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Parvoviruses
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Members of the family Parvoviridae are small, resilient, non-enveloped viruses with linear, single-stranded DNA genomes of 4-6 kb. Viruses in two subfamilies, the Parvovirinae and Densovirinae, are distinguished primarily by their respective ability to infect vertebrates (including humans) versus invertebrates. Being genetically limited, most parvoviruses require actively dividing host cells and are host and/or tissue specific. Some cause diseases, which range from subclinical to lethal. A few require co-infection with helper viruses from other families. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the Parvoviridae, which is available at www.ictv.global/report/parvoviridae.
Significance
The majority of viral genomic sequences available today are fewer than 50 years old. Parvovirus B19 (B19V) is a ubiquitous human pathogen causing fifth disease in children, as well as other conditions. By isolating B19V DNA from human remains between ∼0.5 and 6.9 thousand years old, we show that B19V has been associated with humans for thousands of years, which is significantly longer than previously thought. We also show that the virus has been evolving at a rate an order of magnitude lower than estimated previously. Access to viral sequences isolated from individuals living thousands of years ago greatly improves our understanding of the timescales of virus evolution, spatiotemporal distribution, and their substitution rates, and can uncover genetic diversity that is now extinct.
Parvovirus B19 (B19V) is pathogenic to humans and causes bone marrow failure diseases and various other inflammatory disorders. B19V infection exhibits high tropism for human erythroid progenitor cells (EPCs) in the bone marrow and fetal liver. The exclusive restriction of B19V replication to erythroid lineage cells is partly due to the expression of receptor and co-receptor(s) on the cell surface of human EPCs and partly depends on the intracellular factors essential for virus replication. We first summarize the latest developments in the viral entry process and the host cellular factors or pathways critical for B19V replication. We discuss the role of hypoxia, erythropoietin signaling and STAT5 activation in the virus replication. The B19V infection-induced DNA damage response (DDR) and cell cycle arrest at late S-phase are two key events that promote B19V replication. Lately, the virus infection causes G2 arrest, followed by the extensive cell death of EPCs that leads to anemia. We provide the current understanding of how B19V exploits the cellular resources and manipulate pathways for efficient virus replication. B19V encodes a single precursor mRNA (pre-mRNA), which undergoes alternate splicing and alternative polyadenylation to generate at least 12 different species of mRNA transcripts. The post-transcriptional processing of B19V pre-mRNA is tightly regulated through cis-acting elements and trans-acting factors flanking the splice donor or acceptor sites. Overall, in this review, we focus on the recent advances in the molecular virology and pathogenesis of B19V infection.
Next-generation sequencing and metagenomics have revolutionized the discovery of novel viruses. In recent years, three novel protoparvoviruses have been discovered in fecal samples of humans: bufavirus (BuV) in 2012, tusavirus (TuV) in 2014, and cutavirus (CuV) in 2016. BuV has since been studied the most, disclosing three genotypes that also represent serotypes. Besides one nasal sample, BuV DNA has been found exclusively in diarrheal feces, but not in non-diarrheal feces, suggesting a causal relationship. According to both geno- and seroprevalences, BuV appears to be the most common of the three novel protoparvoviruses, whereas TuV DNA has been found in only a single fecal sample, with antibody detection being equally rare. Moreover, the TuV sequence is closer to those of non-human protoparvoviruses, and so the evidence of TuV being a human virus is thus far insufficient. Interestingly, besides in feces, CuV has also been detected in skin biopsies of patients with cutaneous T-cell lymphoma and a patient with melanoma, while all other skin samples have tested PCR negative. Even if preliminary disease associations exist, the full etiological roles of these viruses in human disease are yet to be resolved.
Parvovirus B19 (B19V) DNA persists lifelong in human tissues, but the cell type harbouring it remains unclear. We here explore B19V DNA distribution in B, T and monocyte cell lineages of recently excised tonsillar tissues from 77 individuals with an age range of 2–69 years. We show that B19V DNA is most frequent and abundant among B cells, and within them we find a B19V genotype that vanished from circulation 440 years ago. Since re-infection or re-activation are unlikely with this virus type, this finding supports the maintenance of pathogen-specific humoral immune responses as a consequence of B-cell long-term survival rather than continuous replenishment of the memory pool. Moreover, we demonstrate the mechanism of B19V internalization to be antibody dependent in two B-cell lines as well as in ex vivo isolated tonsillar B cells. This study provides direct evidence for a cell type accountable for B19V DNA tissue persistence.
