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Systematic review of longitudinal Shigella outcomes in children.
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Shigella is associated with continued diarrhea and linear growth faltering.
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There is a need for standardized measurement and reporting of Shigella outcomes.
Abstract
Objectives
We conducted a systematic review of the longitudinal consequences of Shigella infection in children to inform the value proposition for an effective vaccine.
Methods
We searched PubMed and Embase for studies published from January 01, 1980 to December 12, 2022 and conducted in low- and middle-income countries that included longitudinal follow-up after Shigella detection among children aged <5 years, irrespective of language. We collected data on all outcomes subsequent to Shigella detection, except mortality.
Results
Of 2627 papers identified, 52 met inclusion criteria. The median sample size of children aged <5 years was 66 (range 5-2172). Data were collected in 20 countries; 56% (n = 29) of the publications included Bangladesh. The most common outcomes related to diarrhea (n = 20), linear growth (n = 14), and the mean total cost of a Shigella episode (n = 4; range: $ 6.22-31.10). Among children with Shigella diarrhea, 2.9-61.1% developed persistent diarrhea (≥14 days); the persistence was significantly more likely among children who were malnourished, had bloody stool, or had multidrug-resistant Shigella. Cumulative Shigella infections over the first 2 years of life contributed to the greatest loss in length-for-age z-score.
Conclusion
We identified evidence that Shigella is associated with persistent diarrhea, linear growth faltering, and economic impact to the family.
Burden of enterotoxigenic Escherichia coli and Shigella non-fatal diarrhoeal infections in 79 low-income and lower middle-income countries: a modelling analysis.
]. The mortality rates from Shigella have declined substantially over the last few decades due to the apparent disappearance of the highly virulent Shiga toxin-producing Shigella dysenteriae 1 serotype, measles vaccination, antibiotics, improvements in nutritional status, and economic development [
]. Despite these gains, antibiotic resistance to first and secondline antibiotics that have historically been effective in reducing disease severity, diarrhea duration, and pathogen excretion threatens the progress that has been made in reducing Shigella mortality [
In addition to its contribution to childhood mortality, Shigella is responsible for substantial morbidity among children aged <5 years. This gram-negative bacterium is often the leading cause of moderate-to-severe diarrhea (MSD) and is the leading cause of dysentery among children aged <5 years living in low- and middle-income countries (LMICs) [
Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
]. EED and linear growth faltering both have links to poor longer-term outcomes, including delayed cognitive development, poor school performance, and reduced economic potential [
Linear growth faltering is associated with subsequent adverse child cognitive developmental outcomes in the Democratic Republic of the Congo (REDUCE program).
]. Shigella infections also pose a significant financial burden on families and health systems due to the treatment/hospitalization cost of Shigella diarrhea [
Based on the clinical severity, disease burden, links to longer-term outcomes, and the emergence of antimicrobial resistance, Shigella is a priority for vaccine development in the target population of young children living in LMICs [
]. As pediatric Shigella vaccines move toward licensure and policy makers consider vaccine introduction, there is a need to synthesize evidence on the long-term consequences of Shigella to aid global and country decision-making to support vaccine adoption [
]. We conducted a systematic review of the consequences of Shigella infection among children in LMICs to help characterize the potential value of a Shigella vaccine.
Methods
We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [
] to identify literature on the consequences of Shigella infection in children aged <5 years in LMICs. We aimed to gather data on the breadth of sequelae attributable to Shigella infection among young children, including but not limited to diarrhea persistence, linear growth faltering, ponderal growth faltering, neurodevelopmental delay, economic impacts, immune response, and systemic and enteric inflammation. In addition to characterizing the evidence and direction of effect, we sought to identify evidence gaps that could be addressed in future research studies.
Search strategy and selection criteria
We searched PubMed and Embase for articles published from January 01, 1980 to December 12, 2022 that indicated longitudinal follow-up of children after detection of Shigella in fecal samples or blood by any laboratory method. We included terms that described LMICs, as well as the names of all countries categorized as LMICs by the World Bank in 2020 (see Appendix 1 for full search strings).
