J.G. Hunter

Guillain-Barré syndrome associated with preceding hepatitis E virus infection

Objective: The aim of the study was to determine whether Guillain-Barré syndrome (GBS) is associated with preceding hepatitis E virus infection. Methods: 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. Results: 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. Conclusions: 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.

Neuralgic amyotrophy and hepatitis E virus infection

Objective: To determine whether there is an association between an acute preceding hepatitis E virus (HEV) infection and neuralgic amyotrophy (NA), and if so, whether patients with HEV-related NA differ from patients without an associated HEV infection. Methods: HEV testing was conducted in a retrospective cohort of 28 Cornish patients with NA (2011–2013) and a prospective cohort of 38 consecutive Dutch patients with NA (2004–2007). Acute-phase serum samples were analyzed for the presence of anti-HEV immunoglobulin (Ig) M and IgG and HEV RNA (quantitative real-time PCR). Results: Five cases (10.6%) of acute hepatitis E infection were identified in a total group of 47 patients with NA of whom serum samples were available. In 4 patients, HEV RNA was detected in serum samples taken at presentation. All patients with HEV-associated NA had clinical and electrophysiologic evidence of bilateral brachial plexus involvement. Anti-HEV IgM positivity was not related to age, sex, disease severity, disease course, or outcome. Conclusions: Acute hepatitis E is found in 10% of patients with NA from the United Kingdom and the Netherlands. Further research is required to investigate the role of HEV in NA in other geographical locations and to determine pathophysiologic mechanisms.

Characteristics of Epstein–Barr virus hepatitis among patients with jaundice or acute hepatitis

Abnormal liver blood tests are common in Epstein–Barr virus (EBV) infection, but symptomatic hepatitis is rare. The demographics, clinical features and outcome of EBV hepatitis are incompletely understood, particularly in the elderly people.

Hepatitis E seroprevalence in recipients of renal transplants or haemodialysis in southwest England: A case–control study†

Locally acquired HEV infection is increasingly recognized in developed countries. Anti‐HEV IgG seroprevalence has been shown to be high in haemodialysis patients in a number of previous studies, employing assays of uncertain sensitivity. The aim of this study was to investigate anti‐HEV IgG seroprevalence in recipients of haemodialysis and renal transplants compared to a control group using a validated, highly sensitive assay. Eighty‐eight patients with functioning renal transplants and 76 receiving chronic haemodialysis were tested for HEV RNA and anti‐HEV IgG and IgM. Six hundred seventy controls were tested for anti‐HEV IgG. Anti‐HEV IgG was positive in 28/76 (36.8%) of haemodialysis and 16/88 (18.2%) of transplant patients. HEV RNA was not found in any patient. 126/670 (18.8%) of control subjects were anti‐HEV IgG positive. After adjusting for age and sex, there was a significantly higher anti‐HEV IgG seroprevalence amongst haemodialysis patients compared to controls (OR = 1.97, 95% CI = 1.16–3.31, P = 0.01) or transplant recipients (OR = 2.63, 95% CI = 1.18–6.07, P = 0.02). Patients with a functioning transplant showed no difference in anti‐HEV IgG seroprevalence compared to controls. The duration of haemodialysis or receipt of blood products were not significant risk factors for HEV IgG positivity. Patients receiving haemodialysis have a higher seroprevalence of anti‐HEV IgG than both age‐ and sex‐matched controls and a cohort of renal transplant patients. None of the haemodialysis patients had evidence of chronic infection. The reason haemodialysis patients have a high seroprevalence remains uncertain and merits further study. J. Med. Virol. 85:266–271, 2013.

Hepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre study

BACKGROUND & AIMS Hepatitis E virus (HEV) has been associated with a number of neurological syndromes, but causality has not yet been established. The aim of this study was to explore the relationship between HEV and neurological illness by prospective HEV testing of patients presenting with acute non-traumatic neurological injury. METHODS Four hundred and sixty-four consecutive patients presenting to hospital with acute non-traumatic neurological illnesses were tested for HEV by serology and PCR from four centres in the UK, France and the Netherlands. RESULTS Eleven of 464 patients (2.4%) had evidence of current/recent HEV infection. Seven had HEV RNA identified in serum and four were diagnosed serologically. Neurological cases in which HEV infection was found included neuralgic amyotrophy (n=3, all PCR positive); cerebral ischemia or infarction (n=4); seizure (n=2); encephalitis (n=1); and an acute combined facial and vestibular neuropathy (n=1). None of these cases were clinically jaundiced and median ALT at presentation was 24IU/L (range 8-145). Cases of HEV-associated neuralgic amyotrophy were found in each of the participating countries: all were middle-aged males with bilateral involvement of the brachial plexus. CONCLUSIONS In this cohort of patients with non-traumatic neurological injury, 2.4% had evidence of HEV infection. Symptoms of hepatitis were mild or absent and no patients were jaundiced. The cases of HEV-associated neuralgic amyotrophy had similarities with other HEV-associated cases described in a large retrospective study. This observation supports a causal relationship between HEV and neuralgic amyotrophy. To further understand the relevance of HEV infection in patients with acute neurological illnesses, case-control studies are warranted. Lay summary: Hepatitis E virus (HEV), as its name suggests, is a hepatotropic virus, i.e. it causes damage to the liver (hepatitis). Our findings show that HEV can also be associated with a range of injury to the nervous system.

Hepatitis E virus infection, Papua New Guinea, Fiji, and Kiribati, 2003-2005.

To the Editor: We report hepatitis E virus (HEV) infection rates in 3 South Pacific island countries—Papua New Guinea (PNG), Fiji, and Kiribati—determined from results of HEV IgG testing. During 2003–2005, specimens were collected from volunteers as part of a study of the epidemiology of viral hepatitis (1,2). Participants recruited were apparently healthy adults in the community and mother–infant pairs (specifically infants who were receiving, or had recently completed, their vaccinations). No specific inclusion/exclusion criteria were applied. Samples were collected from outpatient clinics and hospitals in PNG from Port Moresby, Goroka, Mt Hagen, Madang, and Daru. Samples from Fiji were collected in Suva from outpatient clinics and hospital wards. A proportion of samples from children were taken from nonjaundiced inpatients in PNG and Fiji. In Kiribati, samples were collected from participants at village preschools, vaccination clinics, and outpatient clinics on North Tarawa and North Tabiteuea (2). These were convenience samples and therefore might not be nationally representative cohorts. We obtained ethics permission for the study from appropriate national agencies. Signed informed consent was obtained from each participant or, for children, from a parent or guardian. From this sample pool, in a time sequential manner, the first serum samples were assayed: 545 from PNG (48 Goroka, 99 Mt Hagen, 87 Daru, 47 Madang, 156 Port Moresby), 265 from Fiji, and 238 from Kiribati. We evaluated samples using the Wantai (PE2) HEV IgG ELISA kit (Wantai Pharmaceutical Enterprise, Beijing, China), which detects IgG for all 4 known strains of human HEV. The assays were used according to the manufacturer’s instructions, and repeat equivocal results were defined as negative (3,4). HEV IgG positivity was highest in PNG (15.2%), followed by Kiribati (8.8%) and Fiji (2.2%) (Table). IgG positivity did not differ significantly between adults and children (<16 years of age) (PNG: 16.1% vs. 11.4%, p = 0.23; Kiribati: 6.0% vs. 13.3%, p = 0.06; and Fiji: 1.7% vs. 3.3%, p = 0.42 [Fisher exact test]). Table Seroprevalence of HEV, Papua New Guinea, Fiji, and Kiribati, 2003–2005* To investigate potential parent–child transmission, we tested mother/child (MC); father/child (FC); and when possible, mother/father/child (MFC) sets. We found no transmission association: In PNG, we tested 88 sets (67 MC, 2 MFC, and 19 FC); in Fiji, 29 sets (20 MC and 9 MFC); and in Kiribati, 65 sets (59 MC and 6 MFC); of the 11 PNG, 1 Fijian, and 8 Kiribati HEV IgG–positive children, none had IgG-positive parents. Because these samples were tested retrospectively, ascertaining the HEV IgG status of other family members was not possible. The high percentage of HEV-seropositive children <5 years of age in PNG and Kiribati implies active viral circulation in these countries. This is an unusual finding, compared with findings from seroprevalence studies in developing countries where IgG prevalence increases with age (3). The reason for this difference remains to be determined. It is unlikely to relate to acute HEV infection in hospitalized children sampled because the Wantai assay measures IgG, not IgM. The finding that these young seropositive children commonly have seronegative parents suggests that parent–child transmission is not the primary mechanism of infection in the population studied, which is in accord with published data (4). To investigate whether HEV seropositivity was higher in certain areas, we partitioned the data into regions defined by participant’s place of birth and tribal ethnicity. In Fiji and Kiribati, no significant region association was detected. However, in PNG, the proportion of HEV antibody–positive specimens was greater among participants from highland communities (altitude >1,500 m) than from lowland communities (20.4% vs. 9.7%, p = 0.01). (Port Moresby has a mixed immigrant population and was excluded from this analysis). The reason for the higher proportion of HEV IgG–positive specimens among participants in highland than lowland communities is unclear but might be explained by increased zoonotic transmission. In highland regions, pigs are more frequently kept, and the animals are kept closer to home (5). HEV genotypes 1 and 2 are hyperendemic to many developing countries and typically cause waterborne outbreaks of acute hepatitis in humans (6). Genotypes 3 and 4 are endemic to industrialized countries and are known to be a porcine zoonosis (7). Genotype 3 has been found in pigs in New Caledonia (8). In our investigation of 3 developing nations in Oceania, we found that HEV IgG positivity varies substantially between, and within, countries; it is high in PNG (15.2%) and low in Fiji (2.2%). By using the same sensitive, diagnostic assay, the seroprevalence of HEV in blood donors in New Zealand was reportedly 4% (9). In New Caledonia, 1.7% of 351 military recruits tested positive (10). In our study, the sampling method limits the applicability of the data to the general population. Nevertheless, our findings suggest HEV infection should be considered in cases of unexplained hepatitis.

