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A national survey of acute hepatitis E in France

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A national survey of acute hepatitis E in France
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  A national survey of acute hepatitis E in France C. RENOU 1 , X. MOREAU 2 , A. PARIENTE 3 , J.-F. CADRANEL 4 , E. MARINGE 5 , T. MORIN 6 , X. CAUSSE 7 ,J.-L. PAYEN 8 , J. IZOPET 9 , E. NICAND 10 , M. BOURLIE`RE 11 , G. PENARANDA 11 , J. HARDWIGSEN 11 ,R. GEROLAMI 11 , J.-M. PE´RON 9 , N. PAVIO 12 & THE ANGH, FRANCE 1 Hye`res;  2 Ollioules;  3 Pau;  4 Creil; 5 Beaune;  6 Tarbes;  7 Orle´ans; 8 Montauban;  9 Toulouse;  10 Paris; 11 Marseille;  12 Maisons-Alfort, France.Correspondence to:Dr C. Renou, Hoˆpital de Jour, Hoˆpitald’Hye`res, BP 82, 83407 Hye`res Cedex,France.E-mail: crenou@ch-hyeres.fr  Publication data Submitted 3 February 2008First decision 20 February 2008Resubmitted 28 February 2008 Accepted 5 March 2008Epub OnlineAccepted 14 March 2008 SUMMARY  Background Few data are available on the incidence, risk factors and contaminationpathways involved in acute indigenous hepatitis E in developed countries.  Aims To draw up an overall picture of hepatitis E cases, to confirm whether or not the majority of the cases were indigenous and to attempt to identify the risk factors and contamination pathways involved in hepatitis E. Methods This study was performed in the framework of a national network (ANGH) including 96 participating centres. The 19 centres with at leastone case of acute HEV reported a total number of 53 cases. Results  A decreasing South-to-North geographic gradient was observed. A non-specific clinical profile was observed in many cases. Acute hepatitis Ewas of indigenous origin in 90% of the patients. The most relevantand   ⁄   or frequent possible risk factors among the 47 indigenous metro-politan cases were water consumption from a personal water supply,uncooked shellfish consumption and the recent acquisition of a pet pig. Conclusions This national survey confirmed that acute indigenous hepatitis E is anemerging disease in developed countries such as France, and suggeststhat various risk factors are responsible for acute indigenous hepatitis Econtamination in non-endemic countries. Aliment Pharmacol Ther   27 , 1086–1093  Alimentary Pharmacology   &  Therapeutics 1086  ª  2008 The Authors Journal compilation  ª  2008 Blackwell Publishing Ltddoi:10.1111/j.1365-2036.2008.03679.x  INTRODUCTION The hepatitis E virus (HEV) is an enterically transmit-ted RNA virus responsible for large waterborne epi-demics of acute hepatitis in endemic regions. Although acute hepatitis E is relatively rare in devel-oped countries, an increasingly large number of indig-enous cases have been recently reported in WesternEurope, especially in the UK, 1 the Netherlands 2 andFrance. 3 Until now, few studies on the incidence of acute hepatitis E have been available, and no completenational surveys on acute hepatitis E have ever beenconducted to our knowledge in developed countries. Although water is a well-known vector in endemicregions, the potential causes of indigenous contamina-tion in non-endemic countries such as France stillremain to be elucidated.The aims of this retrospective French survey were todraw up an overall picture of recent acute hepatitis Ecases, to confirm whether or not a majority of thesecases were indigenous, to document the clinical andepidemiological features of HEV infection, and toidentify the risk factors involved in HEV exposure andthe contamination pathways responsible for indige-nous acute hepatitis E. PATIENTS AND METHODS  An email was sent to 96 French General Hospitalsaffiliated to the ANGH (Association Nationale desHoˆpitaux Ge´ne´raux) in January 2007, with a view tocollecting information about all the cases of acutehepatitis E observed at the respective gastroenterologi-cal departments since January 2004. All practitionersdealing with acute hepatitis E patients had to completean anonymous questionnaire in which they were askedto assess the epidemiological, clinical and biologicalcharacteristics of the acute infection and the risk fac-tors possibly involved in HEV contamination. Case definition  Acute hepatitis E diagnosis was based on alanine ami-notransferase (ALT) levels more than 10 times higher than the normal value and the presence of increasinganti-HEV IgG titres and   ⁄   or the presence of anti-HEV IgM and   ⁄   or HEV RNA in the serum and   ⁄   or stools. Allthe patients were found to be negative in the follow-ing tests: IgM antibodies to hepatitis A virus; AgHBs,anti-HBc