Neglected tropical diseases (NTDs) are a group of communicable diseases affecting the poorest populations around the world.
To assess the effectiveness of interventions, including mass drug administration (MDA), water, sanitation, and hygiene (WASH), vector control, health education, and micronutrients supplementation, for NTDs among children and adolescents.
We conducted a literature search on the Cochrane Controlled Trials Register, Medline, and other databases until December 2020. We included randomized controlled trials and quasi-experimental studies conducted among children and adolescents. Two authors independently screened studies for relevance. Two authors independently extracted data, assessed the risk of bias, performed metaanalysis, and rated the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation.
We included 155 studies (231 articles) involving 262 299 participants. For soil-transmitted helminthiasis, MDA may reduce the prevalence of Ascaris, Trichuris, and hookworm by 58%, 36%, and 57%, respectively. We are uncertain of the effect of health education, WASH, and iron supplementation on soil-transmitted helminthiasis prevalence. For Schistosomiasis, health education probably reduces the intensity and prevalence of S. mansoni, whereas micronutrient supplementation may reduce anemia prevalence and the infection intensity of S. hematobium compared with no supplementation. We are uncertain of the effect of MDA and vector control on Schistosomiasis outcomes. For trachoma, health education probably reduces the prevalence of active Trachoma, whereas we are uncertain of the effect of MDA, WASH, and vector control on Trachoma outcomes. There is limited data on the effectiveness of interventions for NTDs targeting children and adolescents.
Future studies are needed to evaluate the relative effectiveness and cost-effectiveness of various interventions specifically targeting children and adolescents.
Neglected tropical diseases affect millions of children globally, and the World Health Organization recommends interventions like mass drug administration, providing safe water, sanitation, and hygiene, vector control, and providing adequate nutrition.
We systematically analyzed the effectiveness of interventions, including mass drug administration, water, sanitation and hygiene, vector control, health education, and micronutrients supplementation, for neglected tropical diseases, specifically in children and adolescents aged 0 to 18 years.
Neglected tropical diseases (NTDs) include a variety of communicable diseases affecting >1 billion people throughout the world, with increased prevalence in tropical countries.1 These diseases include (but are not limited to) soil-transmitted helminthiasis (STH), schistosomiasis, trachoma, leprosy, dengue, rabies, and leishmaniases. Collectively, NTDs contribute to ∼500 000 deaths annually.2 These diseases are termed “neglected” because they disproportionately affect the poor population groups and historically have not received as much attention as other diseases. Most of these infections mainly affect children, young adults, and pregnant women.3 In Sub-Saharan Africa, ∼50 million children are infected with hookworm alone, and in southeast Asia, ∼120 million children require periodic management for STH.4,5 For older school-aged children and adolescents, STH infections and Schistosomiasis are the leading causes of disability-adjusted life years (DALYs).6 These infections result in significant morbidity and long-term sequelae. Most infected individuals suffer from iron deficiency anemia leading to poor growth and development.7 Infections can result in further complications like blindness, rectal prolapse, and bladder cancer, leading to a vicious cycle of infections and poverty.7 According to the World Health Organization, NTDs disproportionately affect the poorest populations, costing developing economies billions of dollars.1 Likely, every person living below the World Bank poverty line of US $1.90, (corresponding to 10% of the global population) is affected by at least 1 NTD.8
According to the World Health Organization, multiple measures can be taken to decrease the burden of these infections. These include mass drug administration (MDA), safe water, sanitation, and hygiene (WASH) measures, vector control, health education, and adequate nutrition and micronutrient supplementation to prevent and manage anemia.1 Despite the high burden of NTDs and consequent DALYs among children and adolescents, there is limited information on the effectiveness of interventions to prevent and manage NTDs, specifically in this age group. A recent analysis suggests that children made up 34% of the 20 million DALYs resulting from NTDs, but 17% of the trials studying these conditions contributed data from pediatric populations. Conditions that were particularly underrepresented in pediatric populations compared with adults included rabies, leishmaniasis, scabies, and dengue.9 There have been studies done in the past assessing the effectiveness of interventions to control NTDs, such as MDA,10 WASH,11 footwear,12 and vector control.13,14 However, there is a lack of recent reviews evaluating the effectiveness of various interventions on NTD control among children and adolescents. In this article, we aim to systematically analyze the effectiveness of interventions for NTDs among children and adolescents.
Methodology
Objective
The objective of this review is to assess the effectiveness of various interventions (MDA, WASH, vector control, micronutrient supplementation, and health education) on NTDs among children and adolescents aged 0 to 18 years.
This systematic review follows the guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).15 The PRISMA checklist is presented in Supplemental Table 1.
Types of Studies and Participants
We included studies that were randomized control trials (RCTs) (both cluster- and individual-level randomization) and quasi-randomized studies. Our target population was children and adolescents between the ages of 0 and 18 years. Studies including a subset of eligible participants were included only if the results provided information for the relevant subgroup separately.
Types of Interventions
We included studies evaluating the effectiveness of any intervention targeting NTDs in the age group of our interest. Examples of these interventions include MDA, WASH, health education, vector control measures, and nutrition interventions. Based on the studies included in the review, we report the following comparisons:
MDA versus no MDA/placebo
Health education versus standard of care
WASH versus standard of care
Vector control versus no vector control
Micronutrient supplementation versus no micronutrient supplementation
School-based MDA delivery strategies versus community-based MDA delivery strategies
We excluded studies evaluating the effectiveness of any of the above interventions with each other.
