact. Plantar warts, found on the soles of the feet, may be very painful. Venereal warts, found on the internal or external genitalia or perianal region, are hyperkeratotic, exophytic papules, either sessile or pedunculated, and are sexually transmitted. Laryngeal papillomas in children presumably are acquired during passage through the birth canal. Malignant transformation can occur, particularly in patients receiving radiation therapy.

Differential Considerations.: The diagnosis of warts usually is made clinically. Condyloma acuminatum must be distinguished from the condyloma latum of syphilis.

Diagnostic Strategies.: Diagnosis of cervical HPV infections can be made during colposcopy with previous application of a 3 to 5% acetic acid solution to the internal genital tract. Flat condylomata appear as shiny white patches with ill-defined borders and irregular surfaces. Acetowhitening also can reveal subclinical vulvar or penile warts.

Management.: Genital warts generally regress spontaneously within months or years, and it is unclear whether their removal decreases infectivity or decreases the chance of malignant transformation. Therapy is at the discretion of the patient and the caregiver. Patient-applied therapies use podofilox 0.5% gel or imiquimod 5% cream. Freezing with liquid nitrogen, surgical removal, and intralesional interferons also are effective for most accessible lesions. Combination therapies also can be used. Salicylic acid plasters and curettage are useful for plantar warts. Laryngeal warts require surgery or laser therapy.

Principles of Disease.: Parvovirus B19 has been implicated as the causal agent in several epidemics of erythema infectiosum or fifth disease. It also is associated with transient aplastic crisis in patients with chronic hemolytic disease, particularly those with sickle cell disease. Infections during pregnancy have been associated with hydrops fetalis and spontaneous abortion.⁶⁴ Humans constitute the only reservoir for parvovirus B19. Transmission usually occurs through contact with aerosol or respiratory secretions. Transmission by contaminated blood products has been documented.

Clinical Features.: Erythema infectiosum is a mild, usually nonfebrile disease of children between 4 and 10 years of age, characterized by a striking erythema of the cheeks—a “slapped-cheek” appearance (Fig. 130-6). The rash usually appears after an incubation period of 4 to 14 days without a prodrome. One to 4 days later, an erythematous rash on the extremities may be seen spreading to the trunk in a lacelike pattern. The rash generally fades within a week but can persist for several weeks, and recrudescence can be precipitated by skin trauma or sunlight exposure. Constitutional symptoms generally are mild in children, but adults with the disease commonly have associated arthralgias and arthritis. Rare cases of encephalitis and pneumonia have been reported.

Parvovirus B19 infects and causes a marked reduction in erythroid cell precursors and is a cause of transient aplastic crisis in patients with chronic hemolytic anemia. Recovery is associated with reappearance of reticulocytes in the peripheral smear 7 to 10 days after their disappearance. In patients with AIDS and other immunosuppressive illnesses, parvovirus B19 infection can be manifested as chronic anemia. These patients often have persistent parvovirus infection without an appropriate immunoglobulin response.

Differential Considerations.: In children, erythema infectiosum resembles other viral exanthems. The slapped-cheek appearance of the rash is characteristic.

Management.: Erythema infectiosum generally is a mild disease, and no treatment is required. Patients with parvovirus B19–associated aplastic crisis may require blood transfusions. Therapy with immune globulin can lessen the need for transfusions in immunosuppressed patients with chronic anemia. Women in whom parvovirus infection develops during pregnancy should be observed closely for the development of nonimmune fetal hydrops. The role of intrauterine blood transfusions in the treatment of this disorder remains controversial.⁶⁵

Principles of Disease.: EBV, or human herpesvirus 4, most commonly is associated with infectious mononucleosis, an acute viral syndrome characterized by fever, exudative pharyngotonsillitis, lymphadenopathy, and peripheral lymphocytosis with atypical lymphocytes.

EBV infects and transforms B lymphocytes. Infection is common and widespread in early childhood in developing countries, where it usually is mild or asymptomatic. In developed countries, infectious mononucleosis usually is manifested in older children and young adults, commonly among high school and college students. It is transmitted by way of the oropharyngeal route, often by kissing. The incubation period may be as long as 4 to 6 weeks, and pharyngeal excretion can persist for 1 year or more. A chronic form of the disease has been suggested as the cause of chronic fatigue syndrome, but recent data do not support this association.⁶⁶

EBV also has been strongly implicated in the pathogenesis of African Burkitt’s lymphoma and nasopharyngeal carcinoma. EBV is also expressed by Hodgkin’s lymphoma cells and is more frequently seen in certain groups of patients with Hodgkin’s lymphoma, such as children.⁶⁷ Other lymphomas in immunocompromised patients, such as renal transplant recipients or persons with AIDS, also have been associated with EBV infection.

Clinical Features.: Acute mononucleosis is a mild disease in most children. Those who acquire the disease as adults tend to have more symptomatic disease classically described as a syndrome of severe exudative pharyngitis, fevers, lymphadenopathy, and fatigue. About 95% of young adults have abnormal transaminases and 4% have jaundice. Hepatosplenomegaly is common. The disease generally resolves in 1 to 3 weeks, but malaise and fatigue rarely can persist for several months. On occasion, tonsillar swelling causes respiratory compromise. Splenic rupture is rare but should be considered in patients with left upper quadrant pain and a falling hematocrit. Neurologic complications, including encephalitis, aseptic meningitis, transverse myelitis, Guillain-Barré syndrome, optic neuritis, and peripheral neuropathies, occur in less than 1% of patients.

Diagnostic Strategies and Differential Considerations.: Laboratory diagnosis is based on the finding of lymphocytosis (more than 50% of the total white blood cell count) or an elevation in heterophil antibodies (Monospot test). Heterophil antibodies are sensitive and specific antibodies that usually appear early in the illness. Other assays for virus-specific antibodies are available but rarely are needed to diagnose mononucleosis because the patient is heterophil seropositive in 90% of cases.

A presumptive diagnosis can be made on the basis of the finding of significant cervical lymphadenopathy, particularly posterior cervical, and exudative pharyngitis coupled with a lymphocytosis and the presence of atypical lymphocytes on a blood smear. HHV-6, CMV, and Toxoplasma can cause syndromes that are clinically and hematologically similar to infectious mononucleosis.

Management.: Treatment is supportive only, except when rare complications of organ compromise are present. The use of corticosteroids in uncomplicated illness is controversial. These agents generally are used for impending airway obstruction, hemolytic anemia, or severe thrombocytopenia. Infection confers a high degree of resistance to reinfection. Patients should be cautioned about potential communicability to previously uninfected people.

Principles of Disease.: CMV, or human herpesvirus 5, commonly is associated with heterophil-negative infectious mononucleosis syndrome and is clinically and hematologically similar to EBV-associated mononucleosis. More severe infections with CMV occur in the perinatal period and among immunocompromised patients. Severe CMV infections also are found in transplant recipients when organs from CMV-seropositive donors are transplanted into CMV-seronegative recipients.

Primary infection with CMV often is associated with a vigorous T-lymphocyte response. CMV persists indefinitely, probably within multiple cell types in various organs. Reactivation leading to CMV-associated disease may occur in response to a variety of external stimulants.

