Hepatitis A in the Eastern Mediterranean Region: a comprehensive review

ABSTRACT Introduction With 583 million inhabitants, the Eastern Mediterranean Region (EMR) is a worldwide hub for travel, migration, and food trade. However, there is a scarcity of data on the epidemiology of the hepatitis A virus (HAV). Methods The MEDLINE and grey literature were systematically searched for HAV epidemiological data relevant to the EMR region published between 1980 and 2020 in English, French, or Arabic. Results Overall, 123 publications were extracted. The proportion of HAV cases among acute viral hepatitis cases was high. HAV seroprevalence rate ranged from 5.7% to 100.0% and it was decreasing over time while the average age at infection increased. Conclusion In the EMR, HAV remains a significant cause of acute viral hepatitis. The observed endemicity shift will likely increase disease burden as the population ages. Vaccinating children and adopting sanitary measures are still essential to disease prevention; vaccinating at-risk groups might reduce disease burden even further.


Introduction
Exposure to the hepatitis A virus (HAV) causes viral hepatitis which is characterized by inflammation of the liver. Globally, more than 100 million HAV infections and 30,000-35,000 deaths are reported annually. 1 HAV is transmitted through the fecal-oral route, entering via the mouth and replicating in the liver. 1 The ingestion of contaminated food or water, poor sanitation, and contact with an infected individual are the primary sources of infection. 1,2 Clinically, HAV infection is similar to other types of acute hepatitis, with elevated levels of liver enzymes, dark-colored urine, and the onset of jaundice. It is accompanied by broad symptoms like fatigue, malaise, and abdominal pain. 3 The severity and outcome of the disease is negatively correlated with the age at infection. Infected children under six years of age are usually asymptomatic (~70% cases), while older children and adults show symptoms of jaundice (~70% cases). 3 The fatality rate increases with increasing age, from 0.1% (<15 years of age), to 0.3% (15-39 years of age) and 2.1% (≥40 years of age). 4 Infection due to HAV can be diagnosed by serological testing in the presence of anti-HAV immunoglobulin M (IgM) and immunoglobulin G (IgG). 5 The presence of IgM antibodies is indicative of a recent HAV infection, while the detection of IgG antibodies suggests previous exposure to HAV or vaccination, as IgG antibodies persist over time and confer lifelong immunity. 3,5 The measurement of IgG antibodies is an indirect method of measuring seroprevalence, overall and by age, and can be used to assess the endemicity level (i.e., the circulation of the HAV) in a given population. 2 Inactivated and live attenuated hepatitis A vaccines have proven to be immunogenic, well tolerated and safe in the target-vaccine population. [6][7][8] The World Health Organization (WHO) recommends the inclusion of hepatitis A immunization into the national immunization schedule for children ≥1 year of age, taking into consideration the incidence of acute HAV cases, the endemicity level (high to moderate), and cost-effectiveness data. 2 Notwithstanding this recommendation, the WHO states that vaccination should be part of a comprehensive plan for the prevention and control of viral hepatitis, including measures to improve hygiene, sanitation and outbreak control. 2 Broader access to clean water and sanitation, and improved socio-economic conditions are changing the epidemiology of HAV infection. 9,10 Due to globalization, rising income, and better infrastructure, low-to middle-income countries are undergoing a shift from high/intermediate to low HAV incidence rates, and high-income countries are now non-endemic to HAV infection. 11 Importantly, countries reporting low or intermediate HAV endemicity, including those countries in transition from high to low HAV endemicity, are particularly susceptible to recurrent outbreaks of symptomatic disease. 12 Given this context of evolving HAV epidemiology, the WHO Eastern Mediterranean Region (EMR) deserves attention. The EMR includes 21 member states and Palestine comprising nearly 600 million people. 13 This region is comprised of middle-income (11) as well as high-income (6) and low-income (5) countries as classified by the World Bank (2017). 14 In the last decade, EMR countries have documented a significant improvement in their socio-economic conditions. Advances in modern transportation and global accessibility, in particular, have boosted the travel and food industries. However, the EMR has also seen a rise in armed conflict, which has increased the rate of human migration and disease mobility. As a result, the EMR reports the highest global number of people displaced from their home countries. 15 Refugees displaced from high endemicity countries represent a source of contagion for their new country, especially if their housing is crowded and with poor sanitation and hygiene conditions.
There is limited information on the epidemiology of HAV disease in EMR countries, specifically in relation to shifts of HAV endemicity. 16,17 This review aims to explore HAV epidemiology by collecting and summarizing the serological data from the EMR region. The review highlights the importance of the EMR as a globalized hub for travel, migration, and food trade to bring awareness toward the probability of future global outbreaks of HAV disease ( Figure 1).

