Population-based Trends in Pediatric Hemolytic Uremic Syndrome in California, 1994–1999: Substantial Underreporting and Public Health Implications

Kate C. Cummings, Janet C. Mohle-Boetani, S. Benson Werner and Duc J. Vugia

From the Disease Investigations and Surveillance Branch, Division of Communicable Disease Control, California Department of Health Services, Berkeley, CA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 REFERENCES
 
This paper describes the epidemiology of childhood hemolytic uremic syndrome (HUS) in California, for which hospitalization data were used, and the proportion of cases reported to public health authorities. HUS discharge data for children <=17 years of age were extracted from the population-based California Patient Discharge Data Set for 1994–1999 and were linked electronically with HUS reports to public health authorities. Incidence rates per 100,000 children were calculated. The authors identified 585 HUS hospitalizations; 369 were incident cases. The average HUS incidence rate was 0.67 (95% confidence interval: 0.61, 0.74); rates rose modestly from 1994 (0.59, 95% confidence interval: 0.44, 0.78) to 1997 (0.80, 95% confidence interval: 0.63, 10.0) and decreased modestly thereafter (0.59, 95% confidence interval: 0.45, 0.77). Rates were highest for northern California children <=5 years of age (1.85, 95% confidence interval: 1.55, 2.19). The hospital case-fatality rate was 2.7% (95% confidence interval: 1.1, 4.4); the median charge was $39,500 per child. Only 43.9% of HUS cases in the California Patient Discharge Data Set were reported to public health authorities. Despite heightened efforts to control Shiga toxin-producing Escherichia coli exposures (the predominant cause of childhood HUS in the United States), HUS incidence rates remained relatively stable in California. Reporting HUS cases to public health authorities is important for disease control.

child; Escherichia coli infections; Escherichia coli O157; hemolytic-uremic syndrome; hospitalization; public health

Abbreviations: HUS, hemolytic uremic syndrome; STEC, Shiga toxin-producing Escherichia coli.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 REFERENCES
 
Hemolytic uremic syndrome (HUS) is a leading cause of acute renal failure in North American children and is characterized by acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (1Go). Adult HUS patients present with heterogeneous clinical manifestations and have variable outcomes, reflecting multiple underlying etiologies (2Go). In contrast, about 90 percent of childhood HUS cases develop after a diarrheal prodrome (3Go, 4Go); childhood HUS is distinct from adult HUS (2Go).

Current evidence suggests that Shiga toxin-producing Escherichia coli (STEC) infections cause most postdiarrheal HUS in North American and European children (4GoGoGoGoGoGoGoGo–12Go). Specifically, in studies restricted to children, between 77 and 88 percent of HUS patients had evidence of STEC infection, as documented by either stool culture or serologic antibodies (6GoGoGoGoGo–11Go). Among the many STEC serotypes, E. coli O157:H7 is the most commonly isolated in North America (3Go, 4Go, 6Go, 12Go). A minority of childhood E. coli O157:H7 infections progress to HUS; however, risk increases with decreasing age. In recent studies, approximately 10–14 percent of symptomatic and culture-confirmed E. coli O157:H7 infections in children <=5 years of age progressed to HUS (6Go, 13Go). Other non-O157 STEC serotypes can also cause HUS (14GoGo–16Go), but the prevalence of these serotypes is unknown (17Go), as is the associated risk of HUS. Although STEC infections and postdiarrheal HUS cases can occur in geographically and temporally circumscribed outbreak settings, most infections (3Go, 18Go) and HUS cases occur sporadically.

Reliable surveillance data of sporadic HUS and STEC infections are critical to targeting and evaluating STEC exposure control measures (5Go, 19Go). Immediate telephone reporting of HUS and E. coli O157 infection by health care providers to public health authorities became mandatory in California in 1996 (20Go). However, the extent of such reporting is likely low because identification of STEC infections (including E. coli O157) is subject to significant clinical ascertainment and laboratory detection biases (3Go, 4Go, 6Go, 21GoGoGo–24Go). Furthermore, the system is passive (health care providers and laboratory staff must remember to report) and of limited coverage. Of the many STEC serotypes, reporting of only E. coli O157:H7 is required. Other investigators have addressed these limitations by conducting active, targeted HUS surveillance using a sentinel corps of pediatric nephrologists (5Go, 25Go, 26Go). One such federally funded program operates in two northern California counties (5Go, 25Go).

