Sporadic Acute Hepatitis Research Articles

Identification of genotype 4 hepatitis E virus strains from a patient with acute hepatitis E and farm pigs in Bali, Indonesia

A previous study revealed that antibodies to hepatitis E virus (HEV) (anti-HEV) are highly prevalent among healthy individuals and farm pigs in Bali, Indonesia, and suggested that HEV infection may occur via zoonosis among Balinese people. However, there were no reports of acute hepatitis E in Bali. To elucidate whether Balinese HEV strains recovered from infected humans and pigs have significant sequence similarity, serum samples obtained from 57 patients (age, mean +/- standard deviation, 31.1 +/- 11.9 years) with sporadic acute hepatitis and from one hundred and one 2- or 3-month-old farm pigs in Bali were tested for anti-HEV and HEV RNA. Among the 57 patients, 2 (3.5%) had high-titer IgM/IgA class anti-HEV antibodies and one of them had detectable HEV RNA (BaliE03-46). Overall, 58 pigs (57.4%) tested positive for anti-HEV, while 5 pigs (5.0%) had detectable HEV RNA. Based on the 412-nucleotide sequence within open reading frame 2, the BaliE03-46 isolate and the 5 swine HEV isolates recovered from the viremic pigs were phylogenetically classified in genotype 4, but were only 77.3-90.8% identical to the genotype 4 HEV isolates reported thus far in China, India, Japan, Taiwan, and Vietnam. The BaliE03-46 isolate of human origin shared high identities of 97.3-98.3% with 4 of the 5 Balinese swine isolates, but differed by 16.1% from the remaining swine isolate. These results suggest that indigenous HEV strains of genotype 4 with marked heterogeneity are circulating in Bali, Indonesia, and that pigs are reservoirs of HEV for Balinese people who have a habit of ingesting uncooked pigs.

Intrafamilial hepatitis E in France

Hepatitis E virus (HEV), a small, non-enveloped RNA irus, is a causative agent of acute hepatitis that is transmited principally via the fecal–oral route. The virus can cause pidemic hepatitis in developing countries and sporadic outreaks in non-endemic areas. In endemic areas, hepatitis E ccurs predominantly in young adults. However, the main oncern is for pregnant women who are subject to a high fatalty rate of up to 15–20% (Buti et al., 2004). In non-endemic reas, HEV infection in patients without any travel history is xceptional. Traditionally, North America and Europe have een considered as non-endemic regions with a seroprevaence of anti-HEV antibodies among blood donors around –5% (Mansuy et al., 2004). In these geographic areas, the ajority of HEV infections were thought to be imported. owever, in the last few years, some HEV strains associated ith sporadic acute hepatitis have been isolated from human erum samples in North America, European countries (Italy, reece, Spain, United Kingdom, The Netherlands, France) nd East Asia (Japan), without history of travel to endemic egions. Molecular analyses revealed that these strains idenified from non-endemic countries were close to genotype 3, nitially identified from a patient living in the United States Pina et al., 2000; Zanetti et al., 1999). We report a familial history of acute HEV diagnosed in estern France. No evidence of other viral infections or

Liver histology in patients with sporadic acute hepatitis E: a study of 11 patients from South-West France

Hepatitis E virus is a ribonucleic acid (RNA) enterically transmitted virus that causes both epidemics and sporadic cases of acute hepatitis E in many countries of Asia and Africa. Domestically acquired (non-travel-associated) hepatitis E has been reported recently in many industrialized countries including the USA, Europe, and Japan. There is little information available on liver histology in these patients. We report a series of 11 patients with sporadic acute hepatitis E and needle liver histology in South-West France. Hepatitis E was diagnosed based on elevated transaminases (>10 upper limit normal) and the presence of specific serum antibodies (immunoglobulin-G class, present in all 11 patients) and/or viral RNA detection in serum and/or stools. Acute hepatitis lesions were observed in all cases with marked necro-inflammatory activity in nine patients. Confluent necrosis was present in five cases. Anisocaryosis and Kupffer's cell aggregates with siderosis were observed in most of the 11 patients. Cholangitis was frequent (9/11 cases). Cholestasis was observed in eight cases. Pseudo-glandular pattern was present in only one case but without zonal repartition. Characteristic pathological signs of acute hepatitis E were severe intralobular necrosis, polymorph inflammation, and acute cholangitis with numerous neutrophils.