We included clinical trials and observational studies that followed up at least five children with Shigella detected for any duration beyond 1 hour, regardless of symptoms. We restricted to studies conducted in LMICs that reported outcome data for children aged <5 years (0-60 months) to focus on the population with the highest morbidity and mortality burden attributed to Shigella [
]. We excluded cross-sectional studies and outcomes that were assessed contemporaneously with Shigella detection. Conference abstracts were included if they met other inclusion criteria and contained outcome data. We translated non-English publications using DeepL Translator (Cologne, Germany) or Google Translate.
Two reviewers (FA, MD, or TL) independently screened the title and abstract of each article for eligibility using Covidence (Veritas Health Innovation, Melbourne, Australia). Any disagreements were resolved by a third reviewer (PP) or through group discussion and consensus. If a decision could not be made using the information available in the abstract or if no abstract was available, the article was passed to full-text review. The same methods (dual review and conflict resolution using Covidence) were used during full-text review. The review's International prospective register of systematic reviews registration number is CRD42021241169 (link).
Data analysis
The summary data were abstracted from full-text reports of included publications. We abstracted information on the original study design and methodology (e.g., length of follow-up, inclusion criteria), the location of study, the number of children and/or stools with Shigella detected, laboratory method of detection, Shigella species identified, co-infections, and funding source. For each outcome identified, we abstracted the method of measurement, time point of measurement or duration of follow-up, any adjustment variables, and the effect estimate. All longitudinal outcomes were abstracted except mortality because this outcome was recently summarized in a systematic review of case fatality rates for common diarrheal pathogens [
]. Clinical characteristics and outcomes reported only at medical presentation or study enrollment were not abstracted because it was not possible to determine temporality in relation to Shigella detection. Data from randomized trials were abstracted for each randomization arm; the measures of excess risk comparing randomization arms were not abstracted unless they compared children with and without Shigella detected.
Because all data in this review were treated as a cohort study (Shigella as the exposure), we did not feel it would be relevant to assess the risk of bias for the original study design (e.g., randomized control trial) nor would it be possible to uniformly apply a risk of bias assessment tool to the variety of designs included in this review because many questions are not suited to our included outcomes. Instead, we conducted a quality assessment of included studies using a modified version of a composite quality construct based on the Strengthening the Reporting of Observational Studies in Epidemiology statement [
]. In this assessment, each article was awarded points (10 maximum) for satisfying components of the methods section of the Strengthening the Reporting of Observational Studies in Epidemiology statement checklist, which includes an assessment of efforts to address potential sources of bias (Appendix 2). A rating of ‘poor’ was assigned to articles with zero to four points, ‘fair’ with five to seven points, and ‘good’ with eight to 10 points. As part of our quality assessment, we reviewed information contained within a given publication, as well as the text of referenced articles as needed.
Data abstraction was performed by a single reviewer (FA, MD, or TL) and quality checks were performed on a random subset of the data (20%). The study data were collected and managed using Research Electronic Data Capture tools hosted at the University of Washington Institute of Translational Health Sciences [
Research Electronic Data Capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support.
]. We performed a descriptive summary of the study characteristics and longitudinal outcomes. The definitions of acute and persistent diarrhea were accepted from included studies, but the review adapted the distinction of <14 and ≥14 days, distinguishing the two as described in WHO diarrhea treatment guidelines [
]. We intended to conduct a meta-analysis for any outcomes that were reported consistently by more than two studies. Due to heterogeneity in the measurement methods, comparison groups, and follow-up duration, we report a narrative summary of the evidence for each outcome.
Results
Our final search identified 2627 potentially eligible records from PubMed and Embase after deduplication (Figure 1). We completed the dual review of titles and abstracts passing 368 (14%) publications to full-text review, of which 52 met the inclusion criteria (Figure 1). The 316 studies excluded at full-text review are described in Appendix 3. The key characteristics of the 52 included articles are shown in Table 1 and summarized in Table 2. The data on Shigella outcomes were collected in 20 different countries; although 56% (n = 29) of the publications were from studies conducted at least partially in Bangladesh. There were 13 publications from studies conducted on the African continent. Five publications reported data from multiple countries either collected as part of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study (n = 3) [
MAL-ED Network. Investigators The MAL-ED study: a multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, physical growth, cognitive development, and immune responses in infants and children up to 2 years of age in resource-poor environments.