Types of Outcomes
We included all the studies that met our inclusion criteria, but only those studies that had revealed the following prespecified outcomes were included in the quantitative synthesis. Our outcomes of interest included the prevalence of NTDs, cure rate, reinfection rate, infection intensity (eggs per gram of feces), number of children with clean faces, the prevalence of anemia, hemoglobin concentration, weight gain, and prevalence of stunting, wasting, and underweight.
Search Methods
The search was conducted on the following databases: the Cochrane Controlled Trials Register, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and clinical trials registry (clinicaltrials.gov) until December 2020 (for search strategies see Supplemental Table 2). We did not apply any restrictions on publication date, language, or publication status. References of included articles, relevant reviews, and annotated bibliographies were scanned for eligible studies. We ran citation searches of included studies in Google Scholar to identify any recent studies missing from the database searches.
Data Collection and Analysis
Two independent reviewers screened the titles and abstracts of the included studies in duplicate. Studies that passed this stage had their full texts reviewed by 2 reviewers. Any conflicts were resolved by using a third reviewer. We combined multiple reports of the same study so that each study was the unit of interest in the review. All the studies that were deemed eligible for inclusion at the full-text screening were double-data extracted onto a standardized abstraction sheet. We extracted data on demographics of the population (age, number of males and females, etc), setting, duration of the study, intervention, comparison group details, and outcomes. We conducted the metaanalysis for individual studies using the software Review Manager 5.4.1.16 The risk ratios (RR) were calculated for categorical variables with a 95% confidence interval (CI) whereas for continuous data, we reported mean difference (MD) with a 95% CI if the outcomes were measured in the same units in the studies included and standardized mean difference with 95% CIs to combine studies revealing similar outcomes with different units of measurement. Heterogeneity was assessed by using I2 and χ2 statistics along with a visual inspection of the forest plots. A random-effects model was used in all forest plots because we expected variations in interventions. To avoid double-counting in studies with multiple arms, a number of participants in the comparison group were split among all the intervention arms. Subgroup analysis was done according to the following:
Baseline prevalence of infection (0% to 19% was defined as mild, 20% to 49% was moderate, and 50% or more was severe)
Duration of the intervention (defined as ≤1 year versus >1 year)
Age group (defined as ≤5 years or >5 years of age)
The type of drug used in MDA
The mode of intervention delivery (school-based or community-based interventions)
Quality Assessment
For RCTs, we used the Cochrane risk of bias tool,17 which assesses selection bias, performance bias, detection bias, attrition bias, and reporting bias. We rated each component as “high,” “low,” or “unclear” risk of bias. For quasi-experimental studies, we used the Cochrane Effective Practice and Organization of Care risk of bias criteria (based on additional criteria, including similar baseline outcome measurements, similar baseline characteristics, knowledge of the intervention allocation adequately prevented during the study, protection against contamination, intervention independent of other changes, the shape of intervention effect prespecified, and intervention unlikely to affect data collection) and rated the studies as low-risk, high-risk, or unclear risk.18 Two independent reviewers performed the quality appraisal, and any disagreements were resolved with discussion. We summarized the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation criteria.19 A grade of “high,” “moderate,” “low,” or “very low” was used to grade the overall evidence that indicates the strength of an effect on the specific health outcome. Two reviewers discussed the grading, and any conflict was resolved with the help of a third reviewer.
Results
Results of the Search
We identified a total of 88 384 titles from the search conducted in all the databases. After screening titles and abstracts, 878 full texts were reviewed, of which 155 studies (231 articles) including 262 299 participants were included in the review. Figure 1 depicts the search flow diagram and Supplemental Table 3 presents the characteristics of included studies.
Description of Included Studies
Of the 155 included studies, 88 studies were RCTs20–106 and 67 studies were quasirandomized studies.107,108–173 All of the studies were conducted in low- and middle-income countries, including in Sub-Saharan Africa,28–30,32–36, 38–50,53,56,59,60,64–68,75,77,78,82,83, 85,87–89,91,94–104,106,113,116,118,119, 121,124–130,132–134,144,146,147,149,150,152, 155,167–170,172 South-East Asia,37,51, 52,54,55,57,58,61–63,69–74,79,80,84,86, 110–112,114,117,120,122,123,135–140,142, 143,145,151,153,154,156,158–162, 164–166,171,173 the Caribbean Islands,81 the South Pacific,109,141 Central America,93,148,157 and South America.31,76,90,92,105,108,122,131,163 Eighty-two studies focused on STH20,21,24,26,27,48–50,52–61,63–72, 74–83,85–93,107,130,132–141,143–152, 154–163,165,166,174 ; 38 on Schistosomiasis22,25,30–39, 41–46,95,105,106,112–119,121–129 ; 15 on Trachoma23,94,96–104,167–170 ; and 20 studies focused on other NTDs, including scabies, pediculosis, lymphatic filariasis, dengue, rabies, leishmaniasis, hand-foot-mouth disease, and Wuchereria bancrofti infections.28,29,40,51,62,73,84,108–111,120, 131,142,153,164,171–173,175 MDA was the most common intervention evaluated (n = 91), followed by health education (n = 26), WASH interventions (n = 18), micronutrient supplementation (n = 14) and vector control (n = 11). All of the studies targeted children and adolescents aged 0 to 18 years with some studies including youths up to the age of 25 years. Both male and female participants were included. Figure 2 summarizes the risk of bias for included RCTs and quasi-experimental studies. The characteristics for the included studies are detailed in Supplemental Table 3.