Clinical Features.: CMV infection in immunocompetent older children and adults generally is subclinical. It is characterized by fever, lymphadenopathy, exudative pharyngitis, and peripheral lymphocytosis, with atypical lymphocytes present on peripheral blood smears. The acute infection resolves in 2 to 4 weeks, but malaise and viral excretion can persist for months. In the perinatal period, severe, generalized infection can occur and may be associated with lethargy, convulsions, jaundice, petechiae, hepatosplenomegaly, chorioretinitis, and pulmonary infiltrates. Survivors may exhibit various degrees of neurologic impairment. Fetal infection can occur after primary or reactivated maternal infections, with primary infections carrying a much higher risk. Severe, generalized disease can occur in immunocompromised patients and often is associated with severe end-organ disease, such as colitis, esophagitis, pneumonitis, retinitis, and adrenalitis. Retinitis caused by CMV was the most common cause of blindness among people with AIDS in the era before highly active antiretroviral therapy, but its incidence has fallen precipitously. CMV can cause a polyradiculopathy and other, less common neurologic manifestations in patients with AIDS or other conditions of immunocompromise. Therapy with ganciclovir and foscarnet is indicated, but treatment results may be disappointing.

Diagnostic Strategies and Differential Considerations.: Mononucleosis caused by CMV may be clinically indistinguishable from syndromes caused by EBV or Toxoplasma. In the perinatal period, infants with generalized infections require evaluation for other common perinatal infections, such as toxoplasmosis, rubella, syphilis, and HSV infection. Recipients of organ transplants and other immunocompromised patients with fever and other signs and symptoms of generalized infection require intensive evaluation for bacterial and viral causes of infection. Diagnosis of CMV infection depends on viral isolation, detection of CMV pp65 antigen, or the demonstration of a fourfold rise in antibody to viral antigens.

Management.: Only supportive care is indicated for infected immunocompetent adults and children, and they generally can be managed at home. CMV infection in the perinatal period or complicated by impairment of immune function can be life-threatening, and patients in whom such infections are suspected generally require hospitalization for aggressive evaluation, monitoring, and specialized care. Valganciclovir, ganciclovir, foscarnet, and cidofovir are useful in treatment of CMV infections in immunocompromised patients.

Principles of Disease.: The enteroviruses are spread from person to person by the fecal-oral route. As with poliovirus, inapparent infections greatly outnumber symptomatic cases.

All enteroviruses enter the body through the oropharynx and multiply in the tissues around the oropharynx. The viruses are stable in acid conditions and are capable of passing through the stomach to the intestines.

Clinical Features.: Most enteroviral infections are inapparent. The most common clinical presentation is that of a nonspecific febrile illness. Young children may be hospitalized with enteroviral fevers that simulate bacterial sepsis. Coxsackievirus B and some of the echoviruses may cause severe perinatal infection associated with fever, meningitis, myocarditis, and hepatitis.

Febrile diseases with rashes often are associated with enteroviruses. Exanthems resembling rubella occurring during the summer months have been seen with the echoviruses and Coxsackie A viruses. Vesicular lesions are seen, such as with the hand-foot-and-mouth syndrome caused by some Coxsackieviruses A and B. Herpangina, a specific disease characterized by a vesicular rash on the cheeks and soft palate and associated with fever, sore throat, and severe pain on swallowing, is caused by the Coxsackievirus A. Roseola-like exanthems and petechial exanthems also are associated with Coxsackievirus and echovirus infections.

The enteroviruses are the most common causes of viral meningitis. The course generally is benign, but enteroviral infections often can be confused with a bacterial process, particularly in the acute phase, when CSF analysis may show a neutrophil predominance.

Coxsackie B viruses are strongly associated with myocarditis, although echoviruses and Coxsackie A viruses also can cause the disease. Severe cases may lead to dysrhythmias, heart failure, or death.

Enteroviruses cause upper respiratory tract infections similar to other causes of the common cold. Interstitial pneumonias also can occur. Pleurodynia (Bornholm’s disease—the “devil’s grippe”) generally is associated with the Coxsackie B viruses. This disease involves the intercostal muscles and can last for several weeks.

Differential Considerations.: Other proven or suggested associations of the enteroviruses and disease include enterovirus 70 with acute hemorrhagic conjunctivitis, Coxsackieviruses and echoviruses with diarrhea and gastroenteritis, Coxsackieviruses and echoviruses with hemolytic-uremic syndrome, and enteroviruses with acute myositis. Other possible associations include chronic cardiomyopathy, aortitis, hepatitis, pancreatitis, orchitis, diabetes mellitus, lymphadenopathy, a mononucleosis-like syndrome, and infectious lymphocytosis. A progressive, dementing, chronic meningitis associated with enteroviruses has been reported in persons with common variable immunodeficiency syndromes.

Management.: No specific treatments are available for infections caused by the enteroviruses. Care is supportive. Vaccination against poliovirus and hepatitis A is recommended, and immune serum globulin also can prevent the acquisition of hepatitis A infection.

Principles of Disease.: Colorado tick fever, or mountain fever, is caused by a coltivirus similar to the orbiviruses that are transmitted to humans through the bite of the hard-shelled wood tick Dermacentor andersoni. It occurs primarily in the western United States, but a serotype has been isolated from the Ixodes ricinus tick in Germany and from the dog tick, Dermacentor variabilis, in Long Island, New York. Illness generally occurs in late spring through summer (see Chapter 134).

Clinical Features.: The incubation period for Colorado tick fever is 3 to 6 days, and a history of tick exposure is elicited in 90% of patients. The disease generally occurs in people engaged in activities that bring them into contact with ticks. The fever is biphasic, as indicated by a “saddle-back” curve plotting temperatures over time, with the patient initially acutely experiencing chills, lethargy, prostration, headache, ocular pain, photophobia, abdominal pain, and severe myalgias. The initial fever lasts 2 to 3 days, recedes for a similar period, and then is followed by a second fever lasting approximately 3 days. Rash, occasionally petechial, is uncommon, occurring in 5 to 10% of patients. Meningoencephalitis is a rare but serious complication in children. Convalescence lasts 1 to 3 weeks; half of infected persons are viremic 4 weeks after the onset of illness.⁶⁸

Differential Considerations.: Colorado tick fever commonly is misdiagnosed as Rocky Mountain spotted fever. Patients with fever and rash after tick bites in endemic areas should be treated for Rocky Mountain spotted fever. Confirmation of the diagnosis of Colorado tick fever is by mouse inoculation or fluorescent staining of erythrocytes.

Management.: Treatment is supportive and symptomatic.

Principles of Disease.: Rhinoviruses are the most common cause of the common cold. More than 100 strains exist. Rhinovirus transmission generally occurs primarily by hand contact and through inoculation of the eye or nasal mucosa and less commonly by aerosolization of respiratory secretions. Viral replication probably occurs on the epithelial surface of the nasal mucosa.

Clinical Features.: After a 1- to 4-day incubation period, the usual signs and symptoms of rhinoviral infection occur, including nasal obstruction, sneezing, sore throat, cough, and malaise. Severe tracheobronchitis and pneumonia occur rarely. Fever and lower respiratory tract infections are more common in children than in adults with rhinovirus infections.

Differential Considerations.: Other respiratory pathogens, such as coronaviruses, respiratory syncytial virus (RSV), parainfluenza viruses, influenza viruses, adenoviruses, and enteroviruses, can produce clinical syndromes similar to those produced by the rhinoviruses. The rhinoviruses in general cause less morbidity than that typical for the parainfluenza viruses and RSV.

Diagnostic Strategies.: Definitive diagnosis is made by the demonstration of a rise in antibody titer. New commercially available molecular assays include detection of rhinovirus in their viral panel.⁶⁹

Management.: Treatment is aimed at relief of symptoms. Routine vaccination appears to be an unlikely prospect because of the number of serotypes. Because hand-to-face inoculation appears to be the predominant means of transmission, frequent handwashing during epidemic periods may decrease the spread of rhinovirus infections.

Principles of Disease.: Adenoviruses are the most clinically important viruses because of their capacity to cause upper respiratory tract infections, conjunctivitis, and gastroenteritis. Nevertheless, no drugs or therapeutic measures specifically effective for adenoviral infections are available. Adenovirus is used as a vector in many vaccines that are being studied against viral pathogens (including rotavirus, hepatitis B, RSV, HIV, and Ebola), a growing area of vaccine research.

