Interventions for High-Burden

Infectious Diseases in Children and

Adolescents: A Meta-analysis
Durray Shahwar A. Khan, MBBS,a Rabia Naseem, MBBS,a Rehana A. Salam, PhD,a Zohra S Lassi, PhD,b,c Jai K. Das, MD,a,b
Zulfiqar A Bhutta, PhD, MBBS, FRCPCH, FAAP,d,e

BACKGROUND: Approximately 2.2 million deaths were reported among school-age children and young abstract
people in 2019, and infectious diseases remain the leading causes of morbidity and mortality, especially
in low and middle-income countries. We aim to synthesize evidence on interventions for high-burden
infectious diseases among children and adolescents aged 5 to 19 years.
METHODS: We conducted a comprehensive literature search until December 31, 2020. Two review authors
independently screened studies for relevance, extracted data, and assessed risk of bias.
RESULTS: We included a total of 31 studies, including 81 596 participants. Sixteen studies focused on
diarrhea; 6 on tuberculosis; 2 on human immunodeficiency virus; 2 on measles; 1 study each on acute
respiratory infections, malaria, and urinary tract infections; and 2 studies targeted multiple diseases. We
did not find any study on other high burden infectious diseases among this age group. We could not
perform meta-analysis for most outcomes because of variances in interventions and outcomes. Findings
suggests that for diarrhea, water treatment, water filtration, and zinc supplementation have some
protective effect. For tuberculosis, peer counseling, contingency contract, and training of health care
workers led to improvements in tuberculosis detection and treatment completion. Continuation of
cotrimoxazole therapy reduced the risk of tuberculosis and hospitalizations among human
immunodeficiency virus-infected children and reduced measles complications and pneumonia cases
among measles-infected children. Zinc supplementation led to a faster recovery in urinary tract
infections with a positive effect in reducing symptoms.
CONCLUSIONS: There is scarcity of data on the effectiveness of interventions for high-burden infectious
diseases among school-aged children and adolescents.

WHAT’S KNOWN ON THIS SUBJECT: Approximately 2.2 million

deaths were reported among children and young people aged 5 to
24 years, and infectious diseases remain the leading causes of
a morbidity and mortality, especially in low and middle-income
Division of Women and Child Health, Aga Khan University Hospital, Karachi, Pakistan; bRobinson Research Institute countries.
and cAdelaide Medical School, The University of Adelaide, Adelaide, Australia; dInstitute of Global Health and
Development, Aga Khan University, Karachi, Pakistan; and eCentre for Global Child Health, The Hospital for Sick WHAT THIS STUDY ADDS: There is scarcity of data on the
Children, Toronto, Ontario, Canada effectiveness of interventions for high-burden infectious diseases
among children and adolescents. This review summarizes the
Dr Khan and Dr Naseem formed the search strategy, identified the relevant articles, extracted data, limited existing evidence for diarrhea, tuberculosis, human
analyzed data, performed the risk of bias and quality assessment, and conducted initial drafts and immunodeficiency virus, measles, acute respiratory infections,
correction of reviews; Dr Salam, Dr Das, and Dr Bhutta conceptualized and designed the study, malaria, and urinary tract infections in this age group.
reviewed and finalized every step of the review, reviewed and finalized the manuscript, and
provided guidance to other authors throughout the process; and all authors approved the final To cite: Khan DSA, Naseem R, Salam RA, et al. Interventions
manuscript as submitted and agree to be accountable for all aspects of the work. for High-Burden Infectious Diseases in Children and
DOI: https://doi.org/10.1542/peds.2021-053852C Adolescents: A Meta-analysis. Pediatrics.