Methods
A comprehensive review utilizing a systematic approach was performed to identify published literature on HAV incidence and seroprevalence in the WHO-EMR 13 covering 22 countries according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. 18 According to these guidelines, we defined search sources, search strategy, the inclusion, and exclusion criteria to identify and select relevant publications, and the scope of data extraction prior to the conduct of the review.

Search sources and strategy
The search was conducted in MEDLINE (via PubMed) and complemented with a search of gray literature sources such as Ministry of Health (MoH) websites and reports from universities. We developed a broad search strategy using free-text terms ("HAV"; "COUNTRY NAME") and medical subject heading (MeSH) terms linked by Boolean operators. Searches were limited to a period of 40 years, i.e., from 1980 to July 2020. The lower limit of the period was considered appropriate by the authors as it allows to observe shifts in the burden of disease, if any. The countries of interest, based on the geographic scope of this review, were limited to the WHO-EMR covering 22 countries. Searches were conducted in both English and the local language of each included country (Table 1).

Screening and selection
The identified publications were screened in two phases by two reviewers in an independent process using the inclusion and exclusion criteria listed in Table 1. The retrieved articles were initially screened by title and abstract for eligibility by one reviewer (AO, MK, YL, or OO) followed by a second step which included screening of the full text of articles using the eligibility criteria specified in Table 1. All discrepancies were discussed with an additional reviewer (SB).
Original research from non-interventional studies or from gray literature sources was included if it reported data on the occurrence of hepatitis A (defined as previous exposure to HAV confirmed by laboratory detection of HAV IgM) and seroprevalence of HAV (defined as previous exposure to HAV confirmed by laboratory detection of HAV IgG or total HAV immunoglobulin (Ig) in blood samples). Case reports and other publication formats such as commentaries, editorials, and letters were excluded from this review. Reviews and meta-analyses were consulted with the intention to screen their reference lists for eligible articles.

Data extraction and reporting
The information extracted from selected studies included study characteristics (year of publication, study design, main objective of the study and sample size), age group of the study population and case definition (e.g., laboratory confirmation methods). The occurrence of HAV (HAV cases expressed as a proportion of all acute viral hepatitis cases) and HAV seroprevalence (expressed as a percentage of patients with previous exposure to HAV measured according to the test kit specifications) were extracted and reported. When available, the same outcomes were reported and compared by age group, socioeconomic status, year, type of setting (rural versus urban), and acute viral hepatitis caused by other types (hepatitis B virus, hepatitis E virus, etc.).

Occurrence of HAV among acute viral hepatitis cases
A total of 41 studies provided data on HAV occurrence among all acute viral hepatitis cases. Overall, the proportion of HAV cases among acute viral hepatitis cases was large and ranged from 1.5% to 97.0% (Table 3)   group. 89 In patients with acute viral hepatitis, coinfection with hepatitis B, C, and E was documented in nine studies 83,86,87,91,92,98,116,120,133 (Table 3).

