Parvoviruses

Individuals with erythema infectiosum have a fever and a rubelliform rash that begins on the face and spreads to the trunk and limbs. In patients with a preexisting hemolytic anemia (e.g., sickle cell anemia), the disease can cause aplastic crisis (transient bone marrow erythroid aplasia). In women, disease late in pregnancy can cause spontaneous abortion and edematous anemic stillbirth (hydrops fetalis).

Parvoviruses are non-enveloped, icosahedral particles 18 to 26 nm in diameter. Plus and minus DNA strands are packaged into separate virions in approximately equal proportion. There are two capsid proteins.

Parvoviruses are classified by size, morphology, and genomic organization. A single antigenic type is associated with human disease.

Replication takes place in the nucleus of dividing cells. The single-stranded DNA genome forms an intermediate double-stranded form, which replicates to form progeny-positive and -negative single-stranded DNA. Positive and negative strands are packaged separately in viral capsids in equal numbers.

The disease is transmitted by the respiratory route. The virus replicates in committed erythroid precursor cells in the bone marrow, leading to erythroid aplasia. Aplastic anemia develops in patients with underlying hemolytic anemia, and rash and arthralgia develop at the time specific antibody appears.

Specific IgM and IgG antibodies develop in response to infection.

Erythema infectiosum is found worldwide. Outbreaks occur predominantly in spring, mainly in school children and young adults, with peaks of activity at 4- to 5-year intervals.

Diagnosis is by detecting viral DNA in serum and a rise in parvovirus-specific IgM or IgG.

No specific antiviral therapy or vaccine is yet available.

The parvoviruses (parvo meaning small) are a group of very small DNA viruses that are ubiquitous and infect many species of animals. The small amount of DNA contained in the viruses does not carry sufficient genetic information to direct its own replication in host cells. As a result, parvoviruses have unusual requirements for replication, such as a simultaneous helper virus or rapidly dividing cells. They are divided into two groups on the basis of these requirements. The parvoviruses that multiply only in cells coinfected with a helper adenovirus constitute the genus dependovirus (previously called the adeno-associated viruses [AAVs]). These viruses have not been shown to cause disease in humans. The second group of parvoviruses, constituting the genus Parvovirus, do not require a helper virus for replication. However, they multiply only in cells that are in the process of replicating their own DNA. The diseases caused by autonomous parvoviruses reflect their requirement for actively dividing cells. The human autonomous parvovirus, B19 virus, replicates in erythroid precursor cells and hence produces aplastic crisis in predisposed individuals with underlying hemolytic anemia or immunodeficiency. Other clinical manifestations of B19 virus infection are due to the host immune response to the virus.

Erythema infectiosum, also known as fifth disease, is the most common clinical manifestation of B19 virus infection. Clinical symptoms develop in a biphasic fashion. Some 7 to 8 days after infection, a prodromal influenza-like illness develops, characterized by headache, malaise, chills, and pyrexia. Individuals are then asymptomatic for a week. The second phase of illness occurs 17 to 18 days after infection, with the development of a mild febrile illness and a maculopapular rash. The first sign of illness is marked erythema of the cheeks (“slapped-cheeks” appearance) followed by a rash on the trunk and limbs. The rash initially has a discrete erythematous maculopapular appearance and then becomes reticular, disappearing in 1 to 3 weeks. Erythema infectiosum often resembles the rash of rubella. A rash does not always occur following B19 virus infection, and the only manifestation of the second phase of the illness may be a mild, influenza-like illness. Joint involvement occurs in most women and much less frequently in men and children. The most common presentation is of an acute-onset, symmetric arthritis involving the small joints of the hands, wrists, ankles, and knees. Recovery usually occurs within 2 to 4 weeks. B19 arthropathy may also occur in the absence of the rash. Transient lymphopenia, neutropenia, and thrombocytopenia are complications of B19 virus infection, but are rarely severe enough to cause problems.