Bocaparvoviruses are emerging pathogens of the Parvoviridae family. Human bocavirus 1 (HBoV1) causes severe respiratory infections and HBoV2 to HBoV4 cause gastrointestinal infections in young children. Recent reports of lifethreatening cases, lack of direct treatment or vaccination, and a limited understanding of their disease mechanisms highlight the need to study these pathogens on a molecular and structural level for the development of therapeutics. Toward this end, the capsid structures of HBoV1, HBoV3, and HBoV4 were determined to a resolution of 2.8 to 3.0 Å by cryo-electron microscopy and three-dimensional image reconstruction. The bocaparvovirus capsids, which display different tissue tropisms, have features in common with other parvoviruses, such as depressions at the icosahedral 2-fold symmetry axis and surrounding the 5-fold symmetry axis, protrusions surrounding the 3-fold symmetry axis, and a channel at the 5-fold symmetry axis. However, unlike other parvoviruses, densities extending the 5-fold channel into the capsid interior are conserved among the bocaparvoviruses and are suggestive of a genus-specific function. Additionally, their major viral protein 3 contains loops with variable regions at their apexes conferring capsid surface topologies different from those of other parvoviruses. Structural comparisons at the strain (HBoV) and genus (bovine parvovirus and HBoV) levels identified differences in surface loops that are functionally important in host/tissue tropism, pathogenicity, and antigenicity in other parvoviruses and likely play similar roles in these viruses. This study thus provides a structural framework to characterize determinants of host/tissue tropism, pathogenicity, and antigenicity for the development of antiviral strategies to control human bocavirus infections.
We tested serum samples from 387 free-ranging wolves ( Canis lupus ) from 2007 to 2013 for exposure to eight canid pathogens to establish baseline data on disease prevalence and spatial distribution in Minnesota's wolf population. We found high exposure to canine adenoviruses 1 and 2 (88% adults, 45% pups), canine parvovirus (82% adults, 24% pups), and Lyme disease (76% adults, 39% pups). Sixty-six percent of adults and 36% of pups exhibited exposure to the protozoan parasite Neospora caninum . Exposure to arboviruses was confirmed, including West Nile virus (37% adults, 18% pups) and eastern equine encephalitis (3% adults). Exposure rates were lower for canine distemper (19% adults, 5% pups) and heartworm (7% adults, 3% pups). Significant spatial trends were observed in wolves exposed to canine parvovirus and Lyme disease. Serologic data do not confirm clinical disease, but better understanding of disease ecology of wolves can provide valuable insight into wildlife population dynamics and improve management of these species.
Human parvovirus 4 (‘PARV4’) is a small DNA tetraparvovirus, first reported in 2005. In some populations, PARV4 infection is uncommon, and evidence of exposure is found only in individuals with risk factors for parenteral infection who are infected with other blood-borne viruses. In other settings, seroprevalence studies suggest an endemic, age-associated transmission pattern, independent of any specific risk factors. The clinical impact of PARV4 infection remains uncertain, but reported disease associations include an influenza-like syndrome, encephalitis, acceleration of HIV disease, and foetal hydrops. In this review, we set out to report progress updates from the recent literature, focusing on the investigation of cohorts in different geographical settings, now including insights from Asia, the Middle East, and South America, and discussing whether attributes of viral or host populations underpin the striking differences in epidemiology. We review progress in understanding viral phylogeny and biology, approaches to diagnostics, and insights that might be gained from studies of closely related animal pathogens. Crucial questions about pathogenicity remain unanswered, but we highlight new evidence supporting a possible link between PARV4 and an encephalitis syndrome. The unequivocal evidence that PARV4 is endemic in certain populations should drive ongoing research efforts to understand risk factors and routes of transmission and to gain new insights into the impact of this virus on human health.
Background
Human parvovirus B19 (B19V) is a frequent contaminant of blood and plasma-derived medicinal products. To ensure the quality and safety of plasma-derived products, European regulations, Plasma Protein Therapeutics Association (PPTA) standard and FDA guidelines require testing of manufacturing plasma for parvovirus B19 DNA to limit the load of this virus. In China, however, there have been no related documentation and technical guiding principles for monitoring B19V, moreover, an adequate level of information on the prevalence of B19V in Chinese plasma donations is not available.
Findings
By using an in-house quantitative polymerase chain reaction (qPCR) assay adapted for all three genotypes of B19V, 235 source plasma pools from three regional different Chinese manufacturers of blood products were screened and quantified. Results showed that 71.91 % (169/235) of plasma pools were contaminated by B19V, with the concentrations of 5.18 × 102–1.05 × 109 IU/mL. Approximately 31.95 % of the DNA-positive plasma pools were only moderately contaminated (<104 IU/mL), while 68.05 % contained >104 IU/mL.
Conclusions
The high level of B19V in plasma pools could present a great risk in plasma derivatives. Therefore, the implementation of B19V NAT (Nucleic Acid Testing) assays capable of detecting all B19V genotypes and discard donations with high titer B19V DNA for Chinese blood products manufacturers seems to be necessary.
Human parvovirus 4 (Parv4) is a relatively new virus. Association of this virus with any human disease is yet to be established.
We detected human parvovirus 4 in the cerebrospinal fluid (CSF) of two patients presenting with acute encephalitis syndrome
in northern India. This is the first report of the Parv4 genome sequence from northern India.
High seroprevalence of parvovirus B19 (B19V) coinfection with Plasmodium falciparum has been previously reported. However, the impact of B19V-infection on the clinical course of malaria is still elusive. In this study, we investigated the prevalence and clinical significance of B19V co-infection in Gabonese children with malaria.
B19V prevalence was analyzed in serum samples of 197 Gabonese children with P. falciparum malaria and 85 healthy controls using polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and direct DNA-sequencing.
