Human herpesvirus-6, HHV-8 and parvovirus B19 after allogeneic hematopoietic cell transplant: the lesser-known viral complications.

PURPOSE OF REVIEW: Viral infections continue to burden allogeneic hematopoietic cell transplant (HCT) recipients. We review the epidemiology, diagnosis, and management of human herpesvirus (HHV)-6, HHV-8 and parvovirus B19 following HCT. RECENT FINDINGS: Advances in HCT practices significantly improved outcomes but impact viral epidemiology: post-transplant cyclophosphamide for graft-versus-host disease prevention increases HHV-6 reactivation risk while the impact of letermovir for CMV prophylaxis - and resulting decrease in broad-spectrum antivirals - is more complex. Beyond the well established HHV-6 encephalitis, recent evidence implicates HHV-6 in pneumonitis. Novel less toxic therapeutic approaches (brincidofovir, virus-specific T-cells) may enable preventive strategies in the future. HHV-8 is the causal agent of Kaposi's sarcoma, which is only sporadically reported after HCT, but other manifestations are possible and not well elucidated. Parvovirus B19 can cause severe disease post-HCT, frequently manifesting with anemia, but can also be easily overlooked due to lack of routine screening and ambiguity of manifestations. SUMMARY: Studies should establish the contemporary epidemiology of HHV-6, and other more insidious viruses, such as HHV-8 and parvovirus B19 following HCT and should encompass novel cellular therapies. Standardized and readily available diagnostic methods are key to elucidate epidemiology and optimize preventive and therapeutic strategies to mitigate the burden of infection.

An unusual outbreak of parvovirus B19 infections, France, 2023 to 2024.

From April 2023 to May 2024, an unusual epidemic of parvovirus B19 (B19V) infections occurred in France. The number of B19V IgM-positive serologies was four times higher than in the previous epidemic in 2019. Clinical data from emergency networks corroborated this observation. Morbidity and mortality consequences were observed in children through all data sources. In adults, the increase was only observed in laboratory-confirmed data. Physicians and decisionmakers should be informed in order to better prevent, diagnose and manage at-risk patients.

New atypical epidemiological profile of parvovirus B19 revealed by molecular screening of blood donations, France, winter 2023/24.

In France, blood donations are tested in pools of 96 samples for parvovirus B19 (B19V) DNA to discard plasma for fractionation when it contains high viral loads. Between January 2015 and March 2024, B19V-positive donations decreased during the COVID-19 pandemic, followed by a strong rebound in 2023 and unusually high circulation during winter 2023/24 (ca 10 times higher December 2023-March 2024 vs the pre-pandemic period). Variations over time are probably related to measures implemented to limit SARS-CoV-2 spread.

Epidemic of parvovirus B19 and disease severity in pregnant people, Denmark, January to March 2024.

We report an epidemic of parvovirus B19 infections in Denmark during the first quarter of 2024, with a peak incidence 3.5 times higher than during the most recent epidemic in 2017. In total, 20.1% (130/648) of laboratory-confirmed cases were pregnant. Severe adverse outcomes were observed among 12.3% (16/130) of pregnant people and included foetal anaemia, foetal hydrops and miscarriage. Parvovirus B19 infection is not systematically monitored, but a national laboratory-based surveillance system is currently being established in Denmark.

Prevalence of Parvovirus B19 Viremia Among German Blood Donations and the Relationship to ABO and Rhesus Blood Group Antigens.

BACKGROUND: Asymptomatic blood donors can transmit human parvovirus B19 (B19V). METHODS: We assessed the B19V prevalence among a large cohort of blood donations collected in Germany during 2015-2018. RESULTS: In total, 167 123 donations were screened for B19V deoxyribonucleic acid with 22 cases of viremia identified (0.013% positive). Infections peaked at a 4-year interval and the highest number of cases occurred in the summer months. All 22 infections were found in rhesus D-antigen-positive donations, suggesting a protective factor in donors who lack this antigen. CONCLUSIONS: These findings contribute to our understanding of risk factors for B19V infection among central European blood and plasma donors.

Incidence and Impact of Parvovirus B19 Infection in Seronegative Solid Organ Transplant Recipients.

