1. 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

2. Canadian Institutes of Health Research Knowledge Synthesis
Acknowledgements
Canadian Institutes of Health Research Knowledge Synthesis

3. Geohelminths and schistosomiasis
Necator americanus and Ancylostoma duodenale
(hookworm)
Ascaris lumbricoides (roundworm)
Schistosomiasis
Trichuris Trichiura (whipworm)

4. Ascaris lumbricoides Necator Americanus Trichuris trichiura
Infection Process
Light Infection Symptoms
Heavy Infection Symptoms
Approximate # of people infected
Ascaris lumbricoides
swallows food or soil  
Often no symptoms
Cough, fever, discomfort passing worms
800 million
Necator Americanus
absorbed through skin.
diarrhea, cramps and weight loss that can lead to anorexia.
anaemia  
million
Ancylostama Duodenale
contact of skin with soil contaminated with larvae
Light infection causes abdominal pain, loss of appetite
protein deficiency or iron-deficiency anaemia
100 million
Trichuris trichiura
Ingestion of eggs
iron-deficiency anaemia, Vitamin A loss.
Schistosomiasis
swimming or playing in infected water.
anaemia, stunting and reduced ability to learn
243 million

7. The greatest burden of STH occurs in Sub-Saharan Africa (SSA)
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

8. 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%)

9. What do we know about effects of deworming?

10. 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: Kremer and Miguel 2004, Ozier 2011, Baird 2011

12. 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”

13. DEVTA- “largest trial ever”
1 million children in India, aged 1-6 years
No difference in mortality (deaths per child-care 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))

14. Why such discordant conclusions?

15. Possible reasons for discordance…
Spillover effects/positive externalities
All intestinal worms are not the same
Not all intestinal worms respond to the same deworming medication.
Only moderate and heavy intestinal helminth infections typically cause measurable disease.
Reinfection
Underlying host and environment factors
Non-standard measures of school attendance and cognitive performance
Heterogeneity within and between studies
mebendazole produces only a 15% cure rate against hookworm infection, and indeed the Smith and Brooker analysis confirmed that mebendazole does not improve anemia whereas albendazole does

16. 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.
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

17. Campbell review on deworming: a network meta-analysis
IDCG review

18. Research questions
Effect of deworming according to the WHO guidelines compared to placebo (or control)?
Effect of deworming for STH vs. schistosomiasis vs. combined approaches?
Effect of adding hygiene education, sanitation, micronutrients or feeding programs compared to deworming alone
What factors contribute to heterogeneity of effect (e.g. endemicity, child age, baseline nutritional status, infection intensity)?

19. Hygiene promotion and/or sanitation Vectors: soil drinking water
washing water
feces
hands
food
Reduced
reinfection
Deworming (STH treatment +/ or schistoso-miasis treatment)
Reduced symptoms 3
(eg. diarrhoea, abdominal
pain, general malaise,
weakness, intestinal blood
loss, anemia, fever, dysuria,
intestinal obstruction,
haematuria, and organ damage)
Improved longer
term outcomes
Reduced
proportion
of wasted children
Improved weight
and height
Improved social,
physical,
emotional and
cognitive
functioning
Effects of improved
health outcomes
Improved
overall well-being
Increased
school
attendance
and achievement
Improved labour
market outcomes
Target
Population
Children (1-16 yrs) in worm endemic areas [Ascaris lumbricoides Trichuris trichura Ancylostoma duodenale,Necator americanus, and Schistosoma]
Decreased worm
burden in
treated children 1
Improved short term outcomes
Improved
nutrient absorption
nutritional status
Spillover
decreased
worm burden in
control children 2
Nutritional therapy (eg. micronutrient, feeding, iron)
Decreases the gap between
the poor and least poor
Improves health equity
Risk factors/conditions for implementation and up-take:
Individual
Environment
Intervention
anaemia,
high worm burden,
supervision, dosage, time of day, place of administration
undernutrition,
high endemicity of other infectious disease, poor sanitation, poor hygiene, poverty
low socioeconomic
status
LEGEND
Intermediary outcomes
Final outcomes
Interventions/ co-interventions
Causal pathway
Cyclical effect

20. Mixed treatment comparisons
Assessment of heterogeneity due to multiple components (i.e. hygiene, sanitation, micronutrients, feeding and type of deworming);
Identification of areas where evidence is limited
Meta-regression allows more complete consideration of covariates (such as age, study duration, nutritional status and intensity of worm infection)

21. What is a network meta-analysis?

22. 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

23. 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

24. Eligible studies Randomized and quasi-randomized controlled trials
Quasi-experimental studies which use statistical methods to account for confounding and sample selection bias

