Human Parvovirus B19

This X-ray crystallographic image of the B19 VP2 particle was obtained from Bärbel Kaufmann et al, Parvovirus B19 does not bind to membrane-associated globoside in vitro, Virology, Volume 332, Issue 1, 5 February 2005, Pages 189-198.(http://www.sciencedirect.com/science/article/B6WXR-4F4H9R9-1/2/c23e78f4d6ee08770bc6df8523e617de)

I. Background
II. Biology of B19 Infection
III. Clinical Progression
IV. Clinical Syndromes
V. Epidemiology
VI. References


I. Background

The B19 virus is the only virus in the parvoviridae family that infects humans (Strauss 271). Its name, B19, refers to the blood bank code of a viremic donor in which it was first observed under the electron microscope (Fields 2364). This virus is responsible for flu-like symptoms (fever, malaise, and myalgia) as well as fifth disease, which leads to an erythematous rash on the face known as slapped check. In adults, symptoms of B19 infection can be even more severe, with joint inflammation similar to rheumatoid arthritis (Strauss 271; Fields 2365). Thus, fifth disease provides an example where disease progression is not caused directly by the pathology of the virus, but rather is manifested in the immune systems over-response to the viral infection. Healthy individuals with intact immune systems mount a robust immune response and develop immunity to B19. However, people with preexisting hemolytic disorders, people who are immunocompromised, as well as fetuses, are at higher risk for developing more severe or life-threatening anemias (Strauss 273).

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II. Biology of B19 Infection

A) B19 in erythroid protenitor cells

B19 has a tropism for human erythroid protenitor cells in vitro, consistent with the parovivirus's necessity for infecting rapidly dividing cells in the S phase of the cell cycle (Fields 2362). It is believed to suppress erythropoiesis for 5 to 7 days. It is discovered that B19 is responsible for inhibiting the erythroid progenitor cell from forming colonies. In addition, bone marrow cells became more susceptible to B19 infection as they matured and differentiated along the erythroid lineage (Takahashi 1990). Consistent with this finding, the propagation of viral infection depends on the presence of the protein erythropoietin, suggesting that the cell's susceptibility to B19 may be related to the role of this protein in directing cells toward erythropoietin differentiation (Shimomura 1992).However, some cell lines that were positive for P antigen failed to bind B19, whereas some cell lines had an ability to bind B19 despite undetectable expression of P antigen.

B) B19's cellular receptor

Erythrocyte P antigen (or globoside) was discovered to the cellular receptor for B19. This receptor is expressed on all erythroid cells, and accounts for B19's extremely specific tropism. However, only precursor erythroid cells are actually infected because they are rapidly dividing, whereas mature erythrocytes are not infected because they are terminally differentiated (Strauss 272). Recently, two proteins, alpha5beta1 integrin (Blood. 2003; 102: 3927) and the Ku80 autoantigen (Blood. 2005: 106:3449),were subsequently identified as the cellular coreceptors for B19 infection. Nevertheless, the mechanism underlying the specific cellular tropism of B19 still remains a mystery.

C) Immunology of B19 Infection

1. Antibody response
In response to B19 infection, the immune system responds by producing IgM and IgG antibodies. IgM antibodies are detected at approximately 10 to 12 days after infection, whereas IgG antibodies can be found 2 weeks after the infection and persist for life. Initially, the early antibodies are produced against VP2, the main viral capsid protein. As the B19 infection continues, antibodies react primarily to the VP1 minor capsid protein (Fields 2368).

2. Role of antibodies
Interestingly, antibodies may serve two roles in B19 infections. While neutralizing antibodies help patients clear the virus in both acute and persist infections, the antibodies may also be critical in forming immune-complexes which worsen the clinical outcomes of B19 infection (Fields 2369).

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III. Clinical Progression

A) Biphasic course

Following intranasal inoculation of B19 in healthy adult volunteers, the first phase of B19 pathogenesis occurs after one week, characterized by mild illness with fever, chills, headache, pyrexia, and myalgia (pain in the muscle). Approximately 17 to18 days after infection, a second phase of clinical progression is associated with rash and arthalgia (pain in the joints) (Heegaard, 2002).

