Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden of Disease 2015 study

Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global... Int J Public Health (2018) 63 (Suppl 1):S109–S121 https://doi.org/10.1007/s00038-017-1008-z O R I G IN AL ARTI CL E Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden of Disease 2015 study GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Received: 30 April 2017 / Revised: 20 June 2017 / Accepted: 28 June 2017 / Published online: 3 August 2017 The Author(s) 2017. This article is an open access publication Abstract deaths, 95% UI: 53,640–79,486). DALYs per 100,000 Objectives Diarrheal diseases (DD) are an important cause ranged from 304 (95% UI 228–400) in Kuwait to 38,900 of disease burden, especially in children in low-income (95% UI 25,900–54,300) in Somalia. settings. DD can also impact children’s potential livelihood Conclusions Our findings will guide evidence-based health through growth faltering, cognitive impairment, and other policy decisions for interventions to achieve the ultimate sequelae. goal of reducing the DD burden. Methods As part of the Global Burden of Disease study, we estimated DD burden, and the burden attributable to Keywords Eastern Mediterranean Region  Burden of specific risk factors and etiologies, in the Eastern disease  Diarrheal diseases Mediterranean Region (EMR) between 1990 and 2015. We calculated disability-adjusted life-years (DALYs)—the sum of years of life lost and years lived with disability—for Introduction both sexes and all ages. Results We estimate that over 103,692 diarrhea deaths Rigorous public health efforts resulted in a significant occurred in the EMR in 2015 (95% uncertainty interval: decline in mortality due to diarrheal diseases (DD) over the 87,018–124,692), and the mortality rate was 16.0 deaths past 20 years. However, these diseases continue to cause a per 100,000 persons (95% UI: 13.4–19.2). The majority of major global disease burden, especially in children under these deaths occurred in children under 5 (63.3%) (65,670 5 years of age. In addition, the incidence of childhood diarrhea in low-income countries has not declined as rapidly as mortality (GBD 2015 Risk Factors Collaborators This article is part of the supplement ‘‘The state of health in the 2016). In the most recent Global Burden of Disease (GBD) Eastern Mediterranean Region, 1990–2015’’. study, DD was the fourth-leading cause of death among children under 5, responsible for 499,000 deaths (95% UI: The members of GBD (Global Burden of Disease) 2015 Eastern Mediterranean Region Diarrhea Collaborators are listed at the end of 447,000–558,000), representing 8.6% of all deaths in this the article. Ali H. Mokdad, on behalf of GBD 2015 Eastern age group (GBD 2015 Risk Factors Collaborators 2016). Mediterranean Region Diarrhea Collaborators, is the corresponding For those who survive these illnesses and suffer from author. repeated infections by enteric pathogens during the critical Electronic supplementary material The online version of this early years of life; DD can lead to serious, lifelong health article (doi:10.1007/s00038-017-1008-z) contains supplementary consequences such as environmental enteric dysfunction material, which is available to authorized users. (EED), growth faltering, impaired cognitive development, & GBD 2015 Eastern Mediterranean Region Diarrhea and reduced immune response to infection and vaccina- Collaborators tions (Guerrant et al. 2013). mokdaa@uw.edu DD pathogen etiologic contribution may vary depending on the study’s geographic location, duration, or the popu- Institute for Health Metrics and Evaluation, 2301 5th Ave, lation sampled (Lindsay et al. 2015). These infections are Suite 600, Seattle, WA 98121, USA 123 S110 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators believed to be different in the developing world compared measured in deaths, incidence, and disability-adjusted life- to the developed world with regard to a number of features, years (DALYs), which are the sum of years of life lost including earlier age of onset, multiple repeated exposures, (YLLs) and years lived with disability (YLDs). The etio- greater diversity of pathogens, nutritional status of the host, logical burden was also estimated for 13 pathogens asso- and a number of others, such as co-infection, diet, and ciated with diarrhea. genetics (Heidt et al. 2014). All estimates are produced by year and by age, for both The Eastern Mediterranean Region (EMR) is home to sexes, and for all countries. In accordance with the more than 500 million people, representing a diverse group guidelines for accurate and transparent health estimates of 22 countries. EMR countries have diverse historical reporting (GATHER), code for each step of the estimation backgrounds, political and social contexts, and fiscal and process is available online on GitHub (http://www.ghdx. cultural influences on their health care systems. The region healthdata.org/gbd-2015-code) (Institute for Health Met- has wide variation in per capita gross national product rics and Evaluation). The methods of each of these steps (GNP) (The World Bank 2016), which has a major influ- are summarized below. ence on overall health spending and results in substantial health inequities both within and across countries. During Study region recent years DD prevention efforts that focus on vaccines in the short term and improvements in water, sanitation, The EMR countries were grouped according to per capita and hygiene in the long term have been impeded by war- gross national income (GNI) into low-income countries fare and political unrest in the region. These conflicts and (LICs) [Islamic Republic of Afghanistan (Afghanistan), wars also resulted in a huge problem of internal displace- Djibouti, Somalia, Republic of Yemen (Yemen)]; middle- ment and refugees (Mokdad et al. 2016). income countries (MICs) [Arab Republic of Egypt (Egypt), Many countries in the EMR achieved important suc- Islamic republic of Iran (Iran), Iraq, Jordan, Lebanon, cesses in the fight against DD in the 1970s and 1980s with Libya, Morocco, Pakistan, Palestine, Sudan, Syrian Arab the support of United Nations International Children’s Republic (Syria), Tunisia]; and high-income countries Emergency Fund (UNICEF) and the World Health Orga- (HICs) [Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and nization (WHO) through the National Control of Diarrheal the United Arab Emirates (UAE)]. We defined LICs as Diseases Project (NCDDP) (WHO 1992; Enzley et al. those having a per capita GNI of $1045 or less, MICs as 1997). For example, Egypt’s program, which spanned from those with a per capita GNI between $1046 and $12,735, 1981 to 1991, was credited with significantly improving and HICs as countries with per capita GNI of $12,736 or diarrheal case management (National Control Of Diarrheal greater (The World Bank 2016). Diseases Project 1988; El-Rafie et al. 1990; Cobb et al. 1996). However, over the last two decades, momentum has Mortality slowed (Forsberg et al. 2007). As of the date of this report, rotavirus vaccines have been introduced through National Cause-specific mortality estimates for diarrheal diseases Immunization Programs in only nine countries in the were modeled using a Bayesian ensemble modeling pro- region: Djibouti, Jordan, Libya, Morocco, Qatar, Saudi cess (GBD 2015 Mortality and Causes of Death Collabo- Arabia, Sudan, United Arab Emirates, and Yemen rators 2016). Diarrhea mortality data included vital (PATH 2017). registration and verbal autopsy sources. The modeling In this report, we are updating our previous burden process estimated the mortality rate due to diarrhea for both estimates (Khalil et al. 2016), pathogen distribution, and sexes from 1990 to 2015 for all age groups in every country risk factors for diarrhea in children and adults in the EMR and subnational regions in select countries. We considered for 1990–2015. the following covariates: education, lag-dependent income, underweight, latitude, population density, improved water and sanitation sources, diarrhea risk factors summary, Methods Socio-demographic Index (SDI), and rotavirus vaccine coverage. The ensemble model approach allows for a suite The Global Burden of Disease Study (GBD 2015) is a of models, weighted by out-of-sample predictive validity, systematic, comprehensive effort to quantify health loss to inform the final estimates. from more than 300 diseases and injuries, including diar- rheal diseases and associated risk factors. The GBD esti- Morbidity mation strategy, including for diarrheal diseases, has been described in detail elsewhere (Foreman et al. 2012; Flax- Diarrheal cases were defined as three or more loose stools man et al. 2015). The burden of diarrheal diseases is in a 24-h period. As with mortality, morbidity was modeled 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S111 were estimated using proportion data from published at every year, sex, age, and geographic location in GBD 2015. The morbidity model used DisMod-MR 2.1, a studies to calculate an expected number of annual cases