Effect of Interventions
We report the effect of the interventions separately for each NTD. The overall summary of the findings is presented in Table 1, whereas the summary effect estimates from subgroup analysis are presented in Table 2. The forest plots for all the analyses are added as figures in the Supplemental Material, and all the summary estimates are provided in Supplemental Table 4.
Summary of Findings
Outcomes . | MDA . | WASH . | Health Education . | Vector Control . | Micronutrient Supplement . |
---|---|---|---|---|---|
Soil-transmitted helminths | |||||
Prevalence of Ascaris | Low qualitya | Very low qualityb | Very low qualityb | — | — |
Prevalence of Trichuris | Low qualitya | Very low qualityb | Very low qualityb | — | — |
Prevalence of Hookworm | Low qualitya | Very low qualityb | Very low qualityb | — | — |
Prevalence of any STH | Very low qualityb | Very low qualityb | — | — | — |
Prevalence of anemia | Very low qualityb | Very low qualityb | — | — | — |
Hemoglobin levels | Very low qualityb | — | — | — | Very low qualityb |
Change in hemoglobin | Very low qualityb | — | — | — | Very low qualityb |
End of intervention height | Very low qualityb | — | — | — | — |
Overall change in height | Low qualitya | — | — | — | — |
Prevalence of stunting | — | Very low qualityb | — | — | — |
Prevalence of E. Vermicularis | — | — | Low qualitya | — | — |
Schistosoma | |||||
Prevalence of S. Mansoni | Very low qualityb | — | Moderate qualitya | Very low qualityb | — |
S. Haematobium | — | — | Very low qualityb | Very low qualityb | Low qualitya |
Intensity of S. Mansoni | — | — | Moderate qualitya | — | — |
Intensity of S. hematobium | — | — | — | — | Low qualitya |
Cure rate | Very low qualityb | — | — | — | — |
Reinfection rate | — | — | — | — | Moderate qualitya |
Prevalence of anemia | — | — | — | — | Low qualitya |
Hemoglobin levels | — | — | — | — | Moderate qualitya |
Trachoma | |||||
Ocular chlamydial infection | Very low qualityb | — | — | Very low qualityb | — |
Active trachoma infections | — | Very low qualityb | Very low qualityb | — | |
Prevalence of trachoma | — | — | Moderate qualitya | Very low qualityb | — |
Ocular Chlamydial infections | — | — | — | Very low qualityb | — |
Intense active trachoma | — | — | — | Very low qualityb | — |
Children with clean faces | — | — | Very low qualityb | — | — |
Other NTDs | |||||
Incidence of microfilairasis | Very low qualityb | — | — | — | — |
Prevalence of lice infestation | — | — | Very low qualityb | — | — |
Incidence of Leishmaniasis | — | — | — | Very low qualityb | — |
Outcomes . | MDA . | WASH . | Health Education . | Vector Control . | Micronutrient Supplement . |
---|---|---|---|---|---|
Soil-transmitted helminths | |||||
Prevalence of Ascaris | Low qualitya | Very low qualityb | Very low qualityb | — | — |
Prevalence of Trichuris | Low qualitya | Very low qualityb | Very low qualityb | — | — |
Prevalence of Hookworm | Low qualitya | Very low qualityb | Very low qualityb | — | — |
Prevalence of any STH | Very low qualityb | Very low qualityb | — | — | — |
Prevalence of anemia | Very low qualityb | Very low qualityb | — | — | — |
Hemoglobin levels | Very low qualityb | — | — | — | Very low qualityb |
Change in hemoglobin | Very low qualityb | — | — | — | Very low qualityb |
End of intervention height | Very low qualityb | — | — | — | — |
Overall change in height | Low qualitya | — | — | — | — |
Prevalence of stunting | — | Very low qualityb | — | — | — |
Prevalence of E. Vermicularis | — | — | Low qualitya | — | — |
Schistosoma | |||||
Prevalence of S. Mansoni | Very low qualityb | — | Moderate qualitya | Very low qualityb | — |
S. Haematobium | — | — | Very low qualityb | Very low qualityb | Low qualitya |
Intensity of S. Mansoni | — | — | Moderate qualitya | — | — |
Intensity of S. hematobium | — | — | — | — | Low qualitya |
Cure rate | Very low qualityb | — | — | — | — |
Reinfection rate | — | — | — | — | Moderate qualitya |
Prevalence of anemia | — | — | — | — | Low qualitya |
Hemoglobin levels | — | — | — | — | Moderate qualitya |
Trachoma | |||||
Ocular chlamydial infection | Very low qualityb | — | — | Very low qualityb | — |
Active trachoma infections | — | Very low qualityb | Very low qualityb | — | |
Prevalence of trachoma | — | — | Moderate qualitya | Very low qualityb | — |
Ocular Chlamydial infections | — | — | — | Very low qualityb | — |
Intense active trachoma | — | — | — | Very low qualityb | — |
Children with clean faces | — | — | Very low qualityb | — | — |
Other NTDs | |||||
Incidence of microfilairasis | Very low qualityb | — | — | — | — |
Prevalence of lice infestation | — | — | Very low qualityb | — | — |
Incidence of Leishmaniasis | — | — | — | Very low qualityb | — |
—, No exiting data.
