Donor‐transmitted parvovirus infection in a kidney transplant recipient presenting as pancytopenia and allograft dysfunction

Abstract: Parvovirus B19 is a nonenveloped single‐stranded DNA virus that commonly causes a benign childhood infection typically manifesting as a ‘slapped‐cheek’ rash. In immunodeficient hosts, this infection can cause persistent anemia and occasionally pancytopenia. Recently, direct renal involvement has been reported in renal transplant recipients leading to various forms of glomerulopathy and allograft dysfunction. Most cases are primary infections and are donor transmitted through the transplanted organ. Clinical and virological response to intravenous immunoglobulin (Ig) is usually excellent. We describe a case of donor‐transmitted parvovirus infection in a 23‐year‐old male who received his first cadaver renal transplant. The patient had an uncomplicated postoperative course with immediate graft function. Eight weeks after transplantation, he presented with fever, polyarthralgia, pancytopenia, and allograft dysfunction. Serological studies revealed elevated IgM titers against parvovirus B19. A renal biopsy was performed, which showed no evidence of acute rejection but with moderate degree of tubular damage. Parvovirus B19 viral DNA was detected in the renal tissue via polymerase chain reaction (PCR). The patient received a 10‐day course of intravenous Ig (400 mg/kg/day) with excellent response. His blood count normalized and the allograft improved to baseline function. The incidence of parvovirus infection in renal transplant patients is probably underestimated, because patients are not routinely screened for it and anemia and/or pancytopenia in these patients are often ascribed to immunosuppressive drugs. Because this infection is treatable, we conclude that parvovirus B19 infection should be actively considered in transplant patients presenting with pancytopenia and allograft dysfunction.     

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.     

Variability of parvovirus B19 genotype 2 in plasma products with different compositions in the inactivation sensitivity by liquid-heating

Background and Objectives Our previous report showed that parvovirus B19 genotype 1 in different solutions derived from plasma preparations showed different heat‐sensitivity patterns during liquid‐heating. In this study, we similarly examined B19 genotype 2. Materials and Methods Two plasma samples one containing B19 genotype 1 and the other genotype 2 DNA were used. Four process samples collected immediately before the heat treatment step in the manufacture of albumin, immunoglobulin, haptoglobin and antithrombin preparations were spiked with B19 and subsequently treated at 60°C for 10 h. A low pH immunoglobulin solution was also spiked with B19 and treated at room temperature for 14 days. Infectivity was then measured. Results B19 genotype 2, similar to genotype 1, showed three patterns of inactivation: (i) a rapid inactivation in the albumin and immunoglobulin preparations, (ii) a slow inactivation in the haptoglobin preparation and (iii) only limited inactivation in the antithrombin preparation. Its sensitivity in the low pH immunoglobulin solutions also resembled that of genotype 1. Conclusion Both genotypes 1 and 2 of B19 varied in sensitivity to liquid‐heating and low pH among different plasma preparations.     

Reconstituted immunity against persistent parvovirus B19 infection in a patient with acquired immunodeficiency syndrome after highly active antiretroviral therapy.

We discovered a patient with AIDS with persistent B19 infection who had slow resolution of anemia after he commenced receiving HAART without intravenous immunoglobulin. The patient's anemia recurred when the initial course of HAART failed, but it remitted slowly after salvage therapy was instituted. However, circulating B19 was still detectable by nested polymerase chain reaction 1 year after commencement of salvage therapy. Immunoglobulin G and immunoglobulin M antibodies against B19 were not detected by means of enzyme-linked immunosorbent assay when the anemia initially resolved, but they were detected after the patient commenced receiving salvage therapy. The absence of antibody response after the initial remission of parvovirus B19 infection suggested that cellular immunity was an important component of reconstituted immune function against B19 after the patient received HAART. The humoral response that was restored later was abnormal; it had strong reactivity to nonstructural protein NS-1 and poor generation of neutralizing antibodies against linear epitopes unique to minor capsid protein VP1.     

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.     

Acute flaccid paralysis syndrome associated with echovirus 19, managed with pleconaril and intravenous immunoglobulin.

We describe a 39-year-old woman who had undergone bilateral lung and renal transplantation and who was admitted to the hospital with acute onset of flaccid paralysis of the left leg due to echovirus 19 infection. The patient was treated with pleconaril and intravenous immunoglobulin, which correlated with clinical and laboratory evidence of improvement.     

Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis

Treatment options for cutaneous leishmaniasis in the United States are problematic because the available products are either investigational, toxic, and/or of questionable effectiveness. A retrospective review of patients receiving liposomal amphotericin B through the Walter Reed Army Medical Center for the treatment of cutaneous leishmaniasis during 2007-2009 was conducted. Twenty patients who acquired disease in five countries and with five different strains of Leishmania were treated, of whom 19 received a full course of treatment. Sixteen (84%) of 19 experienced a cure with the initial treatment regimen. Three patients did not fully heal after an initial treatment course, but were cured with additional dosing. Acute infusion-related reactions occurred in 25% and mild renal toxicity occurred in 45% of patients. Although the optimum dosing regimen is undefined and the cost and toxicity may limit widespread use, liposomal amphotericin B is a viable treatment alternative for cutaneous leishmaniasis.     

Functional Antibacterial Activity of a Human Intravenous Immunoglobulin Preparation: in vitro and in vivo Studies

The functional antibacterial activity of an intravenous immunoglobulin preparation (Swiss Red Cross Immunoglobulin, SRK-Ig) was tested both in vitro and in vivo. Using type III group B streptococci as a model system, the intravenous immunoglobulin preparation was shown to enhance phagocytosis and killing of the bacteria by human neutrophils. There was good activity to several type III strains, and for efficient opsonization both antibody and complement were required. In an animal model of neonatal group B streptococcal sepsis, passively administered immunoglobulin enhanced survival with 27/37 (73%) treated animals surviving compared to only 3/16 (19%) controls. These studies demonstrate that the intravenous immunoglobulin preparation SRK-Ig has retained functional activity and may have potential value for prophylaxis or therapy of certain bacteria infections.     

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.     

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.     

Successful re‐transplantation in patient with recurrent parvovirus B19 pure red cell aplasia

Impaired cell‐mediated, as well as antibody‐mediated immunity predisposes a renal transplant recipient to a wide variety of atypical infection. With an increasing number of re‐transplant, the balance between immunosuppression and the risk of recurrent disease poses a clinical and therapeutic challenge. Here, we report a successful re‐transplantation in a case of parvovirus B19 infection leading to anaemia and collapsing glomerulopathy in the allograft managed with intravenous immunoglobulin (IVIG) and reduction of immunosuppression. This case emphasizes re‐consideration to renal transplant after clearance of the virus in a previous renal allograft lost to PVB19 infection.     

Red cell aplasia responsive to immunoglobulin therapy as initial manifestation of human immunodeficiency virus infection.

A patient who presented with pure red cell aplasia as the initial manifestation of human immunodeficiency infection is described. The patient had no signs of other autoimmune processes or immunologic or histologic evidence of parvovirus B19 infection, although we detected parvovirus B19 DNA in his serum. This patient had a complete, although temporary, response to a single course of immunoglobulin therapy and is currently responding to a second treatment.     

Variability of parvovirus B19 to inactivation by liquid heating in plasma products

BACKGROUND AND OBJECTIVES: Previously, we reported that although human parvovirus B19 in albumin and intravenous immunoglobulin preparations was rapidly inactivated during liquid heating, in contrast to other parvoviruses such as canine parvovirus, sensitivity to heat was highly dependent on the composition of the solution. In this study, we aimed to further elucidate the sensitivity to heat of B19 in haptoglobin and antithrombin (previously named antithrombin III) preparations during liquid heating. MATERIALS AND METHODS: Two different solutions collected immediately before heat treatment of haptoglobin and antithrombin preparations were spiked with B19 and subsequently treated at 60 degrees C for 10 h. B19 DNA-positive, anti-B19 IgG/IgM-negative plasma was used as a source of B19. The residual infectivity in each sample was measured using a B19 cell-based infectivity assay with an mRNA polymerase chain reaction. RESULTS: B19 in different plasma preparations showed different heat-sensitivity patterns during liquid heating: (i) slow inactivation in haptoglobin preparations, and (ii) only limited inactivation in antithrombin preparations. The kinetics of inactivation was greatly different from that in our previous studies in which the virus was shown to be rapidly inactivated in albumin and intravenous immunoglobulin preparations. CONCLUSION: B19 has unique properties in terms of heat sensitivity, depending on the composition of the solution during liquid heating. This finding may indicate the need for caution when interpreting the sensitivity of B19 to heat.     