B19V was detected in 29/282 (10.28%) of Gabonese children. B19V was observed more frequently in P. falciparum malaria patients (14.21%) in comparison to healthy individuals (1.17%) (P<0.001). Notably, the mild-malaria group revealed significantly lower hematocrit levels in B19V/P. falciparum co-infection than in P. falciparum mono-infection (P<0.05). Genetic analysis revealed a predominance of B19V genotype-1 (71.43%) in the studied population. However, B19V-genotype 2 was observed significantly more often in children with severe-malaria than in mild-malaria (P=0.04).
Our findings reveal that B19V-infection is frequent in Gabonese children with P. falciparum malaria and signifies a possible contribution of B19V on the clinical course of malaria in a genotype-dependent manner. B19V co-infection should be considered as a additional diagnostic measure in malaria patients with life threatening anemia.
To determin the extent to which parvovirus B19 (B19V) and co-infection of B19V and malaria contribute to risk of anaemia in children.
B19V DNA and malaria parasites were screened for 234 children at the PML Children's Hospital in Accra. The role of B19V and co-infection with B19V and malaria in anaemia was evaluated by analysing full blood cell counts, malaria and B19V DNA results from these children.
The prevalence of B19V, malaria and co-infection with B19V and malaria was 4.7%, 41.9% and 2.6%, respectively. Malaria posed a greater risk in the development of mild anaemia compared to severe anaemia (OR=5.28 vrs 3.15) whereas B19V posed a higher risk in the development of severe anaemia compared to mild anaemia (OR=4.07 vrs 1.00) from a non-anaemic child. Persons with co-infection with B19V and malaria had 2.23 times the risk (95% CI=0.40-12.54) of developing severe anaemia should they already have a mild anaemia. The degree of anaemia was about three times affected by co-infection (Pillai's trace=0.551, P=0.001) as was affected by malaria alone (Pillai's trace=0.185, P=0.001). B19V alone did not significantly affect the development of anaemia in a non-anaemic child. Microcytic anaemia was associated with B19V and co-infection with B19V and malaria more than normocytic normochromic anaemia.
B19V was associated with malaria in cases of severe anaemia. The association posed a significant risk for exacerbation of anaemia in mild anaemic children. B19V and co-infection with B19V and malaria may be associated with microcytic anaemia rather than normocytic normochromic anaemia as seen in cases of B19V infection among persons with red cell abnormalities.
There are few detailed etiologic studies of severe anemia in children from malaria-endemic areas and none in those countries with holoendemic transmission of multiple Plasmodium species.
We examined associates of severe anemia in 143 well-characterized Papua New Guinean (PNG) children aged 0.5-10 years with hemoglobin concentration <50 g/L (median [inter-quartile range] 39 [33]-[44] g/L) and 120 matched healthy children (113 [107-119] g/L) in a case-control cross-sectional study. A range of socio-demographic, behavioural, anthropometric, clinical and laboratory (including genetic) variables were incorporated in multivariate models with severe anemia as dependent variable. Consistent with a likely trophic effect of chloroquine or amodiaquine on parvovirus B19 (B19V) replication, B19V PCR/IgM positivity had the highest odds ratio (95% confidence interval) of 75.8 (15.4-526), followed by P. falciparum infection (19.4 (6.7-62.6)), vitamin A deficiency (13.5 (5.4-37.7)), body mass index-for-age z-score <2.0 (8.4 (2.7-27.0)) and incomplete vaccination (2.94 (1.3-7.2)). P. vivax infection was inversely associated (0.12 (0.02-0.47), reflecting early acquisition of immunity and/or a lack of reticulocytes for parasite invasion. After imputation of missing data, iron deficiency was a weak positive predictor (6.4% of population attributable risk).
These data show that severe anemia is multifactorial in PNG children, strongly associated with under-nutrition and certain common infections, and potentially preventable through vitamin A supplementation and improved nutrition, completion of vaccination schedules, and intermittent preventive antimalarial treatment using non-chloroquine/amodiaquine-based regimens.
Nonparenteral transmission might contribute to human parvovirus 4 (PARV4) infections in sub-Saharan Africa. PARV4 DNA was detected in 8 (0.83%) of 961 nasal samples and 5 (0.53%) of 943 fecal samples from 1,904 children in Ghana. Virus concentrations ≤6-7 log(10) copies/mL suggest respiratory or fecal-oral modes of PARV4 transmission.
Human bocavirus 1 (HBoV1) has been identified as one of the etiological agents of wheezing in young children with acute respiratory-tract infections. In this study, we have obtained the sequence of a full-length HBoV1 genome (including both termini) using viral DNA extracted from a nasopharyngeal aspirate of an infected patient, cloned the full-length HBoV1 genome, and demonstrated DNA replication, encapsidation of the ssDNA genome, and release of the HBoV1 virions from human embryonic kidney 293 cells. The HBoV1 virions generated from this cell line-based production system exhibits a typical icosahedral structure of approximately 26 nm in diameter, and is capable of productively infecting polarized primary human airway epithelia (HAE) from the apical surface. Infected HAE showed hallmarks of lung airway-tract injury, including disruption of the tight junction barrier, loss of cilia and epithelial cell hypertrophy. Notably, polarized HAE cultured from an immortalized airway epithelial cell line, CuFi-8 (originally derived from a cystic fibrosis patient), also supported productive infection of HBoV1. Thus, we have established a reverse genetics system and generated the first cell line-based culture system for the study of HBoV1 infection, which will significantly advance the study of HBoV1 replication and pathogenesis.
