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.

Plain Language Summary

What is the context?

• Hepatitis A is a viral liver disease caused by the hepatitis A virus.

• It is generally transmitted by ingestion of contaminated food or water or through contact with an infected person.

• Disease severity increases with age. Children under 6 years of age are usually asymptomatic, while adults are the most affected.

• Limited information exists on the number of cases and transmission of hepatitis A in the Eastern Mediterranean region, which includes 21 countries and Palestine, as defined by the World Health Organization.

What is new?

• We performed a literature review to summarize data on hepatitis A disease in the Eastern Mediterranean region over the last 40 years (1980-2020). As information for many countries is scarce or outdated, most of the data is from Egypt, Iran and Saudi Arabia.

• We found that:

  • Hepatitis A virus is the most common cause of acute viral hepatitis.

  • Hepatitis A exposure varied according to the country’s income level.

  • Low- and middle-income countries showed a universal immunity to hepatitis A virus, although this is not the case anymore.

What is the impact?

• Hepatitis A infections have decreased worldwide. Lower exposure to the virus has led to an increase in the susceptible population (including adolescent and adults).

• Hepatitis A vaccination for children and high-risk groups such travelers should be considered in the Eastern Mediterranean region.

KEYWORDS:

• Eastern Mediterranean Region
• endemicity
• hepatitis A
• incidence
• seroprevalence

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.^6–8 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).

Figure 1. Plain language summary.

Methods

A comprehensive review utilizing a systematic approach was performed to identify published literature on HAV incidence and seroprevalence in the WHO-EMR¹³ 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).

Table 1. Inclusion and exclusion criteria.

	Inclusion criteria	Exclusion criteria
Population	Hepatitis A disease (not limited to risk groups or specific ages)	Populations with chronic diseases or underlying comorbidities that are not representative of the general population
Intervention	Not restricted by intervention	N.A.
Comparator	Not restricted by comparator	N.A.
Outcome	Proportion of HAV among all acute viral hepatitis (HAV IgM)	N.A.
	HAV seroprevalence (HAV IgG)
Study design	Primary peer-reviewed research observational studies	Non-primary research
	Cohort studies	Systematic reviews
	Case-control studies	Meta-analyses
	Cross-sectional studies	Narrative reviews (without methods)
	Ecological studies	Predictions via modeling methods
	Outbreak investigations	Case reports
	Periodic surveys	Letter to editor
	Non-peer-reviewed research	Newspaper
	Reports from national and regional databases or websites	Editorial
		Comment
		Opinions
Limits
Publication date	From 1980 onwards	All publications before 1980
Geographic scope	Afghanistan, Bahrain, Djibouti, Egypt, Islamic Republic of Iran, Republic of Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syrian Arab Republic, Tunisia, United Arab Emirates, Yemen	All countries apart from those considered eligible
Language	English, French, Arabic	-

Note: HAV, hepatitis A virus; IgG, immunoglobulin G; IgM, immunoglobulin M; N.A, not applicable.

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.).

Results

Included studies and their characteristics

Overall, the search yielded 315 publications (MEDLINE: n = 296; gray literature: n = 19). Of these, 157 were excluded at the title or abstract screening phase and 35 were further excluded after full-text review. Finally, a total of 123 publications for 22 countries in the EMR were included in the final review (Figure 2).

Figure 2. PRISMA flow diagram showing the study research and selection process.

Among the 123 publications which provided data on hepatitis A disease for the 21 countries in the EMR and Palestine (Table 2), the distribution of publications by country was: Saudi Arabia (n = 30),^19–46 followed by Iran (n = 28),^47–74 Egypt (n = 19),^75–93 Pakistan (n = 8),^94–101 Lebanon (n = 6),^102–107 Tunisia (n = 6),^108–113 Iraq (n = 4),^114–117 Kuwait (n = 3),^118–120 Somalia (n = 3),^121–123 Djibouti (n = 2),^124,125 Jordan (n = 2),^126,127 Syria (n = 2),^128,129 UAE (n = 2),^130,131 Yemen (n = 2),^132,133 Afghanistan (n = 1),¹³⁴ Libya (n = 1),¹³⁵ Morocco (n = 1),¹³⁶ Palestine (n = 1),¹³⁷ Qatar (n = 1)¹³⁸ and Sudan (n = 1) (Figure 3).¹³⁹

Figure 3. Classification of included countries by income level and hepatitis a vaccination status.

