Peggy Sue Weintrub
Human parvovirus (HPV) B19 was first discovered in 1975 in serum specimens from healthy blood donors.1 Parvovirus B19 belongs to the genus Parvovirus, an autonomously replicating, small single-stranded DNA virus. It is the infectious agent of a number of clinical syndromes, including erythema infectiosum (formerly known as fifth disease), acute arthritis, and aplastic crises in patients with congenital hemolytic anemia.2-4 When acquired by a pregnant woman, it can lead to spontaneous abortion, intrauterine fetal hy-drops, and stillbirths.5,6
EPIDEMIDOLOGY
Parvovirus infections are most commonly recognized in school-age children. Infections can be sporadic, although epidemics occasionally do occur, most commonly in late winter or spring. Approximately 70% of recognized infections occur in children between 5 and 15 years of age. Children younger than 5 years have a seroprevalence of 2% to 9%, children 5 to 18 years old have a seroprevalence of 15% to 60%, and adults have a seroprevalence of 30% to 60%.7 Secondary attack rates are approximately 50% within households and variable in school outbreaks.7
Because the virus is present in respiratory secretions of viremic patients, transmission occurs most frequently via respiratory droplets. Patients with erythema infectiosum are infectious before, not during, the rash, whereas patients with an aplastic crisis are likely to be most infectious at the time of the acute presentation.9 Parvovirus is rarely transmitted by transfusion of blood or, more commonly, clotting factor concentrates. Vertical transmission from mother to infant also occurs.
PATHOPHYSIOLOGY
The virus enters cells by binding to a receptor called globoside or erythrocyte P antigen. Individuals lacking this receptor cannot be infected with HPV B19.10 Intranasal infection of HPV in human volunteers resulted in fever, malaise, and itching approximately 1 week after infection. During this period, susceptible volunteers were viremic and had respiratory shedding. During the second week of infection, IgM developed, and there was reticulocytopenia. Development of arthritis or rash during the third week of infection coincided with the development of an IgG response.11 Therefore, the pathogenesis in patients with erythema infectiosum or arthritis is believed to be secondary to immune complex disease. The pathogenesis of some of the more serious complications is related to the viral effect on erythrocyte precursors, leading to pronormo-blast arrest.
CLINICAL MANIFESTATIONS
Erythema Infectiosum
Many infected individuals have no recognizable symptoms; however, when a clinical syndrome does occur, it causes erythema infectiosum (EI), also known as fifth disease, a common childhood exanthem. It is characterized by a prodromal illness, usually consisting of malaise, pharyngitis, and low-grade fever, followed by a rash. The classic feature of the rash is a “slapped cheek” appearance on the face, which may be accompanied by circumoral pallor or fine desquamation (Fig. 319-1A). The rash then spreads to the trunk and the extremities. It is described as erythematous and macular, often with confluent areas, giving it a reticular or latticelike appearance (Fig. 319-1B). The rash is pruritic in approximately 50% of patients and may come and go. It may also be precipitated by a variety of stimuli, such as heat and sun. This symptom may persist after all others have resolved. Occasionally, patients may also have an exanthem. Lymphadenopathy may be seen. In general, patients feel relatively well, which helps differentiate fifth disease from measles and other acute exanthems. Adults with EI tend to be sicker than children.
Other Associated Conditions
Arthritis Arthritis is a common syndrome associated with parvovirus B19 infection. It tends to occur more in women and in adults. It often occurs after the rash, but it may be the sole manifestation of the infection. It most often causes symmetric disease, particularly in the hands. The knees and wrists are other commonly involved joints. The symptoms are usually self-limited, but they have been reported to last for months or years. Occasionally, children have arthritis during infection, and case reports suggest that human parvovirus (HPV) may precipitate or be responsible for some juvenile idiopathic arthritis.12There have been reports of the following presumed rheumatic diseases preceding or in association with parvovirus infection: chronic fatigue syndrome, fibromyalgia, systemic lupus erythematosis, Kawasaki disease, Henoch-Schönlein purpura, and petechial “glove and stocking” syndrome.13-15
FIGURE 319-1. A: The classic feature of the rash is a “slapped cheek” appearance on the face, which may be accompanied by circumoral pallor or fine desquamation. (Source: Wolff K, Johnson RA. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill; 2009.) B: The rash then spreads to the trunk and the extremities. It is described as erythematous and macular, often with confluent areas, giving it a reticular or latticelike appearance.
