Deworming and adjuvant interventions for
children in low and middle income
countries: systematic review and network
meta-analysis
Vivian Welch, Chris Cameron, Shally Awasthi, Chisa
Cumberbatch, Robert Fletcher, Jessie McGowan,
Shari Krishnaratne, Salim Sohani, Peter Tugwell,
George Wells
1
Acknowledgements
• Canadian Institutes of Health Research
Knowledge Synthesis
2
Geohelminths and schistosomiasis
Ascaris
lumbricoides
(roundworm)
Necator
americanus
and
Ancylostoma
duodenale
(hookworm)
Schistosomiasis
Trichuris
Trichiura
(whipworm)
3
Infection
Process
Light Infection
Symptoms
swallows food Often no
Ascaris
symptoms
lumbricoides or soil
Necator
Americanus
absorbed
through skin.
diarrhea, cramps
and weight loss
that can lead to
anorexia.
Ancylostama
Duodenale
contact of skin
with soil
contaminated
with larvae
Ingestion of
eggs
Light infection
causes abdominal
pain, loss of
appetite
Often no
symptoms
Trichuris
trichiura
Schistosomia swimming or
playing in
sis
infected water.
Heavy Infection Approximate
Symptoms
# of people
infected
Cough, fever,
800 million
discomfort
passing worms
anaemia
500-600
million
protein
deficiency or
iron-deficiency
anaemia
iron-deficiency
anaemia,
Vitamin A loss.
anaemia,
stunting and
reduced ability to
learn
100 million
500-600
million
243 million
4
5
6
The greatest burden
of STH occurs in
Sub-Saharan Africa
(SSA). This map
shows the predicted
distribution of STHs
in SSA with Ascaris
Lumbricoides.
Source: Global Atlas of
Helminth Infections
7
WHO Guidelines for Deworming, 2011
• For soil-transmitted helminths, annual treatment in areas
where prevalence rate of soil-transmitted helminthiases is
between 20% and 50%, and, a bi-annual treatment in areas
with prevalence rates of over 50%.
• For schistosomiasis, annual treatment with praziquantel in
high risk communities (>50%), once every two years in
medium risk (>10% and <50%), twice during primary school
in low risk communities (<10%)
8
What do we know
about effects of
deworming?
9
Deworm the World
• School-based deworming identified as one of the most
efficient and cost-effective solutions to the global
challenges facing us today (Copenhagen Consensus
Meeting)
• School-based deworming proven to reduce school
absenteeism by 25%, and can lead to an additional year of
attendance for only $3.50.
• Children regularly dewormed are shown to earn over 20%
more and work 12% more hours as adults
• Children less than one year old at the time of school-based
deworming in their communities are shown to have large
cognitive improvements equivalent to half a year of schooling.
• Source: www.Dewormtheworld.org; Kremer and Miguel 2004,
Ozier 2011, Baird 2011
10
11
Taylor-Robinson et al 2012, Cochrane
• Aimed to summarize the effects of deworming to children to
treat soil-transmitted intestinal worms (nematode
geohelminths) on weight, haemoglobin, and cognition; and
the evidence of impact on physical well being, school
attendance, school performance, and mortality
• 42 randomized and quasi-randomized trials satisfied
eligibility criteria
• Author’s conclusion: “it is probably misleading to justify
contemporary deworming programmes based on evidence of
consistent benefit on nutrition, haemoglobin, school
attendance or school performance as there is simply
insufficient reliable information to know whether this is so”
12
DEVTA- “largest trial ever”
• 1 million children in India, aged 1-6 years
• No difference in mortality (deaths per childcare centre at ages 1·0–6·0 years during the
5-year study were 3·00 (SE 0·07) albendazole
versus 3·16 (SE 0·09) control, difference 0·16
(SE 0·11, mortality ratio 0·95, 95% CI 0·89 to
1·02, p=0·16))
13
Why such discordant
conclusions?
14
Possible reasons for discordance…
1. Spillover effects/positive externalities
2. All intestinal worms are not the same
3. Not all intestinal worms respond to the same
deworming medication.
4. Only moderate and heavy intestinal helminth
infections typically cause measurable disease.
5. Reinfection
6. Underlying host and environment factors
7. Non-standard measures of school attendance
and cognitive performance
8. Heterogeneity within and between studies
15
Mechanism of action of selected drugs
Name of drug
Mechanism of Action
Target Disease
Praziquantel
Allows rapid entrance of Calcium ions
into cell membrane of worm. Leads to
parasitic death
• Schistosomiasis
Levamisole
Causes muscle paralysis and parasitic
death
• Ascariasis
Pyrantel
Causes paralysis in worms. They
detach from the host’s intestinal walls.