2022;149(s6):e2021053852C
Accepted for publication Feb 16, 2022

PEDIATRICS Volume 149, number s6, May 2022:e2021053852C SUPPLEMENT ARTICLE

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 An estimated 5.2 million children
under 5 years of age died in 2019
alone, mainly from preventable
causes.1 An additional 2.2 million
deaths were reported among
children and young people aged 5 to
24 years, and although lower than
under 5 mortality, is still a
substantial number.1 The Global
Burden of Diseases, Injuries, and
Risk Factors 2017 study suggested
that between 1990 and 2017, child
and adolescent deaths decreased
51.7% from 13.77 million in 1990 to
6.64 million in 2017.2 The progress
achieved over the past 2 decades,
however, has been unequitable and
the causes of morbidity and
mortality vary widely by
geographical region. Countries with
lower sociodemographic index (SDI)
and low-middle-SDI (a composite
indicator of development status
generated for the Global Burden of
Diseases report) account for over
80% of deaths in this age group
with major causes of morbidity
being neonatal disorders, lower
respiratory infections, diarrhea,
malaria, and congenital birth
defects.2 On the contrary, in
countries with high SDI, the major
causes of morbidity in this age
group include neonatal disorders,
congenital birth defects, headache,
dermatitis, and anxiety.2 Moreover,
it is estimated that approximately
23 million deaths will occur
between the years 2020 and 2030
among children and young adults
globally.1
During the Millennium Development
Goal era, much of the global focus
has been on reducing morbidity and
mortality among children under
5 years of age. This increased focus
on under 5 mortality has led to
enormous amounts of research in
this age group over the past few
decades, during which time there
has been almost 60% reduction in
under 5 mortality since 1990.1,3
However, there has been a
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simultaneous rise in morbidity and
mortality among children over
5 years of age and adolescents as
the survival beyond 5 years of age
improved. With the emergence of
Sustainable Development Goals, the
focus has expanded beyond the
under 5 years age group to include
older children and adolescents.
Interventions for improved case
detection and management of high
burden diseases in this age group
are imperative to reduce the burden
and consequent mortality. According
to the Global Burden of Disease
Study 2019, 6 infectious diseases
were among the top 10 causes of
the disability adjusted life years
(DALYs) in children younger than
10 years, including lower
respiratory infections, diarrheal
diseases, malaria, meningitis,
whooping cough, and sexually
transmitted infections (mainly
congenital syphilis).4 Pneumonia,
malaria, diarrhea, typhoid or
paratyphoid, human
immunodeficiency virus (HIV) and
acquired immunodeficiency
syndrome (AIDS), tuberculosis,
measles, meningitis, syphilis,
hepatitis B and C, and urinary tract
infections (UTI) remain the leading
causes of morbidity and mortality,
especially in low and middle-income
countries, among this age group.4–7
Some of the potential interventions
for improved case detection and
management of common illness in
this age group include micronutrient
supplementation as an adjunct to
the treatment of common infections;
antibiotic treatment of pneumonia;
comprehensive care packages;
improving caregiver’s recognition of
childhood illnesses, such as malaria
and pneumonia, for better and
prompt treatment; and water,
sanitation, and hygiene (WASH)
measures to prevent
transmission.8–10 The purpose of
this review is to assess the current
evidence on interventions for high-
burden infectious diseases in school-
aged children and adolescents aged
5 to 19 years.
METHODS
Objective
The authors of this study aim to
synthesize existing evidence on
interventions for high-burden
infectious diseases among school-
aged children and adolescents aged
5 to 19 years.
This systematic review follows the
guidelines recommended by the
Preferred Reporting Items for
Systematic Reviews and Meta-
analyses.11 The Preferred Reporting
Items for Systematic Reviews and
Meta-analyses checklist is presented
in Supplemental Table 1.
Types of Studies and Participants
We included randomized controlled
trials (RCT) (both cluster- and
individual-level randomization),
quasi-experimental studies, and
controlled before-after studies
assessing interventions for
improved detection and/or case
management of high-burden
infectious diseases. Our target
populations were school-aged
children and adolescents aged 5 to
19 years from across the globe.
Studies including participants with a
mean or median age falling in our
age group of interest were included,
as were studies that reported
outcomes according to age
categories. We included the
following high-burden infectious
diseases based on the Global Burden
of Disease Study 2019 for this age
group: diarrhea, cholera, shigellosis,
Campylobacter, acute respiratory
infections (ARI), adenovirus, Hib,
pertussis, typhoid or paratyphoid
intestinal infections, malaria, HIV
and AIDS, tuberculosis, measles,
meningitis, syphilis, hepatitis B and
C, and UTIs. Any intervention
targeted toward prompt detection
or effective management of these
KHAN et al
 diseases were included. Examples of
interventions of interest include
counseling and awareness, water
treatment, shorter course of
treatment of better compliance,
prophylactic treatments for disease
prevention, micronutrient
supplementation as adjunct therapy,
and improving detection and
management. We included studies
that were conducted after the
year 2000 to focus on the current
plausible management strategies.
