Human parvovirus B19-associated disease in bone marrow transplantation

Summary Human parvovirus B19 can persist in immunocompromised patients and may produce severe clinical illness. In this retrospective study the incidence of B19-associated infections in bone marrow transplant patients was investigated. During 1 year 60 patients received bone marrow grafts (eight autografts and 52 allogeneic transplantations). In case of early onset, atypical or steroid-resistant erythrodermia the patients' blood and/or tissue specimens were screened for B19 infection by polymerase chain reaction (PCR). Additionally, specimens of patients with severe organ failure were tested. A total of 64 PCRs was performed in 27 patients. Seven patients with erythrodermia and one with vulvovaginitis proved to be PCR positive. In patients with organ failure B19 DNA was detected in the myocardium and liver. The incidence of B19 infections in this cohort was 15% and the B19-associated mortality rate 7%. In conclusion, parvovirus B19-associated infections may be more common in immunocompromised patients than previously anticipated.     

Relapsing pure red cell aplasia associated with B-cell chronic lymphocytic leukemia successfully treated by intravenous immunoglobulin concentrate

Pure red cell aplasia (PRCA) is a rare syndrome characterized by a normochromic normocytic anemia and the absence of mature erythroid precursors in an otherwise normocellular bone marrow. Acquired PRCA has been associated with autoimmune, viral or neoplastic conditions. We report the case of a patient with B-cell chronic lymphocytic leukemia (B-CLL) and PRCA. Conventional antileukemic treatment had no effect on the PRCA, while the B-CLL showed partial remission according to the International Workshop on Chronic Lymphocytic Leukemia response criteria. The patient was treated with cyclosporin A that resulted in complete response of the PRCA lasting 12 months. PRCA relapse, suggested by a hemoglobin decrease and by bone marrow biopsy, did not respond to prednisone and cyclophosphamide treatment. Fludarabine treatment was started in July 1999; the B-CLL remained stable according to the International Workshop on Chronic Lymphocytic Leukemia response criteria, the PRCA did not improve. In October 1999, because of intercurrent pneumonia, the patient was treated with intravenous immunoglobulin (IVIG) concentrate. This treatment resulted in total resolution of the pneumonia and a complete response of the PRCA. Therefore the patient remained on monthly IVIG. In view of the known efficacy of IVIG in the treatment of PRCA induced by parvovirus B19 and since serial polymerase chain reaction determinations of parvovirus B19 were repeatedly negative in our subject, we hypothesize that the IVIG per se may have a therapeutic effect on PRCA. The present case suggests that IVIG may be of benefit for PRCA patients even if the disease is unrelated to parvovirus B19 infection.     

Parvovirus B19 as a cause of acquired chronic pure red cell aplasia

Parvovirus B19 infection causes chronic anaemia in immunodeficient individuals by selective suppression of erythropoiesis. The bone marrow morphology is character-istic of pure red cell aplasia (PRCA). To determine the frequency of B19-induced PRCA we retrospectively analysed a series of 57 PRCA patients. B19 DNA was present in serum of eight patients (14%) and could be extracted from bone marrow aspirate slides from five of these patients. Recent exposure to the virus was confirmed by the presence of anti-B19 IgM in sera from four and by the finding of giant pronormoblasts in marrow aspirates from five of the B19 DNA-positive patients. The sensitivities of anti-B19 IgM and of giant pronormoblasts were only 50% and 63%, respectively; specificites were 90% and 92%. Unexpectedly, PRCA in two B19 DNA-positive patients remitted after antilymphocyte globulin or cyclosporin A therapy, suggesting that the clinical course of B19-induced PRCA may be indistinguishable from other forms of PRCA. As therapy with immunoglobulin is uniformly effective for treatment of B19-associated anaemia, our data suggest that all patients with acquired PRCA should be evaluated for evidence of B19 infection. B19 DNA analysis is the most reliable method to demonstrate infection.     