• Ascariasis
• Necatoriasis
• Trichinosis
Ivermectin
Disrupts the permeability of the cell
membrane to chloride ions. Leads to
paralysis then death of parasite
• Onchocerciasis
• Strongyloidiasis
• Soil-transmitted
helminths
Mebendazole
Gradually kills the larvae secreted by
adult worms
More effective when used
in combination therapy
Albendazole
Inhibits assembly of tubulin into
microtubles , inhibits uptake of
glucose, worm immobilized, then dies
• Ascariasis
• Necatoriasis
16
Campbell review on
deworming: a network
meta-analysis
IDCG review
17
Research questions
1. Effect of deworming according to the WHO
guidelines compared to placebo (or control)?
2. Effect of deworming for STH vs.
schistosomiasis vs. combined approaches?
3. Effect of adding hygiene education, sanitation,
micronutrients or feeding programs compared
to deworming alone
4. What factors contribute to heterogeneity of
effect (e.g. endemicity, child age, baseline
nutritional status, infection intensity)?
18
Vectors:
• soil
• drinking
water
• washing
water
Hygiene
promotio
n and/or
sanitatio
n
• feces
• hands
• food
Target
Population
Reduced
reinfection
Deworming (STH
treatment +/ or
schistoso-miasis
treatment)
Children (1-16 yrs)
in worm endemic
areas [Ascaris
Decreased worm
burden in
treated children 1
lumbricoides Trichuris
trichura Ancylostoma
duodenale,Necator
americanus, and
Schistosoma]
Spillover
decreased
worm burden in
control children 2
Reduced symptoms 3
Improved longer
Effects of improved
(eg. diarrhoea, abdominal
term outcomes
health outcomes
pain, general malaise,
• Reduced
• Improved
weakness, intestinal blood
proportion
overall well-being
loss, anemia, fever, dysuria,
of wasted children • Increased
intestinal obstruction,
• Improved weight
school
haematuria, and organ damage)
and height
attendance
• Improved social,
and achievement
Improved short term outcomes
physical,
• Improved labour
• Improved
emotional and
market outcomes
nutrient absorption
cognitive
• Improved
functioning
nutritional status
Decreases the gap between
the poor and least poor
Nutritional
therapy (eg.
micronutrient,
feeding, iron)
Improves health equity
LEGEND
Risk factors/conditions for implementation and up-take:
Individual
anaemia,
undernutrition,
low socioeconomic
status
Environment
high worm burden,
high endemicity of
other infectious
disease, poor
sanitation, poor
hygiene, poverty
Intervention
supervision, dosage,
time of day, place of
administration
Intermediary outcomes
Final outcomes
Interventions/ co-interventions
Causal pathway
Cyclical effect
19
Mixed treatment comparisons
1. Assessment of heterogeneity due to multiple
components (i.e. hygiene, sanitation,
micronutrients, feeding and type of deworming);
2. Identification of areas where evidence is limited
3. Meta-regression allows more complete
consideration of covariates (such as age, study
duration, nutritional status and intensity of worm
infection)
20
What is a network meta-analysis?
21
Methods
• Bayesian Mixed Treatment Comparison Network
Meta-analysis using WinBUGS software
• Normal likelihood model which allows for the use
of multi-arm trials
• Both fixed and random-effects Bayesian network
meta-analyses were conducted
• Choice of model was based on assessment of the
Deviance Information Criterion (DIC) and
comparison of residual deviance to number of
unconstrained data points
• Compared deviance and DIC statistics in fitted
consistency and inconsistency models
• Vague or flat priors were assigned for basic
parameters throughout Bayesian analyses
22
PICO
• Population: 6 months- 16 years of age
• Intervention: Mass drug administration for
chemoprevention of STH or schistosomiasis, alone
or in combination with cointerventions
• Comparison: placebo, control, active