Statistically significant impact.
Statistically nonsignificant/uncertain effect.
Summary of the Intervention Effects by Subgroups
Subgroup . | Outcomes (Estimates and 95% CI) . | ||||
---|---|---|---|---|---|
. | Prevalence of Ascaris . | Prevalence of Trichuris . | Prevalence of Hookworm . | Any STH infection . | |
MDA | |||||
Age | |||||
≤5 y | RR, 0.42 | RR, 0.57 | RR: 0.42 | — | |
CI, 0.25 to 0.70 | CI, 2.39–18.09 | CI: 0.33 to 0.53 | |||
n = 4 | n = 1 | n = 3 | |||
N = 5583 | N = 187 | N = 340 | |||
Low quality | Low quality | Low quality | |||
>5 y | RR, 0.44 | RR, 0.68 | RR, 0.47; | — | |
CI: 0.44 to 0.56 | CI: 0.57 to 0.81 | CI, 0.31 to 0.71; | |||
n = 12 | n = 11 | n = 9 | |||
N = 2948 | N = 7693 | N = 7066 | |||
Low quality | Low quality | Low quality | |||
Drug type | |||||
Albendazole | RR, 0.32 | RR,0.73 | RR, 0.39 | — | |
CI, 0.21 to 0.48 | CI, 0.58 to 0.93 | CI, 0.28 to 0.53 | |||
n = 9 | n= 8 | n= 7 | |||
N = 7834 | N = 2501 | N= 7474 | |||
Low quality | Low quality | Low quality | |||
Mebendazole | RR, 0.51 | RR, 0.43 | RR, 0.50 | — | |
CI, 0.37 to 0.71 | CI, 0.22 to 0.84 | CI, 0.26 to 0.97 | |||
n = 6 | n = 6 | n = 6 | |||
N = 5121 | N = 5221 | N = 5121 | |||
Low quality | Low quality | Low quality | |||
Pyrantel pamoate | RR, 0.54 | RR, 1.02 | — | ||
CI, 0.41 to 1.01 | CI, 0.90 to 1.16 | — | |||
n = 2 | n = 1 | — | |||
N = 222 | N = 158 | — | |||
Low quality | Low quality | — | |||
Delivery strategy | |||||
School-based | RR, 0.42 | RR, 0.58 | RR, 0.34 | — | |
CI, 0.32 to 0.54 | CI, 0.47 to 0.72 | CI, 0.18 to 0.64 | |||
n = 12 | n = 11 | n = 10 | |||
N = 7264 | N = 7108 | N = 6798 | |||
Low quality | Low quality | Low quality | |||
Community-based | RR, 0.40 | RR: 0.84 | RR, 0.63 | — | |
CI, 0.25 to 0.62 | CI: 0.46 to 1.51 | CI, 0.42 to 0.93 | |||
n = 7 | n = 4 | n = 5 | |||
N = 7412 | N = 2016 l | N = 7181 | |||
Low quality | Low quality | Low quality | |||
Duration of intervention | |||||
≤1 y | RR, 0.47 | RR, 0.63 | RR, 0.40 | — | |
CI, 0.28 to 0.58 | CI, 0.49 to 0.80 | CI, 0.28 to 0.58 | |||
n = 16 | n = 12 | n = 11 | |||
N = 8004 | N = 4554 | N = 4236 | |||
Low quality | Low quality | Low quality | |||
>1 y | RR, 0.23 | RR, 0.64 | RR, 0.42 | — | |
CI, 0.05 to 1.00 | CI, 0.25 to 1.61 | CI, 0.14 to 1.28 | |||
n = 2 | n = 2 | n = 3 | |||
N = 5430 | N = 3328 | N = 8493 | |||
Low quality | Low quality | Low quality | |||
WASH | |||||
Age | |||||
≤5 y | — | — | — | RR, 1.36 | |
CI, 0.92 to 2.01 | |||||
n = 4 | |||||
N = 7124 | |||||
Low quality | |||||
>5 y | — | — | — | RR, 1.62 | |
CI, 0.33 to 7.88 | |||||
n = 3 | |||||
N = 826 | |||||
Low quality |
Subgroup . | Outcomes (Estimates and 95% CI) . | ||||
---|---|---|---|---|---|
. | Prevalence of Ascaris . | Prevalence of Trichuris . | Prevalence of Hookworm . | Any STH infection . | |
MDA | |||||
Age | |||||
≤5 y | RR, 0.42 | RR, 0.57 | RR: 0.42 | — | |
CI, 0.25 to 0.70 | CI, 2.39–18.09 | CI: 0.33 to 0.53 | |||
n = 4 | n = 1 | n = 3 | |||
N = 5583 | N = 187 | N = 340 | |||
Low quality | Low quality | Low quality | |||
>5 y | RR, 0.44 | RR, 0.68 | RR, 0.47; | — | |
CI: 0.44 to 0.56 | CI: 0.57 to 0.81 | CI, 0.31 to 0.71; | |||
n = 12 | n = 11 | n = 9 | |||
N = 2948 | N = 7693 | N = 7066 | |||
Low quality | Low quality | Low quality | |||
Drug type | |||||
Albendazole | RR, 0.32 | RR,0.73 | RR, 0.39 | — | |
CI, 0.21 to 0.48 | CI, 0.58 to 0.93 | CI, 0.28 to 0.53 | |||
