PEDIATRICS Vol. 100 No. 1 July 1997,
p. e12
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Predictors of Hemolytic Uremic Syndrome in Children During a
Large Outbreak of Escherichia coli O157:H7 Infections
,
, and
From the * Epidemic Intelligence Service and the Division of
Field Epidemiology, Epidemiology Program Office, and the
Foodborne
and Diarrheal Diseases Branch, National Center for Infectious Diseases,
Centers for Disease Control and Prevention, Atlanta, Georgia; the
§ Department of Pediatrics, University of Washington School of
Medicine, Seattle, Washington; the
Washington State Department of
Health, Seattle, Washington; the ¶ Department of Microbiology,
University of Washington School of Medicine, Seattle, Washington; and
the # Children's Hospital and Medical Center, Seattle, Washington.
Objective. To evaluate risk factors for progression of Escherichia coli O157:H7 infection to the hemolytic uremic syndrome (HUS).
Study Design. We conducted a retrospective cohort study among 278 Washington State children <16 years old who developed symptomatic culture-confirmed E coli O157:H7 infection during a large 1993 outbreak. The purpose of the study was to determine the relative risk (RR) of developing HUS according to demographic characteristics, symptoms, laboratory test results, and medication use in the first 3 days of illness.
Results. Thirty-seven (14%) children developed HUS. In
univariate analysis, no associations were observed between HUS risk and
any demographic characteristic, the presence of bloody diarrhea or of
fever, or medication use. In multivariate analysis, HUS risk was
associated with, in the first 3 days of illness, use of antimotility
agents (odds ratio [OR] = 2.9; 95% confidence interval [CI]
1.2-7.5) and, among children <5.5 years old, vomiting (OR = 4.2;
95% CI 1.4-12.7). Among the 128 children tested, those whose white
blood cell (WBC) count was
13 000/µL in the first 3 days of
illness had a 7-fold increased risk of developing HUS (RR 7.2; 95% CI
2.8-18.5). Thirteen (38%) of the 34 patients with a WBC count
13 000/µL developed HUS, but only 5 (5%) of the 94 children whose
initial WBC count was <13 000/µL progressed to HUS. Among children
who did not develop HUS, use of antimotility agents in the first 3 days
of illness was associated with longer duration of bloody diarrhea.
Conclusions. Prospective studies are needed to further evaluate measures to prevent the progression of E coli O157:H7 infection to HUS and to assess further clinical and laboratory risk factors. These data argue against the use of antimotility agents in acute childhood diarrhea. Our finding that no intervention decreased HUS risk underscores the importance of preventing E coli O157:H7 infections.
Key words: antibiotics, antimotility agents, Escherichia coli O157:H7, kidney failure, leukocytosis.Escherichia coli O157:H7 causes bloody and nonbloody diarrhea that progresses to hemolytic uremic syndrome (HUS) in a subset of patients.1,2 Though the gastrointestinal manifestations of infection with E coli O157:H7 can be severe, HUS accounts for the major acute and chronic morbidity and mortality caused by this organism.
Associations between certain host-specific factors and the risk of progression of enteric infection with E coli O157:H7 to HUS have been reported. In population-based studies of HUS, age-specific incidence was highest among children <5 years of age, but these studies did not evaluate risk factors for progression of diarrhea or hemorrhagic colitis to HUS.3 In some studies of children with E coli O157:H7 infection, girls were more likely than boys to develop HUS.7,8 Patients who are infected with E coli O157:H7 and at the time of presentation to medical care have elevated white blood cell counts, fever, or bloody stools also have been noted to have a higher risk of progression to HUS than patients without these findings.9
Considerable interest has been focused on the effect of antimicrobial agents on the risk of patients with E coli O157:H7 infections developing HUS. In one prospective, randomized controlled trial, antimicrobial agents administered to 47 children late in the course of infection failed to demonstrate any effect.13
In 1993, a large outbreak of E coli O157:H7 infections resulted from the consumption of inadequately cooked hamburgers in restaurants of Chain A in Washington State, resulting in more than 500 cases.14 Using interviews and medical-record review, we conducted a study among the cohort of children who sought medical attention during the outbreak to evaluate possible risk factors for progression of E coli O157:H7 infection to HUS.