The Global Enteric Multicenter Study (GEMS) of diarrheal disease in infants and young children in developing countries: epidemiologic and clinical methods of the case/control study.
aStudies that were excluded for “no follow-up of Shigella cases/cross-sectional outcomes only” include some studies that were longitudinal in nature, but presented outcomes cross-sectionally such that the likelihood of longitudinal outcomes given Shigella infection could not be determined (e.g., given all children with an outcome, the percent of children that had Shigella infection) either from direct interpretation of tables or through back calculations.
Abbreviations: LMIC, low– or middleincome country.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. II. Incidence of diarrhea and association with known pathogens.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
A randomized, controlled, single-blind study comparing furazolidone with trimethoprim-sulfamethoxazole in the empirical treatment of acute invasive diarrhea.
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
Diarrhea
Diarrhea, fever in subsequent Shigella-attributable diarrhea episode, hospitalization
Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: findings from three birth cohorts over eight years.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
Bangladesh, The Gambia, India, Kenya, Mali, Mozambique, Pakistan
South-East Asia, Africa
Case-control
Dec 2007 - Mar 2011
0-59
Children with acute diarrhea (any severity) enrolled in GEMS
Culture
1,736
Diarrhea
Economic outcomes
Abbreviations: EED, environmental enteric dysfunction; GEMS, the Global Enteric Multicenter Study; MAL-ED, Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development; RCT, randomized controlled trial; qPCR, quantitative polymerase chain reaction; MSD, moderate-to-severe diarrhea; WAZ, weight-for-age z-score.
a The number of children with Shigella detected was not specified in some studies; see Appendix 4 for the # of Shigella-positive stools or diarrhea episodes attributable to Shigella, which were used to verify inclusion criteria of 5+ children with Shigella.
b The months (if available) and years of participant enrollment.
c The age range of enrolled children for whom outcomes were measured/reported.
Publications included a median of 66 children with Shigella, ranging from five to 2172 (Table 2). Of note, some of the included studies did not specify the number of children with Shigella but provided other information that made it possible to estimate the number of children with Shigella as being five or more (Appendix 4). Although most publications were among children with Shigella diarrhea only, nine (17%) publications also included Shigella detected in asymptomatic patients (Table 1). The study setting and initial inclusion criteria varied widely, such as malnourishment, current diarrhea, participation in birth and community-based cohorts or randomized controlled trials, admittance to hospitals, and presentation at health care facilities. Culture was the most common primary Shigella detection method (71%), followed by quantitative polymerase chain reaction (21%; Tables 1, 2). Most studies were rated ‘good’ quality (n = 35; 67%), followed by ‘fair’ quality (n = 16; 31%) and ‘poor’ quality (n = 1; 2%) (Appendix 5).
The most commonly reported outcomes of Shigella were related to diarrhea (n = 20) and linear growth (n = 14). Other anthropometric measures, such as ponderal growth (e.g., change in weight-for-height z-score [WHZ]) or weight gain (e.g., change in weight or weight-for-age z-score [WAZ]), were reported in 10 studies (Table 2). In each of these categories, fewer than three studies reported on the same outcome using a similar comparison group, thus precluding meta-analyses.
Diarrhea outcomes
There were three general categories of measurement among studies of diarrhea outcomes: duration of diarrhea measured continuously (n = 9); duration of diarrhea measured categorically (<7 days, 7-<14 days, ≥14 days) and presented as corresponding percentages, odds ratios (ORs), and risk ratios (n = 11); and characteristics of subsequent diarrhea episodes (both Shigella and unspecified) that occurred after diarrhea-free days (n = 3). The measurement details are summarized in Table 3.
Table 3Diarrhea outcomes, by measurement and follow-up duration.