25. Search strategy LILACS, Social Services Abstracts, Econlit,
Database name and coverage
Search date
Total Retrieved
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present
1946 to April 18, 2013
5664
Ovid Embase Classic+Embase to 2013 January 16
1947 to April 18, 2013
1582
Wiley Cochrane Library , Issue 2 of 12, Feb 2013
April 18, 2013
260
EbscoHost CINAHL, 1982-March 2013
1982- April 18, 2013 95
LILACS,
316
Social Services Abstracts, 2
Econlit, 11
Public Affairs Information Service 1
Global Health CABI and CAB Abstracts
4455
Total without Duplicates
9790

26. PRISMA Flow diagram 9,790 identified through database searching
Impact evaluation databases remain to be searched
9790 screened for eligibility
9,619 Excluded
Studies retrieved in full text (n=171)
143 Excluded
7 awaiting data from authors
RCTs included in quantitative synthesis (n=21)

27. Characteristics of studies
# arms: 14 two arm, 5 three arm, 2 four arm
Age range: < 6 months: 1; month: 9; >60 month: 11
Endemicity: low: 8; moderate: 5; high: 8
Size of study: <100: 3; : 7; >500: 7; >1000: 4
Study duration: <6 months: 3; 6 months-1 year: 11; > 1 year: 7
# cluster RCTs: 7 out of 21

28. Evidence Network – Deworming-Weight gain (Kg)
21 RCTs
16 Treatments
N=42,197

29. Results vs. Placebo – Weight gain in Kg
Pyrantel Pamoate
Albendazole
Albendazole-high dose
Albendazole+iron
iron
Mebendazole
vitamin A
Albendazole + vitamin A
Levamisole
Piperazine
Metronizadole (anti giardia)
Piperazine+metronizadole
Albendazole + Praziquantel
Praziquantel (for schistosomiasis)
Metrifonate (also for schistosomiasis)
0.19(0.01,0.37)
0.24(-0.43,0.92)
0.15(0.11,0.19)
0.28(-0.01,0.57)
0(-0.35,0.34)
0.09(-0.84,1.02)
0.06(-0.21,0.33)
-0.07(-0.89,0.67)
0.09(-0.04,0.23)
0.12(-0.48,0.69)
0.02(-0.09,0.14)
-0.08(-0.62,0.45)
0.43(0.13,0.74)
0.38(-0.48,1.26)
1.42(1.06,1.79)
1.38(0.12,2.64)
0.93(0.71,1.16)
0.93(0.02,1.85)
0.03(-0.32,0.37)
0.02(-0.92,0.97)
0.22(-0.11,0.55)
0.22(-0.73,1.16)
0.35(-0.31,1.01)
0.35(-0.75,1.44)
0.2(-0.22,0.62)
0.2(-0.78,1.18)
1.2(0.92,1.48)
1.2(0.27,2.13)
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

30. Results vs. Placebo, RE Model– Weight gain in Kg
Pyrantel Pamoate
Albendazole
Albendazole-high dose
Albendazole+iron
iron
Mebendazole
vitamin A
Albendazole + vitamin A
Levamisole
Piperazine
Metronizadole (anti giardia)
Piperazine+metronizadole
Albendazole + Praziquantel
Praziquantel (for schistosomiasis)
Metrifonate (also for schistosomiasis)
0.24(-0.43,0.92)
0.28(-0.01,0.57)
0.09(-0.84,1.02)
-0.07(-0.89,0.67)
0.12(-0.48,0.69)
-0.08(-0.62,0.45)
0.38(-0.48,1.26)
1.38(0.12,2.64)
0.93(0.02,1.85)
0.02(-0.92,0.97)
0.22(-0.73,1.16)
0.35(-0.75,1.44)
0.2(-0.78,1.18)
1.2(0.27,2.13)
1.41(0.47,2.35)
0.20(-0.01,0.41), I2-na
0.31(0.10, 0.53), i2, 94% na
0.14 (-0.04, 0.32), I2=0%
0.10 (-0.07, 0.26), i2=0%
-0.07 (-0.41, 0.28), i2=87%
0.14 (-0.20, 0.49), i2=0%
0.93 (0.71, 1.15), i2-na
0.03 (-0.32, 0.37), i2=na
0.22 (-0.11, 0.55), i2=na
0.35 (0.02, 0.68), i2=na
0.20 (-0.21, 0.61), i2=na
1.2(0.92, 1.47), i2-=na
1.40 (1.09, 1.71), i2=na
Deworming 0.29 (0.13, 0.45)
Overall I2=92%

31. 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

32. Questions?