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Environmental Enteropathy Pilot Study
Cleaner households are associated with improved
gut function in Bangladesh
Audrie Li...
555 million preschool children in developing countries:
32% stunted & 20% underweight
WHO 2011, Humphrey 2009, Lunn 1991, ...
555 million preschool children in developing countries:
32% stunted & 20% underweight
WHO 2011, Humphrey 2009, Checkley 20...
Proposed Causal Pathway of Environmental Enteropathy
555 million preschool children in developing countries:
32% stunted &...
Small Intestine Has Large Absorptive Area
Absorptive surface area of small intestine = 250 m2
Mara 2009
Healthy Intestine Environmental Enteropathy
What is Environmental Enteropathy (EE)?
• Healthy villi
• Absorb nut...
Lactulose Mannitol Diagnostic Assay for EE
Lactulose sugar
– Too large to be absorbed by healthy intestine
– L is a measur...
Adapted by Christine Stewart from Victora et al., 2010
Critical Period For Growth Faltering
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
T...
EE Background Studies
• In Bangladesh, L:M ratio increases from age 3 – 12
months in a rural subdistrict (Goto et al Br J ...
Photo : throbule www.panoeramio.com
Study
Question
Is environmental
enteropathy a
potential mechanism
to explain the
assoc...
SHEWA-B Evaluation
Sanitation Hygiene Education and Water Supply, Bangladesh
• Government of Bangladesh /
UNICEF program
•...
Would Children in Relatively Clean Households Have
Less EE Than Children in Dirtier Households?
Dirty Clean
5.4% 6.4%
SHEW...
WASH Benefits?
Definitions and Household Selection Criteria
Clean
• flush/septic/piped sewerage
or pit latrine with slab &...
Finding the study children
• SHEWA-B evaluation
– 993 households
– July 2007 – Oct 2009
• Environmental enteropathy
assess...
Data Collection
1 Stool Sample
1 Urine Sample
1 Finger prick
Blood Sample
• Soil Transmitted Helminths
• Giardia lamblia
•...
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....
Clean Households Were Objectively Cleaner But Not
Radically Different From Dirty Households
Measure Clean Dirty P
stool vi...
Children in Clean Households Were 0.9 SDs Taller
Mean HAZ
(2010)
Stunting %
(2010)
Dirty –2.57 74%
Clean –1.66 33%
Differe...
Children in Clean Households
Were Taller and Less Likely to be Stunted
Mean age (mo) 9 35 9 35
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...
Children < 5 Years in Clean Households
Have Lower Ascaris Infection Prevalence
Parasite infection was a secondary outcome ...
Contaminated Clean
0
1
2
3
4
5
6
Ln Total IgG
LnTotalIgGmg/ml
Contaminated Clean
3.0
3.5
4.0
4.5
5.0
5.5
Ln EndoCAb
LnEndo...
LM Ratio Levels in Context
Campbell et al. 2003
UK Infants
Clean Environment
Dirty Environment
Rural Bangladeshi children
with somewhat
– Cleaner water
– Better toilets
– Better equipped
handwashing stations
Had
– Les...
WASH Benefits Main Trial
WASH Benefits Hypotheses
Improvements in:
– Water quality (WA)
– Sanitation (S)
– Hygiene (H)
– Nutrition
– WASH
– WASH + ...
WASHB Main Trial Overview of the Design
6 treatment arms + a double-sized control
Kenya WASH Interventions
Chlorine dispensers at water
sources
Water Quality
Improved Tippy Taps + soap provision
Handwashi...
Bangladesh WASH Interventions
Safe StorageAquatabs (NaDCC) +
(www.aquatabs.co
m)
Soapy water dispensers +
soap provision
S...
Bangladesh & Kenya Nutrition Interventions
Nutrition
Promotion
Daily LNS
(6 – 24 mos)
+
 Exclusive breastfeeding
through ...
In a subsample of 1,500 children in each cohort, we will collect
urine, blood, and stool specimens to measure EE biomarker...
Bangladesh & Kenya Sample Types and Assays
Stool
Urine
Venous
Blood
• Alpha 1-Antitrypsin
• Myeloperoxidase
• Neopterin
• ...
Acknowledgments
Field Research Officer
Md. Mamun-Ar-Rashid
Field Team Leaders:
Mahadi Hasan
Syeda Luthfa Famida
Shanzida T...
Extra Slides
Geography of Environmental Enteropathy
50 – 95% incidence in developing countries
McKay 2010, Menzies 1999
Correlation of EE with GDP Per Capita
Menzies 1999
GDP correlates with absorptive capacity GDP correlates with intesti...
Variation in Lactulose:Mannitol Ratio
With Age in The Gambia
Lactulose:MannitolPermeabilityRatio
Age Group (Years)
Campbel...
Children from Clean Households
are 22 percentage points less likely to be stunted
Diff
Stunting
95% CI P
Unadjusted –0.40 ...
Enteropathy biomarkers
clean versus dirty
Biomarker * Clean Dirty Difference
Mean Mean in SDs 95% CI
Ln Total IgG –0.14 0....
Enteropathy biomarkers
clean versus dirty
Biomarker Clean Dirty
Mean Mean
Total IgG (mg/ml) 28.19 38.77
EndoCAb (MU/ml) 50...
EndoCAb Levels in Context
Campbell et al. 2003
UK Infants
Clean Env.
Dirty Env.
