ACP medicine, 3rd Edition

Infectious Disease

Measles, Mumps, Rubella, Parvovirus, and Poxvirus

Martin S. Hirsch MD1

Professor of Medicine

1Harvard Medical School; Director of Clinical AIDS Research and Physician, Massachusetts General Hospital

The author has served as an advisor or consultant for Cetek Corp., Merck and Co., Inc., Schering-Plough Corp., and Tibotec Pharmaceuticals, Ltd.

February 2007

Measles

Measles (rubeola) is a highly infectious disease caused by a paramyxovirus of worldwide distribution. The measles virus was once one of the most common and important global pathogens, but infections caused by this agent are now becoming rare in developed countries, where vaccine use is widespread. In areas where vaccines are not widely used, measles remains a major health problem. It is estimated that worldwide, more than 30 million people are infected, and over 450,000 deaths occur each year from measles.1

Epidemiology

Humans are the principal reservoirs of measles virus, which is spread by respiratory droplet aerosols produced by sneezing and coughing. The disease may be contagious from several days before the onset of rash to up to 5 days after lesions appear. The attack rate for exposed susceptible contacts may exceed 90%; asymptomatic infections are rare.

Vaccines have dramatically reduced the incidence of measles in developed countries, and the United States has been declared free of endemic measles.2 However, large outbreaks still occur in unvaccinated or suboptimally vaccinated populations, and an outbreak has even been reported in a highly vaccinated population.3,4 In the United States, women born after the licensure of measles vaccine transfer less measles antibody to their infants than do older women, which may leave infants of vaccinated mothers with heightened susceptibility to measles.5

In undernourished children in developing countries, measles can cause a devastating illness, and case-fatality rates may reach or exceed 25%.6 Before widespread vaccine use, epidemics occurred every 2 to 3 years in developed countries, and the illness developed in 95% of urban dwellers before they reached 15 years of age. Outbreaks occurred primarily in late winter and early spring. In 1989, the World Health Assembly instituted major efforts to reduce measles morbidity and mortality through implementation of control strategies. By 2004, measles vaccination coverage had dramatically reduced measles cases and measles deaths in most areas of the world, exceptions being in sub-Saharan Africa and certain areas in Southern and East Asia.7 Molecular epidemiologic studies suggest that most cases in the United States now result from importation of virus.1,8,9

Pathogenesis

The portals of entry for measles virus include cells of the respiratory tract and possibly the conjunctivae. After undergoing local replication and spreading to regional lymph nodes, measles virus is disseminated to distant sites, particularly skin and mucous membranes, by a leukocyte-associated viremia. Lesions on mucous membranes (Koplik spots) appear as bluish-white specks on an erythematous base. Histologically, Koplik spots are composed of epithelioid giant cells with cytoplasmic and nuclear inclusions that contain microtubular aggregates; inflammatory cells and intercellular edema are present. Lesions of the skin also demonstrate inclusions and microtubular aggregates, suggesting that active viral replication occurs in skin as well as in mucous membranes. Infectious virus can be isolated from leukocytes, urine, conjunctivae, and respiratory secretions. Antibody appears in the serum as viremia ceases. Leukopenia may accompany the illness, together with lymphocyte hyporesponsiveness.

Diagnosis

Clinical Features

Approximately 9 to 11 days after a person is initially exposed to the virus, malaise, fever, conjunctivitis, photophobia, periorbital edema, coryza, and cough develop. Cough may be severe, although generally nonproductive, and temperature may reach 40.6° C (105.1° F). Within 2 to 3 days, Koplik spots may appear on the buccal mucosa and occasionally on the conjunctivae. The skin rash, which erupts 2 to 3 days later, usually appears at the hairline and spreads downward during the next 3 days as systemic symptoms subside [see Figure 1]. Lesion density is greatest above the shoulders, where macular lesions may coalesce. The rash lasts 4 to 6 days and then fades from the head downward. Desquamation may be present but is usually not severe. Complete recovery without scarring generally occurs within 7 to 10 days from the onset of the rash.

 

Figure 1. A case of measles in a young man is characterized by maculopapular rash and conjunctivitis.

A severe atypical presentation of measles has occurred in persons who were immunized between 1963 and 1967 with killed measles virus vaccine and who were later exposed to the wild virus. After a prodrome of fever, headache, abdominal pain, and myalgias, a rash developed on the hands and feet and advanced toward the head. The eruption could be vesicular, urticarial, maculopapular, or hemorrhagic and was most prominent along body creases. Pneumonia, pleural effusion, and hilar lymphadenopathy were common in atypical measles. All persons vaccinated after 1967 received the live attenuated measles vaccine, which is rarely, if ever, associated with the atypical measles syndrome.