Does co‐infection with multiple viruses adversely influence the course and outcome of sporadic acute viral hepatitis in children?

This study looked at the frequency of co-infection with multiple hepatotropic viruses and the effect of such infection on the course and outcome of acute sporadic viral hepatitis (AVH) and fulminant hepatic failure (FHF) in children. Consecutive children up to 15 years of age presenting with AVH or FHF between January 1998 and July 2002 were evaluated prospectively. The following viral markers were assessed in all children: immunoglobulin M (IgM) anti-hepatitis A virus (HAV), IgM anti-hepatitis E virus (HEV), hepatitis B surface antigen (HBsAg), IgM anti-hepatitis B core (HBc), and anti-hepatitis C virus (HCV). A total of 149 children were included in the study, 122 with AVH and 27 with FHF. Co-infection with multiple viruses was detected in 30 (24.6%) AVH patients (A+E in 24, A+B in three, and E+B, A+C and A+E+B in one each) and seven (26%) FHF patients (A+E in five, and A+B and E+B in one each). The majority of single infections were due to HAV (AVH 70/92, FHF 14/20) followed by HEV (AVH 9/92, and FHF 5/20). HEV infection was associated with infection with another agent in 88% of patients with AVH (odds ratio 53, 95% confidence interval 15-186, P<0.0001). Frequency of anicteric state, prolonged cholestasis, relapsing hepatitis, ascites, hemolysis and mortality rates were similar in the single and multiple infection groups for both AVH and FHF patients. Co-infection with multiple viruses is observed in one-quarter of patients with sporadic AVH in childhood. Such infection does not produce a more severe disease. HEV positivity is a strong marker for multiple infections.

Molecular detection and sequence analysis of a new hepatitis E virus isolate from Pakistan

Sporadic and epidemic acute viral hepatitis E in many developing countries is caused by hepatitis E virus (HEV). The HEV genome has been classified into three major genotypes. However, extensive diversity has been noted among HEV isolates from patients with acute hepatitis in China and Taiwan. Some reports indicated that multiple genotypes of HEV could cocirculate in the same area; even distinct genotypes of HEV could exist in the same patient. Pakistan is a highly endemic area for hepatitis E. So far only two Pakistan HEV isolates Sar-55 (87-Pakistan-A) and Abb-2B (88-Pakistan-2B) have been characterized, and the nucleotide sequences of these two HEV isolates show only 90% homology. In this study, a third HEV isolate from Pakistan (87-Pakistan-B) is reported. The sequences of a 438-bp fragment from ORF-2 and a 259-bp fragment from the ORF-1-3 region of this new HEV isolate were obtained and sequenced. The sequence analysis showed that this new HEV isolate was very closely related to the Sar-55 but different from the Abb-2B HEV isolate. These results indicated that the Sar-55 (87-Pakistan-A) genotype is the main endemic HEV strain in the Sargodha area. These data will be useful for HEV epidemiological studies, diagnosis and vaccine development.

A Novel Virus Culture System for Hepatitis C Virus

Hepatitis C virus (HCV) is a principal cause of post-transfusion and sporadic acute hepatitis. HCV infection persists and causes chronic liver diseases, including cirrhosis and hepatocellular carcinoma. Despite HCV’s importance, understanding of its life cycle has been hampered by the lack of an appropriate in vitro viral culture system. We isolated full-length HCV cDNA of the JFH-1 strain from a fulminant hepatitis patient, and constructed a JFH-1 subgenomic replicon that replicated efficiently in cultured cells without adaptive mutations. Full-length RNA transcripts were transfected into Huh7 cells, resulting in efficient replication of JFH-1 RNA and secretion of recombinant viral particles into the culture medium. The secreted viral particles were infectious for cultured cells and in a chimpanzee. The infectivity of these viral particles was greater for permissive cell lines than for original Huh7 cell lines. This infectious HCV system is a powerful tool for studying the HCV life cycle and for developing antiviral strategies and effective vaccines.