Clinical Features.: Adenoviruses cause respiratory diseases ranging from pharyngitis and tracheitis to fulminant bronchiolitis and pneumonia. Cough, fever, sore throat, and rhinorrhea are the most common symptoms and generally last only a few days. Pneumonitis with interstitial infiltrates is occasionally seen with some strains. Upper respiratory findings may be associated with conjunctivitis (pharyngoconjunctival fever). Adenoviruses may cause an epidemic keratoconjunctivitis, which in severe cases may be associated with conjunctival scarring. Other syndromes associated with adenoviruses include hemorrhagic cystitis, infantile diarrhea, intussusception, encephalitis, and meningoencephalitis.

Differential Considerations.: Other pathogens causing similar atypical pneumonia syndromes include influenza and parainfluenza viruses and Mycoplasma pneumoniae. Diarrheal syndromes may be similar to those caused by rotaviruses.

Diagnostic Strategies.: New molecular diagnostic assays may detect and differentiate adenovirus types (B, E); however, these are not widely available, and confirmatory testing is usually not performed, although it may be helpful for epidemiologic purposes.

Management.: Treatment of adenovirus infections is supportive.

Principles of Disease.: The severe acute respiratory syndrome (SARS) was first documented in China’s Guangdong province in November 2002. By the time the epidemic was contained in July 2003, it had affected approximately 8000 persons in 29 countries, with a case fatality rate of approximately 10%.⁷⁰ The causative agent was identified as a novel coronavirus (SARS-CoV).^71,72 Early in the epidemic, astute researchers noted that the illness was more prevalent among restaurant workers and focused attention on live animals that were being sold for human consumption. Their efforts revealed that the virus was transmitted to humans by handling and consumption of wild mammals, such as the civet.⁷³

By 2003, 161 cases of SARS had been reported in the United States, but no deaths were reported that were attributable to SARS.⁷⁰ Most patients had traveled to an area of documented or suspected SARS transmission.

The SARS epidemic posed a challenge to national and international agency–based medical personnel and public health authorities. Public health measures were implemented to contain the infection and to establish sentinel systems to warn of recurrent outbreaks. Health care practitioners, especially ED personnel, should notify local public health authorities of suspected or confirmed cases of SARS.

Clinical Features.: The current CDC case definition for SARS-CoV disease includes the presence of laboratory-confirmed infection or severe respiratory illness in the setting of epidemiologic criteria for likely exposure to SARS-CoV.⁷⁰ Early disease is defined by the presence of two or more of the following features: fever (which may be subjective), chills, rigors, myalgia, headache, diarrhea, sore throat, and rhinorrhea. Mild to moderate disease requires presence of fever with temperature higher than 38° C and evidence of lower respiratory tract illness. Severe respiratory illness is defined as noted previously but also includes radiographic evidence of pneumonia or acute respiratory distress syndrome.⁷⁴ Laboratory diagnosis of the disease relies on SARS-CoV antibody testing, cell culture, or reverse transcription–PCR (RT-PCR) techniques. Epidemiologic criteria for possible exposure include travel within the past 10 days to an area with documented or suspected recent transmission of SARS-CoV or close contact with a symptomatic person who recently engaged in such travel. Epidemiologic criteria for likely exposure require that transmission be somehow linked to a person with confirmed disease.⁷⁵

Retrospective analyses of the SARS-CoV infection outbreak suggest an incubation period of 3 to 10 days with an ensuing viral prodrome characterized by headache, malaise, and myalgias. Fever, clinical evidence of upper and lower respiratory infection, dyspnea, and gastrointestinal disturbances also may be features. Chest radiographs are normal in appearance in up to 25% of patients with early infection, despite the presence of fever and respiratory complaints. CT scans may be more useful in identifying early pulmonary involvement. Hypoxemia, with clinical and radiographic evidence of pneumonitis, develops as the disease progresses. In a minority of patients, progressive respiratory failure and acute respiratory distress syndrome may follow. Patients older than 60 years and those with comorbid illness, such as diabetes mellitus, have worse outcomes.74–76 A Hong Kong study reported reliable results when diagnostic criteria were combined with variables including exposure, history, and laboratory findings.⁷⁷

Diagnostic Strategies.: Laboratory findings are nonspecific but include lymphopenia, thrombocytopenia, elevated lactate dehydrogenase, and prolonged activated partial thromboplastin time. Hemolytic anemia and electrolyte disturbances, such as severe hypomagnesemia with associated tetany, have been reported.⁷⁸ Serologic testing for antibody to SARS-CoV is most reliable if it is performed more than 21 days after infection, and PCR analysis may be negative early in the course of illness.

Differential Considerations.: The clinical features of SARS-CoV mimic those of many community and nosocomial respiratory infections, so the differential diagnosis is broad in scope. The initial workup should include routine laboratory and radiographic evaluations similar to those for other, more common respiratory infections. A greater level of suspicion for SARS-CoV infection should be entertained on the basis of travel or exposure history. Specific testing for coronavirus can be conducted through the health department.

Several outbreaks of SARS-CoV infection have occurred after exposure of patients or medical staff to a sentinel case or to a clinical specimen.⁷⁹ Therefore, effective evaluation and management of suspected or proven cases of SARS-CoV disease should begin with a travel and occupational history, astute clinical observation, appropriate triaging, and patient isolation measures. Quarantine of persons who may be in the incubation period has proved useful in containing outbreaks.⁸⁰ Contact and airborne precautions should be instituted, and protective eyewear should be considered. Detailed guidelines for the diagnosis, isolation, treatment, and disposition of patients with suspected or proven SARS-CoV infection are continually being updated by the WHO and the CDC. These guidelines are available at www.cdc.gov and www.who.int; local health officials also can be contacted for guidance.

Management.: No therapeutic measures beyond supportive care have been shown to be clearly effective for the treatment of SARS-CoV infection. Patients with signs and symptoms of lower respiratory tract infection should be treated with conventional antibiotic and supportive therapy, even if they are suspected of having SARS-CoV infection.

Disposition.: It is not necessary to hospitalize all patients who are thought to have been exposed to or to have a respiratory syndrome that could be attributed to SARS-CoV infection. Persons well enough to be cared for at home should be placed in home quarantine with contact and airborne precautions. Termination of quarantine precautions for suspected SARS-CoV infection should be done in consultation with public health officials. Infection control is of the utmost importance, given the increased risk to health care workers and of nosocomial transmission; particular care must be paid to procedures at high risk for aerosolization of the virus, including intubation and nebulization.80,81 Expert consultation from an infectious disease specialist and public health authorities is recommended.

Principles of Disease.: Coronaviruses are agents of the common cold in adults and of lower respiratory tract disease in children. More commonly causing epidemic diarrheal disease in pigs and cows, they have recently been implicated in diarrheal disease in children.

Clinical Features.: Coronaviruses primarily cause upper respiratory tract disease in adults. Lower respiratory tract infections caused by coronaviruses occur uncommonly in adults and more commonly in children. They appear to cause diarrheal disease in children younger than 1 year.

Differential Considerations.: Coronaviruses probably account for 15% of adult colds. Rhinoviruses account for most of the rest, with parainfluenza viruses, influenza viruses, RSVs, adenoviruses, and enteroviruses also causing upper respiratory infections and colds. Rotaviruses, Norwalk viruses, and enteroviruses cause most viral cases of gastroenteritis in children.

Management.: Treatment of most coronavirus infections is supportive only, including oral or intravenous fluids.

Clinical Features.: The parainfluenza viruses are the most common causes of croup in children and, along with RSV, are the most common causes of lower respiratory tract infections that require hospitalization in infants.

