Environmental Enteropathy in Undernourished Pakistani Children: Clinical and Histomorphometric Analyses

Abstract

Abstract.Despite nutrition interventions, stunting thought to be secondary to underlying environmental enteropathy (EE) remains pervasive among infants residing in resource-poor countries and remains poorly characterized. From a birth cohort of 380 children, 65 malnourished infants received 12 weeks of nutritional supplementation with ready-to-use therapeutic food (RUTF). Eleven children with insufficient response to RUTF underwent upper endoscopy with duodenal biopsies, which were compared with U.S., age-matched specimens for healthy, celiac disease, non-celiac villous atrophy, non-celiac intraepithelial lymphocytosis, and graft-versus-host disease patients. Of the 11 children biopsied, EE was found in 10 (91%) with one subject with celiac disease. Morphometry demonstrated decreased villus-to-crypt (V:C) ratios in EE relative to healthy and non-celiac lymphocytosis patients. Environmental enteropathy villus volumes were significantly decreased relative to healthy controls. In EE, average CD3+ cells per 100 epithelial cells and per 1,000 µm2 of lamina propria and the number of lamina propria CD20+ B-cell aggregates were increased relative to all other groups. Our results indicate that V:C ratios are reduced in EE but are less severe than in celiac disease. Environmental enteropathy intraepithelial and lamina propria T lymphocytosis is of greater magnitude than that in celiac disease. The increases in lamina propria B and T lymphocytes suggest that non-cytolytic lymphocytic activation may be a more prominent feature of EE relative to celiac disease. These results provide new insights into shared yet distinct histological and immunological features of EE and celiac disease in children.

A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth

“…Our data demonstrate similarities and differences between the cohorts that warrant comment. While EED and GSE cohorts share histopathologic similarities, as suggested by prior studies [26,40,[57][58][59][60], our index showed differences in the main histologic features that are classically associated with GSE, including intraepithelial lymphocytes. We also had the Environmental enteric dysfunction histology index opportunity to compare a GSE case from Pakistan (excluded from this analysis) whose total histologic score was somewhat less severe than the median scores of the St. Louis GSE cohort, although overall showed a similar pattern of tissue injury (detailed comparison of scores to St. Louis GSE and Pakistani cohorts in S4 Table).…”

“…We also had the Environmental enteric dysfunction histology index opportunity to compare a GSE case from Pakistan (excluded from this analysis) whose total histologic score was somewhat less severe than the median scores of the St. Louis GSE cohort, although overall showed a similar pattern of tissue injury (detailed comparison of scores to St. Louis GSE and Pakistani cohorts in S4 Table). A single case does not permit generalizations about the overlap between EED and GSE pathology, but raises the possibility that GSE disease may be distinguishable from EED by histopathology, as has been suggested in previous literature as well [26,40,57,59,60]. This may be most important in settings where both enteropathies co-exist.…”

“…Endoscopic duodenal biopsies from four cohorts were analyzed: (1) Hospitalized 6-36 month olds with SAM and persistent diarrhea in Lusaka, Zambia [39]; (2) children 18-22 months with non-edematous wasting not requiring hospitalization recruited from a community-based birth cohort in rural Pakistan, and undergoing endoscopy if unresponsive to 2 months of outpatient nutritional intervention [40]; (3) children <18 years with clinically suspected GSE; and (4) children <18 years with normal tissue transglutaminase (tTG) IgA concentrations, no known inflammatory bowel disorders or prior GSE diagnosis, and in whom a diagnostic upper endoscopy was indicated ( Table 1). The latter two groups underwent endoscopy as part of routine clinical care at the Washington University School of Medicine/St.…”

“…Specifically, the degree of discordance of overall histologic scores was greater between biopsies of the same child than between those of different children in the Pakistani cohort. The greatest intraindividual variability related to the assessment of intramucosal Brunner glands, which are known to have a focal and nodular appearance when increased in the duodenum [40]. Because of its patchy nature, EED mucosal biopsy studies should include multiple biopsies, but pieces obtained can be considered as a pooled specimen set, to reduce the possibility of missing a case, to more comprehensively assess affected tissue, and to reduce analytic variability from sampling bias.…”

Assessment of Machine Learning Detection of Environmental Enteropathy and Celiac Disease in Children

“… 15 , 16 , 17 Environmental enteropathy and CD have been described as overlapping enteropathies. 17 , 18 , 19 , 20 , 21 Currently, the standard diagnostic criteria for these diseases is the evaluation of a small-intestinal biopsy obtained via an endoscopic procedure, which requires sedation. 17 , 22 Between 4 and 6 biopsies are required for diagnosis, 23 and because only parts of the bowel are affected in some cases, patients may require multiple endoscopic procedures.…”