[Rhabdomyolysis with tetraparesis secondary to hepatitis E virus infection in a patient on statins]. / Rhabdomyolyse avec tétraparésie secondaire à une hépatite virale E chez un patient sous statines.

INTRODUCTION: Neurologic and muscular damage associated with acute hepatitis due to hepatitis E virus (HEV) are rare and may be underdiagnosed. CASE REPORT: We report the case of a 56-year-old man, presenting with flaccid tetraparesis secondary to an acute rhabdomyolysis induced by acute E virus hepatitis. He fully recovered after one month under supportive treatment. DISCUSSION: Rare cases of acute rhabdomyolysis induced by HEV infection have been reported in the literature. We discuss the potential adjuvant role of statin treatment in our patient. Unexplained acute neurological conditions should prompt the search for HEV infection.

Reduced progression of bone erosion in cytomegalovirus seropositive rheumatoid arthritis patients.

BACKGROUND: Human cytomegalovirus (HCMV) seropositivity has been associated with higher inflammation during rheumatoid arthritis (RA). However, no data are available on the impact of HCMV seropositivity on bone erosion progression during RA. METHODS: We selected 487 individuals of ESPOIR cohort who fulfilled the 2010 ACR/EULAR criteria for RA. HCMV serology for these patients was determined using Architect CMV IgG assay. Baseline and 1-year central X-ray reading using modified Total Sharp Score (mTSS), Erosion Sharp Score, and joint space narrowing Sharp score were used to quantify structural damage progression. We performed univariate and multivariate analyses to investigate the association between HCMV status and bone erosion progression. RESULTS: We analyzed 273 HCMV seropositive (HCMV+) and 214 HCMV seronegative (HCMV-) RA patients. At inclusion, HCMV+ patients were less frequently ACPA+ (49.8% versus 58.9%, p < 0.0465) and had a higher DAS28-ESR (5.55 ± 1.24 versus 5.20 ± 1.14, p < 0.0013) in comparison with HCMV-. At 1 year, bone erosion progression (delta erosion Sharp score > 1 point) was lower in HCMV+ patients (16.1% versus 25.2%, p = 0.0128) in comparison with HCMV-. HCMV+ status remained independently associated with lower bone erosion progression in multivariate analysis. CONCLUSIONS: Our findings suggest that, independently of other confounding factors, HCMV seropositivity is associated with a lower progression of bone erosion during RA.

HEV and transfusion-recipient risk.

HEV infections are mainly food- and water-borne but transfusion-transmission has occurred in both developing and developed countries. The infection is usually asymptomatic but it can lead to fulminant hepatitis in patients with underlying liver disease and pregnant women living in developing countries. It also causes chronic hepatitis E, with progressive fibrosis and cirrhosis, in approximately 60% of immunocompromised patients infected with HEV genotype 3. The risk of a transfusion-transmitted HEV infection is linked to the frequency of viremia in blood donors, the donor virus load and the volume of plasma in the final transfused blood component. Several developed countries have adopted measures to improve blood safety based on the epidemiology of HEV.

Parsonage-Turner syndrome due to autochthonous acute genotype 3f hepatitis E virus infection in a nonimmunocompromised 55-year-old patient.

Hepatitis E virus (HEV) infection is an emerging autochthonous disease in industrialized countries. Extra-hepatic manifestations, in particular neurologic manifestations, have been reported in HEV infection. Only a few cases of hepatitis E-associated Parsonage-Turner syndrome have been reported, and HEV genotypes were rarely determined. Here, we report the case of a Parsonage-Turner syndrome associated with an acute autochthonous HEV infection in a 55-year-old immunocompetent patient. HEV genomic RNA was detected in serum and cerebrospinal fluid samples (CSF), and molecular phylogenetic analysis of HEV was performed. The interest of this case lies in its detailed description notably the molecular analysis of HEV RNA isolated from serum and CSF. HEV infection should be considered in diagnostic investigations of neurologic manifestations associated with liver function perturbations.

New insights into the natural history of hepatitis E virus infection through a longitudinal study of multitransfused immunocompetent patients in France.

