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We report the case of a patient who presented with a prodromal illness suggestive of viral infection, subsequently confirmed as parvovirus B19, who had a lupus anticoagulant present. Her IgG anti-cardiolipin antibody was normal (7.0 units/ml) but her IgM anti-cardiolipin was elevated (55 units/ml). These later returned to normal. Parvovirus B19 infection may be associated with the presence of lupus anticoagulant.
In the literature, heterozygosity for haemoglobins S and E is known as a clinically benign condition. Nevertheless, we present a case of double heterozygosity manifesting as an infarctive sickle cell-like crisis with acute chest syndrome and reversible bone marrow necrosis. Importantly, these complications were associated with serologically documented parvovirus B19 infection. Reviewing the literature, this case emphasizes a specific role of parvovirus B19 as a precipitating cause. Furthermore, it demonstrates how important the consideration of haemoglobin disorders can be even outside of the historically known areas.
BACKGROUND AND OBJECTIVES: To date there has been no published report on a systematic evaluation of the heat sensitivity of human parvovirus B19 (B19) and the related safety of the plasma-derived fractionated products. In this study, we examined the heat sensitivity of B19 by using the infectivity assay with cultured cells. MATERIALS AND METHODS: The heat sensitivity of B19 was examined by measuring the reduction in viral infectivity titres after heating liquid containing B19 at 60 degrees C. Viral infectivity was assayed by detection of viral antigens or viral mRNA in infected cells. As a control, canine parvovirus (CPV) was also heat-treated. RESULTS: B19 displayed quite different inactivation kinetics to CPV when both were heated in liquid at 60 degrees C. In sharp contrast to the latter, B19 was rapidly inactivated within 1 h when the virus was suspended in 5% or 25% human serum albumin solution, phosphate-buffered saline, or complete medium. However, B19 appeared to be resistant to heat inactivation in liquid containing 60% sucrose. CONCLUSIONS: The heat sensitivity of B19 in liquid was clearly different from that of CPV. Significantly, the efficiency to inactivate B19 and reduce its infectivity following heating in liquid was mainly affected by the composition of the solutions used for virus suspension.
Parvovirus B19 infection during pregnancy causes up to 27% cases of non-immune hydrops in anatomically normal fetuses. The virus is believed to cause arrest of maturation of red blood cell precursors at the late normoblast stage and also causes a decrease in the number of platelets. Fetal anemia is presently thought to be responsible for the development of skin edema and effusions. Myocarditis leading to heart failure may contribute to the development of fetal hydrops. We reviewed the literature regarding prevalence, transmission rates, clinical presentation, diagnostic techniques, current invasive vs. conservative management options, outcome and postmortem findings in a total of 82 studies involving 230 invasively and 435 conservatively managed pregnancies. In this non-selected population, the proportion of seronegative susceptible mothers ranged from 19 to 65%, seroconversion with an incubation time of up to 20 days occurred in 5.7-12.1%, and 188/230 (82%) who were transfused infected fetuses had a normal outcome as opposed to only 239/435 (55%) in the conservatively managed group. The average time from diagnosis to resolution in both groups was 6 weeks (range, 3-12 and 2-12 weeks, respectively). The most promising diagnostic techniques were PCR of amniotic fluid or fetal blood and electron microscopy. There are some reports of fetal abnormalities occurring (probably coincidentally) in cases of parvovirus, but the majority of postmortem findings were infection-related, in particular myocarditis and hepatic abnormalities. Although management guidelines cannot be derived from this study due to the variable degree of hydrops in the analyzed studies, the present data suggest a benefit of transfusion therapy over conservative management in infected fetuses. The only study which was corrected for severity of hydrops using ultrasound criteria showed a clear benefit of intrauterine transfusion.
