Samir Haffar

Making the case for the development of a vaccination against hepatitis E virus

Hepatitis E virus (HEV) infection is a global problem that affects 20 million individuals, and cause acute hepatitis in 3.5 million, with approximately 70 000 deaths worldwide per year. While the acute disease is generally self‐limited, however, it may progress to fatal fulminant liver failure in certain individuals. Contaminated water supplies disseminate this virus through the faecal–oral route, and swine is thought to be its zoonotic reservoir. Attempts have been made to develop effective HEV vaccines, and two candidates have undergone successful clinical trials. In this review, we discuss HEV epidemiology, genotypes, microbiological structure, as well as the most recent advances in vaccination developments.

Methodological quality and synthesis of case series and case reports

Case reports and case series are uncontrolled study designs known for increased risk of bias but have profoundly influenced the medical literature and continue to advance our knowledge. In this guide, we present a framework for appraisal, synthesis and application of evidence derived from case reports and case series. We propose a tool to evaluate the methodological quality of case reports and case series based on the domains of selection, ascertainment, causality and reporting and provide signalling questions to aid evidence-based practitioners and systematic reviewers in their assessment. We suggest using evidence derived from case reports and case series to inform decision-making when no other higher level of evidence is available.

Frequency and prognosis of acute pancreatitis associated with fulminant or non-fulminant acute hepatitis A: A systematic review

BACKGROUND Acute pancreatitis (AP) in patients with fulminant viral hepatitis is well recognized and its mortality depends on the severity of hepatitis rather than pancreatitis. Acute pancreatitis associated with non-fulminant acute hepatitis A (AHA) has been rarely described, and is considered to have a benign course with good response to conservative management. OBJECTIVE To perform a systematic review of the frequency and prognosis of AP associated with fulminant or non-fulminant AHA. RATIONALE An increasing number of reports describe AP associated with AHA. Some life-threatening complications related to AP may occur, and death has been reported. In addition, it is possible that early diagnosis of these cases may help in reducing the morbidity and mortality. DATA SOURCES Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, Google Scholar, and reference lists of relevant articles. STUDY SELECTION All available studies discussing AP associated with fulminant or non-fulminant AHA. DATA EXTRACTION AND ASSESSMENT Two blinded independent observers extracted and assessed the frequency of AP associated with AHA based on large studies including all cases of AHA observed during a prolonged period of time, diagnosis of AHA based on anti-HAV IgM, diagnosis of fulminant hepatitis (FH) based on the American Association for the study of Liver Diseases (AASLD) position paper, diagnosis of AP based on the American College of Gastroenterology (ACG) guidelines, diagnosis of AP associated with AHA based on Makharias association, and diagnosis of AP severity based on the Revision of the Atlanta Classification (RAC). We have developed a tool for risk of bias assessment of case reports and case-series and applied it to the included studies. RESULTS The frequency of reported AP associated with AHA is 0-0.1%. Thirty-eight publications with a total of 54 patients meeting the inclusion criteria have been published. Twenty-two studies had a low risk for bias, 10 had moderate risk and 6 had high risk. Patients originated from all continents but most of them were from Asia. The median age at diagnosis was 16 years (range: 2-81) with a male to female ratio of 2. The median interval between the onset of jaundice and onset of AP pain was 4 days (range: 0-30). AP was severe in 9% of patients. The median hospital stay for AP was 8 days (range: 3-35). Most cases occur in patients without FH (94%). Mortality was reported in 2 patients (3.7%). CONCLUSION Acute pancreatitis associated with AHA is rare with an estimated frequency of 0-0.1%. Fifty-four documented cases, mostly in Asian patients, have been reported. The median age of patients is 16 years with a M/F ratio of 2. Acute pancreatitis occurs less than one week after the onset of jaundice and mostly in patients without FH. Acute pancreatitis in this setting is severe in 9% of patients with a mortality rate similar to all other causes of AP.

Systematic review of mixed cryoglobulinemia associated with hepatitis E virus infection: association or causation?

