audrie 2013 07-31 delhi conference ee pilot final
TRANSCRIPT
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Environmental Enteropathy Pilot StudyCleaner households are associated with improved
gut function in Bangladesh
Audrie Lin, PhDBen Arnold, PhDSadia Afreen, MPHJack Colford, MD, MPH, PhDSteve Luby, MDWASH Benefits Team
3 August 2013
Photo: Audrie Lin
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555 million preschool children in developing countries: 32% stunted & 20% underweight
WHO 2011, Humphrey 2009, Lunn 1991, Campbell 2003, Bhutta 2008
Vitamin A & Zinc supplementation
Protein supplementation
Complementary feeding
Breastfeeding promotion
Micronutrient supplementation in pregnancy
Decrease stunting at 36 months by
36%
Increased Child Morbidity & Mortality Poor Cognitive Development Reduced Adult Economic Productivity
Inadequate Diet
Undernutrition & Growth Faltering
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555 million preschool children in developing countries: 32% stunted & 20% underweight
WHO 2011, Humphrey 2009, Checkley 2008
Increased Child Morbidity & Mortality Poor Cognitive Development Reduced Adult Economic Productivity
Poor Sanitation & Hygiene
Diarrhea
Inadequate Diet
Undernutrition & Growth Faltering
25% of all stunting in 24-month-old children
attributable to having ≥ 5 diarrheal episodes in first 2
years of life
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Proposed Causal Pathway of Environmental Enteropathy
555 million preschool children in developing countries: 32% stunted & 20% underweight
WHO 2011, Humphrey 2009, Lunn 1991, Campbell 2003
Environmental Enteropathy
??
Increased Child Morbidity & Mortality Poor Cognitive Development Reduced Adult Economic Productivity
Poor Sanitation & Hygiene
Diarrhea
Inadequate Diet
Undernutrition & Growth Faltering
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Small Intestine Has Large Absorptive Area
Absorptive surface area of small intestine = 250 m2
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Mara 2009
Healthy Intestine Environmental Enteropathy
What is Environmental Enteropathy (EE)?
• Healthy villi • Absorb nutrients• Pathogen barrier
• Villous atrophy• Malabsorption• “Leaky” intestine
Inflammatory disorder of small intestine that reduces nutrient absorption and increases intestinal permeability
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Lactulose Mannitol Diagnostic Assay for EE
Lactulose sugar– Too large to be absorbed by healthy intestine– L is a measure of barrier efficacy– EE lactulose absorption
Mannitol sugar– Small and moves across intestine in quantities
proportional to absorptive surface area– M is a measure of absorptive capacity– EE mannitol absorption
Healthy Intestine = Low L:M ratio EE = High L:M ratio
LM Dose
5-Hour Urine Collection
Measure L:M in Urine
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Adapted by Christine Stewart from Victora et al., 2010
Critical Period For Growth Faltering
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Increase in Lactulose:Mannitol Ratios with Age in Gambian Village Children
1-3 3-6 6-9 9-12 12-15
Age (Months) Lunn 1991
The Gambia
United Kingdom
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EE Background Studies
• In Bangladesh, L:M ratio increases from age 3 – 12 months in a rural subdistrict (Goto et al Br J Nutr 2009; Trans Roy Soc of Trop
Med Hyg 2009)
• Enteropathy develops in people who move from more developed countries to more contaminated environments (e.g., Peace Corps volunteers). (Lindenbaum et al. Ann Intern Med 1966)
• Within 17 months after the Peace Corps volunteers’ return to New York City, the biopsies normalized and within 1 to 35 months, most of the volunteers had normal, functioning small intestines. (Lindenbaum et al. Ann Intern Med 1971)
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Photo : throbule www.panoeramio.com
Study Question
Is environmental enteropathy a potential mechanism to explain the association between environmental contamination and stunting?
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SHEWA-B EvaluationSanitation Hygiene Education and Water Supply, Bangladesh
• Government of Bangladesh / UNICEF program
• Targeting 20 million people• icddr,b contracted with the
evaluation– 50 intervention and 50 matched
control clusters
– Clusters randomly selected
– 10 households per cluster
– Monthly follow up for 2 years
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Would Children in Relatively Clean Households Have Less EE Than Children in Dirtier Households?
Dirty Clean
5.4% 6.4%
SHEWA-B WASH Survey• 993 households • July 2007 – Oct 2009
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WASH Benefits?
