Maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and the impact of HIV status:a cross-sectional study in Namibia

Background & Aims: Namibia has been suffering from an outbreak of hepatitis E genotype 2 since 2017. As nearly half of hepatitis E-related deaths were among pregnant and postpartum women, we analysed maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and assessed whether HIV-status impacted on outcome. Methods: A retrospective cross-sectional study was performed at Windhoek Hospital Complex. Pregnant and postpartum women, admitted between 13 October 2017 and 31 May 2019 with reactive IgM for Hepatitis E, were included. Outcomes were acute liver failure (ALF), maternal death, miscarriage, intra-uterine fetal death and neonatal death. Odds ratios (OR) and 95% confidence interval (CI) were calculated. Results: Seventy women were included. ALF occurred in 28 (40.0%) of whom 13 died amounting to a case fatality rate of 18.6%. Sixteen women (22.9%) were HIV infected, compared to 16.8% among the general pregnant population (OR 1.47, 95% CI 0.84-2.57, P =.17). ALF occurred in 4/5 (80%) HIV infected women not adherent to antiretroviral therapy compared to 1/8 (12.5%) women adherent to antiretroviral therapy (OR 28.0, 95% CI 1.4-580.6). There were 10 miscarriages (14.3%), five intra-uterine fetal deaths (7.1%) and four neonatal deaths (5.7%). Conclusions: One in five pregnant women with Hepatitis E genotype 2 died, which is comparable to genotype 1 outbreaks. Despite small numbers, HIV infected women receiving antiretroviral therapy appear to be less likely to develop ALF in contrast with HIV infected women not on treatment. As there is currently no curative treatment, this phenomenon needs to be assessed in larger cohorts

Licit and illicit substance use patterns among university students in Germany using cluster analysis

Schilling L, Zeeb H, Pischke C, et al. Licit and illicit substance use patterns among university students in Germany using cluster analysis. SUBSTANCE ABUSE TREATMENT PREVENTION AND POLICY. 2017;12(1): 44.The use of multiple licit and illicit substances plays an important role in many university students' lives. Previous research on multiple substance use patterns of university students, however, often fails to examine use of different illicit substances and/or hookah. Our objective was to complement and advance the current knowledge about common consumption patterns regarding illicit substances and hookah use in this group. Students from eight German universities completed an online survey as part of the INSIST study ('INternet-based Social norms Intervention for the prevention of substance use among STudents') regarding their consumption of alcohol, tobacco, hookah, cannabis and other illicit substances. Cluster analysis identified distinct consumption patterns of concurrent and non-concurrent substance use and multinomial logistic regressions described key sociodemographic factors associated with these clusters. Six homogeneous groups were identified: 'Alcohol Abstainers' (10.8%), 'Drinkers Only' (48.2%), 'Drinkers and Cigarette Smokers' (14.6%), 'Cannabis and Licit Substance Users' (11.2%), 'Hookah Users with Co-Use' (9.8%) and 'Illicit Substance Users with Co-Use' (5.4%). Illicit substance use clustered with the consumption of alcohol, tobacco and cannabis. Hookah use was regularly associated with alcohol consumption, less commonly associated with tobacco or cannabis use and very rarely associated with use of other illicit substances. Individuals consuming licit and illicit substances or hookah were mostly male and lived together with other students. Characteristics such as the number of years an individual had spent studying at a university, subject of study, immigrant background and religious affiliation were less commonly associated with cluster membership. Although we found substance use patterns in our sample largely similar to previous reports, we identified an important subgroup of individuals using both illicit and licit substances. These individuals may benefit especially from targeted interventions that focus on modifying addictive behavior patterns

Moderating or mediating effects of family characteristics on socioeconomic inequalities in child health in high-income countries – a scoping review