Abstract Background and aim: Mixed cryoglobulinemia (MC) has been associated with several viral infections, and chronic hepatitis C is recognized as a major cause. MC associated with hepatitis E virus (HEV) has been described and little is known about this rare association. The aim of this study is to perform a systematic review of MC associated with HEV, and examine the presence of a causal relationship. Methods: An experienced librarian conducted a search of databases from each database’s inception to 12 December 2016 based on a priori criteria. The risk of bias was assessed, and Hill’s criteria were applied to determine causality. Results: Five publications met inclusion criteria, with a total of 15 cases. Three studies had low, one low to moderate and one moderate risk of bias. Median age was 43 years, and all patients came from Western Europe. Two patients were immunocompetent, while 13 were immunosuppressed, post solid organ transplant and had chronic hepatitis E. Renal involvement was observed in seven patients, mild to moderately severe cryoglobulinemic disease in one patient and severe cryoglobulinemic disease in three patients. One patient improved spontaneously, and another was treated with immunosuppressant reduction leading to viral clearance. Ten patients treated with peg-interferon or ribavirin for 3 months achieved loss of cryoglobulinemia and end-of-treatment response, but sustained virologic response was reported and achieved in two. Immunosuppressant achieved loss of cryoglobulinemia in three patients. One case of chronic renal failure, three cases of end-stage renal disease and one death were observed. Five of the nine Hill’s criteria were fulfilled. Conclusion: MC has been described with HEV infection. A causal relationship between HEV infection and cryoglobulinemia is highly probable.

Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review

BACKGROUND The association of acute pancreatitis (AP) with viral hepatitis is well known, and is usually attributed to HAV, HBV, or HCV. AP related to acute hepatitis E (AHE) has been rarely described, and the typical profile is that of a young male, residing in an endemic area, presenting with mild to moderate pancreatitis, and improving with conservative management. RATIONALE An increasing number of reports describe AP associated with AHE. Some life-threatening complications related to AP may occur, and death has been reported. In addition, it is possible that early diagnosis of these cases may help in reducing the morbidity and mortality. OBJECTIVE Perform a systematic review to study cases of AP associated with AHE and to assess their prognosis. DATA SOURCES PubMed, EMBASE, Scopus, and the Cochrane library. STUDY SELECTION All available studies discussing AP associated with AHE. DATA EXTRACTION AND ASSESSMENT Two blinded independent observers extracted and assessed the studies for diagnosis of AHE based on serological and/or molecular techniques, diagnosis of fulminant hepatitis based on the American Association for the study of Liver Diseases (AASLD) position paper, diagnosis of AP based on the American College of Gastroenterology (ACG) guidelines, diagnosis of AP associated with AHE based on Makharias association, and diagnosis of AP severity based on the Revision of the Atlanta Classification (RAC). RESULTS Thirteen case reports and 4 case series were found with 55 patients meeting the inclusion criteria. All patients originated from Southern Asia or had a recent travel to that area. The mean age at diagnosis was 28 years with a male to female ratio of 18:1. The mean interval between the onset of jaundice and the onset of AP pain was 10 days. AP was mild or moderately severe in 45 patients (82%), and severe in 10 patients (18%). Mortality was reported in 2 patients (3.6%). CONCLUSION Fifty-five cases of acute pancreatitis associated with AHE are reported in the literature. Acute pancreatitis in this setting is severe in approximately one fifth of patients with an overall mortality rate similar to all other causes of AP.

HEV-associated cryoglobulinaemia and extrahepatic manifestations of hepatitis E

268 www.thelancet.com/infection Vol 15 March 2015 but similar to what has been described in other extrahepatic manifestations related to HEV infection. In all reported cases thus far, HEV RNA in the cryoprecipitate was not assessed. In view of the growing interest in HEV infection and prevention, especially in immunosuppressed patients, more studies are needed to further delineate the HEV extrahepatic manifestations and their immunopathogenesis.

