Systematic review of diarrhea duration and severity in children and adults in low- and middle-income countries

Background Diarrhea is a leading cause of morbidity and mortality globally; yet the overall burden of diarrhea in terms of duration and severity has not been quantified. As improvements in treatment lead to decreases in diarrhea mortality, it is important to understand the substantial impact of diarrhea morbidity on disability among children and adults worldwide. Methods We conducted a systematic review to generate estimates of duration and severity outcomes for individuals 0-59 mos, 5-15 yrs, and ≥ 16 yrs, and for 3 severity indexes: mild, moderate, and severe. Results We estimate that among children under-five, 64.8% of diarrheal episodes are mild, 34.7% are moderate, and 0.5% are severe. On average, mild episodes last 4.3 days, and severe episodes last 8.4 days and cause dehydration in 84.6% of cases. We estimate that among older children and adults, 95% of episodes are mild; 4.95% are moderate; and 0.05% are severe. Among individuals ≥ 16 yrs, severe episodes typically last 2.6 days and cause dehydration in 92.8% of cases. Conclusions Moderate and severe episodes constitute a substantial portion of the total envelope of diarrhea among children under-five (35.2%; about 588 million episodes). Among older children and adults, moderate and severe episodes account for a much smaller proportion of the total envelope of diarrhea (5%), but the absolute number of such episodes is noteworthy (about 21.5 million episodes among individuals ≥ 16 yrs). Hence, the global burden of diarrhea consists of significant morbidity, extending beyond episodes progressing to death.


Background
Diarrhea is a leading cause of morbidity and mortality across all age groups and regions of the world. Among children 0-59 months of age, diarrhea is responsible for 1.236 million deaths annually and is the second leading cause of death in this age group [1]. Though mortality rates among older children, adolescents, and adults are lower than those observed in children under five, diarrhea still poses a substantial burden accounting for approximately 2.8 billion diarrhea episodes among older children, adolescents, and adults [2].
Given the importance of diarrhea as one of the foremost causes of global morbidity and mortality, it is essential to quantify factors, such as duration and severity, critical to quantifying the overall burden of disease attributable to diarrhea. Comprehensive estimates of diarrheal duration and severity will allow for the more accurate assignment of disability adjusted life years (DALYs) in terms of years lost to disability due to diarrheal illness. While various studies conducted throughout the world report on the duration and severity of diarrhea, comprehensive estimates do not exist in the literature. Furthermore, there is a lack of consistency in methods for defining severe, moderate, and mild diarrheal episodes despite the existence of severity scales, such as the Hjelt, Vesikari, and Clark scoring systems, which assign an overall degree of severity based on the sum presentation of symptoms [3][4][5]. We therefore conducted a systematic literature review with the goal of consolidating available data on the duration and severity of diarrhea and describing the overall burden of episodes among children and adults in low-and middleincome countries.

Search strategy and selection criteria
We systematically reviewed all literature published from 1990 to 2010 to identify studies reporting measures of diarrhea duration and severity in children and adults. From May 20-27, 2010, we searched in Pubmed using combinations of MeSH search terms: diarrhea, gastroenteritis, duration, persistence, severity, infant, child, teenage, and adult.
We initially screened all unique publications for eligibility based on the relevancy of title and abstract; we then screened the full manuscripts for inclusion and exclusion criteria. We included randomized controlled trials (RCTs), cohort, and observational studies published in any language and conducted in any country. Included studies contained data on diarrhea duration and/or severity in children and/or adults. We excluded studies with unclear methodology and diarrhea recall beyond 2 weeks. We accepted studies defining diarrhea as the passage of ≥ 3 watery stools in a 24-hour period; we also considered mother's report of a change in usual stool consistency or frequency for infants ≤ 11 mo of age, and the diagnosis of diarrhea by a physician or nurse as valid case definitions. We excluded studies describing diarrhea deaths alone since duration and severity outcomes of episodes resulting in death are not generalizable to all diarrhea episodes. We also excluded reports of nosocomial outbreaks, diarrhea due to known chronic or non-infectious illness, and studies that limited inclusion to one etiologic agent. For analytical purposes, we did not include studies that combined outcomes across child/adult age categories or inpatient/ outpatient status. Furthermore, for duration outcomes, we included studies on the natural course of diarrhea episodes and excluded those reporting on acute or persistent episodes alone.