Probability of acute diarrhea being self-limiting (less than 4 days of treatment in rehydration facility needed before discharge home and no past month or following months admissions to a rehydration facility) given Shigella present
0.74; i.e., significantly higher (P <0.05) than when Shigella is not present
Adjusted OR (95% CI) for Shigella diarrhea (as opposed to non-Shigella diarrhea) among children with illness duration of 3 or more days, adjusting for fever, vomiting, severe dehydration and bloody stool
Percent of children with Shigella dysentery at baseline who had not recovered by day 7 (defined as children who were 'three or fewer formed stools in a day, were afebrile, did not have visible blood or mucous in stools and did not have abdominal pain or tenderness)
Prevalence ratio (95% CI) for prolonged diarrhea (≥7 days) comparing children with diarrhea attributable to Shigella vs those not attributable to Shigella
Based on results in Taylor et al. [34] Table 3 (there is a discrepancy in number of children with Shigella spp. isolated on day 0 in the erythromycin group reported in results text and in Table 3).
; control group: (1/7) 14%
Relative proportion/risk of diarrhea on Day X (RR)
The site-adjusted risk ratio (95% CI) comparing the percent of Shigella-attributed episodes leading to prolonged diarrhea (7+ days) in the first year compared to the second year of life
The site and age-adjusted risk ratios (95% CI) for prolonged diarrhea (7+ days) comparing Shigella episodes with co-etiologies to single etiology
Viral co-etiology: 1.15 (95% CI: 0.83, 1.60); Bacterial co-etiology: 1.18 (95% CI: 0.77, 1.80); RR for parasitic co-etiology not estimated due to small numbers
The percent of Shigella-attributable diarrhea episodes where persistent diarrhea (14+ days) was present, by co-etiology status (RRs not calculated due to small numbers of episodes)
Percent of Shigella diarrhea episodes that became persistent (14+ days) among children with and without multiple antibiotic resistance (ampicillin, trimethoprim-sulfamethoxazole, and nalidixic acid)
With multiple antibiotic resistance: 66.7% (4/6); without: 20.4% (20/98); p<0.05
The site-adjusted risk ratio (95% CI) comparing the percent of Shigella-attributed episodes leading to persistent diarrhea (14+) in the first year compared to the second year of life
Age-adjusted RR (95% CI) of persistent diarrhea (14+ days) comparing Shigella-positive to Shigella-negative diarrhea episodes, overall and by the presence of blood
Overall: 1.83 (95% CI: 1.19, 2.81; P <0.01); Bloody diarrhea: 1.06 (95% CI: 0.60, 1.86; P >0.05); Nonbloody diarrhea: 2.31 (95% CI: 1.24, 4.30; P <0.01)
Age-adjusted RR (95% CI) for persistent diarrhea (14+ days) comparing children who have shigellosis with bloody diarrhea to children who have shigellosis with nonbloody diarrhea
Age-adjusted RR (95% CI) of persistent diarrhea (14+ days) with S. dysenteriae 1 and other Shigella serotypes, compared to risk of persistent diarrhea with S. flexneri
RRdys 1 vs flex: 1.25 (95% CI: 0.49, 3.18); RRother serotypes vs flex: 0.78 (95% CI: 0.34, 1.77)
Age-adjusted RR (95% CI) for persistent diarrhea (14+ days) comparing children with shigellosis with multiple antibiotic resistance (resistant to ampicillin, trimethoprim-sulfamethoxazole, and nalidixic acid) to children with shigellosis without multiple antibiotic resistance
Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. II. Incidence of diarrhea and association with known pathogens.
Mean duration (days) of diarrhea episodes that occurred in the 6-month follow-up (95% CI) in the zinc group and the control group (no zinc supplementation)
Zinc: 9.8 (95% CI: 6.0, 15.9); No zinc: 7.1 (95% CI: 3.2, 12.6); P = 0.1
Mean number of diarrhea episodes during the 6-month follow-up (95% CI) following an episode of Shigella diarrhea comparing children randomized to zinc group vs control group (no zinc supplementation)
Zinc: 2.2 (95% CI: 1.6, 4.1); No zinc: 3.3 (95% CI: 2.7, 4.1); P = 0.03
Number of diarrhea episodes per child in the 6-month follow-up period among children who received 14 days of high-protein diet and those who received standard-protein diet and the RR (95% CI) comparing standard to high protein.