Laboratory Tests

In an epidemic setting, observation of the characteristic rash, fever, coryza, and conjunctivitis is sufficient to establish the diagnosis. However, as measles has declined in prevalence, clinical acumen in diagnosis has also diminished. Multinucleated giant cells can often be detected in stained smears of nasal secretions; measles antigen or RNA can be demonstrated in such cells by immunofluorescence or reverse-transcriptase polymerase chain reaction (RT-PCR) methods, respectively. The virus can be isolated from nasal secretions or urine by cultivation of such materials on primate cell monolayers. A rise in hemagglutination inhibition antibodies during a period of 2 to 3 weeks confirms the diagnosis. Confirmation by measles-specific IgM enzyme immunoassay is also available.

Differential Diagnosis

Sporadic cases of measles must be differentiated from other viral exanthems, secondary syphilis, scarlet fever, and drug reactions. Atypical measles may resemble Rocky Mountain spotted fever, meningococcemia, or varicella.

Complications

Measles is usually benign and uncomplicated. Complications occur more commonly in adults, malnourished children, and immunocompromised patients. Measles is associated with severe pulmonary and neurologic complications in up to 80% of immunocompromised children and adults with cancer or HIV infection, with case-fatality rates of 40% to 70%; rash is absent in 30% of cases.10,11 Measles virus may further suppress host immune responses, leading to the reactivation of latent tuberculosis or the superimposition of new bacterial pneumonia in measles patients, particularly in malnourished children with measles.

Measles virus infection often involves the central nervous system, but clinically apparent encephalomyelitis is rare (one in every 1,000 to 2,000 measles patients). CNS involvement may precede the rash but usually begins 4 to 7 days after the eruption appears. The onset of encephalomyelitis is often precipitous and is characterized by a rise in fever, sudden mental deterioration, and seizures; motor defects and cerebellar ataxia are common. An autoimmune demyelinating process may be involved in the pathogenesis of measles encephalomyelitis, which is fatal in about 10% of patients.

Subacute measles encephalitis may complicate measles in immunocompromised hosts 1 to 7 months after exposure; the patient has seizures and altered mental status, but results of cerebrospinal fluid analysis are normal.12 Diagnosis may require brain biopsy for histology, immunocytochemical analysis, or PCR detection of viral RNA.12 Uncommonly, a subacute sclerosing panencephalitis occurs as a complication of measles in children infected before 2 years of age, but the panencephalitis develops after a latent period of several years.13 Other measles complications include thrombocytopenia with associated purpura or bleeding, myocarditis, pericarditis, hepatitis, and severe keratitis progressing to blindness.

Treatment and Prevention

Therapy for measles is mainly supportive. A meta-analysis has suggested that in areas where vitamin A deficiency may be present, an oral dose of 200,000 IU of vitamin A for 2 days can reduce morbidity and mortality in children younger than 2 years.14 Ribavirin, either intravenous or aerosolized, has been proposed for certain complications of measles (i.e., encephalitis or pneumonitis),10,11 but controlled trials are lacking. Postexposure prophylaxis can be provided for high-risk patients (e.g., pregnant women and immunosuppressed children) by administering immunoglobulin intramuscularly at a dosage of 0.25 to 0.50 ml/kg body weight within 6 days after exposure.15

In vaccination guidelines in the United States, two immunizations are suggested for children before school enrollment to reduce the chance of primary vaccine failure. Vaccination is recommended for nonpregnant women of childbearing years and may be considered for institutionalized adults or individuals working in day care centers [see CE:V Adult Preventive Health Care]. Severely immunocompromised individuals should avoid measles vaccination because of the risk of vaccine-associated diseases, such as inclusion body encephalitis or pneumonitis.16,17

The effort to eradicate measles from the United States relies on identification and immunization of susceptible children, adolescents, and adults; on strict enforcement of more comprehensive school immunization requirements; and on strengthening of surveillance and outbreak-control measures.

