Pure Red Cell Aplasia and Antibody-Mediated Rejection: Double Trouble in 1 Kidney Transplant Recipient Solved by Intravenous Immunoglobulin Infusion: A Case Report.

Acquired pure red cell aplasia (PRCA) is characterized by severe normocytic (rarely macrocytic) and normochromic anemia, a low reticulocytes count in peripheral blood, and near absence of erythroid precursors in the bone marrow, with a normal level of erythropoietin. We describe a case of the kidney transplant recipient, diagnosed with PRCA induced with parvovirus B19 infection. Our case demonstrates that although this complication is rare, it should be considered in a differential diagnosis of anemia diagnostics in immunocompromised patients. In our case reduced immune response resulted from post-transplant immunosuppressive therapy. In our patient, apart from infection by parvovirus B19, graft dysfunction due to polyomavirus BK virus infection was also detected together with histologic and serologic features of antibody-mediated renal graft rejection. Considering the entire clinical picture, intravenous immunoglobulin therapy (IVIg) was successfully introduced.

The Role of Human Parvovirus B19 in the Pediatric Patients with Pancytopenia?

BACKGROUND: Parvoviruses are small DNA viruses causing erythema infectiosum, which is known as the fifth disease. The aim of this study was to investigate the presence of Parvovirus B19 DNA by Real-Time-PCR retrospectively in clinical samples of children diagnosed as acute leukemia and aplastic anemia when investigating the cause of pancytopenia and to investigate its relationship with the clinical manifestations. METHODS: The study samples were collected between March 2014 and March 2018 in Gazi University, Faculty of Medicine, Department of Pediatric Hematology. Sixty pediatric patients; 37 males and 23 females, were included in the study. Nucleic acid isolation was performed by using MagNA-Pure Compact Nucleic Acid Isolation Kit (Roche, Germany). Extracted DNA was studied with LightCycler® 2.0 using the Real-Time PCR method and LightCycler® Parvovirus B19 Quantification Kit (Roche, Germany), and the results were evaluated quantitatively. Parvovirus B19 DNA detection interval of the kit was 101 - 106 copies/mL. RESULTS: Sixty serum samples were investigated and 8.3% (5/60) Parvovirus B19 DNA positivity was determined. Of the five patients with Parvovirus B19 DNA positivity, three had acute lymphoblastic leukemia and two were diagnosed as aplastic anemia. Regarding viral load; 2/5, 1/5, 1/5, and 1/5 of the samples had a viral load of 102, 103, 104, and 105 copies/mL, respectively. Parvovirus B19 DNA positivity was detected in samples from March (2/5), April (2/5), and August (1/5). CONCLUSIONS: Patients with acute leukemia and aplastic anemia in childhood using immunosuppressive drugs, blood, and blood products during chemotherapy, encounter Parvovirus B19 infections in the follow-up period and are diagnosed by serological and molecular methods. As a result of the study, we suggest that the detection of Parvovirus B19 DNA by Real-Time PCR method in children being admitted with pancytopenia and diagnosed as acute leukemia and aplastic anemia is useful in the follow-up and treatment.

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.

Aggressive large B-cell lymphoma triggered by a parvovirus B19 infection in a previously healthy child.

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.

Post-infectious acute glomerulonephritis with podocytopathy induced by parvovirus B19 infection.

Human parvovirus B19 infection causes a variety of glomerular diseases such as post-infectious acute glomerulonephritis and collapsing glomerulopathy. Although each of these appears independently, it has not been fully determined why parvovirus B19 provokes such a variety of different glomerular phenotypes. Here, we report a 68-year-old Japanese man who showed endocapillary proliferative glomerulonephritis admixed with podocytopathy in association with parvovirus B19 infection. The patient showed acute onset of heavy proteinuria, microscopic hematuria and kidney dysfunction with arthralgia and oliguria after close contact with a person suffering from erythema infectiosum. In the kidney biopsy specimen, glomeruli revealed diffuse and global endocapillary infiltration of inflammatory cells, with some also showing tuft collapse with aberrant vacuolation, swelling, and hyperplasia of glomerular epithelial cells. Immunofluorescence revealed dense granular C3 deposition that resembled the "starry sky pattern". Intravenous glucocorticoid pulse therapy followed by oral prednisolone and cyclosporine combination therapy resulted in considerable amelioration of the kidney dysfunction and urinary abnormalities. The present case reveals that parvovirus B19 infection can induce different glomerular phenotypes even in the same kidney structure. This finding may provide hints useful for the further elucidation of the pathogenesis of parvovirus B19-induced glomerular lesions.

