By Craig Litz, M.D.
A 45-year-old HIV+ male presented with a 2-month history of progressive fatigue and dyspnea on exertion. Physical exam revealed a thin male with cervical lymphadenopathy. Hemoglobin was 5.9 gm/dl and white count was 0.9 K/ul. Platelet count was normal. Bone marrow biopsy revealed a marked erythroid hypoplasia with giant pronormoblasts. Immunohistochemical stains for Parvovirus B19 capsid protein were positive. The patient was treated for 10 days with a commercial immunoglobulin preparation that contained antibodies to the virus. A reticulocytosis resulted and hemoglobin levels returned to 11.0 gm/dl after several weeks. Immunoglobulin infusions were given periodically for several months.
Originally discovered in 1975, Parvovirus B19 (PV B19) is a small, non-enveloped, 5.6Kb DNA virus of icosahedral symmetry and with a diameter of 15-28nm. It is stable to physical inactivation due to the lack of an envelope and limited DNA content (Cossart et al, 1975; Young, 1995).
Clinically, PV B19 is responsible for the childhood exanthema referred to as erythema infectiosum (fifth disease); a self-limited disorder in the immunocompetent characterized by headache, malaise, pyrexia and a fiery red “slapped cheek” facial erythema followed by a lacy, maculopapular eruption on the trunk and extremities. Viral cultures are rarely positive as symptomatology is immune complex-mediated and follows the immune response and clearance of viral particles.
PV B19 infection is mediated via the P antigen. Although this antigen is also expressed on megakaryocytes, endothelial cells, placental trophoblasts, and fetal myocardial and liver cells, PV 19 preferentially infects and lyses the mature marrow erythroid precursors. Individuals congenitally lacking P antigen are not susceptible to PV B19 infection. PV B19 infection results in the consistent ablation of erythroid precursors early in the disease course with accompanying reticulocytopenia. The degree of resulting anemia largely depends on the red cell half-life and immune status of the individual. PV B19 infection in immunocompetent patients with a normal red cell half-life typically results in a decrease of hemoglobin by 1-2 gm/dl before the immune response clears the infection after two weeks. Individuals with hemolytic anemias may suffer a severe fall in hemoglobin before immune clearance occurs leading to a syndrome referred to as “transient aplastic crisis” or TAC. Persistent PV B19 infections may occur in patients with immunodeficiency syndromes manifesting as severe aregenerative anemias with no detectable immune response and persistent viremia. (Anderson et al, 1985; Brown et al, 1993; Brown et al, 1994; Kurtzman et al, 1989; Ozawa et al, 1987)
Hematologically, red cells, reticulocytes, neutrophils, platelets, and lymphocytes progressively decline until an immune response is elicited 10-14 days after infection. Marrow manifestations are maximal 10 days after infection and include a profound erythroid hypoplasia with early pronormoblasts showing a characteristic viral cytopathic effect. These “giant normoblasts” originally described by Owren in 1948 are enlarged (25-32 um) erythroid progenitors with multiple eosinophilic nuclear inclusions and cytoplasmic vacuoles. More mature erythroid precursors are absent. With the normal immune response, the marrow normalizes with erythroid regeneration. The erythroid hypoplasia may persist in immunodeficient individuals. (Frickhoven et al, 1990, Frickhoven et al 1994; Kurtzman et al, 1989; Owren, 1948)
Diagnosis usually rests on the clinical picture with serological documentation of immune response or confirmation of viremia by PCR techniques. Histologic recognition of marrow erythroid hypoplasia with the characteristic viral cytopathic effect and confirmatory immunohistochemical staining for the viral capsid protein is important in identifying clinically cryptic cases. The disease is self-limited in immunocompetent individuals. Immunocompromised patients require immunoglobulin preparations to clear the virus. Reticulocytosis heralds clinical resolution. (Vadlamudi et al, 1999)
1. Anderson MJ, Higgins PG, Davis LR et al. Experimental parvoviral infection in humans. J Infect Dis 152:257-265, 1985.
2. Brown K, Anderson SM, Young NS. Erythrocyte P antigen: cellular receptor for B19 Parvovirus. Science 262:114-117, 1993.
3. Brown K, Young NS, Liu JM. Molecular, cellular and clinical aspects of Parvovirus B19 infection. Crit Rev Oncol Hematol 19:1-31, 1994.
4. Cossart YE, Field AM, Cant B, Widdows D. Parvovirus-like particles in human sera. Lancet 1:72-73, 1975.
5. Frickhoven N, Abkowitz JL, Safford M et al. Persistent B19 Parvovirus infection in patients infected with Human Immunodeficiency Virus Type 1 (HIV-1): a treatable cause of anemia in AIDS. Ann Intern Med 113:926-933, 1990.
6. Frickhoven N, Chen ZJ, Young NS et al. Parvovirus B19 as a cause of acquired chronic pure red cell aplasia. Brit J Haematol 87:818-824, 1994.
7. Kurtzman G, Frickhofen N, Kimball J et al. Pure red cell aplasia of 10 years’ duration due to persistent Parvovirus B19 infection and its cure with immunoglobulin therapy. N Engl J Med 321:519-523, 1989.
8. Owren PA. Congenital hemolytic jaundice: the pathogenesis of the “hemolytic crisis”. Blood 3:231-248, 1948.
9. Ozawa K, Kurtzman G, Young N. Productive infection by B19 parvovirus of human erythroid bone marrow cells in vitro. Blood 70:384-391, 1987.
10. Vadlamudi G, Rezuke WN, Ross JW et al. The use of monoclonal antibody R92F6 and polymerase chain reaction to confirm the presence of parvovirus B19 in bone marrow specimens of patients with acquired immunodeficiency syndrome. Arch Pathol Lab Med 123:768-773, 1999.
11. Young NS. B19 Parvovirus. Bailliere’s Clinic Haematol 8:25-56, 1995.