Infection with parvovirus B19

Human parvovirus B19 is common and widespread. Major manifestations of B19 infection are transient aplastic crisis, erythema infectiosum, hydrops fetalis, acute and chronic rheumatoid-like arthropathy and, in the immunocompromised host, chronic or recurrent bone marrow infection. Less common presentations include skin eruptions, isolated cytopenias, vasculitis, hepatitis, and neuropathies. Increasing awareness of the clinical manifestations of B19 infection makes parvovirus B19 an emerging virus. B19 may persist in healthy or immunocompromised individuals. B19 has been suggested as a candidate agent in rheumatic diseases.     

Parvovirus B19-related anemia in HIV-infected patients

Persistent infection with parvovirus B19 (B19) is an important treatable cause of anemia in HIV-infected patients. B19 has a tropism for erythroid progenitors and causes pure red cell aplasia (PRCA). The failure to produce neutralizing antibodies to the virus following B19 infection in immunodeficient persons may result in persistent viremia and chronic PRCA (B19-PRCA). The seroprevalence rates for B19 in unselected persons with HIV infection are high, similar to those seen in the general population. Reports of B19-related anemia in HIV infected patients, however, are infrequent. A partial explanation may be that B19-PRCA is predominantly a complication associated with advanced immunodeficiency. The condition is probably underdiagnosed as well. The finding of an unexplained normocytic anemia with absent reticulocytes, in an afebrile HIV-infected patient without renal dysfunction suggests a diagnosis of B19-PRCA. The diagnosis is established when the following criteria are met: (1) bone marrow biopsy showing PRCA, (2) serum or bone marrow positivity for B19 DNA by PCR or dot-blot hybridization, and (C) no alternate explanation for the PRCA. Serological methods are unreliable for the diagnosis because these patients often lack IgM and IgG antibodies to B19. Nearly all patients with B19-PRCA respond to treatment with intravenous immunoglobulin (IVIg) with a rise in the hemoglobin to levels appropriate for the clinical condition of the patient. An alternative explanation for the anemia must be sought in patients not responding to IVIg. Most patients with CD4+ T-lymphocyte counts of < or = 100 cells/mm3 relapse to anemia, usually within 6 months of IVIg therapy. Such patients must be retreated with IVIg 2 g/kg given over 2 to 5 days. The routine use of maintenance IVIg 0.4 g/kg q 4wk may be considered in these patients to prevent relapse.     

Parvovirus B-19 induced acute pure red cell aplasia in patients with chronic lymphocytic leukemia and neurofibromatosis type-1

Parvovirus B19 induced pure red cell aplasia (PRCA) has been previously reported in a variety of settings. We present two cases, an adult patient with chronic lymphocytic leukemia (CLL) and a child with neurofibromatosis type-1 (NF-1), where the abrupt appearance of severe anemia raised ominous clinical suspicions. Evidence of recent parvovirus B19 infection in association with the selective erythroid precursor deficiency in marrow helped exclude other etiologies.

We emphasize the importance of bearing this infectious agent in mind, even when there are associated disorders (such as CLL) that may independently cause PRCA. An association of NF-1 with acute PRCA has not been described in indexed English literature in the past.     

Clinical interpretation of antineutrophil cytoplasmic antibodies: parvovirus B19 infection as a pitfall

BACKGROUND: While antibodies directed against proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) have a high specificity for the diagnosis of systemic vasculitis, they may also be found as an epiphenomenon of acute viral infection. OBJECTIVE: To investigate whether positive ANCA test results may be a common feature of acute parvovirus B19 infection. METHODS: Sera were analysed from 1242 patients from a rheumatology outpatient clinic for reactivity with parvovirus B19 and EBV antibodies. They were tested for the presence of PR3-ANCA and MPO-ANCA, along with sera known to contain IgM antibodies to these viruses obtained from among 41,366 samples submitted for virological screening. RESULTS: ANCA were found in 10% (5/50) of the sera positive for IgM antibodies to parvovirus and in 3/51 sera containing IgM antibodies to EBV. Three of six patients with arthritis and concomitant parvovirus infection were found positive for PR3-ANCA and two were found positive for MPO-ANCA. All six patients tested negative for ANCA after six months of follow up. CONCLUSIONS: PR3-ANCA and MPO-ANCA may occur transiently in patients with acute B19 infection or infectious mononucleosis, highlighting the importance of repeated antibody tests in oligosymptomatic clinical conditions in which systemic autoimmune disease is suspected.     