A Case Report of Parvovirus B19 Infection in a Renal Allograft.

Parvovirus B19 infection is undiagnosed in recipients undergoing solid organ transplantation. It is usually responsible for unexplained acute and chronic red blood cell aplasia that does not respond to erythropoietin therapy. Cases of parvovirus B19 infection associated with pancytopenia, solid organ dysfunction, and allograft rejection have been described in the literature. The deterioration of the immune system as a result of severe immunotherapy favors the reactivation of a previous infection or the acquisition of a new one. We present a case of a 32-year-old woman with a 1-year history of renal allograft transplant and previous cytomegalovirus (CMV) infection who presented with chest pain, polyarthritis, pancytopenia, and renal dysfunction. A serum sample using polymerase chain reaction showed a parvovirus titer of 13.8 trillion IU/mL and a CMV titer of 800 IU/mL. The renal biopsy revealed nucleomegaly with focal viral inclusions, along with changes associated with immunotherapy toxicity. Electron microscopy demonstrated capillary and tubular epithelial cells with "viral factories," thereby confirming the diagnosis. Thus, screening for parvovirus B19 is advised in high-risk patients who present with refractory anemia to avoid the complications of a chronic infection associated with the fatal rejection of the transplanted organ.

Genotype 1 of human parvovirus B19 in clinical cases.

INTRODUCTION:: Virus surveillance strategies and genetic characterization of human parvovirus B19 (B19V) are important tools for regional and global control of viral outbreak. In São Paulo, Brazil, we performed a study of B19V by monitoring the spread of this virus, which is an infectious agent and could be mistakenly reported as a rash and other types of infection. METHOD:: Serum samples were subjected to enzyme immunoassay, real time polymerase chain reaction, and sequencing. RESULTS:: From the 462 patients with suspected cases of exanthematic infections, the results of the 164 serum samples were positive for B19V immunoglobulin M. Among these cases, there were 38 patients with erythema infections and B19-associated with other infections such as encephalitis, hydrops fetalis, chronic anemia, hematological malignancies. These samples were sequenced and identified as genotype 1. CONCLUSION:: This study showed patients with infections caused by B19V and sequencing genotype 1. Continuous monitoring is necessary to detect all known genotypes, and the emergence of new genotypes of these viruses for case management in public health control activities.

Genotype 1 of human parvovirus B19 in clinical cases / Genótipo 1 do parvovírus humano em casos clínicos

Summary Introduction: Virus surveillance strategies and genetic characterization of human parvovirus B19 (B19V) are important tools for regional and global control of viral outbreak. In São Paulo, Brazil, we performed a study of B19V by monitoring the spread of this virus, which is an infectious agent and could be mistakenly reported as a rash and other types of infection. Method: Serum samples were subjected to enzyme immunoassay, real time polymerase chain reaction, and sequencing. Results: From the 462 patients with suspected cases of exanthematic infections, the results of the 164 serum samples were positive for B19V immunoglobulin M. Among these cases, there were 38 patients with erythema infections and B19-associated with other infections such as encephalitis, hydrops fetalis, chronic anemia, hematological malignancies. These samples were sequenced and identified as genotype 1. Conclusion: This study showed patients with infections caused by B19V and sequencing genotype 1. Continuous monitoring is necessary to detect all known genotypes, and the emergence of new genotypes of these viruses for case management in public health control activities.