BACKGROUND: Double inactivation by solvent/detergent treatment plus heating at 100 degrees C for 30 minutes after lyophilization has been adopted to improve viral safety of factor VIII and factor IX concentrates, particularly with respect to non-lipid-enveloped viruses. The aim of this study was to evaluate the safety of concentrates exposed to these virucidal methods. STUDY DESIGN AND METHODS: Twenty-six previously untreated hemophiliacs, 19 with factor VIII deficiency and 7 with factor IX deficiency, were investigated in a prospective multicenter study over a 12-month follow-up period by the use of serologic and virologic markers for lipid- and non-lipid-enveloped viruses (human immunodeficiency virus types 1 and 2; hepatitis A, B, and C viruses; B19 parvovirus antibodies; and B19 DNA). Overall, 270,000 U of factor VIII and 102,000 U of factor IX concentrate were administered during the study period. RESULTS: None of the 26 patients seroconverted for human immunodeficiency virus or hepatitis C virus. Hepatitis B virus markers remained negative in the 10 unvaccinated hemophiliacs. No hepatitis A virus seroconversion occurred among 17 susceptible patients. B19 seroconversion (IgM) and B19 viremia were observed within 2 weeks of the first concentrate infusion in 8 of 15 susceptible patients, 5 of 11 treated with factor VIII and 3 of 4 with factor IX concentrate. CONCLUSION: This prospective study indicates that very high temperatures applied to lyophilized concentrates appear to prevent the transmission of hepatitis A virus to hemophiliacs. However, B19 parvovirus still contaminates concentrates despite the use of this robust virucidal method.
The generation and accumulation of genetic mutations have been associated with carcinogenesis. Epidemiological and experimental evidence implicate parvoviruses in growth inhibition (oncosuppression) and selective destruction (oncolysis) of tumor cells. It is proposed here that parvoviruses can preferentially target genetically unstable tumor cells, which are deficient in DNA repair mechanisms. This selective strategy may serve as a virus-based therapeutic approach against cancer.
After a period of general nonspecific symptoms (weakness; nocturnal sweating) for a few days a 29-year-old man suddenly developed a purpura-like rash on both hands and feet ("glove and sock") with mild itching and oedema. A blood count demonstrated leukopenia (2100/microliters) with neutropenia (1100/microliters), thrombocytopenia (81,000/microliters) and reticulocytopenia (1/1000), while haemoglobin content was normal. The bone-marrow showed almost complete reduction of erythropoiesis with the presence of giant proerythroblasts. Granulopoiesis and megakaryopoiesis were unremarkable. Positive tests for IgM and IgG antibodies against parvovirus B19 established the diagnosis of infection with this organism. The rash, blood picture and bone-marrow changes all regressed spontaneously, without any treatment, within a week. The petechial or purpuric "glove and sock" syndrome may be a special form of parvovirus B19 infection.
Canine parvovirus (CPV) is an emerging DNA virus that was first observed to cause disease in canines in 1978 and has since become a ubiquitous pathogen worldwide. CPV emerged from feline panleukopenia parvovirus (FPLV) or a closely related virus, differing at several key amino acid residues. Here we characterize the evolutionary processes underlying the emergence of CPV. Although FPLV has remained an endemic infection in its host populations, we show that, since the 1970s, the newly emerged CPV has undergone an epidemic-like pattern of logistic/exponential growth, effectively doubling its population size every few years. This rapid population growth was associated with a lineage of CPV that acquired a broader host range and greater infectivity. Recombination played no role in the emergence of CPV. Rather, any preexisting variation in the donor species and the subsequent rapid adaptation of the virus to canines were likely dependent on a high rate of mutation and the positive selection of mutations in the major capsid gene. Strikingly, although these single-stranded viruses have a DNA genome and use cellular replication machinery, their rate of nucleotide substitution is closer to that of RNA viruses than to that of double-stranded DNA viruses.