A case of pure red cell aplasia complicated by Evans syndrome

A 33-year-old woman complaining of severe anemia was admitted to our hospital for polyclonal hyperglobulinemia. She was diagnosed with pure red cell aplasia (PRCA) associated with Evans syndrome. Initially, the presence of human parvovirus B19 (HPV B19) IgM appeared to indicate that the cause of PRCA was HPV B19 infection. Evans syndrome improved with steroid therapy, but PRCA was refractory. Cyclosporine was administered; consequently, the patient markedly recovered from PRCA and was discharged. PRCA complicated by Evans syndrome occurred during the course of polyclonal hyperglobulinemia. The most direct etiology for the onset of PRCA was unclear; however, immunological disorders such as polyclonal hyperglobulinemia, in addition to HPV B19 infection, may have been partly responsible for the etiology of PRCA.     

Development of pure red cell aplasia by transmission and persistent infection of parvovirus B19 through a kidney allograft

We report a case of pure red cell aplasia (PRCA) caused by parvovirus B19 (PVB19) infection, which was transmitted through a kidney allograft. The patient underwent a living‐donor kidney transplant from his wife at the age of 60. Despite successful engraftment with a normal creatinine level, he developed severe anemia that required frequent blood transfusions 2 months after transplantation. Renal anemia was unlikely as his serum erythropoietin level was extremely high. A bone marrow aspiration test demonstrated the existence of large proerythroblasts. Although anti‐PVB19 IgM antibody levels were not increased, polymerase chain reaction (PCR) detected PVB19 DNA in his serum. Thus, he was diagnosed as having PRCA induced by PVB19 infection. PCR analysis of total DNA isolated from 0‐hour biopsy sections showed the existence of PVB19 DNA. Furthermore, PVB19 proteins was detected on renal tubules of 0‐hour allograft by immunoperoxidase staining. Thus, transmission of PVB19 through the allograft was confirmed. A single course of intravenous immunoglobulin (IVIG) therapy resulted in substantial improvement; however, the effect was limited, and severe anemia relapsed after 5‐6 months. Several courses of IVIG with adjustment of immunosuppressive drugs resulted in long‐term remission. Our case demonstrates that donor‐transmitted PVB19 infection should be suspected in kidney transplant recipients who develop refractory anemia during the early post‐operative phase.     

CASE REPORT: Pure Red Cell Aplasia Associated with Parvovirus B19 Infection in a Patient with Ulcerative Colitis

Anemia is a common problem that results from various causes in patients with ulcerative colitis (UC), but there is little information on the association of UC with pure red cell aplasia (PRCA). We describe the first case of parvovirus-induced PRCA in UC. A 28-year-old woman with chronic UC was admitted to the hospital for treatment of active pancolitis. Three courses of pulse therapy with methylprednisolone provided complete remission. However, the patient developed reticulocytopenia and a subsequent fall in hemoglobin to 6.2 g/dl. Bone marrow examination revealed selective aplasia of red cell precursors and giant pronoromoblasts. Enzyme immunoassay identified specific immunoglobulin M antibody against parvovirus B19 in the serum. Based on these findings, the diagnosis of PRCA caused by the virus was made. The patient was treated with a 3-day course of intravenous immunoglobulin (5 g/day), resulting in brisk reticulocytosis, folowed by normalization of hemoglobin level. In conclusion, Chronic or acute blood loss in UC associated with enhanced red cell turnover might be a risk factor for PRCA when affected patients contract parvovirus B19 infection.     