Resumo Introdução: Estratégias de vigilância para o parvovírus humano B19 e caracterização genética são ferramentas importantes para o controle regional e global do surto viral. Em São Paulo, Brasil, foi realizado um estudo de parvovírus B19, monitorando a disseminação desse vírus, que é um agente infeccioso e poderia ser erroneamente relatado como uma erupção cutânea e outros tipos de infecções. Método: As amostras de soro foram submetidas ao ensaio imunoenzimático, PCR quantitativo em tempo real e sequenciamento. Resultados: Dos 462 pacientes com casos suspeitos de infecções exantemáticas, os resultados das 164 amostras de soro foram positivos para parvovírus B19 imunoglobulina M. Entre eles, 38 pacientes com eritema infeccioso apresentaram B19 associado com outras infecções, como encefalite, hidropisia fetal, anemia crônica, doenças hematológicas malignas. Essas amostras foram sequenciadas e identificadas como genótipo 1. Conclusão: Os pacientes foram infectados com parvovírus B19 e apresentaram genótipo 1. Monitoração contínua é necessária para detectar todos os genótipos conhecidos e o surgimento de novos genótipos para o controle de casos em saúde pública.

Molecular diversity of human parvovirus B19 during two outbreaks of erythema infectiosum in Brazil

Abstract This study was conducted to provide information on the genetic diversity of human parvovirus B19 (B19V) circulating in the municipality of Niterói, Rio de Janeiro, Southeast Brazil during 1996-2006, a period with two distinct outbreaks of B19V infection: 1999-2000 and 2004-2005. A total of 27 sera from patients with erythema infectiosum and five sera from HIV-infected patients that tested positive for B19V DNA during the study period were analyzed. To genotype B19V strains, a semi-nested PCR for partial amplification of the capsid gene was performed and sequence analysis revealed that 31 sequences belonged to subgenotype 1a (G1a) of the main genotype 1 and one sequence was characterized as subgenotype 3b (G3b). The phylogenetic tree supported the division of the G1a into two well-defined clades with 1.3% of divergence. The low diversity of the G1a strains may be explained by the fact that all patients had acute B19V infection and 30/32 sera were collected during two distinct outbreaks. The G3b strain was from an HIV-infected patient who seroconverted to anti-B19 IgG antibodies in September/2005. This is the first report of G3b in the state of Rio de Janeiro.

Parvovirus B19 infection presenting concurrently as papular-purpuric gloves-and-socks syndrome and bathing-trunk eruption.

Parvovirus B19 infection can cause a wide range of cutaneous manifestations, including papular-purpuric gloves-and-socks syndrome (PPGSS) and petechial bathing trunk eruption. We report a case of an immunocompetent woman with a primary parvovirus B19 infection presenting as concurrent PPGSS and petechial bathing trunk eruption. Parvovirus B19 seroconversion was confirmed several days after the onset of the clinical manifestations. The coexistence of these two cutaneous manifestations of primary parvovirus B19 infection has rarely been reported in the literature. It is important to recognize parvovirus B19 infection early, based on the cutaneous manifestations, to avoid potentially serious systemic complications in susceptible individuals.

Betaferon in chronic viral cardiomyopathy (BICC) trial: Effects of interferon-ß treatment in patients with chronic viral cardiomyopathy.