n = 9 | n= 8 | n= 7 | |||
N = 7834 | N = 2501 | N= 7474 | |||
Low quality | Low quality | Low quality | |||
Mebendazole | RR, 0.51 | RR, 0.43 | RR, 0.50 | — | |
CI, 0.37 to 0.71 | CI, 0.22 to 0.84 | CI, 0.26 to 0.97 | |||
n = 6 | n = 6 | n = 6 | |||
N = 5121 | N = 5221 | N = 5121 | |||
Low quality | Low quality | Low quality | |||
Pyrantel pamoate | RR, 0.54 | RR, 1.02 | — | ||
CI, 0.41 to 1.01 | CI, 0.90 to 1.16 | — | |||
n = 2 | n = 1 | — | |||
N = 222 | N = 158 | — | |||
Low quality | Low quality | — | |||
Delivery strategy | |||||
School-based | RR, 0.42 | RR, 0.58 | RR, 0.34 | — | |
CI, 0.32 to 0.54 | CI, 0.47 to 0.72 | CI, 0.18 to 0.64 | |||
n = 12 | n = 11 | n = 10 | |||
N = 7264 | N = 7108 | N = 6798 | |||
Low quality | Low quality | Low quality | |||
Community-based | RR, 0.40 | RR: 0.84 | RR, 0.63 | — | |
CI, 0.25 to 0.62 | CI: 0.46 to 1.51 | CI, 0.42 to 0.93 | |||
n = 7 | n = 4 | n = 5 | |||
N = 7412 | N = 2016 l | N = 7181 | |||
Low quality | Low quality | Low quality | |||
Duration of intervention | |||||
≤1 y | RR, 0.47 | RR, 0.63 | RR, 0.40 | — | |
CI, 0.28 to 0.58 | CI, 0.49 to 0.80 | CI, 0.28 to 0.58 | |||
n = 16 | n = 12 | n = 11 | |||
N = 8004 | N = 4554 | N = 4236 | |||
Low quality | Low quality | Low quality | |||
>1 y | RR, 0.23 | RR, 0.64 | RR, 0.42 | — | |
CI, 0.05 to 1.00 | CI, 0.25 to 1.61 | CI, 0.14 to 1.28 | |||
n = 2 | n = 2 | n = 3 | |||
N = 5430 | N = 3328 | N = 8493 | |||
Low quality | Low quality | Low quality | |||
WASH | |||||
Age | |||||
≤5 y | — | — | — | RR, 1.36 | |
CI, 0.92 to 2.01 | |||||
n = 4 | |||||
N = 7124 | |||||
Low quality | |||||
>5 y | — | — | — | RR, 1.62 | |
CI, 0.33 to 7.88 | |||||
n = 3 | |||||
N = 826 | |||||
Low quality |
N = number of participants, n = number of studies. —, no existing data.
Soil-Transmitted Helminths
A total of 82 studies focused on STHs, of which 48 were RCTs and 34 were quasi-experimental studies.20,21,24,26,27,48–50,52–61,63–72, 74–83,85–93,107,130,132–141,143–152, 154–163,165,166,174 A total of 50 studies were pooled for metaanalyses. Studies assessed the effectiveness of MDA (n = 45), health education (n = 7), WASH (n = 17), and iron supplementation (n = 13). All the forest plots are shown in Supplemental Figs 1–27.
Comparison: MDA Versus No MDA/Placebo
A total of 28 studies were meta-analyzed and these included a total of 116 585 participants.26,47,52,53,61, 65,68–71,77,79,80,85,93,137,140,141,144–148, 150,152,163,165,166 Out of these, 13 studies were conducted in schools and 7 studies took place in a community setting. Findings suggest that MDA may reduce the prevalence of infection with Ascaris by 58% (RR, 0.42; 95% CI, 0.35 to 0.52; 19 studies; 14 676 participants; I2 92%; low-quality evidence), Trichuris infection by 36% (RR, 0.64; 95% CI, 0.53 to 0.77; 15 studies; 9124 participants; I2 96%; low-quality evidence), and hookworm infection by 57% (RR, 0.43; 95% CI, 0.29 to 0.64; 15 studies; 13 979 participants; I2 97%; low-quality evidence) compared with no MDA (Fig 3). MDA may also improve height (RR, 0.35; 95% CI, 0.01 to 0.68; 5 studies; 1043 participants; I2 93%; low-quality evidence) compared with no MDA. We are uncertain of the effect of MDA on the overall prevalence of any STH, prevalence of anemia, hemoglobin levels, and height at the end of intervention period. The results for the subgroup analysis are summarized in Table 2.