for each country and year, and those estimates were compared Bayesian meta-analytic, age-integrating, mixed-effects model which is available online on EpiViz (http://www. to the World Health Organization case notification data (WHO 2016) to estimate underreporting of cholera. Cho- vizhub/healthdata.org/epi) (Kassebaum et al. 2016). Diar- rhea prevalence and incidence data from a systematic lit- lera deaths were estimated using case fatality data in Dis- Mod-MR. Since C. difficile is frequently associated with erature review, population-representative surveys, and hospital and health care utilization data informed the non- hospital and health care utilization, hospital incidence data were modeled in DisMod-MR using hospital and health fatal model. care utilization data with ICD codes for C. difficile. Etiologies All etiologies were estimated independently and for each year, geography, age, and sex. Diarrhea cases and deaths were attributed to pathogens Risk factors using a counterfactual approach that accounts for exposure to pathogens and for the association between each patho- We also assessed diarrheal DALYs, YLLs, and YLDs gen and diarrhea. A systematic literature review on the proportion of diarrhea cases that test positive for a set of attributable to childhood stunting, suboptimal breastfeed- ing, vitamin A deficiency, zinc deficiency, and water, pathogens was updated for GBD 2015. These data were used in the DisMod-MR framework to estimate the age, sanitation, and hygiene (WASH). Risk factor attribution sex, year, and geographic distribution of pathogens in follows a general counterfactual approach where the exposure and relative risk of diarrhea were used to estimate diarrheal episodes. The population attributable fraction (PAF) was used to identify the fraction of diarrhea cases the burden of the aforementioned risk factors (GBD 2015 Risk Factors Collaborators 2016). and deaths due to each pathogen. The PAF was calculated as: (GBD 2015 Mortality and Causes of Death Collabora- Socio-demographic Index tors 2016). PAF ¼ Proportion  1  ; We evaluate associations between diarrhea and socio-de- OR mographic status using the Socio-demographic Index where Proportion is the proportion of cases positive for a (SDI). The SDI is a composite measure developed for GBD pathogen and the odds ratio (OR) is the odds of diarrhea 2015 that accounts for fertility rate, lag-dependent income given pathogen detection. The odds ratios were from a per capita, and education (GBD 2015 Mortality and Causes systematic reanalysis of the Global Enteric Multicenter of Death Collaborators 2016). To capture the average Study (GEMS) (Kotloff et al. 2013), a multi-site case– relationships for each age–sex group, we applied a simple control study of moderate-to-severe diarrhea in children least squares spline regression of the diarrhea mortality rate under 5 that systematically tested nearly half of the original on SDI. The predicted diarrhea mortality rates from this GEMS samples using a molecular quantitative polymerase regression were used as expected mortality rates based on chain reaction (qPCR) diagnostic (Liu et al. 2016). A SDI. The SDI is scaled from 0 to 1 where 0 represents the mixed-effects conditional logistic regression model esti- lowest possible observed SDI and 1 is the highest. SDI in mated the odds ratios for diarrhea including random effects 2015 in the EMR ranged from 0.27 in Somalia to 0.83 in on site to account for geographic variation. Kuwait. Since the odds of diarrhea given pathogen presence were calculated using the qPCR diagnostic, we adjusted our proportion estimates to be comparable to qPCR-based Results estimates. The sensitivity and specificity of the non- molecular diagnostic techniques from GEMS were evalu- There were 103,692 diarrhea deaths in the EMR in 2015 ated compared to the qPCR diagnostic, and these values (95% uncertainty interval (UI): 87,018–124,692), and the were used to make this adjustment with this formula mortality rate was 16.0 deaths per 100,000 persons (95% (Wickham 2009): UI: 13.4–19.2). The majority of these deaths occurred in children under 5 years old (63.3%) (65,670 deaths, 95% ðProportion  Specificity  1Þ Observed Proportion ¼ : True UI: 53,640–79,486). Although the greatest number of ðSensitivity þ Specificity  1Þ diarrhea deaths occurred in children under 5, diarrhea Vibrio cholerae and Clostridium difficile were estimated mortality was also high in the 70? year age group. In fact, separately from the other pathogens in GBD. Cholera cases of the 22 countries in the EMR, the mortality rate was 123 S112 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Table 1 The number of diarrhea deaths and mortality rate (per 100,000) in 2015 in the Eastern Mediterranean Region for each age group and sex (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 2015) Age Sex Deaths Rate All ages Both 103,691.7 (87,018.3–124,692.2) 15.99 (13.42–19.23) All ages Female 50,679.8 (40,407.1–63,194.3) 16.14 (12.87–20.12) All ages Male 53,011.9 (42,617.5–65,304.5) 15.86 (12.75–19.53) Under 5 Both 65,670.3 (53,639.7–79,485.9) 81.82 (66.83–99.04) Under 5 Female 34,729.4 (26,435.3–45,011.1) 89.09 (67.81–115.46) Under 5 Male 30,940.9 (23,892.9–39,342.5) 74.96 (57.89–95.32) 5–14 years Both 4986.1 (3724.4–6501.8) 3.67 (2.74–4.78) 5–14 years Female 2540.1 (1839.4–3414.2) 3.84 (2.78–5.16) 5–14 years Male 2446 (1623.7–3486.2) 3.5 (2.32–4.99) 15–49 years Both 11,546.4 (7917.3–18,792.8) 3.36 (2.3–5.47) 15–49 years Female 4827.5 (3205.6–8471.4) 2.93 (1.94–5.13) 15–49 years Male 6718.9 (4339.3–10,599.2) 3.76 (2.43–5.94) 50–69 years Both 9457.6 (6095.2–15,147.7) 13.21 (8.51–21.16) 50–69 years Female 3836.5 (2060–6875.3) 10.93 (5.87–19.58) 50–69 years Male 5621.1 (3578.4–8787.7) 15.41 (9.81–24.08) 70? years Both 12,031.2 (9097.8–15,593.3) 70.83 (53.56–91.8) 70? years Female 4746.3 (3404.3–6304.8) 53.74 (38.55–71.39) 70? years Male 7285 (5054.7–10,119.4) 89.34 (61.99–124.1) higher in the 70? age group than the under-5 age group in Diarrhea was also responsible for a large number of 17 countries. Diarrhea mortality in the elderly was highest illness episodes. In 2015, diarrhea incidence was 2.1 (95% in Somalia (1695 per 100,000, 95% UI: 709–2896), fol- UI: 1.9–2.4) per child-year, totaling more than 171 million lowed by Djibouti and Pakistan (Table 1). Diarrhea mor- episodes across the EMR. The incidence was much lower tality decreased over time in the EMR (Table 2; Fig. 1). in adults, including those 70? years old (0.7 per person- Between 1990 and 2015, the number of diarrhea deaths year, 95% UI: 0.69–0.75). The case fatality, expressed as decreased by 54% among all ages (95% UI: 43–62%) and the number of deaths over the number of cases, was 0.1% 65% among children under 5 (95% UI: 55–73%). The in those 70? years old, significantly greater than in chil- fastest rate of decrease among children under 5 occurred in dren under 5 years (0.038%). Case fatality increased non- Iran (97%, 95% UI: 93–99%) and Syria (97%, 95% UI: linearly with incidence (e-Figure 1). Despite the large 94–99%) and the slowest occurred in Somalia (11%, 95% observed reductions in diarrhea mortality between 1990 UI: -40 to 45%) and Qatar (33%, 95% UI: -65 to 72%). and 2015, diarrhea incidence decreased much more mar- Diarrhea mortality among children under 5 varied by ginally (20.7%). time and country. The under-5 diarrhea mortality rate was Among diarrheal etiologies, rotavirus was the leading highest in Somalia, followed by Pakistan, Sudan, and cause of death in 2015 among children under 5 (13,180 Afghanistan (Figs. 2, 3). Due to its high population, the deaths, 95% UI: 9807–17,738), followed by Shigella greatest number of under-5 deaths occurred in Pakistan (10,964 deaths) and enterotoxigenic E. coli (ETEC) (6885 (55,500 deaths, 95% UI: 43,258–70,027). Diarrhea mor- deaths) (Table 3 and e-Figure 1). Among all ages, Shigella tality was associated with trends in the Socio-demographic was the leading cause of diarrheal deaths (19,450 deaths, Index in most geographies (Figs. 2b, 3), but the mortality 95% UI: 10,026–33,996), followed by Aeromonas and rate was much lower in Palestine and Iraq than would be rotavirus. Overall, 99% of diarrheal deaths in 2015 were expected based on SDI alone. The ratio of the observed attributed to at least one etiology (e-Figure 2). mortality rate to the expected mortality rate based on SDI Unsafe water, sanitation, and hygiene were responsible alone was lowest in Syria and Palestine, where mortality for over 95% of diarrhea DALYs in the EMR in 2015 was 3% of the expected value, and highest in Bahrain, (95.1%, 95% UI: 89.2–98.1%), which is comparable with where the mortality was 65% higher than expected based the global total in 2015. The proportion of diarrhea DALYs on SDI alone. Syria and Palestine have moderate SDI and due to unsafe WASH was lowest in Jordan (87.0%) and very low diarrhea mortality rates. highest in Sudan (97.0%) (e-Figure 3). Childhood 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S113 undernutrition was the second-leading risk factor for diar- rheal DALYs, responsible