Hemolytic uremic syndrome risk and Escherichia coli O157:H7.

We reviewed medical records of 238 hospitalized patients with Escherichia coli O157:H7 diarrhea to identify risk factors for progression to diarrhea-associated hemolytic uremic syndrome (HUS). Data indicated that young age, long duration of diarrhea, elevated leukocyte count, and proteinuria were associated with HUS.

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In the United States, Escherichia coli O157:H7 causes [approximately equal to] 73,000 infections and 60 deaths annually (1). Infection progresses to hemolytic uremic syndrome (HUS) in 2% to 15% of cases (2). In studies of E. coli O157:H7 outbreaks, female sex, young age, elevated leukocyte count, antimicrobial drug use, vomiting, and fever have been reported as risk factors for HUS (3-11). Previously, a possible association between HUS and female sex, young age, and prolonged duration of diarrhea was shown in a study that evaluated the New York state surveillance system for post-diarrheal HUS (12). This report extends that study to investigate hospitalized patients with E. coli O157:H7 infection to assess potential risk factors for progression of infection to HUS by using a case-control study.

The Study

Medical charts of all persons who were hospitalized and reported with confirmed cases of E. coli O157:H7 to the New York State Department of Health's Communicable Disease Surveillance System (CDSS) in 1998 and 1999 were reviewed according to a standardized survey form. A HUS case was defined as occurring in a patient with acute diarrhea who was hospitalized with E. coli O157:H7 infection and in whom confirmed or probable postdiarrheal HUS developed. A confirmed HUS case was defined as occurring in a patient with a clear history of acute diarrhea who showed the following signs: hemolytic anemia with microangiopathic changes, renal insufficiency (creatinine level [greater than or equal to] 1.0 mg/dL in a child <13 years of age or [greater than or equal to] 1.5 mg/dL in an adult, or [greater than or equal to] 50% increase over baseline), and thrombocytopenia (platelet count <150,000/[micro]L). A probable HUS case was defined as occurring in a patient with acute diarrhea with all the above signs except microangiopathic changes in the blood smear. Controls were hospitalized patients with E. coli O157:H7 infection without HUS. Demographic, clinical, and laboratory characteristics were abstracted from medical charts. Statistical analysis was performed by using SAS software (SAS Institute, Cary, NC, USA). A multiple logistic regression analysis was performed to identify factors associated with development of HUS.

In 1998 and 1999, the CDSS received reports of 1,170 cases of E. coli O157:H7 infection. Of these, 255 patients (21%) were hospitalized and 238 (93%) had medical charts available for review. Thirty-six (15%) patients were confirmed (n = 29) or probable (n = 7) HUS case-patients, and 202 E. coli O157:H7-infected patients without HUS were identified as controls. The risk of HUS was highest among children <5 years of age, compared with patients >65 years (odds ratio [OR] 4.9, 95% confidence interval [CI] 2.2-11.8). Sixty-nine percent of HUS patients were female compared with 61% of controls (OR 1.5, 95% CI 0.8-3.4). The hospital stay was significantly longer for HUS patients than controls (median hospital stay 13 vs. 3 days). Five HUS patients (14%) died, including 2 children <5 years of age, compared with 2 controls (1%).

Forty percent of all patients had vomiting, and 85% had bloody stool. These factors were not significantly different between patients and controls. Eleven (31%) case-patients and 78 (38%) controls were treated with antimicrobial drugs (not significant). Antimicrobial treatment was reported in 11 patients before the diagnosis of HUS: 6 received antimicrobial drugs primarily for other conditions (e.g., urinary tract infection, otitis media, venous line sepsis), 1 had treatment stopped once E. coli O157:H7 was diagnosed, and we could not tell whether drug regimens were completed or discontinued in 4 patients. HUS patients were more likely than non-HUS controls to have fever (OR 3.2, 95% CI 1.6-6.5). The duration of diarrhea before hospitalization was significantly longer for HUS patients than for non-HUS controls (median 4 vs. 2 days).