BACKGROUND: Chronic viral infections of the heart are considered one antecedent event leading to progressive dysfunction of the myocardium, often with an impaired prognosis due to a virus- or immune-mediated myocardial injury. Symptomatic treatment does not influence the viral cause of heart failure, and the effect of antiviral treatment has not been determined, yet. METHODS AND RESULTS: In this phase II study 143 patients with symptoms of heart failure and biopsy-based confirmation of the enterovirus (EV), adenovirus, and/or parvovirus B19 genomes in their myocardial tissue were randomly assigned to double-blind treatment, and received either placebo (n = 48) or 4 × 10(6) (n = 49) and 8 × 10(6) IU (n = 46) interferon beta-1b (IFN-ß-1b) for 24 weeks, in addition to standard heart failure treatment. Patients with active myocarditis or other specific causes of heart failure were excluded. Compared to placebo, virus elimination and/or virus load reduction was higher in the IFN-ß-1b groups (odds ratio 2.33, p = 0.048), similarly in both interferon groups and both strata. IFN-ß-1b treatment was associated with favourable effects on NYHA functional class (p = 0.013 at follow-up week 12), improvement in quality of life (Minnesota Heart Failure score; p = 0.032 at follow-up week 24) and patient global assessment (follow-up week 12 to follow-up week 24; p = 0.039). The frequency of adverse cardiac events was not higher in the IFN-ß-1b groups compared to the placebo group. CONCLUSIONS: Immunomodulatory IFN-ß-1b treatment is a well-tolerated and safe treatment option, leading to effective virus clearance or reduction of the virus load in patients with chronic viral cardiomyopathy. Favourable clinical effects assess quality of life, NYHA functional class, and patient global assessment. ClinicalTrials.gov identifier: NCT001185250.

Spectrum of adult Parvovirus B19 infection according to the underlying predisposing condition and proposals for clinical practice.

The virological diagnosis of Parvovirus B19 (PvB19) infection is currently based on sero-diagnosis, molecular methods or both, yet without clear recommendations. We retrospectively identified patients with polymerase chain reaction-positive PvB19 and/or positive serological assay between 2007 and 2013. Eighty-two adults with at least one diagnostic criterion of recent PvB19 infection (IgM antibodies, viral DNA in blood and/or in marrow) were included and classified into three homogeneous groups: 30 patients had no underlying predisposing condition, 25 a hereditary haemolytic anaemia, 27 an underlying immunodeficiency. The classical PvB19-related manifestations were less frequent in immunocompromised than in immunocompetent patients (arthromyalgia: 5 vs. 14; erythema: 4 vs. 17, respectively). Only 41·4% of patients with no underlying disease were anaemic. Bicytopenia and pancytopenia were observed mainly in immunocompromised patients. Classical pure red cell aplasia was observed in only 9 of the 27 marrow smears performed. Specific IgM were found in 93% of immunocompetent patients, whereas only 58% had detectable viral DNA in blood. IgM and DNA were present alone or together in all patients with hereditary haemolytic anaemia. In immunocompromised patients, the diagnosis was confirmed by marrow analysis in 91% of cases. We make some proposals based on this large series of PvB19-infected patients.

Impaired Endothelial Regeneration Through Human Parvovirus B19-Infected Circulating Angiogenic Cells in Patients With Cardiomyopathy.

Human parvovirus B19 (B19V) is a common pathogen in microvascular disease and cardiomyopathy, owing to infection of endothelial cells. B19V replication, however, is almost restricted to erythroid progenitor cells (ErPCs). Endothelial regeneration attributable to bone marrow-derived circulating angiogenic cells (CACs) is a prerequisite for organ function. Because of many similarities of ErPCs and CACs, we hypothesized that B19V is a perpetrator of impaired endogenous endothelial regeneration. B19V DNA and messenger RNA from endomyocardial biopsy specimens, bone marrow specimens, and circulating progenitor cells were quantified by polymerase chain reaction analysis. The highest B19V DNA concentrations were found in CD34(+)KDR(+) cells from 17 patients with chronic B19V-associated cardiomyopathy. B19V replication intermediates could be detected in nearly half of the patients. Furthermore, chronic B19V infection was associated with impaired endothelial regenerative capacity. B19V infection of CACs in vitro resulted in expression of transcripts encoding B19V proteins. The capsid protein VP1 was identified as a novel inducer of apoptosis, as were nonstructural proteins. Inhibition studies identified so-called death receptor signaling with activation of caspase-8 and caspase-10 to be responsible for apoptosis induction. B19V causally impaired endothelial regeneration with spreading of B19V in CACs in an animal model in vivo. We thus conclude that B19V infection and damage to CACs result in dysfunctional endogenous vascular repair, supporting the emergence of primary bone marrow disease with secondary end-organ damage.