for 74.0% (95% UI: 67.4–79.1%), which is significantly higher than the global total (59.8%, 95% UI: 56.2–63.0%). Suboptimal breast- feeding was responsible for 39.5% of diarrhea DALYs among children under 5 (95% UI: 27.1–52.3%). Vitamin A and zinc deficiency were responsible for less than 10% of diarrhea DALYs among children under 5 (8 and 5%, respectively) and were lower than the global average for these risk factors (12.9 and 6.5%, respectively). Childhood undernutrition PAF ranged from 41.1% in the United Arab Emirates to 86.2% in Sudan. Diarrhea standardized expo- sure variables (SEV), a measure of the prevalence-weigh- ted risk of diarrhea, was highest in Sudan, Afghanistan, and Yemen and lowest in the UAE, Jordan, and Kuwait. Discussion Our study is the most comprehensive assessment of diar- rheal disease burden and the contributions of specific pathogens and risk factors in the EMR to date. In 2015, the estimated diarrhea-associated deaths and DALYs showed a slight decline from the GBD 2013 estimates of 125,000 and nearly 10 million, respectively. We also continue to find significant variation within the region, with LICs and MICs experiencing social unrest bearing the vast majority of diarrheal burden. Our data clearly illustrate the gross health inequity in the region: the HICs experienced a nominal diarrhea burden compared to the substantial burden in all LICs and some MICs. There were no major methodological changes in diar- rhea mortality modeling between GBD 2013 and GBD 2015 but there were updates to the cause of death and non- fatal data. A major difference between GBD 2013 and 2015 was the introduction of the molecular diagnostic case definition for diarrheal etiologies (Liu et al. 2014; GBD 2015 Mortality and Causes of Death Collaborators 2016; GBD 2015 Risk Factors Collaborators 2016; Kassebaum et al. 2016). In the current round of GBD, we used a sys- tematic reanalysis of the Global Enteric Multicenter Study (GEMS) that retested roughly half of the original 22,000 moderate-to-severe stool samples with quantitative poly- merase chain reaction (qPCR) (Liu et al. 2016). In transi- tioning to a molecular diagnostic case definition, we attribute a much larger proportion of diarrhea cases and deaths to etiologies compared to previous rounds of GBD that used non-molecular diagnostics. The Socio-demographic Index was designed to be a measure of the socio-demographic status of a country and is well correlated with the Human Development Index (GBD 2015 Mortality and Causes of Death Collaborators 2016). Still, dramatic changes in development such as Table 2 The number of deaths, disability-adjusted life-years (DALYs), and episodes of diarrhea in the Eastern Mediterranean Region and the diarrhea mortality (per 100,000) and incidence (per person-year) rates among under-5 and all ages in 1990, 2000, and 2015 (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 1990–2015) Year Age Deaths DALYs Cases Number Rate Number Number Rate 1990 Under 5 185,910 (127,308–243,615) 150.3 (102.9–196.9) 16,345,715 (11,335,370–21,282,470) 165,987,520 (146,655,489–187,730,433) 1.34 (1.19–1.52) 2000 Under 5 117,162 (76,746–160,181) 90.8 (59.5–124.1) 10,439,937 (6,959,185–14,117,350) 159,618,414 (140,515,118–181,990,713) 1.24 (1.09–1.41) 2015 Under 5 65,670 (42,393–95,304) 40.9 (26.4–59.4) 6,058,681 (4,045,101–8,618,353) 171,316,814 (152,549,199–193,090,921) 1.07 (0.95–1.20) 1990 All ages 225,746 (162,335–289,224) 30.5 (21.9–39.1) 18,258,180 (13,023,737–23,353,030) 244,994,495 (225,000,870–266,982,282) 0.33 (0.30–0.36) 2000 All ages 159,795 (113,345–210,958) 16.9 (12–22.4) 12,429,100 (8,755,478–16,336,533) 267,079,653 (247,580,591–290,033,675) 0.28 (0.26–0.31) 2015 All ages 103,692 (73,304–145,718) 8 (5.7–11.2) 7,816,119 (5,569,985–10,745,255) 318,037,078 (298,328,603–340,822,655) 0.25 (0.23–0.26) S114 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Fig. 1 Diarrhea mortality rate per 100,000 population, by age, 1990–2015. The mortality rate in the Eastern Mediterranean Region is shown for six age groups over time from 1990 to 2015. Points represent mean estimates and error bars represent 95% uncertainty intervals (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 1990–2015) those that have occurred since the start of political unrest in Fig. 2 Diarrhea mortality among children under 5 in the Easternc Mediterranean Region, 2015. a The diarrhea mortality rate per some of the EMR countries, such as the Syrian civil war, 100,000 among children under 5 in 2015. b Ratio of the observed may be missed or at least result in a lag in the components under 5 diarrhea mortality rate in 2015 to the expected mortality rate that make up the SDI including income, fertility, and based on the Socio-demographic Index only. Values below 1 indicate education. We have previously shown that the SDI is a that the diarrhea mortality rate is lower than would be expected based on the global relationship between mortality and SDI, and values good marker of disease burden, but it may not entirely above 1 indicate higher mortality rates than would be expected capture major sociopolitical upheavals (GBD 2015 Mor- (Global Burden of Disease 2015 study, Eastern Mediterranean tality and Causes of Death Collaborators 2016). Countries, 2015) The introduction of vaccines against diarrheal pathogens may exacerbate inequalities in diarrhea burden. For example, although rotavirus infection was the largest humanitarian emergency would meet WHO cost-effec- contributor to the diarrheal burden of disease, in some tiveness benchmarks (Gargano et al. 2015). countries in the region, rotavirus vaccine is only available One unique contribution of this analysis is the inclusion in the private market. This means that wealthier families, of all age groups. Due to the high disease burden in young who have less need for the vaccine, will gain the primary children, nearly all diarrhea interventions and most diar- benefit from its availability. This is troubling because rhea burden studies are limited to those under 5 years of economic analyses of rotavirus vaccine introduction among age (Boschi-Pinto et al. 2008; Fischer Walker et al. 2012; a number of EMR countries have uniformly suggested that Walker et al. 2013). However, the burden among those vaccine introduction would be cost-beneficial from a over age 70 is substantial, with diarrheal disease-associated societal perspective (Ortega et al. 2009; Connolly et al. deaths totaling nearly one sixth of the number among those 2012; Javanbakht et al. 2015). One study in Somalia (the under 5. The elderly may face increased diarrhea risk due only LIC country) suggested that introduction of rotavirus to immunosenescence and comorbidities, which may also as a special immunization program during a complex necessitate special consideration in their treatment (Trinh 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S115 123 S116 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Fig. 3 The diarrhea mortality rate per 100,000 for the Eastern SDI values in 2015. Error bars illustrate the 95% uncertainty interval Mediterranean Region by country among children under 5 in 1990, for the estimates (Global Burden of Disease 2015 study, Eastern 2000, and 2015. Countries are ordered from top to bottom from lowest Mediterranean Countries, 2015) Socio-demographic Index (Somalia) to highest SDI (Qatar) based on Table 3 The number of diarrhea deaths and the population attributable fraction (PAF) for 13 diarrheal etiologies among under-5 and all ages in the Eastern Mediterranean Region, 2015 (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 2015) Etiology Under 5 All ages Deaths PAF Deaths PAF Adenovirus 4392.37 (1553.83 to 9530.86) 6.69 (2.47 to 13.85) 5285.33 (1885.13 to 11,110.37) 5.1 (1.87 to 10.34) Aeromonas 3850.51 (0 to 29,059.34) 5.83 (-35.98 to 15,315.61 (0 to -44,627.46) 14.72 (-12.52 to 42.15) 41.55) Amoebiasis 1446.31 (0 to 12,799.8) 2.19 (-10.65 to 20.4) 3075.66 (0 to 17,604.66) 2.97 (-3.01 to 17.06) Campylobacter enteritis 5478.32 (1421.6 to 11,408.45) 8.3 (2.35 to 16.53) 5878.95 (1504.27 to 12,465.87) 5.66 (1.51 to 11.74) Cholera 5142.08 (2784.31 to 9223.41) 7.86 (4.27 to 14.08) 9682.46 (5614.73 to 16,600.13) 9.38 (5.37 to 16.13) Clostridium difficile 8.24 (4.89 to 13.04) 0.01 (0.01 to 0.02) 12.59 (8.99 to 17.62) 0.01 (0.01 to 0.02) Cryptosporidiosis 4569.06 (801.68 to 11,545.02) 6.92 (1.26 to 16.99) 4796.2 (699.01 to 12,482.23) 4.62 (0.71 to 11.52) Enteropathogenic E. coli 1639.06 (132.28 to 4608.33) 2.49 (0.21 to 6.85) 1708.03 (141.29 to 4833.27) 1.64 (0.14 to 4.68) infection Enterotoxigenic E. coli infection 6885.39 (2931.74 to 12,386.47) 10.47 (4.76 to 18.53) 11,102.89 (5152.14 to 10.7 (4.92 to 18.28) 20,035.61) Norovirus 2402.25 (769.72 to 5439.75) 3.64 (1.26 to 8.03) 3935.54 (1027.17 to 8670.77) 3.78 (1.06 to 8.32) Other salmonella infections 5559.16 (1663.31 to 12,323.64) 8.46 (2.57 to 18.31) 8752.77 (3002.34 to 18,462.75) 8.43 (3.01 to 17.61) Rotaviral enteritis 13,180.3 (9807.01 to 17,738.4) 20.08 (16.37 to 25.56) 14,454.5 (10,983.35 to 13.96 (11.13 to 17.68) 18,974.79) Shigellosis 