Epidemiology
Parvovirus B19 infection occurs most commonly in school-age children in outbreaks during late winter and spring. Only 2% to 15% of pre-school-age children have antibodies, but seropreva-lence increases to 35% to 60% by 11 to 19 years of age and to greater than 75% in persons older than 50 years.41 Respiratory transmission is likely and is facilitated by close contact. Hospital outbreaks have also been described and are often traced to patients with aplastic crises who carry large amounts of virus in blood and respiratory secretions.42,43 Maternal infection can lead to fetal anemia, hydrops fetalis, heart failure, and death, resulting in spontaneous abortion, most commonly 4 to 6 weeks after infection. When women are infected during the first 20 weeks of pregnancy, the risk of parvovirus-related fetal death is approximately 9% to 10%.4445 Routine antenatal screening is not recommended.38,46
Pathogenesis
Replication of parvovirus B19 has been demonstrated in human erythroid progenitor cells, and the receptor appears to be the P blood group antigen globoside, a neutral glycosphin-golipid, which occurs in erythrocytes, erythroblasts, megakar-yocytes, endothelial cells, placenta, and fetal liver and heart cells.47 Expression of this glycosphingolipid in tissues helps to determine parvovirus B19 tropism.48 Persons who lack erythro-cyte P antigen (p phenotype) are naturally resistant to infec-tion,37,49 and the distribution of parvovirus in infected individuals is linked to the presence of the P antigen. Although little is known about the pathogenesis of parvovirus, antiviral antibod-ies—particularly those directed against the capsid protein VP1— appear to be responsible for viral clearance. The presence of certain HLA class I and class II alleles may be associated with more symptomatic parvovirus infections.50
Diagnosis
Clinical Features
The rash caused by parvovirus B19, erythema infectiosum, usually appears without prodromal symptoms after an incubation period of 4 to 14 days. The exanthem progresses through three stages. Initially, a fiery-red rash develops on both cheeks (giving them the appearance of having been slapped), accompanied by relative pallor around the mouth. From 1 to 4 days later, an erythematous maculopapular eruption appears on the proximal extremities and spreads to the trunk in a lacelike, reticular pattern. The third stage, during which the eruption waxes and wanes, may persist for several weeks and may be precipitated by skin trauma, exposure to sunlight, or extremes of temperature. Arthralgia and arthritis are seen in up to 80% of infected adults; arthralgia is particularly common in women, may occur without rash, and may linger for weeks. Joint involvement is often symmetrical in the hands, wrists, knees, and ankles. He-molytic anemias and encephalopathies are rare complications.
Laboratory Tests
Parvovirus-specific IgM antibodies usually appear within 3 days after symptoms develop; these antibodies persist for several weeks and then rapidly decline. IgG antibodies, however, persist for years. Viral DNA can also be detected in blood, tissues, and secretions, although culture techniques for virus isolation are unsatisfactory.
Complications
Transient aplastic crises associated with parvovirus B19 occur in patients who have sickle cell anemia, hereditary spherocyto-sis, thalassemia, and various other hemolytic anemias.51 These aplastic crises are abrupt in onset and associated with giant pronormoblasts in the bone marrow. They generally last 1 to 2 weeks and go into remission spontaneously. In immunocompro-mised hosts (e.g., patients with HIV infection), acute infection may lead to viral persistence and chronic bone marrow suppres-sion.40 A significant proportion of patients with AIDS who develop severe anemia while receiving zidovudine (AZT) have persistent parvovirus infection.51 Pneumonia, hepatitis, and myocarditis have also been associated with parvovirus infections in immunocompromised as well as immunocompetent adults and children.52-57 Although parvovirus B19 has been implicated in a variety of rheumatic diseases, there is no definitive evidence for a causal role.
Treatment
Pooled human immune globulin contains anti-parvovirus B19 antibodies and has been used to treat persistent infections as well as acute exposures.40 Prevention of nosocomial infections is of great concern: pregnant health care workers should not care for patients with aplastic crises. Droplet isolation is recommended for such patients, including the use of gowns, gloves, and masks during close contact. Because certain blood products (e.g., clotting factors) contain parvovirus B19 DNA, screening of products, donors, and recipients has been suggested.58
Poxvirus Infections
Poxviruses are the largest (200 to 320 nm) and most complex human viruses. They replicate in cell cytoplasm and may produce eosinophilic cytoplasmic inclusion bodies. They preferentially infect skin epithelial cells and may cause a variety of human diseases. Smallpox (variola), once among the most devastating and feared worldwide pestilences, has been virtually eliminated. Other human poxvirus diseases include vaccinia, molluscum contagiosum, orf (contagious pustular dermatitis), and paravaccinia (milker’s nodules).