Gastroenteritis is a common illness causing considerable morbidity and mortality worldwide. Despite improvements in detection methods, a significant diagnostic gap still remains. Human bocavirus (HBoV)s, which are associated with respiratory infections, have also frequently been detected in stool samples in cases of gastroenteritis, and a tentative association between HBoVs, and in particular type-2 HBoVs, and gastroenteritis has previously been made. The aim of this study was to determine the role of HBoVs in gastroenteritis, using archived DNA samples from the case-control Infectious Intestinal Disease Study (IID). DNA extracted from stool samples from 2,256 cases and 2,124 controls were tested for the presence of HBoV DNA. All samples were screened in a real time PCR pan-HBoV assay, and positive samples were then tested in genotype 1 to 3-specific assays. HBoV was detected in 7.4% but no significantly different prevalence was observed between cases and controls. In the genotype-specific assays 106 of the 324 HBoV-positive samples were genotyped, with HBoV-1 predominantly found in controls whilst HBoV-2 was more frequently associated with cases of gastroenteritis (p<0.01). A significant proportion of HBoV positives could not be typed using the type specific assays, 67% of the total positives, and this was most likely due to low viral loads being present in the samples. However, the distribution of the untyped HBoV strains was no different between cases and controls. In conclusion, HBoVs, including HBoV-2 do not appear to be a significant cause of gastroenteritis in the UK population.
Four species of human bocaviruses (HBoV1-4) have been identified based on phylogenetic analysis since its first report in 2005. HBoV1 has been associated with respiratory disease, whereas HBoV2-4 are mainly detected in enteric infections. Although the prevalence of HBoVs in humans has been studied in some regions, it has not been well addressed globally.
Cross-reactivity of anti-VP2 antibodies was detected between HBoV1, 2, 3, and 4 in mouse and human serum. The prevalence of specific anti-VP2 IgG antibodies against HBoV1-4 was determined in different age groups of healthy individuals aged 0-70 years old in Beijing, China, using a competition ELISA assay based on virus-like particles of HBoV1-4. The seroprevalence of HBoV1-4 was 50%, 36.9%, 28.7%, and 0.8%, respectively, in children aged 0-14 years (n = 244); whereas the seroprevalence of HBoV1-4 was 66.9%, 49.3%, 38.7% and 1.4%, respectively, in healthy adults (≥ 15 years old; n = 142). The seropositive rate of HBoV1 was higher than that of HBoV2, HBoV3, and HBoV4 in individuals older than 0.5 years. Furthermore, IgG seroconversion of HBoV1 (10/31, 32.3%), HBoV2 (8/31, 25.8%), and HBoV3 (2/31, 6.5%) was found in paired sera collected from children with respiratory tract infections who were positive for HBoV1 according to PCR analysis.
Our data indicate that HBoV1 is more prevalent than HBoV2, HBoV3, and HBoV4 in the population we sampled in Beijing, China, suggesting that HBoV species may play differential roles in disease.
Primary maternal infection with cytomegalovirus (CMV), parvovirus B19 (B19V), and varicella-zoster virus (VZV) may result in adverse pregnancy outcomes like congenital infection or foetal loss. Women working in child day care have an increased exposure to CMV, B19V, and VZV. By comparing the seroprevalence of IgG-class antibodies against CMV, VZV and B19V in female day care workers (DCW) with the seroprevalence in women not working in day care this study aimed to assess the association between occupation and infection.
A cross-sectional design was used. Out of a random sample of 266 day care centres, demographic data, data on work history, and blood samples were collected from 285 women from 38 centres. In addition, blood samples and basic demographics from women who participated in a cross-sectional survey of the Amsterdam population (2004) were used. All blood samples were tested for IgG-class antibodies against CMV, B19V, and VZV.
Twenty-seven percent of the DCW were still susceptible to B19V or CMV. Working in day care was independently associated with B19V infection in all DCW (prevalence ratio [PR] 1.2; 95 % CI 1.1-1.3), and with CMV infection in DCW of European origin only (PR 1.7; 95 % CI 1.3-2.3). Almost all women born outside Europe tested seropositive for CMV (96 %). All DCW tested seropositive for VZV, compared to only 94 % of the women not working in day care.
This study confirms the clear association between employment in child day care centres and infection with CMV and B19V. Intervention policies, like screening of new employees and awareness campaigns emphasizing hygienic measures among DCW, should be implemented urgently to improve the maternal health of these women and the health of their offspring.
Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV)
infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and
HCV-infected individuals (n = 469) and the correlations with disease status. We found that PARV4 infection frequently occurred
in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations
between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms,
although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet
clear.
To the Editor.—
Human parvovirus is already known to be responsible for aplastic crisis in chronic hemolytic anemia,1 for erythema infectiosum or fifth disease,2 and for arthropathies,3,4 and it has recently been isolated from the serum of patients with vascular purpura.5 We report the case of Henoch-Schonlein purpura associated with human parvovirus infection.
H. T., a 6-year-old girl, without any significant past history, was admitted on March 8, 1985, for joint pain and swelling (wrists, knees, ankles) associated with intense abdominal pain.