Definitions and Household Selection Criteria
Clean
• flush/septic/piped sewerage or pit latrine with slab & water seal
• [E. coli] < 10 CFU/100 ml
• handwashing station w/ water and soap
Dirty
• open defecation, hanging toilet, open pit latrine, pit latrine with slab but no water seal, or flush/pour to “somewhere else”
• [E. coli] ≥ 10 CFU/100 ml
• No handwashing station or handwashing station w/o water and/or w/o soap
Photo: Flickr zafarbaig08
Illustrations: practicalaction.org
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Finding the study children
• SHEWA-B evaluation– 993 households– July 2007 – Oct 2009
• Environmental enteropathy assessment– May 2010– 136 children– 49 sub-districts
Ages: 8 – 48 months
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Data Collection
1 Stool Sample
1 Urine Sample
1 Finger prick Blood Sample
• Soil Transmitted Helminths• Giardia lamblia• Cryptosporidium parvum• Entamoeba histolytica
Anthropometry Data
• IgG endotoxin core antibodies • Total IgG
• Dose of lactulose-mannitol solution• 5 Hour urine collection• L:M absorption ratio
Household WASH Survey
• Weight• Length/Height• Head circumference
• Drinking water source
• Toilet facility• Handwashing station
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Household Characteristics Clean Dirty P-value (n=67) (n=55)
Female 0.54 0.58 0.62
Age in months at enrollment 10.5 12.5 0.39
Have electricity 72% 36% <0.01
Own
radio 30% 16% 0.08
b/w television 31% 15% 0.04
color television 24% 5% 0.01
refrigerator 7% 0 0.02
# of people living in the household 5.91 6.31 0.47
# of rooms 2.94 1.8 <0.01
earth/bamboo floor 69% 93% 0.001
Clean Households Were Wealthier
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Clean Households Were Objectively Cleaner But Not Radically Different From Dirty Households
Measure Clean Dirty P
stool visible on slab or floor 22% 72% <0.01
child < 5 yr feces disposal in no specific place/bush/field
78% 81% 0.67
fingernails of the child are clean 20% 10% 0.12
palms of the child are clean 42% 21% 0.03
finger pads of the child are clean 42% 17% 0.01
fingernails of the respondent are clean 37% 13% <0.01
palms of the respondent are clean 67% 56% 0.29
finger pads of the respondent are clean 66% 55% 0.28
Note: These indicators were not used to categorize households
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Children in Clean Households Were 0.9 SDs Taller
Mean HAZ(2010)
Stunting %(2010)
Dirty –2.57 74%
Clean –1.66 33%
Difference 0.91 40%
This effect is 3x the magnitude seen in many nutritional interventions
---Height-for-Age Z-score (HAZ)
Severe Stunted
Clean (N=66) Dirty (N=53)
HAZ was a primary outcome in the WASH Benefits Pilot
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Children in Clean Households Were Taller and Less Likely to be Stunted
Mean age (mo) 9 35 9 35
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HAZ Diff 95% CI P R2
Unadjusted 0.91 ( 0.17, 1.65) <0.001 0.12
Adjusted for age + sex 0.96 ( 0.51, 1.41) <0.001 0.15
Fully Adjusted * 0.54 ( 0.06, 1.01) 0.028 0.31
* Adjusted for age, sex, housing materials, household electricity, household size, land ownership, household head occupation, durable good ownership (bike, tables, chairs, beds, radio, tv).
Children From Clean Households Have Higher HAZ (+0.54) After Adjustment
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Children < 5 Years in Clean Households Have Lower Ascaris Infection Prevalence
Parasite infection was a secondary outcome in the WASH Benefits Pilot
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Environmenal Enteropathy BiomarkersChildren in Clean Households had:
Inflammation(Total IgG)
Dirty
Antibody Response(EndoCAb)
CleanDirty
Better Gut Function(LM Ratio)
CleanDirtyCleanLn
L:M
Rati
o
Ln E
ndoC
Ab M
U/m
l
Ln T
otal
IgG
mg/
ml
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LM Ratio Levels in Context
Campbell et al. 2003
UK Infants
Clean Environment
Dirty Environment
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Rural Bangladeshi children with somewhat– Cleaner water– Better toilets– Better equipped
handwashing stations
Had– Less environmental
enteropathy– Less parasitic
infection– Better growth
?WASH Benefits
Conclusion: Cleaner Households were Associated with Improved Gut Function in Bangladesh
Photo: ICDDR,B
Cross-sectional Study
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WASH Benefits Main Trial
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WASH Benefits Hypotheses
Improvements in: – Water quality (WA)– Sanitation (S)– Hygiene (H)– Nutrition – WASH – WASH + Nutrition
Less diarrhea Fewer parasites Less environmental
enteropathy Improved child
growth Improved child
development
Objective: Measure the effect of water, sanitation, handwashing, and nutrition interventions on child health, growth and development
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WASHB Main Trial Overview of the Design
6 treatment arms + a double-sized control
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Kenya WASH Interventions
Chlorine dispensers at water sources
Water Quality
Improved Tippy Taps + soap provision
Handwashing
Sani-scoop Child Potties Improved Latrines+ +
Sanitation
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Bangladesh WASH Interventions
Safe StorageAquatabs (NaDCC) +
(www.aquatabs.com)
Soapy water dispensers + soap provision
Sani-scoop Child Potties Dual Pit Latrines+ +
Water Quality
Sanitation
Handwashing
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Bangladesh & Kenya Nutrition Interventions
NutritionPromotion
Daily LNS(6 – 24 mos)
+
Exclusive breastfeeding through 6 months
Continued breastfeeding with LNS (6 – 24 months)
Encourage preparation of micronutrient-dense food
Feed child at least 2-3 times per day (6-8 mos) and 3-4 times per day (9-24 mos)
Next-generation Nutributter (iLiNS project)
(Draws heavily from Alive & Thrive)
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In a subsample of 1,500 children in each cohort, we will collect urine, blood, and stool specimens to measure EE biomarkers
WASHB Main Trial EE Subsample
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Bangladesh & Kenya Sample Types and Assays
Stool
Urine
Venous Blood
• Alpha 1-Antitrypsin • Myeloperoxidase • Neopterin • Regenerating Protein 1?• Calprotectin?• Giardia lamblia • Cryptosporidium parvum • Entamoeba histolytica
• Total IgG • Micronutrients, Lead, Genetics• C-Reactive Protein? • EndoCAb?• IFAB-P?• IL-6?• Zonulin?• Citrulline?