The virus is passed by way of the respiratory route, and hand–to–mucous membrane transmission is the likely mode of spread. The incubation period most often is 1 to 4 days, and the clinical picture is that of a febrile illness lasting approximately 4 days.

Infection with the parainfluenza viruses does not confer lasting immunity. Parainfluenza virus type 1 is the predominant cause of croup, or laryngotracheobronchitis, occurring during the autumn months in children younger than 3 years. Parainfluenza virus type 2 also is associated with croup, causes less morbidity than type 1, and often occurs in alternate years with type 1. Parainfluenza type 3 infections occur in the spring and are associated with bronchiolitis and pneumonia in infants younger than 1 year, similar to RSV. Parainfluenza type 3 also is associated with croup in children younger than 3 years and with tracheobronchitis in older children. Parainfluenza type 4 is recovered less often but appears to be associated with mild respiratory illness. Severe croup or bacterial superinfection of laryngotracheitis may lead to respiratory compromise.

Differential Considerations.: Viruses causing upper respiratory tract infection similar to that caused by the parainfluenza viruses include adenoviruses, rhinoviruses, influenza virus, RSV, echoviruses, Coxsackieviruses, and coronaviruses. Identification of parainfluenza viral infection can be made by demonstrating a fourfold rise in antibody titer between acute and convalescent serum.

Management.: Croup may be worse at night; mist inhalation often is helpful. Nebulized racemic epinephrine can be used to treat severe croup, but the relief it affords can be short-lived, and return to pretreatment state can be seen within 2 hours of therapy. Intramuscular steroids have been shown to be helpful, and their use has been associated with a decreased requirement for hospitalization of children with croup.⁸² A single dose of oral dexamethasone at 0.6 mg/kg has been shown to reduce return visits to a health care practitioner.⁸³ The parainfluenza viruses can cause reinfection within months of the primary infection, so prevention of infection is unlikely to be feasible. More aggressive tracheal diseases, such as laryngotracheobronchitis and laryngotracheobronchopneumonitis, may be caused by viruses, but most are often a result of superinfection with bacteria, including Staphylococcus aureus and group A streptococci.⁸⁴

Principles of Disease.: Influenza generally is a self-limited infection of the upper respiratory tract associated with fever, cough, coryza, sore throat, and malaise. Three types of influenza are recognized. Type A has been associated with most widespread epidemics and pandemics and is associated with most of the deaths caused by influenza. Influenza B causes regional or widespread epidemics every 2 to 3 years. Influenza C is associated with sporadic cases.⁸⁵

Clinical Features.: The usual clinical disease caused by influenza begins 1 to 4 days after exposure to aerosol respiratory secretions. Clinical manifestations include fever accompanied by myalgias, coryza, conjunctivitis, headache, and nonproductive cough. Patchy infiltrates can be seen on the chest radiograph. Signs and symptoms generally last only a few days, but fatigue and malaise may persist for weeks. The most common serious complications of influenza, particularly among elders and persons with chronic diseases, are pneumonia caused by influenza itself and pneumonia attributable to secondary bacterial infections. More than 90% of deaths during seasonal epidemics are due to exacerbation of cardiopulmonary disease in elders.⁸⁵ Rare complications of influenza infection include aseptic meningitis, pericarditis, and a postinfectious neuritis that resembles the Guillain-Barré syndrome.

Diagnostic Strategies.: Viral culture remains the “gold standard” modality for the laboratory diagnosis of influenza, but results often are not timely enough to aid in clinical decisions for therapy. Several rapid assays using nasal specimens for the diagnosis of influenza A or B are commercially available. Rapid influenza diagnostic tests are direct antigen tests that provide results in less than 30 minutes. Some can distinguish between type A and B viruses; however, their sensitivity varies from 10 to 70% and may be greater in children and during the first 48 hours of illness when viral shedding is highest.⁸⁶ Positive bedside test results are associated with increased use of antivirals and decreased use of antibiotics in both pediatric and adult patients^87,88; however, because of their low sensitivity, they are best used for screening and for “ruling in” disease, but they cannot reliably exclude influenza in a patient presenting with influenza-like illness.⁸⁹ Therefore, clinical decisions should be based on clinical suspicion of influenza-like illness. Real-time PCR assays are now available for confirmation of influenza, with enhanced sensitivity and specificity and the capability of specific influenza type detection, including novel H1N1.⁹⁰

Differential Considerations.: The syndromes produced by the influenza viruses overlap with those produced by other viruses, such as the parainfluenza viruses, RSV, adenoviruses, coronaviruses, and echoviruses.

Management.: General supportive measures will ameliorate the symptoms of influenza. The neuraminidase inhibitors zanamivir and oseltamivir have been approved for treatment of both influenza A and B. The dose of oseltamivir should be decreased to 75 mg once daily in patients with creatinine clearance less than 30 mL/min. Zanamivir or oseltamivir should be administered within 2 days of onset of symptoms if efficacy is to be expected.¹⁶ Vaccination is recommended yearly for all children 6 months to 5 years of age, adults older than 50 years, and persons at high risk for significant morbidity or death from influenza; these include immunosuppressed patients, those with chronic illnesses, and pregnant women. Vaccination is also recommended for health care workers and persons who are household contacts of infected persons younger than 5 years or older than 50 years. In addition, the CDC recommends annual vaccination for all persons “who want to reduce the risk of becoming ill with influenza or of transmitting influenza to others.” Aspirin and aspirin-containing products should be avoided, especially among children and adolescents, particularly during influenza epidemics, because of the association between the use of aspirin during a bout of influenza and the subsequent development of Reye’s syndrome.⁵²

A highly pathogenic strain of avian influenza virus, H5N1, was first reported in a farmed goose in China in 1996.⁹¹ Since then, the virus has spread among wild birds and poultry across the Asian continent into large parts of Europe and some areas in Africa. H5N1 has yet to be reported among fowl in the Americas or Australia. Human disease attributable to highly pathogenic avian influenza virus has been reported in several countries of Asia, the Middle East, and Africa. Although direct human contact with affected birds appears to be the major mode of transmission, human-to-human spread has been documented, and cases of unexplained transmission indicate that environment-to-human transmission may be possible.⁹² The incubation period is less than a week. Clinical disease can range in severity from an asymptomatic or mildly symptomatic viral syndrome to a highly fulminant and deadly illness and includes influenza-like illness, often prominent conjunctivitis, and gastrointestinal manifestations.⁹³

Highly pathogenic avian influenza virus infection should be suspected in a person who is at risk for contraction of the illness because of exposure to a known disease reservoir and who has a progressive respiratory illness.⁹⁴ Public health officials should be contacted if the disease is suspected, and full infection control measures should be instituted. Early antiviral therapy with oseltamivir at high doses (150 mg twice a day) and possibly with amantadine or rimantadine is recommended along with appropriate supportive care.⁹⁵ Oseltamivir-resistant H5N1 has been described.⁹³ Postexposure prophylaxis and the use of antiviral medication for asymptomatic persons during an outbreak should be prescribed in consultation with disease experts.

As of January 2011, there have been 525 laboratory-confirmed cases with 310 deaths reported by the WHO; actual morbidity and mortality figures probably are higher.⁹⁶ Despite aggressive public health measures, such as culling of affected fowl populations, many experts think that avian influenza can become a serious global pandemic.

Principles of Disease.: Infections with RSV occur worldwide, mostly in midwinter to late spring. Infants with pneumonia show marked inflammation in the interstitial tissue and alveoli of the lungs, whereas infants with bronchiolitis show less alveolar involvement but may exhibit marked changes in the bronchioles. Severe disease may result in obstruction of bronchioles with evidence of peripheral airway obstruction or emphysema. Transmission is through contact with respiratory secretions and probably also by hand-to-nose or eye droplet inoculation.

