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.