Because most children with HUS are hospitalized (27Go, 28Go), population-based HUS incidence rates derived from hospitalization data should be relatively reliable. Because childhood postdiarrheal HUS in the United States arises primarily from STEC infections, HUS rates may also provide important population-based information about trends in childhood STEC infection. In this paper, we describe the epidemiology of and charges for hospitalizations of children with HUS in California by using hospital discharge data. We directly assessed compliance with mandatory HUS reporting regulations by determining the proportion of hospitalized patients reported to public health authorities. We indirectly determined detection and reporting of E. coli O157:H7 infections by comparing the expected number of such infections (based on HUS cases identified from hospitalization data) with the number of E. coli O157:H7 infections reported through passive surveillance.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 REFERENCES
 
Data sources
We studied a population-based cohort of California children <=17 years of age who were hospitalized in California with HUS from January 1, 1994, through December 31, 1999. Our study was approved by the Committee for the Protection of Human Subjects, California Health and Human Services Agency. To identify our cohort, we extracted 585 records from the California Patient Discharge Data Set; this database describes hospital discharges from all general acute care hospitals in California licensed to serve civilian patients (29Go). Eligible records listed International Classification of Diseases, Ninth Revision, Clinical Modification, code 283.11 (for "hemolytic uremic syndrome") among any of 25 diagnostic codes (30Go); 94.7 percent (554) of records listed HUS among the first five diagnoses. From each HUS discharge record identified, we extracted age, date of birth, race, sex, patient's county of residence, facility name, dates of admission and discharge, total hospital charges (excluding hospital-based physician fees), length of stay, comorbid conditions, procedures, and vital status upon discharge.

To identify HUS cases reported to California local public health authorities, we linked HUS cases identified in the Patient Discharge Data Set for 1996–1999 (inclusive) with the Confidential Morbidity Reports database. This database includes information on all HUS and E. coli O157:H7 infections reported by physicians and laboratories to California public health authorities (20Go). We electronically linked the two databases by match merging records on date of birth, sex, and county of residence. To ensure complete identification of reported hospitalized HUS case patients, we considered a report to local health authorities of either HUS or E. coli O157:H7 infection as a public health notification. To verify the linkage, we manually compared match results against other identifying information such as Social Security number (available for 60.9 percent of discharge records), race, ethnicity, facility name, and admission and discharge dates (each available for over 95 percent of discharge records).

We calculated HUS case rates by using HUS cases identified in the Patient Discharge Data Set and E. coli O157:H7 infection notification rates by using E. coli O157:H7 infections identified in the Confidential Morbidity Reports database. We used 1994–1999 population projections published by the California Department of Finance (31Go) for our denominator data.

Data definitions
We defined as an incident case the first HUS hospital admission for each child. Discharge records with the same date of birth, sex, and county of residence were attributed to one child; results were verified as described in the Data Sources section of this paper. We assumed that nearly all children diagnosed with HUS would be hospitalized and that incident HUS hospitalization admission rates were equivalent to population incidence rates. We defined each child's geographic region of residence as either southern California (the counties of Imperial, Kern, Los Angeles, Orange, Riverside, San Bernardino, San Diego, San Luis Obispo, Santa Barbara, and Ventura) or northern California (all remaining counties). When we calculated HUS incidence rates, we assigned children whose county of residence was unknown (3.3 percent) to the geographic region in which they were first hospitalized. When we calculated the proportion of HUS cases reported to local public health authorities, we excluded children whose county of residence was unknown. We defined a child requiring dialysis as one for whom hemodialysis, peritoneal dialysis, or venous catheterization for renal dialysis (International Classification of Diseases, Ninth Revision, Clinical Modification, codes 39.95, 54.98, and 38.95, respectively) was listed among any of 20 procedure codes during any HUS hospitalization.