B) Hematological changes


During the viremic stage, reticulocyte (immature red blood cell) numbers fall to undetectable levels, and then recover after 7 to 10 days. In temporary drop in hemoglobin levels follow the decrease in reticulocyte numbers, which later recover back to normal (Heegaard, 2002).

C) B19 DNA


B19 virus can be detected and diagnosed by isolating viral DNA, and performing direct hybridization or PCR. In direct hybridization, a nearly-full-length viral DNA, radioactively labeled probe is used, allowing for high sensitivity (Heegaard, 2002).

D) B19 Viremia and Antibody Responses


In 10 to 12 days after initial infection of the volunteers with B19 virus, IgM antibodies are detected in the serum, lasting for approximately 3 months. Beginning at approximately 2 weeks, IgG antibodies are also detected, which are believed to persist for life-long immunity (Heegaard, 2002).

This figure was obtained from Erik D. Heegaard and Kevin E. Brown. “Human Parvovirus B19.” Clin Microbiol Rev. 2002 July; 15(3): 485–505. doi: 10.1128/CMR.15.3.485-505.2002.
 

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IV. Clinical Syndromes

A. Fifth Disease

Fifth Disease is a common childhood exanthema, characterized by "slapped cheek" facial erythema, as well as a maculopapular rash over the trunk and the extremities. During the viremic phase of the infection, excess antibodies lead to the formation of immune complexes, which induce these characteristic childhood rashes. In adults, B19 infection leads to more severe symptoms of polyarthropathy, or inflammatory polyarthritis, rather than a rash (as in children). These symptoms often resemble those or rheumatoid arthritis in the distribution of the joints affected and the characteristics of the inflammation (Fields 2369). [Click here for a comparison beween Fifth Disease, Transient aplastic crisis, and Pure red-cell aplasia]

B. Transient aplastic crisis (TAC)


Because B19 suppresses erythropoiesis for 5 to 7 days, patients with hemolytic diseases of the blood (like sickle cell anemia, thalassemias, or acquired hemolytic anemias) tend to develop transient aplastic crisis (TAC). TAC is an abrupt cessation of red blood cell production, leading to reticulocytopenia (an abnormal decrease in the amount of immature red blood cells in the blood), the absence of erythroid precursors in the bone marrow, massive viremia, and more severe anemia (Fields 2370).As patients with hemolytic diseases have a high turnover rate of new red blood cells (to compensate for the diseased cells in the blood), a disruption of these cells can lead to severe anemia. Also, the higher turnover rate implies a larger percentage of immature precursor erythroid cells, producing more susceptible cells for the viral infection Bridges 2002). [Click here for a comparison beween Fifth Disease, Transient aplastic crisis, and Pure red-cell aplasia]

B19 Infection in an Acute Host
Acute Host Disease Clinical Manifestations
Normal child Fifth's Disease Facial erythema, "slapped cheek", maculopapular eruption over body
Normal adult Polyarthropathy Inflammation of the joints, mimicking symptoms of rheumatoid arthritis
Chronic hemolytic anemia Transient aplastic crisis Severe acute anemia




 

This table was modified from: Bridges, Kenneth. Information Center for Sickle Cell and Thalassemic Disorders. “Transient Aplastic Crisis in Hemolytic Anemias.” Updated 2002. Available Online. http://sickle.bwh.harvard. edu/aplastic_crisis.html, Accessed November 15, 2005; Knipe and Howley. Fields Virology. 2005.


C. Pure red-cell aplasia (PRCA)


Pure red-cell aplasia (PRCA) develops both in immunocompromised individuals, those patients are those with congenital and acquired immune diseases, including congenital immunodeficiency, AIDS, leukemia in remission, and organ transplantations. The inability to produce antibodies against B19 leads to a persistent infection, leading to severe anemia, and the patient's subsequent reliance on blood transfusions. Because they do not produce antibodies against B19 virus (either neutralizing or in an immune-complex), they do not have the symptoms of fifth disease (Fields 2371). [Click here for a comparison beween Fifth Disease, Transient aplastic crisis, and Pure red-cell aplasia]

D. Hydrops fetalis


When a fetus is infected in B19 in utero, the fetus can develop severe anemia, cardiac failure, and subsequently die. Erythroblasts in the fetal liver, where hemotopoiesis occurs in the fetus, shows cytopathology, viral DNA, and B19 antigen. B19-associated myocarditis is also factor into the pathogenesis of the disease (Fields 2370).

