Human parvovirus B19

Parvovirus B19 (B19) was discovered in 1974 and is the only member of the family Parvoviridae known to be pathogenic in humans. Despite the inability to propagate the virus in cell cultures, much has been learned about the pathophysiology of this virus, including the identification of the cellular receptor (P antigen), and the control of the virus by the immune system. B19 is widespread, and manifestations of infection vary with the immunologic and hematologic status of the host. In healthy immunocompetent individuals B19 is the cause of erythema infectiosum and, particularly in adults, acute symmetric polyarthropathy. Due to the tropism of B19 to erythroid progenitor cells, infection in individuals with an underlying hemolytic disorder causes transient aplastic crisis. In the immunocompromised host persistent B19 infection is manifested as pure red cell aplasia and chronic anemia. Likewise, the immature immune response of the fetus may render it susceptible to infection, leading to fetal death in utero, hydrops fetalis, or development of congenital anemia. B19 has also been suggested as the causative agent in a variety of clinical syndromes, but given the common nature, causality is often difficult to infer. Diagnosis is primarily based on detection of specific antibodies by enzyme-linked immunosorbent assay or detection of viral DNA by dot blot hybridization or PCR. Treatment of persistent infection with immunoglobulin reduces the viral load and results in a marked resolution of anemia. Vaccine phase I trials show promising results.     

Fatal parvovirus B19-associated myocarditis clinically mimicking ischemic heart disease: an endothelial cell-mediated disease

We report the case of a 34-year-old female patient who died 4 days after hospital admission of acute heart failure clinically mimicking ischemic heart disease. Microscopic examination of the heart showed severe myocarditis. Polymerase chain reaction (PCR), including quantitative real-time PCR, disclosed exclusively parvovirus B19 (PVB19), with a high viral load of 4.3x10(5) PVB19 viral genome equivalents per microg myocardial nucleic acid. Radioactive in situ hybridization detected viral genomes in endothelial cells (ECs) predominantly in the venular compartment and (to a lesser degree) in small arteries and arterioles of the heart, but not in cardiac myocytes or other tissue components. Concomitant with EC infection, marked expression of the adhesion molecule E-selectin was noted, accompanied by margination, adherence, penetration, and perivascular infiltration of T lymphocytes. We speculate that, due to the high viral load in cardiac ECs, PVB19 infection of endothelial cells was sufficient to induce impaired coronary microcirculation with secondary cardiac myocyte necrosis.     

Human parvovirus B19 in rheumatoid arthritis

Viral arthritis occurs transiently in most cases, because the infection is self limiting. The arthropathy associated with human parvovirus B19, however, often lasts for more than 2 years and their clinical symptoms may resemble with those of rheumatoid arthritis. Data have been accumulating for the link of B19 infection with chronic polyarthropathy or rheumatoid arthritis (RA), and we discuss the possible mechanism for the role of B19 in the etiopathology of RA.     

Human parvovirus B19: ELISA and immunoblot assays

An ELISA for the detection of specific IgM and IgG against human parvovirus B19 (anti-B19 IgM and IgG) and B19 antigen is described. With ELISA anti-B19 IgM could be detected for up to 20 weeks after viraemia. Four to five months after B19 infection anti-B19 IgG titres range between 10(-6) and 10(-7). Nonspecific reactions with rheumatoid factor or IgM against rubella were not found. The ELISA for B19 antigen was shown to be as sensitive as DNA hybridisation. With immunoblotting two viral proteins of 83 kd (VP1) and 58 kd (VP2) were demonstrated. After acute infection antibodies to VP2 appear before antibodies to VP1. Immunoblotting might be used in pregnancy to determine the time of maternal infection. In a survey of a B19 outbreak in a school for medical technology, 6 (28.6%) of 21 non-immune females seroconverted.     

Human parvovirus B19 infection and antiphospholipid antibodies

Erythema infectiosum is the main manifestation of human parvovirus B19 infections. Further B19-related diseases commonly associated with the acute infection are flue-like symptoms, transient aplastic crisis, transient arthralgias, leukopenia and thrombocytopenia, spontaneous abortion and hydrops fetalis in pregnant women. Hepatitis, myocarditis, meningitis, encephalitis as well as pure red cell anemia may occur occasionally. In addition parvovirus B19 infections have been frequently described as cause or trigger of various forms of autoimmune diseases affecting all blood cell lines, joints, connective tissue, uvea, large and small vessels. Molecular mimicry may be one major contribution to the appearance of autoimmune antibodies, f.e. antiphospholipid and antineutrophil cytoplasmic antibodies as well as antinuclear antigens. These mechanisms implicated in the pathogenesis of parvovirus B19 triggered autoimmune diseases, especially focused on the development of antiphospholipid antibodies will be discussed in this short review.     