Infections caused by RSV account for up to 18% of ED visits in children younger than 5 years and the largest number of hospitalizations for respiratory infections in infants.¹⁰⁰ Bronchiolitis and pneumonia, the most severe manifestations of RSV infection, commonly occur in children younger than 6 months. Risk factors include prematurity and low birth weight, but most children who acquire the disease are healthy.^101–103 Children older than 1 year are less likely to have lower respiratory tract infection. Older children and adults commonly have upper respiratory symptoms and cough, but older patients may have severe disease. Furthermore, RSV may be an important contributor to adult asthma exacerbations.

Clinical Features.: The average incubation time for RSV infections is 2 to 8 days. The most common manifestations are bronchiolitis and pneumonia in infants; tracheobronchitis, croup, and otitis media in young children; and upper respiratory infections in older children and adults. Bronchiolitis in infancy may lead to an increased risk of asthma and the development of chronic obstructive airway disease in later life. Fatal disease can occur in immunocompromised infants.

Diagnostic Strategies.: The diagnosis of RSV infection can be made definitively by culture of the virus or detection of RSV antigens from respiratory secretions, nasal wash specimens, or nasopharyngeal or throat swabs. Commercial viral panels based on molecular technology include testing for RSV; however, these are not readily available in most EDs and may be more useful to determine the need for isolation precautions in patients, particularly infants.

Differential Considerations.: The syndromes associated with RSV infections overlap those due to other upper and lower respiratory tract pathogens, including rhinovirus, parainfluenza and influenza viruses, echoviruses, Coxsackieviruses, and coronaviruses. RSV infection can be presumptively diagnosed in an infant with pneumonia or bronchiolitis when no bacterial pathogens are noted. Noninfectious causes of hypoxemia in infants, such as foreign body aspiration and asthma, also should be considered.

Management.: Therapy for RSV infection is largely supportive. For infants sick enough to be hospitalized, aerosolized ribavirin has been shown to shorten the duration of illness and to ameliorate hypoxemia in normal infants. Corticosteroids have not been shown to be beneficial. During the winter, high-risk infants can be protected against RSV infection with monthly infusions of human RSV immune globulin or with monthly intramuscular injections of palivizumab, a monoclonal anti-RSV antibody preparation.¹⁰⁴ Palivizumab is recommended in cardiac disease, preterm infants, chronic lung disease, and immunocompromised children and may decrease intensive care unit admission and mortality^105–107; however, cost-effectiveness analysis suggests that prophylaxis is best used in high-risk groups.¹⁰⁸ Severe disease may occur in immunocompromised infants, and respiratory precautions are required to prevent transmission from patient to patient and staff to patient. After failed attempts at a vaccine in the 1960s, which paradoxically caused exacerbations of RSV disease, efforts are ongoing to create live attenuated virus and purified subunit vaccines, and early results have been encouraging.¹⁰⁹

Principles of Disease.: Human metapneumovirus is a recently discovered paramyxovirus associated with respiratory illness during the winter months. It causes lower respiratory tract disease that is typically more severe in infants and young children.110,111 Initial symptoms are similar to those of the common cold but occasionally can lead to acute respiratory distress syndrome, especially in immunocompromised children.

Diagnostic Strategies.: Diagnosis can be made by RT-PCR as part of molecular viral respiratory assays that detect a broad range of pathogens from nose, throat, and nasopharyngeal washes.¹¹²

Management.: Treatment is supportive. Consultation with a pediatric infectious disease or pulmonary specialist is recommended for hospitalized patients.

Principles of Disease.: St. Louis encephalitis occurs in the summer in most areas of the Western Hemisphere. After an incubation period of 4 to 21 days, infection with the St. Louis encephalitis virus can produce fever and headache, aseptic meningitis, or encephalitis. The mortality rate associated with the encephalitis approaches 10%. The disease commonly affects elders.

West Nile virus causes a febrile illness, with potential for meningoencephalitis. It was first described in the United States in 1999 but also has caused illness in many areas of Africa, Asia, and Europe.¹¹³ In 2003, the CDC confirmed 9858 cases and 262 deaths attributable to West Nile virus, qualifying this epidemic as the largest outbreak of arboviral meningoencephalitis recorded in the Western Hemisphere.¹¹⁴ However, in 2010, only 1021 cases were reported, suggesting decreasing activity or reporting of this illness in humans.¹¹⁵ The primary cycle of infection is maintained by vector mosquitoes in bird populations. Humans are infected by cross-feeding mosquitoes. The virus has disproportionately affected certain bird populations in the United States, resulting in bird deaths. Recognition of this phenomenon led to early elucidation of the life cycle and has helped in characterization of the zoonotic activity of the virus.

Non–arthropod-borne human cases from laboratory transmission and person-to-person transmission by blood transfusion, organ transplantation, maternal-fetal transmission, or breast-feeding have been documented. These modes of transmission account for a small number of cases.¹¹³ It is now clear that the virus has established itself in North America, and yearly outbreaks are to be expected. The peak incidence of disease is during the months of July through October; however, as the disease has moved into the southern states, transmission is being reported as early as April and as late as December.¹¹³

Clinical Features.: The incubation period for West Nile virus appears to be 3 to 14 days. West Nile fever will develop in 20% of infected persons, and meningitis or encephalitis will develop in 1 in 150.116,117 West Nile fever usually is characterized by fever, headache, myalgia, anorexia, and lymphadenopathy; half of infected patients have a maculopapular central rash. West Nile virus meningoencephalitis is characterized by fever, headache, mental status changes, and motor disturbances that range from generalized weakness to myoclonus, tremor, and parkinsonian movement disorders. A poliomyelitis-like syndrome has been described.¹¹⁸ Cranial nerve and bulbar abnormalities can be seen.¹¹⁵

Diagnostic Strategies.: Laboratory testing is nonspecific. CSF findings in patients with meningoencephalitis are similar to those with other viral infections: elevated protein level, normal glucose level, and a mild-to-moderate pleocytosis with a lymphocytic predominance. Viremia usually clears by the onset of meningoencephalitis, but immunoglobulin M (IgM) can be detected in the CSF. IgM levels in the serum can remain elevated long after clinical illness has resolved. Imaging studies are nondiagnostic, but the MRI scan can show nonspecific leptomeningeal inflammation.¹¹⁵

Disease outcome is related to age of the patient; elders are at significantly higher risk for the development of encephalitis and death from West Nile virus infection.114,115 Patients with disease severe enough to necessitate hospitalization often have long-term sequelae.

Principles of Disease.: Arboviruses (arthropod-borne viruses) are transmitted to humans by an arthropod vector; humans usually are an unimportant host in the reproductive cycle of the virus. Most arboviruses are mosquito borne, but ticks, sandflies, gnats, and midges serve as important vectors for some diseases. The alphaviruses and flaviviruses are the most common arboviruses causing disease in humans, but some bunyaviruses, reoviruses, rhabdoviruses, filoviruses, arenaviruses, and orthomyxoviruses also are transmitted by arboviral vectors.

The alphaviruses are transmitted by the bite of a mosquito. The three alphaviruses that cause human disease in the United States are the agents of eastern equine encephalitis, western equine encephalitis, and Venezuelan equine encephalitis. Other important alphaviruses include the chikungunya (Africa, Southeast Asia, Philippines), Mayaro (South America), o’nyong-nyong (Africa), Ross River (Australia, South Pacific), and Sindbis (Africa, Asia, Soviet Union, Australia, and Scandinavia) viruses.