E. Congenital red-cell aplasia


Many fetus that do not die from the B19 viral infection go on to develop congenital red-cell aplasia. This is characterized by a severe chronic anemia and persistent viral infection in the bone marrow (but not the blood) (Fields 2370-2371).

B19 Infection in a Chronic Host
Chronic Host Disease Clinical Manifestations
Immunocompromised patient Pure red cell aplasia Chronic anemia
Fetus Congenital anemia Aregenerative chronic anemia
Fetus Hydrops fetalis Fatal anemia, heart failure

 

 

 

This table was modified from: Bridges, Kenneth. Information Center for Sickle Cell and Thalassemic Disorders. “Transient Aplastic Crisis in Hemolytic Anemias.” Updated 2002. Available Online. http://sickle.bwh.harvard. edu/aplastic_crisis.html, Accessed November 15, 2005; Knipe and Howley. Fields Virology. 2005.

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V. Epidemiology

B19 is a common viral infection. About 50% of adults have IgG antibodies against the virus (which persist in the blood stream for life after an infection with B19), suggesting a previous infection. In the elderly, as many as 90% have antibodies against B19 (Fields 2372). Importantly, while B19 antibody is prevalent in the population, viremia or presence of viral DNA is rare. It has been estimated that the frequency of B19 viremia is between 1:167 to 1:35,000 (Heegaard, 2002). Both fifth disease and TAC are seasonally-dependent, with peak occurrences in the late winter, spring, and summer (Fields 2372).

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VI. References

Andreas Gigler, Simone Dorsch, Andrea Hemauer, Constance Williams, Sonnie Kim, Neal S. Young, Susan Zolla-Pazner, Hans Wolf, Miroslaw K. Gorny, and Susanne Modrow. “Generation of Neutralizing Human Monoclonal Antibodies against Parvovirus B19 Proteins.”J Virol. 1999 March; 73(3): 1974–1979.

Bärbel Kaufmann, Ulrich Baxa, Paul R. Chipman, Michael G. Rossmann, Susanne Modrow and Robert Seckler, Parvovirus B19 does not bind to membrane-associated globoside in vitro, Virology, Volume 332, Issue 1, 5 February 2005, Pages 189-198. (http://www.sciencedirect.com/science/article/B6WXR-4F4H9R9-1/2/c23e78f4d6ee08770bc6df8523e617de)

Bridges, Kenneth. Information Center for Sickle Cell and Thalassemic Disorders. “Transient Aplastic Crisis in Hemolytic Anemias.” Updated 2002. Available Online. http://sickle.bwh.harvard.edu/aplastic_crisis.html, Accessed November 15, 2005

Erik D. Heegaard and Kevin E. Brown. “Human Parvovirus B19.” Clin Microbiol Rev. 2002 July; 15(3): 485–505. doi: 10.1128/CMR.15.3.485-505.2002.

Knipe and Howley. Fields Virology. 2005.

Luc Mouthon, Loïc Guillevin and Zera Tellier, Intravenous immunoglobulins in autoimmune- or parvovirus B19-mediated pure red-cell aplasia, Autoimmunity Reviews, Volume 4, Issue 5, June 2005, Pages 264-269. (http://www. sciencedirect.com/science/article/B6W8V-4DSPTXP-1/2/0ebeb6de90fd00e8e302240deb4d1723)

Shimomura S, Komatsu N, Frickhofen N, et al. First continuous propagation of B19 parvovirus in a cell line. Blood 1992;79:18–24.

Strauss, J. and Strauss E. “Viruses and Human Disease.” Academic Press, 2002.

Takahashi T, Ozawa K, Takahashi K, et al. Susceptibility of human erythropoietic cells to B19 parvovirus in vitro increases with differentiation. Blood 1990;75:603–610.