Etiology

Parvovirus B19 (B19) is a member of the genus Erythrovirus in the family Parvoviridae. Parvoviruses are small DNA viruses that infect a variety of animal species. As a group, parvoviruses include a number of important animal pathogens, such as canine parvovirus and feline panleukopenia virus; B19 does not infect other animals, and animal parvoviruses do not infect humans. B19 is one of only two parvoviruses that are pathogenic in humans. The other such virus is the newly described human bocavirus. Although the clinical significance of human bocavirus is not yet fully defined, this virus may be associated with upper and lower respiratory tract infection in young children and will not be further discussed in this chapter.

B19 is composed of an icosahedral protein capsid without an envelope and contains a single-stranded DNA genome of approximately 5.5 kb. It is relatively heat and solvent resistant. It is antigenically distinct from other mammalian parvoviruses and has only one known serotype. Parvoviruses replicate in mitotically active cells and require host cell factors present in late S phase to replicate. B19 can be propagated in vitro only in erythropoietin-stimulated erythropoietic cells derived from human bone marrow, umbilical cord blood, or primary fetal liver culture.

Epidemiology

Infections with parvovirus B19 are common and occur worldwide. Clinically apparent infections, such as the rash illness of erythema infectiosum and transient aplastic crisis, are most prevalent in school-aged children, 70% of cases occurring in patients between 5 and 15 yr of age. Seasonal peaks occur in the late winter and spring, with sporadic infections throughout the year. Seroprevalence increases with age, 40-60% of adults having evidence of prior infection.

Transmission of B19 is by the respiratory route, presumably via large droplet spread from nasopharyngeal viral shedding. The transmission rate is 15-30% among susceptible household contacts, and mothers are more commonly infected than fathers. In outbreaks of erythema infectiosum in elementary schools, the secondary attack rates range from 10% to 60%. Nosocomial outbreaks also occur, with secondary attack rates of 30% among susceptible health care workers.

Although respiratory spread is the primary mode of transmission, B19 is also transmissible in blood and blood products, as documented among children with hemophilia receiving pooled-donor clotting factor. Given the resistance of the virus to solvents, fomite transmission could be important in child-care centers and other group settings, but this mode of transmission has not been established.

Pathogenesis

The primary target of B19 infection is the erythroid cell line, specifically erythroid precursors near the pronormoblast stage. Viral infection produces cell lysis leading to a progressive depletion of erythroid precursors and a transient arrest of erythropoiesis. The virus has no apparent effect on the myeloid cell line. The tropism for erythroid cells is related to the erythrocyte P blood group antigen, which is the primary cell receptor for the virus and is also found on endothelial cells, placental cells, and fetal myocardial cells. Thrombocytopenia and neutropenia are often observed clinically, but the pathogenesis of these abnormalities is unexplained.

Experimental infection of normal volunteers with B19 revealed a biphasic illness. From 7 to 11 days after inoculation, subjects had viremia and nasopharyngeal viral shedding with fever, malaise, and rhinorrhea. Reticulocyte counts dropped to undetectable levels but resulted in only a mild, clinically insignificant fall in serum hemoglobin. With the appearance of specific antibodies, symptoms resolved and serum hemoglobin returned to normal. Several subjects experienced a rash associated with arthralgia 17-18 days after inoculation. Some manifestations of B19 infection, such as transient aplastic crisis, appear to be a direct result of viral infection, whereas others, including the exanthem and arthritis, appear to be postinfectious phenomena related to the immune response. Skin biopsy of patients with erythema infectiosum reveals edema in the epidermis and a perivascular mononuclear infiltrate compatible with an immune-mediated process.

Individuals with chronic hemolytic anemia and increased red blood cell (RBC) turnover are very sensitive to minor perturbations in erythropoiesis. Infection with B19 leads to a transient arrest in RBC production and a precipitous fall in serum hemoglobin, often requiring transfusion. The reticulocyte count drops to undetectable levels, reflecting the lysis of infected erythroid precursors. Humoral immunity is crucial in controlling infection. Specific immunoglobulin M (IgM) appears within 1-2 days of infection and is followed by anti-B19 IgG, which leads to control of the infection, restoration of reticulocytosis, and a rise in serum hemoglobin.

Individuals with impaired humoral immunity are at increased risk for more serious or persistent infection with B19, which usually manifests as chronic RBC aplasia, although neutropenia, thrombocytopenia, and marrow failure are also described. Children undergoing chemotherapy for leukemia or other forms of cancer, transplant recipients, and patients with congenital or acquired immunodeficiency states (including AIDS) are at risk for chronic B19 infections.

Infections in the fetus and neonate are somewhat analogous to infections in immunocompromised persons. B19 is associated with nonimmune fetal hydrops and stillbirth in women experiencing a primary infection but does not appear to be teratogenic. Like most mammalian parvoviruses, B19 can cross the placenta and cause fetal infection during primary maternal infection. Parvovirus cytopathic effects are seen primarily in erythroblasts of the bone marrow and sites of extramedullary hematopoiesis in the liver and spleen. Fetal infection can presumably occur as early as 6 wk of gestation, when erythroblasts are first found in the fetal liver; after the 4th mo of gestation, hematopoiesis switches to the bone marrow. In some cases, fetal infection leads to profound fetal anemia and subsequent high-output cardiac failure (Chapter 97). Fetal hydrops ensues and is often associated with fetal death. There may also be a direct effect of the virus on myocardial tissue that contributes to the cardiac failure. However, most infections during pregnancy result in normal deliveries at term. Some of the asymptomatic infants from these deliveries have been reported to have chronic postnatal infection with B19 that is of unknown significance.

Clinical Manifestations

Many infections are clinically inapparent. Infected children characteristically demonstrate the rash illness of erythema infectiosum. Adults, especially women, frequently experience acute polyarthropathy with or without a rash.