• Outcomes: anthropometry, educational status,
cognition, well-being, adverse events
23
Eligible studies
• Randomized and quasi-randomized controlled
trials
• Quasi-experimental studies which use statistical
methods to account for confounding and sample
selection bias
24
Search strategy
Database name and coverage
Search date
Ovid MEDLINE(R) In-Process & Other NonIndexed Citations and Ovid MEDLINE(R) 1946
to Present
Ovid Embase Classic+Embase
1947 to 2013 January 16
1946 to April 18,
2013
5664
1947 to April
18, 2013
April 18, 2013
1582
1982- April 18,
2013
April 18, 2013
95
316
April 18, 2013
2
April 18, 2013
11
April 18, 2013
1
April 18, 2013
4455
Wiley Cochrane Library , Issue 2 of 12, Feb
2013
EbscoHost CINAHL, 1982-March 2013
LILACS,
Social Services Abstracts,
Econlit,
Public Affairs Information Service
Global Health CABI and CAB Abstracts
Total without
Duplicates
Total Retrieved
260
25
9790
PRISMA Flow diagram
9,790 identified through
database searching
9790 screened for eligibility
Studies retrieved in full text
(n=171)
Impact evaluation databases
remain to be searched
9,619 Excluded
143 Excluded
7 awaiting data from
authors
RCTs included in
quantitative synthesis
(n=21)
26
Characteristics of studies
• # arms: 14 two arm, 5 three arm, 2 four arm
• Age range: < 6 months: 1; 12-60 month: 9; >60
month: 11
• Endemicity: low: 8; moderate: 5; high: 8
• Size of study: <100: 3; 100-500: 7; >500: 7;
>1000: 4
• Study duration: <6 months: 3; 6 months-1 year:
11; > 1 year: 7
• # cluster RCTs: 7 out of 21
27
Evidence Network – Deworming-Weight gain (Kg)
21 RCTs
16 Treatments
N=42,197
Results vs. Placebo – Weight gain in Kg
Pyrantel Pamoate
0.19(0.01,0.37)
0.24(-0.43,0.92)
Albendazole
0.15(0.11,0.19)
0.28(-0.01,0.57)
Albendazole-high dose
0(-0.35,0.34)
0.09(-0.84,1.02)
Albendazole+iron
0.06(-0.21,0.33)
-0.07(-0.89,0.67)
iron
0.09(-0.04,0.23)
0.12(-0.48,0.69)
Mebendazole
0.02(-0.09,0.14)
-0.08(-0.62,0.45)
vitamin A
0.43(0.13,0.74)
0.38(-0.48,1.26)
Albendazole + vitamin A
1.42(1.06,1.79)
1.38(0.12,2.64)
Levamisole
0.93(0.71,1.16)
0.93(0.02,1.85)
Piperazine
0.03(-0.32,0.37)
0.02(-0.92,0.97)
Metronizadole (anti giardia)
0.22(-0.11,0.55)
0.22(-0.73,1.16)
Piperazine+metronizadole
0.35(-0.31,1.01)
0.35(-0.75,1.44)
Albendazole + Praziquantel
0.2(-0.22,0.62)
0.2(-0.78,1.18)
Praziquantel (for schistosomiasis)
1.2(0.92,1.48)
1.2(0.27,2.13)
Metrifonate (also for schistosomiasis)
1.4(1.09,1.7)
1.41(0.47,2.35)
FE: Resdev=161 vs 51; DIC=60.65
RE: Resdev=52.7 vs 51; DIC=-35.9
29
Results vs. Placebo, RE Model– Weight gain in Kg
Pyrantel Pamoate
0.24(-0.43,0.92)
0.20(-0.01,0.41), I2-na
Albendazole
0.28(-0.01,0.57)
0.31(0.10, 0.53), i2, 94%
Albendazole-high dose
0.09(-0.84,1.02)
na
Albendazole+iron
-0.07(-0.89,0.67)
0.14 (-0.04, 0.32), I2=0%
iron
0.12(-0.48,0.69)
0.10 (-0.07, 0.26), i2=0%
Mebendazole
-0.08(-0.62,0.45)
-0.07 (-0.41, 0.28), i2=87%
vitamin A
0.38(-0.48,1.26)
0.14 (-0.20, 0.49), i2=0%
Albendazole + vitamin A
1.38(0.12,2.64)
na
Levamisole
0.93(0.02,1.85)
0.93 (0.71, 1.15), i2-na
Piperazine
0.02(-0.92,0.97)
0.03 (-0.32, 0.37), i2=na
Metronizadole (anti giardia)
0.22(-0.73,1.16)
0.22 (-0.11, 0.55), i2=na
Piperazine+metronizadole
0.35(-0.75,1.44)
0.35 (0.02, 0.68), i2=na
Albendazole + Praziquantel
0.2(-0.78,1.18)
0.20 (-0.21, 0.61), i2=na
Praziquantel (for schistosomiasis)
1.2(0.27,2.13)
1.2(0.92, 1.47), i2-=na
Metrifonate (also for schistosomiasis)
1.41(0.47,2.35)
1.40 (1.09, 1.71), i2=na
Deworming 0.29 (0.13, 0.45)
Overall
I2=92%
30
Next steps
• Hand searching reference lists, impact
evaluation databases, contacting authors
• Educational outcomes
• Quasi-experimental studies
• Risk of bias
• Causal pathway analysis
• Covariate analysis to explore heterogeneity and
improve consistency of model
31
Questions?
• Vivian.welch@uottawa.ca
32