Forest plot for the effectiveness of MDA for the prevalence of NTDs.
Comparison: Health Education Versus Standard of Care
Five studies with 2412 participants were metaanalyzed.27,90,134,136,139 Health education included dissemination of information on the transmission and life cycle of various NTDs along with preventive habits (eg, handwashing, avoiding swimming in contaminated water bodies). We are uncertain of the effect of health education on the prevalence of Ascaris, Trichuris, and hookworm compared with no health education. Health education may reduce the prevalence of E. vermicularis by 70% compared standard of care (RR, 0.30; 95% CI, 0.21 to 0.41; 3 studies; 1397 participants; I2 0%; low-quality evidence).
Comparison: WASH Versus No WASH Intervention
Twelve studies with 23 311 participants were metaanalyzed.21,24, 54,57,58,63,64,66,82,86,107,143 WASH interventions included building latrines, use of safe storage vessels to treat and store drinking water, education on the importance of hygiene practices like handwashing before meals and after using the washroom, and building handwashing stations. We are uncertain of the effect of WASH interventions on the prevalence of Ascaris, Trichuris, hookworm, any STH, stunting, and anemia compared with groups with no WASH interventions. The results of the subgroup analysis are summarized in Table 2.
Comparison: Iron Supplementation Versus Placebo
Six studies with 1265 participants were metaanalyzed.60,75,79,88,140,161 Out of these, 5 studies included both iron supplementation and MDA whereas 1 study only included iron supplementation. We are uncertain of the effect of iron supplementation on change in hemoglobin or to the end of treatment hemoglobin compared with children who received placebo (Fig 4).
Forest plot for the impact of iron supplementation on hemoglobin. aVitamin A + iron versus placebo. bWeekly iron supplementation versus placebo 16 week follow-up. cDaily iron supplementation versus placebo 16 week follow-up.
Forest plot for the impact of iron supplementation on hemoglobin. aVitamin A + iron versus placebo. bWeekly iron supplementation versus placebo 16 week follow-up. cDaily iron supplementation versus placebo 16 week follow-up.
Schistosomiasis
A total of 38 studies focused on Schistosomiasis,22,25,30–39,41–46,95, 105,106,112–119,121–129 of which 21 were RCTs and 17 were quasi-experimental studies; 22 included studies were pooled for meta-analysis. Studies assessed the effectiveness of MDA (n = 22), health education (n = 9), micronutrient supplementation (n = 2), vector control (n = 4), and school- versus community-based MDA (n = 7). The forest plots are shown in Supplemental Figs 28–46.
Comparison: MDA Versus No MDA
Comparison: Health Education Versus Standard of Care
A total of 5 studies were meta-analyzed with 3215 participants.25,35,36,115,119 We are uncertain of the effect of health education on the prevalence of S. hematobium infection compared with the standard of care. Health education probably reduces the infection intensity of S. mansoni (MD, −40.10; 95% CI, −49.32 to −30.88; 1 study; 1284 participants; moderate-quality evidence) and the prevalence of S. mansoni by 90% (RR, 0.10; 95% CI, 0.05 to 0.19; 1 study; 1284 participants; moderate-quality evidence) compared with standard of care.
Comparison: Micronutrient Supplementation Versus No Supplementation
Two studies with 1014 participants were metaanalyzed.32,118 The micronutrients included were zinc or iron supplements. Micronutrient supplementation may reduce the infection intensity of S. hematobium (MD, −0.50; 95% CI, −0.69 to −0.31; 1 article; 234 participants; low-quality evidence) and the prevalence of S. hematobium infections (RR, 0.76; 95% CI, 0.60 to 0.98; 1 article; 195 participants; low-quality evidence), and anemia (RR, 0.34; 95% CI, 0.14 to 0.81; 1 article; 324 participants; low-quality evidence) compared with no supplementation. The findings also suggest that micronutrient supplements probably improve hemoglobin levels (MD, 0.34; 95% CI, 0.07 to 0.61; 1 article; 324 participants; moderate-quality evidence) and decrease the reinfection rate of S. hematobium infections (MD, −0.30; 95% CI, −0.72 to 0.12; 1 article; 261 participants; moderate-quality evidence).
Comparison: Vector Control Versus No Vector Control
Comparison: School-Based Versus Community-Based MDA
A total of 7 studies with 12 772 participants were metaanalyzed.22,31, 39,41,43,44,121 The intervention was MDA given either in school settings or distributed in community settings. We are uncertain of the effects of community-based MDA compared with school-based MDA on the prevalence of S. mansoni infections (RR, 1.28; 95% CI, 0.91 to 1.80; 5 studies; 10 138 participants; I2 90%; low-quality evidence) (Fig 5), whereas school-based MDA may reduce the prevalence of wasting compared with community-based MDA (RR, 0.18; 95% CI, 0.05 to 0.68; 2 studies; 272 participants; low-quality evidence). We are uncertain of the effect of community-based MDA on hemoglobin, village-level arithmetic mean infection intensity, the cure rate for Schistosoma, any STH infection, reinfection rate, the prevalence of stunting, and anemia compared with school-based MDA.
Forest plot for the comparison of school versus community MDA, number infected Tx, treatment.
Forest plot for the comparison of school versus community MDA, number infected Tx, treatment.
