|Normal child||Fifth's Disease|
|Chronic hemolytic anemia||Transient aplastic crisis|
Many types of viral infections can suppress bone marrow activity. The most important etiologic agent in transient aplastic crisis is parvovirus B19 (1). The genome of this virus, one of the smallest known, consists of single-stranded DNA. The virus commonly causes the childhood illness, "Fifth Disease", which usually is a minor ailment. Malaise, low-grade fever, arthralgias and a skin rash (often manifested as red, "slapped", cheeks) are hallmarks of the condition. Parvovirus B19 infection in adults frequently is associated with transient arthropathy.
In patients with hemolytic anemia, parvovirus B19 supresses bone marrow erythropoietic activity, leading to transient aplastic crisis. Parvovirus B19 infections can also produce serious complications in patients who are immune compromised. People with defective cell mediated immunity (e.g., severe combined immunodeficiency syndrome; acquired immunodeficiency syndrome) can develop pure red cell aplasia, in which suppression of erythroid precursors is permanent. In utero exposure to parvovirus B19 occasionally produces a congenital anemia.
|Immunocompromised patient||Pure red cell aplasia|
Parvovirus B-19 is a member of the family of adenoviruses, and has a strong trophism for hematopoietic stem cells (2). The virus integrates into a specific site in the human genome. The infected cells fail to divide, impairing the production of new erythrocytes. Reticulocyte counts often fall to as low as 0.1% to 0.5% from the routine values of 6% to 20% in patients with hemolytic anemias.
Hemolytic anemias per se do not predispose patients to infection with parvovirus B19. The prevalence of antibody to the virus is equal in patients with hemolytic anemias and normal controls (3). In one study of patients with sickle cell disease who had transient aplastic crisis, 70% had prior parvovirus B19 infections (4). Normal children probably have an arrest of red cell production when infected with parvovirus B19. Since normal red cells are lost at a rate of only about 1% per day, a 5-day shut down would drop the hematocrit by about 5%, e.g. from a hematocrit of 38% down to 36%. This negligible change is clinically insignificant. In contrast, a person with sickle cell disease or thalassemia may turnover 10% of their red cells each day. A 5-day hiatus in red cell production could cause a hematocrit of 24% to fall to less than 12%. Anemia of this magnitude would be potentially fatal.
Parvovirus B19 has been cultured from the respiratory tract, and is presumed to be transmitted as an aerosol. The globoside gene product on erythroid cells, also known as the group P antigen, is the receptor for the virus (5). Rarely, the P antigen is completely absent on erythroid cells, which confers immunity to parvovirus B19 infection. Only one strain of the virus exists, so that immunity is lifelong following infection.
|Pk2||k||Very rare||Very rare|
|Pk1||P1, Pk||Very rare||Very rare|
Reticulocytopenia is the sine que non of transient aplastic crisis. Bone marrow examination shows giant, multinucleated erythroblasts and pronormoblasts. Late normoblasts are almost completely absent. Pronormoblasts can show mild dysplastic changes. Parvovirus B19 infects mature erythroid progenitors (CFU-E), preventing further replication and maturation (6). The more primitive erythroid precursors (BFU-E) are affected minimally. Evidence exists that a non-structural gene product promotes apoptosis of the cells in the erythroid lineage.
In contrast to the erythroid series, the the numbers of granulocytic cells and megakaryocytes are normal (the M:E ratio is elevated, naturally, due to the paucity of normoblasts.) Consistent with this, peripheral blood polymorphonuclear leukocyte and platelet counts are normal.
Marked viremia can last for up to a week in patients with parvovirus B19 infection. Subsequently, the IgM antibody against the virus rises abruptly and peaks at 21 days. The IgG antibody to the virus then rises and remains elevated.
The diagnosis of transient aplastic crisis due to parvovirus B19 is often presumptive, based on a falling hemoglobin value and a low reticulocyte count in a patient with a hemolytic anemia. Specific DNA probes allow definitive diagnosis by PCR since the viremia is robust. A rising IgM antibody to the virus is another means of diagnosing parvovirus B19 infection.
Transient aplastic crisis usually is self-limiting and requires only supportive measures. Rare patients require more than a single transfusion to bridge the gap between marrow suppression and recovery. The fact that the BFU-E's are not suppressed by the virus means that the bone marrow is poised for a rapid response once the virus is tamed. Rare patients will need immunoglobulin treatment, which is dramatically effective in reversing the aplasia. Immunoglobulin concentrate is the treatment of choice and is delivered as 0.4 g/kg/day for 5 days.
Although viremia precedes the onset of Fifth disease and the associated transient aplastic crisis, viral titers are high even during the clinically manifest portion of the disorder. Consequently, precautions should be taken to avoid exposing other patients with hemolytic anemias or pregnant women to affected individuals. Physicians should warn patients and parents of patients with hemolytic disorders of the signs and symptoms of Fifth disease. Hospital personnel must be careful to avoid cross infection to other patients by those hospitalized with transient aplastic crisis (7). Although the disorder is endemic, epidemic outbreaks occur, during which people with hemolytic disorders must exercise even greater care. Since only one strain of the virus exists and the virus is extremely immunogenic, a vaccine to parvovirus B19 should be feasible. Early clinical trials of a prototype vaccine are underway. The absence of a known animal reservoir raises the possibility that parvovirus B19, like small pox, could be eradicated entirely.