B19 parvovirus, the cause of fifth disease and transient aplastic crisis, has been successfully propagated in suspension cultures of human erythroid bone marrow cells obtained from patients with sickle cell disease and stimulated by erythropoietin. B19 inoculation in vitro resulted in a marked decline in identifiable erythroid cells over seven to nine days of incubation. Characteristic giant early erythroid cells were seen on Wright's-Giemsa stain of infected cultures. By in situ hybridization, 30% to 40% of erythroblasts were infected at 48 hours; a similar proportion of cells showed B19 capsid protein by immunofluorescence. B19 DNA was present in erythroblasts but not in the leukocyte fraction of bone marrow. B19 replication, as determined by Southern analysis, and B19 encapsidation, as determined by sensitivity of isolated cell fractions to DNase I, were restricted to the nuclei. B19 DNA was detectable in the nuclei from infected cultures beginning at 18 hours and in the supernatant at 32 hours; B19 genome copy number was estimated at about 25,000 to 30,000/infected cell at 48 hours. Recovery of virus depended on the multiplicity of infection (moi); at low moi, approximately 200x input virus was recovered from total cultures and 50x from the culture supernatants. Virus released into the supernatant was as infectious or more infectious than virus obtained from sera of infected patients. Human erythroid bone marrow culture represents a safe in vitro system for the elucidation of the cellular and molecular biology of the pathogenic B19 parvovirus.
From March to August 1984, 26 patients with hereditary hemolytic anemia in northeastern Ohio developed acute, profound red cell aplasia. The patients included 14 males and 12 females 2 to 23 years old, with sickle cell anemia (20 cases), hemoglobin SC-disease (4 cases), sickle- beta-thalassemia (1 case), or hereditary spherocytosis (1 case). All had an acute onset of severe reticulocytopenia and anemia and prodromal symptoms of illness including fever, abdominal symptoms, headache, and arthralgias. Twenty-two received transfusions. Reticulocytosis occurred spontaneously within 2 to 14 days of presentation. In five acute-phase sera, 10(8) to 10(12) viral particles/mL were detected by electron microscopy. Human parvovirus B19 DNA was demonstrated in high concentration by hybridization in the same five acute-phase sera and in low concentration in sera of eight additional patients. The five highly viremic sera inhibited erythroid colony formation in vitro. B19- specific IgM was detected in sera of 24/26 patients, and B19-specific IgG in 21 of 22 patients tested. Our results indicate that human parvovirus B19 was the etiologic agent in this large epidemic of life- threatening acute red cell aplasia in patients with hereditary hemolytic anemia.
Parvoviruses are structurally simple viruses with linear single-stranded DNA genomes and nonenveloped icosahedral capsids. They infect a wide range of animals from insects to humans. Parvovirus B19 is a long-known human pathogen, whereas adeno-associated viruses are nonpathogenic. Since 2005, many parvoviruses have been discovered in human-derived samples: bocaviruses 1–4, parvovirus 4, bufavirus, tusavirus, and cutavirus. Some human parvoviruses have already been shown to cause disease during acute infection, some are associated with chronic diseases, and others still remain to be proven clinically relevant—or harmless commensals, a distinction not as apparent as it might seem. One initially human-labeled parvovirus might not even be a human virus, whereas another was originally overlooked due to inadequate diagnostics. The intention of this review is to follow the rocky road of emerging human parvoviruses from discovery of a DNA sequence to current and future clinical status, highlighting the perils along the way.
Expected final online publication date for the Annual Review of Virology Volume 6 is September 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success.
Papular purpuric gloves and socks syndrome (PPGSS) is a self-limited exanthem that presents as painful or pruritic edema, erythema, petechiae, and purpura of the palms and soles with occasional extension to the dorsal hands and feet. The majority of PPGSS cases reported in the literature are associated with parvovirus B19 and occur in children and young adults. In a recent literature search, there were 11 PPGSS cases in adults with none reporting Epstein-Barr virus (EBV) as a viral etiology. However, there have been PPGSS cases related to EBV in children. We report the case of a 72-year-old man with PPGSS associated with Epstein-Barr virus. This case report serves as a reminder that PPGSS can present not only in the setting of pediatric and young adult parvovirus B19 infection, but also in immunocompetent adults with other viral infections.
Parvovirus B19 infections are typically mild in healthy individuals, but can be life threatening in individuals with sickle cell disease (SCD). A Saccharomyces cerevisiae-derived B19 VLP vaccine, now in pre-clinical development, is immunogenic in wild type mice when administered with the adjuvant MF59. Because SCD alters the immune response, we evaluated the efficacy of this vaccine in a mouse model for SCD. Vaccinated mice with SCD demonstrated similar binding and neutralizing antibody responses to those of heterozygous littermate controls following a prime-boost-boost regimen. Due to the lack of a mouse parvovirus B19 challenge model, we employed a natural mouse pathogen, Sendai virus, to evaluate SCD respiratory tract responses to infection. Normal mucosal and systemic antibody responses were observed in these mice. Results demonstrate that mice with SCD can respond to a VLP vaccine and to a respiratory virus challenge, encouraging rapid development of the B19 vaccine for patients with SCD.