Aplastic Crisis Parvovirus B19 is associated with aplastic crises in individuals with an underlying hemolytic anemia, including those persons with sickle cell disease, hereditary spherocytosis, thalassemia, pyruvate kinase deficiency, autoimmune hemolytic anemia, and others.4 It appears to be responsible for approximately 90% of aplastic crises in these patients, although not all patients who are seropositive have experienced an aplastic crisis. Occasional reports have also been noted of patients with a pancytopenia.
B19 has a tropism for dividing red-cell precursors, leading to reticulocytopenia.11 Patients with an underlying hemolytic process, who have shortened red-cell survival, are unable to compensate for the erythrocyte destruction and have an abrupt decrease in hematocrit. They may present with pallor, weakness, or heart failure in severe infection. Erythropoiesis increases 6 to 8 days after the hematocrit reaches its nadir.
Infection in Pregnancy In the majority of maternal (HPV) B19 infections, the fetus suffers no adverse effects, although the fetus is commonly HPV positive by IgM or polymerase chain reaction. The virus has been found in abortus tissue, and IgM antibodies to B19 have been detected in cord blood.16 There are reports of fetal wastage, fetal hy-drops, and stillbirths following maternal infection in the first, second, and third trimesters, respectively. Numerous studies show that the risk of fetal loss is 5% to 10%.17-19 There are no clinical trials that address the appropriate therapy if one identifies an HPV-induced hydropic fetus, although most specialists agree that early fetal erythrocyte transfusion increases survival. There are no reports of consistent congenital abnormalities attributed to HPV infection during gestation, but rare cases of hydrocephalus, intracranial calcifications, and other central nervous system structural abnormalities have been described.22 The precise risk of parvovirus B19 to the fetus has not been determined. A suggested algorithm for the management of an exposed pregnant woman is seen in eFigure 319.1 .
Chronic Anemia A chronic and severe anemia can be seen in patients with immune dysfunction, including primary immune deficiency syndromes, HIV-infected patients, and those who have had organ transplants.23-25 These patients have inadequate antibody responses and are unable to adequately clear the virus, leading to ongoing bone marrow suppression.
Other Disorders Rare presentations are hemophagocytic syndrome, glomerulonephritis, myocarditis, numerous neurologic complications, and fulminant hepatitis.26-31
DIAGNOSIS AND TREATMENT
The diagnoses of erythema infectiosum and aplastic crises are made primarily on clinical grounds. Under certain circumstances, such as an exposed pregnant woman, one may want to make a specific diagnosis. In many locations, both IgM and IgG assays are available only on a research basis or through the Centers for Disease Control and Prevention (CDC) or state health departments. Polymerase chain reaction (PCR) testing for DNA in serum is now also available. This allows for viral detection even in those hosts who do not make antibody. PCR should be performed before bone marrow examination in patients with chronic unexplained anemia.
There is currently no specific antiviral therapy for treating human parvovirus (HPV) B19, and patients with erythema infectiosum are clinically well. For patients with aplastic crises, supportive care (eg, oxygen and, if needed, transfusions) is often lifesaving. A number of reports describe an excellent response to immunoglobulin therapy in patients with immunodeficiency and/or a chronic anemia related to persistent HPV infection.32-34 There does not appear to be any role for immunoglobulin at this time for patients with erythema infectiosum or aplastic crises. There is no role for immunoglobulin in postexposure prophylaxis for high-risk patients.
In the hospital setting, those with an aplastic crisis or chronic anemia secondary to parvovirus should be placed in isolation, and health care workers should wear masks for droplet precautions. Pregnant women at high risk of acquiring parvovirus (teachers, childcare workers, women with young school-age children) might consider serologic testing for IgG to determine their susceptibility. A suggested algorithm for the management of an exposed pregnant woman is provided in eFigure 319.1 .