Background: By explaining the development of health inequalities, eco-social theories highlight the importance of social environments that children are embedded in. The most important environment during early childhood is the family, as it profoundly influences children’s health through various characteristics. These include family processes, family structure/size, and living conditions, and are closely linked to the socioeconomic position (SEP) of the family. Although it is known that the SEP contributes to health inequalities in early childhood, the effects of family characteristics on health inequalities remain unclear. The objective of this scoping review is to synthesise existing research on the mediating and moderating effects of family characteristics on socioeconomic health inequalities (HI) during early childhood in high-income countries. Methods: This review followed the methodology of “Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews”. To identify German and English scientific peer-reviewed literature published from January 1st, 2000, to December 19th, 2019, the following search term blocks were linked with the logical operator “AND”: (1) family structure/size, processes, living conditions, (2) inequalities, disparities, diversities, (3) income, education, occupation, (4) health and (5) young children. The search covered the electronic databases PubMed, PsycINFO, and Scopus. Results: The search yielded 7,089 records. After title/abstract and full-text screening, only ten peer-reviewed articles were included in the synthesis, which analysed the effects of family characteristics on HI in early childhood. Family processes (i.e., rules /descriptive norms, stress, parental screen time, parent–child conflicts) are identified to have mediating or moderating effects. While families’ living conditions (i.e., TVs in children’s bedrooms) are suggested as mediating factors, family structure/size (i.e., single parenthood, number of children in the household) appear to moderate health inequalities. Conclusion: Family characteristics contribute to health inequalities in early childhood. The results provide overall support of models of family stress and family investment. However, knowledge gaps remain regarding the role of family health literacy, regarding a wide range of children’s health outcomes (e.g., oral health, inflammation parameters, weight, and height), and the development of health inequalities over the life course starting at birth.Peer Reviewe

Absence of chronic hepatitis E in a German cohort of common variable immunodeficiency patients

Cases of chronic or prolonged hepatitis E virus (HEV) infections have been described in solid organ transplant recipients, HIV infected patients and in patients with malignancies or idiopathic CD4+ T lymphopenia. It is unknown if HEV infection also takes chronic courses in patients with common variable immunodeficiency (CVID). We studied a cohort of 73 CVID patients recruited in a low endemic Central European country. None of the subjects tested positive for HEV RNA or anti-HEV IgG. Immunoglobulin transfusions (n=10) tested negative for HEV RNA but all were anti-HEV positive. To verify that such pooled blood products contain anti-HEV protective antibodies we measured the anti-HEV IgG optical density (OD) values in patients before and after transfusion. Anti-HEV OD values increased after infusion but did not reach the cut-off considered as positive. Thus, chronic HEV infections seem to be rare events in CVID patients in Germany. Commercially available immuno globulin infusions contain anti HEV antibodies and may contribute to protection from HEV infectio

Clinical features of hepatitis E infections in patients with hematologic disorders

Hepatitis E virus is increasingly being reported to cause chronic infection in immunocompromised patients. However, less is known about patients with an underlying hematologic disease. In particular, the impact of hepatitis E infection on oncological therapy has been poorly described. In this retrospective single-center study, we analyzed 35 hematologic patients with hepatitis E, including 20 patients under active oncological treatment and 15 patients who were in the posttreatment follow-up or under active surveillance. The primary aim was to describe the clinical courses with particular focus on any hepatitis E-related therapy modifications of cancer-directed therapy. In the majority (60%) of patients who were under active oncological treatment, hepatitis E-related therapy modifications were made, and 25% of deaths were due to progression of the hematologic disease. In patients receiving concomitant oncological treatment, no hepatitis Erelated deaths occurred. In contrast, two patients in the follow-up group died from hepatitis E-associated acute-onchronic liver failure. Chronic hepatitis E was observed in 34% of all cases and 43% received ribavirin therapy; of those, 27% achieved a sustained virological response. CD20-directed therapy was the only independent risk factor for developing chronic hepatitis E. We conclude that CD20-directed treatment at any time point is a risk factor for developing chronic hepatitis E. Nevertheless, since mortality from the progression of hematologic disease was higher than hepatitis E-related mortality, we suggest careful case-by-case decisions on modifications of cancer treatment. Patients in the posttreatment follow-up phase may also suffer from severe courses and hepatitis E chronicity occurs as frequently as in patients undergoing active therapy

Proof of infectivity of hepatitis E virus particles from the ejaculate of chronically infected patients

Recently, hepatitis E virus (HEV, Paslahepevirus balayani) particles were detected for the first time in the ejaculate of two chronically infected patients. Since then, we have been able to detect HEV in ejaculate in five further patients, and thus in a total of seven out of nine (78%) chronically infected men (age 36–67 years, median 56 years). In five patients, the HEV RNA concentration was more than 100-fold higher compared to the serum, while in two patients, the viral load was more than 10-fold lower. However, it has remained unclear whether viral particles shed in the ejaculate were infectious, as a previous cell culture model had failed to demonstrate the infectivity. In the current study, we employed an optimized HEV cell culture system based on overconfluent PLC/PRF/5 cells to investigate the infectivity of HEV particles from ejaculate and other body fluids. With this approach, we were able to show for the first time that HEV particles in the ejaculate from several patients were infectious. HEV replicated to high viral loads of 1e9 HEV RNA copies per ml. This indicates that HEV-positive ejaculate could bear a risk of infection for sexual partners

