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Hepatitis E virus (HEV) is transmitted by the faecal–oral route and is responsible for both sporadic infections and outbreaks in developing countries with poor sanitation . In these countries, the prevalence of anti-HEV IgG is high and increases with age, reflecting evidence of HEV infection. However, the overall prevalence remains lower than the prevalence of hepatitis A virus infection (anti-HAV antibody) and is much lower in younger age groups .
In rural Egypt the reported prevalence of anti-HEV antibody is among the highest in the world [2,3], starting early in life with >60% of 10-year-old children having detectable antibodies. However, compared with developing countries, where massive outbreaks have been reported such as in Darfur (Sudan)  and Uganda , outbreaks have not been reported in Egypt. Furthermore, sporadic acute hepatitis caused by HEV is uncommon  and none of 34 seroconversions reported in a study conducted in rural Egypt were symptomatic . Isolates of HEV circulating in Egypt belong to genotype 1 and are close to North African isolates but a limited number of isolates have been characterized so far in urban  or rural areas .
In this context, there is a need to further document the public health burden of hepatitis E in Egypt, in particular, to study the clinical impact, to describe the at-risk population, to explore the modes of transmission, and to see how it may differ from other enteric pathogens such as hepatitis A, as this has implications for the control measures, including future vaccination policies. In this paper, we describe the main clinical and epidemiological characteristics of symptomatic acute hepatitis E in comparison to hepatitis A in Greater Cairo, which comprises both rural and urban areas, and we present the results of the phylogenetic analysis in relation to the epidemiological characteristics.
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Between April 2002 and December 2007, 1950 patients with acute hepatitis were recruited from Abassaia and Imbaba Fever Hospitals. Of these, 858, 771 and 318 were diagnosed with acute hepatitis A, B and C, respectively.
Seventeen patients met the case definition for acute hepatitis E. All were positive for anti-HEV IgM and IgG. Of these, almost two-thirds occurred in the last 4 months of each year. Median age was 16 years (interquartile range (IQR) 13–22) and only three were female, aged 6, 9 and 26 years, respectively. Main clinical characteristics and laboratory findings are presented in Table 1. All but two patients were jaundiced and 12 presented with fever. Median serum bilirubin was 164.2 μmol/L (IQR 121.4–218.4) and median ALT was 1496 IU/L (IQR 848–2359). None of the patients presented with thrombocytopenia.
Table 1. Demographic, clinical characteristics, laboratory findings. Patients with acute hepatitis E, Greater Cairo, April 2002–December 2007
|Variable|| n = 17|
|Male sex||14 (82.3)|
|Rural residency||8 (47.0)|
| Fever||12 (70.6)|
| Abdominal pain||13 (76.5)|
| Dark urine||16 (94.1)|
| Scleral icterus||17 (100)|
| Jaundice||15 (88.2)|
| Total bilirubin (μmol/L)||164.2 (121.4–218.4)|
| Total bilirubin (× ulna)||9.7 (7.1–12.8)|
| Aspartate transaminase (IU/L)||1181 (720–1797)|
| Aspartate transaminase (× uln)||31.9 (19.4–48.6)|
| Alanine transaminase (IU/L)||1496 (848–2359)|
| Alanine transaminase (× uln)||40.4 (22.9–63.8)|
| Platelets (× 103)b||223.5 (172.5–357.5)|
Compared with hepatitis A patients (n = 858), those with hepatitis E were slightly older (median age 12 years, IQR 8–18 and 16 years, IQR 13–22 for hepatitis A and hepatitis E, respectively, p 0.03) and more likely to be male (82.3% versus 61.3%, respectively) although the latter difference was not significant (p 0.07). In terms of laboratory findings, bilirubin and AST were higher in HEV than in sex-matched and age-matched control HAV patients (Table 2).