Routine monitoring of parvovirus B19 (B19V) the first 6 months posttransplantation was performed in 241 seronegative solid organ transplant (SOT) recipients. Incidence rates during the first month and the second to sixth months posttransplantation were 1.2 (95% confidence interval [CI], .33-3.2) and 0.21 (95% CI, .06-.57) per 100 recipients per month, respectively. Of the 6 SOT recipients with positive B19V polymerase chain reaction, 3 (50%) were admitted to hospital and 2 (33%) were treated with intravenous immunoglobulin. Thus, routine monitoring of B19V in seronegative SOT recipients may not be necessary. Targeted screening 1 month posttransplantation and screening upon clinical suspicion could be an alternative strategy.

Screening for parvovirus B19 antigen through chemiluminescent enzyme immunoassay is equivalent to B19 nucleic acid amplification test-based screening of pooled plasma.

BACKGROUND: Human parvovirus B19 (B19) is a pathogen that threatens the quality of plasma products. Therefore, health authorities have mandated measures against B19 contamination of plasma pools. The US FDA has recommended a B19 genome level of 104 IU/ml or lower in pooled plasma lots. Therefore, the B19 nucleic acid amplification test (B19-NAT) has been introduced in many plasma fractionators. However, in the Japanese Red Cross, which is the only approved blood collector in Japan, the B19 antigen test has been introduced for screening donated blood in Japan. Therefore, to clarify whether the antigen test is robust enough to screen blood samples according to the FDA recommendation, we evaluated B19 genome levels in each pooled plasma lot from 2003 to 2020. STUDY DESIGN AND METHODS: Data of 5576 pooled plasma lots from factories A and B, which were derived from plasma bags and passed the B19 antigen-based tests, receptor-mediated hemagglutination assay (B19-RHA), or chemiluminescent enzyme immunoassay (B19-CLEIA), during 2003 to 2020, were evaluated. The amount of B19 genome in each lot was determined using quantitative or semiquantitative B19-NAT. RESULTS: The B19 genome levels in pooled plasma lots screened using B19-RHA did not meet the FDA recommendation, whereas the lots derived from B19-CLEIA fulfilled the FDA recommendation, even during the B19 epidemic in Japan. DISCUSSION: The results suggest that the B19-CLEIA donor screening for plasma pools is also useful in light of the US FDA recommendation.

Presence of Parvovirus B19 but Not Herpesvirus Genome in Acute Skin Rash after Allogeneic Stem Cell Transplantation Correlates with Outcome.

INTRODUCTION: Skin rash is a first symptom of acute graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (ASCT) but can also be caused by viruses. The relevance of virus DNA analyses in skin rash for diagnosis and clinical outcome is unknown. OBJECTIVES: To record the frequencies of detection of herpes and parvovirus B19 (ParvoB19) DNA in skin rash within 100 days after ASCT and to analyze their relevance for diagnosis, clinical course, and non-relapse mortality (NRM). METHODS: We retrospectively identified 55 patients with virus DNA analysis for CMV, EBV, HHV6, HHV8, HSV, VZV, or ParvoB19. We assessed the rate of virus DNA detection and studied associations with histological diagnosis, virus DNA from concomitantly analyzed blood, clinical presentation, exanthema treatment, and NRM. RESULTS: CMV, EBV, HHV6, HHV8, HSV, VZV and ParvoB19 DNA were detected in 12.5, 11.8, 10, 0, 0, 2.9, and 26.7% of exanthemas. Histopathological diagnosis was not associated with virus polymerase chain reaction (PCR) results. Detection of CMV, EBV, or HHV6 DNA but not ParvoB19 in skin and blood was associated with PCR results (p = 0.016; p < 0.001; p = 0.067; p = n.a.). Detection of CMV, EBV, HHV6, or ParvoB19 DNA in the skin was not significantly associated with patient, ASCT, or GvHD characteristics. Detection of ParvoB19 but not herpes virus DNA was associated with less immunosuppressive treatment (p = 0.015) and lower NRM (p = 0.041). In multivariate analyses, detection of ParvoB19 was associated with a lower NRM. CONCLUSIONS: Detection of ParvoB19 DNA in exanthema after ASCT might be associated with lower NRM.

Detection of hepatitis C virus and parvovirus B19 in human plasma pools by nucleic-acid amplification techniques - Trends in results of EDQM proficiency testing studies from 2004 to 2018.

