Dear Editor:

Parvovirus B19 (PvB19) is a small, nonenveloped, single-stranded DNA virus of the Parvoviridae family that is a common human infectious agent worldwide. The clinical manifestations of PvB19 infection vary depending on the hematologic and immunologic status of the patient.¹ It can be accompanied by erythema infectiosum in immuno­competent individuals, by transient aplastic crisis in those with chronic hemolytic anemia, hydrops fetalis during pregnancy, and also by chronic anemia and pure red cell aplasia in immunocompromised patients.^1,2 Herein, we report a case of erythropoietin-resistant anemia diagnosed as pure red cell aplasia caused by PvB19 in a pediatric kidney transplant recipient.

The recipientwas a 13-year-old boy who had been diagnosed with end-stage renal disease due to Alport syndrome 2 years previously and who had undergone preemptive living-related kidney transplant from his father in June 2015. The donor was seronegative for PvB19 immunoglobulin M (IgM), hepatitis C, and human immunodeficiency virus(HIV) antibodies and was seropositive for antihepatitis B and PvB19 immunoglobulin G (IgG). The recipient was sero­negative for hepatitis C and HIV antibodies and seropositive for antihepatitis B, PvB19 IgM, and PvB19IgG.The postoperative period was uneventful, and the immunosuppressive therapy consisted of tacrolimus (0.15 mg/kg/day), mycophenolate sodium (750 mg/m²/day), and prednisolone (started at a dose of 30 mg/kg/day and reduced gradually to 20 mg/kg/day). He was evaluated for anemia and moderate graft dysfunction with hemoglobin level of 7.8 g/dL and creatinine level of 1.2 g/dL at the first month visit after transplant. Serum iron, vitamin B12,and folate levels were normal, and polymerase chain reaction (PCR) tests for Cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, BK virus, and JC virus were negative.

Initially, the patient was considered to have drug-related anemia; therefore, mycophenolate sodium was reduced to 360 mg/m²/day and trimethoprim sulfamethoxazole was discontinued. One week later, however, he was hospitalized because of pallor and weakness. Complete blood count findings were as follows: hemoglobin of 4.4 g/dL, hematocrit of 13.2%, leukocyte count of 5 × 10⁹/L, and platelet count of 258 ×10⁹/L. His reticulocyte countwas 0.02%. Normochromic and normocytic red blood cells were seen in the peripheral blood smear. Biochemical findings revealed increased urea (38 mg/dL) and creatinine (1 mg/dL). Direct Coombs test was negative, and urinalysis and culture tests were unremarkable. A bone marrow aspirate showed giant pronormoblasts with signs of suppression on erythroid series. The formulation was as follows: 9% myelocytes, 9% metamyelocytes, 4% neutrophils, 58% polymorphonuclear leukocytes, 10% lymphocytes, 3% monocytes, 1% eosinophils, and 6% normoblasts (Figure 1). The myeloid-to-erythroid ratio of the bone marrow was 12:1. Severe reticulocytopenia and giant pronormoblasts in the bone marrow aspirate raised suspicion for PvB19 infection. Tests for PvB19 IgM and PvB19 IgG were again found to be negative. The PvB19 serology findings for the donor and the patient before and after transplant are summarized in Table 1.

The patient received a blood transfusion, and erythropoietin was started at a dose of 100 U/kg/week. As severe anemia persisted, erythro­poietin was increased to 150 U/kg/week, mycop­henolate was discontinued, and azathioprine was started at a dose of 2 mg/kg/day.Three more erythrocyte transfusions were required. Erythropoietin antibody test was negative. Based on bone marrow aspiration and clinical findings suggesting pure red cell aplasia, PvB19 DNA PCR test was conducted. The results were positive for both peripheral blood and previously obtained and stored bone marrow samples. Tacrolimus was discontinued due to its effect of parvovirus infection and replaced with cyclosporine at a dose of 7 mg/kg/day. Concomitantly, intravenous immunoglobulin (IVIG) was initiated at dose of 400 mg/kg/day for 5 days. Mycophenolate was started again at a dose of 360 mg/day, and erythropoietin was discontinued. On day 5 of treatment, hemoglobin was 8 g/dL and serum creatinine was 1 mg/dL, compatible with baseline creatinine level. Six weeks afterthe IVIG therapy, the patient’s hemoglobin was 12 g/dL, PvB19 PCR was negative, and renal graft dysfunction had totally improved (Figure 2).

Anemia is commonly observed during the early renal posttransplant period and is usually attributed to iron deficiency, blood loss, and bone marrow suppression due to immunosuppressive and antiviral drugs, although it is more common with viral infections.¹ One viral agent known to cause anemia in these transplant patients is PvB19. There are limited data regarding the prevalence of PvB19 infection after organ transplant, especially in children as the literature consists of mostly adult series and adult case reports.^1,3 This virus can be transmitted by inhalation of aerosol droplets, vertically from mother to fetus; it is less commonly transmitted through transfusion of blood products, bone marrow transplant, and solid-organ transplant.¹ In our case, we could not determine how PvB19 infection had occurred.

The clinical spectrum of parvovirus infections varies from mild to a life-threatening condition depending on the age and hematologic and immuno­logic status of the host.^1,4 As a result of an impaired immune response, production of anti-PvB19 antibodies might be inadequate and typical signs of clinical syndrome may be absent. Thus, the diagnosis of parvovirus infections in renal transplant patients remains challenging, and parvovirus DNA PCR is required to determine the diagnosis.4 A specific antiviral therapy has not been defined yet. Intravenous immunoglobulin at a dose of 400 mg/kg per day for 5 to 10 consecutive days is the recommended choice of treatment, in addition to reduction of immunosuppressive medications. In the present case, anemia was ameliorated and control testing for PvB19 DNA PCR was negative after 6 weeks of IVIG therapy.

Several authors concluded that PvB19 infection in transplant patients is aggravated by the use of tacrolimus through impairment of its clearance by tacrolimus, which cannot be simply explained by a state of heightened immunosuppression.Therefore, some clinicians have suggested switching from tacrolimus to cyclosporine in recipients presenting with infection.⁵ There are no available data on whether this alteration enhances viral clearance.

Parvovirus B19 infection and pure red cell aplasia should be kept in mind in erythropoietin-resistant anemia accompanied by reticulocytopenia and in renal graft dysfunction in renal transplant patients. Serologic tests should not be relied on, and DNA PCR analysis should be appliedfor diagnosis.

References:

1. Waldman M, Kopp JB. Parvovirus B19 and kidney. Clin J Am Soc Nephrol. 2007;2(Suppl 1):S47-56.
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2. Alves MT, Vilaça SS, Carvalho MD, Fernandes AP, Dusse LM, Gomes KB. Human parvovirus B19 infection in a renal transplant recipient: a case report. BMC Res Notes. 2013;6:28.
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3. Liefeldt L, Buhl M, Schweickert B, et al. Eradication of parvovirus B19 infection after renal transplantation requires reduction of immunosuppression and high-dose immunoglobulin therapy. Nephrol Dial Transplant. 2012;17(10):1840-1842.
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4. Waldman M, Kopp JB. Parvovirus-B19-associated complications in renal transplant recipients. Nat Clin PractNephrol. 2007;3(10):540-550.
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5. Wong TY, Chan PK, Leung CB, Szeto CC, Tam JS, Li PK. Parvovirus B19 infection causing red cell aplasia in renal transplantation on tacrolimus. Am J Kidney Dis. 1999;34(6):1132-1136.