Among children who had more than one Shigella-attributable diarrhea episode, the percent of subsequent episodes that were severe (CODA score 4+) and the site and age-adjusted risk ratio for severe diarrhea comparing the first episode to subsequent episodes (95% CI)
Among children who had more than one Shigella-attributable diarrhea episode, the percent of subsequent episodes with blood and the site and age-adjusted risk ratio for bloody diarrhea comparing the first episode to subsequent episodes (95% CI)
Among children who had more than one Shigella-attributable diarrhea episode, the percent of subsequent episodes that were prolonged (7+ days) and the site and age-adjusted risk ratio for prolonged diarrhea comparing the first episode to subsequent episodes (95% CI)
Among children who had more than one Shigella-attributable diarrhea episode, the percent of subsequent episodes that were persistent (14+ days) and the site and age-adjusted risk ratio for persistent diarrhea comparing the first episode to subsequent episodes (95% CI)
Among children who had more than 1 Shigella-attributable diarrhea episode, the percent of subsequent episodes with high frequency (>6 loose stools in 24 hours) and the site and age-adjusted risk ratio comparing the first episode to subsequent episodes (95% CI)
19%; RR: 1.21 (95% CI: 0.89, 1.63)
Abbreviations: CI, confidence interval; OR, odds ratio; RR, relative risk; SE, standard error; SEM, Standard error of the mean; CODA, a diarrheal severity score (Community Diarrhea).
a "Illness" was presumed to mean diarrhea because stool samples were taken when diarrheal episodes were detected.
Table 3 (there is a discrepancy in number of children with Shigella spp. isolated on day 0 in the erythromycin group reported in results text and in Table 3).
]. Six studies reported on persistent diarrhea (duration ≥14 days) and in these studies, 2.9-61.1% of children with Shigella diarrhea developed persistent diarrhea [
]. Two of these studies reported on risk factors of diarrhea persistence among Shigella diarrhea cases, with a statistically significantly higher likelihood of persistence among children who were malnourished (malnourished: 19.2% vs well-nourished: 3.2%) [
]. Of note, a study comparing likelihood of persistent diarrhea between children with Shigella-positive diarrhea compared with Shigella-negative diarrhea found Shigella to be significantly associated with persistent diarrhea (relative risk: 1.83; 95% confidence interval [CI]: 1.91, 2.81) [
]. Similarly, another study reported a longer duration of diarrhea in children with Shigella diarrhea than those with other causes of diarrhea (OR of duration longer than 3 days: 1.4; 95% CI: 1.0-2.0) [
]. Across the studies, the continuously measured mean duration of diarrhea ranged from 2 to 22.2 days, with substantial variation by intervention status in trials and anthropometric groups [
Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. II. Incidence of diarrhea and association with known pathogens.
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: findings from three birth cohorts over eight years.
] stools (Table 4). There was substantial heterogeneity in measurement time points (ranging from 21 days to 8 years) and comparison groups (Table 4). Linear growth was commonly operationalized as the mean change in the length-for-age z-score (LAZ) between two time points (n = 3) or the difference in LAZ between two groups, defined by presence/absence of Shigella or high/low quantity of Shigella (n = 7). The effect estimates from these studies are summarized in Figure 2. The differences in LAZ comparing high with low Shigella prevalence in nondiarrheal stools ranged from -0.14 (95% CI: -0.27, -0.01) at 2 years to -0.32 (95% CI: -0.56, -0.08) at 6-8 years [
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: findings from three birth cohorts over eight years.