Data analyses
We calculated annual and average age- and region-specific incidence rates per 100,000 children <=17 years of age. In addition, we calculated average race/ethnicity-, sex-, and month-of-admission-specific incidence rates per 100,000 children <=5 years of age, stratified by geographic region of California. To assess temporal trends, we calculated smoothed annual HUS incidence rates per 100,000 children <=5 years of age by using the median polish procedure (32Go). This distribution-free smoothing method separated the data into an additive component (which describes the underlying pattern of rates over time) and a residual component (which describes nonsystematic fluctuations in the pattern); the smoothed rates express the additive data. We also tested the overall trend of HUS rates over time, controlling for age and geographic region, by Poisson regression.

We calculated the distribution of disease severity and vital status for HUS case patients <=17 years of age. We directly assessed compliance with mandatory HUS reporting by calculating the proportion of HUS cases in the Patient Discharge Data Set reported to public health authorities. E. coli O157:H7 infection is also a mandatorily reportable condition. Unlike HUS, which is a severe, distinct disease that is more likely to be recognized (5Go, 26Go), E. coli O157:H7 infections are more apt to go undetected (3Go, 6Go, 21GoGoGo–24Go). If detected, infections may also go unreported. Therefore, we indirectly assessed detection and reporting of E. coli O157:H7 infections in children <=5 years of age by comparing the number of such infections reported to public health authorities with the number of expected E. coli O157:H7 infections (based on HUS case patient data extracted from the Patient Discharge Data Set). The number of expected E. coli O157:H7 infections was derived as follows. We assumed that approximately 85 percent of HUS in children could be attributed to an antecedent STEC infection (6GoGoGoGoGo–11Go) and that at least 80 percent of STEC infections in the United States were of the O157:H7 serotype (12Go). We therefore assumed that at least 68 percent (85 percent of 80 percent) of all HUS in California children could be attributed to E. coli O157:H7. Furthermore, we assumed that roughly 12 percent of children <=5 years of age with symptomatic, culture-confirmed E. coli O157:H7 infection would progress to HUS (6Go, 13Go). We calculated the expected number of such infections by dividing the number of children with HUS attributed to E. coli O157:H7 by 12 percent.

We assumed that HUS incidence rates followed a Poisson probability distribution. Poisson rate ratios, 95 percent confidence intervals, and exact p values were calculated by using StatXact 4.0 software for Windows (Cytel Software Corporation, Cambridge, Massachusetts), smoothed rates were calculated by using Microsoft Excel 97 software (Microsoft Software Corporation, Redmond, Washington), and Poisson regression was conducted by using SAS version 8.0 software (The SAS System; SAS Institute, Inc., Cary, North Carolina).

RESULTS
HUS incidence rates, epidemiologic profile, and temporal trends
From 1994 through 1999, we identified 585 HUS hospital admissions of California children <=17 years of age; 369 were incident cases. The average annual statewide HUS incidence rate over the study period was 0.67 per 100,000 children <=17 years of age (95 percent confidence interval: 0.61, 0.74). The crude annual HUS incidence rate increased from 1994 to 1997 (0.59 to 0.80 per 100,000, a relative increase of 35.6 percent); rates then decreased through 1999 (0.59 per 100,000, a relative decrease of 26.3 percent) (figure 1).



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FIGURE 1. Annual hemolytic uremic syndrome (HUS) case counts, incidence rates, and 95% confidence intervals among California children <=17 years of age, 1994–1999.

 
Among children with incident HUS, 56.6 percent (209) were <=3 years of age and 70.7 percent (261) were <=5 years of age. The average HUS incidence rate among children <=5 years of age was four times higher than that of children 6–17 years of age (1.28 vs. 0.31 per 100,000, p < 0.001). Children <=5 years of age who resided in northern California were two times more likely to be hospitalized with HUS than similarly aged children in southern California (1.85 vs. 0.97 per 100,000, p < 0.001) (figure 2). Northern California children <=5 years of age were also 4.6 times more likely to have a reported E. coli O157:H7 infection than children in southern California (3.79 vs. 0.82 per 100,000, p < 0.001) during the period 1996–1999. Among children in northern California, girls were almost 1.5 times more likely than boys to develop HUS (2.22 vs. 1.49, p = 0.02), whereas there was no sex-related difference among southern California children (0.93 vs. 1.00, p = 0.65) (table 1). Northern California girls, White non-Hispanic children, and Hispanic children <=5 years of age in northern California were more likely than their counterparts in southern California to develop HUS (table 1).