Notes: NIP, national immunization program; UAE: United Arab Emirates.

Table 2. Demographic characteristics and HAV vaccination status of the 22 EMR countries.

COUNTRY	Geographic region	World bank classification (2017)^Citation14	GAVI eligibility (2017)^Citation140	HAV vaccination in NIP	Year of vaccination implementation	Availability of vaccine (private/public)	Recommendation status	Reimbursement
Afghanistan	Asia	LIC	Yes	No	N.A.	Private	-	No
Bahrain	Middle East	HIC	No	Yes	2012	Public	15 and 24 months High risk groups and travellers^Citation141	Reimbursed
Djibouti	Middle East	LMIC	NIP through GAVI support	No	-	-	No	-
Egypt	Africa	LMIC	No	No	-	Private	-	No
Iran, Islamic Republic Of	Asia	UMIC	No	No	-	Private	-	No
Iraq	Middle East	UMIC	No	High risk group	-	Private	-	No
Jordan	Middle East	UMIC	No	No	-	Private	-	No
Kuwait	Middle East	HIC	No	No	-	Private	Citizens born prior to 1990 and healthcare personnel^Citation141	No
Lebanon	Middle East	UMIC	No	No	-	Private	-	No
Libya	Africa	UMIC	No	No	-	-	No	-
Morocco	Africa	LMIC	No	No	-	Private	18 and 24 months	In private market: covered by insurance
Oman	Middle East	HIC	No	Yes	2020	Both	13 and 24 months	Reimbursed
Pakistan	Asia	LMIC	Yes	No	N.A.	Private	*	No
Palestine	Middle East	LIC	No	No	-	Private	18 and 24 months	No
Qatar	Middle East	HIC	No	Yes	2012	Both	12 and 18 months	Reimbursed
Saudi Arabia	Middle East	HIC	No	Yes	2008	Both	18 and 24 months	In private market: covered by insurance, Public: FoC for Saudi, non-Saudi and illegal immigrants
Somalia	Asia	LIC	Yes	No	-	-	-	-
Sudan, Republic of	Africa	LIC	Yes	No	-	-	-	No
Syrian Arab Republic	Middle East	LMIC	Yes	No	-	Private	-	No
Tunisia	Africa	LMIC	No	Yes	2019	Both	12 months and 6 years	In private market: covered by insurance, Public: FoC
United Arab Emirates	Middle East	HIC	No	No	-	Private	High risk groups and travelers^Citation141	No
Yemen	Middle East	LIC	Yes	No	-	-	-	-

*No local recommendations. Recommended by international bodies for HAV in case people are traveling to Pakistan.

FoC, free of charge; GAVI, the vaccine alliance; HIC, high-income countries; LIC, low-income countries; LMIC, low- middle- income countries; N.A., Not applicable; NIP, national immunization programs; UMIC, Upper-middle income countries; WHO-EMR, World Health Organization—Eastern Mediterranean Region.

No study dealing with HAV could be identified for Bahrain and Oman. Among the countries included in this review, childhood hepatitis A vaccination has been implemented in the national immunization programs (NIP) of Bahrain, Oman, Qatar, Saudi Arabia, and Tunisia and only for high-risk groups in Iraq (Table 2). In most countries, however, hepatitis A vaccination is available in the private market (Table 2 and Figure 3).

Main findings from the review

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). One study reported an increase in the proportion of HAV from 2001–2004 (40.2%) to 2014–2017 (89.7%); and reported a reduction in the proportion of patients infected with HAV before five years of age and an increase in the proportion of patients infected in an older age 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).

Table 3. Occurrence of HAV among acute viral hepatitis cases (41 studies).