IgM and DNA to hepatitis B (Cobas Amplicor HBV Monitor; Roche diagnostics, Branchburg, NJ,USA); antibodies and RNA to hepatitis C (Cobas Am-plicor HCV Monitor; Roche diagnostics); IgM antibod-ies for Cytomegalovirus (Vidas CMV IgG and IgM;BioMe´rieux, Lyon, France) and Epstein Barr Virus(ImmunoDOT EBV MONO G and M; BioMe´dical Diag-nostics, Marne la Valle´e, France). Antinuclear (exceptfor two patients with low positive titres of 1   ⁄   40), anti-smooth muscle and anti-LKM-1 antibodies were alsonegative in all the patients. Hepatitis E testing Serum anti HEV IgG and IgM were measured by per-forming an enzyme immunoassay (HEV ELISA; Genel-abs Diagnotics, St Ingbert, Germany): the samemethod was used by all the referral laboratories. Thepositivity of the serum antibodies was defined by anoptical density > cut-value. HEV RNA was detected inthe serum samples using reverse transcription-PCR for open reading frame (ORF-2). The amplified fragmentswere sequenced directly and aligned with those of other HEV strains (Centre National de Re´fe´rence, Hoˆpi-tal du Val de Graˆce, Paris; Laboratoire de Virologie,Hoˆpital Purpan, Toulouse, France). Statistical analysis The chi-squared test was used to compare paired pro-portions. Cochran–Mantel–Haenszel test was used tocompare multiple proportions. Normally distributeddata were compared using either the parametric chi-squared test or Student’s  t  -test. Non-normally distrib-uted data were compared using the nonparametric Wilcoxon test. The Shapiro–Wilks test was used to testnormality. Significance level was defined as  P   < 0.05,based on two-sided tests. RESULTS Geographic distribution of the ANGH centres Ninety-four of the 96 French General Hospitals partici-pating were located in metropolitan France (53% inthe North and 47% in the South) and two in overseasdepartments. The response rate from the hospitals inmetropolitan France and the two overseas departmentswas 78% (75   ⁄   96), including 56 centres without any cases of acute hepatitis E and 19 centres with at leastone case. The response rates obtained from the South ACUTE HEPATITIS E: A NATIONAL SURVEY IN FRANCE  1087 ª  2008 The Authors,  Aliment Pharmacol Ther   27 ,  1086–1093 Journal compilation  ª  2008 Blackwell Publishing Ltd  and North of France were nearly identical, amountingto 78% in the north and 77% in the south (Figure 1a).The response rate from the hospitals in the two over-seas departments was 100%: the first one (in FrenchGuiana) reported one case of acute hepatitis E, whereasthe second one reported that no cases had been noted(Island of Reunion). Apart from the overseas depart-ments, the negative response rate (no cases of acutehepatitis E) was 90% (39   ⁄   43 centres) in the North and53% (16   ⁄   30 centres) in the South ( P   = 0.0009). Con- versely, the positive response rate (at least one case of acute HEV) was 10% (4   ⁄   43 centres) in the North and47% (14   ⁄   30 centres) in the South, which indicates thatthe incidence of acute hepatitis E obeys a decreasingSouth-to-North geographic gradient. Including theoverseas departments, the 19 centres giving positiveresponses reported a total number of 53 cases (12, 10,9, 5, 2 and 1 cases in 1, 1, 1, 1, 2 and 13 hospitals,respectively). All the three centres reporting the largestnumber of cases were located in the South of France:the first two were in South-Eastern France, in the Var (12 and 9 cases, respectively) and the third one in theSouth-West, in Pyre´ne´es-Atlantiques (10 cases). Theexistence of a decreasing South-to-North geographicgradient was confirmed by the fact that 44 cases werereported by 14 centres in the South, whereas only eight cases were reported by four centres in the North(Figure 1b).The number of cases increased during the 3-year retrospective study period: 10 cases occurred in 2004,14 cases in 2005 and 24 cases in 2006. Five prospec-tive cases were reported during the first 6 months of the year 2007. Patients’ epidemiological, clinical and biologicalfeatures Epidemiological data were available on all 53 patients:these data showed that 47 patients had not travelledoutside Europe or had any contact or relationshipswith persons who had been to an endemic country 6 months or less before the onset of the symptoms.However, six patients had travelled outside Europe toan HEV-endemic country, including three to Pakistan,one to Algeria, one to Morocco and the last one toUzbekistan and Tajikistan. The last patient, who hadput the health recommendations into practice duringthe entire journey, had a 3f genotype, correspondingto French indigenous strains. This brought the propor-tion of indigenous cases of acute hepatitis E up to90% (48   ⁄   53 patients).The mean age (  s.d.) of the 53 patients was56.1    15.6 years (36 males, 17 females; Table 1).Forty-nine were of Caucasian srcin, three were from Asia and one from the Middle East (Algeria). Twenty-seven patients lived in rural areas and 17 had retired(Table 1). High rates of alcohol consumption(>40 g   ⁄   day) were noted in the case of 11 patients, butnone of the 53 patients was found to have chronicliver disease. 