Abstract Hepatitis E virus (HEV) infections are not limited to the liver but may also affect other organs. Several diseases, including Guillain-Barré syndrome, neuralgic amyotrophy, ...glomerulonephritis, cryoglobulinemia, pancreatitis, lymphoma, thrombopenia, meningitis, thyreoiditis and myocarditis have been observed in the context of hepatitis E. To date the definite pathophysiological links between HEV and extrahepatic manifestations are not yet established. However, it is suggested that HEV-infection might be causative based on serological studies, case series, in vitro data and animal models. In particular neuronal and renal diseases as well as pancreatitis seem to be caused by HEV, while a causative relationship between HEV and other diseases is more doubtful. Either direct cytopathic tissue damage by extrahepatic replication or immunological processes induced by an overwhelming host immune response are possible origins of HEV-associated extrahepatic manifestations. Hepatologists should be aware of the possibility of acute or chronically HEV-infected patients to develop extrahepatic manifestations while neurologists, nephrologists, rheumatologists and other groups of physicians should consider HEV-infection as a potential differential diagnosis when observing one of the hereby described diseases. Ribavirin and steroids have been used in small groups of patients with extrahepatic manifestations, but the efficacy of these drugs still needs to be verified by large, multicenter studies. This article comprehensively reviews the published literature regarding HEV and extrahepatic manifestations and discusses the probability of specific extrahepatic diseases to be caused by previous or ongoing HEV-infection and summarizes the published knowledge about antiviral treatment in extrahepatic disorders.
The aim of the study was to determine whether Guillain-Barré syndrome (GBS) is associated with preceding hepatitis E virus infection.
The frequency of hepatitis E virus (HEV) infections was ...determined by anti-HEV serology in a cohort of 201 patients with GBS and 201 healthy controls with a similar distribution in age, sex, and year of sampling. Blood samples from patients with GBS were obtained in the acute phase before treatment. In a subgroup of patients with GBS, blood, stool, and CSF samples were tested for HEV RNA.
An increased ratio of anti-HEV immunoglobulin (Ig) M antibodies was found in 10 patients with GBS (5.0%) compared with 1 healthy control (0.5%, odds ratio 10.5, 95% confidence interval 1.3-82.6, p = 0.026). HEV RNA was detected in blood from 3 of these patients and additionally in feces from 1 patient. Seventy percent of anti-HEV IgM-positive patients had mildly increased liver function tests. All CSF samples tested negative for HEV RNA. The presence of anti-HEV IgM in patients with GBS was not related to age, sex, disease severity, or clinical outcome after 6 months.
In the Netherlands, 5% of patients with GBS have an associated acute HEV infection. Further research is required to determine whether HEV infections also precede GBS in other geographical areas.
Genotype 3 (gt3) hepatitis E virus (HEV) infections are emerging in Western countries. Immunosuppressed patients are at risk of chronic HEV infection and progressive liver damage, but no adequate ...model system currently mimics this disease course. Here we explore the possibilities of in vivo HEV studies in a human liver chimeric mouse model (uPA(+/+)Nod-SCID-IL2Rγ(-/-)) next to the A549 cell culture system, using HEV RNA-positive EDTA-plasma, feces, or liver biopsy specimens from 8 immunocompromised patients with chronic gt3 HEV. HEV from feces- or liver-derived inocula showed clear virus propagation within 2 weeks after inoculation onto A549 cells, compared to slow or no HEV propagation of HEV RNA-positive, EDTA-plasma samples. These in vitro HEV infectivity differences were mirrored in human-liver chimeric mice after intravenous (i.v.) inoculation of selected samples. HEV RNA levels of up to 8 log IU HEV RNA/gram were consistently present in 100% of chimeric mouse livers from week 2 to week 14 after inoculation with human feces- or liver-derived HEV. Feces and bile of infected mice contained moderate to large amounts of HEV RNA, while HEV viremia was low and inconsistently detected. Mouse-passaged HEV could subsequently be propagated for up to 100 days in vitro In contrast, cell culture-derived or seronegative EDTA-plasma-derived HEV was not infectious in inoculated animals. In conclusion, the infectivity of feces-derived human HEV is higher than that of EDTA-plasma-derived HEV both in vitro and in vivo Persistent HEV gt3 infections in chimeric mice show preferential viral shedding toward mouse bile and feces, paralleling the course of infection in humans.