Table 2. Comparison of the main clinical and laboratory findings between acute symptomatic hepatitis E patients and sex-matched and age-matched hepatitis A controls,Greater Cairo, April 2002–December 2007
|Variable||HEV cases (n = 17)||HAV controls (n = 68)||pa|
|Total bilirubin (× ulnb)||9.7 (7.1–12.8)||6.9 (4.2–10.3)||0.05|
|Aspartate transaminase (× uln)||31.9 (19.5–48.6)||13.5 (5.1–24.9)||0.02|
|Alanine transaminase (× uln)||40.4 (22.9–63.8)||19.2 (14.1–41.6)||0.09|
|Platelets (× 103)c||223.5 (172.5–357.5)||290 (224–380)||0.12|
Co-infection with HEV was diagnosed in four patients: one tested positive for HCV RNA, anti-HCV antibody and HBs antigen (IgM anti-HBc negative), one had a diagnosis of acute hepatitis C (HCV RNA positive and anti-HCV antibody negative) and two were HBs antigen positive (IgM anti-HBc negative) (Table 4). None of these four patients presented with clinical features of decompensation such as ascites or hepatic encephalopathy.
Seventeen case subjects with acute hepatitis E and 68 individually matched control subjects with acute hepatitis A were included in the case–control study. In univariate matched analysis, rural residency was significantly associated with hepatitis E (mOR 7.9; 95% CI 2.0–30.4). HEV cases were more likely to live in a household with more than seven occupants and to have unsanitary toilets than HAV controls, with mOR 6.0 (95% CI 1.4–25.4) and mOR 10.2 (95% CI 1.8–46.2), respectively. Rural residency and unsanitary toilets were highly correlated variables. Living close to an animal shed (inside or outside the house) had an association with hepatitis E but it was not significant (mOR 2.6; 95% CI 0.6–11.9) (Table 3).
Table 3. Exposures in the 6 months before onset of symptoms in hepatitis E cases and sex-matched and age-matched hepatitis A controls, Greater Cairo, April 2002–December 2007
| ||HEV cases, n (%) (n = 17)||HAV controls, n (%) (n = 68)||Matched OR (95% CI)|
| Rural residency||8 (47.1)||7 (10.3)||7.9 (2.0–30.4)|
| Travel outside Egypt||1||0||–|
| Travel in Egypt||3 (17.6)||10 (14.7)||1.3 (0.3–6.8)|
| Number of persons in the house >7a||5 (29.4)||4 (6.0)||6.0 (1.4–25.4)|
| Ratio of household occupants to sleeping rooms >4a||3 (17.7)||4 (6.0)||3.0 (0.7–13.4)|
|Contact with a jaundiced personb||0||6 (9.2)||–|
| Water outside the house||0||1||–|
| Unsanitary toiletsc||7 (41.2)||6 (8.8)||10.2 (1.8–46.2)|
| Consumption of unwashed vegetables||12 (70.6)||42 (61.8)||1.7 (0.4–6.8)|
|Contact with animals|
| Any contact at home or work||4 (23.5)||9 (13.2)||2.2 (0.5–9.6)|
| Animal shed (inside or outside the house versus none)||3 (17.6)||5 (7.3)||2.6 (0.6–11.9)|
| Rats a nuisance in the house||6 (35.3)||19 (28.4)||1.3 (0.5–3.9)|
Hepatitis E virus could be sequenced in 16 of the 17 cases and all were genotype 1. All but one of the 16 isolates belonged to the same cluster, sharing from 94% to 98.5% identity in the open-reading frame 2 region. The isolate that did not belong to the cluster was close to those from the Indian sub-continent and corresponded to a patient who reported travel abroad. The 15 other isolates had 93.8–97.9% identity with the two isolates from rural central Egypt (FJ423078-Egypt)  but only 89.2– 91.3% identity with an isolate from urban Cairo (AF051352)  (Fig. 1). One group of two and one group of three strains with closed genetic identity were identified. The two individuals from the first group (AF00386; AF00415) were diagnosed in November and December 2002 and lived in the same urban district (Table 4). Of the three individuals from the second group, (AF01642; AF03010; AF03037), the last two were diagnosed in September and October 2005 and lived in the same rural district.