We excluded studies that targeted
noninfectious causes of morbidity
and mortality in this age group
(such as neoplasms, road traffic
accidents, etc), or were addressing
interventions only toward upper
respiratory tract infections (eg, otitis
media, tonsillitis, pharyngitis, etc) or
vaccinations. We also excluded
studies assessing drug safety and
efficacy.
Types of Outcomes
We included studies that satisfied
our eligibility criteria and
reported outcomes on the selected
high-burden diseases. Studies that
reported the effects of the
intervention on detection or
management of the selected
diseases, including detection rates,
compliance to medication,
duration of illness, need for
hospitalization, incidence and
prevalence of high-burden
diseases, time is taken for
resolution of symptoms, etc, were
included. Studies reporting only
on behavior change outcomes,
such as frequency of handwashing
etc, were excluded from the
review.
Search Methods
We conducted an electronic search
until December 31, 2020, using
PubMed, Cochrane CENTRAL, and
Google Scholar and exported the
search results to the Covidence
application.12 A few of the terms
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used in the search strategy were as
follows: “case management,”
“infectious disease,” “school-age
children,” “adolescent,” etc. The
complete search strategy is
presented in Supplemental Table 2.
We also screened the reference lists
of relevant reviews to identify any
additional studies that might have
been missed in the electronic
searches.
Data Collection and Analysis
Two reviewers (D.S.K. and R.N.)
screened titles and abstracts on
Covidence.12 We retrieved the full
text of all remaining studies and
screened them based on the
eligibility criteria. Any conflicts were
resolved by reviewers R.A.S. and
J.K.D. Data were extracted from the
included studies on study
background, population and setting,
intervention group details,
comparison group details, outcomes,
and other relevant information. We
attempted to conduct a meta-
analysis (where possible) for
dichotomous and continuous
variables using Review Manager
version 5.1.4.13 For continuous data,
we used mean difference and for
dichotomous data, we used risk
ratios (RR) with a 95% confidence
interval (CI). Heterogeneity was
assessed using I2 and s2 values,
along with visual inspection of
forest plots. We used the Cochrane
risk of bias tool for the quality
assessment of the included RCTs.14
This tool assesses selection bias,
performance bias, detection bias,
attrition bias, and reporting bias.
Every study was rated to be at
“high,” “low,” or “unclear” risk of
bias for each component of the risk
of bias tool. We summarized the
quality of evidence that we
extracted using the Grading of
Recommendations, Assessment,
Development, and Evaluation
criteria.
RESULTS
Results of the Search
Our search yielded a total of 15 320
results that underwent title and
abstract screening. A total of 1550
studies were selected for full-text
review, and after cross-referencing
of included articles and relevant
systematic reviews, we included a
total of 31 studies as shown in Fig 1.
Description of Included studies
A total of 31 studies were included,
of which 20 were individually RCTs,
10 were cluster RCTs, and 1 study
was a crossover trial.15–45 All
studies were conducted between the
years 2002 and 2020. The studies
were conducted in the high-, middle-
, and low-income countries. Among
the included studies, 4 studies were
conducted in India, 3 from Mongolia,
3 from Kenya, 2 each from
Bangladesh and Pakistan, 1 study
each from Colombia, Cambodia,
Congo, Egypt, Ethiopia, Greece,
Guatemala, Guinea-Bissau, Iran,
Peru, Philippines, Tanzania, Uganda,
and United States; whereas 3 studies
were multicounty studies
(1 conducted in Bolivia and Bosnia
and 2 studies from Uganda and
Zimbabwe). Eighteen studies were
conducted in a community setting,
5 in schools, 4 in outpatient settings,
and 4 in inpatient settings. Out of
the 31 included studies, 14 studies
targeted individual participants,
whereas the remaining 17 targeted
whole communities (including
households, schools, diagnostic
centers, etc.) but reported the
outcomes separately for our
population of interest.
The included studies in this review
targeted 81 596 individuals; with
1 single study including 44 451
individuals.42 Five studies failed to
mention the number of individuals
and reported only the number of
households included in each study.
In terms of diseases targeted; a
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 ARI,15,16,39 5 studies assessed zinc
supplementation, and 1 study
assessed multiple micronutrients
along with zinc supplementation
for pneumonia and diarrhea.19
Home or community-based
management strategies included
counseling and contingency
contract (incentives for children
adhering to prescribed treatment)
(n 5 1)31 and increasing awareness
among health care workers
(n 5 2).32,38 Among studies
assessing use of antibiotics, 1 study
assessed the impact of shortening
the antibiotic course,33 whereas
3 studies assessed the use of
cotrimoxazole as prophylaxis in
HIV patients (n 5 2)34,35 and
prevention of measles
complications (n 5 1).27 The table
for the characteristics of included
studies is added as Supplemental
Table 3. Figure 2 summarizes the
risk of bias of the included studies.