Hepatitis E virus (HEV) genotype 3 infections are emerging in Western countries and are of great concern for immunosuppressed patients at risk for developing chronic HEV infection. Lack of adequate model systems for chronic HEV infection hampers studies on HEV infectivity and transmission and antiviral drugs. We compared the in vivo infectivity of clinical samples from chronic HEV patients in human liver chimeric mice to an in vitro virus culture system. Efficient in vivo HEV infection is observed after inoculation with feces- and liver-derived HEV but not with HEV RNA-containing plasma or cell culture supernatant. HEV in chimeric mice is preferentially shed toward bile and feces, mimicking the HEV infection course in humans. The observed in vivo infectivity differences may be relevant for the epidemiology of HEV in humans. This novel small-animal model therefore offers new avenues to unravel HEV's pathobiology.
This study aimed to explore the loneliness of several groups of older immigrants in Canada compared to native-born older adults. Data from the Canadian General Social Survey, Cycle 22 (N older adults ...= 3,692) were used. The dependent variable is the 6 item De Jong Gierveld loneliness scale. Determinants of loneliness included country of birth, ethnic background (cultural context); belongingness (community context) and social networks (social context). Results showed that only some immigrant groups are significantly lonelier than older adults born in Canada. Immigrants with similar language and culture are not lonelier; while those from countries that differ in native language/culture are significantly higher on loneliness. Multivariate analyses showed the importance of cultural background, of composition of the network of relatives and friends, and of local participation and feelings of belonging to the Canadian society in explaining loneliness of older immigrants.
Miscarriage Associated with Zika Virus Infection van der Eijk, Annemiek A; van Genderen, Perry J; Verdijk, Rob M ...
The New England journal of medicine,
2016-Sep-08, Letnik:
375, Številka:
10
Journal Article
Abstract Background Hepatitis E virus (HEV) genotype 3 is recognised as an emerging pathogen in industrialised countries. The currently commercially available HEV-specific enzyme linked immunosorbent ...assays (ELISAs) are primarily designed for the detection of antibodies against genotypes 1 (Burma) and 2 (Mexico) and may not sensitively detect HEV genotypes 3 or 4. Objectives This study aimed to evaluate the analytical and clinical performances of eight commercially available HEV serum antibody immunoglobulin M (IgM)- and immunoglobulin G (IgG)-specific ELISAs for genotype 1 and 3 HEV infections in a clinical setting and to study the antibody responses against HEV of immunocompromised versus immunocompetent patient groups. Study design Analytical performance and diagnostic sensitivity and specificity were assessed using well-defined reference samples and samples from patients with polymerase chain reaction (PCR)-confirmed HEV infection ( n = 88) and a specificity panel ( n = 98). Results Limiting dilutions indicated that the highest analytical sensitivity in head-to-head comparison was measured for the Mikrogen_new IgG assay. Taking the serum working dilutions of each assay into account, the Wantai IgG assay was the most sensitive assay. Receiver operator curve (ROC) analysis showed area under the curve (AUC) values of 0.943, 0.964, 0.969, 0.971, 0.974 and 0.994 for the DSI, Mikrogen_old, MP Diagnostics, Mikrogen_new, Wantai and DiaPro anti-HEV IgM assays, respectively. The highest specificity of currently available assays was found for the IgM Wantai assay (>99%). If anti-HEV IgM and IgG results from each supplier were combined, DSI and Wantai assays were able to detect the highest number of (passed) HEV infections. Conclusions Our study showed that current commercial HEV ELISAs could be used to diagnose HEV genotype 3 infection adequately in a clinical setting.
A high genetic barrier to resistance to the integrase strand transfer inhibitor (INSTI) dolutegravir has been reported in vitro and in vivo. We describe the dynamics of INSTI resistance-associated ...mutations (INSTI-RAMs) and mutations in the 3'-polypurine tract (3'-PPT) in relation to virologic failure (VF) observed in the randomized Dolutegravir as Maintenance Monotherapy for HIV-1 study (DOMONO, NCT02401828).