Little is known about the natural history of Hepatitis E virus (HEV) infection in immunocompetent individuals. The prevalence, the course of infection and the occurrence of transmission by transfusion were investigated in multitransfused immunocompetent patients/blood donor pairs included in a longitudinal sample repository collection and followed up between 1988 and 2010. Ninety-eight subjects aged 6-89 years and suffering from acquired haemoglobinopathies were tested for HEV markers (IgM, IgG and RNA) in serial samples collected every 2 or 3 years. Eighteen patients (18.4%) were positive for HEV-IgG at baseline with a prevalence increasing from 12.5% below 26 years to 32% above 56 years. Nine patients remained IgG positive along the study and nine lost their antibodies after a mean follow-up of 7.4 years (1-22 years). One seropositive patient showed an increase of IgG level and RNA-HEV reappearance 1 year after inclusion, suggesting a reinfection and one seroconversion, probably acquired through blood transfusion was observed. This first longitudinal study including immunocompetent individuals confirms that HEV infection is common in Western Europe and that transfusion transmission occurs probably less frequently than expected. In addition, seroreversion and reinfection seem to be common. This suggests that the anti-HEV may not persist overtime naturally. However, repeat exposure to the virus related to the high prevalence of HEV infection may result in a sustainable specific IgG response.

Neurologic Disorders in Immunocompetent Patients with Autochthonous Acute Hepatitis E.

Neurologic disorders, mainly Guillain-Barré syndrome and Parsonage­Turner syndrome (PTS), have been described in patients with hepatitis E virus (HEV) infection in industrialized and developing countries. We report a wider range of neurologic disorders in nonimmunocompromised patients with acute HEV infection. Data from 15 French immunocompetent patients with acute HEV infection and neurologic disorders were retrospectively recorded from January 2006 through June 2013. The disorders could be divided into 4 main entities: mononeuritis multiplex, PTS, meningoradiculitis, and acute demyelinating neuropathy. HEV infection was treated with ribavirin in 3 patients (for PTS or mononeuritis multiplex). One patient was treated with corticosteroids (for mononeuropathy multiplex), and 5 others received intravenous immunoglobulin (for PTS, meningoradiculitis, Guillain-Barré syndrome, or Miller Fisher syndrome). We conclude that pleiotropic neurologic disorders are seen in HEV-infected immunocompetent patients. Patients with acute neurologic manifestations and aminotransferase abnormalities should be screened for HEV infection.

Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients.

BACKGROUND: The NS5A protein of the hepatitis C virus has been shown to be involved in the development of hepatocellular carcinoma. OBJECTIVES: In a French multicenter study, we investigated the clinical and epidemiological features of a new HCV genotype 1b strain bearing a wide insertion into the V3 domain. STUDY DESIGN: We studied NS5A gene sequences in 821 French patients infected with genotype 1b HCV. RESULTS: We identified an uncharacterized V3 insertion without ORF disruption in 3.05% of the HCV sequences. The insertion comprised 31 amino-acids for the majority of patients; 3 patients had 27 amino-acids insertions and 1 had a 12 amino-acids insertion. Sequence identity between the 31 amino-acids insertions and the V3 domain ranged from 48 to 96% with E-values above 4e(-5), thus illustrating sequence homology and a partial gene duplication event that to our knowledge has never been reported in HCV. Moreover we showed the presence of the duplication at the time of infection and its persistence at least during 12 years in the entire quasispecies. No association was found with extrahepatic diseases. Conversely, patients with cirrhosis were two times more likely to have HCV with this genetic characteristic (p=0.04). Moreover, its prevalence increased with liver disease severity (from 3.0% in patients without cirrhosis to 9.4% in patients with both cirrhosis and HCC, p for trend=0.045). CONCLUSIONS: We identified a duplicated V3 domain in the HCV-1b NS5A protein for the first time. The duplication may be associated with unfavorable evolution of liver disease including a possible involvement in liver carcinogenesis.

Seroprevalence in blood donors reveals widespread, multi-source exposure to hepatitis E virus, southern France, October 2011.