Effect of Interventions
We report our findings according to
FIGURE 1 the diseases. We could not conduct a
Flow diagram. meta-analysis for most of the
interventions evaluated under each
total of 16 studies targeted (n 5 5),21,24,25,30,42 building water disease’s category (except diarrhea)
diarrhea,17,18,20–26,28–30,37,43–45 and sanitation facilities (n 5 1),37 because of the variety of the
6 targeted tuberculosis,15,19,31–33,39 and water disinfectant use interventions included and the
2 targeted HIV,34,35 2 targeted (n 5 4).17,20,22,28 Among studies outcomes reported.
measles,27,36 1 study each targeted assessing micronutrient
ARI,16 malaria,38 and UTI,40 supplementation, 3 studies Diarrhea
whereas 2 studies targeted assessed supplementation with A total of 16 studies were included
multiple diseases.41,42 We did not vitamin D3 for tuberculosis and assessing the interventions for
find any study targeting any other
high burden infectious diseases
among this age group. The
interventions assessed in these
studies were WASH interventions
(n 5 15), micronutrient
supplementation (n 5 9), antibiotic
prophylaxis or shortened course of
antibiotic treatment (n 5 4), and
home or community-based
managements (n 5 3). Among the
studies assessing WASH
interventions, the interventions
included filter use FIGURE 2
(n 5 5),18,29,43–45 hand hygiene Risk of bias summary.

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 diarrhea among school-aged
children and adolescents age 5 to
19 years.17,18,20–26,28–30,37,43–45
Fourteen studies assessed the
impact of WASH interventions on
the incidence of diarrhea, whereas 2
assessed the use of zinc
supplementation on diarrhea
duration.23,26 Among studies
assessing WASH intervention, 5
studies evaluated the impact of
different water filtration techniques
on diarrhea incidence,18,29,43–45
4 studies used water treatment with
disinfectants as an
intervention,17,20,22,28 1 study
assessed the impact of building
sanitation infrastructure and the
provision of hygiene kits on
diarrhea-related school absence,37
and another 4 assessed impact of
hand hygiene practices.21,24,25,30
Findings suggest that water
treatment probably reduces
diarrhea by 39% (RR, 0.61; 95% CI,
0.49–0.75; 4 studies; I2 0%;
moderate evidence quality; Fig 3).
The different types of water
treatments used are highlighted in
Supplemental Table 3; these
included lifestraw filter treated
water, ceramic water purifier,
iron-rich ceramic purifier, and water
treatment with concrete BioSand
filter. We are uncertain the effect of
hand hygiene on diarrhea
FIGURE 3
Impact of water treatment and hand hygiene on diarrhea. aIron rich ceramic. bCeramic water purifier.
c
Soap. dSanitizer.
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(RR, 0.79; 95% CI, 0.61–1.03;
1 study; very low-quality evidence;
Fig 3).