Successful treatment of persistent erythroid aplasia caused by parvovirus B19 infection in a patient with common variable immunodeficiency with low-dose immunoglobulin

Parvovirus B19 causes persistent erythroid aplasia in immunocompromised hosts. From April through July 1996, we encountered five adult patients presenting with reticulocytopenia and fever caused by parvovirus B19 infection. The reticulocyte count of four patients with normal immunity recovered within two weeks after the onset of fever. However, in the one remaining patient with common variable immunodeficiency (CVI), reticulocytopenia, and other symptoms including fever and the elevation of lactate dehydrogenase (LDH) levels persisted beyond 16 days of onset. Although the DNA of parvovirus B19 was detected in the peripheral blood of the CVI patient, neither immunoglobulin Ig-G nor Ig-M antibodies specific to the virus were detectable. We administered 50 mg/kg of Ig to the CVI patient for six days. The reticulocyte count recovered promptly on the sixth day of the treatment and parvovirus B19 DNA was not detectable 30 days after therapy. This indicates that although patients with CVI may be susceptible to persistent erythroid aplasia during an endemic of parvovirus B19, the complication can be treated successfully with relatively low-dose Ig.     

Parvovirus B-19 induced acute pure red cell aplasia in patients with chronic lymphocytic leukemia and neurofibromatosis type-1

Parvovirus B19 induced pure red cell aplasia (PRCA) has been previously reported in a variety of settings. We present two cases, an adult patient with chronic lymphocytic leukemia (CLL) and a child with neurofibromatosis type-1 (NF-1), where the abrupt appearance of severe anemia raised ominous clinical suspicions. Evidence of recent parvovirus B19 infection in association with the selective erythroid precursor deficiency in marrow helped exclude other etiologies. We emphasize the importance of bearing this infectious agent in mind, even when there are associated disorders (such as CLL) that may independently cause PRCA. An association of NF-1 with acute PRCA has not been described in indexed English literature in the past.     

Persistence of parvovirus B19 in synovial fluid and bone marrow.

OBJECTIVES--To determine whether parvovirus B19 (B19) persists in rheumatoid arthritis (RA). METHODS--Polymerase chain reaction (PCR) was used to detect parvovirus B19 genome in the synovial fluid cells or peripheral blood mononuclear cells from 61 patients with early RA; bone marrow from one patient was also studied. The synovium or synovial fluid cells from 28 patients with advanced RA, and synovial fluid cell samples from 18 patients with reactive arthritis (as controls) were studied. Two separate sets of primers and probe were used. RESULTS--Parvovirus B19 specific gene sequences were detected in two patients with early arthritis fulfilling the criteria for RA. CONCLUSION--Parvovirus B19 does not play a significant role in the aetiopathogenesis of RA. However, a few cases of a disease indistinguishable from RA may be triggered by parvovirus B19 infection.     

Successful high-titer immunoglobulin therapy for persistent parvovirus B19 infection in a lymphoma patient treated with rituximab-combined chemotherapy

A 40-year-old female diagnosed with follicular lymphoma was treated with rituximab-combined chemotherapy. Although she achieved complete remission, she developed progressive anemia and reticulocytopenia. Bone marrow examination revealed features of pure red cell aplasia and hemophagocytosis. In addition, the appearance of large pronormoblasts suggested that she was infected with parvovirus B19. Excess viral DNA in her bone marrow confirmed that her illness was caused by persistent parvovirus B19 infection. Serum immunoglobulin levels decreased beyond the lower normal limit, which indicated that her humoral immunity was impaired after rituximab-combined chemotherapy. Although she had been infected with parvovirus B19, she was re-infected and failed to control the viral expansion. High-titer immunoglobulin against parvovirus B19 was intravenously administrated and resulted in remarkable reticulocytosis and improvement of anemia. High-titer immunoglobulin, which contained a sufficient amount of neutralizing antibodies against parvovirus B19, likely inactivated most viruses in vivo. We successfully eradicated the virus after 2 courses of high-dose therapy at 0.5 g/kg/day every week followed by 8 courses of maintenance therapy at 0.1 g/kg/day every other week. It is important to consider that parvovirus B19 infection is a possible cause of progressive anemia in B-cell lymphoma patients treated with rituximab-combined chemotherapy. We propose that the use of high-titer immunoglobulin against parvovirus B19 may enable such immunocompromised patients to eradicate the virus before sufficient immune system reconstruction.     