Clinical Features.: These arboviruses can cause outbreaks of encephalitis. The few annual cases of eastern equine encephalitis in the United States occur predominantly near freshwater swamps of the eastern seaboard. Although more than 95% of cases are subclinical, the mortality rate among patients presenting with clinical encephalitis approaches 50%. Infections occur most commonly in children younger than 10 years or in elders. The onset of symptoms often is fulminant, with headache, fever, and convulsions progressing rapidly to decreasing level of consciousness and death. Focal neurologic deficits also may develop. Western equine encephalitis is present throughout the United States but occurs mostly in the western and central parts of the nation. Children younger than 1 year and elders are most often affected. More than 99% of cases are inapparent, and the encephalitis usually is mild, with an associated mortality rate of approximately 3%. Venezuelan equine encephalitis is found predominantly in Central and South America, but the disease has been seen in Texas and Florida. Venezuelan equine encephalitis usually is manifested as an influenza-like illness. One third of patients have encephalitis, with a mortality rate of less than 1%, predominantly in children.

Diagnostic Strategies.: The white blood cell count in the CSF of persons with eastern equine encephalitis may be very high, and the diagnosis of meningoencephalitis must be considered. Diagnoses can be confirmed by a rise in antibody titers.

Differential Considerations.: Other viral causes of encephalitis in the United States include HSV, HIV, St. Louis encephalitis (a flavivirus), California (La Crosse) encephalitis (a bunyavirus), and the recently encountered West Nile–like encephalitis (a flavivirus). Other viruses, such as mumps, rabies, polio, and other enteroviruses, can also be manifested as encephalitides.

Management.: Management is supportive only. For people with expected intensive exposure to these viruses, an investigational vaccine may be available from the U.S. Army Medical Research Institute for Infectious Diseases in Fort Detrick, Maryland.

Principles of Disease.: JC virus and BK virus are human polyomaviruses that cause ubiquitous but asymptomatic infection in populations worldwide. Progressive multifocal leukoencephalopathy (PML) is a rare, slowly progressive, demyelinating CNS disease associated with JC virus. The demyelinated lesions of PML slowly enlarge to become large plaques, associated with progressive neurologic deterioration, dementia, and eventually death. The disease occurs mostly in severely immunocompromised patients.¹¹⁹ Similarly, BK virus viruria is relatively common in immunosuppressed patients or pregnant women. Rare, symptomatic infection can be manifested as urethral stenosis in renal transplant recipients and as hemorrhagic cystitis in bone marrow transplant recipients.

Clinical Features.: Initial presentations of PML in immunocompromised patients include paresis, personality changes, and impaired higher cortical functioning. The disease generally is rapidly progressive, usually progressing to death within 2 to 4 months of the initial neurologic symptoms. PML commonly is seen in people with advanced AIDS.

Diagnostic Strategies.: A lack of enhancement on contrast-enhanced CT and MRI scans is helpful in making the diagnosis. PCR assay identification of JC virus in the appropriate clinical setting with consistent radiographic findings establishes the diagnosis.

Differential Considerations.: Considerations in the differential diagnosis include other causes of progressive neurologic disease in immunocompromised patients—toxoplasmic encephalitis, primary CNS lymphoma, HIV encephalopathy, tuberculous meningitis, vascular disease, and others.

Management.: No specific treatment of PML is available; the disease generally is rapidly progressive, and ultimate transfer to appropriate nursing care facilities often is necessary. There have been reports of significant improvements in persons with AIDS who have been prescribed potent antiretroviral (anti-HIV) therapy.¹²⁰

Principles of Disease.: Poliomyelitis is an acute viral infection that ranges in severity from an inapparent infection to a nonspecific febrile illness to aseptic meningitis to severe paralysis and death. Since the introduction of polio vaccination in the United States, only a handful of cases of paralytic poliomyelitis have been diagnosed each year, and most of these cases are either imported or vaccine associated. Since OPV was replaced by IPV in 2000, there have been no reports of vaccine-associated paralytic polio in the United States, although rare cases of imported paralytic polio have been reported.¹²¹

Poliovirus is transmitted during close contact; transmission both by the fecal-oral route and through contact with respiratory secretions has been documented. Susceptibility to poliovirus is universal, but paralytic infections are rare, increasing in incidence with age at the time of infection. At least 95% of infections are inapparent or asymptomatic.

Clinical Features.: With paralytic poliomyelitis, the usual incubation period is 7 to 14 days. The disease in children usually is biphasic, with a brief viremic phase lasting 1 to 3 days. After recovery for 2 to 5 days, an abrupt onset of headache, fever, malaise, vomiting, and CSF pleocytosis ensues. This meningitic phase lasts 1 to 2 days before the beginning of weakness and flaccid paralysis. Bulbar paralytic poliomyelitis involves paralysis of the muscle groups innervated by the cranial nerves. The most important complications of paralytic poliomyelitis are respiratory, especially respiratory failure caused by paralysis of the respiratory muscles, aspiration pneumonia, and pulmonary embolism. Myocarditis may rarely occur. Muscle paralysis usually lasts only 1 to 3 days after its onset. A postparalytic paralysis syndrome has been described in which neuromuscular weakness recurs several decades after resolution of the acute poliovirus infection.

Differential Considerations.: Paralytic poliomyelitis usually can be recognized on clinical presentation. Other enteroviruses can cause a similar syndrome. Guillain-Barré syndrome and postencephalitic syndromes may resemble paralytic poliomyelitis. Considerations in the differential diagnosis for nonparalytic poliomyelitis include any of the causes of bacterial and viral meningitis and encephalitis. The definitive diagnosis is made by isolation of the virus from fecal material or respiratory secretions.

Management.: Specific antiviral treatment of poliomyelitis is not available. Management is supportive, and reporting to local health authorities is mandatory. In the acute phase of paralytic poliomyelitis, patients require hospitalization.

Routine vaccination in the United States has dramatically reduced the number of cases of paralytic poliomyelitis. The Salk IPV is recommended for most indications in the United States. IPV has the advantage of preventing paralytic disease, but it does not protect susceptible contacts by secondary spread. The Sabin OPV protects susceptible contacts, but it is associated with vaccine-associated cases of paralytic disease. In 2000 the CDC recommended that all U.S. children receive four doses of IPV at ages 2, 4, and 6 to 18 months and 4 to 6 years.⁵

Principles of Disease.: Caliciviruses and astroviruses are small RNA viruses that have been implicated in outbreaks of gastroenteritis, predominantly in children. The noroviruses (which include the Norwalk virus) and the sapoviruses are caliciviruses. The sapoviruses cause gastroenteritis in children, whereas the noroviruses affect people of all ages. Norovirus may peak in the winter months and often is associated with outbreaks in populations living in close quarters (such as cruise ships).¹²²

Clinical Features.: All age groups are affected and the clinical presentation is that of gastroenteritis. The incubation period probably is 1 to 4 days, and the disease lasts 1 to 3 days. Norovirus is very contagious and is responsible for up to half of all reported gastroenteritis outbreaks.¹²³ The disease is generally mild and accompanied by low-grade fever, although more prolonged and severe cases can occur among young children and elders. Vomiting appears to be less common with astroviral disease than with calicivirus infections. One third of outbreaks of gastroenteritis can be attributed to a Norwalk virus–like agent. Diarrhea induced by these agents is associated with transient fat malabsorption. Outbreaks have occurred in schools and other institutions and through the ingestion of inadequately cooked shellfish. The mode of transmission is unknown but probably is by the fecal-oral route. Vomiting and diarrhea occur along with myalgias, malaise, headache, and low-grade fever. Severe diarrhea is rare and stools are not bloody. Electron microscopy can make the definitive diagnosis.

