Erik D. Heegaard

Human Parvovirus B19

SUMMARY 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.

Prevalence of Parvovirus B19 and Parvovirus V9 DNA and Antibodies in Paired Bone Marrow and Serum Samples from Healthy Individuals

ABSTRACT Parvovirus B19 (hereafter referred to as B19) exhibits a marked tropism to human bone marrow (BM), and infection may lead to erythema infectiosum, arthropathy, hydrops fetalis, and various hematologic disorders. Recently, a distinct parvovirus isolate termed V9 with an unknown clinical spectrum was discovered. In contrast to the many studies of B19 serology and viremia, valid information on the frequency of B19 or V9 DNA in the BM of healthy individuals is limited. To develop a reference value, paired BM and serum samples from healthy subjects were tested for the presence of B19 and V9 DNA and specific antibodies. Immunoglobulin M (IgM) was not found in any of the serum samples. The prevalence of IgG showed a gradual and steady increase from 37% in children aged 1 to 5 years to 87% in people aged >50 years. When 190 well-characterized subjects were examined, B19 DNA was detected in the BM of 4 individuals (2.1%; 95% confidence interval, 0.58 to 5.3%) while none of the paired serum samples showed evidence of circulating viral DNA. V9 DNA was not found in any of the BM or serum samples. The finding of B19 DNA probably indicated a primary infection in one 7-year-old individual and reinfection or reactivation of persistent infection in the remaining three persons, aged 47 to 58 years. Serving as a benchmark for future studies, these findings are useful when interpreting epidemiologic data, performing BM transplantation, or considering clinical implications of parvovirus infection.

Parvovirus B19 transmitted by bone marrow

We describe a case of symptomatic parvovirus B19 infection transmitted by bone marrow (BM). The infection caused prolonged anaemia, thrombocytopenia, arthralgia and erythema infectiosum in a 16‐year‐old girl with acute myeloid leukaemia receiving a BM transplant (BMT). The BM donor was a 19‐year‐old asymptomatic brother who had parvovirus B19 viraemia at the time of BM harvest. Sequencing of the VP2 gene from the patient and the donor showed a perfect match of DNA sequences, confirming the mode of transmission. Parvovirus B19 represents a potential complicating factor in patients undergoing BMT, but screening by polymerase chain reaction (PCR) of donor BM may reduce the risk of infection.

Parvovirus B19 Infection Associated with Myocarditis Following Adult Cardiac Transplantation

A 56-year-old woman underwent an uneventful cardiac transplantation due to dilated cardiomyopathy. One week later the patient developed clinical and histological signs of myocarditis. We report for the first time a case of myocarditis in an adult heart transplant recipient, possibly induced by parvovirus B19, as evidenced by the finding of specific IgM in serum and specific DNA in the myocardial cells. Furthermore, this is the first time parvovirus B19 DNA has been observed in the myocardium of an adult. In conclusion, parvovirus B19 should be recognized as a potential pathogen causing myocarditis in heart transplant recipients. In order to establish a definite and rapid diagnosis, a search for specific IgM should be supplemented with PCR investigations of serum and myocardial biopsies when available.

THE ROLE OF PARVOVIRUS B19 INFECTION IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

The authors hypothesized that parvovirus B19 with its hematotropic effects has the potential to precipitate varying forms of cytopenia in patients prior to or at the diagnosis of acute lymphoblastic leukemia (ALL). Consequently, and in view of the increasing number of cases reported, this retrospective study evaluated, for the first time, the possible role of parvovirus B19 infection in pediatric patients suffering from ALL, by investigating the frequency and clinical relevance of this infection at the time of the malignant diagnosis or, when applicable, during a phase of pre-ALL. Furthermore, a review of reported parvovirus B19 infections in pediatric ALL patients is presented. The serum of 65 consecutive pediatric patients with a diagnosis of ALL was examined for possible parvovirus B19 infection employing the polymerase chain reaction and ELISA techniques. Specific IgG was demonstrated in 30% of the patients. One patient diagnosed with pre-ALL had evidence of parvovirus B19 DNA in the serum during pancytopenia 5 months prior to the onset of ALL. The results suggest that there is an insignificant chance of finding a parvovirus B19 infection in pediatric patients with ALL at the time of diagnosis. However, parvovirus B19 infection may infrequently serve as a prodrome to ALL.

