CHAPTER 93: PARVOVIRUS INFECTIONS

Parvoviruses, members of the family Parvoviridae, are small (diameter, ~22 nm), nonenveloped, icosahedral viruses with a linear single-strand DNA genome of ~5000 nucleotides. These viruses are dependent on either rapidly dividing host cells or helper viruses for replication. At least four groups of parvoviruses infect humans: parvovirus B19 (B19V), dependoparvoviruses (adeno-associated viruses; AAVs), PARV4/5 virus, and human bocaviruses (HBoVs). Human dependoparvoviruses are nonpathogenic and will not be considered further in this chapter.

DEFINITION

B19V is the type member of the genus Erythroparvovirus. On the basis of viral sequence, B19V is divided into three genotypes (designated 1, 2, and 3), but only a single B19V antigenic type has been described. Genotype 1 is predominant in most parts of the world; genotype 2 is rarely associated with active infection; and genotype 3 appears to predominate in parts of western Africa.

EPIDEMIOLOGY

B19V exclusively infects humans, and infection is endemic in virtually all parts of the world. Transmission occurs predominantly via the respiratory route and is followed by the onset of rash and arthralgia. By the age of 15 years, ~50% of children have detectable IgG; this figure rises to >90% among the elderly. In pregnant women, the estimated annual seroconversion rate is ~1%. Within households, secondary infection rates approach 50%.

Detection of high-titer B19V in blood is not unusual (see “Pathogenesis,” below). Transmission can occur as a result of transfusion, most commonly of pooled components. To reduce the risk of transmission, plasma pools are screened by nucleic acid amplification technology, and high-titer pools are discarded. B19V is resistant to both heat and solvent-detergent inactivation.

PATHOGENESIS

B19V replicates primarily in erythroid progenitors. This specificity is due in part to the limited tissue distribution of the primary B19V receptor, blood group P antigen (globoside). Infection leads to high-titer viremia, with >10¹² virus particles (or IU)/mL detectable in the blood at the apex (Fig. 93-1), and virus-induced cytotoxicity results in cessation of red cell production. In immunocompetent individuals, viremia and arrest of erythropoiesis are transient and resolve as the IgM and IgG antibody response is mounted. In individuals with normal erythropoiesis, there is only a minimal drop in hemoglobin levels; however, in those with increased erythropoiesis (especially with hemolytic anemia), this cessation of red cell production can induce a transient crisis with severe anemia (Fig. 93-1). Similarly, if an individual (or, after maternal infection, a fetus) does not mount a neutralizing antibody response and halt the lytic infection, erythroid production is compromised and chronic anemia develops (Fig. 93-1).

The immune-mediated phase of illness, which begins 2–3 weeks after infection as the IgM response peaks, manifests as the rash of fifth disease together with arthralgia and/or frank arthritis. Low-level B19V DNA can be detected by polymerase chain reaction (PCR) in blood and tissues for months to years after acute infection. The B19V receptor is found in a variety of other cells and tissues, including megakaryocytes, endothelial cells, placenta, myocardium, and liver. Infection of these tissues by B19V may be responsible for some of the more unusual presentations of the infection. Rare individuals who lack P antigen are naturally resistant to B19V infection.

CLINICAL MANIFESTATIONS

Erythema infectiosum

Most B19V infections are asymptomatic or are associated with only a mild nonspecific illness. The main manifestation of symptomatic B19V infection is erythema infectiosum, also known as fifth disease or slapped-cheek disease (Fig. 93-2 and Fig. 93-1A). Infection begins with a minor febrile prodrome ~7–10 days after exposure, and the classic facial rash develops several days later; after 2–3 days, the erythematous macular rash may spread to the extremities in a lacy reticular pattern. However, its intensity and distribution vary, and B19V-induced rash is difficult to distinguish from other viral exanthems. Adults typically do not exhibit the “slapped-cheek” phenomenon but present with arthralgia, with or without the macular rash.

Polyarthropathy syndrome

Although uncommon among children, arthropathy occurs in ~50% of adults and is more common among women than among men. The distribution of the affected joints is often symmetrical, with arthralgia affecting the small joints of the hands and occasionally the ankles, knees, and wrists. Resolution usually occurs within a few weeks, but recurring symptoms can continue for months. The illness may mimic rheumatoid arthritis, and rheumatoid factor can often be detected in serum. B19V infection may trigger rheumatoid disease in some patients and has been associated with juvenile idiopathic arthritis.

Transient aplastic crisis

Asymptomatic transient reticulocytopenia occurs in most individuals with B19V infection. However, in patients who depend on continual rapid production of red cells, infection can cause transient aplastic crisis (TAC). Affected individuals include those with hemolytic disorders, hemoglobinopathies, red cell enzymopathies, and autoimmune hemolytic anemias. Patients present with symptoms of severe anemia (sometimes life-threatening) and a low reticulocyte count, and bone marrow examination reveals an absence of erythroid precursors and characteristic giant pronormoblasts. As its name indicates, the illness is transient, and anemia resolves with the cessation of cytopathic infection in the erythroid progenitors.