The identification of new virus species is a key issue for the study of infectious disease but is technically very difficult. We developed a system for large-scale molecular virus screening of clinical samples based on host DNA depletion, random PCR amplification, large-scale sequencing, and bioinformatics. The technology was applied to pooled human respiratory tract samples. The first experiments detected seven human virus species without the use of any specific reagent. Among the detected viruses were one coronavirus and one parvovirus, both of which were at that time uncharacterized. The parvovirus, provisionally named human bocavirus, was in a retrospective clinical study detected in 17 additional patients and associated with lower respiratory tract infections in children. The molecular virus screening procedure provides a general culture-independent solution to the problem of detecting unknown virus species in single or pooled samples. We suggest that a systematic exploration of the viruses that infect humans, "the human virome," can be initiated.
Identification of previously unrecognized viral agents in serum or plasma samples is of great medical interest but remains a major challenge, primarily because of abundant host DNA. The current methods, library screening or representational difference analysis (RDA), are very laborious and require selected sample sets. We have developed a simple and reproducible method for discovering viruses in single serum samples that is based on DNase treatment of the serum followed by restriction enzyme digestion and sequence-independent single primer amplification (SISPA) of the fragments, and have evaluated its performance on known viruses. Both DNA viruses and RNA viruses at a concentration of approximately 10(6) genome equivalents per ml were reproducibly identified in 50 microl of serum. While evaluating the method, two previously unknown parvoviruses were discovered in the bovine sera used as diluent. The near complete genome sequence of each virus was determined; their classification as two species (provisionally named bovine parvoviruses 2 and 3) was confirmed by phylogenetic analysis. Both viruses were found to be frequent contaminants of commercial bovine serum. DNase treatment of serum samples may prove to be a very useful tool for virus discovery. The DNase-SISPA method is suitable for screening of a large number of samples and also enables rapid sequence determination of high-titer viruses.
The pathogenic human parvovirus B19 is an autonomously replicating virus with a remarkable tropism for human erythroid progenitor cells. Although the target cell specificity for B19 infection has been suggested to be mediated by the erythrocyte P-antigen receptor (globoside), a number of nonerythroid cells that express this receptor are nonpermissive for B19 replication. To directly test the role of expression from the B19 promoter at map unit 6 (B19p6) in the erythroid cell specificity of B19, we constructed a recombinant adeno-associated virus 2 (AAV), in which the authentic AAV promoter at map unit 5 (AAVp5) was replaced by the B19p6 promoter. Although the wild-type (wt) AAV requires a helper virus for its optimal replication, we hypothesized that inserting the B19p6 promoter in a recombinant AAV would permit autonomous viral replication, but only in erythroid progenitor cells. In this report, we provide evidence that the B19p6 promoter is necessary and sufficient to impart autonomous replication competence and erythroid specificity to AAV in primary human hematopoietic progenitor cells. Thus, expression from the B19p6 promoter plays an important role in post-P-antigen receptor erythroid-cell specificity of parvovirus B19. The AAV-B19 hybrid vector system may also prove to be useful in potential gene therapy of human hemoglobinopathies.
To develop a strategy that promotes efficient antiviral immunity, hybrid virus-like particles (VLP) were prepared by self-assembly of the modified porcine parvovirus VP2 capsid protein carrying a CD8(+) T cell epitope from the lymphocytic choriomeningitis virus nucleoprotein. Immunization of mice with these hybrid pseudoparticles, without adjuvant, induced strong cytotoxic T lymphocyte (CTL) responses against both peptide-coated- or virus-infected-target cells. This CD8(+) class I-restricted cytotoxic activity persisted in vivo for at least 9 months. Furthermore, the hybrid parvovirus-like particles were able to induce a complete protection of mice against a lethal lymphocytic choriomeningitis virus infection. To our knowledge, this study represents the first demonstration that hybrid nonreplicative VLP carrying a single viral CTL epitope can induce protection against a viral lethal challenge, in the absence of any adjuvant. These recombinant particles containing a single type of protein are easily produced by the baculovirus expression system and, therefore, represent a promising and safe strategy to induce strong CTL responses for the elimination of virus-infected cells.