Parvovirus B19 and parvovirus V9 are not associated with henoch-schönlein purpura in children

Background. Based on single case reports, parvovirus B19 (B19) has repeatedly been proposed as an etiologic agent in patients with Henoch-Schönlein purpura (HSP), perhaps causing vasculitis by direct invasion of vascular endothelial cells because of the tissue distribution of the cellular B19 receptor. A cohort of children with HSP and other vasculitic diseases was investigated and compared with healthy control children to assess the role of B19 as well as parvovirus V9 (a putative emerging B19-like virus). Patients and methods. Serum samples from 36 children with HSP (n = 29) or other vasculitic diseases (n = 7) were examined, and 38 healthy bone marrow donors were used as controls. The presence of specific B19 and V9 IgM and IgG antibodies was determined with a recently developed enzyme-linked immunosorbent assay, and viral DNA was detected by a novel nested PCR. Results. Specific IgM was not present in any of the patient or control serum samples. B19 DNA was detected in one patient, a previously healthy 8-year-old boy diagnosed with HSP, whereas none of the controls was B19-positive. V9 was not detected in any of the clinical or control samples. It seems likely that B19 infection might have triggered the development of HSP in the B19-positive patient, because B19 viremia is otherwise uncommon. Conclusions. Although causality is difficult to construe in single cases, the data indicate that B19 is not a common contributing factor in the pathogenesis of vasculitis and that this pathogen is only rarely associated temporally with HSP or vasculitic diseases in children.

Transient pancytopenia preceding acute lymphoblastic leukaemia (pre-ALL) precipitated by parvovirus B19

A preleukaemic phase, typified by pancytopenia and bone marrow (BM) hypoplasia, is an uncommon but well‐documented prelude to acute lymphoblastic leukaemia (pre‐ALL) in children. Parvovirus B19 (B19) exhibits a marked tropism to human BM and replicates only in erythroid progenitor cells acting as a confounding, but treatable agent in immunocompromised patients. We present the first case of B19‐associated pre‐ALL characterized by severe and recurring transient pancytopenia in a child who developed ALL 5 months later. The advent of B19‐specific IgG at the time of infection and the subsequent disappearance 1·5 years later has not previously been described. In this patient the observed cytopenias were probably the result of B19 acting in concert with the failing BM and B19 is possibly one of several factors capable of triggering the onset of pre‐ALL.

Serologic study on parvovirus b19 infection in childhood acute lymphoblastic leukemia during chemotherapy: clinical and hematologic implications.

Purpose To present a first descriptive serologic study on the clinical and hematologic implications of parvovirus B19 (B19) infection in children with acute lymphoblastic leukemia from the time of initial admission until discontinuation of chemotherapy. Patients and Methods Seventy-five patients were studied by polymerase chain reaction, enzyme-linked immunosorbent assay, sequencing, and immunodiffusion. Results During the period of observation, 8% (4/48) of B19-seronegative patients seroconverted and infection triggered profound anemia and thrombocytopenia. B19-specific IgG disappeared in 26% (8/31) of B19-seropositive patients, and these patients were significantly younger and the B19 IgG titers were lower on admission compared with patients who continuously displayed B19 IgG. B19 DNA was detected in the seroconverting patients, and this helped in determining the time of infection, which coincided with a B19 epidemic in 75% (3/4) of patients. Patients typically presented with fever and myalgia; a rash, indicative of B19 infection, was observed in only one patient. Conclusions B19 infection was able to mimic a leukemic relapse or therapy-induced cytopenia and led to hospital admission, frequent blood sampling, renewed bone marrow aspirates, multiple transfusions of red blood cells or platelets, and cessation of maintenance chemotherapy for up to 3 weeks. The peculiar disappearance of B19-specific IgG, which could not be ascribed to a generalized low level of serum immunoglobulins, has not been previously reported. The results indicate that B19 should be assayed at diagnosis of leukemia to avoid subsequent diagnostic uncertainty, and during treatment in B19-seronegative patients exhibiting unexplained cytopenia.

Parvovirus B19 Infection Associated with Encephalitis in a Patient Suffering from Malignant Lymphoma

A parvovirus B19 infection was established in a 58-year-old woman undergoing treatment for malignant lymphoma. Clinically, the patient displayed a variety of neurologic symptoms that could not readily be explained by the mere presence of lymphoblastic cells within the central nervous system. This is the first time parvovirus B19 DNA has been detected in the cerebrospinal fluid of a patient suffering from encephalitis.

Parvovirus B19 infection and Diamond-Blackfan anaemia.

It is the purpose of the study to report the frequency of parvovirus in children with a diagnosis of Diamond‐Blackfan anaemia and to discuss the possible aetiological role of parvovirus in Diamond‐Blackfan anaemia. We found parvovirus DNA in 3 of 11 bone marrow smears. Giant pronormoblasts showed low sensitivity (33%) and poor specificity (75%). The presence of giant pronormoblasts was associated with a very high myeloid: erythroid ratio, and may not be specific for parvovirus infection, but a feature of severely suppressed erythropoiesis. The three parvovirus‐positive patients were the only children who experienced a remission, and who are free of medication. The seven surviving parvovirus‐negative patients are all currently on steroid treatment.