Pure red-cell aplasia/chronic anemia

Chronic B19V infection has been reported in a wide range of immunosuppressed patients, including those with congenital immunodeficiency, AIDS (Chap. 97), lympho-proliferative disorders (especially acute lymphocytic leukemia), and transplantation (Chap. 16). Patients have persistent anemia with reticulocytopenia, absent or low levels of B19V IgG, high titers of B19V DNA in serum, and—in many cases—scattered giant pronormoblasts in bone marrow. Rarely, nonerythroid hematologic lineages are also affected. Transient neutropenia, lymphopenia, and thrombocytopenia (including idiopathic thrombocytopenic purpura) have been observed. B19V occasionally causes a hemophagocytic syndrome.

Recent studies in Papua New Guinea and Ghana, where malaria is endemic, suggest that co-infection with Plasmodium and B19V plays a major role in the development of severe anemia in young children. Further studies must determine whether B19V infection contributes to severe anemia in other malarial regions.

Hydrops fetalis

B19V infection during pregnancy can lead to hydrops fetalis and/or fetal loss. The risk of transplacental fetal infection is ~30%, and the risk of fetal loss (predominantly early in the second trimester) is ~9%. The risk of congenital infection is <1%. Although B19V does not appear to be teratogenic, anecdotal cases of eye damage and central nervous system (CNS) abnormalities have been reported. Cases of congenital anemia have also been described. B19V probably causes 10–20% of all cases of nonimmune hydrops.

Unusual manifestations

B19V infection may rarely cause hepatitis, vasculitis, myocarditis, glomerulosclerosis, or meningitis. A variety of other cardiac manifestations, CNS diseases, and autoimmune infections have also been reported. However, B19V DNA can be detected by PCR for years in many tissues; this finding is of no known clinical significance, but its interpretation may cause confusion regarding B19V disease association.

DIAGNOSIS

Diagnosis of B19V infection in immunocompetent individuals is generally based on detection of B19V IgM antibodies (Table 93-1). IgM can be detected at the time of rash in erythema infectiosum and by the third day of TAC in patients with hematologic disorders; these antibodies remain detectable for ~3 months. B19V IgG is detectable by the seventh day of illness and persists throughout life. Quantitative detection of B19V DNA should be used for the diagnosis of early TAC or chronic anemia. Although B19V levels fall rapidly with the development of the immune response, DNA can be detectable by PCR for months or even years after infection, even in healthy individuals; therefore, quantitative PCR should be used. In acute infection at the height of viremia, >10¹² B19V DNA IU/mL of serum can be detected; however, titers fall rapidly within 2 days. Patients with aplastic crisis or B19V-induced chronic anemia generally have >10⁵ B19V DNA IU/mL.

TREATMENT

PREVENTION

No vaccine has been approved for the prevention of B19V infection, although vaccines based on B19V virus-like particles expressed in insect cells are known to be highly immunogenic. Phase 1 trials of a putative vaccine were discontinued because of adverse side effects.

DEFINITION

The PARV4 viral sequence was initially detected in a patient with an acute viral syndrome. Similar sequences, including the related PARV5 sequence, have been detected in pooled plasma collections. The DNA sequence of PARV4/5 is distinctly different from that of all other parvoviruses, and this virus is now classified as a member of the newly described genus Tetraparvovirus.

EPIDEMIOLOGY

PARV4 DNA is commonly found in plasma pools but at lower concentrations than levels of B19V DNA found before in plasma pools prior to screening. The higher levels of PARV4 DNA and IgG antibody in tissues (bone marrow and lymphoid tissue) and sera from IV drug users than in the corresponding specimens from control patients suggest that the virus is transmitted predominantly by parenteral means in the United States and Europe. Evidence for nonparenteral transmission in other parts of the world is limited.

CLINICAL MANIFESTATIONS

To date, PARV4/5 infection has been associated only with mild clinical disease (rash and/or transient aminotransferase elevation).

DEFINITION

Animal bocaviruses are associated with mild respiratory symptoms and enteritis in young animals. HBoV1 was originally identified in the respiratory tract of young children with lower respiratory tract infections. More recently, HBoV1 and the related viruses HBoV2, HBoV3, and HBoV4 have all been identified in human fecal samples.

EPIDEMIOLOGY

Seroepidemiologic studies with HBoV virus-like particles suggest that human bocavirus infection is common. Worldwide, most individuals are infected before the age of 5 years.

CLINICAL MANIFESTATIONS

HBoV1 DNA is found in respiratory secretions from 2–20% of children with acute respiratory infection, often in the presence of other pathogens; in these circumstances, the role of HBoV1 in disease pathogenesis is unknown. Clinical disease due to HBoV1 is associated with evidence of primary infection (IgG seroconversion or the presence of IgM), HBoV1 DNA in serum, or high-titer HBoV1 DNA (>10⁴ genome copies/mL) in respiratory secretions. Symptoms are not dissimilar from those of other viral respiratory infections, and cough and wheezing are commonly reported. There is no specific treatment for bocavirus infection. The role of human bocaviruses in childhood gastroenteritis remains to be established.