10,963.91 (5480.23 to 16.65 (9.02 to 28.57) 19,450.5 (10,025.55 to 18.71 (10.32 to 30.61) 19,387.69) 33,996.23) 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S117 and Prabhakar 2007). The increasing cholera burden in five factors like infectious diseases, acute malnutrition, and EMR countries (Jordan, Palestine, Syria, Bahrain, and inappropriate infant and young child feeding. The lack of Oman) is a cause for concern, as neighboring countries safe drinking water as well as adequate sanitation and remain at high risk of transmission due to the presence and hygiene is especially concerning as a major risk factor for movement of refugee populations among them. DD. Provision of a safe water supply, sanitation, and We found no systematic difference in under-5 diarrhea hygiene is a crucial priority, even in these emergency deaths or DALYs when comparing females to males. A situations. hypothesis that there may exists evidence of differential diarrhea mortality burden by sex is supported by a previous Study limitations analysis of global demographic and health survey (DHS) data. This analysis suggested that reported that girls Our estimates of diarrhea mortality, morbidity, and etiol- 1–4 years old, particularly in the Middle Eastern crescent, ogy attribution are limited by data availability, and are at a mortality disadvantage compared to boys (Hill and although our modeling process seeks to make use of all Upchurch 1995). This could be explained by differences in available data, the number of relevant publications in the health care access and nutritional status. Furthermore, an region is limited and unbalanced between countries. The Egyptian study found some evidence that, even when hierarchical modeling approach allows us to ‘‘borrow’’ parents sought care for their daughters with diarrhea, strength across time and geography to generate the best regional health care providers provided biased treatment in possible estimates. Second, since we only account for the favor of boys (Yount 2003). In contrast, other studies, such acute phase of diarrhea in our YLD estimates, the resulting as a 2009 verbal autopsy study in Iraq, found no difference DALYs severely underestimate diarrhea-associated mor- in under-5 mortality by sex (Awqati et al. 2009). bidity. In future GBD updates, we expect to include long- term sequelae such as stunting and cognitive impairment, Public health consequences of emergencies (Moore et al. 2010; MacIntyre et al. 2014; Colombara et al. in the region 2016) which will better estimate the true burden of disease. Despite these limitations, this analysis also has several The EMR is facing numerous health challenges as a result strengths. GBD methodology ensures internal consistency of previous wars, and recent revolutions and the wars that so that morbidity and mortality cannot be simultaneously followed (Mokdad et al. 2016; Charara et al. 2017) resulted ascribed to competing causes and allows for comparability in a huge refugee problem with millions of refugees and between countries and across regions. massive consequences for the health and well-being of millions of displaced people. The EMR now carries the largest burden of displaced populations globally. Conclusion Out of a total of 50 million refugees and internally displaced persons (IDPs) worldwide, more than 29 million Increased momentum of public health efforts is needed to (9 million refugees and 20 million IDPs) came from the reduce the burden of diarrhea in the EMR, especially in region (WHO EMRO 2015). Syria is currently the world’s lower-income countries and countries experiencing politi- largest source of refugees and IDPs, with more than 40% of cal and social unrest. the population now displaced both inside the country and in Health inequities revealed in our study show that a neighboring states. Afghanistan and Somalia face two of coordinated approach that involves prevention and treat- the longest-spanning refugee situations, with Afghanis ment is needed to address the multiple causes of diarrheal constituting the second-largest refugee group in the world, diseases. Regional health systems need to be strengthened and Somalia facing one of the world’s most complex to achieve the widespread availability and use of oral refugee situations (WHO EMRO 2015). Over the past few rehydration salts, improved nutrition, better sanitation and years, the region saw massive internal displacement in Iraq, hygiene, and increased coverage of rotavirus immuniza- with more than 3 million people fleeing their homes since tion. Improved rates of breastfeeding should be strongly June 2014, and in Yemen, where more than 2.3 million emphasized as one of the effective tools to prevent DD in people have been internally displaced since March 2015 countries’ public health programs. (ACAPS 2015). Due to the high relevance of rotavirus infections in the The impact of these emergencies on public health is EMR (Malek et al. 2010), there is also an urgent need to profound and enduring, affecting both the displaced pop- accelerate the rollout of rotavirus vaccine in the region ulations and host communities. The risk of DD is increased through government immunization programs that would in these settings due to limited access to safe water, rota- ensure access for the children who are most in need. In virus vaccines, and oral rehydration salts, along with other addition, regional governments should begin deliberation 123 S118 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Medicine, Jeddah, Makkah, Saudi Arabia. Khalid A. Altirkawi, MD, to integrate Shigella, ETEC, and other diarrheal vaccines King Saud University, Riyadh, Saudi Arabia. Nelson Alvis-Guzman, that are currently in preclinical and clinical trials into their PhD, Universidad de Cartagena, Cartagena de Indias, Colombia. Nahla Expanded Programs on Immunization (EPI) as soon as they Anber, PhD, Mansoura University, Mansoura, Egypt. Palwasha are approved and licensed. Anwari, MD, Self-employed, Kabul, Afghanistan. Tesfay Mehari Atey, MS, Mekelle University, Mekelle, Ethiopia. Euripide Frinel G. 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Salamati, MD, Sina Trauma and Surgery Research Center, Tehran L. Murray, DPhil, Institute for Health Metrics and Evaluation, University of Medical Sciences, Tehran, Iran. Abdallah M. Samy, PhD, University of Washington, Seattle, Washington, United States. Ain Shams University, Cairo, Egypt. Juan Ramon Sanabria, MD, J Edwards School of Medicine, Marshall Univeristy, Huntington, WV, Compliance with ethical standards United States; Case Western Reserve University, Cleveland, OH, United States. Benn Sartorius, PhD, Public Health Medicine, School of Ethical approval This manuscript reflects original work that has not Nursing and Public Health, University of KwaZulu-Natal, Durban, previously been published in whole or in part and is not under 123 S120 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators consideration elsewhere. All authors have read the manuscript and Foreman KJ, Lozano R, Lopez AD, Murray CJ (2012) Modeling have agreed that the work is ready for submission and accept causes of death: an integrated approach using CODEm. Popul responsibility for its contents. The authors of this paper have com- Health Metr 10:1. doi:10.1186/1478-7954-10-1 plied with all ethical standards and do not have any conflicts of Forsberg BC, Petzold MG, Tomson G, Allebeck P (2007) Diarrhoea interest to disclose at the time of submission. The funding source case management in low- and middle-income countries—an played no role in the design of the study, the analysis and interpre- unfinished agenda. Bull World Health Organ 85:42–48 tation of data, and the writing of the paper. The study did not involve Gargano LM, Tate JE, Parashar UD et al (2015) Comparison of human participants and/or animals; therefore, no informed consent impact and cost-effectiveness of rotavirus supplementary and was needed. routine immunization in a complex humanitarian emergency. Somali case study. Confl Health 9:5. doi:10.1186/s13031-015- 0032-y Funding This research was funded by the Bill & Melinda Gates GBD 2015 Mortality and Causes of Death Collaborators (2016) Foundation. Global, regional, and national life expectancy, all-cause mortal- ity, and cause-specific mortality for 249 causes of death, Conflict of interest The authors declare that they have no conflicts of 1980–2015: a systematic analysis for the Global Burden of interest at this time. Disease Study 2015. Lancet Lond Engl 388:1459–1544. doi:10. 1016/S0140-6736(16)31012-1 Open Access This article is distributed under the terms of the GBD 2015 Risk Factors Collaborators (2016) Global, regional, and Creative Commons Attribution 4.0 International License (http://crea national comparative risk assessment of 79 behavioural, envi- tivecommons.org/licenses/by/4.0/), which permits unrestricted use, ronmental and occupational, and metabolic risks or clusters of distribution, and reproduction in any medium, provided you give risks, 1990–2015: a systematic analysis for the Global Burden of appropriate credit to the original author(s) and the source, provide a Disease Study 2015. Lancet Lond Engl 388:1659–1724. doi:10. link to the Creative Commons license, and indicate if changes were 1016/S0140-6736(16)31679-8 made. Guerrant RL, DeBoer MD, Moore SR et al (2013) The impoverished gut—a triple burden of diarrhoea, stunting and chronic disease. 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Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden of Disease 2015 study