Acute sporadic hepatitis E in children: diagnostic relevance of specific immunoglobulin M and immunoglobulin G compared with nested reverse transcriptase PCR

This study was carried out to investigate the putative role played by the hepatitis E virus (HEV) in acute hepatic dysfunction in paediatric patients with acute non-A-C hepatitis. We also evaluated the diagnostic value for anti-HEV immunoglobulin G (IgG) and IgM enzyme-linked immunosorbent assays relative to nested reverse transcriptase PCR (RT-PCR) for HEV RNA detection. Sixty-four children with acute hepatitis were included in the study, in addition to sixteen healthy children with matched age and sex. All studied subjects were negative for IgM antibody to hepatitis A virus, hepatitis B virus surface antigen, IgM antibody to hepatitis B virus core antigen, antibody to hepatitis C virus, and by RT-PCR for HCV RNA. HEV RNA was detected in 23.4% of patients, followed by detection of specific IgM in 17.2% and IgG in 12.5% of patients. Two cases were positive for IgG in the control group (12.5%). The sensitivity, specificity and accuracy were 26.7%, 85.7%, 71.9%, respectively, for IgM, and 26.7%, 91.8%, and 76.6%, respectively, for IgG. From this study we can conclude that HEV is a frequent virus found sporadically with acute hepatitis among paediatric patients. We cannot depend upon serology alone for diagnosis; rather, both molecular and serological methods must be applied for accurate diagnosis.

153 Acute hepato-cellular failure with encephalopathy in French patients with autochthonous acute sporadic hepatitis E

153 Acute hepato-cellular failure with encephalopathy in French patients with autochthonous acute sporadic hepatitis E

Infection with hepatitis A, B, C, and delta viruses among patients with acute hepatitis in Mongolia

One hundred ten consecutive patients (60 males and 50 females; age, mean +/- standard deviation [SD], 22.6 +/- 6.4 years; range 16-48 years) who were clinically diagnosed with sporadic acute hepatitis between December 2004 and January 2005 in Ulaanbaatar, Mongolia, were studied. IgM antibodies to hepatitis A virus were detected in 18 patients (16.4%), IgM antibodies to hepatitis B core (anti-HBc IgM) in 38 patients (34.5%) including two patients with concurrent hepatitis delta virus (HDV) infection, and hepatitis C virus RNA in nine patients (8.2%). There were 30 hepatitis B virus (HBV) carriers who had detectable hepatitis B surface antigen and antibodies to HDV but were negative for anti-HBc IgM, suggesting that they acquired type D acute hepatitis due to superinfection of HDV on a background of chronic HBV infection. None had IgM antibodies to hepatitis E virus (HEV). Consequently, 16.4, 32.7, 6.4, 1.8, and 27.3% of the patients were diagnosed as having acute hepatitis of type A, B, C, type B + D (HBV/HDV coinfection), and type D (superinfection of HDV), respectively. The cause of hepatitis was not known in the remaining 17 patients (15.5%). All 18 HAV isolates were genotyped as IA, all 9 HCV isolates were genotyped as 1b, and all 32 HDV isolates were classified into genotype I. The distribution of HBV genotypes among the 67 HBV isolates was A (1.5%, n = 1) and D (98.5%, n = 66). The present study indicates that de novo infections of HAV, HBV, HCV, and HDV are prevalent among young adults in Mongolia.