From 10 patients with VF, plasma samples were collected before the start of cART and during VF, and were used to generate Sanger sequences of integrase, the 5' terminal bases of the 3' long terminal repeat (LTR), and the 3'-PPT.
Median human immunodeficiency virus RNA load at VF was 3490 copies/mL (interquartile range 1440-4990 copies/mL). INSTI-RAMs (S230R, R263K, N155H, and E92Q+N155H) were detected in 4 patients, no INSTI-RAMs were detected in 4 patients, and sequencing of the integrase gene was unsuccessful in 2 patients. The time to VF ranged from 4 weeks to 72 weeks. In 1 patient, mutations developed in the highly conserved 3'-PPT. No changes in the terminal bases of the 3'-LTR were observed.
The genetic barrier to resistance is too low to justify dolutegravir maintenance monotherapy because single INSTI-RAMs are sufficient to cause VF. The large variation in time to VF suggests that stochastic reactivation of a preexisting provirus containing a single INSTI-RAM is the mechanism for failure. Changes in the 3'-PPT point to a new dolutegravir resistance mechanism in vivo.
NCT02401828.
Efficient detection of human respiratory viral pathogens is crucial in the management of patients with acute respiratory tract infection. Sequence-independent amplification of nucleic acids combined ...with next-generation sequencing technology and bioinformatics analyses is a promising strategy for identifying pathogens in clinical and public health settings. It allows the characterization of hundreds of different known pathogens simultaneously and of novel pathogens that elude conventional testing. However, major hurdles for its routine use exist, including cost, turnaround time, and especially sensitivity of the assay, as the detection limit is dependent on viral load, host genetic material, and sequencing depth. To obtain insights into these aspects, we analyzed nasopharyngeal aspirates from a cohort of 81 Thai children with respiratory disease for the presence of respiratory viruses using a sequence-independent next-generation sequencing approach and routinely used diagnostic real-time reverse transcriptase PCR (real-time RT-PCR) assays. With respect to the detection of rhinovirus and human metapneumovirus, the next-generation sequencing approach was at least as sensitive as diagnostic real-time RT-PCR in this small cohort, whereas for bocavirus and enterovirus, next-generation sequencing was less sensitive than real-time RT-PCR. The advantage of the sequencing approach over real-time RT-PCR was the immediate availability of virus-typing information. Considering the development of platforms capable of generating more output data at declining costs, next-generation sequencing remains of interest for future virus diagnosis in clinical and public health settings and certainly as an additional tool when screening results from real-time RT-PCR are negative.
Hepatitis E virus (HEV) is increasingly acknowledged as a cause of hepatitis in healthy individuals as well as immunocompromised patients. Little is known of HEV infection in recipients of allogeneic ...hematopoietic stem cell transplantation (alloHSCT). Therefore, we set out to study the incidence and sequelae of HEV as a cause of hepatitis in a recent cohort of 328 alloHSCT recipients. HEV RNA was tested in episodes of liver enzyme abnormalities. In addition, HEV RNA and HEV serology were assessed pre- and post-alloHSCT. We found 8 cases (2.4%) of HEV infection, of which 5 had developed chronic HEV infection. Seroprevalence pre-alloHSCT was 13%. Four patients died with HEV viremia, with signs of ongoing hepatitis, having a median time of infection of 4.1 months. The 4 surviving patients cleared HEV after a median period of 6.3 months. One patient was diagnosed with HEV reactivation after a preceding infection prior to alloHSCT. Although the incidence of developing acute HEV post-alloHSCT is relatively low, the probability of developing chronic hepatitis in severely immunocompromised patients is high. Therefore, alloHSCT recipients should be screened pretransplantation by HEV serology and RNA. Furthermore, a differential diagnosis including hepatitis E is mandatory in all alloHSCT patients with severe liver enzyme abnormalities.
•The incidence of acute HEV infection after alloHSCT is relatively low, in contrast to a high probability of developing chronic hepatitis.•HEV infection or reactivation should be included in the differential diagnosis of liver enzyme abnormalities in alloHSCT recipients.
We screened 1,200 living heart, lung, liver, and kidney transplant recipients for hepatitis E virus infection by reverse transcription PCR. In 12 (1%) patients, hepatitis E virus infection was ...identified; in 11 patients, chronic infection developed. This immunocompromised population is at risk for hepatitis E virus infection.
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