Inclusion Criteria
Patients were eligible for inclusion in the study if they had either symptomatic, culture-confirmed E coli O157:H7 infection or HUS beginning in January or February 1993, were <16 years of age, and resided in Washington State. They were considered to have primary cases of infection if illness began within 10 days of eating at a Chain A restaurant. Patients who became ill within 10 days of close contact with a case-patient and who had not eaten at Chain A during that time were considered to have secondary cases.Data Collection
Data were collected from three sources. First, county health department staff, using a standard questionnaire, interviewed by telephone a parent of each patient within 2 weeks of illness onset and collected demographic data, the dates of illness onset and signs and symptoms of the illness, and the date of eating and food consumed at Chain A. Second, interviewers contacted patients' parents again by telephone 2 to 4 months later. Using a different standard questionnaire, they verified information obtained by the county health department and recorded more detailed information on patients' signs and symptoms, medication use, physician visits and hospitalization. Third, a study coordinator or one of the authors (B.P.B. or P.L.), using a standard data collection form, abstracted recorded signs and symptoms, medications, and test results from medical records.Case Definition and Variables Examined
We used the onset dates of illness and signs and symptoms first reported by the parent. Diarrhea and vomiting were determined to be present if the family or patient reported these signs. Bloody diarrhea was defined as visible blood in the stool, also by parental report. Fever was defined as any temperature
38.5°C at any site. When the
parent offered different dates at the time of the second interview, we
compared the dates collected from the three sources and used those on
which two sources agreed. When considering prescription medication use,
we included only those patients where parental report and the medical
record agreed on whether the medication was taken. We used the date the
medication was started and the number of days taken as reported by the
parent for both prescription and nonprescription medication.
Microbiology
Stool samples were submitted to local laboratories, and tested for the presence of E coli O157:H7 by inoculation onto sorbitol-MacConkey agar. Serotyping, confirmation, and toxin typing of E coli O157:H7 recovered were performed as previously reported.14Statistics
The
2 test, Fisher's exact test, Student's
t test, and Pearson correlation coefficients were used to
examine relationships among independent variables and HUS. Relative
risks (RRs) and 95% confidence intervals (CIs) were calculated using
standard methods or the exact method of Martin and Austin where
appropriate.15,16 Normality was assessed using the
Shapiro-Wilk statistic, and for data that were not normally
distributed, the Wilcoxon 2-sample and Kruskal-Wallis tests were used.
In stratified analyses, possible differences in associations among
strata were examined using Cochran-Mantel-Haenzel statistics and the
Breslow-Day test. Logistic regression modelling was conducted using SAS
(SAS Institute, Inc, Cary, NC) software.17 Variables
associated with the outcome in the univariate analysis at
P
.1 and possible confounding variables were
included in the initial model. The most parsimonious model was
developed by evaluating the effects of covariates using the
2 Log
Likelihood criteria.
Study Population
The study population consisted of 278 (86%) of the 324 children eligible for participation. Of the 46 children who did not participate, the parents of 10 (22%) refused to be interviewed, 25 (54%) refused medical record review, 8 (17%) could not be located, and 3 (7%) had either no medical record or had not visited a physician. The median age of study subjects was 6 years (range 0 to 15); 145 (52%) were female; 245 (88%) were white. Two hundred eighteen (78%) acquired their infection by eating a hamburger at Chain A and 30 (11%) had cases of secondary infection. The source of infection could not be determined in 30 (11%). Ninety-two (33%) patients were hospitalized.Outcomes Identified
There were 33 children (12%) with complete HUS and 4 (2%) with incomplete HUS. These 4 patients had anemia (median hematocrit 27%; range 23-29) and thrombocytopenia (median 42 000/µL; range 29 000 to 122 000), but no azotemia; 3 had proteinuria or hematuria. The median interval between onset of the first symptom to hospitalization for HUS was 6 days (range 1 to 12).Demographic Risk Factors Analyzed
We found no association between the risk of HUS and age, sex, or annual household income (Table 1). Although 2 of the 3 fatalities (all from complications of HUS) occurred in children who had secondary cases of infection, patients with secondary cases were no more likely to develop HUS (3/30; 10%) than were patients with primary cases (30/218; 14%). A similar proportion of patients with mental retardation or developmental delay developed HUS (1/8; 13%) as patients without these conditions (36/169; 21%).|
Table 1. Risk of HUS by Selected Demographic Characteristics |
Clinical Risk Factors Analyzed
We initially examined clinical characteristics present at any time before HUS developed. Children whose parents reported vomiting had 3 times the risk of developing HUS (29/153 [19%]) compared with children who did not (8/125 [6%]; RR = 3.0; 95% CI 1.4-6.2). HUS developed in a larger proportion of children with bloody diarrhea compared with children who had diarrhea without blood, and in a larger proportion of children with fever, but the differences were not statistically significant: 34/243 (14%) with bloody diarrhea developed HUS vs 2/28 (7%) without bloody diarrhea (RR = 2.0; 95% CI .5-7.7); 11/56 (20%) with fever developed HUS vs. 20/169 (12%) without fever (RR = 1.8; 95% CI .8-4.1).