Studies by country	Data period, year(s)	Study population (number, age restrictions)	HAV, % (n)
Djibouti
Coursaget et al., 1998^Citation125	1992–1993	111 pts, 2–65 y	33% (37)
Egypt
Fouad et al., 2018^Citation85	2015–2017	268 pts, 1–18 y	97% (260)
Talaat et al., 2019^Citation89	2014–2017	9,321 pts, all ages	93.4% (7,806)
Hasan et al., 2016^Citation86	2007–2008	123 pts, 2–18 y	13.8% (17)
Eldin et al., 2010^Citation84	2007–2008	235 pts, 1–65 y	8.1% (19)
Meky et al., 2006^Citation88	2002–2005	47 community residents, 2–77 y	8.5% (4)
Talaat et al., 2010^Citation90	2001–2004	5,909 pts, all ages	28.5% (1,684)
Zakaria et al., 2007^Citation92	2001–2002 1983	200 pts, all ages 235 pts, all ages	34% (68) 2.1% (5)
Hyams et al., 1992^Citation87	1987–1988	73 outpatients, ≤13 y	41% (30)
Divizia et al., 1999^Citation83	1993	202 hospitalized pts, 1–73 y	10.4% (21)
Youssef et al., 2013^Citation91	n.r.	33 hospitalized children	33% (11)
Zaki Mel et al., 2008^Citation93	n.r.	162 children	34.1% (n.r)
Darwish et al., 1992^Citation82	n.r.	200 adult pts, 20–40 y	4.5% (9)
Iran
Karimi et al., 2015^Citation57	2010	70 pts	68.6% (48)
Iraq
Al-Naaimi et al., 2012^Citation114	2010–2011	2,629 pts, all ages	44.8% (1,206)
Turky et al., 2011^Citation117	2005–2006	2,975 pts, all ages	41% (1,219)
Marcus et al., 1993^Citation115	n.r.	107 pts, 1.5–65 y	40.2% (43)
Rassam et al., 1989^Citation116	n.r.	253 hospitalized pts, 3–65 y	15% (39)
Kuwait
Al-Kandari et al., 1986^Citation120	1983–1984	1,788 pts, all ages	1.5% (26)
Al-Kandari et al., 1987^Citation119	1980–1984	52 pregnant pts, 15–44 y	11.5% (6)
Lebanon
Shamma’a et al., 1984^Citation106	1980–1981	93 pts, >12 y	35.5% (33)
Pakistan
Khan et al., 2011^Citation99	2007–2008	89 pts, all ages	6.1% (4)
Ahmed et al., 2010^Citation97	1987–2007	346 outpatients, all ages	3.5% (12)
Waheed-uz-Zaman et al., 2006^Citation101	2003–2004	626 pts, all ages	40.6% (252)
Syed et al., 2003^Citation100	1994–1999	658 pts, 11 y and over	64.4% (424)
Haider et al., 1994^Citation98	1991	93 hospitalized pts, all ages	5.4% (5)
Qatar
Glynn et al., 1985^Citation138	1981	126 hospitalized pts, 13–52 y	5.5% (7)
Saudi Arabia
Al-Tawfiq et al., 2008^Citation32	2000–2005	1,214 pts, 1–94 y	10% (120)
Memish et al., 2003^Citation43	1999–2001 • 1999: • 2000: • 2001:	3,490 pts, all ages • 1,194 pts • 1,039 pts • 1,257 pts	8.2% (286) • 6.7% (80) • 6.9% (72) • 10.7% (134)
Fathalla et al., 2000^Citation40	1987–1999	683 pediatric pts	65% (641)
Ayoola et al., 2001^Citation37	1997–1998	246 pts, all ages	37% (91)
Arif et al., 1995^Citation34	1993–1994	133 pts, all ages	38.3% (51)
Yohannan et al., 1990^Citation46	1987	47 pts, <12 y	72% (34)
Al-Majed et al., 1990^Citation28	n.r.	23 pts, all ages	82.6% (19)
Al-Knawy et al., 1997^Citation27	n.r.	132 hospitalized pts, >3 y	81.8% (108)
Sudan
Hyams et al., 1991^Citation139	1987–1988	80 outpatients, <14 y	33.8% (27)
Syria
Al-Azmeh et al., 1999^Citation129	1995–1998	193 pts, >12 y	53.9% (104)
Tunisia
Neffatti et al., 2017^Citation110	2014–2015	92 pts, 1-62 y	21.7% (20)
Gharbi-Khelifi et al., 2012^Citation112	2006–2008	400 pts, 1-60 y	19.8% (79)
Hellera et al., 2014^Citation113	2004–2005	105 pts, 15–65 y	34.3% (36)
Yemen
Gunaid et al., 1997^Citation133	n.r.	78 pts, ≥13 y	5.1% (4)