Diagnostic Strategies.: The majority of clinical virology laboratories perform real-time PCR assays for detection of norovirus; however, these tests are not approved by the Food and Drug Administration. Although there are commercial kits available, they are not widely available. DNA sequencing can be performed on positive specimens to type strains. Enzyme immunoassay results should be confirmed by PCR.¹²⁴ In practice, these assays are most useful to confirm an outbreak, but given the lack of specific treatment of norovirus infection, they are not useful in most cases of clinical illness.

Differential Considerations.: Other causes of gastroenteritis associated with a similar syndrome include adenoviruses, enteroviruses, and coronaviruses.

Management.: Treatment is supportive. The gastroenteritis generally is self-limited and resolves without specific therapy. Oral rehydration solutions generally are adequate; rarely, intravenous therapy is required.

Principles of Disease.: Rotaviruses derive their name from their wheel-like appearance on transmission electron microscopy. These organisms cause severe gastroenteritis in infants and young children, particularly between the ages of 6 months and 2 years; the gastroenteritis is manifested by severe diarrhea and vomiting, which often lead to dehydration and occasionally death. In temperate climates, illness occurs mainly in the winter, commonly is associated with nosocomial infection, and is spread primarily from person to person by the fecal-oral route. The incubation period is approximately 2 days.

Clinical Features.: Mucosal epithelial cells of the small intestine appear to be infected selectively, leading to shortening of villi and decreased absorption of salt and water. A secretory diarrhea is produced with impaired D-xylose absorption. Clinical disease ranges from asymptomatic to severe, fatal diarrhea and dehydration. The illness is abrupt in onset with nausea, vomiting, watery diarrhea, low-grade fever, headache, and myalgias. The course of the disease generally is 3 to 5 days in duration. Fatalities are common in developing countries but rare in developed regions of the world.¹²⁵ In newborns, rotavirus has been associated with neonatal necrotizing enterocolitis. Infections in adults usually are asymptomatic.

Diagnostic Strategies.: Radioimmunoassays, enzyme immunoassays, and latex agglutination methods for detection of antigen are highly reliable and available at most hospital laboratories.

Differential Considerations.: Rotavirus enteritis should be suspected in any child with watery diarrhea occurring during the cooler months of the year. Fecal leukocytes and erythrocytes generally are not seen in rotaviral diarrhea. Other enteric viruses can produce a clinical syndrome similar to that due to rotavirus.

Management.: Specific treatment of rotaviral infections is not currently available. Intravenous fluids provide effective therapy for dehydration, but if the patient tolerates oral fluids, oral rehydration with packaged oral rehydration salts can be used in the outpatient setting for mild to moderate dehydration. An attenuated human rotavirus vaccine and a human-bovine reassortant rotavirus vaccine have been shown to be both efficacious and safe in trials conducted in both developed and developing countries.126,127 Currently, the human bovine reassortant vaccine is approved in the United States as a three-dose (at 2, 4, and 6 months of age) orally administered live vaccine. Although there were concerns about the association of intussusception with rotavirus vaccination, a new oral vaccine (Rotarix) has been shown to be effective and not associated with intussusception in Latin America, Europe, Asia, and Africa. A second vaccine, RotaTeq, is also efficacious.¹²⁸

Principles of Disease.: More than 60 flaviviruses have been identified, with more than 20 causing human disease. Four of the most common, all transmitted to humans by a mosquito vector, are the agents of yellow fever, dengue, St. Louis encephalitis, and West Nile virus.

Clinical Features.: Yellow fever is present in tropical South America and Africa. Fever, chills, headache, nausea, and vomiting follow a 3- to 6-day incubation period. The disease may be biphasic, with fever, jaundice, hemorrhage, and characteristic “black vomit” (from the coagulopathy secondary to an affected liver) occurring after a brief period of remission. The case fatality rate is 5%.

Dengue occurs in tropical areas worldwide. Classic dengue fever (breakbone fever) is a nonfatal disease characterized by fever, headache, arthralgias, weakness, nausea, and anorexia after an incubation period of 5 to 10 days. Patients may experience severe bone pain. A generalized macular rash that occasionally desquamates may be seen. The fever lasts 5 to 7 days, but the recovery period may be prolonged. Dengue hemorrhagic fever, characterized by increased vascular permeability and bleeding associated with thrombocytopenia, carries a mortality rate of less than 5% in people who receive good medical care but up to 50% in those left untreated. Prior exposure to a dengue serotype with the production of cross-reactive antibodies and virulence plays an important role in the pathophysiologic process of dengue hemorrhagic fever.¹²⁹ The number of reports of dengue transmission within the United States on the U.S.-Mexico border in Texas and in Hawaii has been increasing.^130,131 Dengue serotype 2 (DENV-2) has been associated with periodic outbreaks of illness in Puerto Rico and the U.S. Virgin Islands, with a high proportion developing dengue hemorrhagic fever, especially among elders.¹³² With a population that shows evidence of previous exposure to dengue fever and the continued presence of the Aedes aegypti mosquito, the potential for cases of dengue hemorrhagic fever in persons without a recent history of foreign travel certainly exists. The possibility of dengue fever and its hemorrhagic form should be considered in all persons presenting with suggestive symptoms, even if they have not traveled outside the United States.

Diagnostic Strategies.: Viral antigen detected in the blood by enzyme-linked immunosorbent assay provides for a rapid diagnosis. Diagnosis of St. Louis encephalitis is made by serology. West Nile virus infection occurs most often in the summer and fall and may be clinically indistinguishable from other arboviral illnesses. CSF IgM antibody testing is the best means of establishing the diagnosis, but results may be falsely positive after other flaviviral infections, such as St. Louis encephalitis, or after immunization against yellow fever.¹¹⁷

Differential Considerations.: The differential diagnosis for yellow fever is broad in scope; considerations include hepatitis, malaria, typhoid, dengue, and other viral hemorrhagic fevers in endemic areas. The differential diagnosis for dengue is similar to that for yellow fever. Diagnosis is made by viral isolation or serology. St. Louis encephalitis can be manifested like other causes of meningoencephalitis. In elders, it may be misdiagnosed as stroke.

Management.: Treatment of these viral diseases is supportive. The diseases are not contagious through person-to-person contact, but the virus generally is transmissible to the mosquito vector during the period of clinical illness. Control of epidemics is achieved by reducing the mosquito vector populations and limiting access of mosquitoes to infected hosts. Persons traveling to endemic areas should be vaccinated for yellow fever.¹³³

No recommended therapies are currently available. Several vaccine candidates are under investigation, including a chimeric dengue fever–yellow fever vaccine in phase 3 trials.¹³⁴ Physicians should join public health officials in aggressive efforts to educate the public on mosquito control and bite protection measures, such as the use of repellents and protective clothing.

Principles of Disease.: Marburg and Ebola viruses cause a systemic febrile illness associated with multiorgan failure. Although the viruses have infected African green monkeys and cynomolgus monkeys, respectively, the infection is fatal to the monkeys, and the natural reservoir is unknown. Recent reports indicate a possible reservoir in certain bat species, but definitive proof is lacking.¹³⁵ Monkey-to-human and human-to-human transmission through contact with contaminated tissues or materials has been documented. Aerosol transmission has not been reported.

Clinical Features.: The illness is of sudden onset 2 to 10 days after exposure to infected tissue or contact with contaminated materials. Headache, fever, myalgias, arthralgias, and lethargy are early signs. The cardinal sign is diffuse coagulopathy. With both Marburg and Ebola infections, documented mortality rates are greater than 90%. Human infection with Marburg virus was documented in Germany and the former Yugoslavia as a result of contact with imported green monkeys. Human outbreaks also have been documented in the Democratic Republic of the Congo and Angola.¹³⁶ More than 1850 cases of Ebola have been documented worldwide, with more than 1200 deaths.¹³⁵

Diagnostic Strategies.: Diagnosis is made by isolation of the virus from blood or demonstration of rising antibody titers. New diagnostic strategies include enzyme-linked immunosorbent assays to detect filovirus-specific antibodies¹³⁷ as well as RT-PCR.¹³⁸

Differential Considerations.: Marburg and Ebola virus diseases may appear clinically similar to other African hemorrhagic fevers, particularly Rift Valley fever, Lassa fever, and yellow fever.