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has run proficiency testing schemes on the detection of viral contaminants in human plasma pools by nucleic-acid amplification techniques since 1999 for hepatitis C virus and since 2004 for parvovirus B19. A retrospective analysis was performed to assess their impact and identify trends and progress in the results obtained by participating laboratories over a 15-year span, from 2004 to 2018. The results demonstrate that overall performance improved over that time, especially among the regular participants. Participation in these proficiency testing schemes is therefore recommended for all interested control laboratories. This analysis also shows that hepatitis C virus detection now seems well established compared to that of parvovirus B19, which still appears more challenging.

Acute viral encephalitis associated with human parvovirus B19 infection: unexpectedly diagnosed by metagenomic next-generation sequencing.

We report here a case of a 17-year-old boy with viral encephalitis associated with human parvovirus B19 who presented consciousness disturbance, left hemiparesis, and focal neurologic signs. The diagnosis was based on the specific sequence reads corresponding to human parvovirus B19 (PVB19) in a CSF sample as analyzed by metagenomic next-generation sequencing (mNGS). Thus, PVB19 should be considered in the differential diagnosis of encephalitis and encephalopathy of unknown etiology. The introduction of mNGS into the diagnostic protocol of neuropathies, especially for those undiagnosed, could interrogate all genetic information in a biologic sample and facilitate the identification of the etiological agent.

Parvovirus B19 Myocarditis: Looking Beyond the Heart.

Human parvovirus B19 represents the most common etiology of myocarditis in the pediatric population. Although it usually causes a benign exanthematic viral infection, parvovirus B19 may also present as disseminated disease with tropism for the myocardium, causing heart failure with high mortality. We present the case of a 2-year-old patient with fulminating acute myocarditis in whom the histological, immunophenotypic, and microbiological findings in necropsy showed multiorgan involvement caused by parvovirus B19. The autopsy revealed changes due to infection with parvovirus B19 as well as hypoxic-ischemic and secondary autoimmune changes. Medullary aplasia was observed, transmural lymphocyte myocarditis, lymphocytosis in the dermis with endothelial cells positive for parvovirus B19 in immunohistochemistry, cholestatic hepatitis due to ischemia and autoimmune hepatitis, lymphadenitis, and signs of hemophagocytosis. We also found hypoxic-ischemic encephalopathy.

Identification and management of congenital parvovirus B19 infection.

Parvovirus B19 (B19V) infection is well known for its mild, self-limiting clinical presentations in children, such as erythema infectiosum. Approximately 40% of women of childbearing age are susceptible to B19V infection. While maternal B19V infection usually has a good prognosis, B19V can cause severe fetal anaemia and pregnancy loss due to its ability to suppress erythroid progenitor cells. Non-invasive ultrasound monitoring for fetal anaemia is usually performed if maternal seroconversion occurs in the first 20 weeks of gestation, with amniocentesis for fetal infection reserved for those who first present with fetal anaemia or hydrops of unknown cause. Intrauterine transfusion is the standard treatment for severe fetal anaemia and is associated with a significant improvement in survival. However, survivors of hydrops fetalis may have a higher rate of long-term neurodevelopmental complications compared with non-hydropic survivors. This review aims to synthesise published data on the diagnosis, surveillance and outcomes of congenital parvovirus infection to assist clinicians in diagnosing and managing this important condition.

Parvovirus B19 DNAemia in pregnant women in relation to perinatal death: A nested case-control study within a large population-based pregnancy cohort.

INTRODUCTION: Parvovirus B19 (B19V) is the infectious cause of exanthema infectiosum. In Europe around 40% of pregnant women are susceptible to infection. Having small children at home is the main risk factor for contracting an infection during pregnancy. The association between B19V-infection and perinatal death is not yet settled. The aims of the study were to estimate the association between maternal parvovirus B19 infection in pregnancy and perinatal death, and to assess the significance of a positive B19V PCR in pregnancy. MATERIAL AND METHODS: The study population consists of women included in the Norwegian Mother and Child Cohort Study, a prospective population-based pregnancy cohort of nearly 100 000 women. Blood samples were obtained during weeks 17-18 in pregnancy (M1), at birth, and in umbilical cord blood. Within participants in the pregnancy cohort, 138 cases of perinatal death and 1350 controls with live-born children were included in a nested case-control study. Samples were analyzed with B19V serology and B19V PCR according to a predefined test algorithm. For cases, medical records and laboratory results from hospitals were combined with the results of B19V serology and PCR. The reported causes of perinatal death were categorized using the classification system: Causes Of Death and Associated Conditions (CODAC). RESULTS: The B19V seroconversion rates were 9.8% for cases and 6.8% for control mothers. The odds ratio for maternal B19V infection in cases compared with controls was 1.28 (95% CI 0.35-4.70), adjusted for age, parity, body mass index and tobacco use. B19V-PCR-positive samples were detected at weeks 17-18 of gestation in both cases and controls. The proportion of positive samples was similar in cases and controls, 24% and 28.2%, respectively. Mothers with PCR-positive M1 samples transmitted B19V vertically in 9.1% of cases and in 11.9% of the controls. Of all perinatal deaths, 53% were attributed to placental pathology or unknown causes. CONCLUSIONS: B19V PCR positivity was high and similar in both cases and controls. In our study B19V DNAemia was not seen to be associated with fatal outcome of pregnancy. The clinical significance of B19V DNA detection during pregnancy is uncertain. Caution is needed when diagnosing a B19V infection based only on B19V DNAemia.