Proteinuria and hematuria were observed significantly more often among the case-patients. Twenty-three (64%) patients had proteinuria at admission, whereas 37 (18%) controls were admitted with proteinuria (OR 7.8, 95% CI 3.6-17). Hematuria at admission was reported in 23 (64%) patients and 57 (28%) controls (OR 4.5, 95% CI 2.1-9.4). Twenty-nine (81%) HUS patients vs. 90 (44%) controls had leukocyte counts [greater than or equal to] 13,000/[micro]L (OR 5.2, 95% CI 2.2-12.3) at admission (Table 1). Factors associated with HUS in univariate analysis (age <5 years, outbreak case, fever, hematuria, proteinuria, leukocytosis at admission, and duration of diarrhea before hospitalization >3 days) were included in the multivariate analysis. The following variables were associated with HUS development in the multivariate analysis: proteinuria (OR 6.7, 95% CI 1.9-24.1), duration of diarrhea before hospitalization >3 days (OR 6.2, 95% CI 2.2-17.4), age <5 years (OR 5.9, 95% CI 1.9-17.6), and leukocyte count [greater than or equal to] 13,000/mL (OR 4.4, 95% CI 1.6-12.6). Factors such as outbreak involvement, hematuria and fever were not associated with HUS development (Table 2).

Conclusions

This study provides additional information on potential risk factors for progression of E. coli O157:H7 infection to HUS, but unlike other studies, this study used hospitalized rather than outpatient controls. Our data confirmed previous differences in risk for HUS development by age group (3-5). Women and girls have been reported to be at increased risk for HUS development in several studies (10,11), but our study showed no significant increased risk. Several studies have suggested that administration of antimicrobial agents increases risk for HUS development (5,6,9,13), but no significant relationship was observed between HUS and the use of antimicrobial drugs in our sample.

Although reports (5,7) have demonstrated a higher incidence of HUS among patients with bloody diarrhea, fever, or vomiting, our multivariate analysis did not show a significant association between these characteristics and HUS. Since only hospitalized patients with severe diarrhea were studied, some symptoms (bloody stool, fever, or vomiting) might have been reported more often than in the general population with E. coli O157:H7 infection. As a result, some significant associations might have been missed. Buteau et al. (14) reported that a diarrheal prodrome <3 days is an independent predictor of HUS development in children with E. coli O157:H7 infection; however, our study suggested that prolonged diarrhea (>3 days) may increase the risk of HUS.

Our analysis was consistent with results of other studies that found patients with elevated leukocyte counts to be at higher risk for developing HUS (5-8,14). Patients with leukocytes [greater than or equal to] 13,000/[micro]L at admission in our study had 5 times the risk of HUS. Protein and occult blood in urine were described as risk factors for HUS in a study in Japan (15). In the current study, proteinuria at admission was also a risk factor for HUS. However, HUS had already developed in most of these patients by the time of hospitalization, and we could not determine whether these factors preceded HUS development.

In summary, patients hospitalized for E. coli O157:H7 infection, those <5 years of age with >3 days of diarrhea, leukocytes [greater than or equal to] 13,000/[micro]L, and proteinuria should be monitored closely for further complications. Nine (25%) of the HUS patients had 4 risk factors, 11 (31%) patients had 3 risk factors, and 10 (28%) had 2 risk factors. In comparison, none of the controls had these 4 risk factors, 4 (2%) had 3 risk factors, and 47 (23%) had 2 risk factors. Identifying potential risk factors may allow clinicians to develop treatment interventions to prevent progression to HUS.

References

(1.) Mead PS, Slutsker L, Dietz V, McCaig LF, Bresee JS, Shapiro C, et al. Food-related illness in the United States. Emerg Infect Dis. 1999;5:607-25.

(2.) Dundas S, Todd WT, Stewart AI, Murdoc PS, Chaudhuri AKR, Hutchinson SJ. The central Scotland Escherichia coli O157:H7 outbreak: risk factors for hemolytic uremic syndrome and death among hospitalized patients. Clin Infect Dis. 2001;33:923-31.

(3.) Griffin PM, Ostroff SM, Tauxe RV, Greene KD, Wells JG, Lewis JH, et al. Illnesses associated with E. coli O157:H7 infections: a broad clinical spectrum. Ann Intern Med. 1988;109:705-12.

(4.) Griffin PM, Tauxe RV. The epidemiology of infections caused by E. coli O157:H7, other enterohemorrhagic E. coli and associated hemolytic uremic syndrome. Epidemiol Rev. 1991;13:60-98.

(5.) Pavia AT, Nichols CR, Green DP, Tauxe RV, Mottile S. Hemolytic uremic syndrome during an outbreak of Escherichia coli O157:H7 infections in institutions for mentally retarded persons: clinical and epidemiologic observations. J Pediatr. 1990;116:544-51.