Data abstraction
We abstracted measures of diarrhea duration and severity for all ages; for presentation purposes we grouped these data into 3 distinct age categories: 0-59 mos, 5-15 yrs, and ≥ 16 years of age. For studies stratifying outcomes by treatment or HIV-status, we only abstracted data on placebo and HIV-negative individuals, respectively.
We abstracted three outcomes describing diarrhea duration: mean or median duration-reported as the number of days per episode of diarrhea, and the proportion of total diarrheal episodes that became persistent (≥ 14 or ≥ 15 days). If the proportion of persistent cases was skewed due to an intentional sampling bias or matching, we did not include the study for this outcome. To ensure capture of the full length of diarrheal episodes, we also excluded studies solely reporting the duration of diarrheal episodes at baseline.
Multiple outcomes were reported as measures of severity. We abstracted the proportion of individuals suffering from diarrhea with mild, moderate, severe, or any dehydration; vomiting; and bloody stools. We classified necessitating ORS or intravenous fluids as any dehydration. For studies assessing dehydration by both physician perception and WHO classification for dehydration, we utilized the latter. Likewise, if possible, we abstracted outcomes assessed by physicians or trained health workers in place of those estimated by mothers or caregivers. Additional severity outcomes included the mean stool volume (g/kg/day) and mean stool frequency (stools/day). We also abstracted the proportion with low (< 40 g/kg/day), medium (40-70 g/kg/day), and high (> 70 g/kg/day) stool volume. For stool frequency, we abstracted the proportion low (1-5 stools/day), medium (6-9 stools/day), and high (≥ 10 stools/day), as well as the proportion with > 5 stools/day and > 3 stools/day. We did not find any studies able to quantify the proportion of episodes that remain mild/moderate or that progress to severe. We therefore used care-seeking behavior among caregivers of children < 5 years of age as a proxy for diarrhea severity in this age group. We abstracted care-seeking behavior from the Demographic Health Surveys (DHS) [6]. The DHS reports the number of children ≤ 35 months of age with diarrhea in the two weeks preceding the survey for whom care was sought, as well as the number who were not taken to a health provider.

Data analysis
We used STATA 10.1 to generate combined estimates and 95% confidence intervals for all duration and severity outcomes [7]. To ensure that confidence intervals were lower bound by zero for all outcomes and upper bound by one for proportions, we fit a logistic regression model to data reported as proportions and a Poisson regression model to continuous outcomes. All outcomes were weighted by sample size, which consisted of the total number of episodes. For study designs assessing only one episode per individual, the number of children or adults with diarrhea was considered the total number of episodes. We used the reported diarrheal incidence (number of episodes per child-year) to estimate the sample size for studies evaluating multiple episodes per child without reporting the total number of episodes. We conducted separate analyses for each study type-community, hospital-based inpatient and hospital-based outpatient.
Using the DHS data, we calculated region-specific averages for diarrhea care-seeking. We also calculated the median global estimate of diarrhea care-seeking across regions. The global estimate was used to inform our model describing the total envelope of diarrhea among children under five. Mild cases were defined as those for which no care was sought, and moderate cases were defined as those for which care was sought through a health provider. We assumed that mild and moderate episodes were best described by the duration and severity outcomes derived from community-based studies and hospital outpatient studies, respectively. We used the proportion of outpatient cases presenting with severe dehydration to determine the percentage of moderate cases which progress to severe. Duration and severity outcomes derived from hospital inpatient studies were assumed to best describe severe cases. Table 1 summarizes the algorithms used to determine the proportion of mild, moderate and severe cases occurring among children 0-59 mos of age; Table 1 also lists the source of duration and severity outcomes assumed to best describe each diarrhea category.
We also designed a model to describe the total envelope of diarrhea among individuals ≥ 16 years of age. We assumed that mild cases were comprised of cases occurring in the community without dehydration, and moderate cases were comprised of the proportion of community cases with any dehydration. In keeping with the assumptions made for the model describing the total envelope of diarrhea among children under-five, we used the proportion of outpatient cases presenting with severe dehydration to determine the percentage of moderate cases progressing to severe. We also assumed that community, hospital outpatient, and hospital inpatient studies best described the duration and severity profiles of mild, moderate, and severe cases, respectively (See Table 1).