All of the studies assessing the effect
of water filtration techniques
reported a reduction in diarrheal
illness,18,29,37,43,45 except 1, which
reported inconclusive findings due
to limited evidence.44 The reduction
in longitudinal prevalence ratio
ranged between 34% and 52% in
school-aged children and
adolescents aged 5 to 15 years. For
zinc supplementation, 1 study
supplementing 30 mg of zinc
reported a significant reduction in
duration of diarrhea (64.1 hours in
zinc supplementation group versus
72.8 hours in the control group,
P 5 .028),26 whereas the other
study supplementing 20 mg zinc
reported no reduction in episodes of
diarrhea or its duration (hazard
ratio: 0.89; 95% CI 0.63–1.24).23
Building proper water and
sanitation infrastructure in schools
led to a significant reduction in odds
of school absence due to diarrhea
(OR 5 0.10; 95% CI, 0.05–0.22;
P < .001).37
Tuberculosis
We identified 6 studies assessing
interventions for
tuberculosis.15,19,31–33,39 Two studies
assessed the effect of vitamin D3
supplementation,15,39 2 studies
assessed improvement in
compliance of antituberculosis
treatment31,33 (1 used counseling
strategies as an intervention,31
whereas the other assessed shorter
antituberculosis treatment durations
and its impact on compliance),33
1 study assessed the effect of
multiple micronutrients and zinc
supplementation,19 and 1 study
assessed the effect of increasing
awareness and training health care
workers on tuberculosis detection
rates.32
Vitamin D3 supplementation did not
lower the risk of tuberculosis
infection (RR, 1.10; 95% CI,
0.87–1.38; P 5 .42) or tuberculosis
disease (RR, 0.87; 95% CI, 0.49–1.55)
when compared with placebo, and
the incidence of adverse events did
not differ between the 2 groups.15
Vitamin D3 supplementation
significantly improved growth in
stature with mean increase in stature
of 2.9 ± 1.6 cm in the vitamin D
group and 2.0 ± 1.7 cm in the
placebo group (95% CI, 2.16–2.81;
P 5 .003), along with fewer
tuberculin skin test conversions from
negative to positive (RR, 0.41; 95%
CI, 0.16–1.09; P 5 .06).39 Multiple
micronutrient supplementation, zinc
supplementation, or multiple
micronutrients, including zinc
supplementation did not have an
impact on anthropometric indices
and chest radiograph improvement
compared with placebo. However,
children who received
micronutrients had a faster gain in
height over 6 months of intervention
compared with those who did not
receive micronutrients (change in
height-for-age z-score 5 0.08;
P 5 .014).19
Peer counseling along with
contingency contract (84.8%) and
peer-counseling alone (80.3%) led
to a significantly higher treatment
completion rate, compared with
usual care (77.8%).31 Shorter course
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 combination therapy (4 months
compared with 9 months) led to
increased compliance (P 5 .011 for
4 months versus 9 months course).
The radiographic findings of
participants from the standard care
group were also more commonly
suggestive of possible active disease
as compared with those from
shorter course regimens (P 5 .001
for 9 months versus 4 months).33
Increasing general awareness and
training of health care workers
regarding tuberculosis detection
reported a 3-fold increase in
tuberculosis detection in the
intervention group from 3.8% to
12% when compared with its
baseline.32
HIV
We included 2 studies assessing
interventions targeting HIV in this
age group.34,35 Both studies
assessed the continuation or
cessation of cotrimoxazole
antibiotics among children as part of
the antiretroviral research for
Watoto trial. tuberculosis risk was
reported to be higher among
children who stopped cotrimoxazole
therapy after 96 weeks of
commencing antiretroviral therapy
(ART) compared with those children
who continued therapy (hazard
ratio [HR]: 3.0; 95% CI, 1.1–8.3;
P 5 .028).34 Continuation of
cotrimoxazole therapy after
96 weeks of ART was also found to
be beneficial in reducing
hospitalizations for malaria or
infections not related to malaria
compared with those who stopped
cotrimoxazole prophylaxis (HR,1.64;
95% CI, 1.14–2.37; P 5 .007).35
Measles
We included 2 studies assessing the
interventions for the prevention of
complications due to measles,
particularly pneumonia in children
with measles.27,36 One study
evaluated the effect of zinc
supplementation on the duration of
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measles rash and the time taken for
resolution of symptoms36; while the
other study assessed the effect of
cotrimoxazole in children with
measles on the development of
pneumonia or other severe
symptoms and need for hospital
admission.27
Zinc supplementation with 20 mg
tablets taken once daily for 6 days
did not provide additional benefit in
the treatment of children with
measles accompanied by pneumonia
as compared with standard
treatment with antibiotics and
vitamin A therapy alone.36 In
children with measles, prophylactic
treatment with cotrimoxazole was
observed to prevent measles
complications, with fewer lesser
pneumonia cases (odds ratio, 0.08;
95% CI, 0–0.56).27
ARI
We included only 1 study that
evaluated the impact of vitamin D3
fortified milk on ARI.16 Findings
from this study suggest that milk
fortified with vitamin D3
significantly reduced the risk of ARIs
among children (RR, 0.52; 95% CI,