Management.: No vaccine or specific treatment exists; treatment is supportive. A number of vaccine candidates are being developed and have been shown to be effective in animal models; however, human studies are thus far lacking.¹³⁹

Principles of Disease.: California encephalitis viruses, including the La Crosse and Johnson Canyon viruses, are transmitted by mosquito bites, predominantly in the northern United States in the summer and fall. Approximately 100 cases are reported yearly. Infection is mostly asymptomatic, but the mortality rate associated with the encephalitis is up to 3%.¹⁴⁰

The Bunyaviridae family of viruses includes the Crimean-Congo hemorrhagic fever virus, the Rift Valley fever virus, and the hantaviruses, a genus of viruses that cause a hemorrhagic fever with renal syndrome.

Rodents carry hantaviruses; the disease is transmitted by way of aerosols from infected rodent excretions. Hantaviruses can be divided into Old World and New World varieties. Old World hantaviruses, which predominate in Europe and Asia, tend to cause milder disease and have been associated with hemorrhagic fever with renal syndrome. New World hantaviruses occur mainly in the Americas. In 1994, a previously unknown New World hantavirus was found to cause a pulmonary syndrome associated with tachypnea, hemoconcentration, thrombocytopenia, and leukocytosis.¹⁴¹ Cases occurred predominantly in the southwestern United States and were associated with a mortality rate higher than 50%. The disease was transmitted from the deer mouse, Peromyscus maniculatus, and the risk of human infection is likely to be related to a large population of deer mice in concert with human activities.¹⁴² The virus has been designated the Sin Nombre virus.

Several other hantavirus species have been identified in Central and South America that also have been associated with hantavirus pulmonary syndrome or hantavirus cardiopulmonary syndrome.¹⁴³ Rift Valley fever virus is carried by a mosquito and generally produces a nonspecific febrile disease. Up to 100,000 cases occur yearly in Africa. In some patients, a severe retinitis develops that may lead to blindness. Crimean-Congo hemorrhagic fever is a severe, rare, tick-transmitted disease that occurs in Africa and Asia, with a mortality rate approaching 50%.

Management.: Treatment of all of these diseases is supportive. The CDC provides intravenous ribavirin for investigational use. Ribavirin is active against Crimean-Congo hemorrhagic fever virus, but it has not been definitively shown to be efficacious in humans.¹⁴⁴

Principles of Disease.: The arenaviruses are carried by parasites of rodents and probably are passed to humans from contact with infected rodent urine. Four arenaviruses are known to cause human disease. Lymphocytic choriomeningitis (LCM) virus causes a meningoencephalitis that may be severe but is rarely fatal. Junin and Machupo viruses, from Argentina and Bolivia, respectively, and the Lassa virus, from Africa, cause severe and often fatal hemorrhagic fevers.

Clinical Features.: LCM virus infection commonly is transmitted from person to person. LCM virus occurs in the Americas, Europe, and Asia and usually is passed from house mice, pet hamsters, or laboratory animals. Influenza-like symptoms follow a 1- to 3-week incubation period, and recovery is generally complete. Meningitis may ensue, but even severe cases are associated with good recovery. Orchitis and parotitis may accompany the disease. LCM virus still poses a hazard in research settings in the United States.¹⁴⁵

Lassa fever is a highly contagious disease occurring in West Africa, with a case fatality rate of up to 25% in hospitalized patients.¹⁴⁶ The vector is a common rat species. Transmission is thought to occur by contact with the rats or their droppings or by contact with infected persons. In certain areas of Africa, the rate of seropositivity in the general population can be as high as 55%. A gradual onset of fever and malaise after an incubation period of 6 to 21 days is characteristic. The disease is mild or asymptomatic in up to 80% of infected persons, but in approximately 20% it causes high fever, exudative pharyngitis, and diffuse pain (headache, chest pain, abdominal pain) and often is accompanied by vomiting and diarrhea. Worsening disease is characterized by multiorgan failure, mucosal bleeding, coma, and death. Pneumonitis and respiratory distress may develop. Early lymphopenia followed by neutrophilia and elevated transaminases is associated with a poor prognosis.¹⁴⁶

Argentine hemorrhagic fever, due to the Junin virus, causes a rash and petechiae and is more likely to be hemorrhagic than Lassa fever. The disease is manifested after a 7- to 10-day incubation period with fever, malaise, anorexia, and myalgias. Petechiae and gastrointestinal bleeding occur between days 4 and 6, and shock may follow. Case fatality rates range up to 30%. Bolivian hemorrhagic fever, caused by Machupo virus, is similar to Argentine hemorrhagic fever but occurs much less commonly.

Differential Considerations.: LCM virus infection can resemble other viral causes of meningitis or encephalitis. The diagnosis of arenavirus infections requires a fourfold rise in antibody titer.

Management.: Only supportive care is required for LCM. Ribavirin has been used effectively to treat Lassa fever and can result in decreased mortality with a low seroconversion rate.¹⁴⁷ Argentine hemorrhagic fever and possibly Bolivian hemorrhagic fever can be successfully treated with convalescent plasma from a recovered patient. Prevention of arenavirus infections is best accomplished by control of the infected vectors. Special care must be taken to prevent person-to-person spread of Lassa fever.

Principles of Disease.: The coined term prion (proteinaceous infectious particle [-on]) refers to the transmissible agent putatively responsible for a group of chronic neurodegenerative disorders sharing certain pathologic features. Prions have not been found to contain nucleic acid. Other terms for these agents have included unconventional virus and virino. The group of diseases caused by these agents, also referred to as slow virus infections or simply slow infections, includes Creutzfeldt-Jakob disease (CJD), kuru, and Gerstmann-Sträussler syndrome. There is growing evidence that cells infected with prions develop abnormal protein aggregations that force cell apoptosis accompanied by neuronal vacuolation resulting in spongiform encephalopathy.¹⁴⁸

Bovine spongiform encephalopathy in cattle (sometimes referred to as mad cow disease), or new-variant CJD in humans, occurred primarily in the United Kingdom in the early 1990s and is thought to have been perpetuated in the cattle population by the feeding of bone meal to animals. Although there have been cases of bovine spongiform encephalopathy identified in the United States, there have been only a handful and the last case was identified in 2006.¹⁴⁹ Fortunately, owing to changes in handling of meat byproducts and cattle feed, the incidence of bovine spongiform encephalopathy appears to be decreasing in many of the previously affected countries.

Clinical Findings.: CJD is a rare disease, usually manifested in late middle age with a progressive dementia combined with ataxia and myoclonic jerking. Distribution is worldwide and sporadic. CJD has been transmitted from person to person by direct inoculation (e.g., in corneal transplants and dura mater grafts). Kuru and the Gerstmann-Sträussler syndrome are manifested as cerebellar syndromes, with dementia occurring late in the course of the disease. Kuru has been associated with cannibalism confined to a few tribes in the highlands of New Guinea. With both CJD and kuru, progression is rapid, with death usually occurring in less than 1 year. The Gerstmann-Sträussler syndrome follows a more slowly progressive course of up to 10 years.

Diagnostic Strategies.: CT and MRI scans usually are nondiagnostic, but the electroencephalogram often shows changes characteristic of CJD.

Differential Considerations.: CJD can be confused with Alzheimer’s disease or other slowly progressive dementing diseases. Other diseases to consider in the differential diagnosis include multi-infarct dementia, nutritional deficiency syndromes, and primary brain tumors.