Mumps

Mumps virus is a pleomorphic, enveloped, single-stranded RNA paramyxovirus capable of causing parotitis, epididymo-orchitis, and CNS disease. Because of widespread vaccination efforts, its role as a major cause of childhood morbidity has greatly diminished. However, sporadic outbreaks continue to occur, the most recent of which involved over 2,500 cases, most of which occurred in the midwestern United States.15

Epidemiology

Mumps virus has worldwide distribution, and infection is seen more commonly in winter and spring. Humans are the only natural host. Infection is uncommon in persons younger than 1 year, and congenital infection is rare but can lead to fetal loss in the first trimester. Historically, 11% of cases of mumps were observed in children between 1 and 4 years of age, 52% in children between 5 and 14 years of age, and 11% in children older than 15 years. However, in the most recent large United States outbreak, the median age was 21 years, and the highest incidence occurred among persons 18 to 24 years of age.15

A live mumps virus vaccine was approved for use in the United States in 1967; its use was facilitated by subsequent incorporation with measles and rubella (MMR) vaccine. Since its widespread use, mumps cases have fallen by over 99.5%, from 185,691 cases in 1968 to 906 cases in 1995.16 Although Healthy People 2010, a comprehensive set of health objectives created under the auspices of the United States Department of Health and Human Services, has targeted mumps for elimination in the United States by 2010,17 recent outbreaks make this goal less certain.

Pathogenesis

Mumps virus spreads from person to person by direct contact with nasopharyngeal secretions. Virus is shed in saliva from as long as 6 days before to 5 days after clinical onset. Incubation ranges from 2 to 4 weeks (mean, 18 days). Initial replication occurs in the pharynx, followed by viremic dissemination. Both humoral and cell-mediated immune responses are induced and correlate with cessation of viremia and salivary virus excretion.

Diagnosis

Clinical Features

Two thirds of cases are symptomatic, with initial symptoms of malaise and fever predominating. Painful swelling of the parotid gland is the characteristic feature of infection. It may be unilateral, and other salivary glands may be involved. However, parotitis occurs in only 30% to 40% of all cases of mumps virus infection.

An unvaccinated child who presents with tender parotitis generally has mumps; further diagnostic testing is not required. Vaccinated children and adolescents, however, may have other viral illnesses and may present with signs and symptoms similar to those of mumps (e.g., Epstein-Barr virus, parainfluenza viruses, and adenovirus).18 In older age groups, other factors and conditions (e.g., sarcoidosis, tumors, alcohol abuse, drug side effects, and other viral or bacterial infections) should be considered. In persons without parotitis who have orchitis, aseptic meningitis, encephalitis, or other obscure syndromes (e.g., myocarditis or pancreatitis), mumps should also be considered [see Complications, below].

Laboratory Tests

Definitive diagnosis of mumps can be made by virus isolation from the oropharynx, CSF, or urine or by virus serology. Rapid detection by PCR techniques is now possible in some laboratories; PCR may be useful for epidemiologic surveillance.19

Complications

Epididymo-orchitis occurs in up to 38% of postpubertal males with mumps and is usually unilateral. Subsequent sterility is uncommon, although testicular atrophy may occur.

CSF pleocytosis occurs in at least 50% of patients with mumps,20 although symptomatic meningitis is less common. A lymphocytic pleocytosis is seen, and patients have an elevated protein level and a normal to low (10%) glucose level. Symptomatic encephalitis occurs in one of 6,000 cases and presents as decreased consciousness and focal neurologic deficits. Most patients with encephalitis recover completely, although 0.5% to 2.3% of patients with mumps encephalitis may die. Other neurologic complications may include hydrocephalus; deafness; and rare cases of demyelinating disorders, transverse myelitis, Guillain-Barré syndrome, and cerebellar ataxia.21Deafness may be sudden, unilateral, and permanent.16

Pancreatitis, mastitis, and oophoritis have been observed in patients with mumps. Myocarditis occurs and in rare cases can be fatal.22Endocardial fibroelastosis, an infrequent sequela of myocarditis, has been associated with mumps infection.23 Mumps can cause polyarticular or monoarticular arthritis; it generally affects adult males and is self-limited (usually lasting less than 8 weeks).24

Treatment and Prevention

Treatment of patients with mumps is largely supportive, although anti-inflammatory agents may be useful in cases of severe orchitis or arthritis. Administration of immune globulin does not prevent mumps and is not recommended. Prevention can be achieved in well over 90% of persons by the use of live attenuated mumps vaccine, administered twice, as part of the recommended MMR vaccine regimen15,25 [seeCE:V Adult Preventive Health Care]. Guidelines for the control and elimination of mumps have recently been updated; included in the guidelines are revised standards for acceptable presumptive evidence of immunity to mumps.25 The updated guidelines recommend routine vaccination for health care workers. For health care workers born during or after 1957, adequate mumps vaccination consists of two doses of a live mumps virus vaccine. Health care workers without a history of mumps vaccination or other evidence of immunity should receive two doses, with a minimum interval of 28 days between doses.25 During an outbreak, the guidelines further suggest that health care facilities should strongly consider recommending two doses of a live mumps virus vaccine to unvaccinated workers born before 1957 who have no evidence of mumps immunity.25

Rubella

Rubella, or German measles, is usually a benign febrile exanthem, but when it occurs in pregnant women, it can produce major congenital malformations. The infective agent is a single-stranded RNA virus of the Togaviridae family.