0.31–0.89).16
Malaria
We included 1 study assessing the
use of rapid diagnostic tests (RDT)
by community health workers
(CHWs) and the number of children
prescribed artemisinin-based
combination therapy (ACT). CHWs
were trained to give out ACT based
on RDT results or clinical diagnosis
alone, suggesting that RDT use by
CHWs can be safe and effective for
targeting ACT treatment in patients
with uncomplicated malaria. This
also led to a significant reduction in
ACT prescription (by 45%)
compared with the group which was
treated based on clinical diagnosis
alone.38
UTI
We included a single study that was
conducted on hospitalized children
with UTI,40 assessing the
effectiveness of zinc
supplementation in treating children
with UTI. It was reported that once
daily 1 mg/kg per day of zinc
supplementation in addition to
standard treatment led to a faster
recovery with a positive effect in
reducing symptoms such as dysuria
and urine frequency. However, zinc
supplementation was also noted to
exacerbate abdominal pain in
children and increased its
duration.40
Studies Targeting Multiple Diseases
Two studies assessed the impact of
interventions on 2 or more high-
burden infectious diseases.41,42 One
study assessed the impact of zinc
and iron supplementation on the
incidence of malaria, ARI, and
diarrhea.41 The other study assessed
the impact of hand hygiene on the
incidence of influenza-like-illness
(ILI), school absenteeism due to ILI,
diarrhea, and conjunctivitis.42
Findings from these 2 studies
suggest that supplementation with
20 mg zinc reduces diarrhea
morbidity by 23%, while iron
supplementation was reported to
increase morbidity due to malaria
and diarrhea in children. There was
no effect of micronutrient
supplementation on ARI or
anthropometric indices.41 Hand
hygiene led to a 50% reduction in
laboratory-confirmed influenza
disease (P < .0001), a 40% reduction
in school absences due to ILI, a 30%
reduction in absences due to
diarrhea, and 67% reduction in
conjunctivitis, when compared with
the control group (P < .0001).42
DISCUSSION
Our review summarizes evidence on
interventions to improve detection
and/or effective case management
for high-burden infectious diseases
KHAN et al
 among school-aged children and
adolescents aged 5 to 19 years. We
included a total of 31 studies
including 81 596 participants and
the interventions assessed in these
studies were WASH interventions,
micronutrient supplementation,
antibiotic prophylaxis or shortened
course of antibiotic treatment, and
home or community-based
management. All of the included
studies were judged to be at low
risk of bias for sequence generation,
although a majority of the studies
were judged to be at high or unclear
risk of bias for allocation
concealment and blinding of
participants or personnel and
outcome assessors. Most of the
studies were judged to be at unclear
risk of bias for attrition due to the
lack of reported data.
We could not perform meta-analysis
for a majority of the interventions
evaluated under each disease
category (except diarrhea) because
of the variances in the interventions
included and outcomes reported.
Our review findings suggest that for
diarrhea, water treatment probably
reduces diarrhea by 39%, whereas
the effect of hand hygiene on
diarrhea is uncertain. Water
filtration techniques reduce
diarrheal illness by 34% to 52%.
Building water and sanitation
infrastructure, including water
storage systems, latrines, hand-
washing facilities, and water points
indicated that the odds of being
absent from school with diarrhea
was almost 10-fold lower.
Supplementation with 30 mg of zinc
led to a significant reduction in the
duration of diarrhea, while
supplementing 20 mg of zinc
reported no reduction in episodes of
diarrhea or its duration. For
tuberculosis, vitamin D3
supplementation did not lower the
risk of tuberculosis infection or
tuberculosis disease, though it did
improve height. Multiple
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micronutrient supplementation did
not have any effect on
anthropometric indices and chest
radiograph improvement, however it
led to an increase in height gain.
Peer counseling along with
contingency contract and peer-
counseling alone led to a
significantly higher treatment
completion rate, whereas shorter
course combination therapy
(4 months compared with
9 months) led to increased
compliance. Increasing general
awareness and training of health
care workers regarding tuberculosis
detection also led to a 3-fold
increase in tuberculosis detection.
For HIV, a continuation of
cotrimoxazole therapy after
96 weeks of commencing ART
reduced the risk of tuberculosis and
hospitalizations for malaria or
infections not related to malaria. For
measles, zinc supplementation did
not provide any additional benefit,
whereas prophylactic treatment
with cotrimoxazole led to reduced
measles complications and fewer
pneumonia cases. For ARI, milk
fortified with vitamin D3
significantly reduced the risk of
ARIs. For malaria, training CHWs to
give out ACT based on RDT results
suggest a significant reduction in
ACT prescription. For UTI, once
daily 1 mg/kg of zinc
supplementation in addition to
standard treatment led to a faster
recovery with a positive effect in
reducing symptoms such as dysuria
and urine frequency.