Duration of diarrheal episodes
Among children 0-59 months of age, the weighted mean duration was 4.3 days among cases assessed in the community and 8.4 days among hospital inpatients in LMICs ( Table 2). The mean and median duration reported by the included study conducted in a highincome country were 2.2 days and 1 day, respectively.
The sole study conducted among children 5-15 years of age reported a mean duration of 2.7 days for episodes assessed in the community ( Table 2). The reported mean duration of episodes among adults ≥ 16 years of age was 3 days in the community and 2.6 days among hospital outpatients in LMICs (Table 2); in high-income countries, the mean duration of diarrhea was 2.6 days in the community and 4.6 days among outpatients.

Severity of diarrheal illness
Any dehydration was the outcome most frequently cited as a measure of diarrhea severity among children under five. The weighted mean proportion of episodes categorized with any dehydration was 7.3% for episodes assessed in the community, 84.6% among hospital inpatients and 51.4% among hospital outpatients (Table 3). Any dehydration was also the most frequently reported measure of diarrhea severity among individuals ≥ 16 years of age (Table 4). The weighted mean proportion of episodes presenting with any dehydration was 92.8% for hospital inpatient studies, 30.1% for hospital outpatient studies, and 5.0% for community studies.

Diarrhea care-seeking practices
The DHS-based regional average and global median proportions of care-seeking for diarrhea among children under three years are presented in Table 5 Estimating the total envelope of diarrhea Figure 3 describes the total envelope of diarrhea morbidity among children 0-59 mos of age. Using care-seeking as a proxy for quantifying the proportion of diarrhea episodes which might be considered "mild", we estimate that 64.8% of episodes are mild and the remaining 35.2% of cases are moderate. Of these moderate cases, 1.4% will become severe (i.e. 0.5% of all cases). Using the data from community-based studies we estimate that mild cases last for 4.3 days. We estimate that 15.4% of moderate cases become persistent and 51.4% involve some dehydration. For severe cases, we applied the estimates derived from inpatient studies and thus assumed that severe cases endure 8.4 days with 84.6% resulting in dehydration. Since included outpatient studies did not report mean duration, we estimated the mean duration of moderate cases by averaging that of mild and severe cases; thus, moderate cases last approximately 6.4 days. Figure 4 describes the total envelope of diarrhea burden among individuals ≥ 16 years of age. Since severe dehydration was not reported by any of the outpatient studies included in this review, we determined the inadequate definition of diarrhea (n = 15); overlapping age categories (n = 17); no outcome of interest (n = 12); diarrhea recall beyond 2 weeks (n = 11); unclear/problematic methodology (n = 11); data in unusable form (n = 6); full episodes not followed (n = 6); not representative of general population (n = 4); combined data on hospital inpatients & outpatients (n = 7). 2 Main reasons for exclusion: report of one etiologic agent (n = 20); overlapping age categories (n = 12); not representative of general population (n = 5); report of nosocomial infection (n = 3); unclear/problematic methodology (n = 3); diarrhea recall beyond 2 weeks (n = 4); inadequate definition of diarrhea (n = 1); no outcome of interest (n = 1); combined data on hospital inpatients & outpatients (n = 1). 3 All studies reported data on children 0-59 mos of age; one study reported data on children 5-15 yrs of age. 4 Study design: cohort (n = 27); RCT (n = 10); case-control (n = 4). Study location: community-based (n = 34); hospital-based (n = 7). 5 All studies reported data on children 0-59 mos of age, only. 6 Study design: cohort (n = 15); RCT (n = 5); casecontrol (n = 7). Study location: community-based (n = 10); hospital-based (n = 17). 7 Study design: cohort (n = 2); RCT (n = 2). Study location: community-based (n = 2); hospital-based (n = 2). 8 Study design: cohort (n = 4); RCT (n = 2). Study location: community-based (n = 2); hospitalbased (n = 4).