(6.) Bell BP, Griffin PM, Lozano P, Christie DL, Kpbayashi JM, Tarr PI. Predictors of hemolytic uremic syndrome in children during a large outbreak of Escherichia coli O157:H7 infections. Pediatrics. 1997;100:E12.

(7.) Ikeda K, Ida O, Kimoto K, Takatorige T, Nakanish N, Tatara K. Predictors for the development of haemolytic uremic syndrome with Escherichia coli O157:H7 infections: with focus on the day of illness. Epidemiol Infect. 2000;124:343-9.

(8.) Kawamura N, Yamazaki T, Tamai H. Risk factors for the development of Escherichia coli O 157:H7 associated with hemolytic uremic syndrome. Pediatr Int. 1999;41:218-22.

(9.) Carter AO, Borczyk AA, Carlson JA, Harvey B, Hockin JC, Karmali MA, et al. A severe outbreak of Escherichia coli O157:H7--associated hemorrhagic colitis in a nursing home. N Engl J Med. 1987;317:1496-1500.

(10.) Cimolai N, Carter JE, Morrison BJ, Anderson JD. Risk factors for the progression of Escherichia coli O157:H7 enteritis to the hemolytic uremic syndrome. J Pediatr. 1990;116:589-92.

(11.) Rowe PC, Walop W, Lior H, Mackenzie AM. Hemolytic anemia after childhood Escherichia coli O157:H7 infection: are females at increased risk? Epidemiol Infect. 1991;106:523-30.

(12.) Chang HH, Tserenpuntsag B, Kacica M, Smith PF, Morse DL. Hemolytic uremic syndrome in New York. Emerg Infect Dis. 2004; 10:928-31.

(13.) Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342:1930-6.

(14.) Buteau C, Proulx F, Chaibou M, Raymond D, Clermont MJ, Mariscalco MM, et al. Leukocytosis in children with Escherichia coli O157:H7 enteritis developing the hemolytic uremic syndrome. Pediatr Infect Dis J. 2000; 19:642-7.

(15.) Joh K. Predictive indicators for progression to severe complications (hemolytic-uremic syndrome and encephalopathy) and their prevention in enterohemorrhagic Escherichia coli infection. Nippon Rinsho. 1997;55:700-5.

Boldtsetseg Tserenpuntsag, * Hwa-Gan Chang, ([dagger]) Perry F. Smith, * ([dagger]) and Dale L. Morse * ([dagger])

* University at Albany, Albany, New York, USA; and 1-New York State Department of Health, Albany, New York, USA

Address for correspondence: Hwa-Gan Chang, New York State Department of Health, Coming Tower Building, Room 1143, Empire State Plaza, Albany, NY 12237, USA; fax: [phone]; email: [e-mail]

Ms Tserenpuntsag is a DrPH student majoring in epidemiology at the State University of New York at Albany. Her research interests include infectious disease epidemiology.

Table 1. Characteristics of hospitalized Escherichia coli O157:H7
patients by HUS case status, New York, 1998-1999 *

                               Total (N = 238)   HUS (n = 36)
Characteristic                      n (%)            n (%)

Age (y)
  0-4                              34 (14)          18 (49)
  5-14                             52 (22)           6 (17)
  15-65                            96 (24)           6 (17)
  >65                              56 (40)           6 (17)
Sex
  Female                          147 (62)          25 (69)
  Male                             91 (38)          11 (31)
Outcome
  Dead                              7 (3)            5 (14)
  Alive                           231 (97)          31 (86)
Outbreak
  Yes                              49 (21)          15 (42)
  No                              189 (79)          21 (58)
Hospital stay (d)
  >4                              121 (51)          31 (86)
  1-4                             117 (49)           5 (14)
Bloody stool
  Yes                             203 (85)          30 (84)
  No                               35 (15)           6 (16)
Fever
  Yes                              71 (30)          19 (53)
  No                              167 (70)          17 (47)
Vomiting
  Yes                              96 (40)          14 (39)
  No                              142 (60)          22 (61)
Antimicrobial drug use
  Yes                              89 (37)          11 (31)
  No                              149 (63)          25 (69)
Proteinuria at admission
  Yes                              60 (25)          23 (64)
  No                              178 (75)          13 (36)
Hematuria at admission
  Yes                              80 (34)          23 (64)
  No                              158 (66)          13 (36)
Leukocyte count at admission
  [greater than or equal
    to] 13,000/[micro]L           119 (50)          29 (81)
  <13,000/[micro]L                119 (50)           7 (19)
Duration of diarrhea before
hospitalization
  >3 days                          70 (29)          24 (67)
  [less than or equal
    to] 3 days                    168 (71)          12 (33)