Characterisation of the specificity, functionality and durability of host T-cell responses against the full-length hepatitis E virus.

The interplay between host antiviral immunity and immunopathology during hepatitis E virus (HEV) infection determines important clinical outcomes. We characterized the specificity, functionality, and durability of host T‐cell responses against the full‐length HEV virus and assessed a novel “Quantiferon” assay for the rapid diagnosis of HEV infection. Eighty‐nine volunteers were recruited from Oxford, Truro (UK), and Toulouse (France), including 44 immune‐competent patients with acute HEV infection, 18 HEV‐exposed immunosuppressed organ‐transplant recipients (8 with chronic HEV), and 27 healthy volunteers. A genotype 3a peptide library (616 overlapping peptides spanning open reading frames [ORFs] 1‐3) was used in interferon‐gamma (IFN‐γ) T‐cell ELISpot assays. CD4+/CD8+ T‐cell subsets and polyfunctionality were defined using ICCS and SPICE analysis. Quantification of IFN‐γ used whole‐blood stimulation with recombinant HEV‐capsid protein in the QuantiFERON kit. HEV‐specific T‐cell responses were detected in 41/44 immune‐competent HEV exposed volunteers (median magnitude: 397 spot‐forming units/106 peripheral blood mononuclear cells), most frequently targeting ORF2. High‐magnitude, polyfunctional CD4 and CD8+ T cells were detected during acute disease and maintained to 12 years, but these declined over time, with CD8+ responses becoming more monofunctional. Low‐level responses were detectable in immunosuppressed patients. Twenty‐three novel HEV CD4+ and CD8+ T‐cell targets were mapped predominantly to conserved genomic regions. QuantiFERON testing demonstrated an inverse correlation between IFN‐γ production and the time from clinical presentation, providing 100% specificity, and 71% sensitivity (area under the receiver operator characteristic curve of 0.86) for HEV exposure at 0.3 IU/mL. Conclusion: Robust HEV‐specific T‐cell responses generated during acute disease predominantly target ORF2, but decline in magnitude and polyfunctionality over time. Defining HEV T‐cell targets will be important for the investigation of HEV‐associated autoimmune disease. (Hepatology 2016;64:1934‐1950).

Clinical and laboratory features and natural history of seronegative hepatitis in a nontransplant centre.