Epidemiology

Humans are the only known natural hosts for the rubella virus, which appears to be spread by respiratory droplets. The virus is moderately contagious but less so than measles. Before the introduction of a rubella vaccine, in 1969, epidemics occurred in the United States at 6- to 9-year intervals, predominantly in children younger than 15 years. Since the widespread use of rubella vaccine, the incidence of rubella has decreased by 99%.26 Outbreaks have occurred, primarily in young adults in hospitals, colleges, prisons, and prenatal clinics, but no major epidemics have occurred in the United States since 1964. Since 2001, annual rubella cases have been the lowest ever recorded in the United States (23 in 2001, 18 in 2002, 7 in 2003, and 9 in 2004). During this period (2001–2004), four congenital rubella cases were reported in the United States; the mothers of three of these infants were born outside the United States. In October 2004, the Centers for Disease Control and Prevention (CDC) concluded that, although rubella continues to be endemic in certain parts of the world, it is no longer endemic in the United States.26

Pathogenesis

Initially, the rubella virus replicates in the nasopharynx and regional lymph nodes. After the virus invades the bloodstream, it may spread to the skin and distal organs or, transplacentally, to the developing fetus. The virus may be present in throat washings or blood for several days before the appearance of the rash and up to 2 weeks after its onset. In rare cases of rubella arthropathy, the virus may persist in peripheral leukocytes or in synovial cells for months to years.

A pregnant woman infected with rubella is at risk for transmitting the virus to her fetus. Damage to the fetus is most likely to occur if the mother is infected within the first 2 months of gestation; fetal abnormalities are observed in 40% to 85% of such cases.27,28 Infection within the third month is associated with fetal defects in 20% to 40% of cases, whereas infection during the fourth month is associated with fetal defects in 10% of cases. Mechanisms of fetal damage are not clear but may include viral cytolysis, chromosomal breaks, reduced cell multiplication, and alteration of fetal blood supply. As a result, fetal growth may be retarded, and defects may develop in multiple organ systems. Despite the production of fetal antibodies, the rubella virus can persist in the fetus and newborn and can be excreted for months to years after birth.

Diagnosis

Clinical Features

After an incubation period of 12 to 23 days, a mild prodrome of malaise, headache, fever, and mild conjunctivitis may develop. Postauricular, suboccipital, and posterior cervical lymphadenopathy often precede the rash, which begins on the face and forehead. Within 1 to 5 days, the discrete maculopapular lesions spread over the trunk and extremities and may coalesce. The rash usually disappears within 3 days.

Laboratory Tests

The presence of rubella can be confirmed by virus isolation, by PCR detection, or by demonstration of seroconversion in response to rubella antigens.29 Virus isolation is often difficult because rubella virus does not cause cytopathic effects on the cell lines that are generally employed in diagnostic laboratories. Antibodies are often present shortly after rash appears and increase in titer during the next 2 to 3 weeks. Measurements of specific IgM antibodies to rubella virus are particularly useful in newborns: raised IgM levels denote recent infection and are specific for fetal infection because IgM antibodies do not cross the placenta. Elevated IgM antibodies may return to nondiagnostic levels by 3 to 6 months, and persistence of IgG antibodies beyond this period may also help diagnose neonatal infection.

Differential Diagnosis

Rubella may be confused with other viral exanthems (e.g., those caused by enteroviruses, parvoviruses, or adenoviruses), scarlet fever, or drug eruptions.

Complications

The most common complications of rubella are arthropathies of the fingers, wrists, and knees; they occur predominantly in young women. Such arthropathies consist of arthralgia or frank arthritis, and recurring joint symptoms may persist for a year or more. Encephalitis and thrombocytopenia are rare complications of acute rubella. Encephalitis occurs in one in 6,000 cases,16 and thrombocytopenia, which is sometimes associated with purpura or hemorrhage, occurs most often in children.