Epidemiology of hepatitis A and E virus infection in Brazil

This review has the objective to discuss the epidemiological aspects of the enterically transmitted hepatitis A and E in Brazil. The prevalence of hepatitis A varies greatly in different Brazilian regions, from 56% in South and Southeast to 93% in North region (Manaus, Amazon). Such differences are also found in different socioeconomic levels among age groups. A significantly higher prevalence was seen in the low socioeconomic group between 1-30 years. This difference is most striking in the first 10 years of age (23.5% vs 60.0%, high/middle vs low, respectively). Despite the improvements in sanitary conditions, hepatitis A is still endemic and outbreaks may occur. As an increasing proportion of the population is becoming susceptible to hepatitis A virus infection and as adult individuals may present more severe forms of the disease, the authors conclude that the implement of hepatitis A vaccination should be considered. Some Brazilian data have shown that the genotype found in our country were IA and IB. Isolates from this study were closely related genetically (or even identical) to isolates originating in other South American countries and overseas, providing firm evidence for epidemiological links between persons who travel to endemic areas. In spite of favorable environmental conditions, outbreaks of hepatitis E have never been reported in Brazil. Nevertheless, reports have demonstrated the evidence of anti-hepatitis E virus antibodies in some Brazilian regions. The seroprevalence of IgG anti-hepatitis E virus among normal populations shows positivities of 6.1% in gold-miners, 3.3% in general population, 2.0-7.5% in blood donors, 1.0% in pregnant women, and 4.5% in children, with no differences among regions. In populations at risk the prevalence of anti-hepatits E virus varies greatly. Among patients with acute non-A, non-B, non-C hepatitis 2.1% was detected in the Southeast to 29% in the Northeast, in 10.6% of acute non-A, non-B, non-C hepatitis relatives in the Amazon basin, in 12% of acute sporadic non-A non-B hepatitis patients in the Northeast, a co-infection with acute hepatitis A in 25 to 38% in the Northeast, in 14 to 18% among prostitutes and women considered at risk for human immunodeficiency virus in the Southeast, and in 12% of the intravenous drug users in the Southeast.

Hepatitis E Virus Infection with Nonimmune Hemolytic Anemia

Hepatitis E Virus Infection with Nonimmune Hemolytic Anemia

京浜地区Ｅ型肝炎国内感染例１０例の疫学的特徴とＨＥＶ分離株塩基配列

A total of 10 Japanese patients with acute sporadic hepatitis E in Tokyo and Kanagawa area from 1998 to 2004 were analyzed for epidemiological and viro-genetic characteristics of their HEV infections. Our findings therefrom corroborated the previous ones on the middle-aged male predominance. Noteworthy was that all were alcohol drinkers except for one female patient. Two of the drinkers had a fondness for eating uncooked or undercooked pork meat or liver. The one and only non-drinker among the subjects was engaged in the job of building-sanitation. Molecular analyses indicated that most of the HEV isolates from these patients segregated to a cluster within genotype III, suggesting these strains (if not all) might be autochthonous in the Tokyo and Kanagawa area.

富山県からは初報告例となる散発性Ｅ型急性肝炎の１例

富山県からは初報告例となる散発性Ｅ型急性肝炎の１例

Prevalence of antibodies to hepatitis E virus among Japanese blood donors: identification of three blood donors infected with a genotype 3 hepatitis E virus.

Risk factors for acquiring hepatitis E among individuals in industrialized countries including Japan are not fully understood. We investigated whether Japanese blood donors with or without an elevated alanine aminotransferase (ALT) level are likely to have hepatitis E virus (HEV) infection. Serum samples were collected from 5,343 voluntary blood donors including 1,087 donors with elevated ALT of 61-966 IU/L and 4,256 donors with normal ALT (< or = 60 IU/L) at two Japanese Red Cross Blood Centers, and were tested for the presence of anti-HEV IgG by in-house enzyme-linked immunosorbent assay (ELISA). Overall, 200 donors (3.7%) were positive for anti-HEV IgG, including 32 (2.9%) with elevated ALT and 168 (3.9%) with normal ALT. Serum samples with anti-HEV IgG were further tested for the presence of anti-HEV IgM by in-house ELISA and for HEV RNA by reverse transcription (RT)-polymerase chain reaction (PCR). Three donors with ALT of 966, 62 or 61 IU/L were positive for anti-HEV IgM and HEV RNA. The HEV isolates obtained from the three viremic donors segregated into genotype 3, were 91.5-93.4% similar to each other in the 412 nucleotide sequence of open reading frame 2, and had the highest identity of 91.5-94.9% with the JRA1 isolate which was recovered from a Japanese patient with sporadic acute hepatitis E who had never been abroad, suggesting that these three HEV isolates are indigenous to Japan. This study suggests that a small but significant proportion of blood donors in Japan with or without elevated ALT are viremic and are potentially able to cause transfusion-associated hepatitis E.