Novel cytomorphology of the giant proerythroblasts of parvovirus B19 infection

The morphology of the giant proerythroblasts (GPE) in air-dried and Wright-Giemsa-stained smears of bone marrow in 16 patients with pure red cell aplasia (PRCA) caused by parvovirus B19 infection is described. B19 infection was diagnosed by the presence of the virus or viral DNA and/or IgM antibodies. Twelve patients had chronic hemolytic anemia and aplastic crisis and 4 patients had AIDS with chronic PRCA. In patients with chronic hemolytic anemia and aplastic crisis, GPE were not detectable in bone marrow biopsies that showed any degree of recovery of erythropoiesis. The GPE morphology was quite variable. The early (basophilic) GPE measured 25 to 35 μm in diameter, had a narrow rim of intensely blue and often vacuolated cytoplasm with pseudopodia, round nuclei with compact uncondensed chromatin, and an indistinct and inclusion-like purple-colored tinctorial change. The “intermediate” and “late” GPE measured 25 to 45 μm in diameter and showed cytoplasmic swelling, gradual loss of cytoplasmic basophilia, and fraying of the cytoplasm with focal rupture; the nuclei showed an increase in volume, a highly uncondensed and coarse sieve-like chromatin, and 1 to 3 prominent, pale to moderate purple inclusion-like nucleoli or inclusions. Bare nuclei similar in size and chromatin pattern to those of the GPE were present in proximity to the GPE and may have arisen from the GPE by dissolution of the cytoplasm. The glassy intranuclear inclusions with central clearing, the so-called lantern cells described in formalin-fixed tissues of patients with B19 infection, were absent in all cases. These findings suggest that direct toxic cell injury rather than apoptosis may be involved in the pathogenesis of erythroid aplasia in B19 infection. Am. J. Hematol. 58:95–99, 1998. © 1998 Wiley-Liss, Inc.     

Pure red cell aplasia induced by B19 parvovirus during allogeneic bone marrow transplantation

We report a patient who had abrupt onset of pure red cell aplasia (PRCA) induced by B19 parvovirus during allogeneic bone marrow transplantation (BMT). A 14-year-old girl with APL in complete remission was admitted in February 1988, for the purpose of BMT. She was received marrow from HLA identical sister on March 17, 1988 (day 0). She received 120 mg/kg cyclophosphamide and 12 Gy total body irradiation for conditioning of BMT. For graft-versus-host disease (GVHD) prophylaxis she was given cyclosporine and short term methotrexate. She did not develop acute GVHD after BMT, but on the day 28 a bone-marrow aspirate revealed findings of PRCA. During this course the number of white blood cell and platelet favorably recovered. B 19 parvovirus DNA was detected in the serum of the day 30 and day 42. Antihuman B 19 parvovirus (HPV) antibody titers were increased: the values of anti-HPV IgM were suddenly elevated and those of anti-HPV IgG were elevated. Serum on the day 42 inhibited erythroid progenitors (CFU-E, BFU-E) but not inhibited myeloid progenitors (CFU-C). A reticulocyte count recovered on the day 50. As the patient was HPV-IgG negative prior to BMT and the donor was HPV-IgG seronegative, the source of infection may be platelet transfusion (day 7 through 14).     