The apparent seroprevalence of hepatitis E Virus (HEV)varies greatly among developed countries depending on the geographical area and the sensitivity of immunoassays. We used a validated assay to determine the prevalence of HEV IgG and IgM antibodies among 3,353 blood donors living in southern France,who gave blood during the two first weeks of October 2011 and participated in the study. Demographic and epidemiological information was collected using aspecific questionnaire. We also screened 591 samples for HEV RNA. Overall IgG seroprevalence was 39.1%and varied from 20% to 71.3% depending on the geographical area (p < 0.001) while IgM seroprevalence was 3.31%. Anti-HEV IgG was significantly correlated with increasing age (p < 0.001), eating uncooked pork liver sausages (p < 0.001), offal (p = 0.003), or mussels(p = 0.02). Anti-HEV IgM was associated with being male (p = 0.01) and eating uncooked pork liver sausages(p = 0.02). HEV RNA was detected in one of the 99 anti-HEV IgM-positive samples, but in none of the 492 anti-HEV IgM-negative samples. HEV is hyperendemic in southern France. Dietary and culinary habits alone cannot explain the epidemiology of HEV in this region, indicating that other modes of contamination should be investigated.

[Acute hepatitis E infection associated with Guillain-Barré syndrome in an immunocompetent patient]. / Hépatite E aiguë associée à un syndrome de Guillain-Barré chez un patient immunocompétent.

INTRODUCTION: Hepatitis E virus (HEV) infection is now recognized to be an emerging autochthonous disease in several countries. There have been several reports of neurological manifestations associated with HEV infections. Immunocompromised patients seem to be particularly vulnerable. CASE REPORT: We report a 73-year-old man who presented with an acute polyradiculopathy and an acute hepatitis. HEV RNA was positive in serum and cerebrospinal fluid. Serum antiganglioside antibodies were also detected. Liver function tests returned to normal rapidly and HEV RNA was undetectable 4 weeks after initial testing. The neurological features improved gradually with the use of intravenous immunoglobulins. CONCLUSION: We report a case of Guillain-Barré syndrome related to acute hepatitis E in an immunocompetent patient. The outcome was favorable after intravenous immunoglobulins administration. HEV screening should be systematic in patients who present with an acute polyradiculopathy and abnormal liver function tests.

Hepatitis E virus.

Hepatitis E virus (HEV) is responsible for major outbreaks of acute hepatitis in developing countries where it was first described as a waterborne disease, transmitted by drinking water contaminated with feces. Attention was focused on HEV in developed countries and its associated diseases in recent years as a result of increasing reports of autochthonous infections. Hepatitis E is the zoonotic cause of these acute infections, and mainly in men over 50 years of age. The clinical manifestations and laboratory abnormalities of hepatitis E infections in immunocompetent patients cannot be distinguished from those caused by other hepatitis viruses. HEV is a major public health concern in immunocompromised patients because their infections can become chronic. The specific etiology of cases of hepatitis E infection can be diagnosed by serological testing and detecting viral RNA. Ribavirin is currently the reference treatment for HEV infections in immunocompromised patients. Several vaccines have proved safe and effective in clinical trials, but none have been approved for use in Europe yet.

Hepatitis E virus: what transplant physicians should know.

Hepatitis E virus (HEV) infection is an underdiagnosed disease in the developed world. In pediatric and adult organ transplant patients HEV infection can cause chronic hepatitis, which can lead to cirrhosis. Extra-hepatic manifestations, such as neurological symptoms and kidney injury, have been also reported in transplant patients. In this comprehensive minireview, we summarize the current knowledge on HEV infection in transplant patients, that is, its prevalence, incidence, natural history and therapy.

Epidemiological and virological characteristics of symptomatic acute hepatitis E in Greater Cairo, Egypt.

The aim of the study was to describe the characteristics of acute hepatitis E in Greater Cairo. Patients with acute hepatitis E were identified through a surveillance of acute hepatitis using the following definition: recent (<3 weeks) onset of fever or jaundice, alanine aminotransferase at least three times the upper limit of normal (uln), negative markers for other causes of viral hepatitis and detectable hepatitis E virus (HEV) RNA. Comparison of the liver tests between acute hepatitis E and hepatitis A virus (HAV), case-control analysis (four sex-matched and age-matched (±1 year) HAV controls per case) to explore risk factors and phylogenetic analyses were performed. Of the 17 acute HEV patients identified between 2002 and 2007, 14 were male. Median age was 16 years (interquartile range 13-22). Compared with HAV (n = 68 sex-matched and ±1 year age-matched), HEV patients had higher bilirubin (mean (SD) 10.9 (5.7) uln versus 7.5 (4.4) uln, p 0.05) and aspartate aminotransferase levels (38.6 (27.1) uln versus 18.3 (18.1) uln, p 0.02). Co-infection (hepatitis C virus RNA or hepatitis B surface (HBs) -antigen positive/IgM anti-hepatitis B core (HBc) anitgen negative) was diagnosed in four patients. In univariate matched analysis (17 cases, 68 matched controls), HEV cases were more likely to live in a rural area than HAV controls (matched OR 7.9; 95% CI 2.0-30.4). Of the 16 isolates confirmed as genotype 1, 15 belonged to the same cluster with 94-98.5% identity in the open-reading frame 2 region. Our findings documented the sporadic nature of HEV in Greater Cairo, characterized a large number of Egyptian HEV genotype 1 strains and identified living in a rural area as a potential risk factor for infection.