Trachoma
A total of 15 studies focused on Trachoma,23,94,96–104, 167–170 of which 11 were RCTs, 4 were quasi-experimental studies, and 10 were included studies pooled for metaanalysis. Studies assessed the effectiveness of MDA (n = 8), health education (n = 3), and WASH (n = 1), and vector control (n = 3). All the forest plots are shown in Supplemental Figs 47–55.
Comparison: MDA Versus No MDA/Placebo
Comparison: Health Education Versus Standard of Care
A total of 3 studies with 5271 participants were metaanalyzed.99,103,167 The findings from our analysis suggest that health education probably reduces the mean prevalence of active trachoma infections compared with standard of care (MD, −4.00; 95% CI, −7.80 to −0.20; 1 study; 364 participants; moderate-quality evidence). We are uncertain of the effect of health education on the prevalence of children with clean faces (as an outcome for face washing intervention) compared with the standard of care.
Comparison: WASH Interventions Versus No WASH Interventions
Only 1 study with 1353 participants was included.168 We are uncertain of the effect of WASH interventions on the prevalence of active trachoma infections compared with no WASH interventions.
Comparison: Vector Control Measures Compared With No Vector Control Measure
A total of 3 studies with 1025 participants were metaanalyzed.94,102,104 Vector control included insecticide spraying near breeding grounds and insecticide-treated bed nets. We are uncertain of the effect of vector control on the prevalence of C. trachomatis infection, active trachoma, mean prevalence of clinically active trachoma, mean prevalence of ocular Chlamydia, or prevalence of intense active trachoma infections compared with no vector control measures.
Other Diseases
A total of 20 studies focused on other diseases, including scabies, pediculosis, lymphatic filariasis, dengue, rabies, leishmaniasis, hand-foot-mouth disease, and Wuchereria bancrofti infections.28,29,40,51,62, 73,84,108–111,120,131,142,153,164, 171–173,175 Out of these, 8 studies were RCTs and 12 were quasi-experimental studies. A total of 6 included studies were pooled for meta-analysis. Studies assessed the effectiveness of MDA (n = 9), health education (n = 7), and vector control (n = 4). All the forest plots are shown in Supplemental Figs 56–58.
Comparison: MDA Versus No MDA/Placebo
Comparison: Health Education Versus Standard of Care
Comparison: Vector Control Measures Compared With No Vector Control Measure
A total of 2 studies with 7111 participants were included.84,131 We are uncertain of the effect of vector control measures on the incidence of Leishmaniasis (RR, 0.40; 95% CI, 0.29 to 0.56; 2 studies; 7111 participants; I2 27%; very- low-quality evidence) compared with the groups who received no vector control measures.
Discussion
This review summarizes the findings of 155 studies (231 articles) including 262 299 participants. Eight of these studies were RCTs and 67 were quasi-experimental studies. Most of the included studies were judged to be at high risk of bias for blinding of the participants and personnel as well as a high risk of bias for allocation concealment. The majority of the outcomes were rated as low-quality evidence and the outcomes were mainly downgraded because of study limitations and high heterogeneity. For STH, MDA may reduce the prevalence of Ascaris, Trichuris, and hookworm, whereas MDA may also improve height compared with no MDA. Health education may reduce the prevalence of E. Vermicularis. For Schistosomiasis, health education probably reduces the intensity and prevalence of S. mansoni, micronutrient supplementation may reduce the infection intensity and prevalence of S. hematobium and the prevalence of anemia and probably improves hemoglobin levels. Community-based MDA for Schistosomiasis probably decreases the prevalence of S. mansoni infections compared with school-based MDA, whereas school-based MDA may reduce the prevalence of wasting compared with community-based MDA. For Trachoma, health education probably reduces the mean prevalence of active trachoma infections compared with standard of care.
Our review findings suggest that MDA was the most effective intervention for reducing the burden of STH, whereas the findings are uncertain for the effect of WASH interventions. These findings are in concordance with the review by Majorin,176 in which WASH and child feces disposal messages may have an impact in preventing diarrhea and STH infections, although the evidence was reported to be limited and of low certainty. Another systematic review by Strunz12 suggested that WASH access is generally associated with a decreased risk of infections with STH. For Schistosomiasis, our review suggests that health education was an effective intervention strategy for decreasing the prevalence of infections. A similar finding was also reported in a review by Zhou,177 in which health education revealed a significant reduction in Schistosoma infections. Community-based MDA was found to be more effective in decreasing the prevalence of Schistosoma infections in our review.41,121 Similar findings were reported in another systematic review in which community-based interventions were found to be more effective than school-based interventions in decreasing the prevalence of Schistosoma and STH infections. Our review suggested that micronutrient supplementation might reduce the risk of infection with Schistosoma, wasting, and anemia. These findings are also in concordance with the review by Morales-Suarez-Varela178 in which micronutrient supplementation was associated with a decreased risk of infections with Schistosoma species, mainly because micronutrients, including iron and zinc, play a key role in improving immune function and, hence, decrease the risk of infection.38 For Trachoma, our review findings are inconclusive because of limited and low-quality evidence. Similar results have been revealed by previous systematic reviews179,180 For other NTDs, community-based interventions have been reported to be more effective in decreasing the prevalence of infections.14,181 However, we were unable to find enough studies to assess the impact of such interventions on these NTDs. This could be attributable to the fact that our review focused on a specific population group including children and adolescents.