Pure red cell aplasia due to parvovirus B19 infection transmitted probably through hematopoietic stem cell transplantation

Abstract: Human parvovirus B19 is a very common infectious pathogen in humans. In healthy subjects, B19 infection is the cause of a self-limiting subclinical erythroid aplasia, followed by rash or arthralgia. In immunocompromised patients B19 can cause chronic anemia. This report presents the case of a 19-year-old male who developed severe anemia shortly after successful allogeneic hematopoietic stem cell transplantation. His marrow showed selective erythroid aplasia, and real-time polymerase chain reaction assay confirmed parvovirus B19 infection. Despite repeated high-dose immunoglobulin treatment, he remained anemic. His hematological status markedly improved after cessation of immunosuppression. Retrospective examination of the donor's blood suggests that hematopoietic stem cells could be the source of infection.     

Chronic neutropenia of childhood: frequent association with parvovirus infection and correlations with bone marrow culture studies

Summary. Children with neutropenia of more than 3 months duration often have evidence of immune-mediated destruction of mature neutrophils and variable abnormalities of myeloid precursors in their bone marrow. These patients often have anti-neutrophil antibodies which persist for several months. To further investigate the aetiology of neutropenia in such patients, bone marrow cells were evaluated for the presence of common viruses. Fifteen of 19 patients tested had evidence for parvovirus infection by PCR amplification of bone marrow DNA with parvovirus specific primers. Of these 15, six also had serologic evidence of parvovirus infection. Anti-neutrophil antibodies were identified in nine of 12 patients with parvovirus infection. Bone marrow culture studies done on six patients revealed varying degrees of myeloid and erythroid inhibition by patient plasma. These studies indicate that parvovirus may be a common cause of immune-mediated neutropenia in children.     

Parvovirus B19 infection in children with acute lymphoblastic leukemia is associated with cytopenia resulting in prolonged interruptions of chemotherapy.

BACKGROUND: Parvovirus B19 infection causes severe cytopenia and can mimic a leukemic relapse or therapy-induced cytopenia in patients with hematologic malignancies. We evaluated the complications of parvovirus B19 infection, including delays in the scheduled course of chemotherapy, in children with acute lymphoblastic leukemia (ALL). METHODS: Consecutive bone marrow samples were collected from 117 children with ALL and were analyzed for parvovirus B19 DNA by polymerase chain reaction. Clinical and laboratory data were collected from the Nordic Childhood Leukemia Registry and from medical records. RESULTS: Among the 117 children with ALL, 18 (15%) were found to be parvovirus B19 DNA positive. The infection was suspected on clinical grounds in only 1 of these 18 patients. Patients with viremia at diagnosis or during therapy for infection had lower viral loads (median viral load, 7 x 10(4) copies/mL) than did those who became viremic during maintenance therapy (median viral load, 2 x 10(8) copies/mL). The former group also had fewer clinical complications. Indeed, when parvovirus B19 DNA was present during the maintenance treatment, the number of complications (including cytopenia) increased, causing significantly longer periods without chemotherapy (median duration without chemotherapy, 59 days vs. 30 days; P < or = .05) and a higher number of blood transfusions (P = .018) in parvovirus B19 DNA-positive patients than in parvovirus B19 DNA-negative patients. CONCLUSIONS: Children with ALL who were infected with parvovirus B19 became cytopenic, leading to reduced treatment intensity and to complications during treatment. Screening for parvovirus B19 DNA by quantitative polymerase chain reaction in pediatric patients with ALL and unexplained cytopenia is suggested.     

A case of pure red cell aplasia and systemic lupus erythematosus caused by human parvovirus B19 infection

Human parvovirus B19 (B19) rarely induces pure red cell aplasia (PRCA) in healthy hosts. Meanwhile B19 infection is often clinically similar to systemic lupus erythematosus (SLE), and several cases have been reported wherein B19 actually stimulated SLE exacerbation in an immunocompetent subject. An 82-year-old healthy woman was diagnosed to have complicated with B19 infection and PRCA. Four weeks later, she had high fever, polyarthritis, and oral ulcers, additionally diagnosed with SLE, and subsequently, 15 mg of prednisone was started. This is the first case wherein B19 infection caused both PRCA and SLE in a healthy patient as far as our investigations are concerned.