                               Non-HUS (n = 202)
Characteristic                       n (%)           OR (95% CI)

Age (y)
  0-4                               16 (8)          4.9 (2.2-11.8)
  5-14                              46 (23)         1.1 (0.4-3.1)
  15-65                             90 (44)         0.6 (0.2-1.7)
  >65                               50 (25)              1.0
Sex
  Female                           122 (61)         1.5 (0.8-3.4)
  Male                              80 (39)              1.0
Outcome
  Dead                               2 (1)         16.1 (2.9-86.8)
  Alive                            200 (99)              1.0
Outbreak
  Yes                               34 (17)         3.6 (1.6-7.5)
  No                               168 (83)              1.0
Hospital stay (d)
  >4                                90 (45)         7.7 (2.8-20.6)
  1-4                              112 (55)              1.0
Bloody stool
  Yes                              173 (86)         0.8 (0.3-2.4)
  No                                29 (14)              1.0
Fever
  Yes                               52 (26)         3.2 (1.6-6.5)
  No                               150 (74)              1.0
Vomiting
  Yes                               82 (40)         0.9 (0.4-1.9)
  No                               120 (60)              1.0
Antimicrobial drug use
  Yes                               78 (38)         0.7 (0.3-1.5)
  No                               124 (62)              1.0
Proteinuria at admission
  Yes                               37 (18)         7.8 (3.6-17.0)
  No                               165 (82)              1.0
Hematuria at admission
  Yes                               57 (28)         4.5 (2.1-9.4)
  No                               145 (72)              1.0
Leukocyte count at admission
  [greater than or equal
    to] 13,000/[micro]L             90 (44)         5.2 (2.2-12.3)
  <13,000/[micro]L                 112 (56)              1.0
Duration of diarrhea before
hospitalization
  >3 days                           46 (23)         6.7 (3.1-14.6)
  [less than or equal
    to] 3 days                     156 (77)              1.0

Characteristic                 p value

Age (y)
  0-4                          <0.001
  5-14
  15-65
  >65
Sex
  Female                        0.33
  Male
Outcome
  Dead                          0.001
  Alive
Outbreak
  Yes                           0.01
  No
Hospital stay (d)
  >4                            0.001
  1-4
Bloody stool
  Yes                           0.77
  No
Fever
  Yes                           0.009
  No
Vomiting
  Yes                           0.84
  No
Antimicrobial drug use
  Yes                           0.38
  No
Proteinuria at admission
  Yes                          <0.001
  No
Hematuria at admission
  Yes                          <0.001
  No
Leukocyte count at admission
  [greater than or equal
    to] 13,000/[micro]L        <0.001
  <13,000/[micro]L
Duration of diarrhea before
hospitalization
  >3 days                      <0.001
  [less than or equal
    to] 3 days

* HUS, hemolytic uremic syndrome, OR, odds ratio;
CI, confidence interval.

Table 2. Multiple logistic regression analysis of
risk factors associated with HUS, New York, 1998-1999 *

                       No. patients (%)   No. controls (%)
Characteristic             (n = 36)           (n = 202)

Proteinuria                 23 (64)            37 (18)
Duration of diarrhea
  before hospitali-
  zation >3 d               24 (67)            46 (23)
Age <5 y                    18 (50)            16 (8)
Leukocytes >13,000/
  [micro]L                  29 (81)            90 (44)
Outbreak case               15 (42)            34 (17)
Hematuria                   23 (64)            57 (28)
Fever                       19 (53)            52 (26)

Characteristic         Adjusted OR (95% CI)

Proteinuria               6.7 (1.9-24.1)
Duration of diarrhea
  before hospitali-
  zation >3 d             6.2 (2.2-17.4)
Age <5 y                  5.9 (1.9-17.6)
Leukocytes >13,000/
  [micro]L                4.4 (1.6-12.6)
Outbreak case             1.7 (0.6-4.9)
Hematuria                 1.4 (0.4-4.9)
Fever                     1.1 (0.4-3.1)

* HUS, hemolytic uremic syndrome; OR, odds ratio;
CI, confidence interval.