An acute, self-limiting aplastic crisis occurs following B19 virus infection in individuals with underlying hemolytic anemias such as sickle cell anemia, hereditary spherocytosis, β-thalassemia intermedia, pyruvate kinase deficiency, and autoimmune hemolytic anemia. Patients develop acute symptoms of severe anemia with a critically low hemoglobin level, reticulocytopenia, and, occasionally, leukopenia and thrombocytopenia. Bone marrow examination shows a complete absence of erythroid precursors. The anemia is selflimiting, but blood transfusion support is required until the bone marrow recovers. Reticulocytes then reappear in the peripheral blood, and hemoglobin concentrations return to the steady state for this patient group. Individuals who have hemolytic anemias and have recently been transfused may escape the aplastic crisis complication of B19 virus infection.

During B19 virus infection an intense viremia develops. In a pregnant woman the virus may cross the placenta and establish infection in the fetus. The fetus is unable to control and eradicate B19 virus, and accordingly viral replication may continue for several weeks. In the first and second trimesters of pregnancy, B19 virus infection is associated with an increased risk of fetal abortion and nonimmune hydrops fetalis. Severe fetal anemia (akin to the aplastic anemia seen in patients with hemolytic anemia) and edema occur up to 12 weeks after maternal infection and may cause the fetal hydrops. Infection in the third trimester of pregnancy has been less intensively studied, but a macerated stillbirth fetus has been reported at 39 weeks of gestation. The overall incidence of B19 virus-induced fetal loss is not precisely known but appears to be about 9 percent of affected pregnancies. Most pregnancies continue to term with the delivery of normal babies, indicating that this virus does not cause congenital abnormalities.

Human B19 virus is a nonenveloped, icosahedral virus with a diameter of 18 to 26 nm. The virus capsid is composed of two structural proteins. Structural proteins VP-l and VP-2 have molecular weights of 83,000 and 58,000, respectively, and account for 60 to 80 percent of the virion mass. The DNA genome is 5.5 kilobases long and the virus packages plus and minus DNA strands into separate virions with equal efficiency. It is very hardy and viral infectivity is resistant to ether, chloroform, deoxyribonuclease (DNase) and ribonuclease (RNase) treatment.

Both genera in the family Parvoviridae, Dependovirus and Parvovirus, contain members capable of infecting humans, but only one parvovirus strain causes disease. Dependoviruses are defective parvoviruses that require a helper virus, such as an adenovirus, for replication. They have not been shown to cause disease in humans. Parvoviruses are autonomous (capable of independent replication). The parvovirus known as B19 virus, which exists as a single serotype, causes the disease in humans. Other, Parvovirus-like particles have been observed by electron microscopy in feces, but their pathogenic potential is uncertain. Definitive classification of these agents awaits their biochemical characterization.

B19 virus replicates in the nucleus of infected cells. B19 DNA synthesis is assumed to be similar to that of other autonomous parvoviruses and involves the formation of double-stranded replicative intermediates. Progeny DNA is formed by strand displacement and depends on some function found only in the late S phase of the cell cycle. Single positive and negative strands are packaged separately within newly synthesized capsids. Nonstructural proteins cause lysis of the cell, with release of progeny virus.

B19 virus is transmitted most commonly via the respiratory route, although blood-borne transmission following whole blood or factor VIII transfusion has been reported (Fig. 64-1). Virus is detectable in throat secretions for some 5 days, starting 1 week after infection (Fig. 64-2). It is not known whether the virus has a site of replication in the respiratory tract.

Clinical manifestations and pathogenesis of B19 virus infection.

Pathogenesis of B19 virus infection.

The manifestation of clinically apparent disease following parvovirus infection depends on two interacting factors: the survival time of the circulating erythrocytes in the host and the immune response to the virus. The erythrocyte P antigen is the cell receptor for B19 virus. This antigen is found on cells of the erythrocyte lineage, vascular endothelium and fetal myocytes. The virus replicates in erythroid precursor cells, causing lysis of these susceptible cells and transient loss of all erythrocyte precursors from the bone marrow. In hematologically normal hosts this leads to a transient reticulocytopenia without a significant fall in the number of circulating erythrocytes. In patients with hemolytic anemia, however, the life span of erythrocytes is much shorter than normal, so that the loss of erythroid precursors in the marrow leads to a rapid fall in the circulating erythrocyte population and to development of the aplastic crisis of B19 infection.