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Int J Public Health (2018) 63 (Suppl 1):S109–S121 https://doi.org/10.1007/s00038-017-1008-z O R I G IN AL ARTI CL E Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden of Disease 2015 study GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Received: 30 April 2017 / Revised: 20 June 2017 / Accepted: 28 June 2017 / Published online: 3 August 2017 The Author(s) 2017. This article is an open access publication Abstract deaths, 95% UI: 53,640–79,486). DALYs per 100,000 Objectives Diarrheal diseases (DD) are an important cause ranged from 304 (95% UI 228–400) in Kuwait to 38,900 of disease burden, especially in children in low-income (95% UI 25,900–54,300) in Somalia. settings. DD can also impact children’s potential livelihood Conclusions Our findings will guide evidence-based health through growth faltering, cognitive impairment, and other policy decisions for interventions to achieve the ultimate sequelae. goal of reducing the DD burden. Methods As part of the Global Burden of Disease study, we estimated DD burden, and the burden attributable to Keywords Eastern Mediterranean Region  Burden of specific risk factors and etiologies, in the Eastern disease  Diarrheal diseases Mediterranean Region (EMR) between 1990 and 2015. We calculated disability-adjusted life-years (DALYs)—the sum of years of life lost and years lived with disability—for Introduction both sexes and all ages. Results We estimate that over 103,692 diarrhea deaths Rigorous public health efforts resulted in a significant occurred in the EMR in 2015 (95% uncertainty interval: decline in mortality due to diarrheal diseases (DD) over the 87,018–124,692), and the mortality rate was 16.0 deaths past 20 years. However, these diseases continue to cause a per 100,000 persons (95% UI: 13.4–19.2). The majority of major global disease burden, especially in children under these deaths occurred in children under 5 (63.3%) (65,670 5 years of age. In addition, the incidence of childhood diarrhea in low-income countries has not declined as rapidly as mortality (GBD 2015 Risk Factors Collaborators This article is part of the supplement ‘‘The state of health in the 2016). In the most recent Global Burden of Disease (GBD) Eastern Mediterranean Region, 1990–2015’’. study, DD was the fourth-leading cause of death among children under 5, responsible for 499,000 deaths (95% UI: The members of GBD (Global Burden of Disease) 2015 Eastern Mediterranean Region Diarrhea Collaborators are listed at the end of 447,000–558,000), representing 8.6% of all deaths in this the article. Ali H. Mokdad, on behalf of GBD 2015 Eastern age group (GBD 2015 Risk Factors Collaborators 2016). Mediterranean Region Diarrhea Collaborators, is the corresponding For those who survive these illnesses and suffer from author. repeated infections by enteric pathogens during the critical Electronic supplementary material The online version of this early years of life; DD can lead to serious, lifelong health article (doi:10.1007/s00038-017-1008-z) contains supplementary consequences such as environmental enteric dysfunction material, which is available to authorized users. (EED), growth faltering, impaired cognitive development, & GBD 2015 Eastern Mediterranean Region Diarrhea and reduced immune response to infection and vaccina- Collaborators tions (Guerrant et al. 2013). mokdaa@uw.edu DD pathogen etiologic contribution may vary depending on the study’s geographic location, duration, or the popu- Institute for Health Metrics and Evaluation, 2301 5th Ave, lation sampled (Lindsay et al. 2015). These infections are Suite 600, Seattle, WA 98121, USA 123 S110 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators believed to be different in the developing world compared measured in deaths, incidence, and disability-adjusted life- to the developed world with regard to a number of features, years (DALYs), which are the sum of years of life lost including earlier age of onset, multiple repeated exposures, (YLLs) and years lived with disability (YLDs). The etio- greater diversity of pathogens, nutritional status of the host, logical burden was also estimated for 13 pathogens asso- and a number of others, such as co-infection, diet, and ciated with diarrhea. genetics (Heidt et al. 2014). All estimates are produced by year and by age, for both The Eastern Mediterranean Region (EMR) is home to sexes, and for all countries. In accordance with the more than 500 million people, representing a diverse group guidelines for accurate and transparent health estimates of 22 countries. EMR countries have diverse historical reporting (GATHER), code for each step of the estimation backgrounds, political and social contexts, and fiscal and process is available online on GitHub (http://www.ghdx. cultural influences on their health care systems. The region healthdata.org/gbd-2015-code) (Institute for Health Met- has wide variation in per capita gross national product rics and Evaluation). The methods of each of these steps (GNP) (The World Bank 2016), which has a major influ- are summarized below. ence on overall health spending and results in substantial health inequities both within and across countries. During Study region recent years DD prevention efforts that focus on vaccines in the short term and improvements in water, sanitation, The EMR countries were grouped according to per capita and hygiene in the long term have been impeded by war- gross national income (GNI) into low-income countries fare and political unrest in the region. These conflicts and (LICs) [Islamic Republic of Afghanistan (Afghanistan), wars also resulted in a huge problem of internal displace- Djibouti, Somalia, Republic of Yemen (Yemen)]; middle- ment and refugees (Mokdad et al. 2016). income countries (MICs) [Arab Republic of Egypt (Egypt), Many countries in the EMR achieved important suc- Islamic republic of Iran (Iran), Iraq, Jordan, Lebanon, cesses in the fight against DD in the 1970s and 1980s with Libya, Morocco, Pakistan, Palestine, Sudan, Syrian Arab the support of United Nations International Children’s Republic (Syria), Tunisia]; and high-income countries Emergency Fund (UNICEF) and the World Health Orga- (HICs) [Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and nization (WHO) through the National Control of Diarrheal the United Arab Emirates (UAE)]. We defined LICs as Diseases Project (NCDDP) (WHO 1992; Enzley et al. those having a per capita GNI of $1045 or less, MICs as 1997). For example, Egypt’s program, which spanned from those with a per capita GNI between $1046 and $12,735, 1981 to 1991, was credited with significantly improving and HICs as countries with per capita GNI of $12,736 or diarrheal case management (National Control Of Diarrheal greater (The World Bank 2016). Diseases Project 1988; El-Rafie et al. 1990; Cobb et al. 1996). However, over the last two decades, momentum has Mortality slowed (Forsberg et al. 2007). As of the date of this report, rotavirus vaccines have been introduced through National Cause-specific mortality estimates for diarrheal diseases Immunization Programs in only nine countries in the were modeled using a Bayesian ensemble modeling pro- region: Djibouti, Jordan, Libya, Morocco, Qatar, Saudi cess (GBD 2015 Mortality and Causes of Death Collabo- Arabia, Sudan, United Arab Emirates, and Yemen rators 2016). Diarrhea mortality data included vital (PATH 2017). registration and verbal autopsy sources. The modeling In this report, we are updating our previous burden process estimated the mortality rate due to diarrhea for both estimates (Khalil et al. 2016), pathogen distribution, and sexes from 1990 to 2015 for all age groups in every country risk factors for diarrhea in children and adults in the EMR and subnational regions in select countries. We considered for 1990–2015. the following covariates: education, lag-dependent income, underweight, latitude, population density, improved water and sanitation sources, diarrhea risk factors summary, Methods Socio-demographic Index (SDI), and rotavirus vaccine coverage. The ensemble model approach allows for a suite The Global Burden of Disease Study (GBD 2015) is a of models, weighted by out-of-sample predictive validity, systematic, comprehensive effort to quantify health loss to inform the final estimates. from more than 300 diseases and injuries, including diar- rheal diseases and associated risk factors. The GBD esti- Morbidity mation strategy, including for diarrheal diseases, has been described in detail elsewhere (Foreman et al. 2012; Flax- Diarrheal cases were defined as three or more loose stools man et al. 2015). The burden of diarrheal diseases is in a 24-h period. As with mortality, morbidity was modeled 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S111 were estimated using proportion data from published at every year, sex, age, and geographic location in GBD 2015. The morbidity model used DisMod-MR 2.1, a studies to calculate an expected number of annual cases for each country and year, and those estimates were compared Bayesian meta-analytic, age-integrating, mixed-effects model which is available online on EpiViz (http://www. to the World Health Organization case notification data (WHO 2016) to estimate underreporting of cholera. Cho- vizhub/healthdata.org/epi) (Kassebaum et al. 2016). Diar- rhea prevalence and incidence data from a systematic lit- lera deaths were estimated using case fatality data in Dis- Mod-MR. Since C. difficile is frequently associated with erature review, population-representative surveys, and hospital and health care utilization data informed the non- hospital and health care utilization, hospital incidence data were modeled in DisMod-MR using hospital and health fatal model. care utilization data with ICD codes for C. difficile. Etiologies All etiologies were estimated independently and for each year, geography, age, and sex. Diarrhea cases and deaths were attributed to pathogens Risk factors using a counterfactual approach that accounts for exposure to pathogens and for the association between each patho- We also assessed diarrheal DALYs, YLLs, and YLDs gen and diarrhea. A systematic literature review on the proportion of diarrhea cases that test positive for a set of attributable to childhood stunting, suboptimal breastfeed- ing, vitamin A deficiency, zinc deficiency, and water, pathogens was updated for GBD 2015. These data were used in the DisMod-MR framework to estimate the age, sanitation, and hygiene (WASH). Risk factor attribution sex, year, and geographic distribution of pathogens in follows a general counterfactual approach where the exposure and relative risk of diarrhea were used to estimate diarrheal episodes. The population attributable fraction (PAF) was used to identify the fraction of diarrhea cases the burden of the aforementioned risk factors (GBD 2015 Risk Factors Collaborators 2016). and deaths due to each pathogen. The PAF was calculated as: (GBD 2015 Mortality and Causes of Death Collabora- Socio-demographic Index tors 2016). PAF ¼ Proportion  1  ; We evaluate associations between diarrhea and socio-de- OR mographic status using the Socio-demographic Index where Proportion is the proportion of cases positive for a (SDI). The SDI is a composite measure developed for GBD pathogen and the odds ratio (OR) is the odds of diarrhea 2015 that accounts for fertility rate, lag-dependent income given pathogen detection. The odds ratios were from a per capita, and education (GBD 2015 Mortality and Causes systematic reanalysis of the Global Enteric Multicenter of Death Collaborators 2016). To capture the average Study (GEMS) (Kotloff et al. 2013), a multi-site case– relationships for each age–sex group, we applied a simple control study of moderate-to-severe diarrhea in children least squares spline regression of the diarrhea mortality rate under 5 that systematically tested nearly half of the original on SDI. The predicted diarrhea mortality rates from this GEMS samples using a molecular quantitative polymerase regression were used as expected mortality rates based on chain reaction (qPCR) diagnostic (Liu et al. 2016). A SDI. The SDI is scaled from 0 to 1 where 0 represents the mixed-effects conditional logistic regression model esti- lowest possible observed SDI and 1 is the highest. SDI in mated the odds ratios for diarrhea including random effects 2015 in the EMR ranged from 0.27 in Somalia to 0.83 in on site to account for geographic variation. Kuwait. Since the odds of diarrhea given pathogen presence were calculated using the qPCR diagnostic, we adjusted our proportion estimates to be comparable to qPCR-based Results estimates. The sensitivity and specificity of the non- molecular diagnostic techniques from GEMS were evalu- There were 103,692 diarrhea deaths in the EMR in 2015 ated compared to the qPCR diagnostic, and these values (95% uncertainty interval (UI): 87,018–124,692), and the were used to make this adjustment with this formula mortality rate was 16.0 deaths per 100,000 persons (95% (Wickham 2009): UI: 13.4–19.2). The majority of these deaths occurred in children under 5 years old (63.3%) (65,670 deaths, 95% ðProportion  Specificity  1Þ Observed Proportion ¼ : True UI: 53,640–79,486). Although the greatest number of ðSensitivity þ Specificity  1Þ diarrhea deaths occurred in children under 5, diarrhea Vibrio cholerae and Clostridium difficile were estimated mortality was also high in the 70? year age group. In fact, separately from the other pathogens in GBD. Cholera cases of the 22 countries in the EMR, the mortality rate was 123 S112 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Table 1 The number of diarrhea deaths and mortality rate (per 100,000) in 2015 in the Eastern Mediterranean Region for each age group and sex (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 2015) Age Sex Deaths Rate All ages Both 103,691.7 (87,018.3–124,692.2) 15.99 (13.42–19.23) All ages Female 50,679.8 (40,407.1–63,194.3) 16.14 (12.87–20.12) All ages Male 53,011.9 (42,617.5–65,304.5) 15.86 (12.75–19.53) Under 5 Both 65,670.3 (53,639.7–79,485.9) 81.82 (66.83–99.04) Under 5 Female 34,729.4 (26,435.3–45,011.1) 89.09 (67.81–115.46) Under 5 Male 30,940.9 (23,892.9–39,342.5) 74.96 (57.89–95.32) 5–14 years Both 4986.1 (3724.4–6501.8) 3.67 (2.74–4.78) 5–14 years Female 2540.1 (1839.4–3414.2) 3.84 (2.78–5.16) 5–14 years Male 2446 (1623.7–3486.2) 3.5 (2.32–4.99) 15–49 years Both 11,546.4 (7917.3–18,792.8) 3.36 (2.3–5.47) 15–49 years Female 4827.5 (3205.6–8471.4) 2.93 (1.94–5.13) 15–49 years Male 6718.9 (4339.3–10,599.2) 3.76 (2.43–5.94) 50–69 years Both 9457.6 (6095.2–15,147.7) 13.21 (8.51–21.16) 50–69 years Female 3836.5 (2060–6875.3) 10.93 (5.87–19.58) 50–69 years Male 5621.1 (3578.4–8787.7) 15.41 (9.81–24.08) 70? years Both 12,031.2 (9097.8–15,593.3) 70.83 (53.56–91.8) 70? years Female 4746.3 (3404.3–6304.8) 53.74 (38.55–71.39) 70? years Male 7285 (5054.7–10,119.4) 89.34 (61.99–124.1) higher in the 70? age group than the under-5 age group in Diarrhea was also responsible for a large number of 17 countries. Diarrhea mortality in the elderly was highest illness episodes. In 2015, diarrhea incidence was 2.1 (95% in Somalia (1695 per 100,000, 95% UI: 709–2896), fol- UI: 1.9–2.4) per child-year, totaling more than 171 million lowed by Djibouti and Pakistan (Table 1). Diarrhea mor- episodes across the EMR. The incidence was much lower tality decreased over time in the EMR (Table 2; Fig. 1). in adults, including those 70? years old (0.7 per person- Between 1990 and 2015, the number of diarrhea deaths year, 95% UI: 0.69–0.75). The case fatality, expressed as decreased by 54% among all ages (95% UI: 43–62%) and the number of deaths over the number of cases, was 0.1% 65% among children under 5 (95% UI: 55–73%). The in those 70? years old, significantly greater than in chil- fastest rate of decrease among children under 5 occurred in dren under 5 years (0.038%). Case fatality increased non- Iran (97%, 95% UI: 93–99%) and Syria (97%, 95% UI: linearly with incidence (e-Figure 1). Despite the large 94–99%) and the slowest occurred in Somalia (11%, 95% observed reductions in diarrhea mortality between 1990 UI: -40 to 45%) and Qatar (33%, 95% UI: -65 to 72%). and 2015, diarrhea incidence decreased much more mar- Diarrhea mortality among children under 5 varied by ginally (20.7%). time and country. The under-5 diarrhea mortality rate was Among diarrheal etiologies, rotavirus was the leading highest in Somalia, followed by Pakistan, Sudan, and cause of death in 2015 among children under 5 (13,180 Afghanistan (Figs. 2, 3). Due to its high population, the deaths, 95% UI: 9807–17,738), followed by Shigella greatest number of under-5 deaths occurred in Pakistan (10,964 deaths) and enterotoxigenic E. coli (ETEC) (6885 (55,500 deaths, 95% UI: 43,258–70,027). Diarrhea mor- deaths) (Table 3 and e-Figure 1). Among all ages, Shigella tality was associated with trends in the Socio-demographic was the leading cause of diarrheal deaths (19,450 deaths, Index in most geographies (Figs. 2b, 3), but the mortality 95% UI: 10,026–33,996), followed by Aeromonas and rate was much lower in Palestine and Iraq than would be rotavirus. Overall, 99% of diarrheal deaths in 2015 were expected based on SDI alone. The ratio of the observed attributed to at least one etiology (e-Figure 2). mortality rate to the expected mortality rate based on SDI Unsafe water, sanitation, and hygiene were responsible alone was lowest in Syria and Palestine, where mortality for over 95% of diarrhea DALYs in the EMR in 2015 was 3% of the expected value, and highest in Bahrain, (95.1%, 95% UI: 89.2–98.1%), which is comparable with where the mortality was 65% higher than expected based the global total in 2015. The proportion of diarrhea DALYs on SDI alone. Syria and Palestine have moderate SDI and due to unsafe WASH was lowest in Jordan (87.0%) and very low diarrhea mortality rates. highest in Sudan (97.0%) (e-Figure 3). Childhood 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S113 undernutrition was the second-leading risk factor for diar- rheal DALYs, responsible for 74.0% (95% UI: 67.4–79.1%), which is significantly higher than the global total (59.8%, 95% UI: 56.2–63.0%). Suboptimal breast- feeding was responsible for 39.5% of diarrhea DALYs among children under 5 (95% UI: 27.1–52.3%). Vitamin A and zinc deficiency were responsible for less than 10% of diarrhea DALYs among children under 5 (8 and 5%, respectively) and were lower than the global average for these risk factors (12.9 and 6.5%, respectively). Childhood undernutrition PAF ranged from 41.1% in the United Arab Emirates to 86.2% in Sudan. Diarrhea standardized expo- sure variables (SEV), a measure of the prevalence-weigh- ted risk of diarrhea, was highest in Sudan, Afghanistan, and Yemen and lowest in the UAE, Jordan, and Kuwait. Discussion Our study is the most comprehensive assessment of diar- rheal disease burden and the contributions of specific pathogens and risk factors in the EMR to date. In 2015, the estimated diarrhea-associated deaths and DALYs showed a slight decline from the GBD 2013 estimates of 125,000 and nearly 10 million, respectively. We also continue to find significant variation within the region, with LICs and MICs experiencing social unrest bearing the vast majority of diarrheal burden. Our data clearly illustrate the gross health inequity in the region: the HICs experienced a nominal diarrhea burden compared to the substantial burden in all LICs and some MICs. There were no major methodological changes in diar- rhea mortality modeling between GBD 2013 and GBD 2015 but there were updates to the cause of death and non- fatal data. A major difference between GBD 2013 and 2015 was the introduction of the molecular diagnostic case definition for diarrheal etiologies (Liu et al. 2014; GBD 2015 Mortality and Causes of Death Collaborators 2016; GBD 2015 Risk Factors Collaborators 2016; Kassebaum et al. 2016). In the current round of GBD, we used a sys- tematic reanalysis of the Global Enteric Multicenter Study (GEMS) that retested roughly half of the original 22,000 moderate-to-severe stool samples with quantitative poly- merase chain reaction (qPCR) (Liu et al. 2016). In transi- tioning to a molecular diagnostic case definition, we attribute a much larger proportion of diarrhea cases and deaths to etiologies compared to previous rounds of GBD that used non-molecular diagnostics. The Socio-demographic Index was designed to be a measure of the socio-demographic status of a country and is well correlated with the Human Development Index (GBD 2015 Mortality and Causes of Death Collaborators 2016). Still, dramatic changes in development such as Table 2 The number of deaths, disability-adjusted life-years (DALYs), and episodes of diarrhea in the Eastern Mediterranean Region and the diarrhea mortality (per 100,000) and incidence (per person-year) rates among under-5 and all ages in 1990, 2000, and 2015 (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 1990–2015) Year Age Deaths DALYs Cases Number Rate Number Number Rate 1990 Under 5 185,910 (127,308–243,615) 150.3 (102.9–196.9) 16,345,715 (11,335,370–21,282,470) 165,987,520 (146,655,489–187,730,433) 1.34 (1.19–1.52) 2000 Under 5 117,162 (76,746–160,181) 90.8 (59.5–124.1) 10,439,937 (6,959,185–14,117,350) 159,618,414 (140,515,118–181,990,713) 1.24 (1.09–1.41) 2015 Under 5 65,670 (42,393–95,304) 40.9 (26.4–59.4) 6,058,681 (4,045,101–8,618,353) 171,316,814 (152,549,199–193,090,921) 1.07 (0.95–1.20) 1990 All ages 225,746 (162,335–289,224) 30.5 (21.9–39.1) 18,258,180 (13,023,737–23,353,030) 244,994,495 (225,000,870–266,982,282) 0.33 (0.30–0.36) 2000 All ages 159,795 (113,345–210,958) 16.9 (12–22.4) 12,429,100 (8,755,478–16,336,533) 267,079,653 (247,580,591–290,033,675) 0.28 (0.26–0.31) 2015 All ages 103,692 (73,304–145,718) 8 (5.7–11.2) 7,816,119 (5,569,985–10,745,255) 318,037,078 (298,328,603–340,822,655) 0.25 (0.23–0.26) S114 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Fig. 1 Diarrhea mortality rate per 100,000 population, by age, 1990–2015. The mortality rate in the Eastern Mediterranean Region is shown for six age groups over time from 1990 to 2015. Points represent mean estimates and error bars represent 95% uncertainty intervals (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 1990–2015) those that have occurred since the start of political unrest in Fig. 2 Diarrhea mortality among children under 5 in the Easternc Mediterranean Region, 2015. a The diarrhea mortality rate per some of the EMR countries, such as the Syrian civil war, 100,000 among children under 5 in 2015. b Ratio of the observed may be missed or at least result in a lag in the components under 5 diarrhea mortality rate in 2015 to the expected mortality rate that make up the SDI including income, fertility, and based on the Socio-demographic Index only. Values below 1 indicate education. We have previously shown that the SDI is a that the diarrhea mortality rate is lower than would be expected based on the global relationship between mortality and SDI, and values good marker of disease burden, but it may not entirely above 1 indicate higher mortality rates than would be expected capture major sociopolitical upheavals (GBD 2015 Mor- (Global Burden of Disease 2015 study, Eastern Mediterranean tality and Causes of Death Collaborators 2016). Countries, 2015) The introduction of vaccines against diarrheal pathogens may exacerbate inequalities in diarrhea burden. For example, although rotavirus infection was the largest humanitarian emergency would meet WHO cost-effec- contributor to the diarrheal burden of disease, in some tiveness benchmarks (Gargano et al. 2015). countries in the region, rotavirus vaccine is only available One unique contribution of this analysis is the inclusion in the private market. This means that wealthier families, of all age groups. Due to the high disease burden in young who have less need for the vaccine, will gain the primary children, nearly all diarrhea interventions and most diar- benefit from its availability. This is troubling because rhea burden studies are limited to those under 5 years of economic analyses of rotavirus vaccine introduction among age (Boschi-Pinto et al. 2008; Fischer Walker et al. 2012; a number of EMR countries have uniformly suggested that Walker et al. 2013). However, the burden among those vaccine introduction would be cost-beneficial from a over age 70 is substantial, with diarrheal disease-associated societal perspective (Ortega et al. 2009; Connolly et al. deaths totaling nearly one sixth of the number among those 2012; Javanbakht et al. 2015). One study in Somalia (the under 5. The elderly may face increased diarrhea risk due only LIC country) suggested that introduction of rotavirus to immunosenescence and comorbidities, which may also as a special immunization program during a complex necessitate special consideration in their treatment (Trinh 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S115 123 S116 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Fig. 3 The diarrhea mortality rate per 100,000 for the Eastern SDI values in 2015. Error bars illustrate the 95% uncertainty interval Mediterranean Region by country among children under 5 in 1990, for the estimates (Global Burden of Disease 2015 study, Eastern 2000, and 2015. Countries are ordered from top to bottom from lowest Mediterranean Countries, 2015) Socio-demographic Index (Somalia) to highest SDI (Qatar) based on Table 3 The number of diarrhea deaths and the population attributable fraction (PAF) for 13 diarrheal etiologies among under-5 and all ages in the Eastern Mediterranean Region, 2015 (Global Burden of Disease 2015 study, Eastern Mediterranean Region, 2015) Etiology Under 5 All ages Deaths PAF Deaths PAF Adenovirus 4392.37 (1553.83 to 9530.86) 6.69 (2.47 to 13.85) 5285.33 (1885.13 to 11,110.37) 5.1 (1.87 to 10.34) Aeromonas 3850.51 (0 to 29,059.34) 5.83 (-35.98 to 15,315.61 (0 to -44,627.46) 14.72 (-12.52 to 42.15) 41.55) Amoebiasis 1446.31 (0 to 12,799.8) 2.19 (-10.65 to 20.4) 3075.66 (0 to 17,604.66) 2.97 (-3.01 to 17.06) Campylobacter enteritis 5478.32 (1421.6 to 11,408.45) 8.3 (2.35 to 16.53) 5878.95 (1504.27 to 12,465.87) 5.66 (1.51 to 11.74) Cholera 5142.08 (2784.31 to 9223.41) 7.86 (4.27 to 14.08) 9682.46 (5614.73 to 16,600.13) 9.38 (5.37 to 16.13) Clostridium difficile 8.24 (4.89 to 13.04) 0.01 (0.01 to 0.02) 12.59 (8.99 to 17.62) 0.01 (0.01 to 0.02) Cryptosporidiosis 4569.06 (801.68 to 11,545.02) 6.92 (1.26 to 16.99) 4796.2 (699.01 to 12,482.23) 4.62 (0.71 to 11.52) Enteropathogenic E. coli 1639.06 (132.28 to 4608.33) 2.49 (0.21 to 6.85) 1708.03 (141.29 to 4833.27) 1.64 (0.14 to 4.68) infection Enterotoxigenic E. coli infection 6885.39 (2931.74 to 12,386.47) 10.47 (4.76 to 18.53) 11,102.89 (5152.14 to 10.7 (4.92 to 18.28) 20,035.61) Norovirus 2402.25 (769.72 to 5439.75) 3.64 (1.26 to 8.03) 3935.54 (1027.17 to 8670.77) 3.78 (1.06 to 8.32) Other salmonella infections 5559.16 (1663.31 to 12,323.64) 8.46 (2.57 to 18.31) 8752.77 (3002.34 to 18,462.75) 8.43 (3.01 to 17.61) Rotaviral enteritis 13,180.3 (9807.01 to 17,738.4) 20.08 (16.37 to 25.56) 14,454.5 (10,983.35 to 13.96 (11.13 to 17.68) 18,974.79) Shigellosis 10,963.91 (5480.23 to 16.65 (9.02 to 28.57) 19,450.5 (10,025.55 to 18.71 (10.32 to 30.61) 19,387.69) 33,996.23) 123 Burden of diarrhea in the Eastern Mediterranean Region, 1990–2015: Findings from the Global Burden… S117 and Prabhakar 2007). The increasing cholera burden in five factors like infectious diseases, acute malnutrition, and EMR countries (Jordan, Palestine, Syria, Bahrain, and inappropriate infant and young child feeding. The lack of Oman) is a cause for concern, as neighboring countries safe drinking water as well as adequate sanitation and remain at high risk of transmission due to the presence and hygiene is especially concerning as a major risk factor for movement of refugee populations among them. DD. Provision of a safe water supply, sanitation, and We found no systematic difference in under-5 diarrhea hygiene is a crucial priority, even in these emergency deaths or DALYs when comparing females to males. A situations. hypothesis that there may exists evidence of differential diarrhea mortality burden by sex is supported by a previous Study limitations analysis of global demographic and health survey (DHS) data. This analysis suggested that reported that girls Our estimates of diarrhea mortality, morbidity, and etiol- 1–4 years old, particularly in the Middle Eastern crescent, ogy attribution are limited by data availability, and are at a mortality disadvantage compared to boys (Hill and although our modeling process seeks to make use of all Upchurch 1995). This could be explained by differences in available data, the number of relevant publications in the health care access and nutritional status. Furthermore, an region is limited and unbalanced between countries. The Egyptian study found some evidence that, even when hierarchical modeling approach allows us to ‘‘borrow’’ parents sought care for their daughters with diarrhea, strength across time and geography to generate the best regional health care providers provided biased treatment in possible estimates. Second, since we only account for the favor of boys (Yount 2003). In contrast, other studies, such acute phase of diarrhea in our YLD estimates, the resulting as a 2009 verbal autopsy study in Iraq, found no difference DALYs severely underestimate diarrhea-associated mor- in under-5 mortality by sex (Awqati et al. 2009). bidity. In future GBD updates, we expect to include long- term sequelae such as stunting and cognitive impairment, Public health consequences of emergencies (Moore et al. 2010; MacIntyre et al. 2014; Colombara et al. in the region 2016) which will better estimate the true burden of disease. Despite these limitations, this analysis also has several The EMR is facing numerous health challenges as a result strengths. GBD methodology ensures internal consistency of previous wars, and recent revolutions and the wars that so that morbidity and mortality cannot be simultaneously followed (Mokdad et al. 2016; Charara et al. 2017) resulted ascribed to competing causes and allows for comparability in a huge refugee problem with millions of refugees and between countries and across regions. massive consequences for the health and well-being of millions of displaced people. The EMR now carries the largest burden of displaced populations globally. Conclusion Out of a total of 50 million refugees and internally displaced persons (IDPs) worldwide, more than 29 million Increased momentum of public health efforts is needed to (9 million refugees and 20 million IDPs) came from the reduce the burden of diarrhea in the EMR, especially in region (WHO EMRO 2015). Syria is currently the world’s lower-income countries and countries experiencing politi- largest source of refugees and IDPs, with more than 40% of cal and social unrest. the population now displaced both inside the country and in Health inequities revealed in our study show that a neighboring states. Afghanistan and Somalia face two of coordinated approach that involves prevention and treat- the longest-spanning refugee situations, with Afghanis ment is needed to address the multiple causes of diarrheal constituting the second-largest refugee group in the world, diseases. Regional health systems need to be strengthened and Somalia facing one of the world’s most complex to achieve the widespread availability and use of oral refugee situations (WHO EMRO 2015). Over the past few rehydration salts, improved nutrition, better sanitation and years, the region saw massive internal displacement in Iraq, hygiene, and increased coverage of rotavirus immuniza- with more than 3 million people fleeing their homes since tion. Improved rates of breastfeeding should be strongly June 2014, and in Yemen, where more than 2.3 million emphasized as one of the effective tools to prevent DD in people have been internally displaced since March 2015 countries’ public health programs. (ACAPS 2015). Due to the high relevance of rotavirus infections in the The impact of these emergencies on public health is EMR (Malek et al. 2010), there is also an urgent need to profound and enduring, affecting both the displaced pop- accelerate the rollout of rotavirus vaccine in the region ulations and host communities. The risk of DD is increased through government immunization programs that would in these settings due to limited access to safe water, rota- ensure access for the children who are most in need. In virus vaccines, and oral rehydration salts, along with other addition, regional governments should begin deliberation 123 S118 GBD 2015 Eastern Mediterranean Region Diarrhea Collaborators Medicine, Jeddah, Makkah, Saudi Arabia. Khalid A. Altirkawi, MD, to integrate Shigella, ETEC, and other diarrheal vaccines King Saud University, Riyadh, Saudi Arabia. Nelson Alvis-Guzman, that are currently in preclinical and clinical trials into their PhD, Universidad de Cartagena, Cartagena de Indias, Colombia. Nahla Expanded Programs on Immunization (EPI) as soon as they Anber, PhD, Mansoura University, Mansoura, Egypt. Palwasha are approved and licensed. Anwari, MD, Self-employed, Kabul, Afghanistan. Tesfay Mehari Atey, MS, Mekelle University, Mekelle, Ethiopia. Euripide Frinel G. 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All authors have read the manuscript and Foreman KJ, Lozano R, Lopez AD, Murray CJ (2012) Modeling have agreed that the work is ready for submission and accept causes of death: an integrated approach using CODEm. Popul responsibility for its contents. The authors of this paper have com- Health Metr 10:1. doi:10.1186/1478-7954-10-1 plied with all ethical standards and do not have any conflicts of Forsberg BC, Petzold MG, Tomson G, Allebeck P (2007) Diarrhoea interest to disclose at the time of submission. The funding source case management in low- and middle-income countries—an played no role in the design of the study, the analysis and interpre- unfinished agenda. Bull World Health Organ 85:42–48 tation of data, and the writing of the paper. The study did not involve Gargano LM, Tate JE, Parashar UD et al (2015) Comparison of human participants and/or animals; therefore, no informed consent impact and cost-effectiveness of rotavirus supplementary and was needed. routine immunization in a complex humanitarian emergency. Somali case study. Confl Health 9:5. doi:10.1186/s13031-015- 0032-y Funding This research was funded by the Bill & Melinda Gates GBD 2015 Mortality and Causes of Death Collaborators (2016) Foundation. Global, regional, and national life expectancy, all-cause mortal- ity, and cause-specific mortality for 249 causes of death, Conflict of interest The authors declare that they have no conflicts of 1980–2015: a systematic analysis for the Global Burden of interest at this time. Disease Study 2015. Lancet Lond Engl 388:1459–1544. doi:10. 1016/S0140-6736(16)31012-1 Open Access This article is distributed under the terms of the GBD 2015 Risk Factors Collaborators (2016) Global, regional, and Creative Commons Attribution 4.0 International License (http://crea national comparative risk assessment of 79 behavioural, envi- tivecommons.org/licenses/by/4.0/), which permits unrestricted use, ronmental and occupational, and metabolic risks or clusters of distribution, and reproduction in any medium, provided you give risks, 1990–2015: a systematic analysis for the Global Burden of appropriate credit to the original author(s) and the source, provide a Disease Study 2015. Lancet Lond Engl 388:1659–1724. doi:10. link to the Creative Commons license, and indicate if changes were 1016/S0140-6736(16)31679-8 made. Guerrant RL, DeBoer MD, Moore SR et al (2013) The impoverished gut—a triple burden of diarrhoea, stunting and chronic disease. 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