JC virus DNA in the peripheral blood of renal transplant patients: a 1-year prospective follow-up in France.

There is little information on JC virus (JCV) infection in renal transplant patients. A long-term prospective follow-up study was conducted to assess the incidence of JCV DNA in the blood of 103 adult renal transplant patients enrolled prospectively between 1 January and 31 December 2006. Patients were monitored until April 2008. JCV DNA was quantified by a real-time polymerase chain reaction in whole blood samples collected regularly for at least 1 year post-transplant. JCV was detected in seven patients (6.8%) (31/1,487 whole blood samples) at a median time of 139 days post-transplant. The median JC virus load of the first positive DNA blood sample was 3.4 log(10) copies/ml (1.9-5.7 log(10) copies/ml). Induction therapy were either anti-CD25 monoclonal antibodies (n = 5) or antithymocyte globulins (n = 2). Post-transplant immunosuppressive treatment included steroids with tacrolimus/mycophenolate mofetil (MMF) (n = 2), or ciclosporin/MMF (n = 1), or belatacept/MMF (n = 4). Two patients were also treated with rituximab. All seven patients infected with JCV had other viral infections(s): BK virus (3), Epstein-Barr virus (2), Cytomegalovirus (1) or both BK virus and Epstein-Barr virus (1). Three patients had BKV-associated nephropathy and decoy cells shedding. JCV infection was not associated with acute rejection episodes or nephropathy, regardless of the virus load. No patient developed progressive multifocal leukoencephalopathy during follow-up. Thus the incidence of JCV infection in renal transplant patients was low and not associated with any specific clinical manifestations. JCV replication must still be diagnosed and differentiated from BK virus infection because of its non-aggressive course.

Acute hepatitis E in south-west France over a 5-year period.

BACKGROUND: Hepatitis E was found in people living in industrialized countries who had not travelled to highly endemic areas. OBJECTIVES: To study the cases of acute hepatitis E confirmed thanks to viral genomic detection over a 5 years period in south-west France. STUDY DESIGN: 62 cases of hepatitis E were identified between 2003 and 2007. Their demographic, clinical, and virological features were analyzed. RESULTS: Cases of acute hepatitis E occurred regularly throughout this period. No seasonal variation was found. Patients, usually male (sex ratio=1.95), were adults living in both urban and rural areas. Sixty (96.8%) patients had not travelled abroad during the 6 months before diagnosis. Clinical manifestations ranged from asymptomatic infection to severe hepatitis. HEV was genotyped in 55 specimens. All the patients who had not travelled abroad were infected with genotype 3. CONCLUSION: The incidence of hepatitis E in south-west France was stable from 2003 to 2007, 96.8% of the cases were autochthonous. There was an age-related increase in the disease and patients tended to be men. The predominant genotype and subtype was 3f. However, contaminations pathways involved in hepatitis E in our area remain to clarify.

Comparison of two highly automated DNA extraction systems for quantifying Epstein-Barr virus in whole blood.

