Deworming and adjuvant interventions for children in low and middle income countries: systematic review and network meta-analysis

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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
Necator americanus and Ancylostoma
duodenale (hookworm)
Ascaris lumbricoides (roundworm)
Schistosomiasis
Trichuris Trichiura (whipworm)
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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 (gt50),
  once every two years in medium risk (gt10 and
  lt50), twice during primary school in low risk
  communities (lt10)

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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
• Authors 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 1060 years during the 5-year
  study were 300 (SE 007) albendazole versus 316
  (SE 009) control, difference 016 (SE 011,
  mortality ratio 095, 95 CI 089 to 102,
  p016))

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Why such discordant conclusions?
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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

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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 hosts 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
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Campbell review on deworming a network
meta-analysis

• IDCG review

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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)?

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Hygiene promotion and/or sanitation
Reduced reinfection

• Effects of improved
• health outcomes
• Improved
• overall well-being
• Increased
• school
• attendance
• and achievement
• Improved labour
• market outcomes

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

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
• Improved
• nutritional status

Spillover decreased worm burden in control
children 2
Decreases the gap between the poor and least
poor Improves health equity
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
Risk factors/conditions for implementation and
up-take
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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 ClassicEmbase 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 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 (n171)
143 Excluded 7 awaiting data from authors
RCTs included in quantitative synthesis (n21)
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Characteristics of studies

• arms 14 two arm, 5 three arm, 2 four arm
• Age range lt 6 months 1 12-60 month 9 gt60
  month 11
• Endemicity low 8 moderate 5 high 8
• Size of study lt100 3 100-500 7 gt500 7
  gt1000 4
• Study duration lt6 months 3 6 months-1 year
  11 gt 1 year 7
• cluster RCTs 7 out of 21

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Evidence Network Deworming-Weight gain (Kg)
21 RCTs 16 Treatments N42,197
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Results vs. Placebo Weight gain in Kg
Pyrantel Pamoate
Albendazole
Albendazole-high dose
Albendazoleiron
iron
Mebendazole
vitamin A
Albendazole vitamin A
Levamisole
Piperazine
Metronizadole (anti giardia)
Piperazinemetronizadole
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 Resdev161 vs 51 DIC60.65 RE Resdev52.7
vs 51 DIC-35.9
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Results vs. Placebo, RE Model Weight gain in Kg
Pyrantel Pamoate
Albendazole
Albendazole-high dose
Albendazoleiron
iron
Mebendazole
vitamin A
Albendazole vitamin A
Levamisole
Piperazine
Metronizadole (anti giardia)
Piperazinemetronizadole
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), I20
0.10 (-0.07, 0.26), i20
-0.07 (-0.41, 0.28), i287
0.14 (-0.20, 0.49), i20
na
0.93 (0.71, 1.15), i2-na
0.03 (-0.32, 0.37), i2na
0.22 (-0.11, 0.55), i2na
0.35 (0.02, 0.68), i2na
0.20 (-0.21, 0.61), i2na
1.2(0.92, 1.47), i2-na
1.40 (1.09, 1.71), i2na
Deworming 0.29 (0.13, 0.45) Overall I292
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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_at_uottawa.ca