HAV, hepatitis A virus; n, number of study participants who were anti-HAV positive; n.r., not reported; pts, patients; y, years.

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.

Table 4. Seroprevalence of HAV (77 studies).

Studies by country	Data period, year(s)	Study population (number, age restrictions)	HAV seroprevalence (IgG), % (n*)
Afghanistan
Carmoi et al., 2009^Citation134	2008	102 anicteric pts, 5–65 y	99% (101) • <15 y: 91.7% • ≥15 y: 100%
Djibouti
Fox et al., 1988^Citation124	1987	400 healthy adults	98.5% (394)
Egypt
El-Karaksy et al., 2008^Citation77 and El-Karaksy et al., 2006^Citation78	2004	101 children with chronic liver disease (CLD), <18 y	85.1% (86) • <5 y: 62.1% • ≥5 y: 94.4%
Al-Aziz et al., 2008^Citation75	2002–2003	296 children with minor illnesses, 2.5–18 y	61.4% (181) • 2.5–6 y: 53.1% • 6–9 y: 56.4% • 9–18 y: 73.8%
Salama et al., 2007^Citation81	2003–2004	426 children with minor medical problems,3–18 y	86.2% (367) <6 y: 64.3% 6–10 y: 85.3% 11–15 y: 90.3% >15 y: 90%
Darwish et al., 1996^Citation76	1994	155 healthy community residents, 1–67 y	100% (155) • 1–3 y: 100% • ≤67 y: 100%
Kamel et al., 1995^Citation79	1992	1,259 healthy community residents, all ages	97.2% (1224) • 0–4 y: 92.7% • 5–9 y: 97.8% • 10–14 y: 97.9% • 15–19 y: 97.5% • 20–24 y: 96.6% • 25–29 y: 97.9% • 30–34 y: 95.5% • 35–39 y: 100% • 40–44 y: 93.3% • 45–49 y: 100% • 50–54 y: 97.6% • 55–59 y: 93.3% • 60–64 y:100% • 65–69 y: 100% • >70 y: 100%
Omar et al., 2000^Citation80	n.r.	228 community residents, preschool children	26.3% (60)
Iran
Mirzaei et al., 2016^Citation60	2014–2015	108 hemophilic pts, 4–85 y	77.8% (84)
Hesamizadeh et al., 2016^Citation53	2014	559 volunteer blood donors, >18 y	70.7% (395) • 18–27 y: 26.7% • 28–37 y: 59.8% • 38–47 y: 91.2% • >47 y: 94.8%
Hosseini Shokouh et al., 2015^Citation74	2012–2014	270, healthy medical students, 18–30 y	34.8% (94)
Vasmehjani et al., 2015^Citation73	2012–2013	159, CLD pts, 21–68 y	79.2% (126) • 21–30 y: 28.6% • 31–40 y: 91.4% • 41–50 y: 93.9% • <50 y: 95%)
Izadi et al., 2016^Citation55	2011–2013	1,554, healthy soldiers, 18–60 y	80.3% (1,248) • <20 y: 72.2% • 20–30 y: 79.1% • >30 y: 92.4%
Farajzadegan et al., 2014^Citation52	2003–2013	11,857 cumulative population of 16 studies (systematic review), all ages	51%–66%
Jahanbakhsh et al., 2018^Citation56	2012	569 homeless adults, 18–60 y	94.3% (nr) • <42 y: 90.3% • ≥42 y: 98.1%
Asaei et al., 2015^Citation48	2011–2012	1,030, healthy individuals, 0.5–95 y	66.2% (682) • 6–15 y: 18.3% • 16–29 y 79.4% • 30–55 y: 94.3% • ≥56 y: 98.2%
Bayani et al., 2013^Citation50	2011–2012	466 healthy healthcare workers	71% (330) • 20–29 y: 57.8% • 30–39 y: 77.1% • >40 y: 86.3%
Rabiee et al., 2013^Citation63	2011	1,813, healthy university students	39.8% (722)
Shoaei et al., 2012^Citation69	2010–2011	117, chronic hepatitis C pts	94.9% (111) • ≤30 y: 93.1% • 31–40 y: 93.3% • 41–50 y: 100% • 51–60 y: 100% • ≥61 y: 100%