BACKGROUND: Optimal automated molecular methods are needed to monitor Epstein-Barr virus (EBV) infections in transplant recipients. OBJECTIVES: To compare the extraction of EBV DNA from whole blood using the COBAS Ampliprep and the MagNA Pure instruments (Roche) for quantifying EBV DNA by real-time PCR. STUDY DESIGN: EBV DNA content was determined on clinical samples extracted by both systems. RESULTS: The detection limit was 2.16log(10)copies/mL using the COBAS Ampliprep extraction system. Specificity was 100% and we saw no cross-contamination. Extraction was linear from 2.60 to 5.60log(10)copies/mL. The intra-assay variation was 1.91% for 3.60, 2% for 4.60 and 4.51% for 5.60log(10)copies/mL; inter-assay variation was 4.88%. Sixty-six samples were tested: 26 were positive and 28 were negative by both methods. One sample was MagNA Pure positive/COBAS Ampliprep negative (virus load 3.15log(10)copies/mL) and 10 samples were MagNA Pure negative/COBAS Ampliprep positive (virus loads from 1.59 to 3.51log(10)copies/mL) (P<0.0001). Both methods gave similar quantitative results (average difference 0.07log(10)copies/mL) which were well correlated (r=0.73, P<0.001). CONCLUSIONS: The COBAS Ampliprep extraction system is comparable to the MagNA Pure and offers a high reliability for extracting EBV DNA from whole blood.

Hepatitis E virus-related cirrhosis in kidney- and kidney-pancreas-transplant recipients.

Hepatitis E virus (HEV) infection was thought to be responsible for acute hepatitis that did not become chronic. However, we have recently reported that HEV infection can evolve to chronic hepatitis, at least in solid-organ transplant patients. We report on two cases of rapidly progressive of HEV-related cirrhosis that occurred in two organ-transplant patients. Case 1: A kidney-pancreas-transplant patient developed acute HEV hepatitis 60 months after transplantation, which evolved to chronicity as defined by persisting elevated liver-enzyme levels and positive serum HEV RNA. At 22 months after the acute phase, she presented with cirrhosis and portal hypertension, that is ascites and esophagus varices. Case 2: A kidney-transplant patient developed acute hepatitis 36 months after transplantation, which persisted and remained unexplained for 38 months. Then, HEV RNA was searched for in their serum and stools, and was found to be positive in both. Retrospective analysis of available stored serum, mainly the serum obtained at the acute phase, confirmed the diagnosis of chronic hepatitis E. In both cases, a liver biopsy showed cirrhosis. We conclude that HEV infection cannot only evolve to chronic hepatitis, but can also be responsible for rapidly progressing cirrhosis in organ-transplant patients.

[Genotypic recombination and hepatitis C virus]. / Recombinaison génétique et virus de l'hépatite C.

Hepatitis C virus (HCV) is an RNA virus, which belongs to the genus Hepacivirus within the Flaviviridae family. Recombinant viruses have been described in the three genera of this family. HCV is a highly variable virus, whose strains are classified among six genotypes. The first intergenotypic recombinant HCV 2k/1b was identified in 2002 in Saint Petersburg. To date a limited number of intragenotypic or intergenotypic recombinant strains were characterized in vivo. The crossover point of the recombinant strains was mainly found at the NS2-NS3 junction. Regarding the small number of recombinant strains described in the literature, the phenomenon of recombination might be rare. However, its prevalence may be underestimated since these viruses are not routinely searched. The impact of recombination on HCV epidemiology or physiopathology remains to be elucidated.

Detection and quantitation of HCV RNA using real-time PCR after automated sample processing.

There is considerable evidence that the loss of hepatitis C virus (HCV) RNA during the first 3 months of treatment with pegylated interferon plus ribavirin is a prognostic marker of response to therapy. Real-time polymerase chain reaction (PCR) assays for quantifying HCV RNA in plasma or serum are now commercially available. The extraction of HCV RNA can also be automated. This report analyses the performance of the COBAS Ampliprep-COBAS Taqman 48 (CAP/CTM) real-time PCR assay and compares this new test with the COBAS Amplicor HCV Monitor v 2.0 assay (CAM). CAP/CTM was 100% specific. The assay was linear across a wide range of HCV RNA concentrations without sample dilution. The intra-assay variation was 0.3-3.3% and the interassay variation was 1.5-6.7%. A total of 118 clinical samples with different HCV genotypes were assayed using both methods. The results obtained using the two methods were well correlated (r = 0.89, P < 0.001). The mean difference [CAP/CTM-CAM] was 0.17 log IU/ml and it was not influenced by the HCV genotype or by the subtype. It is concluded that the new CAP/CTM system is adequate for quantifying HCV RNA in clinical practice.