Smallpox
No naturally acquired cases of smallpox (variola) have been observed since 1977, as a result of a global eradication effort that was initiated by the World Health Organization in the 1960s.59 Several biologic features of the smallpox virus favored its eradication: only one serotype existed, a stable and effective vaccine had been developed, and there were no nonhuman reservoirs and no human carriers of the smallpox virus. For a time, smallpox was considered a disease of purely historical interest. However, laboratory stocks of the virus were never totally destroyed, and the possibility of dissemination of the stores held in the former Soviet Union has raised concerns that smallpox virus might be used as an agent of biological warfare [see 8:V Bioterrorism].60
|
Table 1 Contraindications to Nonemergency Smallpox Vaccination |
|
Conditions in the Patient or a Household Member |
|
Eczema or atopic dermatitis (even if it is currently inactive or mild or was experienced in childhood) |
|
Skin conditions such as burns, chickenpox, shingles, impetigo, herpes, severe acne, or psoriasis |
|
Weakened immune system (e.g., from corticosteroid treatment, cancer chemotherapy, posttransplantation immunosuppres-sion, HIV infection, or severe autoimmune disorders) |
|
Pregnancy or intent to become pregnant within 1 mo after vaccination |
|
Conditions in the Patient Allergy to the vaccine or any of its ingredients |
|
Age less than 12 mo* |
|
Moderate or severe short-term illness |
|
Current breast-feeding |
|
Use of steroid eyedrops |
Note: Persons who have been directly exposed to the smallpox virus should be vaccinated, regardless of their health status. More information on smallpox vaccination is available at www.cdc.gov/smallpox.
*The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention advises against nonemergency use of smallpox vaccine in children younger than 18 yr, and the vaccine manufacturer does not recommend nonemergency use of the vaccine in geriatric patients.
Pathogenesis
Variola is spread by the respiratory route. Mucosal seeding is followed by spread to lymph nodes, a brief viremia, and spread to the reticuloendothelial system over the next 4 to 14 days. Thereafter a second viremia leads to infection of skin and mucous membranes. Neutralizing antibodies appear during the first week of infection and persist for years.61 Cytotoxic T lymphocyte reactivity also occurs early and persists.62
Diagnosis
Clinical features A prodrome characterized by fever, headache, and backache lasts for 2 to 3 days, after which an oropharyngeal enanthem appears. Smallpox can take several clinical forms [see 8:VBioterrorism]. In its most common form (ordinary smallpox), the disease causes a rash that goes through several stages: papules to vesicles to pustules to crusts over 1 to 2 weeks. Lesions begin on the face and extremities but spread all over the body. Differential diagnosis involves a variety of viral diseases, most notably varicella (chickenpox). The principal clinical differences between smallpox and chickenpox are that, in smallpox, lesions are all in the same stage of development and tend to cluster on the face and extremities (including the palms of the hands and soles of the feet), whereas, in chickenpox, lesions tend to be in various stages of development and to cluster on the torso [see 8:V Bioterrorism]. Smallpox must also be differentiated from drug-induced rashes, most notably Stevens-Johnson syndrome.
Figure 2 The pearly white papular lesions of molluscum contagiosum shown here are 2 to 5 cm in diameter, with a central umbilication.
Complications Visceral involvement can lead to encephalitis (< 1%), arthritis (2%), hypotension, hemorrhage, pneumonia, and death. Case-fatality rates of up to 30% have been reported, often associated with secondary bacteremias.61
Laboratory tests If facilities are available, direct examination of specimens by electron microscopy can readily distinguish variola from other viruses. Antigens can be detected by immuno-histochemical techniques, DNA can be studied by PCR, and variola virus can be isolated in cell cultures.
Treatment
Strict respiratory and contact isolation is essential, preferably in a room with negative air pressure. Hydration is critical because of fluid losses. Vaccination is recommended in patients with early disease (see below).61 Cidofovir has activity against related viruses (vaccinia, cowpox, monkeypox) in animal models and may be tried in severe cases, though it has considerable nephrotoxicity and no proven benefit.
Prevention
Smallpox prevention consists of infection control measures and use of vaccine containing live vaccinia virus.61-63 The exact origin of vaccinia virus is not clear (the virus has no known natural hosts), but vaccinia has long been used as the source of smallpox vaccines. Although the duration of benefit of vaccinia vaccine has never been measured in controlled trials, epidemio-logic studies suggest that increased protection against smallpox may persist for more than 10 years after vaccination.