• Lactulose-Mannitol
PBMCs (Bangladesh)
• Immunologic Assays
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Acknowledgments
Field Research OfficerMd. Mamun-Ar-Rashid
Field Team Leaders:Mahadi HasanSyeda Luthfa FamidaShanzida TaslinAshish Kumar KunduAyesha BegumSamsul HaqueShafi Md. Ali Siddik
ICDDR,BSadia AfreenSania AshrafLeanne UnicombRashidul HaqueTahmeed AhmedRubhana RaqibTarique Md. Nurul HudaSheuli (FRO)FellowsAdministrationA. M. Shamsir AhmedVirology LabHematology Lab Nutritional Biochemistry Lab Atiya Sharmeen & the MAL-ED Clinic
Stanford UC BerkeleySteve Luby Ben Arnold
Jack Colford
ShireeRie GotoNicholas Mascie-TaylorMasud Rana
Field Research AssistantsShabina YesminLubna TaniTania ZahirMd. Shafiqul HaiderIrin AkterMd. AlimojjamanFatema Begum SumiNurul AlamMahmuda AkterShadia AhmedTowhida AkterAfsana Binte BariRahela Akter
Field AssistantsMd. AlamMd. Mohasin KabirMd. Saiful IslamMd. Jamilur RahmanMd. Shah AlamMd. Aminul IslamMd. Junayed Hossain
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Extra Slides
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Geography of Environmental Enteropathy
50 – 95% incidence in developing countries McKay 2010, Menzies 1999
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Correlation of EE with GDP Per Capita
Menzies 1999
GDP correlates with absorptive capacity GDP correlates with intestinal permeability
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Variation in Lactulose:Mannitol Ratio With Age in The Gambia
La
ctu
lose
:Man
nit
ol P
erm
ea
bili
ty R
ati
o
Age Group (Years)Campbell 2002
The Gambia
United Kingdom
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Children from Clean Households are 22 percentage points less likely to be stunted
DiffStunting
95% CI P
Unadjusted –0.40 (–0.57, –0.24) <0.001
Adjusted for age + sex –0.42 (–0.59, –0.26) <0.001
Fully Adjusted * –0.22 (–0.42, –0.02) 0.030
Robustness Checks
Mahalanobis matched** –0.25 (–0.46, –0.04) 0.019
GenMatch** –0.28 (–0.50, –0.05) 0.017
* Adjusted for age, sex, housing materials, household electricity, household size, land ownership, household head occupation, durable good ownership (bike, tables, chairs, beds, radio, tv).
** Matching estimators include the adjustment covariates used in fully adjusted models, plus the propensity score estimated using main effects of the covariates.
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Enteropathy biomarkersclean versus dirty
Biomarker * Clean Dirty Difference
Mean Mean in SDs 95% CI
Ln Total IgG –0.14 0.16 –0.30 (–0.69, 0.08)
Ln EndoCAb –0.12 0.16 –0.29 (–0.64, 0.07)
Ln L:M Ratio –0.19 0.23 –0.42 (–0.77, –0.07)
* Biomarkers standardized by subtracting the sample mean and dividing by the sample SD.
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Enteropathy biomarkersclean versus dirty
Biomarker Clean Dirty
Mean Mean
Total IgG (mg/ml) 28.19 38.77
EndoCAb (MU/ml) 50.02 62.42
L:M Ratio 0.21 0.31
Lactulose (mg/100 ml) 134 207
Mannitol (mg/100 ml) 689 637
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EndoCAb Levels in ContextCampbell et al. 2003
UK InfantsClean Env.Dirty Env.