851313211142310311278%(43/55 centres) (a) (b) 4611Island of the Reunion = 1 centreFrench Guiana = 1 centre77%(30/39 centres)12911012112111111511French Guiana = 1 case85%(44/52 cases)15%(8/52 cases) Figure 1.  (a) Response rate reported by hospitals in southern and northern France. (b) Number of cases of acute hepatitis Ereported by hospitals in southern and northern France. 1088  C. RENOU  et al. ª  2008 The Authors,  Aliment Pharmacol Ther   27 ,  1086–1093 Journal compilation  ª  2008 Blackwell Publishing Ltd  The circumstance of discovery of the acute hepatitisE was nonspecific in many of the cases diagnosed (26cases, 49%): the symptoms included flu-like symptoms(nine cases), abdominal pain with vomiting and diar-rhoea (nine cases), arthralgia with myalgia but nofever (four cases), isolated asthenia (three cases) andan isolated skin rash in the last case. Twenty-fivepatients (47%) were referred for jaundice either alone(21 cases) or associated with fever, flue-like symptomsor vomiting (four cases; Table 1). The last two patientswere asymptomatic; in the first case, acute HEV wasdiscovered as the result of cardiology investigationsand in the second case, as the result of a blood testcarried out prior to chemotherapy. During the follow-up period, the patients’ clinical features ranged fromno symptoms to fulminant hepatic failure, i.e. withencephalopathy and coagulation disorders. Thirty-twopatients required hospitalization, mostly for an aetio-logic assessment of the jaundice (Table 1). Two of the53 patients developed signs of fulminant liver failureand died. The first one, a 76-year-old man known tohave a high rate of alcohol consumption (60 g   ⁄   day)died 34 days after the day of the diagnosis. A post-mortem liver biopsy showed the existence of acutecholestatic hepatitis associated with cholangitic fea-tures and a bridging fibrosis with no cirrhosis compat-ible with an alcoholic srcin, but without the featurestypical of alcoholic hepatitis. This patient had not beenexposed to any risk factors obviously associated withHEV contamination. The second patient, a 59-year-oldman died 52 days after the diagnosis, subsequent totwo liver transplantations. A liver biopsy on the nativeliver brought to light histological features typical of fulminant hepatitis without any specificity and ruledout the possibility of an underlying chronic liver dis-ease. The two patients had not travelled outside France Table 1.  Comparison of the epidemiological, clinical, biological parameters and the risk factors of hepatitis E virus contam-ination between the serological and the sero-virological groups of patientsTotal ( n  = 53)Serologic groupof HEV patients( n  = 39)Sero-viraemic groupof HEV patients( n  = 14)  P   Age (mean    s.d.) 56.1    15.6 52.8    14.9 65.5    13.8 0.001Male gender   n  (%) 36 (65) 27 (69) 9 (64) 0.99Urban area  n  (%) 26 (49) 19 (49) 7 (50) 0.80Drug-induced liver injury consumption  n  (%) 18 (34) 10 (26) 8 (57) 0.08Jaundice as circumstance of discovery   n  (%) 25 (47) 17 (44) 8 (57) 0.74Jaundice  n  (%) 36 (68) 27 (69) 9 (64) 0.99Duration of jaundice (days, mean    s.d.) 17.0    9.8 15.3    11.0 15.1    9.6 0.90Pruritis  n  (%) 14 (26) 12 (31) 2 (14) 0.38 Abdominal pain  n  (%) 16 (30) 13 (33) 3 (21) 0.62 Vomiting  n  (%) 9 (17) 9 (23) – 0.12Diarrhoea  n  (%) 11 (21) 8 (21) 3 (21) 0.70HPM  n  (%) 14 (26) 8 (21) 6 (43) 0.21SPM  n  (%) 2 (4) 2 (5) – 0.98Hospitalization  n  (%) 32 (60) 22 (56) 10 (71) 0.51Hospitalization (day number) 10.1    7.7 9.3    3.5 12.0    12.9 0.54 AST (  N  ) 42.6    41.4 39.5    34.7 51.1    56.7 0.98 ALT (  N  ) 53.1    38.9 54.4    41.3 49.7    32.6 0.83Total bilirubin ( l mol   ⁄   L) 150.5    150.6 128.8    114.1 211.0    214.3 0.35 Alkaline phosphatase (IU   ⁄   L) 233.8    104.5 241.7    120.6 216.9    56.4 0.74Prothrombin index (%) 83.1    18.6 87.4    14.3 71.6    24.3 0.02Risk factors  n  (%) 0.61No personal water or shellfish consumption 26 (49) 17 (44) 9 (64)Shellfish consumption 12 (23) 10 (26) 2 (14)Personal water consumption 11 (21) 8 (21) 3 (22)Personal water and shellfish consumption 4 (7) 4 (9) –HEV, hepatitis E virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase. ACUTE HEPATITIS E: A NATIONAL SURVEY IN FRANCE  1089 ª  2008 The Authors,  Aliment Pharmacol Ther   27 ,  1086–1093 Journal compilation  ª  2008 Blackwell Publishing Ltd  during the previous 6 months. In addition, they had apositive HEV RNA in the serum and stools, whereasthe phylogenetic analysis showed that the strainsinvolved belonged to the 3f genotype, thus confirmingthat an indigenous source of contamination wasresponsible.The main biological features of the 53 patients aregiven in Table 1. All the patients showed biochemicalevidence of hepatitis, including ALT levels more than10 times higher than the normal values. Three patientshad a prothrombin index of <50%. Two of them had ALT levels 51 and 109 times above the normal valuesand died as the result of fulminant liver failure. Thethird one, who had a prothrombin index of 45% andan ALT level 95 times higher than the normal values,recovered spontaneously. Eleven patients had normaltotal bilirubin levels, whereas all but two had elevatedalkaline phosphatase levels. Patients’ serological and virologicalcharacteristics HEV RNA was detected in the serum and   ⁄   or stools of 14 of the 30 patients tested (47%). In the sero-viraemicgroup of 14 patients, the anti-HEV IgG tests were posi-tive in the case of 10 patients and negative in that of the other four patients, whereas the anti-HEV IgM testswere positive in all the patients tested (six of sixpatients). The genomic sequences of all 14 viraemicpatients were available, and genotype 3f was identifiedin all these cases, which indicates that an indigenousHEV contamination process was involved. None of them had visited an endemic country 6 months or lessbefore the first symptoms occurred. The HEV diagnosison the remaining 39 patients was based on an increas-ing anti-HEV IgG titre or a strong reactivity to IgM, or dual IgG and IgM positivity. Positive anti-HEV IgG or anti-HEV IgM or anti-HEV IgG and IgM antibodieswere obtained in 16, 3 and 20 patients, respectively.The presence of HEV RNA was investigated in 16 of the 39 patients, but the results were negative in all thepatients tested. Comparisons were made between theserological and sero-viraemic groups of patients(Table 1). A significant difference was found to existbetween the two groups only in terms of age and theprothrombin index: the mean age was higher and theprothrombin index was lower in the viraemic group(mean age: 65.5    13.8 vs. 52.8    14.9,  P   = 0.001;mean prothrombin index: 71.6    24.3% vs. 87.4   14.3%,  P   = 0.02). All the other epidemiological, clinicaland biological parameters and the risk factors possibly responsible for HEV contamination tested in this study were similar in the two groups. It is worth noting inaddition that a lower rate of patients with drug-induced liver injury occurred in the serological group(26% vs. 57%,  P   = 0.08) (Table 1). Rate of acute indigenous hepatitis E and risk factors possibly associated with the infection Forty-eight of the 53 patients had acute indigenoushepatitis E. The patient in French Guiana was a9-year-old girl who had not been exposed to any obvious HEV contamination risk factors. The indige-nous metropolitan cases amounted to 89%. The mostrelevant and   ⁄   or frequent possible risk factors responsi-ble for the 47 indigenous metropolitan cases werewater consumption from a spring or private well or anearby river (15 cases), uncooked shellfish consump-tion (15 cases) and the recent acquisition of a pet pig(one case) (Table 2). Geographical comparisonsbetween the most relevant and   ⁄   or frequent possiblerisk factors were made to explain the decreasingSouth-to-North geographic gradient. No differenceswere found to exist between the two geographical Table 2.  Combination and separate comparisons of themajor metropolitan indigenous possible risk factorsbetween North and South of FranceSouth North Total*Combination comparisonNo personal water or shellfish consumption18 3 21Personal water and   ⁄   or shellfish consumption24 2 26Total 42 5 47Separate comparisonNo personal water or shellfish consumption18 3 21Shellfish consumption 10 1 11Personal water consumption11 0 11Personal water andshellfish consumption3 1 4Total 42 5 47 P   = 0.40, Cochran–Mantel–Haenszel test. P   = 0.64, Fisher test.* Five non-indigenous cases and one nonmetropolitan caseof acute hepatitis E were excluded of the analysis. 1090  C. RENOU  et al. ª  2008 The Authors,  Aliment Pharmacol Ther   27 ,  1086–1093 Journal compilation  ª  2008 Blackwell Publishing Ltd
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