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| Name | Class |
|---|---|
| University of Virginia | OTHER |
| Children's Hospital Medical Center, Cincinnati | OTHER |
| Bill and Melinda Gates Foundation | OTHER |
| Washington University School of Medicine |
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Environmental Enteropathy (EE) is an acquired sub-clinical inflammatory gut condition in which alterations in intestinal structure, function, and local and systemic immune activation lead to impaired vaccine responses, decreased cognitive potential and undernutrition in low-middle income countries. Approximately half of all global deaths in children aged less than five years are attributable to undernutrition making the study of EE an area of critical priority. However, given the operational limitations and ethical considerations for safely obtaining intestinal biopsies from young children in low resource settings, there have been few detailed investigations of human intestinal tissue in this vulnerable patient group for whom reversal of EE would provide the greatest benefit. EE biomarkers have been studied in different settings but these have not been correlated with the gold standard histopathology confirmation. The Study of Environment Enteropathy and Malnutrition in Pakistan (SEEM Pakistan) is designed to better understand the pathophysiology, predictors, biomarkers, and potential management strategies of EE to inform strategies to eradicate this debilitating pathology.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Moderate/severe malnourishment | Experimental | Pakistani children from age 0 to 6 months with weight for height Z score (WHZ) < -2 at the time of enrollment. Parents/caregivers of all participants will undergo a series of rehabilitative interventions to improve the child's nutrition and growth. Those participants who remain WHZ < -2 despite interventions are eligible for medical evaluation for more advanced workup of malnutrition, including UGI endoscopy and biopsy. |
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| Well nourished children | Active Comparator | Pakistani children from age 0 to 6 months who would be growing normally, with WHZ > 0, to serve as controls. Parents/caregivers of all participants will undergo a series of rehabilitative interventions to improve the child's nutrition and growth. |
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| US children with celiac disease | No Intervention | Comparative group for the Pakistani WHZ <-2 children who undergo UGI endoscopy and biopsy. Environmental Enteropathy and celiac disease have some shared features therefore we plan to enroll children under the age of 6 years with newly diagnosed celiac disease per endoscopy at CCHMC to assess the extent to which gene signatures and associated biologic pathways for children with celiac disease or environmental enteropathy overlap or differ. | |
| US children with Crohn's disease | No Intervention | Comparative group for the Pakistani WHZ <-2 children who undergo UGI endoscopy and biopsy. As some differentially expressed ileal gene signatures for Crohn's disease bear remarkable similarities to individual gene expression patterns previously reported for EE, children under the age of 10 years with newly diagnosed Crohn's disease per endoscopy at CCHMC will be enrolled to study these similarities and any differences |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nutritional education | Other | 4 week home delivered educational program that will focus on breast feeding and complimentary feeding. If child remains WHZ < -2 at by 9 months of age families will be shown 10 minute educational video detailing best practices for complimentary feeding. |
| Measure | Description | Time Frame |
|---|---|---|
| Nutritional status in children assessed by measuring parameters of growth at 3-6 months of age | Our birth cohort will be assessed for nutritional status by measuring parameters of growth, length, weight and height. These measurements will be calculated as Z scores according to WHO tables and children will be divided into the appropriate categories: Stunting as Length for Age Z-score < -2 SD (standard deviation), underweight as Weight-for-Age Z-score < -2 SD and wasting as Weight-for-Length Z-score < -2 SD, or normal-for-age. | Approximately 3-6 months after entry into study |
| Nutritional status in children assessed by measuring parameters of growth at 9 months of age | Our birth cohort will be assessed for nutritional status by measuring parameters of growth, length, weight and height. These measurements will be calculated as Z scores according to WHO tables and children will be divided into the appropriate categories: Stunting as Length for Age Z-score < -2 SD (standard deviation), underweight as Weight-for-Age Z-score < -2 SD and wasting as Weight-for-Length Z-score < -2 SD, or normal-for-age. | At approximately 9 months after entry into study |
| Association of biomarkers with Environmental Enteropathy at 3-6 months of age | Serum, stool, and urine biomarkers of EE will be collected and tested in malnourished and well-nourished children | Approximately 3-6 months after entry into study |
| Association of biomarkers with Environmental Enteropathy at 9 months of age | Serum, stool, and urine biomarkers of EE will be collected and tested in malnourished and well-nourished children | At approximately 9 months after entry into study |