We describe here the case of a renal transplant recipient treated by sirolimus based immunosuppresive therapy, who developed severe and unusual pancytopenia 2 months after renal transplantation. Parvovirus B19 primo-infection was diagnosed. The first course of intravenous immunoglobulin failed. Bone marrow aspiration confirmed megaloblastic anaemia associated with parvovirus B19. Finally, this infection was succesfully treated by the reduction of immunosuppression combined with a second course of intravenous immunoglobulin.
The clinical relevance of parvovirus B19 DNA persistence in bone marrow was examined in 10 immunocompetent individuals undergoing examinations for unexplained fever, arthralgia or chronic leukopenia. Common causes of these symptoms had been ruled out and bone marrow aspiration was indicated at this stage of investigation. In addition to morphological analysis of the bone marrow, a test for B19 DNA was performed with 2 nested PCRs. Five of these 10 selected patients had detectable B19 DNA in their bone marrow, whereas no viraemia was observed. Additional bone marrow samples were collected at least 6 months after the first sample from the B19 DNA-positive patients, of whom 3 were found to be still positive. Indeed, 2 of the patients have been positive for more than 5 y of follow-up. Sera from all patients with persistent B19 DNA in bone marrow could neutralize the virus. One patient responded to treatment with immunoglobulin but later relapsed. No other cause of the symptoms was found, despite extensive investigations, and at least some of the prolonged disease manifestations may be due to parvovirus B19.
We report a previously healthy, immunocompetent 17-year-old male patient, who developed acute glomerulonephritis during the course of Parvovirus B19 infection and this acute glomerulonephritis did not resolve spontaneously. His renal biopsy showed mild mesangial proliferation and focal segmental sclerosis. Parvovirus B19 DNA was detected in renal tissue by polymerase chain reaction.
This study was carried out to detect Parvovirus B19 (PB19) DNA together with its antibodies in the sera of children with a range of hematological disorders to clarify the contribution of this infection to changes observed in hematological picture in those populations. This study included 85 pediatric patients with different hematological disorders. Twenty healthy subjects with matched age and sex were included as controls. Patients were classified into four groups; group I included 25 patients with hemolytic anemia in aplastic crisis, group II included 20 patients with hemolytic anemia without aplastic crisis, group III included 20 acute leukemia patients under chemotherapy, group IV included 20 patients with recently diagnosed acute leukemia. Virological study for PB19 included determination of specific IgG & IgM together with viral DNA by polymerase chain reaction (PCR). In all groups of patients with positive markers for PB19, there were statistically significant differences in the mean Hb concentration and RBC count (P < 0.001 for each), presence of neutropenia (P = 0.003) and lymphocytosis (P < 0.001) compared to controls. There was statistically significant difference in the prevalence of PB19 IgM, IgG and PCR among studied groups compared to control group. In group I and group II IgG had the highest positive rate (56 and 35%, respectively). In group III IgG also had a high positive rate (45%). However, in group IV IgM had the highest positive rate (50%) followed by PCR (45%) then IgG (40%). In conclusion, PB19 infection is detected in high rates among children with hematological disorders. PB19 must be suspected and screened for when there is anemia in those patients associated with neutropenia and lymphocytosis. In patients with acute leukaemia under chemotherapy who have unexpected anemia, neutropenia and lymphocytosis Parvovirus infection should be considered before a change of chemotherapy protocol. Screening of blood for PB19 may be helpful in understanding the epidemiology of infection with this virus. The direct detection of DNA by PCR in sera needs to be coupled with serology for a more reliable diagnosis of PB19 infections in these children.
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.
We report here an unusual presentation of acute nonlymphoblastic leukemia with ocular granulocytic sarcoma who was firstly diagnosed iron deficiency anemia and acute parvovirus infection induced erythroid hypoplasia. To our knowledge this is the first paper of acute myeloblastic leukemia (AML) with granulocytic sarcoma, preceded by acute Parvovirus B19 infection.