Discussion
This systematic review is the first to describe the overall duration and severity of diarrhea among children and adults. To estimate the annual number of diarrhea episodes among children under-five by region, we applied the regional age-adjusted incidences of diarrhea among children 0-59 mos of age to the regional populations of children in that age group. The total number of diarrhea episodes, as well as the breakdown of mild, moderate, and severe episodes in each region, is presented in Table 6. By aggregating the regional numbers, we  Individual studies (n = 27) may contribute more than one study site (N) to each estimate 2 Estimates for ≥ 2 study sites generated by logistic regression model weighted by sample size; mean stool frequency generated by Poisson regression model weighted by sample size 3 Low defined as 1-5 stools/day; medium as 6-9 stools/day; and high as ≥ 10 stools/day estimate that among the 1.67 billion diarrhea episodes occurring among children under-five globally per year 1.08 billion (64.8%) are mild; 580 million are moderate (34.7%); and 8 million (0.5%) are severe. By region, the burden of diarrhea is greatest in Africa and Asia; still, Table 7 illustrates that episodes occurring in Africa tend to be more serious in duration and severity outcomes. The total envelope of diarrhea cases among individuals ≥ 16 years of age is comprised of approximately 430 million annual episodes of diarrhea [2]. We estimate that approximately 408.5 million episodes are mild (95%); 21.3 million are moderate (4.95%); and 0.2 million are severe (0.05%).
The dearth of studies reporting outcomes for children 5-15 years of age inhibits our ability to directly estimate the burden of diarrhea on this age group. However, a comparison of the mean duration of community-based cases seems to suggest that diarrhea outcomes among children aged 5-15 yrs are more similar to individuals ≥ 16 than to children under-five (Table 2). Accordingly, we applied the breakdown of mild, moderate, and severe cases estimated for individuals ≥ 16 to the total number of incident cases among children 5-15 years of age. We estimate that of the 200 million diarrheal episodes that occur per year among children 5-15 years of age [2], 190 million are mild (95%); 9.9 million are moderate (4.95%); and 0.1 million are severe (0.05%).
Our review is limited in that we cannot extrapolate our findings onto the duration and severity of diarrhea episodes occurring among HIV-infected individuals.  Individual studies (n = 4) may contribute more than one study site (N) to each estimate 2 Estimates for ≥ 2 study sites generated by logistic regression model weighted by sample size Research comparing diarrhea morbidity and mortality between individuals of discrepant HIV status has shown that HIV increases susceptibility to infectious diseases, including diarrhea. Of the studies we identified, one excluded study observed that in addition to increased diarrhea incidence, HIV-infected children suffered higher duration and a larger proportion of persistent episodes as compared to uninfected children [69].
Moreover, the same study reported increased diarrhearelated mortality among HIV-infected children.
The proportion of moderate/severe episodes among children under-five, which was estimated using the proportion of episodes for which care was sought, is likely underestimated since appropriate care is sought in less than 30-50% of cases in resource poor settings [70]. Given that facility care is under-utilized, moderate/  severe episodes among children under-five are also assessed in the community; thus, the duration and severity outcomes derived from community-based studies may not accurately describe mild episodes that do not require facility level care. However, the increasing gravity of duration and severity outcomes across community-based, hospital-inpatient, and hospital-outpatient studies, respectively, suggests that these estimates are plausible and although biased, they represent the best summary of available data.

Conclusions
In this review we classified the total envelope of diarrheal episodes among individuals 0-59 mos, 5-15 years, and ≥ 16 years of age according to diarrhea duration and severity. This information is essential to accurately calculate the age-specific burden of disease and the appropriate allocation of DALYs. Given that the global burden of diarrhea consists of large numbers of episodes beyond those progressing to death, the estimated breakdown of mild, moderate, and severe episodes is increasingly important for informing policy decisions on global health. As programs increasingly scale-up and improve diarrhea treatment, especially among children under-five, estimates of diarrhea morbidity should be used to determine the most effective distribution of funds for interventions focused on diarrhea.  Community-based studies, only 2 Hospital-inpatient studies, only Data were generated combining estimates for like study designs and outcomes in overlapping study years