Vakili et al., 2014^Citation72	2010	1,028, healthy 1^st year medical students,17-27 y	68.5% (704)
Saffar et al., 2012^Citation67	2010	984, community residents, 1–30 y	19.2% (189) • 1–2.9 y: 5.7% • 3–6.9 y: 9.1% • 7–10.9 y: 20.4% • 11–17.9 y: 34.8% • 18–30 y: 68.4%
Mostafavi et al., 2016^Citation62 and Hoseini et al., 2016^Citation54	2009–2010	2,494, national health survey participants,10–18 y	50.4%–78.8% across provinces 64% (1,597)
Sofian et al., 2010^Citation70	2009	1,065, pediatric hospital pts, 0.5–20 y	61.6% • 0.5–1.9 y: 61.5% • 2–5.9 y: 51.7% • 6–10.9 y: 52.9% • 11–15.9 y: 65.2% • 16–20 y: 85.0%
Taghavi et al., 2011^Citation71	2008–2009	1,050, pre-marriage lab analysis, 15–63 y	88.2% (927) • <20 y: 79.3% • 20–30 y: 91.3% • >30 y: 99%
Ramezani et al., 2011^Citation64	2008	351, blood donors, 17–60 y	94.9% (333)
Saneian et al., 2014^Citation68	2007	361, healthy medical students	75.3% (272)
Alian et al., 2011^Citation47	2007	1,034, community residents, 1–25 y	38.9% (402) • 1–5 y: 8.9% • 5–15 y: 15.8% • 15–25 y: 64.3%
Mohebbi et al., 2012^Citation61	2006–2007	551, community residents, 1–83 y	90.0% (496) • <30 y: 85.7% • 30–60 y: 90.7% • >60 y: 93.9%
Merat et al., 2010^Citation59	2006	1,869, community residents, 18–65 y	86%
Davoudi et al., 2010^Citation51	2005–2006	247 HIV+, 5–74 y	96.3% (238)
Ataei et al., 2008^Citation49	2006	816, community residents, >6 y	8.3%
Roushan et al., 2007^Citation65	2004–2005	392, HBsAg+ pts, 10–70 y	82.1% (332) • 10–19 y: 59.4% • 20–29 y: 89.8% • >29 y: 97.5%
Mehr et al., 2004^Citation58	2002	1,018, children in pediatric hospital, 0.5–15 y	22.3% (227)
Saberifiroozi et al., 2005^Citation66	n.r.	204, pts in liver clinic, adults	98% (200)
Jordan
Hayajneh et al., 2015^Citation127	2008	3,066, community residents, 0–85 y	51% • ≤1 y: 24% • 1–2 y: 26% • 2–4 y: 32% • 5–9 y: 44% • 10–14 y: 63% • 15–19 y: 78% • >20 y: 94%
Kuwait
Alkhalidi et al., 2009^Citation118	2003–2004	2,851, healthy adults	28.6% (816) • 18–27 y: 24.2% • 28–40 y: 51% • 41–60 y: 56.5%
Lebanon
Melhem et al., 2015^Citation104	2012–2013	283, blood donors	72% • 19–29 y: 60% • 30–39 y: 77% • 40–49 y: 94% • 50–59 y: 91%
Bizri et al., 2006^Citation102	1999–2000	902, school children, 14–18 y	71.3% (643)
Kalaajieh et al., 2000^Citation103	1996–1998	740, pediatric clinic pts, 0.5–15 y	29.3% (217) • 0.5–6 y: 14.7–21% • 7–15 y: 37.6–40.1%
Sacy et al., 2005^Citation105	1999–2000	606, healthy volunteers visiting or working in four hospitals, 1–30 y	43.2% (262) • 1–5 y: 10.5% • 6–10 y: 27.7% • 11–15 y: 57.4% • 16–20 y: 70.1% • 21–30 y: 78.1%
Shamma’a et al., 1982^Citation107	n.r.	772, mixed sample of pts	• Lebanese adults: 97.7% (474/485) • Pediatric group: 79.5% (136/171) • Foreign adults: 38.8% (45/116)
Libya
Gebreel et al., 1983^Citation135	1979–1981	400, school children, 3–18 y	60%–100%
Morocco
Bouskraoui et al., 2009^Citation136	2005–2006	150, children, 0.5-14 y	51% • ≤6 y: 45.2% • >6–14 y: 70.3%
