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Diarrhea Etiology and Risk Factor Study

Tarr, Phillip
Washington University
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Children who report to the Children's Hospital and Regional Medical Center ER and Gastroenterology Clinic with Diarrhea will be invited to enroll in this study. Stool will be evaluated thoroughly for the presence of definite, plausible, and candidate pathogens. Controls will be solicited so that they are age-, geographically-, and temporally-matched. In the second arm of the study, children with reportable enteric infections in three counties (King, Whatcom, and Yakima Counties, Washington) will be administered a thorough questionnaire, and age-, geographically-, and temporally-matched controls will be sought, to study likely vehicles and environmental modes of acquisition, using a case-control analysis.
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NON-TECHNICAL SUMMARY: The cause(s) of many cases of diarrhea remain(s) unexplained. Despite intense microbiologic evaluations, many cases cannot be attributed to a specific agent. Well designed case control studies have not been performed. Also, risk factors for the acquisition of sporadic (i.e., non-epidemic) reportable enteric infections remain often unknown. The purpose of this project is to conduct a case-control study of the causes of unexplained dirrhea, among children whose stools undergo a thorough microbiologic assesssment to identify classic causes. Additionally, we will pursue a prospective, case-control risk factor study of reportable enteric, sporadic (non-epidemic) infections, to determine candidate sources.

APPROACH: Test the hypothesis that candidate pathogens (diarrheagenic E. coli, blastocytocystis hominis, Helicobacter pylori, Clostridium difficile and Listeria monocytogenes) cause unexplained childhood diarrhea. Test the hypothesis that one or more selected reportable enteric infections (i.e., C. jejuni, E. coli 0157:H7, Salmonella, Shigellae, and Yersiniae) can be attributed to foodborne or environmental exposures.

PROGRESS: 2003/08 TO 2007/03
We have completed the subject enrollment, and aims of the grant. Specifically, we enrolled cases and controls to determine hte cause of unexplained diarrea: Cases Controls Census 3 No. of patients 302 547 Gender M:F 53:47 51.49 50:50 Age (mo.) Median (range) 19.8(0.5-18y) 23.0(1.4-18y) Race White 49% 67% 82% African American 6% 7% 3% Asian/Pac Islander 10% 7% 5.5% Native American 1% 0% 1.6% Mixed/Other 13% 18% 7.5% No responsea 10% 1% Ethnicity Hispanic 28% 14% 7.5% Not Hispanic 67% 84% 78.9% No responsea 5% 1% Bacterial pathogens 33(10.9%) C. jejuni 6 (2%) EHECb 11 (3.7%) 1 (0.2%) Salmonellae 13 (4.3%) Shigella 3 (1.0%) Y. enterocolitica 0 (0%) EaggECc 8 (6.2%) 4 (0.7%) C. difficile toxin 9 (7.0%) 2 (0.8%) Virusesd 142 (47.0%) Parasitese 1 (0.3%) ano response or prefers not to indicate; bEHEC are serogroups O26, O111, O121, O177 (1 each), and O157:H7 (n=7); cno positive (% no. tested, but only for specimens without bacterial pathogens or rotavirus); drotavirus, astrovirus, and adenovirus represent 78%, 8%, and 6% of viruses detected, respectively. Noroviruses 1 and 2 represented 3% and 5% of viruses, respectively. eC. parvum oocysts (n=1). C. difficile was found in fewer controls than patients over 2 yo, the converse was noted under age 2. B. hominis was not established as a pathogen in this cohort. PCR analysis of MacConkey broth outgrowths from 56 random cases suggests the presence of some candidate diarrheagenic E. coli (enteroaggregative and EPEC) but not others (ETEC, enteroinvasive E. coli). this cohort. In parallel, we assessed risk factors for acquiring sporadic reportable enteric infections. Two hundred ninety-six subjects were matched to 580 controls. Home food consumption or food preparation practices were associated with Salmonella (shrimp and pork consumption OR, 2.7; CI, 1.1-6.7 and OR, 2.6; CI, 1.2-5.6, respectively) and Campylobacter (pork, beef and shrimp consumption OR, 1.7; CI, 1.0-2.9, OR, 2.2; CI, 1.3-3.6 and OR, 2.3; CI, 1.3-4.3, respectively; touched raw chicken OR, 6.1; CI, 1.4-25.6; sub-optimal cleaning for surfaces in contact with raw meat or chicken (OR, 7.1; CI, 2.1-24.1) infections. Residential farm animal exposure (OR, 3.1; CI, 1.4-6.9), consuming garden hose or untreated surface water (OR, 4.1; CI, 2.0-8.8, OR, 14.5; CI, 3.1-67.7, respectively), and raw herb consumption (OR, 5.3; CI, 2.6-10.9) were additional risk factors for Campylobacter infections. However, recreational water play was the overall most important risk factor associated with all of the bacterial REIs studied (beach exposure--Salmonella OR, 28.3; CI, 7.2-112.2, Shigella OR, 14.5; CI, 1.5-141.0; any recreational water exposure--Campylobacter OR, 3.4; CI, 1.4-8.4, E. coli O157 OR, 7.4; CI, 2.1-26.1). Further study on REI risk factors should include examination of the specific nature of these exposures so as to design interventions to mitigate them as causes of REIs.

IMPACT: 2003/08 TO 2007/03
We expect the unexplained diarrhea part of this study to demonstrate the pathogenicity of a subset of diarrheagenic E. coli , which can then be used to mitigate human exposure to these agents. The specimen archive we have can be used a unique resource with which to move forward the field of pathogen discovery, and assessment of the human pathomicrobiome. The risk factors arm of the study will provide percent attributable risks for acquiring a panel of childhood enteric infections (i.e., those caused by : Campylobacter, Salmonella, Escherichia coli O157, or Shigella). Areas in which improvements should be targeted to reduce these infections include in-home food preparation practices, consumption of food at commercial venues other than fast food restaurants, and improvements in water safety.

Funding Source
Nat'l. Inst. of Food and Agriculture
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Escherichia coli
Meat, Poultry, Game