Congenital rubella syndrome, also a rare complication of acute rubella, may manifest itself as defects in one or many organ systems. Hearing impairment is the most common single defect (60%). Heart malformations, particularly patent ductus arteriosus and peripheral pulmonic stenosis, are also common (45%), as are cataracts (25%), microcephaly (27%), and mental retardation (13%). Malformation of bone metaphyses may also be present, together with hepatosplenomegaly, thrombocytopenia, interstitial pneumonitis, myocarditis, and thrombocytopenic purpura. Congenitally infected infants are often of low birth weight (23%), and they excrete rubella virus for prolonged periods. Late complications may result from imbalances of cellular and humoral immunity, from immune complex deposition, or from prolonged viral replication. Diabetes mellitus and other endocrine abnormalities may be late complications of congenital rubella, as is subacute sclerosing panencephalitis.30

Treatment and Prevention

Beyond the fetal period, rubella is mild and self-limited. Current treatment of congenital rubella syndrome is only supportive. The CDC has developed detailed recommendations for dealing with rubella outbreaks focused on patient isolation, identification and vaccination of susceptible persons who have no contraindications to rubella vaccine, and counseling of susceptible pregnant women.31 These recommendations are available on the Internet at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5012a1.htm.

Pregnant women infected with rubella virus who are asymptomatic may still transmit rubella to their fetuses. Thus, testing of immune status is advisable for women of childbearing age and for hospital employees who have no history of rubella vaccination. About 10% to 15% of such persons are seronegative and should be vaccinated when not pregnant. Women should avoid becoming pregnant for 28 days after vaccination against rubella.32

Measles, Mumps, and Rubella Vaccine

Because they fear possible complications from MMR vaccination, some parents have questioned the safety of the vaccine, and in some cases have refused its use in their children. These parents may cite research suggesting that MMR vaccination may be a risk factor for inflammatory bowel disease33 and autism.34 Subsequent research, however, has not supported this hypothesis.35,36 In addition, although receipt of the MMR vaccine has been associated with an increased risk of febrile seizures 8 to 14 days after vaccination, those children were not found to be at higher risk for subsequent seizures or neurodevelopmental disabilities.37

Parvovirus

Parvovirus B19 is now appreciated as a cause of several syndromes in both children and adults. Parvovirus B19, a small (20 to 26 nm), single-stranded DNA virus, causes erythema infectiosum (fifth disease) in normal persons, aplastic crises in persons with underlying hemolytic disorders, chronic anemia in immunocompromised hosts, and fetal loss in pregnant women.38

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 seroprevalence increases to 35% to 60% by 11 to 19 years of age and to greater than 75% in persons older than 50 years.39 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.40,41Maternal 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%.42,43 Routine antenatal screening is not recommended.44

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 glycosphingolipid, which occurs in erythrocytes, erythroblasts, megakaryocytes, endothelial cells, placenta, and fetal liver and heart cells.45 Expression of this glycosphingolipid in tissues helps to determine parvovirus B19 tropism.46 Persons who lack erythrocyte P antigen (p phenotype) are naturally resistant to infection,47 and the distribution of parvovirus in infected individuals is linked to the presence of the P antigen. A parvovirus nonstructural protein is responsible for the death of erythroid progenitors, which may occur even in the absence of viral replication.48 Although little is known about the pathogenesis of parvovirus, antiviral antibodies—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.49

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; it may occur without rash and may linger for weeks. Joint involvement is often symmetrical in the hands, wrists, knees, and ankles. Hemolytic 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; detection of viral DNA is necessary for the diagnosis of persistent infection, because culture techniques for virus isolation are unsatisfactory.

Complications

Transient aplastic crises associated with parvovirus B19 occur in patients who have sickle cell anemia, hereditary spherocytosis, thalassemia, and various other hemolytic anemias. 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 immunocompromised hosts (e.g., patients with HIV infection and transplant recipients), acute infection may lead to viral persistence and chronic bone marrow suppression.50,51 A significant proportion of patients with AIDS who develop severe anemia while receiving zidovudine (AZT) have persistent parvovirus infection.51Parvovirus B19 may also be an important contributor to anemia in tropical areas, where it may act in concert with other factors such as malaria, iron deficiency, and hookworm infections.52,53 Pneumonia, hepatitis, and myocarditis have also been associated with parvovirus infections in immunocompromised as well as immunocompetent adults and children.54,55,56,57 Although parvovirus B19 has been implicated in a variety of rheumatic diseases, there is no definitive evidence for a causal role.