Palestine
Yassin et al., 2001^Citation137	n.r.	396, school children, 6–14 y	93.7% • 6 y: 87.8% • 14 y: 97.5%
Pakistan
Aziz et al., 2007^Citation95	2002–2004	380, children from squatter settlements,<18 y	≥14 y: 100%
Agboatwalla et al., 1994^Citation94	1990–1991	258, healthy children (239) and adults (19)	55.8% (144) • <5 y: 41% (98/239) • 30–50 y: 100% (19/19)
Hamid et al., 2002^Citation96	n.r.	233, adult outpatients with CLD	• 97.8% (228)
Saudi Arabia
Alshabanat et al., 2013^Citation31	2006–2010	44,679, viral hepatitis pts, all ages	17% (7,566)
Al-Faleh et al., 2008^Citation21	2007–2008	1,357, school children, 16–18 y	18.6% (253)
El-Gilany et al., 2010^Citation39	2006–2007	950, children attending regular vaccination schedule, 1–6 y	33.8% (321)
Almuneff, et al., 2006^Citation29	2001–2005	4,006, healthcare workers	67%
Almuneef et al., 2006^Citation30	2005	2,399, all ages	28.9% (694) • <8 y: 7.1% • 8–11 y: 14.5% • 12–15 y: 30.6% • ≥16 y 52%
Jaber, 2006^Citation41	2004	527, aged 4–14 y	•28.7%
Al-Ghamdi et al., 2004^Citation26	2003	650, children − 1st year primary school	8.2% (53)
Fathalla et al., 2000^Citation40	1987–1999	11,674, healthy children and adults (18–50 y)	86% (10,029) • children: 65% • adults: 78.8% Detailed in children: • <6 y: 3% • 6–<8 y: 62% • 8–<10 y: 71% • 10–<12 y: 83% • 12–<18 y: 93%
Al-Faleh et al., 1999^Citation24	1997	5,355, community residents, children 1–12 y	25% (1,331) • 1–2 y: 16% • 3–4 y: 22% • 5–6 y: 25% • 7–8 y: 29% • 9–10 y: 34% • 11–12 y: 34%
Khalil et al., 1998^Citation42	1995–1996	592, children in regular appointments or inpatient care, <16 y	30.2% (179) • 0.5–2 y: 12.5% • 3–4 y: 14.7% • 5–6 y: 20.3% • 7–8 y: 40.4% • 9–10 y: 32% • 11–12 y: 44.3% • 13–15 y: 48.6%
Al Rashed, 1997^Citation23	1989	4,375, community residents, children, 1–10 y	52.4%
Ashraf et al., 1986^Citation35	1985	55, hemodialysis pts, all ages	100%
Ashraf et al., 1986^Citation36	1984–1985	395, healthy blood donors or minor illness pts, all ages	89% (353) • <0.5 y 65.5% • 0.5–2 y: 60% • 3–5 y: 83.3% • 6–12 y: 97.8% • >13 y: 100%
Babaeer et al., 2011^Citation38	n.r.	1,050, pts, >2 y	33.1% (348) • 2–5 y: 17% • 6–9 y: 21.1% • 10–14 y: 28.8% • 15–19 y: 27.2% • 20–24 y: 34.3% • 25–29 y: 38.2% • 30–34 y: 47.7% • >35 y: 49.2%
Al-Faleh et al., 2010^Citation22	n.r.	1,157, school children, 16–18 y	16.4% (190)
Arif, 1996^Citation33	n.r.	1,418, community residents, all ages	68.0% (964) 1–12 y: Riyadh, 24.7%; Gizan, 35.1% >13 y: Riyadh, 77.6%; Gizan, 90.9%
Ramia, 1986^Citation45	n.r.	1,015, Riyadh residents, all ages	82.5% (837) • <1 y: 67.9% • 1–4 y: 38.6% • 5–9 y: 61.3% • 10–15 y: 81.5% • 16–19 y: 83.5% • 20–29 y: 91% • 30–39 y: 93.5% • ≥40 y: 95%
Somalia
Hassan-Kadle et al., 2018^Citation121	[4 studies published from 1984 to1994]	Participants in the 4 studies, all ages	90.2% • <1 y: 61.5% • 1–10 y: 91.9% • 11–19 y: 96.3% • 20–39 y: 91.3% • ≥40 y: 87%