Table 2.
Risk of HUS by Selected Clinical Characteristics Beginning
5.5 years old (RR = 1.0; 95% CI .4-2.4).
3 Days
After Diarrheal Illness Onset and by Laboratory Values Among Children
Tested Within 3 Days of Diarrheal Illness Onset
Medication Risk Factors Analyzed
Fifty (18.0%) children received an antimicrobial agent, and 34 (12.5%) received an antimotility agent during the first 3 days of illness. No association was observed between treatment with any of these agents and age, sex, or hospitalization. Children treated with antimicrobial agents were more likely to live in households that had annual household incomes of more than $29 000 per year (RR = 1.7; 95% CI 1.0-2.8).
Table 3.
Risk of HUS by Medications Begun Within 3 Days of Diarrheal Illness
Onset
Mulitivariate Modeling
In multivariate modeling, children who were treated with antimotility agents were more likely to develop HUS than were children who did not receive them (odds ratio [OR] = 2.9; 95% CI 1.2-7.5). The relationship between vomiting during the first 3 days of illness and HUS risk identified in the univariate analysis was also observed in the multivariate model, but the adjusted OR for the risk of HUS among children younger than 5.5 years with vomiting was larger (OR = 4.2; 95% CI 1.4-12.7). There was no association between vomiting and HUS risk among children at least 5.5 years old (OR = 1.0; 95% CI .4-3.0).Laboratory Risk Factors Analyzed
Among the 128 children who had a laboratory test in the first 3 days of illness, patients with a total white blood (WBC) cell count >10 500/µL were at a 5-fold increased risk of HUS (Table 2); this association was not modified by age. The risk increased to 7-fold among children with a WBC count
13 000/µL, the upper quartile in this
population. No other laboratory test result on specimens obtained
during the first 3 days of illness was associated with the subsequent
development of HUS.
Less Severe Outcomes
Among children who did not develop HUS, we examined possible relationships between more common, but less severe, outcomes and treatment with antimicrobial or antimotility agents in the first 3 days of illness. We found no statistically significant associations between the number of days of diarrhea or of bloody diarrhea and antimicrobial agent use (Table 4). There was no difference in the median duration of diarrhea among children treated with antimotility agents compared with those who did not receive them, but the median duration of bloody diarrhea was longer (4 vs 3 days, respectively, P < .05) (Table 4).|
Table 4. Duration of Diarrhea and Bloody Diarrhea by Medications Begun Within the First 3 Days of Illness Among Patients Who Did Not Develop HUS |
We demonstrate that an elevated total WBC count early in the course of E coli O157:H7 infection is strongly associated with the development of HUS. Vomiting, the only sign associated with HUS risk, was not previously noted to be a factor for progression of E coli O157:H7 infection to HUS8,9,11,18,19. Vomiting may indicate severe gastrointestinal injury, higher intestinal concentrations of Shiga toxin (Stx), host susceptibility, or systemic toxemia with central nervous system effects.20 We were unable to demonstrate an association between developmental delay and risk of progression to HUS, as has been previously noted.21
13 000/µL in the first 3 days of illness subsequently
developed HUS compared with 18 (14%) of the total of 128 children
tested. However, because a normal WBC count does not absolutely
indicate a benign course, all patients should be followed closely until
diarrhea is resolved for several days to confirm that urine output
remains adequate and mental status is normal.
13 000/µL in the first 3 days of illness,
we would have identified 13 (72%) of the 18 patients who developed HUS
among the 128 patients in whom the laboratory test was obtained.
Twenty-one (16%) patients meeting this criterion failed to develop
HUS.
Dr Bell's present address is: Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333.
Send correspondence and reprint requests to Phillip I. Tarr, MD, Children's Hospital and Medical Center, Division of Gastroenterology and Nutrition, CH-24, 4800 Sand Point Way NE, Seattle, WA 98105.
Received for publication Jul 15, 1996; accepted Mar 4, 1997.
This research was supported by grants from the Children's Hospital Foundation (Seattle) and the American College of Gastroenterology.
We wish to thank Charla deBolt, RN, Marcia Goldoft, MD, MPH, Gail Hansen, DVM, Steven Hooker, MD, MPH, Kathy Carroll, RN, Carole Winegar, RN, Cynthia Miron, RN, Annette Fitzpatrick for assistance in the collection of the data, and the medical record staffs, attending physicians, and family members of patients for supplying clinical information used in this investigation.
HUS, hemolytic uremic syndrome. BUN, blood urea nitrogen. RR, relative risk. CI, confidence interval. TMP/SMZ, trimethoprim/sulfamethoxazole. OR, odds ratio. WBC, white blood cell. Stx, Shiga toxin.
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Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics
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