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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

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Acknowledgements• Canadian Institutes of Health Research

Knowledge Synthesis

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Geohelminths and schistosomiasis

Ascaris lumbricoides (roundworm)

Schistosomiasis

Trichuris Trichiura (whipworm)

Necator americanus and Ancylostoma duodenale(hookworm)

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  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   500-600 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

Often no symptoms

iron-deficiency anaemia, Vitamin A loss.

500-600 million

Schistosomiasis

swimming or playing in infected water.

anaemia, stunting and reduced ability to learn

243 million

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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

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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%)

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What do we know about effects of

deworming?

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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

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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”

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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))

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Why such discordant

conclusions?

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Possible reasons for discordance…1. Spillover effects/positive externalities2. All intestinal worms are not the same3. 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 factors7. Non-standard measures of school attendance and

cognitive performance8. Heterogeneity within and between studies

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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

helminthsMebendazole Gradually kills the larvae secreted

by adult wormsMore effective when used in combination therapy

Albendazole Inhibits assembly of tubulin into microtubles , inhibits uptake of glucose, worm immobilized, then dies

• Ascariasis• Necatoriasis

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Campbell review on deworming: a network

meta-analysisIDCG review

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Research questions1. 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)?

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Reduced reinfection

Vectors:• soil• drinking water • washing water

• feces• hands• food

Target Population

Children (1-16 yrs) in worm

endemic areas [Ascaris lumbricoides

Trichuris trichura Ancylostoma

duodenale,Necator americanus, and

Schistosoma]

Improved short term outcomes• Improved nutrient absorption• Improved nutritional status

Effects of improved health outcomes• Improved

overall well-being• Increased

school attendance

and achievement• Improved labour market outcomes

Decreases the gap between the poor and least poor

Improves health equity

Hygiene

promotion

and/or sanitati

on

Decreased worm burden in

treated children 1

Spilloverdecreased

worm burden in control children 2

Risk factors/conditions for implementation and up-take:

Reduced symptoms 3(eg. diarrhoea, abdominal

pain, general malaise, weakness, intestinal blood

loss, anemia, fever, dysuria, intestinal obstruction,

haematuria, and organ damage)

Nutritional therapy (eg. micronutrient, feeding, iron)

Deworming (STH treatment +/ or schistoso-

miasis treatment)

LEGEND

Intermediary outcomes

Final outcomes

Interventions/ co-interventions

Causal pathway

Cyclical effect

Improved longer term outcomes

•Reduced proportion

of wasted children•Improved weight

and height• Improved social,

physical, emotional and

cognitive functioning

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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)

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What is a network meta-analysis?

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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

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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

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Eligible studies• Randomized and quasi-randomized

controlled trials• Quasi-experimental studies which use

statistical methods to account for confounding and sample selection bias

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Search strategy 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 1947 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, April 18, 2013 316

Social Services Abstracts, April 18, 2013 2

Econlit, April 18, 2013 11

Public Affairs Information Service April 18, 2013 1

Global Health CABI and CAB Abstracts April 18, 2013 4455

  Total without Duplicates

9790

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PRISMA Flow diagram9,790 identified through

database searching

9790 screened for eligibility

RCTs included in quantitative synthesis

(n=21)

Impact evaluation databases remain to be

searched

9,619 Excluded

Studies retrieved in full text (n=171)

143 Excluded7 awaiting data from

authors

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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

Evidence Network – Deworming-Weight gain (Kg)

21 RCTs16 TreatmentsN=42,197

29FE: Resdev=161 vs 51; DIC=60.65RE: Resdev=52.7 vs 51; DIC=-35.9

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)

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)

Results vs. Placebo – Weight gain in Kg

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Results vs. Placebo, RE Model– Weight gain in KgPyrantel 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%

na

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%

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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

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Questions?• Vivian.welch@uottawa.ca