There are a few limitations of our review. Firstly, there was a lack of evidence on the long-term impact and sustainability of the interventions and outcomes. Many of the interventions (including health education, WASH measures, and vector control) require behavior change and, consequently, it is important to assess the long-term outcomes of these interventions to ensure sustainable impact. Secondly, there is limited and low-quality evidence assessing the impact of interventions other than MDA. Thirdly, the WASH interventions included in our review were diverse, and the impact of individual WASH interventions could not be evaluated. And finally, there were few studies evaluating the effectiveness of interventions on NTDs other than STH, Schistosomiasis, and Trachoma.
There are limited data on the effectiveness of MDA, WASH, health education, vector control, and micronutrient supplementation, specifically among children and adolescent population groups. Future studies should focus on assessing the relative effectiveness and cost-effectiveness of such intervention on long-term health outcomes. More high-quality research is needed on other NTDs such as dengue, lice, leishmaniasis, and microfilaremia to assess which interventions can be effective in reducing the burden of these diseases.
Dr Naqvi screened the search results, screened the retrieved papers against the inclusion criteria, appraised the quality of the papers, extracted the data, completed the data analysis, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Raza screened the search results, screened the retrieved papers against the inclusion criteria, appraised the quality of the papers, extracted the data, and completed the data analysis; Drs Das and Salam drafted the initial manuscript, reviewed and revised the manuscript, designed the study, coordinated and supervised the data collection, and critically reviewed and modified the manuscript; Drs Lassi and Bhutta designed the study, coordinated and supervised data collection, and critically reviewed and modified the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: This study was supported by International Development Research Centre (IDRC grant number 109010-001). The funder did not participate in the work. Core funding support was also provided by the SickKids Centre for Global Child Health in Toronto, and the Center of Excellence for Women & Child Health at the Aga Khan University in Karachi.
CONFLICT OF INTEREST DISCLOSURE: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.
Comments
Combining Data from Cluster-Randomized Trials
References:
1. Naqvi FA, Das JK, Salam RA, Raza SF, Lassi ZS, Bhutta ZA. Interventions for Neglected Tropical Diseases Among Children and Adolescents: A Meta-analysis. Pediatrics. 2022;149(Suppl 6):e2021053852E.
2. Higgins JPT, Eldridge S, Li T (editors). Chapter 23: Including variants on randomized trials. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. https://training.cochrane.org/handbook/current/chapter-23#section-23-1-3 (accessed July 11, 2022).
3. Awasthi S, Peto R, Read S, et al. Population deworming every 6 months with albendazole in 1 million pre-school children in North India: DEVTA, a cluster-randomised trial. Lancet. 2013;381(9876):1478-1486.
4. Ebenezer R, Gunawardena K, Kumarendran B, et al. Cluster-randomised trial of the impact of school-based deworming and iron supplementation on the cognitive abilities of schoolchildren in Sri Lanka's plantation sector. Trop Med Int Health. 2013;18(8):942-951.
Caution is need when analyzing the results of cluster randomized controlled trials in meta-analysis
Naqvi et al did not take into account the design effect of the two cluster RCTs 2,3 in the analysis of the effectiveness of MDA for the prevalence of NTDs. According to the guidance of Cochrane Handbook 4, the results of cluster RCTs should be adjusted by the effective sample size to avoid the "unit-of-analysis error" caused by the group effect5. However, in this case the authors did not adjust the results of the included cluster RCTs accordingly. After adjustment, we found that the results for the prevalence of Ascaris (relative risk [RR] 0.41, 95% confidence interval [CI] 0.33 to 0.51) and prevalence of Hookworm (RR 0.44, 95%CI 0.31 to 0.64) differed from those calculated by Naqvi et al1. The change of the results is minor after adjustment because the weight of data in these two studies is very small. If the weight of the cluster RCTs is large, the results would change dramatically. In the future, systematic reviewers should pay attention to design effect of cluster RCTs and use appropriate methods in meta-analyses that include cluster RCTs.
We declare no competing interests.
E-mail: [email protected]; [email protected]
References
1. Naqvi FA, Das JK, Salam RA, Raza SF, Lassi ZS, Bhutta ZA. Interventions for Neglected Tropical Diseases Among Children and Adolescents: A Meta-analysis. Pediatrics. 2022;149(Suppl 6):e2021053852E.
2. Awasthi S, Peto R, Read S, et al. Population deworming every 6 months with albendazole in 1 million pre-school children in North India: DEVTA, a cluster-randomised trial. Lancet. 2013;381(9876):1478-1486.
3. Ebenezer R, Gunawardena K, Kumarendran B, et al. Cluster-randomised trial of the impact of school-based deworming and iron supplementation on the cognitive abilities of schoolchildren in Sri Lanka's plantation sector. Trop Med Int Health. 2013;18(8):942-951.
4. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane. https://training.cochrane.org/handbook/current (accessed June 1, 2022).
5. Donner A, Piaggio G, Villar J. Statistical methods for the meta-analysis of cluster randomization trials. Stat Methods Med Res 2001;10: 325-338.