Human parvovirus B19 infection in acute fulminant liver failure

Summary.  We previously reported detection of human parvovirus B19 DNA in livers from patients requiring transplantation for acute fulminant liver failure. In this study, we used immune adherence PCR (IA-PCR) to bind B19 virions in recipient native liver onto solid phase with specific monoclonal antibodies followed by PCR amplification of virion DNA. IA-PCR had sensitivity and specificity similar to conventional PCR. We examined liver tissue from 16 patients with non-A, non-B, non-C, non-E (NA-E) acute fulminant liver failure (AFLF) (6 of unknown etiology associated with aplastic anemia (AA), 4 of unknown etiology without AA; and 6 patients with AFLF of known etiology). IA-PCR detected B19 virions in 5 of 6 (83%) of livers from patients with idiopathic NA-E AFLF associated with AA and in 2 of 3 (75%) without AA, compared to 1 of 6 (17%) of livers from patients with AFLF of known etiology and to 6 of 34 (18%) of 34 control patients with chronic or neoplastic liver disease. Viral mRNA encoding the structural protein was detected in the liver tissue from three B19 IA-PCR positive patients with AFLF. Detection of B19 virions and mRNA for capsid proteins provided strong evidence for B19 infection during the course of NA-E AFLF and argues for involvement of B19 virus in liver injury. Accepted April 20, 1999     

An association between parvovirus B19 and Kikuchi-Fujimoto disease

Although Kikuchi-Fujimoto disease (KFD) has a higher prevalence among Asian countries, it is a well-defined entity throughout the world. However, its etiology and pathogenesis remain undetermined. To study whether B19 infection is associated with idiopathic KFD (iKFD), we examined the presence of the viral genome and proteins in paraffin-embedded tissues of lymph nodes retrospectively from 33 iKFD patients and 16 age- and sex-matched control subjects by nested PCR (nPCR), in situ hybridization (ISH), and immunohistochemistry (IHC). B19 was detected in 87.1, 69.7, and 57.6% of iKFD specimens by nPCR, ISH, and IHC, respectively, whereas the virus was positive in only 56.3, 31.3, and 25.0% of control tissues by the respective methods (nPCR: p = 0.029; ISH: p = 0.011; IHC: p = 0.032). The IHC-ISH double-staining assay demonstrated that B19-infected cells were mainly lymphocytes and a small number of histiocytes. These results showed for the first time a high frequency of localized persistence of B19 in lymph nodes from iKFD patients, suggesting that B19 might play an important role in the pathogenesis of iKFD.     

Undenatured parvovirus B19 antigens are essential for the accurate detection of parvovirus B19 IgG

Recombinant versions of parvovirus B19 capsid proteins VP1 and VP2 are used for immunodiagnostic assays for detection of antiviral antibodies. The immune response to B19 is characterized by a gradual loss of antibodies directed against linear epitopes of VP2. A similar occurrence for antibodies raised against VP1 protein would represent a limitation to serological assays incorporating denatured versions of either viral antigen. Four detection systems for B19 Ig detection have been developed, including an IgG enzyme immunoassay (EIA) based on undenatured VP2, an immunofluorescence assay (IFA) based on undenatured VP1, a Western blot assay incorporating denatured VP1 and VP2, and an alternative blot system using denatured VP1 but undenatured VP2. Specimens (n = 108) were tested by all four systems and identical results were obtained by EIA, IFA, and alternative blot systems, whereby 75/108 (69%) were B19 IgG-positive. Twelve B19 IgG-positive specimens, representing 16% (12/75) of the confirmed positives, did not react to either viral antigens when tested by Western blot. It is concluded that these sera do not react with linear epitopes of VP1 and VP2 antigens. Eighty-five different specimens, which had previously been shown to be both B19 IgM- and IgG-positive by EIA and IFA, were positive by B19 IgM and IgG Western blot. In the IgG Western blot assay, 69 reacted with both VP1 and VP2 and 16 with VP1 only. It is concluded that there is a requirement for at least one undenatured antigen for the immunological detection of B19 IgG. J. Med. Virol. 57:179–185, 1999. © 1999 Wiley-Liss, Inc.     

Blood donor screening for parvovirus B19

A programme of blood donor screening for parvovirus B19 was conducted from January to May 1990. The main aim of the study was to identify a B19 positive donation that could be used as a source of viral antigen for diagnostic serology. Out of 24000 donors tested one was positive for B19 antigen by counter current immunoelectrophoresis and over 100 ml of undiluted B19 containing material was obtained. However, much of the positive donation was incorporated in a plasma pool of 28 donations. An acid dissociation technique was used to recover B19 antigen from immune complexes formed in the plasma pool.     