A case of diffuse panbronchiolitis with SLE complicated by fungal infection]

We report a patient who developed SLE during the course of diffuse panbronchiolitis (DPB) and had candidiasis later. The patient fulfilled the criteria for diagnosis of SLE after appearance of fever and general peripheral arthritis. Regarding serum virus antibody values at the time of SLE diagnosis, IgG and IgM of human Parvovirus B19 (B19) were positive by the EIA test and also by the serum PCR test. For continuously Pseudomonas aeruginozae in sputum cultures because of existing DPB, immunosuppressasnt therapy with prednisolone and mizoribine was given while suppressing proliferation of bacterial infections with antibiotics. As a result, the intensity of SLE decreased smoothly. About 1 month after beginning of the treatment, the chest X-ray revealed infiltrative densities in the lingual area of the left lobule and in S3 of the right lobule. Judging from the clinical course and various examination findings, concurrence of candidiasis was suspected. Fungal infection in this patient was progressive, so various antifungal agents were used concurrently. Furthermore, immunoglobulin therapy was supplemented while determining serum immunoglobulin levels, and doses of prednisolone and mizoribine were reduced rapidly. Afterward the patient followed a satisfactory clinical course. About 2 years later SLE recurred, aspergillosis developed concurrently and the disease progressed rapidly to its termination. DPB itself is difficult to control and often complicated with various diseases. Therefore, immunosuppresant therapy for complications is sometimes used in addition to the treatment of DPB. More careful observations on the clinical course are necessary in dealing with this disease.     

Successful Bone Marrow Transplantation for Severe Aplastic Anemia in a Patient with Persistent Human Parvovirus B19 Infection

Persistent infection with human parvovirus B19 (B19) is primarily associated with chronic bone marrow failure in immunocompromised patients, but occasionally this organism may also affect immunocompetent hosts. B19 is also suggested as a causative agent of organ failure during bone marrow transplantation (BMT).We herein report the case of a 9-year-old girl with no previous history of immunodeficiency who developed severe aplastic anemia concurrent with B19 persistent infection. Both immunoglobulin (Ig)M antibody to B19 and B19 DNA identified by real-time polymerase chain reaction were found in the patient's serum at time of diagnosis of aplastic anemia. No giant proerythroblasts were found in her bone marrow at diagnosis. Although intravenous administration of Ig (IVIg) reduced serum B19 DNA, the aplastic status of her bone marrow did not improve. Both aplastic anemia and persistent B19 viremia were successfully treated by BMT from an HLA-identical sibling donor. Serum B19 DNA increased temporarily after BMT; however, neither organ nor marrow failure was observed. B19 DNA disappeared from the serum 2 months after BMT, suggesting that a normal immune response was restored by BMT and terminated the B19 viremia. During BMT, use of high-titer IVIg for B19 might prevent B19-associated organ failure.     

Successful Treatment with Cyclosporine and High-Dose Gamma Immunoglobulin for Persistent Parvovirus b19 Infection in a Patient with Refractory Autoimmune Hemolytic Anemia

We describe a patient with persistent pure red cell aplasia due to human parvovirus B19 (HPVB19) infection during immunosuppressive therapy for refractory autoimmune hemolytic anemia (AIHA). The patient had been given corticosteroid (CS) and/or azathioprine for AIHA. During the course of treatment, reticulocyte count and hemoglobin levels decreased suddenly. Bone marrow aspirate showed erythroid lineage-specific aplasia with a few giant proerythroblasts, suggesting the presence of HPVB19 infection. The diagnosis of aplastic crisis due to HPVB19 infection was based on positive test results by polymerase chain reaction for HPVB19 immunoglobulin M (IgM) antibody and B19 DNA. Although splenectomy followed by administration of high-dose gamma globulin (HDIG) and plasma exchange were performed, the crisis and hemolysis recurred. Aplastic crises occurred several times when the B19 IgG result became negative and the CD4+ lymphocyte count was less than 300/microL. The patient showed complete recovery from anemia after CS was switched to cyclosporin A (CsA) and intermittent administration of HDIG. The result for B19 IgG antibody was continuously positive, and the DNA result became negative after these treatments. The results in this case indicated that concomitant administration of CsA and intermittent administration of HDIG can lead to cure of chronic anemia due to HPVB19 infection in patients with refractory AIHA.     