The findings from this systematic
review suggest that water filtration
using different filters and the
provision of sanitation facilities
proved to be effective in reducing
diarrheal illness. These findings are
in concordance with another review
suggesting that clean water supply,
handwashing, and sanitation reduce
diarrheal deaths.46 Another
systematic review on WASH
interventions among children 0 to
5 years reported that water
filtration, water disinfection, and
hygiene education with soap
provision can all be effective in
reducing diarrheal illnesses.47
However, because of the low quality
of evidence and high heterogeneity,
they recommended further research
in this domain.47 Moreover, the
focus of this review was children
under 5 years of age, but the target
population for our review was
school-aged children and
adolescents. Zinc supplementation
for treating diarrhea has been
reported to be effective among
children under
5 years of age.46,48 Our systematic
review targeted school-aged
children and adolescents and
suggested that supplementation
with 30 mg of zinc is effective in
reducing the duration of diarrhea.
For tuberculosis, our findings are
consistent with other reviews
assessing the impact of the Directly
Observed Therapy program for the
treatment of tuberculosis along with
short message service alerts, patient
education and counseling,
psychological interventions,
reminders and tracers, and digital
health technologies and suggesting
improved tuberculosis treatment
outcomes and compliance.49
Findings from another review on
training sessions for nurse
practitioners in the diagnosis of
tuberculosis has previously reported
no clear effect on improved
tuberculosis detection;50 however,
the study included in our review
suggested improved case detection.
There are a few limitations of our
review. First, there were only a
small number of studies conducted
among the age group of our interest.
Second, the age groups varied
within each study, and third, various
measures were reported for similar
outcomes. Based on these
limitations, we could not perform
S7
 meta-analysis for many
interventions and outcomes under
each disease category except for
WASH interventions on diarrhea.
Increased focus on morbidity and
mortality among children under
5 years of age has led to more
evidence on interventions for the
under 5 age group and consequently
a dearth of information on what
works among school-aged children
and adolescents. Moreover, we did
not find any study focusing on
typhoid or paratyphoid, meningitis,
syphilis, and hepatitis, which remain
the leading causes of morbidity and
mortality in low and middle-income
countries among this age group.
Future studies are needed to assess
how the recommended interventions
work for children and adolescents
above 5 years of age, as this age
group provides a second window of
opportunity to target health
interventions to obtain long-term
sustainable impacts. The World
Health Organization has guidelines
for the management and research
gaps for common conditions among
children aged 2 to 59 months, such
as pneumonia, meningitis, diarrhea,
and dysentery. Many of these
common conditions overlap with the
high-burden infectious diseases
among school-aged children and
adolescents. Recommendations for
pneumonia, HIV, dysentery,
meningitis, and diarrhea can be
adapted and modified to target
children over 5 years of age.8
However, further evidence is needed
to assess the effectiveness of certain
interventions that improve detection
of high-burden infectious diseases
and management of these conditions
at home, basic health units, or
tertiary care hospitals among school-
aged children and adolescents.
Moreover, future studies need to
focus on the relative effectiveness
and duration of various
interventions, including
micronutrient supplementation and
prophylactic antibiotic administration
for conditions like HIV and measles
among school-aged children and
adolescents aged 5 to 19 years.
CONCLUSIONS
Findings from our review imply that
a few interventions, including
WASH, micronutrient
supplementation, and prophylactic
antibiotics, might be effective for
high burden infectious diseases
among school-aged children and
adolescents; however, we need more
data on the interventions to detect
and manage these high-burden
diseases among 5 to 19 year old
children and adolescents.
ABBREVIATIONS
ARI: acute respiratory infection
ART: anti-retroviral treatment
CHW: community health worker
HIV: human immunodeficiency
virus
ILI: influenza-like illness
RCT: randomized controlled
trials
UTI: urinary tract infection
WASH: water, sanitation, and
hygiene

Address correspondence to Professor Zulfiqar A. Bhutta, PhD, MBBS, FRCPCH, FAAP, Centre for Global Child Health, The Hospital for Sick Children (SickKids), 686 Bay
St, 11th floor, Suite 11.9731, Toronto, ON M5G 2L3 Canada. E-mail: zulfiqar.bhutta@sickkids.ca
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2022 by the American Academy of Pediatrics
FUNDING: This work was supported by a grant from the International Development Research Centre (#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 DISCLOSURES: The authors have no financial relationships relevant to this article to disclose.

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