Figure 1. Phylogenetic tree of hepatitis E virus (HEV) isolates recovered in Greater Cairo, April 2002 to December 2007. Phylogenetic tree constructed by neighbour-joining based on the open-reading frame 2 region of the HEV genome, 189 nucleotides (a) or 97 nucleotides (b). The phylogenetic analysis includes HEV sequences recovered from Egyptian patients (sequence names are highlighted in grey for the patients of this study) and GenBank reference sequences. HEV sequence names are labelled as follows: name of the sequence, genotype, country of origin and host.
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Table 4. Characteristics and selected exposures of the 16 patients with acute hepatitis E included in the phylogenetic analysis, Greater Cairo, April 2002-December 2007
| Sequence id || Year Month || Age years || Sex || Co-infection || ALT || rural || Contact animals || Travel outside Egypt || Other & comments |
|AF00268||2002 Aug||16||M||No||2646||Yes||Yes||No|| |
|AF00205||2002 Aug||14||M||No||848||Yes||Yes||No|| |
|AF00271||2002 Sep||16||M||No||2513||Yes||No||No|| |
|AF00386||2002 Nov 4||22||M||HBs antigen positive||1496||No||Yes||No||Natural herb consumption for medical purpose Same district as AF00415|
|AF00415||2002 Dec 8||20||M||No||1596||No||No||No||Same district as AF00386|
|AF00934||2003 June||24||M||HBs antigen positive HCV EIA, &PCR positive||5300||No||No||No||Tooth extraction +anesthesia Same governorate as AF01320 and districts next to each other|
|AF01102||2003 Sep||9||F||No||1777||No||No||No|| |
|AF01298||2003 Sep||9||M||No||903||No||No||No|| |
|AF01320||2003 Oct||6||M||No||625||Yes||Yes||No||Same governorate as AF00934 and districts next to each other|
|AF01642||2004 Jan||26||F||HCV PCR positive, HCV EIA negative||500||No||No||No||Cesarean section. IV injections|
|AF01738||2004 Feb||21||M||HBs antigen positive||2359||Yes||Yes||No|| |
|AF02383||2004 Sep||14||M||No||2356||No||No||No|| |
|AF02510||2005 Feb||35||M||No||750||No||No||No|| |
|AF03010||2005 Sept 18||13||M||No||3199||Yes||No||No||Same city/district as AF03037|
|AF03037||2005 Oct 30||19||M||No||442||Yes||No||No||Same city/district as AF03010|
|AF5017||2007 Nov||22||M||No||1390||No||No||Yes|| |
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The surveillance system for symptomatic acute viral hepatitis implemented in two fever hospitals in Greater Cairo since mid-2002 using a systematic and well-defined algorithm for the diagnosis of viral hepatitis yielded only 17 cases of acute symptomatic HEV infection over 5 years. This system was not meant to be exhaustive though, because it was limited to two Cairo hospitals, restricted to symptomatic forms of hepatitis, and used an 80% sensitive method (serum detection of HEV RNA) . Its merits have been to confirm the sporadic nature of acute hepatitis E in Greater Cairo during the study period, and would be to detect an outbreak if it were to happen in the large catchment area of the two hospitals. This study brings to light some important epidemiological and clinical characteristics of hepatitis E in Greater Cairo. Most patients were young, one-third of them being <14 years of age, despite the fact that children are less likely than young adults to present with symptoms, as documented in HAV and hepatitis B virus (HBV) infections [14,15]. Acute HEV infection is mostly asymptomatic. In Nepal, a country where HEV is considered to be endemic, the proportion of infections without symptoms estimated in the context of an outbreak  or during a cohort survey  was ∼70% in young male adults and adolescents. This finding of a young age at infection in Greater Cairo matches earlier observations in rural areas of Egypt where >60% of children aged over 10 years already had anti-HEV IgG . Less than 1% of acute viral hepatitis in Greater Cairo was caused by HEV. These data confirm that most HEV infections take a clinically silent course. The majority of the patients were male, which may reflect either a higher exposure, a higher susceptibility to infection, or a higher risk of developing symptoms once infected. In outbreaks that occurred in developing countries, the male to female ratio is somewhat contrasted, males largely outnumbering females in some outbreaks  but not in others [4,19]. Hence, a difference in exposure is a possible hypothesis for the higher proportion of males in our study of sporadic cases.