Human parvovirus B19 infection in patients with or without underlying diseases

Background/PurposeThe clinical presentations of parvovirus B19 in patients with underlying diseases have greater diversity than previously healthy patients. We retrospectively identified patients with polymerase chain reaction (PCR)-confirmed parvovirus B19 infection in attempt to describe its clinical features especially in these populations.MethodsFrom 2009 to 2018, patients with real-time PCR-confirmed parvovirus B19 infection were collected. Comparisons were done between previously healthy patients and patients with preexisting diseases, as well as patients with high (>5.5 × 10⁵ copies/mL sera) and low viral loads.ResultsParvovirus B19 DNA was detected in 31 patients. Fourteen (45%) patients had underlying diseases, including six (19%) with immunologic diseases, five (16%) with hematologic diseases, and three (10%) with cardiopulmonary diseases. Only seven (23%) patients received an initial impression of erythema infectiosum prior to positive PCR. A higher proportion of patients with underlying diseases presented with fatigue and pallor, and suffered from tachycardia and hepatosplenomegaly compared to previously healthy patients. Among patients with a high viral load, a substantial proportion were of older age, suffered fatigue, and anemia. There was a trend of patients with immunologic comorbidity having a higher viral load.ConclusionThe classical parvovirus B19 manifestations were less frequently observed in patients with a preexisting disease compared with previously healthy patients. Depending on host factors, the symptoms of parvovirus B19 infection can be multifaceted.     

Circulating cytokines and chemokines in acute symptomatic parvovirus B19 infection: negative association between levels of pro-inflammatory cytokines and development of B19-associated arthritis

The aim of the study was to characterise the profile and clinical correlates (arthritis, rash, and fatigue) of cytokines, chemokines, and other mediators in symptomatic acute parvovirus B19 infection. Serum was examined from cases of acute B19 infection (as defined by serum anti-B19 IgM positivity) (n = 84), and in normal persons (n = 43) for B19 markers (serum B19 antibodies and DNA), rheumatoid factor (RF), and antinuclear antibody (ANA). A panel of cytokines/chemokines was measured in duplicate using the Bioplex Protein Array system (BioRad Hemel Hempstead, UK). These included interleukin-1 beta (IL-1 beta), IL-4, IL-5, IL-6, IL-8, IL-13, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), macrophage chemoattractant protein-1 (MCP-1), granulocyte-monocyte colony stimulating factor (GM-CSF), transforming growth factor-beta1 (TGF-beta 1), endothelin-1 (ET-1), and neopterin. Acute symptomatic infection was characterised by specific IgG positivity (83%), serum B19 DNA positivity (96%), and raised levels of IL-4, IL-6, IL-8, TNF-alpha, IFN-gamma, MCP-1, GM-CSF, TGF-beta 1, and ET-1. Patients with acute B19-associated arthritis were found to have lower levels of IL-6, TNF-alpha, and GM-CSF than patients without arthritis, while those with rash had lower levels of TGF-beta 1. It is concluded that cytokine levels following acute symptomatic infection with parvovirus B19 indicate a state of immune activation. The profile of circulating mediators may provide insights into the possible pathogenesis of particular clinical manifestations of this infection.     

Human parvovirus B19 experimental infection in human fibroblasts and endothelial cells cultures

With the aim to detect what kind of cells, in addition to erythroid progenitors, could be involved in the pathogenesis of B19 infection in some connective tissue diseases, primary cultures of human fibroblasts (HF) and endothelial cells (HUVEC) were exposed to a B19 positive serum (350 genome copies/cell). The presence of NS1 and VP1 mRNA, in both HF and HUVEC cultures 1, 2 and 6 days after the exposure, indicated infection by B19 virus. However, no significant increase of B19 DNA level in the infected HF and HUVEC cultures was detectable through the entire incubation period of 6 days. It is possible that HF and HUVEC are not permissive for B19 virus replication or, alternatively, that few cells only get infected by B19 virus. HF and HUVEC stimulation with different growth factors or cytokines could be required for a B19 productive infection to occur.     

Human parvovirus B19 surveillance in patients with rash and fever from Belarus

Human parvovirus B19 (B19V) infection in immunocompetent patients usually has a mild clinical course, but during pregnancy it can cause serious and even fatal complications in the fetus. The most common clinical presentation of B19V infection is erythema infectiosum and in this case laboratory confirmation is required for differentiation from other exanthematous diseases. Measles and rubella negative sera collected in Belarus between 2005 and 2008 from 906 patients with a rash and fever were screened for B19V infection by ELISA. More than 35% of the samples (322/906) were positive for B19V. The proportion ranged from 10.1% in 2008 to 53.2% in 2006 when an outbreak took place in Minsk city. All B19V outbreaks and cluster cases occurred during the winter-spring period, but sporadic cases were recorded basically throughout the year. The majority of the cases (56.5%) occurred among the 2 till 10 year old children, and 27.3% of the cases were observed in adults between 19 and 53 years. All 104 B19V strains sequenced in the NS1/VP1u region belonged to genotype 1 with a maximal genetic distance of 1.75%. The two phylogenetic clusters reflected the geographic origins of the viruses within the country. Forty-two unique nucleotide mutations as compared to sequences downloaded from GenBank were found in the VP1u and NS1 regions; most of these changes were nonsynonymous. This report highlights the importance of B19V infection in patients with a rash and fever in Belarus.