Background:
Nosocomial outbreaks of parvovirus B19 (pB19) have been reported, but they rarely occur among healthcare personnel (HCP). Susceptibility among pregnant HCP was the major concern.
Methods:
An outbreak of pB19 among HCP is described in a paediatric ward with a cross-sectional serologic study in all HCP and patients exposed to the outbreak. Acute infection was diagnosed by polymerase chain reaction or positive anti-parvovirus B19 IgM.
Findings:
Among 48 HCP (three pregnant) and 22 patients included in the outbreak serologic study, 11 (23%) HCP and two (9%) patients had acute infection. Of these, six HCP and no patients were symptomatic. Clinical manifestations included itchy rash (100%) and joint pain following resolution of rash (67%), with median rash duration of four days. Forty percent of HCP and 50% of patients had positive anti-parvovirus IgG, indicating previously immune status. HCP with acute infection and HCP who were susceptible without infection were younger than HCP with previous immunity (mean age 32.2 vs 40.5 years, respectively; P = 0.003). The attack rate was 38% among HCP and 18% among patients who were susceptible, respectively. The outbreak ended within two weeks following strict droplet precaution and segregation of symptomatic HCP.
Conclusion:
Parvovirus B19 infection may cause nosocomial outbreak with high attack rate among HCP. Outbreak control with droplet precaution was highly effective.
Background. Parovirus B19 (B19) infection is known to cause chronic infection leading to anemia in immunocompromised patients, Although nosocomial B19 infections in immunocompetent patients have been documented, no outbreaks in immunocompromised patients have been previously reported. Whether transmission can occur from a patient with chronic infection is also unknown. Methods. An outbreak of B19 infection in a renal transplant unit was investigated by molecular analysis of the virus strains and a case-control study. Results. Three patients had genetically identical virus strains suggesting the occurrence of nosocomial transmission. The index case transmitted infection many weeks after the onset of her clinical symptoms. Other patients at risk of acquiring infection were those most intensively immunosuppressed, Viral load in the serum correlated with the hematological response. A rebound in the viral load was associated with clinical relapse and the failure of i.v. immunoglobulin therapy. Conclusion. Nosocomial transmission of B19 can occur from immunocompromised patients even when they are in the chronic stage of the infection. The clinical and virological response to i.v. immunoglobulin therapy is variable and depends on the overall level of immunosuppression of the patient.
A parvovirus-like antigen has been found in sera of nine healthy blood-donors and two patients. Its pathogenicity is unknown, but 30% of adults possess specific antibody. The new agent can be confused with hepatitis-B antigen both morphologically and serologically.
Parvovirus B19 is a single-stranded DNA virus which preferentially targets the erythroblast resulting in red cell aplasia, which is temporary in immunocompetent persons. Since the discovery of B19 virus in 1975, a wide variety of blood diseases and cytopenias affecting several blood cell lineages have been documented during or following B19 infection. These include cytopenias affecting the erythroid, megakaryoblastoid, myeloid and lymphoid lineages, as well as a variety of bicytopenias, pancytopenia, bone marrow necrosis / fat embolism syndrome, myelodysplastic syndrome, leucoerythroblastopenia, and hemophagocytic lymphohistiocytosis. B19 infection may also complicate and precede the course of acute leukemia, the significance of which remains to be determined. This review describes the current state of knowledge of the abnormalities of individual blood cell lineages encountered during parvovirus B19 infection, over the almost 40 years since its discovery, and reveals some very interesting themes, which improve our understanding of the pathogenesis of B19 infection with particular reference to the bone marrow. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
Pure red cell aplasia (PRCA) due to parvovirus B19 (PVB19) infection after solid organ transplantation has been rarely reported and most of the cases were renal transplant recipients. Few have been described after liver transplantation. Moreover, little information on the management of this easily recurring disease is available at present. We describe the first case of a Chinese liver transplant recipient with PVB19-induced PRCA during immunosuppressive therapy. The patient suffered from progressive anemia with the lowest hemoglobin level of 21 g/L. Bone marrow biopsy showed selectively inhibited erythropoiesis with giant pronormoblasts. Detection of PVB19-DNA in serum with quantitative polymerase chain reaction (PCR) revealed a high level of viral load. After 2 courses of intravenous immunoglobulin (IVIG) therapy, bone marrow erythropoiesis recovered with his hemoglobin level increased to 123 g/L. He had a low-level PVB19 load for a 5-mo follow-up period without recurrence of PRCA, and finally the virus was cleared. Our case indicates that clearance of PVB19 by IVIG in transplant recipients might be delayed after recovery of anemia.
• Human parvovirus B19 has been associated with various clinical effects in a number of uncontrolled reports. To define the usual manifestations of B19 infection in adults and the factors that influence them we present a clinicoepidemiological study of an outbreak of B19 infection centered on a junior school. Four hundred fifty-three of 475 adults in this community were interviewed and blood was obtained for serological diagnosis. Fifty-four cases of recent infection were identified and were HLA typed. Fourteen of the cases were asymptomatic; 32 had an influenzalike illness; 23 a rash; and 26 an acute-onset polyarthropathy that was more common in women and lasted for up to 7 months. HLA-A, -B, and -C antigen frequencies were similar to a local control population and showed no association with symptoms except that HLA-DR1 was absent in those with persistent arthropathy.