In healthy patients, injection of vaccinia virus usually induces a localized papular eruption at the injection site. However, patients with compromised immune function or with skin conditions such as eczema may experience more severe disease after vaccination. Progressive generalized vaccinia, vaccinia gangrenosa, and eczema vaccinatum may complicate such disorders [see 8:V Bioterrorism]. Vaccinia immune globulin and antiviral agents (e.g., cidofovir) have been suggested as possible therapies for vaccinia complications, but their effectiveness has not been established.
Since 1971, routine smallpox vaccination has not been recommended in the United States. Despite concern regarding the use of smallpox as a bioterrorism weapon, vaccination of the general public is still not recommended. Instead, targeted vac-cination may be a more effective intervention against bioterror-ist smallpox.65
Figure 3 Micrograph of a molluscum contagiosum lesion demonstrates basophilic molluscum bodies (arrow) in epidermal cell cytoplasm.
In October 2002, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended voluntary vaccination of people designated to respond to or care for individuals suspected or confirmed of being infected with small-pox.66 Because of the risk of complications, nonemergency vaccination is contraindicated in some cases [see Table 1]. Recently vaccinated persons may transmit vaccinia through contact with susceptible persons, so infection control measures are important. Current information and recommendations on smallpox and smallpox vaccination are available from the CDC at http://www.bt.cdc.gov/agent/smallpox/reference/resource-kit.asp.
Figure 4 Papillomatous lesions of orf (pustular dermatitis) can be observed on the finger of a sheep handler.
Molluscum contagiosum
Molluscum contagiosum is characterized by multiple painless, pearly white nodules 2 to 5 mm in diameter with a central umbilication. They can appear anywhere on the body except the palms and soles [see Figure 2]. The nodules, which are most commonly found in anogenital regions, rupture easily and may be spread by sexual routes, by autoinoculation, or by close familial contact under conditions of poor hygiene. Cases occur predominantly in children, sexually active adults, sports participants who have skin-to-skin contact, and persons with impaired cellular immunity.67 The infection has worldwide distribution, and incidence rates of clinically apparent infection range from 0.1% to 4.5%. Incubation periods vary from several days to several weeks, and lesions may clear rapidly or persist for up to 18 months. Molluscum contagiosum is common in patients with AIDS, in whom the lesions may be large, atypical, and severe68 [see 2:I Cutaneous Manifestations of Systemic Diseases]. Lesions near the eye may be complicated by chronic conjunctivitis or superficial keratitis.
The molluscum contagiosum virus (MCV) has been visualized by electron microscopy but has not been cultivated in vitro. Microscopic observation of large cytoplasmic inclusions, called molluscum bodies [see Figure 3], in appropriately stained, expressed lesion contents or histologic sections confirms a clinical diagnosis. Restriction endonuclease cleavage patterns of DNA from purified virus obtained from skin lesions indicate that there are two distinct MCV genotypes.69
The lesions resolve spontaneously without scarring. A small number of lesions can be removed by gentle curettage, laser, or caustic chemicals if desired. In immunocompetent patients, successful topical treatment with imiquimod 5% cream has recently been reported.
Paravaccinia, orf, and monkeypox
Human paravaccinia, orf, and monkeypox infections result from direct contact with natural animal reservoirs of these agents; humans are only incidental hosts.
Paravaccinia is an infection that produces lesions on the teats and oral mucosa of calves and milk cows. When humans are infected by direct contact, so-called milker’s nodules develop on the fingers or hands and occasionally are associated with lymphadenitis. Lesions develop over a period of 1 to 2 weeks and resolve in 3 to 8 weeks.
The orf virus causes papillomatous lesions (pustular dermatitis) on the mucous membranes and corneas of sheep and goats. Lesions in humans [see Figure 4] are caused by direct contact with infected animals and resemble those caused by paravac-cinia, although paravaccinia and orf viruses are distinct. Most cases are benign, but immunocompromised patients have been successfully treated with cidofovir.71
Monkeypox is caused by an orthopoxvirus related to the smallpox virus. Vaccination against smallpox also protects against monkeypox. Human monkeypox infections occur sporadically in small villages in African tropical rain forests; mon-keypox infections also occur in captive monkeys in European and North American laboratories. Smallpoxlike diseases caused by monkeypox virus have been noted in central Africa in humans who live in close proximity to monkeys.72 Although the primary reservoir for the monkeypox virus remains uncertain, humans appear to be incidental hosts for the virus. Person-to-person transmission has been described. In animal models, cidofovir has been effective for treating monkeypox infections.