Identification of human parvovirus B19 among measles and rubella suspected patients from Cuba.

Between September 2014 and December 2015, 298 sera from rash and fever patients from all over Cuba were investigated for specific IgM antibodies against measles, rubella, dengue, human parvovirus B19 (B19V) and human herpesvirus 6 (HHV6) using a commercial enzyme-linked immunosorbent assay kits. B19V IgM positive and equivocal samples were investigated by a polymerase chain reaction and genotyping. No measles, rubella or dengue cases were detected. HHV6-IgM antibodies were confirmed in 5.7% and B19V-IgM antibodies in 10.7% of the patients. A total of 31.3% of the B19V cases were between 5 and 9 years old and 34.4% were 20 years and older. The only B19V sequence obtained belonged to genotype 1a. Diagnosis was established for only 16% of the rash and fever patients, suggesting that other diseases such as Zika or Chikungunya may play a role.

Parvovirus B19 seroprevalence, viral load, and genotype characterization in volunteer blood donors from southern Brazil.

Usually transmitted via respiratory droplets, parvovirus B19 (B19V) can also be acquired by blood transfusion especially because of viral persistence, resistance to blood treatment procedures, and high viral load during the early infection phase. This is particularly problematic in immunocompromised or anemic patients where the infection can have a severe outcome. As B19V DNA was detected in blood donations from South Brazil during a viral metagenomic survey performed by Next-Generation Sequencing, the objective of this retrospective study was to evaluate the seroprevalence, B19V DNA presence and circulating genotypes in a Hospital Blood Transfusion Service in Santa Maria city in South Brazil (Rio Grande do Sul state). Among 480 volunteer blood donors, 53.9% (n = 258 of 479) were anti-B19V IgG-positive, and 9 (1.9%) plasma samples presented B19V DNA. In almost all cases (n = 7 of 9, 77.8%), B19V DNA load was accompanied by the presence of anti-B19V IgG suggesting a persistent infection. The sequencing of the strains demonstrated that all belong to genotype 1 which is the most prevalent worldwide. The analysis of the recipient information of the positive for B19V DNA units revealed no related posttransfusion adverse effects. Our results demonstrate for the first time, B19V seroprevalence, viral load, and genotypes among blood donors from South Brazil and give a light for the circulation and impact of this B19V in this part of the country.

Parvovirus B19 in South African blood donors.

BACKGROUND: Parvovirus B19 (PVB19) is transmitted via transfusion of blood and blood products. PVB19 is resistant to viral inactivation methods, which poses a threat to blood safety. We investigated the prevalence of PVB19 antibodies and DNA in healthy blood donors from the South African National Blood Bank Service to evaluate the necessity of PVB19 DNA testing. STUDY DESIGN AND METHOD: A retrospective analysis of 1500 residual plasma specimens from healthy blood donors from the SANBS repository were screened in mini-pools of 20 for PVB19 DNA using a quantitative polymerase chain reaction (PCR). Positive pools were resolved by individual viral load testing and screened for PVB19 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to correlate viral loads with serological status. PVB19 IgG prevalence was determined by testing 90 randomly selected specimens from the 1500 plasma specimens. RESULTS: The prevalence of PVB19 IgG, IgM and IgG, and DNA was 62.2%, 0.06%, and 0.9%, respectively. Fourteen of the 1500 blood donor specimens received, had detectable PVB19 viral loads. Nine of the fourteen donors with detectable viral loads were PVB19 IgG seropositive. The PVB19 viral loads ranged from 1.81 to 5.32 log IU/mL. Four of the fourteen viraemic donors had a viraemia >10 4 IU/mL. CONCLUSION: We have demonstrated a low prevalence of PVB19 DNA in SANBS blood donors. The predominance of low-level viraemia and the presence of PVB19 antibodies, suggests that the risk of transfusion transmission of PVB19 among SANBS donors may be relatively low.