| Association of biomarkers with Environmental Enteropathy at the time of endoscopy and biopsy |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Syed Asad Ali, MD, MPH | Aga Khan University | Principal Investigator |
| Sean R Moore, MD | University of Virginia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aga Khan University | Karachi | Sindh | 74800 | Pakistan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35534310 | Derived | Ahmed S, Iqbal J, Sadiq K, Umrani F, Rizvi A, Kabir F, Jamil Z, Syed S, Ehsan L, Zulqarnain F, Sajid M, Hotwani A, Rahman N, Ma JZ, McNeal M, Ann Costa Clemens S, Talat Iqbal N, Moore SR, Ali A. Association of Anti-Rotavirus IgA Seroconversion with Growth, Environmental Enteric Dysfunction and Enteropathogens in Rural Pakistani Infants. Vaccine. 2022 May 31;40(25):3444-3451. doi: 10.1016/j.vaccine.2022.04.032. Epub 2022 May 6. | |
| 34718665 |
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| ID | Term |
|---|---|
| D015362 | Child Nutrition Disorders |
| D007410 | Intestinal Diseases |
| D006130 | Growth Disorders |
| D005767 | Gastrointestinal Diseases |
| ID | Term |
|---|---|
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D004066 | Digestive System Diseases |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D004522 | Educational Status |
| D016145 | Endoscopy, Digestive System |
| D001706 | Biopsy |
| ID | Term |
|---|---|
| D012959 | Socioeconomic Factors |
| D011154 | Population Characteristics |
| D003938 | Diagnostic Techniques, Digestive System |
| D019937 | Diagnostic Techniques and Procedures |
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| OTHER |
| Massachusetts General Hospital | OTHER |
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| Healthy age-matched US children | No Intervention | Comparative group for the Pakistani WHZ <-2 children who undergo UGI endoscopy and biopsy. Number of upper gastrointestinal endoscopies performed in children less than 2 years old are limited in Pakistan, therefore US age-matched controls will be used; healthy children < 3 years old will be enrolled, who will undergo endoscopy at CCHMC as part of a diagnostic workup for digestive symptoms, but whose biopsies and diagnoses are not supportive of eosinophilic esophagitis, celiac disease, or inflammatory bowel disease, and who were not treated with antibiotics ≤ 4 weeks prior to endoscopy. |
|
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| Ready to Use Therapeutic Food | Dietary Supplement | If child remains WHZ < -2 despite nutritional education then will be managed according to Pakistan's Community Management of Acute Malnutrition protocol. This will include provision of ready to use therapeutic food (RUTF) to the child at home with close follow up. Utilization of the RUTF will be monitored closely by bi-weekly home visits. |
|
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| Upper gastrointestinal endoscopy with biopsy | Procedure | If child remains at WHZ < -2 despite educational and dietary interventions, then will undergo medical evaluation for assessment of need for more advanced workup of malnutrition, including UGI endoscopy at AKUH. Results of the advanced work up, including the UGI endoscopy, will guide future management of these children. |
|
|
Serum, stool, and urine biomarkers of EE will be collected and tested in those children who are eligible to undergo upper GI endoscopy and biopsy
| At approximately 15 months after entry into study |
| The use of UGI biopsy tissue for histopathological and multiomic workup for validation of biomarkers associated with EE | Biopsy specimens from UGI endoscopy obtained from eligible children will be used for detailed histopathologic and multiomic work up to study the pathophysiology of EE, validate current biomarkers, and generate novel biomarker candidates | At approximately 15 months after entry into study |
| Derived |
| Zhao X, Setchell KDR, Huang R, Mallawaarachchi I, Ehsan L, Dobrzykowski Iii E, Zhao J, Syed S, Ma JZ, Iqbal NT, Iqbal J, Sadiq K, Ahmed S, Haberman Y, Denson LA, Ali SA, Moore SR. Bile Acid Profiling Reveals Distinct Signatures in Undernourished Children with Environmental Enteric Dysfunction. J Nutr. 2021 Dec 3;151(12):3689-3700. doi: 10.1093/jn/nxab321. |
| 33524399 | Derived | Haberman Y, Iqbal NT, Ghandikota S, Mallawaarachchi I, Tzipi Braun, Dexheimer PJ, Rahman N, Hadar R, Sadiq K, Ahmad Z, Idress R, Iqbal J, Ahmed S, Hotwani A, Umrani F, Ehsan L, Medlock G, Syed S, Moskaluk C, Ma JZ, Jegga AG, Moore SR, Ali SA, Denson LA. Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction. Gastroenterology. 2021 May;160(6):2055-2071.e0. doi: 10.1053/j.gastro.2021.01.221. Epub 2021 Jan 29. |
| 31331393 | Derived | Iqbal NT, Syed S, Sadiq K, Khan MN, Iqbal J, Ma JZ, Umrani F, Ahmed S, Maier EA, Denson LA, Haberman Y, McNeal MM, Setchell KDR, Zhao X, Qureshi S, Shen L, Moskaluk CA, Liu TC, Yilmaz O, Brown DE, Barratt MJ, Kung VL, Gordon JI, Moore SR, Ali SA. Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation. BMC Pediatr. 2019 Jul 22;19(1):247. doi: 10.1186/s12887-019-1564-x. |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003933 | Diagnosis |
| D004724 | Endoscopy |
| D003949 | Diagnostic Techniques, Surgical |
| D013505 | Digestive System Surgical Procedures |
| D013514 | Surgical Procedures, Operative |
| D019060 | Minimally Invasive Surgical Procedures |
| D003581 | Cytodiagnosis |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
| D013048 | Specimen Handling |
| D008919 | Investigative Techniques |