Regarding the biological characteristics, when compared with HAV-infected patients, and taking into account age (and gender), hepatitis E patients had higher values of AST and bilirubin. These differences were not observed between sporadic HEV and HAV infections in Europe [20,21]. However, these HEV infections concerned much older patients.
Infection with HEV has been recognized as a possible cause of hepatic decompensation in patients with liver cirrhosis in endemic regions . This was not observed in this study, despite four patients having co-infection with HBV or HCV. However, these patients were too young to have already developed a severe liver disease as the result of HCV or HBV infection and one of them had an acute HCV infection. It is of interest that the prevalence of chronic HCV infection (1/17) among hepatitis E patients was not different from that expected among young adults of Greater Cairo . It would suggest that chronic HCV infection does not greatly predispose to symptomatic forms of acute hepatitis E. This may not be the case for chronic HBV infection, whose prevalence (3/17) in this group exceeded the 5% expected among young adults of Greater Cairo. One woman, aged 26 years, had evidence of acute HCV infection (positive HCV RNA without HCV antibodies) following a caesarean section without any blood transfusion reported. The simultaneous occurrence of acute HCV and HEV infections, despite different modes of transmission (although cases of hepatitis E after blood transfusions have been reported ), is surprising.
Living in a rural area was associated with a higher risk of hepatitis E. This, together with the absence of waterborne outbreaks reported in Egypt, would indicate contamination from domestic animals raised in close proximity to or within the household. However, contact with animals was not significantly associated with hepatitis E. Stoszek et al.  found positive anti-HEV but no HEV genome in domestic animals and rodents in the two villages (Nile delta and upper Egypt) where they conducted a sero-incidence survey among the residents, and HEV genotype 1 has been detected in work horses in old Cairo . However, a zoonotic reservoir and evidence for possible transmission have been documented only for HEV genotype 3 in Europe and genotype 4 in Japan . In developing countries where outbreaks occurred, they were related to consumption of faecally contaminated drinking water. All the 17 patients in this study had access to water inside their houses. According to the 2008 Egyptian Demographic Health Survey, 90.0%/97.4% of the households in rural/urban areas in lower Egypt have access to water piped into the residence . However, access to water from the tap in the dwelling may not prevent episodes of contamination of the water in cases of leaky water pipes passing through soil that is contaminated with sewage . Although episodes of water contamination can provoke outbreaks, they may not be a common cause for sporadic cases. Groups of strains with closed genetic identity clustered in time and place (same district) observed in this study may support common exposures, among which sporadic contamination of water is a possibility.
The proportion of individuals living in a household with a high number of occupants was significantly higher in patients infected with HEV than in HAV controls. This may reflect poor living conditions and the potential for person-to-person transmission. However, in contrast to HAV , the role of person-to-person transmission of HEV, either in epidemic or in sporadic context, is still debated [28–30].
This study has several limitations. As a result of the limited sample size for the case–control analysis, we could not perform a multivariable analysis. Because of the nature of the comparison group (HAV cases), associations between exposures and acute hepatitis E should be interpreted with caution. Environmental exposures were not fully explored through the questionnaire.
The present work has characterized a large number of Egyptian HEV strains. Our data indicate that the majority belong to an unclassified subtype, different from the one described by Tsarev et al.  and classified as subtype 1e by Lu et al. . Until recently, only genotype 1 strains were found in Egypt in humans [6,8] or in animals . Surprisingly, a genotype 3 virus was recently identified in the stools of a child with acute hepatitis .
In conclusion, this study documented the sporadic nature of acute symptomatic hepatitis E in greater Cairo and the early exposure to HEV in life. Serious clinical disease seems to be rare. Our findings suggest the potential role of living in rural areas as a risk factor for HEV infection which deserves to be further explored in studies including an in-depth environmental investigation and combined virological investigations to identify the source of the different HEV strains circulating in Egypt.