Sporadic cases of acute autochthonous hepatitis E in Spain

Background/Aims In industrialized countries hepatitis E virus (HEV) infection is rare and its diagnosis is difficult because the utility of available tests is not well established. Methods We studied the presence of acute HEV infection markers in a cluster of 11 cases of acute hepatitis with IgG anti-HEV antibodies. Results Three cases were confirmed as acute hepatitis E and 8 as presumptive hepatitis E, two as a past HEV infection and one could not be determined. Three different HEV strains were identified in serum from 3 patients. Two strains belonged to genotype 3, the predominant genotype found in local urban sewage and the other strain belonged to genotype 1 and was considered an imported strain. Conclusions Our findings demonstrate the presence of some autochthonous, sporadic acute hepatitis E cases as well as an imported case in our area and the transitory nature of virological and serological markers for HEV.

Genetic changes in hepatitis E virus of subtype 1a in patients with sporadic acute hepatitis E in Kathmandu, Nepal, from 1997 to 2002

To investigate the genetic changes in hepatitis E virus (HEV) strains in the Kathmandu valley of Nepal, we compared the 412 nt sequence within open reading frame 2 of HEV among HEV isolates recovered from 16 patients in 1999, 14 patients in 2000 and 38 patients in 2002, and additional isolates recovered from 48 patients in 1997 whose nucleotide sequences have been previously published. All 116 HEV-viraemic samples were genotyped as 1 and subtyped further as 1a (n=85, 73 %), 1c (n=29, 25 %) and mixed infection of 1a and 1c (n=2, 2 %): subtype 1c was detected only in 1997. Among the 1a isolates, nucleotide sequence identity with the representative 1a isolate of Ne131-1997 was 96.4+/-2.4 % (mean+/-SD) in 1997, 93.9+/-1.7 % in 1999, 92.2+/-1.0 % in 2000 and 91.7+/-0.5 % in 2002, indicating gradual diversification of HEV sequences. When phylogenetic analysis of the 87 subtype 1a isolates was performed, they further segregated into five clusters, with two predominant clusters of 1a-2 and 1a-3: the annual frequency of cluster 1a-2 isolates decreased from 63 % in 1997, to 50 % in 1999, to 7 % in 2000 and no cases in 2002; cluster 1a-3 isolates were observed in all four years and its annual frequency increased from 5 % in 1997 to 95 % in 2002. Of the remaining three clusters, cluster 1a-1 was detectable only in 1997 and clusters 1a-4 and 1a-5 emerged in 2000 and 2002, respectively. These results indicate that genetic changes and take over of HEV strains may contribute to the genetic variability of HEV in the community.

Hepatitis E vaccines: progress and prospects.

Hepatitis E accounts for the major part of enterally transmitted non-A, non-B hepatitis worldwide. Its agent, the hepatitis E virus (HEV), is a small, single-stranded RNA virus. Only one serotype of HEV is recognised. Infection results in protective immunity with long-lived neutralising antibodies. In developing countries with poor sanitary conditions and high population density, hepatitis E causes water-borne epidemics with substantial mortality rates in pregnant women. In addition, more than 50% of cases of acute hepatic failure and sporadic acute hepatitis are due to hepatitis E. The overall prevalence rates of antibodies to the HEV in populations native to these areas rarely exceed 25%. Hence, many individuals remain susceptible to hepatitis E infection, making hepatitis E an important public health concern. In this context, the development of an HEV vaccine is warranted. Because HEV does not grow adequately in cell cultures the development of a vaccine based on inactivated or attenuated whole-virus particles is not feasible. HEV vaccines currently under study are based on recombinant proteins derived from immunogenic parts of the HEV capsid gene. Other approaches such as DNA-based vaccines or transgenic tomatoes have also been developed. Several recombinant protein-based vaccines elicited neutralising antibodies and protective immunity in vaccinated non-human primates. One such vaccine has passed phase I trial and is currently under further evaluation in field trials. Even so, several questions remain to be answered before vaccination programmes could be implemented.