(Arch Intern Med. 1989;149:1153-1156)
• Parvovirus B19 is a recently described pathogen, associated with an increasing spectrum of clinical manifestations. We present the first reported case, to our knowledge, of parvovirus B19–associated hemophagocytic syndrome, in which the diagnosis of parvovirus infection was documented by the presence of B19-specific IgM and IgG antibodies. Pancytopenia resolved immediately following splenectomy and the patient recovered completely.
(Arch Intern Med. 1990;150:897-899)
Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
Simple and accurate diagnosis of vertical transmission of human parvovirus B19 (B19V) infection remains an important issue in pregnancy. There are few reports on quantitative analysis of B19V in amniotic fluids. Quantitative estimation of B19V DNA in amniotic fluids was comparerd with those in maternal or fetal serum obtained at an early stage of pregnancy with possible mother-to-fetus transmission. All pregnant women contracted B19V infection between 13 to 14 weeks gestation. The B19V DNA amount in 3 maternal serum and amniotic fluid sample pairs collected between 16 to 27 weeks gestation was quantified by a real-time polymerase chain reaction assay. Serum from 2 fetuses was included. The B19V DNA concentrations in maternal sera and amniotic fluids ranged from 104 to 105 copies/ml and from 107 to 108 copies/ml, respectively. The B19V DNA in the amniotic fluids concentration coincided with those of each fetal serum. The concentrations in amniotic fluids are 100 to 5,000 times higher than in those of maternal sera, and corresponded to the matching fetal serum. Amniotic fluids may substitute for the fetal sera in terms of quantitative estimation of fetal B19V infection at an early stage of pregnancy. J. Med. Virol. © 2015 Wiley Periodicals, Inc.
• The relationship between parvovirus B19 infection and classic rheumatoid arthritis remains to be determined. We describe two adult patients with serologically documented acute parvovirus B19 infection who presented with sudden onset of symmetric polyarthritis, skin eruption, and rheumatoid factor positivity. Rheumatoid factor positivity and symptoms resolved within five months. We conclude that a diagnosis of B19 arthropathy should be considered in any patient with recent acute or subacute onset of symmetric polyarthralgia or polyarthritis and rheumatoid factor positivity, which would otherwise suggest a diagnosis of early rheumatoid arthritis.
(Arch Intern Med 1988;148:2587-2589)
• An outbreak of erythema infectiosum (fifth disease) occurred in a North Carolina elementary school. Because rubella virus has been implicated as a possible cause of some cases of erythema infectiosum, we conducted an investigation to determine if the children were infected with rubella virus and to learn whether or not rubella vaccination prevents the disease. Throat swabs were obtained for viral isolation from 20 children with erythema infectiosum and from 25 healthy classmates; questionnaires were completed for 617 of the school's 817 students. One hundred fifty children (24%) reported having an acute exanthematous illness during the study period, and 45% of the ill children had one or more household contacts with a similar rash. No viruses were recovered from the children, and a history of rubella vaccination did not affect the risk of developing erythema infectiosum.
(Am J Dis Child 130:252-254, 1976)
Parvovirus B19 is the causative agent of fifth disease in children, aplastic crisis in those with blood dyscrasias, and hydrops fetalis. Previous parvovirus B19 virus-like-particle (VLP) vaccine candidates were produced by co-infection of insect cells with two baculoviruses, one expressing wild-type VP1 and the other expressing VP2. In humans, the VLPs were immunogenic but reactogenic. We have developed new VLP-based parvovirus B19 vaccine candidates, produced by co-expressing VP2 and either wild-type VP1 or phospholipase-negative VP1 in a regulated ratio from a single plasmid in Saccharomyces cerevisiae. These VLPs are expressed efficiently, are very homogeneous, and can be highly purified. Although VP2 alone can form VLPs, in mouse immunizations, VP1 and the adjuvant MF59 are required to elicit a neutralizing response. Wild-type VLPs and those with phospholipase-negative VP1 are equivalently potent. The purity, homogeneity, yeast origin, and lack of phospholipase activity of these VLPs address potential causes of previously observed reactogenicity.
Background:
It remains unclear whether idiopathic dilated cardiomyopathy (DCM) might ensue as the consequence of viral myocarditis, due to viral persistence in cardiomyocytes. To address this issue, we quantified the levels of enterovirus, Epstein-Barr virus (EBV), Herpes Simplex Virus-1 (HSV-1), Herpes Simplex Virus-2 (HSV-2), adenovirus and parvovirus B19 genomes in endomyocardial biopsies (EMBs) from patients with DCM, active myocarditis and controls.
Methods:
Real-time polymerase chain reaction (PCR)-based methods using TaqMan probes were developed for the quantitative detection of viral genomes in EMBs from 35 patients with DCM and 17 with active myocarditis. A control group included 20 surgical patients with valve or coronary artery disease.
Results:
None of the 72 samples tested positive for enteroviruses, EBV, HSV-1 or -2. One DCM patient tested positive for adenovirus. Of notice, 20/52 (38%) of patients with cardiomyopathy and 8/20 (40%) of controls were positive for parvovirus B19; no significant differences in viral titre were detected between groups.