Acute fulminant vs. acute-on-chronic liver failure in hepatitis E: diagnostic implications

To the Editor, We read with interest the recent report by Festa et al. [1], regarding acute fulminant hepatitis (AFH) with hepatitis E virus (HEV) genotype 3e, and appreciate the opportunity to comment and discuss our opinion. In their report, the authors deduce a diagnosis of end-stage liver disease (ESLD) from radiological fi ndings (e.g. mild hepatic and splenic enlargement, irregularity of the liver profi le, non-homogenous liver parenchyma, and portal vein enlargement), as well as the presence of mild thrombocytopenia. However, hepatic surface nodularity is commonly seen in AFH, and it re fl ects alternating confl uent regenerative nodules and necrosis [2]. Moreover, mild hepatic and splenic enlargement are nonspecifi c features that could be encountered in acute hepatitis, as well as in ESLD. Similarly, portal hypertension and portal vein enlargement are described in AFH, and are related to the severity of liver damage and the presence of ascites [3]. Thrombocytopenia has also been described in AFH, and may result from decreased platelet produc-tion, increased destruction or sequestration [4].There-fore, ESLD diagnosis is best made by biopsy when feasible, and hepatic venous pressure gradient could be measured through the transjugular approach. Additionally, pancreatic head enlargement could occur in the setting of AFH-related pancreatitis [5], although pancreatic hyperenzymemia was not docu-mented in this report. Although the antiviral treatment of this patient may not differ in either case, this distinction becomes relevant in the United States if transplantation was needed, as AFH receives higher listing priority according to the United Network for Organ Sharing (UNOS), in turn decreasing the chances of receiving a life-saving transplant if chronic liver illness was determined. HEV infections continue to emerge in non-endemic regions, and this has led to rising interest in its epidemiology and prevention [6]. We believe that more interesting aspects of this infection will appear in the future, along with the need for research in its pathogenesis, diagnosis, and therapies. Declaration of interest:

Systematic review of acute pancreatitis associated with interferon-α or pegylated interferon-α: Possible or definitive causation?

BACKGROUND Acute pancreatitis (AP) associated with interferon-α or pegylated interferon-α (AP-IFN) has been described, although the causal relation certitude remains elusive. Some recent studies suggest definite causality, although the relation is grouped in class III of Badalov classification of drug-induced AP. OBJECTIVES Perform systematic review of AP-IFN and assess causality. METHODS Two reviewers independently evaluated the data and quality of studies extracted from multiple databases on March 13, 2017. Studies selection was based on a priori criteria. Naranjo scale, and Badalov classification were applied to determine causality. RESULTS We identified 16 studies that reported AP-IFN with a total of 23 patients. Fifteen studies had moderate to good methodological quality. The frequency of AP-IFN was 7/3450 (0.2%). The median age of patients was 50 years. In most cases IFN was used for chronic hepatitis C. The latency between IFN and diagnosis of AP was (>30 days). AP was mild or moderately severe and improved with supportive management. No mortality was observed. Re-challenge was done in 5 patients and resulted in AP recurrence in 3 cases. Twenty-one cases were classified as probable and 2 cases as definitive according to Naranjo scale. Evaluations of studies confirm a status Ia for AP-IFN according to Badalov classification. CONCLUSION AP-IFN is rare and has a probable or definite causal relation according to Naranjo scale. The evidence supports a class Ia of Badalov classification. Hypertriglyceridemia is not a contributing factor. IFN-induced AP is usually mild or moderately severe, and responds favorably to supportive management.

Acute liver failure caused by hepatitis E virus genotype 3 and 4: A systematic review and pooled analysis

Acute liver failure caused by hepatitis E virus genotype 3 and 4 has been rarely described. Because of the presence of a short golden therapeutic window in patients with viral acute liver failure from other causes, it is possible that early recognition and treatment might reduce the morbidity and mortality. We performed a systematic review and pooled analysis of acute liver failure caused by hepatitis E virus genotype 3 and 4.

Range of Normal Liver stiffness and Predictors of Suspected Advanced Fibrosis in Apparently Healthy Individuals: A Pooled Analysis of 16,082 Participants

BACKGROUND & AIMS: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. METHODS: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low‐risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta‐analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index <30 kg/m2 were examined with the medium probe and those with a body mass index ≥30 kg/m2 were examined with the extra‐large probe. Linear regression models were conducted after adjusting for potential confounding factors of LSMs. We performed several sensitivity analyses. RESULTS: We established LSM ranges for healthy individuals measured with both probes—these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. CONCLUSIONS: In a systematic review and meta‐analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra‐large probes.Background & Aims Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. Methods We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index Results We established LSM ranges for healthy individuals measured with both probes—these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. Conclusions In a systematic review and meta-analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.