HAV seroprevalence
A total of 77 studies provided data on HAV seroprevalence. HAV seroprevalence ranged from 3% to 100%, depending on the age of the study population (Table 4). Overall, the EMR region has an intermediate level of HAV seroprevalence, and the data show a remarkable consistency. While seroprevalence studies from before the year 2000 showed nearly universal immunity among the general population in many countries of the EMR, after the year 2000, seroprevalence rates reveal that more adolescents and adults remain susceptible to HAV, although with significant variation within the region.
Main observations from the different countries are summarized in Table 4. In Afghanistan, a high seroprevalence (99%) was documented; HAV seroprevalence was higher among individuals >15 years of age compared to those <15 years of age (100% versus 91.7%). 134 A study from 1987, in Djibouti, reported a prevalence of 98.5%. 124 Seroprevalence surveys conducted in Egypt in the 1990s 76,79 generally depicted a high immunity rate among children ≤5 years of age with 97.2-100% anti-HAV antibody prevalence. Studies from Egypt in the 2000s showed that 61.4% 75 to 86.2% 77,81 of children ≤6 years of age had immunity, and that 85.1% of patients with chronic liver disease had immunity. 77,78 Studies from Iran indicate that most children and teenagers are susceptible to hepatitis A infection 47,48,65,67,70 (Table 4). One study from Jordan provides strong evidence for continuous transition of HAV epidemiology toward intermediate endemicity, with increasing proportions of susceptible adolescents and adults. 126,127 A study conducted in Lebanon in the early 1980s highlighted that 79.5% of children had anti-HAV antibodies. 107 Studies conducted in 1999 and 2000 showed that more than half of teenagers had immunity, and about 20% of young adults remained susceptible to infection. [102][103][104][105] Studies in Pakistan in the 1980s, 1990s, and 2000s indicate that      (4) HAV, hepatitis A virus; n, number of study participants who were anti-HAV positive; n.r., not reported; pts, patients; y, years.   more than half of children acquire immunity by their preschool years and nearly all adolescents and adults are immune. [94][95][96] Earlier seroprevalence surveys conducted in Saudi Arabia generally reported high proportions of children and teenagers with acquired immunity, 23,36,40,45 but noted lower seroprevalence in urban areas. 33,42 In the same population, studies after the 2000s generally report lower immunity levels 21,30,41 (Table 4). Studies from Kuwait, 118 Tunisia, 108 and the United Arab Emirates 131 conducted in the 2000s show 10.2 to 31.5% 131 HAV seroprevalence in children, and immunity in only 21% of young adults. 130 In Morocco, the high overall HAV prevalence reported in 2005-2006 in children confirms that Morocco is an intermediately endemic area for HAV infection and is entering a transitional phase. 136 Infection rates in children were high in other countries, such as in Libya, 135 Yemen, 132 Somalia, 121,122 Syria, 128 Tunisia 111 and in some special populations, such as those living in Palestine. 137

Temporal trends in HAV seroprevalence
Five studies reported HAV seroprevalence over time. 21,24,42,92,109 These studies reveal that the HAV frequency rate is decreasing over time; this reduced force of infection has significantly increased the average age at infection. One study documented an increase in HAV occurrence in a large Egyptian hospital from 2.1% (1983) to 34% (2002); this is likely caused by delayed initial exposure to HAV resulting in symptomatic cases at older ages. 92 Most of these cases occurred in older age groups, with only 20 (29%) of 68 infected patients being younger than five years, compared to 80% in 1983, and 22 (32%) of 68 patients above 9 years of age compared with 1 (20%) of 5 patients in 1983. 92

Socioeconomic aspects of HAV seroprevalence
HAV seroprevalence data by area of residence was reported in 10 studies. Overall, a higher seroprevalence of HAV was generally reported among individuals residing in rural areas compared to urban areas, likely due to limited access to improved water sources and to sanitation facilities. 23,26,47,52,55,59,60,62,89,90 Four studies reported data on HAV seroprevalence by socioeconomic status; 21,23,75,81 collectively the data shows that individuals or families from low-income households (36.8 to 87.7%) had higher HAV seropositivity compared to individuals from middle-or high-income households (5.9 to 50.7%).