Mixed cryoglobulinemia: Clinical aspects and long-term follow-up of 40 patients

The clinical course of 40 patients with significant quantities of mixed cryoglobulins, but without lymphoproliferative, collagen-vascular or chronic infectious diseases, is presented. These cases comprise 51.3 percent of all mixed and 31.7 percent of all types of cryoglobulins evaluated by us over the period 1960–1978. A characteristic clinical syndrome, consisting of recurrent palpable purpura (100 percent), polyarthralgias (72.5 percent) and renal disease (55 percent), was seen. Biopsy specimens of skin lesions showed cutaneous vasculitis, and half had immune reactants in vessel walls. Seventy percent of patients had evidence of hepatic dysfunction, often subclinical, and more than 60 percent of those tested had serologic evidence of prior infection with hepatitis B virus. Hepatic lesions ranged from minimal triaditis to chronic active hepatitis and/or cirrhosis. All 22 patients in whom clinical renal disease developed had significant proteinuria; 63.6 percent had diastolic hypertension, 77.3 percent edema, 45.5 percent renal failure and 22.7 percent were nephrotic. Glomerular disease associated with deposition of immunoglobulin G, immunoglobulin M and complement, often with coexistent renal arteritis, was confirmed pathlologically in 15 cases.All cryoglobulins had rheumatoid factor activity and consisted of IgM and polyclonal IgG; five also contained IgA. Thirteen had a monoclonal IgM kappa component. Serum protein electrophoresis was unremarkable or showed diffuse hyperglobulinemia. Striking depression of early complement components was noted but did not correlate well with the cryoprotein concentration, renal involvement or clinical course.Follow-up for periods up to 21 years from onset of symptoms revealed that renal involvement has a deleterious effect on prognosis. Postmortem examinations of nine patients demonstrated widespread vasculitis in addition to renal involvement. Preterminal infection was found in eight.     

Parovirus B19-induced red cell aplasia in solid-organ transplant recipients: Two case reports and review of the literature

Two solid-organ transplant recipients (one heart and one lung) developed severe anemia with reticulocytopenia. Both were heavily immunosuppressed. Bone marrow aspiration revealed almost complete absence of erythroid precursors. A few giant megaloblastic proerythroblasts with cytoplasmic vacuolisation and intranuclear inclusions were seen. Human parvovirus B19 (B19V)-DNA genome was found by nested-PCR assays in blood and bone marrow samples in both cases. Twelve similar cases are described in the literature. When looked for, B19V DNA was positive either in serum or bone marrow or both. Twelve of the fourteen patients were successfully treated by high dose i.v. immunoglobulin (IVIG). One patient recovered spontaneously and another after treatment with recombinant human erythropoietin (rHu-EPO) only. Transplant patients should be considered at risk for severe erythroblastopenic anemia due to B19V infection. Diagnosis is based on bone marrow examination and detection of B19V DNA by PCR in serum and/or marrow. IVIG is an effective and safe treatment. The role of erythropoietin in this indication needs further study.     

CD5-negative chronic lymphocytic leukemia with indolent clinical course and autoimmune thrombocytopenia, successfully treated with rituximab

A 59-year-old male with lymphocytosis and thrombocytopenia was asymptomatic without lymphadenopathy or hepatosplenomegaly over 10 years. He was admitted to our hospital because his thrombocytopenia had worsened. The clonal lymphocytes appeared as regular small mature lymphocytes on blood films, and bone marrow biopsy showed diffuse infiltration of mature lymphocytes. However, megakaryocytes also presented. The immunophenotypic analysis by flow cytometry revealed that the lymphocytes were positive for CD19, CD20, CD22, and surface membrane immunoglobulin (SmIg) M and D-lambda and were negative for CD5, CD10, CD11c, CD23, and other lineage markers. Expression levels of CD20 and SmIg were strong. The markers were consistent with CD5- CLL with autoimmune thrombocytopenia. He received rituximab, and a rapid decrease of lymphocytes with concomitant increase of platelets was observed. A few cases of CD5- CLL with a stable clinical course have been reported, thought to be B lymphocytosis of undetermined significance (MLUS). This is the first report of CD5- CLL with indolent clinical course associated with autoimmune thrombocytopenia, successfully treated with rituximab.     

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.