Conclusions:
Our preliminary results disfavour the hypothesis that persistent myocardial viral infection might be a frequent cause of DCM. The detection of parvovirus B19 from both cardiomyopathy and non-cardiomyopathy patients supports the notion that this virus is widely spread in the population.
Human parvovirus B19 cannot be cultured in standard cell lines and relatively little is known about the intracellular life-cycle of the virus. In this study, ultrastructural features of B19 infection were examined using haemopoietic cell suspension cultures derived from human fetal liver. Erythroblasts from infected cultures frequently contained crystalline arrays of both full and empty virus-like particles. The number and size of these arrays increased with the duration of culture, and their location changed from exclusively nuclear at 24 h post-infection to both nuclear and cytoplasmic at 3 days post-infection. Arrays were occasionally found in cytoplasmic protuberances which appeared to be pinching off from the cell. The location of the arrays corresponded to the distribution of viral capsid protein determined by immunolabelling at the light microscope level. Cells containing viral crystalline arrays also exhibited nucleolar degeneration, extreme margination of the nuclear heterochromatin, and cytoplasmic vacuolation. These features are typical of cells undergoing individual programmed cell death or ‘apoptosis’. The triggering of apoptosis in erythroid precursors by parvovirus B19 may help to explain the apparent lack of a strong inflammatory response to fetal B19 infection and may have implications for understanding the mechanisms of viral spread throughout the host.
Hydrops fetalis was diagnosed at 22 weeks. An ultrasound examination demonstrated cardiomegaly and a fetal blood specimen obtained by cordocentesis revealed thrombocytopenia, anaemia, and neutropenia. Fetal paracentesis yielded straw-coloured fluid with electrolytes indicative of a transudate. Non-enveloped icosahedral viral particles approximately 23 mm in diameter were visualized in the ascitic fluid by electron microscopy. Immune electron microscopy confirmed human parvovirus B19. Direct fetal digitalization led to a reduction in umbilical artery resistance, a decline in the abdominal circumference from 20·3 to 17·8 cm, and resolution of the ascites within 72 h. Despite this dramatic response to therapy, fetal death occurred on day 5 of treatment. The initial maternal serum was positive for anti-B19 IgM and IgG antibodies. Electron microscopy of fetal cardiac tissue obtained post-mortem revealed intranuclear viral particles typical of B19, confirming the antenatal diagnosis of myocarditis. This case demonstrates that direct viral identification is applicable to prenatal diagnosis. To our knowledge, this is the first reported case of the antenatal diagnosis and palliative treatment of fetal viral infection.
Objective To estimate more precisely the risk of fetal loss and congenital abnormalities after maternal parvovirus B19 infection, and to assess the long term outcome for surviving infants.
Design Prospective cohort study of pregnant women with confirmed B19 infection with follow up of the surviving infants. The rate of fetal loss in the study cohort was compared with that in pregnant women with varicella.
Setting Cases reported by laboratories in England and Wales between 1985‐1988 and 1992–1995.
Sample Four hundred and twenty‐seven pregnant women with B19 infection and 367 surviving infants of whom 129 were followed up at 7–10 years of age.
Methods Questionnaires to obstetricians and general practitioners on outcome of pregnancy and health of surviving infants. Maternal infection confirmed by B19‐specific IgM assay and/or IgG seroconversion.
Results The excess rate of fetal loss in women with B19 infection was confined to the first 20 weeks of gestation and averaged 9%. Seven cases of fetal hydrops followed maternal infections between 9 and 20 weeks of gestation (observed risk 2.9%, 95% CI 1.2–5.9). No abnormalities attributable to B19 infection were found at birth in surviving infants (observed risk 0%, upper 95% CI 0.86%). No late effects were found at 7–10 years.
Conclusions Around 1 in 10 women infected before 20 weeks of gestation will suffer a fetal loss due to B19. The risk of an adverse outcome of pregnancy after this stage is remote. Infected women can be reassured that the maximum possible risk of a congenital abnormality due to B19 is under 1% and that long term development will be normal.
Recently identified human bocavirus (HBoV) types 2 and 3 have been associated with acute gastroenteritis in children. We studied 878 stool specimens from children with acute gastroenteritis and 112 controls (43 children with unspecified fever, 33 with respiratory tract infection and 36 healthy children) for known HBoVs. The same specimens were previously studied for rotaviruses, noroviruses, sapoviruses, adenoviruses, coronaviruses and aichivirus.
HBoVs were detected by PCR and positive amplicons were sequenced to identify HBoV1, HBoV2, HBoV3 and HBoV4.
HBoV of any type was found in 85 (9.7%) cases of acute gastroenteritis and in 6 (5.4%) controls. HBoV1 was detected in 49 (5.6%) cases and 2 (1.8%) controls, HBoV2 in 29 (3.3%) cases and 2 (1.8%) controls and HBoV3 in 8 (0.9%) cases and 2 (1.8%) controls. No HBoV4 was found. HBoV as a single infection was found in 16 (1.8%) cases and in 6 (5.4%) controls; in the remaining cases, a known gastroenteritis virus was also found. Among the single HBoV infections, HBoV2 was the most common type with 8 (50%) cases.
HBoVs are rarely found alone in children with acute gastroenteritis. Further studies are warranted to confirm a possible specific association of HBoV2 with gastroenteritis.