Parvovirus B19 in Endomyocardial Biopsy of Patients With Idiopathic Dilated Cardiomyopathy: Foe or Bystander?

BACKGROUND: Parvovirus B19 (PVB19) has emerged as one of the viruses possibly inducing chronic myocarditis and subsequent idiopathic dilated cardiomyopathy (IDCM). The aim of this work was to investigate the presence and long-term consequences of PVB19-DNA within myocardial biopsies from patients with IDCM and to compare the findings with those from donor hearts (control group). METHODS AND RESULTS: Forty hospitalized IDCM patients (age 47 ± 12 y) with mean left ventricular ejection fraction 27 ± 12% were included. The presence of PVB19-DNA in myocardial biopsies and of IgG and IgM antibodies in patient sera was analyzed. The control group consisted of 20 donor hearts. The follow-up time was 112 ± 57 months. PVB19-DNA was found in myocardial biopsies of both patients (73%) and control samples (55%; P = .25).Three deaths and 8 heart transplantations occurred in the IDCM group, and 6 deaths in the control group (ie, the recipients of the control hearts). No difference in transplantation-free survival between the PVB19-DNA positive/negative IDCM patients or transplant recipients was found. CONCLUSIONS: PVB19-DNA is a common finding in both patients with IDCM and in healthy donor hearts, not affecting prognosis. These findings support the view that PVB19 is an innocent bystander, frequently found in myocardium with low DNA copies, and not a plausible cause of IDCM.

Genetic diversity of primate erythroparvovirus 1 between 2009 and 2016: First report from Turkey.

Parvovirus B19 (B19V) is one of the major viral pathogens that infect only human beings. This study's aim is to determine which genotypes of the B19V are present in Turkey and to perform a phylogenetic analysis. Twelve B19V positive serum specimens already diagnosed by real-time PCR amplifying a partial region of the NS gene were included in this study. The serological markers and viral loads of the patients were determined. The positivity of the specimens was confirmed using semi-nested PCR. To determine the genotype of the B19V, PCR-positive amplicons were sequenced directly and compared to GenBank-referenced strain sequences. The phylogeny of the 12 sequenced strains was constructed with the maximum likelihood method. Two different genotypes of B19V were identified in our study. Genotype 2 of B19V was not detected. All of the B19V genotype 1 sequences were clustered in the common genotype 1a cluster (10/12, 83.3%). The average quantification of the B19V strains was determined to be 2.1 × 107 IU/ml. The nucleotide identities between our strains and those isolated in other countries were 85.8%-99.5%. Compared to the Turkish strains identified in our study, at the nucleotide level, the closest strains based on genotypes 3b and 1a were the Germany and Netherlands isolates respectively. This study was the first to provide the genotypic variation of B19V circulated in Turkey. We determined two distinct subtypes of B19V, including subtype 3b and 1a. While the genotype 1 is common all over the world, genotype 3 has begun to spread outside of Africa.

Human parvovirus B19 in solid organ transplantation: Guidelines from the American society of transplantation infectious diseases community of practice.

Clinical manifestations of human parvovirus B19 infection can vary widely and may be atypical in solid organ transplant (SOT) recipients. However, disease is apparent when there is destruction of erythrocyte progenitor cells leading to severe acute or chronic anemia with lack of an appropriate reticulocyte response in the setting of active parvovirus B19 infection. Serology may not reliably establish the diagnosis. High-level viremia is more likely to be associated with symptomatic disease. Conversely, ongoing DNAemia after infection may not be clinically significant, if detected at low levels. Despite lack of robust data, intravenous immunoglobulin (IVIG) is frequently used for the treatment of SOT recipients with symptomatic parvovirus B19 infection. Although the optimal dosage and duration of IVIG is not known, most patients receive a total of 2 g/kg over a period of 2-5 days. A daily dose of 1 g/kg or more seems to be associated with higher incidence of toxicity. Application of standard and droplet isolation precautions remains the cornerstone for preventing human parvovirus B19 transmission. Additional research is needed to assess the efficacy of current and novel therapies and to develop a safe and effective parvovirus B19 vaccine.