Hepatitis E virus infection is endemic in many developing countries while sporadic HEV infections have also been reported in some developed countries.1 Although HEV infection is usually associated with acute self-limited hepatitis, fulminant hepatic failure with morbidity and mortality may occur especially in immunocompromised hosts.2 High prevalence of HEV infection was reported in Africa, Central and Southeast Asia, and Mexico.3 In France, the seroprevalence of HEV (anti-HEV immunoglobulin G (IgG) and IgM) varied from 21.9% to 71.3%, according to geographic distribution, with average 39.1%.4 People with low educational level may be at a higher risk of exposure and infection than those with higher educational level. In Egypt, low educational level and socioeconomic status resulted in lack of knowledge about avoidable possible risk factors associated with HEV infection. Thus HEV was highly endemic in Egyptian rural communities with genotype 1 subtype 3 most circulating.5,6 There are four documented routes of transmission of HEV including fecal-oral route, vehicle-borne including water-borne and zoonotic foodborne, bloodborne transmission through parenteral blood transfusion, and perinatal via vertical transmission from mother-to-infant.7,8 Chronic HEV infection was acquired in 1.4% of patients following liver transplantion which subsequently resulted in persistent damage of the liver graft.9 Thalassemia is one of the most common genetic diseases worldwide. It is a major public health problem, causing much morbidity, early mortality, and great financial and emotional burden for a family. Thalassemia is the most common form of inherited anemia around the world.10 β-thalassemia frequencies are common in almost all Arab countries.11 In Egypt, β-thalassemia is the most common type with a carrier rate ranging from 5.3% to ≥9%. It was estimated that 1000/1.5 million live births/year suffer from thalassemia disease in Egypt.12 Many thalassemia patients develop chronic liver disease (CLD) like chronic hepatitis C. HAV and HEV infections show more severe clinical courses in the CLD patients.13 Some authors documented HEV seropositivity among hemodialysis and thalassemia patients.14,15 It was reported that HEV RNA detected in blood donations through studies by blood banks in several European countries.16 Therefore, some countries began HEV RNA screening of blood donations and others selectively applied blood screening for high risk patients.17 A previous study conducted on patients with acute viral hepatitis in Egypt reported HEV infection in about 12–42% of all cases.18 Another study carried out on blood samples collected from 134 jaundiced patients in Egypt, revealed that 51 (38.1%) patients were positive for anti-HEV IgG.19 Also, study on children with acute viral hepatitis in Assiut, Egypt, detected 30.9% HEV infection in children.20 The present study aimed to detect the seroprevalence of HEV infection in thalassemic children to assess the role of blood transfusion as a risk factor for HEV infection.

The seroprevalence of HEV antibodies in β-thalassemic patients was 27.15% (38/140 patients); 34 (24.29%) patients were positive for anti-HEV IgG, and four (2.86%) patients were positive for anti-HEV IgM. As shown in Table 1, there was significant association between age and anti-HEV IgG and IgM seropositivity (p=0.004, and 0.044, respectively). HEV seropositivity increased with age. There was significant association between rural residence and anti-HEV IgG (p<0.001). Regarding clinical data, there was significant association between liver enzymes and anti-HEV IgG. No patients in our study had HBV infection. Splenectomy and HCV infection were not significantly associated with HEV seropositivity (Table 2). Table 3. In Univariate analysis, there was significant association between Age, residence, liver enzymes, and amount of blood transfusions per with HEV seropositivity. On multivariate analysis only rural residence and elevated ALT levels were independently associated with HEV seropositivity.

The prevalence of HEV antibodies among thalassemic children in our study was 27.15%, 24.29% anti-HEV IgG positive and 2.86% anti-HEV IgM positive. Results of previous studies showed seroprevalence of HEV antibodies of 2.4% in thalassemic patients in Scandinavia21 and 10.7% in Saudi Arabia.22 In Iran, the seroprevalence of HEV IgG and HEV IgM were 10% and 1.8%, respectively.15 Reasons such as differences in socioeconomic, cultural, hygienic, and climatic factors across geographical areas may explain the lower prevalence rates in developed countries compared to developing countries.24 In our study, age was significantly associated with HEV antibodies. The highest HEV prevalence rate found in the age group 12–18 years indicated that the risk of HEV infection increased with age. Previous studies carried out in Egypt25 and in other geographic regions reported the same finding.26–28 This could be explained by the fact that older children had likely received more transfused blood, in addition to have been more exposed to contaminated junk food than younger children. In this study, the prevalence of HEV antibodies in rural areas (81.6%) was higher than in urban areas (18.4%). In rural Egypt, more than 60% of children with aged over 10 years had positive anti-HEV IgG.29 On the contrary, another study conducted on HCV infected thalassemic patients in Iran reported higher HEV seropositivity in thalassemic patients from urban regions than those from rural areas.6 Regarding liver enzymes, 84.2% of patients with HEV seropositivity showed elevated ALT levels, compared to 68.4% of elevated AST levels. Liver enzymes were higher among those with non-HEV antibodies compared to those with HEV antibodies. This may be due to presence of other causes of hepatitis either viral causes, mostly HCV, or non-viral causes. Although 100% and 75% of anti-HEV IgM positive patients had elevated ALT and AST levels, respectively, there was no significant association between liver enzymes and anti-HEV IgM seropositivity, probably due to small number of anti-HEV IgM positive patients. Previous studies reported that subclinical HEV infection might be the cause of elevated ALT.30 Therefore, in cases of unexplained ALT and AST elevation, HEV may be the reasonable cause. In two studies conducted in Japan on voluntary blood donors with elevated ALT levels, anti-HEV IgG was positive in 3.7% and 7.1% of participants.31,32 These findings suggest that patients with ongoing subclinical HEV infection had the potential to transmit HEV through blood transfusion. Our study revealed that there was significant association between the amount of blood transfused per year and HEV seropositivity (p=0.008). On the other hand, a previous study showed no significant association between the amount of blood transfused and anti-HEV seropositivity in thalassemic patients.21 This difference may be due to geographic difference and use of assays with low sensitivity that could underestimate HEV prevalence.33 Studies conducted in blood banks of several European countries reported that about 0.02–0.14% of blood donations were HEV RNA positive.16,34 This finding supports the possibility of HEV transmission through blood transfusion. Since recently in Ireland, blood donations are routinely screened for HEV RNA. Also in 2017, the UK, and Netherlands began HEV RNA screening in blood donations. In France and Germany, screening selectively occurs in high-risk patients, while blood authorities in Italy, Spain, Portugal and Greece are assessing whether HEV screening should be implemented or not.17 A previous study conducted in Egypt showed that about 0.45% of blood donors have ongoing subclinical HEV infection.35 It was reported that the risk of transmission through blood transfusion is increased in high-risk patients in developing regions than in other locations.23 HEV is endemic in Egypt and besides the possibility of HEV transmission through blood, our study showed significant association between amount of blood transfused and HEV seropositivity. Therefore, further studies should be carried out to detect HEV infection in risk group patients and blood donors.

In conclusion, the seroprevalence of HEV in β-thalassemic patients was relatively high. Therefore, close monitoring of these patients in addition to HEV screening of blood donations should be taken into consideration. Frequent assessment of liver enzymes in β-thalassemic patients to monitor subclinical HEV infections and other viral infections is recommended. Public awareness about HEV endemicity, modes of transmission, and risk hazards, especially in high-risk groups should be done to reduce the disease burden.

The authors received no specific funding for this work.

The authors declare no conflicts of interest.