Bile et al., 1992^Citation122	n.r.	672, children in 2 residential institutions, <18 y	By institution: • 96% (Shebeli) • 59% (Societe Organization Sociale)
Mohamud et al., 1992^Citation123	n.r.	593, 0-83 y	•90%
Syria
Antaki et al., 2000^Citation128	n.r.	849, all ages	89% (754) • 1–5 y: 50% • 6–10 y: 81% • 11–15 y: 95% • 16–20 y: 94% • 21–30 y: 97% • 31–40 y: 98% • 41–50 y: 100%
Tunisia
Neffatti et al., 2017^Citation110	2014–2015	216 pregnant women, 19-46 y	98.6% (212)
Louati et al., 2009^Citation109	2000 & 2007	376 blood donors, 18–30 y		2000	2007
			18–20 y	91.9%	80.6%
			21–25 y	93.7%	84.9%
			>26 y	99.2%	92.1%
			Total	94.9%	85.9%
Rezig et al., 2008^Citation111	n.r.	2,482, community residents, children and young adults	87.9% (2,180) • 5- <10 y: 83.9% • 10–15: 90.5% • 16–25 y: 91.9%
Letaief et al., 2005^Citation108	2002	2,400, school children, 5–20 y	60% • 5–10 y: 44% • 10–15 y: 58% • 15–20 y: 83%
United Arab Emirates
Sheek-Hussein et al., 2012^Citation130	2011–2012	261, healthy medical students	21%
Sharar et al., 2008^Citation131	2004–2005	367 children attending hospital, 1–12 y	20.1% (74) • 1–6 y: 10.2% • 6–12 y: 31.5%
Yemen
Bawazir et al., 2010^Citation132	2005	538, pts attending hospitals, all ages	86.6% (466) • 0–1 y: 53% • <18 y: 80.8% • ≥18 y: 98.8%

CLD, chronic liver disease; HAV, hepatitis A virus; HBsAg, surface antigen of the hepatitis B virus; HIV, human immunodeficiency virus; IgG, immunoglobulin G; n, the number of study participants who were anti-HAV positive (* if available); n.r. not reported; pts, patients; y, year(s).

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.^102–105 Studies in Pakistan in the 1980s, 1990s, and 2000s indicate that more than half of children acquire immunity by their preschool years and nearly all adolescents and adults are immune.^94–96 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 Emirates¹³¹ 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 Tunisia¹¹¹ 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 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.

Authors’ contributions

SB, MAG, MK, YL, OO, and KH performed the literature search. All authors participated in the design or implementation or analysis, and interpretation of the study; and the development of this manuscript. All authors had full access to the data and gave final approval before submission.

Acknowledgements

The authors thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Amandine Radziejwoski coordinated publication development and editorial support. Amrita Ostawal (Arete Communication UG, on behalf of GSK) provided writing support.

Disclosure statement

All authors are employed by the GSK group of companies. SB, SÖ, MAG, MK, YL, KH, and DS hold shares in the GSK group of companies. All authors declare no other financial and non-financial relationships and activities.

Additional information

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.