Background Seronegative hepatitis is a recognized cause of liver failure requiring transplantation. The aetiology is unknown, but might relate to an unidentified virus or immune dysregulation. There are few data on seronegative hepatitis presenting to nontransplant centres. Objectives To describe the clinical/laboratory features and natural history of seronegative hepatitis and compare these with viral/autoimmune hepatitis. Methods Cases of seronegative, viral and autoimmune hepatitis were identified from 2080 consecutive patients attending a rapid-access jaundice clinic over a 14-year period. Results Of 881 patients with hepatocellular jaundice, 27 (3%) had seronegative hepatitis, 44 (5%) autoimmune and 62 (7%) viral hepatitis (acute hepatitis A, B, C and E viruses). Fifteen out of 27 (56%) patients with seronegative hepatitis were male, median age 60 years (range 14–74). Peak bilirubin was 63 &mgr;mol/l (range 9–363), alanine aminotransferase 932 IU/l (range 503–3807). Duration of illness was 7 weeks (range 4–12). No patients developed liver failure or had further bouts of hepatitis. One patient developed acute lymphoblastic leukaemia shortly after presentation. There was no difference in age/sex of patients with seronegative hepatitis and those with viral hepatitis. Compared with autoimmune hepatitis (age 65 years, range 15–91), patients with seronegative hepatitis were younger (P=0.002) and more likely to be male (P=0.004). Patients with autoimmune hepatitis were more likely (P<0.0001) to have an albumin less than 35 g/l, international normalized ratio greater than 1.2, raised IgG and positive antinuclear/smooth muscle antibody, compared with patients with seronegative hepatitis. Conclusion Seronegative hepatitis presenting to a nontransplant centre is generally a self-limiting illness. The aetiology is more likely to be viral than autoimmune.

Coastal clustering of HEV; Cornwall, UK.

Background and aims Autochthonous hepatitis E virus (HEV) infection is a porcine zoonosis and increasingly recognized in developed countries. In most cases the route of infection is uncertain. A previous study showed that HEV was associated geographically with pig farms and coastal areas. Aim The aim of the present research was to study the geographical, environmental and social factors in autochthonous HEV infection. Methods Cases of HEV genotype 3 infection and controls were identified from 2047 consecutive patients attending a rapid-access hepatology clinic. For each case/control the following were recorded: distance from home to nearest pig farm, distance from home to coast, rainfall levels during the 8 weeks before presentation, and socioeconomic status. Results A total of 36 acute hepatitis E cases, 170 age/sex-matched controls and 53 hepatitis controls were identified. The geographical spread of hepatitis E cases was not even when compared with both control groups. Cases were more likely to live within 2000 m of the coast (odds ratio=2.32, 95% confidence interval=1.08–5.19, P=0.03). There was no regional difference in the incidence of cases and controls between west and central Cornwall. There was no difference between cases and controls in terms of distance from the nearest pig farm, socioeconomic status or rainfall during the 8 weeks before disease presentation. Conclusion Cases of HEV infection in Cornwall are associated with coastal residence. The reason for this observation is uncertain, but might be related to recreational exposure to beach areas exposed to HEV-contaminated ‘run-off’ from pig farms. This hypothesis merits further study.

The natural history of autoimmune hepatitis presenting with jaundice.

Background Forty percent of patients with autoimmune hepatitis (AIH) present with acute jaundice/hepatitis. Such patients, when treated promptly, are thought to have a good prognosis. Objectives The objective of this study was to describe the natural history of AIH in patients presenting with jaundice/hepatitis and to determine whether the diagnosis could have been made earlier, before presentation. Methods This study is a retrospective review of 2249 consecutive patients who presented with jaundice to the Jaundice Hotline clinic, Truro, Cornwall, UK, over 15 years (1998–2013) and includes a review of the laboratory data over a 23-year period (1990–2013). Results Of the 955 patients with hepatocellular jaundice, 47 (5%) had criterion-referenced AIH: 35 female and 12 male, the median age was 65 years (range 15–91 years); the bilirubin concentration was 139 &mgr;mol/l (range 23–634 &mgr;mol/l) and the alanine transaminase level was 687 IU/l (range 22–2519 IU/l). Among the patients, 23/46 (50%) were cirrhotic on biopsy; 11/47 (23%) died: median time from diagnosis to death, 5 months (range 1–59); median age, 72 years (range 59–91 years). All 8/11 patients who died of liver-related causes were cirrhotic. Weight loss (P=0.04) and presence of cirrhosis (P=0.004) and varices (P=0.015) were more common among those who died. Among patients who died from liver-related causes, 6/8 (75%) died less than 6 months from diagnosis. Cirrhosis at presentation and oesophageal varices were associated with early liver-related deaths (P=0.011, 0.002 respectively). Liver function test results were available in 33/47 (70%) patients before presentation. Among these patients, 16 (49%) had abnormal alanine transaminase levels previously, and eight (50%) were cirrhotic at presentation. Conclusion AIH presenting as jaundice/hepatitis was mainly observed in older women: 50% of the patients were cirrhotic, and liver-related mortality was high. Some of these deaths were potentially preventable by earlier diagnosis, as the patients had abnormal liver function test results previously, which had not been investigated.