1   lin - 2013-07-31 delhi conference ee pilot final
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1 lin - 2013-07-31 delhi conference ee pilot final

  1. 1. Environmental Enteropathy Pilot Study Cleaner households are associated with improved gut function in Bangladesh Audrie Lin, PhD Ben Arnold, PhD Sadia Afreen, MPH Jack Colford, MD, MPH, PhD Steve Luby, MD WASH Benefits Team 3 August 2013 Photo: Audrie Lin
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. Small Intestine Has Large Absorptive Area Absorptive surface area of small intestine = 250 m2
  6. 6. 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
  7. 7. 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
  8. 8. Adapted by Christine Stewart from Victora et al., 2010 Critical Period For Growth Faltering
  9. 9. 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
  10. 10. 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)
  11. 11. Photo : throbule www.panoeramio.com Study Question Is environmental enteropathy a potential mechanism to explain the association between environmental contamination and stunting?
  12. 12. SHEWA-B Evaluation Sanitation 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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. Children in Clean Households Were Taller and Less Likely to be Stunted Mean age (mo) 9 35 9 35
  21. 21. 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
  22. 22. Children < 5 Years in Clean Households Have Lower Ascaris Infection Prevalence Parasite infection was a secondary outcome in the WASH Benefits Pilot
  23. 23. Contaminated Clean 0 1 2 3 4 5 6 Ln Total IgG LnTotalIgGmg/ml Contaminated Clean 3.0 3.5 4.0 4.5 5.0 5.5 Ln EndoCAb LnEndoCAbMU/ml Contaminated Clean −5 −4 −3 −2 −1 0 1 Ln L:M Ratio LnL:MRatio Environmenal Enteropathy Biomarkers Children in Clean Households had:  Inflammation (Total IgG) Dirty  Antibody Response (EndoCAb) CleanDirty Better Gut Function (LM Ratio) CleanDirtyClean Contaminated Clean 0 1 2 3 4 5 6 Ln Total IgG LnTotalIgGmg/ml Contaminated Clean 3.0 3.5 4.0 4.5 5.0 5.5 Ln EndoCAb LnEndoCAbMU/ml Contaminated Clean −5 −4 −3 −2 −1 0 1 Ln L:M Ratio LnL:MRatio Contaminated Clean 0 1 2 3 4 5 6 Ln Total IgG Contaminated Clean 3.0 3.5 4.0 4.5 5.0 5.5 Ln EndoCAb LnEndoCAbMU/ml Contaminated Clean −5 −4 −3 −2 −1 0 1 Ln L:M Ratio LnL:MRatioLnL:MRatio LnEndoCAbMU/ml LnTotalIgGmg/ml
  24. 24. LM Ratio Levels in Context Campbell et al. 2003 UK Infants Clean Environment Dirty Environment
  25. 25. 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
  26. 26. WASH Benefits Main Trial
  27. 27. 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
  28. 28. WASHB Main Trial Overview of the Design 6 treatment arms + a double-sized control
  29. 29. Kenya WASH Interventions Chlorine dispensers at water sources Water Quality Improved Tippy Taps + soap provision Handwashing Sani-scoop Child Potties Improved Latrines+ + Sanitation
  30. 30. Bangladesh WASH Interventions Safe StorageAquatabs (NaDCC) + (www.aquatabs.co m) Soapy water dispensers + soap provision Sani-scoop Child Potties Dual Pit Latrines+ + Water Quality Sanitation Handwashing
  31. 31. Bangladesh & Kenya Nutrition Interventions Nutrition Promotion 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)
  32. 32. 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
  33. 33. 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
  34. 34. Acknowledgments Field Research Officer Md. Mamun-Ar-Rashid Field Team Leaders: Mahadi Hasan Syeda Luthfa Famida Shanzida Taslin Ashish Kumar Kundu Ayesha Begum Samsul Haque Shafi Md. Ali Siddik ICDDR,B Sadia Afreen Sania Ashraf Leanne Unicomb Rashidul Haque Tahmeed Ahmed Rubhana Raqib Tarique Md. Nurul Huda Sheuli (FRO) Fellows Administration A. M. Shamsir Ahmed Virology Lab Hematology Lab Nutritional Biochemistry Lab Atiya Sharmeen & the MAL-ED Clinic Stanford UC Berkeley Steve Luby Ben Arnold Jack Colford Shiree Rie Goto Nicholas Mascie-Taylor Masud Rana Field Research Assistants Shabina Yesmin Lubna Tani Tania Zahir Md. Shafiqul Haider Irin Akter Md. Alimojjaman Fatema Begum Sumi Nurul Alam Mahmuda Akter Shadia Ahmed Towhida Akter Afsana Binte Bari Rahela Akter Field Assistants Md. Alam Md. Mohasin Kabir Md. Saiful Islam Md. Jamilur Rahman Md. Shah Alam Md. Aminul Islam Md. Junayed Hossain
  35. 35. Extra Slides
  36. 36. Geography of Environmental Enteropathy 50 – 95% incidence in developing countries McKay 2010, Menzies 1999
  37. 37. Correlation of EE with GDP Per Capita Menzies 1999 GDP correlates with absorptive capacity GDP correlates with intestinal permeability
  38. 38. Variation in Lactulose:Mannitol Ratio With Age in The Gambia Lactulose:MannitolPermeabilityRatio Age Group (Years) Campbell 2002 The Gambia United Kingdom
  39. 39. Children from Clean Households are 22 percentage points less likely to be stunted Diff Stunting 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.
  40. 40. Enteropathy biomarkers clean 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.
  41. 41. Enteropathy biomarkers clean 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
  42. 42. EndoCAb Levels in Context Campbell et al. 2003 UK Infants Clean Env. Dirty Env.

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