Discussion
To our knowledge, this is the first comprehensive review of hepatitis A epidemiology in the EMR. We expect the findings of this review to help raise awareness and inform the development of appropriate interventional strategies to manage the evolving epidemiological situation in the region as well as globally. In recent decades, HAV seroprevalence has been declining in most parts of the world, mainly due to improvement in socioeconomic status, better access to clean water, sanitation, and in some cases, to active immunization. In the EMR, HAV seroprevalence rates are generally high with recent evidence indicating a delay of viral exposure into adulthood in most countries of the region. 140 This change leaves older children, adolescents, and adults more likely to develop overt disease. Similar observations have been made in other developing countries in Asia (India, Thailand, and Taiwan), 141 Latin America (Argentina, Brazil, Chile, Dominican Republic, Mexico, and Venezuela) 142 including a recent comprehensive review on all Latin American countries, 143 and Africa (South Africa). 144 Given that the severity of HAV symptoms increases with age, 3 it may be appropriate for the EMR countries with a high proportion of susceptible older children and adults to consider implementing HAV vaccination programs. These programs could target certain populations such as young children, and simultaneously could foster improvements in access to clean water, sanitation, and hygiene in the region. 2 Considering the evolving situation with regard to international trade (specifically food and travel) and rising conflict in the region, the epidemiological context in the EMR is expected to have consequences for global public health. Measures such as immunization of risk groups like travelers and food handlers, and the creation of a common standard for the health, reception, and reporting of asylum seekers and refugees from this region should be considered. Advances in modern transportation and global accessibility have boosted the travel industry in the region. In Europe, travel continues to cause both imported cases and secondary transmission. 145 Travel to and from countries with high or intermediate HAV endemicity is a risk factor for infection in residents of countries with low HAV endemicity, such as countries in Europe and North America. Individuals may be exposed to HAV during their travels and thus may transmit the imported infection within their communities, leading to subsequent outbreaks. 140 GeoSentinel, the global surveillance network of the International Society of Travel Medicine reported 120 cases of hepatitis A among 737 international travelers to India, Egypt, Morocco and Mexico, between 2007 and 2011. 146 Another study reported that 80 cases of HAV infection were diagnosed among European travelers returning from Egypt. 147 Two concurrent travel-related HAV clusters were detected in eight European countries after travel to Morocco. 148 EMR countries have undergone rapid urbanization and changes in lifestyle and consumer demands. These changes have had a profound effect on the production, supply, availability, and consumption of food. 149 In the last few decades, international food trade from the EMR has accelerated but the recent coronavirus disease 2019 (COVID-19) pandemic has, at least temporarily, brought this to a standstill. Notwithstanding the effects of COVID-19 on global travel and trade, risks of HAV contaminated food remain high, with the WHO Foodborne Disease Burden Epidemiology Reference Group estimating that more than 90,000 deaths occurred worldwide due to acute viral hepatitis in 2010. Nearly 30,000 of those deaths could be due to foodborne transmission of HAV. 150 The risk is elevated when food products are imported from high and intermediate HAV endemic countries or from countries with poor food processing practices. 149 Furthermore, the HAV capsid has a highly stable molecular structure which allows it to persist in certain types of foods for extended periods of time and withstand common food processing practices. 151 The European Union has reported two HAV infection outbreaks in 2013 due to frozen strawberries imported from Egypt and Morocco, 152 and imported pomegranate seeds from Egypt have been traced as the source of an HAV infection outbreak in British Columbia, Canada, in 2012. 153 Some areas in the EMR (i.e., Iraq, Iran, Syria, Palestine, and Yemen) are at the center of turmoil, with conflicts having a significant impact in these countries and beyond the region. The economic and health situation in these countries continues to worsen. 154 Regional instability leads to difficulties in addressing public health issues while migratory movements are continuously being reported. One of the ramifications of migration from areas of conflict is the resurgence of infectious diseases such as hepatitis A, especially in low-endemic countries. This could possibly be driven by the influx of refugees and their settlement in underserved camps. Poor sanitation, hygiene, and inadequate supply of clean food and water in refugee camps are likely contributors to the rapid spread of HAV. A HAV outbreak was reported among Syrian refugees residing in hosting camps in Greece in 2016. 155 A 45% increase in HAV cases among asylum seekers was reported in Germany in 2015-2016. 156 In 2015, asylum applications in Europe amounted to approximately 1.35 million-a record since data collection began in 2008 and more than twice the number of applications than in 2014. 157 While the COVID-19 pandemic may have slowed this trend due to restrictions affecting global travel and trade, 158 careful monitoring of the situation and timely action to mitigate the risks of hepatitis A outbreaks are warranted.
There are some limitations of this review which are worth noting in the interpretation of the overall findings. A time limit was applied to the searches to identify publications beginning from 1980 onwards. This was considered appropriate by the authors to notice any shift in the burden of disease. More than half of the eligible studies identified in this review are from three countries (Egypt, Iran, and Saudi Arabia). Therefore, generalizability is limited to the countries from which most studies were reported and should not be extended to countries with very poor data representation, i.e., those with a few relevant studies or none at all. There is also a lack of consistency in study designs and age groups reported across the studies which prevents direct comparisons. This is compounded by the fact that the region is diverse with different income levels and healthcare infrastructure. Another factor that limits comparison is the different time periods considered within the studies. Finally, the data reported in this review e2073146-12 was collected prior to COVID-19 and as such it does not reflect the travel and trade restrictions imposed on the countries in the EMR during the years 2020 and 2021. Due to these reasons, the overall findings should be interpreted with caution.

Conclusion
In the EMR, hepatitis A remains a significant cause of acute viral hepatitis. While the populations in low-income countries show universal immunity to HAV, the middle-and high-income countries report increasing numbers of susceptible older children, adolescents, and adults which co-exist in rapidly developing societies. Given this shift in endemicity, it is expected that most of the countries in this region would experience a transition in HAV endemicity in the next decades, the consequence of which will be a higher burden of disease as the population ages, and the occurrence of outbreaks. The public health value of childhood vaccination against hepatitis A and of vaccinating only high-risk groups such as those traveling from and to the region should be assessed within this changing epidemiological context in the EMR.

Funding
GlaxoSmithKline Biologicals S.A. funded this study and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals S.A. also took in charge and all costs associated with the development and the publishing of this manuscript.