]. Two studies reported on the impact of Shigella diarrhea on linear growth at 3 months after diarrhea: one study found a statistically significant average loss of -0.03 (95% CI: -0.05, -0.00) in LAZ [
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
]. In GEMS, Shigella episodes not treated with antibiotics led to greater declines in linear growth than treated episodes among children aged <24 months [
]. Another study found that Malawian children with Shigella detected at age 18 months had, on average, 0.39 lower LAZ at 24 months than children without Shigella detected [
] found Shigella infection to be associated with a two-fold increase in the odds of stunting (defined as height-for-age z-score <-2) at 9 months of follow-up (OR: 2.01; 95% CI: 1.02, 3.93) [
] reported a statistically significant association between the periods of Shigella diarrhea and change in height-for-age compared with a village standard between the beginning and end of the study period [
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
At 24 months comparing children with Shigella detected at 18 months to those without Shigella detected
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Per additional episode of diarrhea attributable to Shigella
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Per additional episode of diarrhea attributable to Shigella
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Per additional episode of diarrhea attributable to Shigella
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Per additional episode of diarrhea attributable to Shigella
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Comparing children with high (90th percentile) vs low (10th percentile) Shigella prevalence in nondiarrheal stools over 24-month period
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Comparing children with high (90th percentile) vs low (10th percentile) Shigella prevalence in nondiarrheal stools (using culture instead of qPCR)
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Comparing children with high (90th percentile) vs low (10th percentile) Shigella prevalence in nondiarrheal and diarrheal stools over 24-month period
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Per one log increase in Shigella quantity (copy number) per gram of stool over 24-month period
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Comparing children with high (90th percentile) vs low (10th percentile) Shigella prevalence in nondiarrheal stools over 24-month period
Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: findings from three birth cohorts over eight years.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Per one log increase in Shigella quantity per gram of stool over 24-month period
Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: findings from three birth cohorts over eight years.
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Comparing children with high (90th percentile) vs low (10th percentile) Shigella prevalence in nondiarrheal stools over 24-month period
Comparing likelihood of stunting during follow-up among those with Shigella at baseline to those without, after adjusting for age, age, caregiver educational level, breastfeeding, and family size
Regression coefficient for Shigella on change in length (cm) or change in length status expressed as change in percentage of the village reference for age from the beginning to the end of the study period
Shigella coefficient had borderline significance (P = 0.07), but exact coefficient not reported
Regression coefficient for Shigella on change in length status expressed as change in percentage of the village reference height-for-age from the beginning to the end of the study period
Comparison of the percentage of expected linear growth rates (based on all village children) observed during periods of Shigella diarrhea compared to no diarrhea
“Periods with Shigella diarrhea had significantly lower growth rates” (P <0.01)
Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Comparing children in the lowest tertile of change in HAZ to those in the highest tertile of change in HAZ
Average proportional abundance of Escherichia/ Shigella: 0.026 vs 0.030
Abbreviations: CI, confidence interval; LAZ, length-for-age z-score; HAZ, height-for-age z-score; NS, not specified; OR, odds ratio; SD, standard deviation; SE, standard error
a Represents the number of children enrolled in the study because the number with Shigella was not specified (results reported as Escherichia/ Shigella).
Additional anthropometric outcomes are summarized in Appendix 6. Seven studies assessed the ponderal growth and weight-for-age, four of which did not have a comparison group without Shigella infection nor with low levels of Shigella [
]. The MAL-ED study found no significant difference in mean WHZ or WAZ between children with high (90th percentile) and low (10th percentile) Shigella prevalence in nondiarrheal stools [
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
]. Two studies reported on children enrolled in the Bangladesh site of GEMS: one found children with Shigella infection had significantly lower WHZ (-0.11; 95% CI: -0.21, -0.001) than children who were Shigella-negative after 60 days of follow-up [
]. In one of these studies, across seven sites, the mean total household out-of-pocket cost (including inpatient and outpatient medical costs, transportation, and prescriptions) was $10.61 (converted from local currency to 2012 US dollars), ranging from $4.92 in Mozambique to $17.18 in Mali [
]. This same study found no statistically significant difference in the cost between Shigella diarrhea and other pathogens. A study from China, which additionally included self-reported out-of-pocket expenses for overnight stays, estimated the mean cost to be $22 for children aged 0-1 year and $31 for 2-5 years, which represented 12% and 18% of the average monthly income, respectively [
]. Although there was heterogeneity in measurement and adjustment factors across studies, a large proportion of costs were associated with hospitalization or inpatient care.