Six to seven days after acquisition of the virus a viremia develops, coincident with the prodromal influenza-like illness. The second phase of B19 disease depends on the immune response to the virus. Erythema infectiosum and arthralgia develop 17 to 18 days after the acquisition of the virus and at the time of the appearance of specific IgM and IgM-virus immune complexes. The virus is no longer detectable, and the rash is probably due to the antibody response to the virus.

Fetal disease develops when the virus crosses the placenta and establishes infection in the fetal erythroid precursors and cardiac myocytes. Since the fetus cannot mount an adequate immune response, B19 infection becomes chronic and leads to erythroid aplasia and anemia, with consequent fetal loss early in pregnancy and hydrops fetalis and stillbirths following infection later in pregnancy. Chronic B19 virus infection accompanied by chronic anemia has occurred occasionally in immunodeficient patients suffering from leukemia or acquired immune deficiency syndrome (AIDS).

B19-specific IgM is first detectable as the viremia wanes, 9 to 10 days after the onset of infection, and peak levels develop within 1 week. Much of the early antibody is complexed with virus in immune complexes. Specific IgG is not detectable until 2 weeks after the onset of infection, and peak levels develop more slowly over the following 2 weeks. The role of cell-mediated immunity following B19 infection is unknown.

B19 infection is found worldwide and occurs throughout the year, although in temperate zones infection is most common in the spring. In addition, there are longer-term cycles of virus activity with peaks of activity every 4 to 5 years. B19 infection is most commonly acquired between the ages of 4 and 10 years, with outbreaks of erythema infectiosum occurring in junior schools in the spring. Sixty percent of adults have specific IgG, indicating past infection with B19 virus.

B19 virus is not cultivatable in conventional cell culture, although bone marrow suspension and fetal liver culture support very limited viral replication. For this reason, the early diagnosis of B19 infection is established by detection of B19 antigen or DNA in serum or throat secretions. Parvovirus particles are visualized by electron microscopy within 24 hours of the onset of symptoms in 30 percent of patients. Later the diagnosis is established by demonstrating a specific IgM response or a rise of specific IgG (seroconversion). Since normal individuals are viremic and shed virus prior to the onset of characteristic symptoms, the diagnosis is established by antibody testing. Patients with hemolytic anemia may develop aplastic crisis while still viremic, and so antigen and DNA detection tests, along with the antibody test, may be used. To establish the diagnosis of fetal infection, fetal serum should be tested for B19 DNA, as the fetus may fail to make an IgM response and IgG, if present, may reflect passively acquired maternal antibody.

B19 antigen may be detected in serum by countercurrent immunoelectrophoresis, radioimmunoassay, and enzyme immunoassay, although only the last two are sensitive enough to detect B19 antigen in throat secretions. DNA-DNA dot blot hybridization is a very sensitive test for detecting B19 DNA in any infected body fluid.

Anti-B19 antibody is detected by countercurrent immunoelectrophoresis or immune electron microscopy, although the most widely used tests are IgM and IgG capture radioimmunoassays or enzyme immunoassays. B19 IgM persists for 2 to 3 months after the onset of symptoms; IgG is detectable for much longer and probably persists for life, although it may fall below the level of detection by currently available assays.

There is no specific antiviral therapy or vaccine for B19 infection, and most individuals do not require symptomatic therapy. Patients with aplastic crisis require erythrocyte transfusion support until the bone marrow recovers. Administration of normal human immunoglobulins to immunodeficient, B19-infected patients may produce transient amelioration of viremia and anemia.

Most persons infected with B19 virus are asymptomatic when viral shedding is maximal, and therefore control of infection is difficult. Patients presenting with erythema infectiosum are no longer infectious and do not require isolation. Patients with aplastic crisis may be infectious at the time of presentation and should not be cared for near other at-risk patients with hematologis, immunodeficiency, or who are pregnant.