Treatment

Most parvovirus infections do not require specific therapy. In patients receiving immunosuppression, discontinuance of immunosuppressive therapy may enhance recovery. Pooled human immune globulin contains anti-parvovirus B19 antibodies and has been used to treat persistent infections as well as acute exposures. 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 No parvovirus B19 vaccine is currently available.

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), paravaccinia (milker's nodules), monkeypox, and tanapox.

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

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:V Bioterrorism]. 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.

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 immunohistochemical 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 (e.g., 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 the use of vaccine containing live vaccinia virus.61,62,63 The exact origin of vaccinia virus is not clear because the virus has no known natural hosts; however, 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, epidemiologic and laboratory studies suggest that increased protection against smallpox may persist for decades after vaccination.64,65

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 weapon of bioterrorism, vaccination of the general public is still not recommended. Instead, targeted vaccination may be a more effective intervention against bioterrorist smallpox.66 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 smallpox.67 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 athttp://www.bt.cdc.gov/agent/smallpox/reference/resource-kit.asp.

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 immunosuppression, 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 athttp://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.

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.68 The infection has worldwide distribution; 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 severe69 [see 2:I Cutaneous Manifestations of Systemic Diseases]. Lesions near the eye may be complicated by chronic conjunctivitis or superficial keratitis.

 

Figure 2. The pearly white papular lesions of molluscum contagiosum shown here are 2 to 5 cm in diameter, with a central umbilication.

The molluscum contagiosum virus (MCV) has been visualized by electron microscopy but has not been cultivated in vi-tro. The clinical diagnosis is confirmed by microscopic observation of large cytoplasmic inclusions, called molluscum bodies [see Figure 3], in appropriately stained, expressed contents of lesion or histologic sections. Restriction endonuclease cleavage patterns of DNA from purified virus obtained from skin lesions indicate that there are two distinct MCV genotypes.70

 

Figure 3. Micrograph of a molluscum contagiosum lesion demonstrates basophilic molluscum bodies (arrow) in epidermal cell cytoplasm.

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 treatments with imiquimod 5% cream or 10% potassium hydroxide solution have been reported.71,72

Zoonotic Poxvirus Infections in Humans

Several poxviruses of animals can infect humans, including paravaccinia, orf, monkeypox, and tanapox; human infections result from direct contact with natural animal reservoirs of these agents or arthropod vectors, and humans are only incidental hosts.73

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 paravaccinia, although paravaccinia and orf viruses are distinct. Most cases are benign, but immunocompromised patients have been successfully treated with cidofovir.74

 

Figure 4. Papillomatous lesions of orf (pustular dermatitis) can be observed on the finger of a sheep handler.

Monkeypox is caused by an orthopoxvirus related to the smallpox virus. Human monkeypox infections occur sporadically in small villages in African tropical rain forests; monkeypox infections also occur in captive monkeys in European and North American laboratories. Smallpox-like diseases caused by monkeypox virus have been noted in central Africa in humans who live in close proximity to monkeys.75

During May and June of 2003, a monkeypox outbreak occurred in the midwestern United States among persons who had contact with ill pet prairie dogs obtained from a common distributor.76,77,78 The prairie dogs had been exposed to rodents recently imported from West Africa. Patients presented with fevers, sweats, chills, headache, and a vesicular skin eruption. Cough, lymphadenopathy, and sore throat were prominent; encephalitis was also described. Human-to-human transmission occurred rarely.79 There are no proven therapies for human monkeypox, although smallpox vaccine may help protect against disease in some persons.80

Tanapox virus infections occur in East-African nonhuman primates; transmission to humans may occur via arthropod intermediates, from infected humans, or, rarely, from nonhuman primates. Infections can on rare occasion be seen in travelers to East Africa.81 Patients present with fever, a solitary erythematous macule on the skin, and regional lymphadenopathy. Over time, the skin lesion can become painful, umbilicated, and necrotic; it usually resolves in several weeks. Occasionally, several lesions are seen, most commonly on the legs. A variety of laboratory tests, including electron microscopy, histopathology, and DNA testing, can help identify the virus.

Acknowledgments

Figures 1 and 4 Photographs courtesy of Dr. Howard Baden, Department of Dermatology, Massachusetts General Hospital, and Harvard Medical School, Boston.

Figure 2 Photograph courtesy of the American Academy of Dermatology.

Figure 3 Micrograph courtesy of Dr. George W. Hambrick, Department of Dermatology, New York Hospital, New York.

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Editors: Dale, David C.; Federman, Daniel D.