Unadjusted, total household out-of-pocket costs (estimated by caregiver) including inpatient and outpatient medical costs, transportation, prescriptions (local currency converted to 2012 USD)
Total household out-of-pocket costs (estimated by caregiver) after adjustment for co-pathogens, age group, and gender (local currency converted to 2012 USD)
Cost of illness by age group including self-reported out-of-pocket expenditures related to treatment and recovery, lab tests, medicines, treatment, and overnight stays (2002 PPP-adjusted USD)
China
Age 0-1 years: $22.00 (35.00) Age 2-5 years: $31.10 (71.10)
Total costs including drugs, consultations, and transportation before and after attending hospital measured as percent expenditure of monthly household income
Cost of illness by age group including lab tests, medicines, treatment, and overnight stays, as percent of average monthly household income (2002 PPP-adjusted income = $184/month)
China
Age 0-1 years: 12.0% Age 2-5 years: 16.9%
Abbreviations: CI, confidence interval; SD, standard deviation; USD, U.S. dollars; PPP, purchasing power parity.
Three studies reported on the longitudinal markers of gut and/or systemic inflammatory response among children with Shigella (Appendix 7). In a study of children with Shigella treated with antibiotic therapy and randomly assigned to 14 days of zinc supplementation or control, there were no significant differences in concentrations of innate mediators (myeloperoxidase, superoxidase, nitrate) and cytokines (interleukin-2, interferon-γ) in stool or released from mitogen-stimulated mononuclear cells within or between treatment groups over 30 days of follow-up [
] found diarrhea attributable to Shigella to be associated with elevated C-reactive protein levels (increase of 0.24 [95% CI: 0.03, 0.49] per diarrhea episode).
Other outcomes
Two studies assessed neurodevelopmental outcomes but did not find statistically significant associations between the diarrhea episodes attributable to Shigella and neurodevelopmental scores for motor, language, or cognitive skills [
Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: findings from three birth cohorts over eight years.
] (Appendix 7). Four studies assessed the proportion of children with Shigella who were no longer shedding pathogen at various time points (6, 14, or 31 days, or at clinical stabilization) overall [
Burden of enterotoxigenic Escherichia coli and Shigella non-fatal diarrhoeal infections in 79 low-income and lower middle-income countries: a modelling analysis.
A randomized, controlled, single-blind study comparing furazolidone with trimethoprim-sulfamethoxazole in the empirical treatment of acute invasive diarrhea.
The World Health Organization recently articulated the need for evidence synthesis of long-term morbidities associated with key enteric pathogens, such as Shigella [
]. In this systematic review, we document the consequences of Shigella infection and disease in children aged <5 years living in LMICs. We found evidence that Shigella was associated with linear growth faltering and persistent diarrhea [
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
Linear growth faltering is associated with subsequent adverse child cognitive developmental outcomes in the Democratic Republic of the Congo (REDUCE program).
Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: findings from three birth cohorts over eight years.
]. Heterogeneity in measurement and presentation of outcomes and differences in comparison groups between studies prohibited quantitative synthesis of the data, highlighting the need for standardizing methods for characterizing and reporting on enteric pathogen sequelae.
Shigella is a well-known cause of diarrhea, with moderate and severe forms of diarrhea constituting a substantial financial burden on health care systems and families. Our systematic review added to this evidence base by highlighting the consequences of Shigella diarrhea. Notably, children with Shigella diarrhea had an average duration of illness of 2-22 days, with wide variation [
Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. II. Incidence of diarrhea and association with known pathogens.
], and children with acute Shigella diarrhea were more likely to develop persistent diarrhea than children with acute diarrhea caused by other pathogens [
], and poses a greater burden on health care systems due to its increased need for facility-based care. In the few studies that included the economic consequences of Shigella, all were focused on the cost of Shigella diarrhea borne by families, which ranged from 1% to 78% of the monthly household income [
]. With Shigella infections likely having impact on a child's health, even in the absence of diarrhea, assigning an economic value to a Shigella vaccine will require additional data estimating the financial impact of Shigella sequelae beyond diarrhea.
We found Shigella to have modest and inconsistent effects on linear growth. Children who fall off their linear growth trajectories are at substantial risk for stunting, a precursor to poorer school performance, cognitive development, and reduced earning potential [
]. The greatest differences in LAZ were observed in the MAL-ED cohort study evaluating cumulative asymptomatic Shigella infections occurring over the first 24 months of life and their impact at 2, 5, and 6-8 years of life, with magnitudes ranging from -0.32 to -0.14 [
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.
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