Clinical phenotype and outcome of hepatitis E virus - associated neuralgic amyotrophy

Objective: To determine the clinical phenotype and outcome in hepatitis E virus–associated neuralgic amyotrophy (HEV-NA). Methods: Cases of NA were identified in 11 centers from 7 European countries, with retrospective analysis of demographics, clinical/laboratory findings, and treatment and outcome. Cases of HEV-NA were compared with NA cases without evidence of HEV infection. Results: Fifty-seven cases of HEV-NA and 61 NA cases without HEV were studied. Fifty-six of 57 HEV-NA cases were anti-HEV IgM positive; 53/57 were IgG positive. In 38 cases, HEV RNA was recovered from the serum and in 1 from the CSF (all genotype 3). Fifty-one of 57 HEV-NA cases were anicteric; median alanine aminotransferase 259 IU/L (range 12–2,961 IU/L); in 6 cases, liver function tests were normal. HEV-NA cases were more likely to have bilateral involvement (80.0% vs 8.6%, p < 0.001), damage outside the brachial plexus (58.5% vs 10.5%, p < 0.01), including phrenic nerve and lumbosacral plexus injury (25.0% vs 3.5%, p = 0.01, and 26.4% vs 7.0%, p = 0.001), reduced reflexes (p = 0.03), sensory symptoms (p = 0.04) with more extensive damage to the brachial plexus. There was no difference in outcome between the 2 groups at 12 months. Conclusions: Patients with HEV-NA are usually anicteric and have a distinct clinical phenotype, with predominately bilateral asymmetrical involvement of, and more extensive damage to, the brachial plexus. Involvement outside the brachial plexus is more common in HEV-NA. The relationship between HEV and NA is likely to be causal, but is easily overlooked. Patients presenting with NA should be tested for HEV, irrespective of liver function test results. Prospective treatment/outcome studies of HEV-NA are warranted

Mechanisms of CD8+ T cell failure in chronic hepatitis E virus infection

Background and aims In immunosuppressed patients, persistent hepatitis E virus (HEV) infection is common and may lead to cirrhosis and liver failure. HEV clearance depends on an effective virus-specific CD8+ T cell response, however, the knowledge gap of HEV-specific CD8+ T cell epitopes hindered analysis of the mechanisms of T cell failure in persistent infection thus far. Methods We comprehensively studied HEV-specific CD8+ T cell responses in 46 patients with self-limiting (n=34) or chronic HEV infection (n=12), by epitope-specific expansion, functional testing, ex vivo peptide HLA class I tetramer multi-parametric staining, and viral sequence analysis. Results We identified 25 HEV-specific CD8+ T cell epitopes restricted by 9 different HLA class I alleles. In self-limiting HEV infection, HEV-specific CD8+ T cells were vigorous, contracted after resolution of infection, and formed functional memory responses. In contrast, in chronic infection, the HEV-specific CD8+ T cell response was diminished, declined over time, and displayed phenotypic features of exhaustion. However, improved proliferation and interferon-γ production of HEV-specific CD8+ T cells and evolution of a memory-like phenotype was observed upon reduction of immunosuppression and/or ribavirin treatment and was associated with viral clearance. In one patient, mutational viral escape in a targeted CD8+ T cell epitope contributed to CD8+ T cell failure. Conclusion Chronic HEV infection is associated with HEV-specific CD8+ T cell exhaustion, indicating that T cell exhaustion driven by persisting antigen recognition also occurs in severely immunosuppressed hosts. Functional reinvigoration of virus-specific T cells is at least partially possible when antigen is cleared. In a minority of patients, viral escape also contributes to HEV-specific CD8+ T cell failure and thus needs to be taken into account in personalized immunotherapeutic approaches. Lay Summary In immunosuppressed patients, chronic HEV infection is common. For resolution of infection a functional HEV-specific CD8+ T cell response is essential, however, in immunosuppressed individuals CD8+ T cell exhaustion and viral escape contribute to CD8+ T cell failure