The lack of routine surveillance of Parvovirus B19 infection in pregnancy prevents an accurate understanding of this regular cause of fetal loss and the risks posed by occupational exposure.

In Europe, fetal loss due to Parvovirus B19 (B19V) is under-reported and a poorly addressed occupational risk to pregnant women. This is exemplified internationally, where it was unmentioned in the last two European Centre for Disease Prevention and Control (ECDC) annual surveillance reports or its 2009 special report on infections in pregnancy. To assess this potential for underestimating B19V fetal loss in pregnancy, we undertook a systematic review of practice in Northern Ireland in the management and reporting of B19V infections over a 12-month period of heightened transmission, one of six observed in a span of 9 years. Pregnant and non-pregnant women presented with symptomatic infection in 24 and 93 % of confirmed B19V infections, respectively, with no difference in viral loads. There was underinvestigation of viral causes of fetal loss, with only 143/2739 (5 %) tested for B19V, and a failure to follow up most non-immune women tested following rash contact. Occupational exposure was recorded in 31/60 (51.6 %) of pregnancies audited following rash exposure, the majority teachers or day care workers. Against a background seroprevalence of 66.5 % immunity in women of child-bearing years, two patterns of infection were identified. Firstly, pregnant women investigated for a rash or exposure to slapped cheek syndrome, where an infection incidence of 18 % was observed, resulted in 42 confirmed infections, all proceeding to healthy term deliveries. Secondly, pregnant women with unsuspected infection had six cases of confirmed B19V fetal loss, including four of 22 (18 %) diagnosed at autopsy, of which three were non-hydropic. While many studies have reported B19V fetal loss in pregnancy, there are no robust public health surveillance figures to draw on. That all six confirmed fetal losses came from the small number of miscarriages/stillbirths investigated, 143 out of 2739, suggests inadequate follow-up of those pregnancies where B19V-related fetal loss may be most common, and supports the need for enhanced surveillance pilots to address this significant gap in public health knowledge.

Polymicrogyria in a fetus with human parvovirus B19 infection: a case with radiologic-pathologic correlation.

We report the prenatal magnetic resonance imaging (MRI) appearance of polymicrogyria with pathologic correlation in a fetus with congenital parvovirus B19 infection. Prenatal ultrasound revealed non-immune hydrops, but detected no fetal brain abnormalities. A subsequent fetal MRI scan performed at 23 weeks' gestation demonstrated bilateral polymicrogyria, which was confirmed at autopsy. To our knowledge, prenatal diagnosis of polymicrogyria in association with congenital parvovirus B19 infection has not been previously described. This case provides further evidence for brain abnormalities resulting from congenital parvovirus B19 infection, and suggests that fetal neuroimaging with MRI would be of value in suspected cases of congenital parvovirus infection.

Infection and immunity for human parvovirus B19 in patients with febrile exanthema.

The contribution of parvovirus B19 (B19V) as a causative agent of febrile exanthema (FE) in Cordoba, Argentina, was analysed by detection of viral DNA, and specific IgM and IgG. Serum from 141 patients with FE who were negative for measles and rubella, collected during 2005-2009, plus serum from 31 healthy individuals, were assayed. B19V was the aetiological agent in 14·9% of all FE cases, and in 39·1% in an epidemic year (2007). B19V DNA was detected in 47·6% of IgM-positive FE patients, 30·2% of IgM-negative/IgG-positive FE patients, and 9·7% of healthy controls, indicating B19V long-term infection in ~10% of immunocompetent individuals. Persistent B19V DNA was significantly more frequent in children than adults and in males than females. All patients with acute B19V infection had rash and fever, 85·7% had adenopathy, and only 14·3% had arthropathy. This is the first follow-up study of markers of infection and immunity for B19V infection in Argentina.

Productive parvovirus B19 infection of primary human erythroid progenitor cells at hypoxia is regulated by STAT5A and MEK signaling but not HIFα.

Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O(2) (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFα pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways.