Introduction

Although frequently underappreciated as a significant health problem, recent publications have highlighted the potential importance of diarrhea as a continuing cause of morbidity and mortality among older children, adolescents and adults living in low- and middle-income countries [1], [2]. Similar to children under five years of age, diarrhea incidence and mortality estimates among older age groups are highest in Africa and South Asia [1], [2]. The burden of diarrheal episodes beyond early childhood may have substantial public health and economic impact at the family, community and national levels that extends well beyond mortality alone.

Recent global and regional assessments have served to reiterate the importance of cholera, shigellosis and enterotoxigenic Escherichia coli (ETEC) as causes of diarrhea morbidity and mortality among infants and young children <5 years of age [3]–[5]. While, such reviews have illustrated that cholera is of comparatively greater importance among children under-five than among older children and adults, limited data are available to describe the potential contribution of Shigellae and ETEC to diarrhea incidence and mortality among older children, adolescents and adults [6]. Improved estimates of the diarrhea burden due to Shigellae and ETEC are needed in this under-evaluated age group and, in particular, for the regions of South Asia and Africa, which represent 30% of annual diarrhea episodes among persons ≥5 years of age and 82% of global diarrhea deaths among children under-five [2], [7]. Assessing the burden from Shigellae and ETEC is needed because both pathogens represent longstanding World Health Organization (WHO) targets for vaccine development. Given the advent of increasing donor support for enteric vaccine research, vaccine development efforts for both pathogens have been reenergized, and there is a growing need to better define the full range of risk-groups in which new vaccines or other preventive interventions could be used [8].

The purpose of this review is to quantify the overall burden of diarrhea due to Shigellae and ETEC among older children, adolescents, and adults in Africa and South Asia. Improved understanding of the etiology of diarrhea in this population is of critical importance for vaccine development and implementation of more targeted prevention and control strategies in the two regions with the highest level of diarrhea morbidity and mortality in the world.

Methods

With the goal of estimating the annual number of cases, hospitalizations, and deaths due to Shigellae and ETEC among older children and adults in South Asia and Africa, we employed two separate methodological approaches that each relied on published epidemiological data.

Results

Method 1

The database search yielded 5,000 unique titles. Title and abstract review narrowed the results to 327 and 42 papers, respectively. Following full-paper review, one additional article met all inclusion/exclusion criteria (Figure 1) [12]. No published reports of DSS data were identified that met all inclusion and exclusion criteria.

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Figure 1. Results of the systematic review.

Footnotes: ¹Main reasons for exclusion: no outcome of interest (n = 23); review paper (n = 5); under-five data only (n = 5); data combined across under-five and older age groups (n = 4); retrospective review of hospital records (n = 3); special population (n = 1). ² Source: Fischer Walker CL, Black RE (2010) Diarrhoea morbidity and mortality in older children, adolescents, and adults. Epidemiol Infect 138: 1215–1226.

https://doi.org/10.1371/journal.pntd.0002705.g001

Diarrhea accounted for 12.5% of deaths in AFR and 19.85% of deaths in SEAR among persons 5–14 years of age. Among persons ≥15 years of age, diarrhea-proportionate mortality was 6.35% in AFR and 3.7% in SEAR. In 2010, there were approximately 452,348 diarrhea deaths in AFR and 481,189 diarrhea deaths in SEAR. Using previously reported estimates of the proportion of diarrhea hospitalizations due to Shigellae and ETEC as a proxy for death (i.e. 4.3% and 9.5%, respectively) [6], we estimated 19,451 deaths due to Shigellae and 42,973 deaths due to ETEC in AFR; and 20,691 deaths due to Shigellae and 45,713 deaths due to ETEC in SEAR in 2010 (Table 1).

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Table 1. Estimated number of deaths due to Shigellae and ETEC among older children and adults in Africa and South Asia using Method 1.

https://doi.org/10.1371/journal.pntd.0002705.t001

Method 2

We identified a review of studies aiming to isolate at least 4 pathogens, which estimated the mean percentage of ETEC-positive outpatients at 4.6% and the mean percentage of Shigellae-positive outpatients at 9.3% [6]. Using these figures, we estimated an annual incidence of 15.0 million ETEC episodes in AFR, 28.7 million ETEC episodes in SEAR, 30.4 million episodes due to Shigellae in AFR, and 58.1 million episodes due to Shigellae in SEAR among persons ≥5 years of age (Table 2).

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Table 2. Estimated number of episodes due to hospitalizations, and deaths due to Shigellae among older children and adults in Africa and South Asia using Method 2.

https://doi.org/10.1371/journal.pntd.0002705.t002

We were unable to identify a published CFR for ETEC diarrhea among older children and adults and, therefore, did not generate an estimate of ETEC deaths in this population using method 2. The CFR for ETEC diarrhea is extremely low among treated cases, and although most cases go untreated, the CFR for untreated cases is unknown [13].

We applied the CFR for hospitalized cases due to Shigellae ≥5 years of age, 0.33%, to the number of hospitalized cases due to Shigellae and estimated 5,308 Shigellae-associated deaths in AFR and 10,158 Shigellae-associated deaths in SEAR (Table 2) [11]. This estimate is an upper bound, since the CFR was reported as a range from 0–0.33% [11].

Discussion

We employed two distinct methodological approaches to approximate the burden of shigellosis among older children, adolescents and adults. Estimates of deaths due to Shigellae occurring among this population in 2010 were elevated by method 1 compared to method 2 (Shigellae-associated deaths by method 1: 19,451 in AFR and 20,691 in SEAR in 2010; Shigellae-associated deaths by method 2: 5,308 in AFR and 10,158 in SEAR). We were unable to utilize method 2 to derive estimates of the burden of ETEC diarrhea among older children, adolescents and adults; however, method 1 yielded approximately 42,973 ETEC associated deaths in AFR and 45,713 ETEC associated deaths in SEAR in 2010.

Although approaches such as these used to estimate diarrhea mortality may be prone to limitations and bias, such techniques are necessary due to the lack of reliable cause-of-death data in resource-poor settings where vital registration is suboptimal or nonexistent. Verbal autopsy data are widely used to estimate cause of death among children under five years of age [7], but the volume of data available is many times what we found here for older children and adults. The scarcity of these data limits what can be soundly estimated with complex multivariate models.

In this paper, we focused specifically on estimating Shigellae- and ETEC-specific morbidity and mortality among older children, adolescent and adults. The Global Burden of Disease Study (GBD) published estimates of older child and adult mortality attributable to Shigellae and ETEC but, because the study did not outline the specific components of the model used to approximate pathogen-specific incidence and mortality [3], we were unable to draw comparisons between the GBD methods and our own. Globally, the GBD Study reported 779,800 total diarrhea deaths, 79,200 deaths due to Shigellae deaths and 82,100 deaths due to ETEC deaths among persons ≥5 years of age in 2010 [3]. In comparison, our method 1 estimates for AFR and SEAR are greater for total diarrhea and ETEC-associated deaths (i.e. 933,537 and 88,686, respectively) (Table 1). Our method 1 and method 2 estimates of deaths due to Shigellae for these regions are less than the GBD global estimates (i.e. 40,142 by method 1and 15,466 by method 2) (Table 1).

Two recent studies have published data on diarrhea etiology among children <5 years of age. Lanata, et. al. published a review of diarrhea etiology among children hospitalized for diarrhea and estimated that together Shigellae and ETEC may account for 9.8% of child diarrhea deaths [14]. The Global Enteric Multicenter Study (GEMS) published estimates of diarrhea due to Shigellae and ETEC illustrating that both pathogens accounted for about 22% of diarrhea deaths among cases of moderate-to-severe diarrhea aged 0–23 months [4]. Our analysis bolsters and expands upon the findings of these studies, which were conducted among children under-five years of age, to provide evidence that Shigellae and ETEC continue to impact health from early childhood through school, adolescence and adulthood.

Both methodological approaches proposed by our review have strengths and limitations. Method 1 estimates were more than three-fold higher than method 2 estimates for AFR and about two-fold higher for SEAR for Shigellae. The use of hospitalizations as a proxy for estimating pathogen-specific deaths may have led method 1 to overestimate the true number of Shigellae-associated deaths in regions where hospitalizations for moderate episodes due to Shigellae that do not progress to death are higher than expected. While this approach is less than ideal, it is the only alternative in the absence of relevant data on pathogen-specific deaths and is similar to the method used for estimating deaths attributable to rotavirus [15].

On the other hand, the median incidence rates used by method 2 were derived from a systematic review that excluded outbreak studies and studies conducted in high diarrhea season, resulting in presumably underestimated incidence figures [2]. In addition, method 2 utilizes the proportion of annual cases due to Shigellae that occurred at a treatment facility (i.e. 0.053) as a proxy for episodes severe enough to progress to death [11]; since this estimate was derived from a systematic review of 9 studies conducted in 6 Asian countries, it is possible that facility treatment was not sought for a proportion of severe episodes due to Shigellae. Thus, method 1 and method 2 estimates may respectively represent the upper and lower bounds for Shigellae-associated deaths among persons ≥5 years of age in 2010.

A major strength of method 1 is that it enables approximation of regional pathogen-specific mortality in the absence of data on etiologic cause of death. As previously noted, the use of hospitalizations as a proxy for mortality may overestimate the true number of pathogen-specific deaths and is therefore a limitation of method 1; this assumes that the risk of requiring hospitalization for diarrhea due to Shigellae or ETEC is equivalent to the overall risk of death due to these pathogens. The results of method 1 are also limited by the restricted geographic scope of the region-specific proportionate mortality estimates, which were pooled from six studies conducted in four AFR and three SEAR countries. In addition, method 1 used pathogen-specific hospitalization proportions from a previously published review with its own limitations, including scarcity of data, heterogeneity of laboratory methods over time, and limited geographic scope [6].

Method 2 is limited by the dearth of literature on CFRs for shigellosis and ETEC diarrhea among older children, adolescents and adults. For diarrhea due to Shigellae, we were unable to identify CFRs for non-hospitalized cases among persons ≥5 years of age and were thus required to approximate the number of hospitalized cases prior to applying the case-fatality rate. We were unable to identify any CFRs for ETEC diarrhea. Estimates generated by this method would therefore be improved by additional research into the case fatality associated with community cases due to Shigellae and ETEC.

The data are more robust for deaths due to Shigellae and ETEC in SEAR as opposed to AFR and, therefore, estimates for SEAR may be more accurate than those for AFR. The majority of studies contributing to the pathogen-specific hospitalization proportions used by method 1 were conducted in SEAR (5 of 8 Shigella studies and 3 of 4 ETEC studies) and none were conducted in AFR. For method 2, median incidence data were lacking for AFR, and to compensate for this deficit, we applied SEAR incidence rates to the AFR 2010 population as was previously documented in the literature [2].

Although methods 1 and 2 are restricted by the availability of relevant data, we feel that the data are sufficiently robust to draw estimates for AFR and SEAR for both pathogens by method 1 and for Shigellae by method 2. We are unable to generate confidence intervals to illustrate the precision around our estimates due to the unavailability of uncertainty ranges for our models' inputs, and we acknowledge that confidence around our estimates is likely wide. However, we also assert that we have undertaken a transparent approach in forming these estimates and that this is an important strength of this analysis.

In comparison with selected enteric infections, such as typhoid fever and cholera, this study highlights that Shigellae and ETEC are also of importance to diarrhea morbidity among older children, adolescents and adults. Applying published incidence rates for cholera and typhoid to the 2010 population, it is evident that in 2010 the rank of these pathogens from highest to lowest incidence in both SEAR and AFR was: Shigellae, ETEC, typhoid (SEAR: 3.1 million; AFR: 2.9 million) and cholera (SEAR: 1.6 million; AFR: 1.2 million) (Table 2) [5], [16].

While our mortality estimates are grouped together for persons 5–14 and ≥15 years of age, it is noteworthy that there is an age curve of diarrhea deaths among older children, adolescents and adults. DSS data from Bangladesh illustrate that 3%, 11% and 86% of total diarrhea deaths occur among persons 5–14 years, 15–54 years and ≥55 years of age, respectively [17]. Additional data with regard to pathogen-specific mortality rates would be useful to help us understand if this curve is consistent across all pathogens. Furthermore, additional research is warranted to assess age-specific and etiology-specific incidence rates.

The estimates generated by this review shed light on the epidemiology of shigellosis and ETEC diarrhea among older children, adolescents, and adults in AFR and SEAR. Understanding the burden of these pathogens in two regions of high diarrhea incidence is of critical importance for improving prevention and treatment. Together, methods 1 and 2 suggest that Shigellae and ETEC are responsible for a significant degree of morbidity and mortality among persons ≥5 years of age in AFR and SEAR. As such, Shigellae and ETEC contribute to lost productivity and school absenteeism, especially among older children 5–14 years of age. The development of vaccines and other interventions aimed at the prevention of these pathogens among older children, adolescents and adults is thus essential to furthering social and economic development.