Survey of hepatitis B and C in students of faculty of dentistry and dental hygienist school

At present, in Japan, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection by blood transfusion rarely happens. However, according to the national survey, outbreak of sporadic acute hepatitis B and C is reported every year and viral hepatitis induced by iatrogenic infection is also reported. We think that education and enlightenmen for measures of infection control for hepatitis virus in dentisal medical care are important. Therefore, we carried out a questionnaire survey about measures of an infection control including hepatitis B and C for 352 students of a certain faculty of dentistry and a dental hygienist school. 35.5% of the total students thought the defense of oneself against infection was more important than defense of cross infection. Furthermore, the prevalence of the student who thought to permit recycle of a disposer glove and a disposer cartridge of a local anesthesia was 13.1% (46/352), 14.8% (52/352), respectively. The prevalence of students who recognized that HCV and HBV were detected from not only blood but also body fluid such as saliva remained in 65.3%. Consequently, the reality that knowledge of hepatitis virus and understanding about sterilization and disinfection of instruments were low became clear. In conclusion, immediate making of the guideline that aimed at standardization of prevention of hospital infection in domestic dental treatment and education to introduce the curriculum with a high regard for risk management of infection for students of dentistry will be required. In addition, it is an important problem to spread thoughts of standard precautions for dentistry.

A serological study of intrafamilial spread from patients with sporadic hepatitis E virus infection.

Intrafamilial transmission is rare in epidemic hepatitis E; its frequency in sporadic hepatitis E is not known. We followed up 86 household contacts (age range 4-75 years, mean +/- SD 32.4 +/- 15.8; 49 males), who were family members of patients with acute sporadic hepatitis E. Of the 86 contacts, 68 (79%) tested negative for IgG anti-hepatitis E virus antibodies. Four (4.7%) had IgM anti-hepatitis E virus antibodies at the time of diagnosis of hepatitis E in the index case; two of these contacts possibly had hepatitis E virus infection acquired simultaneously with that in the index case, and two could have had intrafamilial transmission. None developed serological evidence of hepatitis E virus infection over a period of 49 +/- 18 days after the diagnosis of index case, although a majority lacked IgG antibodies to hepatitis E virus and were likely to be susceptible. This suggests that person-to-person transmission is uncommon in sporadic hepatitis E.

When and how to treat acute hepatitis C?

Background: Appropriate treatment of acute hepatitis C is still a matter of controversy due to the lack of large controlled trials. Aim: To assess the effectiveness of interferon as treatment for acute hepatitis C by meta-analysis. Methods: MEDLINE search (1985–2002) was supplemented with manual searches of reference lists. Studies were included if they were controlled trials comparing interferon to no treatment and if they included patients with either post-transfusion or sporadic acute hepatitis C. Twelve trials were analyzed (414 patients). The outcome assessed was the sustained virological response (SVR) rate (undetectable hepatitis C virus RNA in serum at least 6 months after cessation of therapy). Results: Interferon significantly increased the SVR (risk difference 49%; 95% confidence interval 32.9–65%) in comparison to no treatment. The risk difference of SVR increased from 5 to 90% when trials were ordered by increasing interferon weekly dose. Delaying therapy by 8–12 weeks after the onset of disease does not compromise the SVR rate. Conclusions: Current evidence is sufficient to recommend interferon treatment of patients with acute hepatitis C. A later initiation of therapy yields the same likelihood of response as early treatment. A daily induction dose during the 1st month is the best option of treatment.