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FIGURE 2. Average annual hemolytic uremic syndrome incidence rates among children <=17 years of age, by geographic region of California, 1994–1999.

 

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TABLE 1. Sex- and race/ethnicity-specific incidence rates of hemolytic uremic syndrome among California children <=5 years of age, 1994–1999

 
Northern California children <=5 years of age were 2.2 times more likely to have HUS from July through October than from November through June (average monthly rate, 0.24 vs. 0.11 per 100,000, p < 0.001). Southern California children <=5 years of age were only 1.4 times more likely to have HUS from July through October (average monthly rate, 0.10 vs. 0.07 per 100,000, p = 0.007).

After adjustment for age and region of California, the adjusted annual HUS incidence rate for children <=5 years of age increased from 1994 to 1997 (0.99 vs. 1.48 per 100,000, a relative increase of 49 percent) and then decreased through 1999 (1.11 per 100,000, a relative decrease of 25 percent). The overall trend was significant (p = 0.02). Smoothed annual HUS incidence rate trends were consistent by age (figure 3).



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FIGURE 3. Smoothed hemolytic uremic syndrome incidence rates among California children <=5 years of age, 1994–1999.

 
Severity of illness and hospital-based charges
Of the 369 incident HUS cases identified, documented evidence of dialysis during at least one hospitalization was available for 32.2 percent of the patients (n = 119), and 2.7 percent (n =10) died while in the hospital. The median number of hospitalized days (summed over all hospitalizations) was 11 (range, 0–325 days) per incident case patient.

Data on charges were available for 88.8 percent (n = 520) of admissions and totaled $30.9 million. When we adjusted for missing data, HUS hospitalizations during 1994–1999 resulted in $34.8 million in charges (excluding physician fees). Data on charges were available for at least one hospitalization incurred by 91.9 percent (n = 339) of incident case patients. The median charge for care (summed over all hospitalizations) was $39,508 (range, $1,597–$1,102,334) per child.

Reports of incident HUS cases and E. coli O157:H7 infections to public health authorities
Of 248 incident HUS cases identified between 1996 (when the reporting requirement began) and 1999, only 43.9 percent (109) were officially reported to public health authorities (figure 4). The proportion of reported cases was higher in northern California than southern California (55.7 percent vs. 32.3 percent, p < 0.001). The proportion of notifications received annually during the study period increased significantly in northern California (26.5 percent in 1996, 64.1 percent in 1997, 72.0 percent in 1998, and 65.4 percent in 1999; p < 0.001) but not in southern California (34.5 percent in 1996, 27.3 percent in 1997, 24.2 percent in 1998, and 44.8 percent in 1999; p = 0.32).



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FIGURE 4. Proportion of incident hemolytic uremic syndrome (HUS) case patients <=17 years of age reported to public health authorities, by geographic region of California, 1996–1999.

 
We identified 183 children <=5 years of age with HUS between 1996 and 1999, and we estimated that at least 124 of these HUS cases (68 percent of 183) could be attributed to E. coli O157:H7 infection. We expected that these 124 children originated from a cohort of 1,033 children with symptomatic, culture-confirmed E. coli O157:H7 infections (124 equals 12 percent of 1,033). Only 253 E. coli O157:H7 infections (24.5 percent of these expected infections) among children <=5 years of age were detected and then reported through mandatory passive surveillance.

DISCUSSION
We have described the epidemiology of HUS in a diverse population-based cohort representing nearly 54 million children-years of observation. Our 6-year study establishes that HUS is endemic in California and significantly impacts child health. Nearly $35 million in nonphysician hospital-based charges were incurred, at least 32 percent of children required acute dialysis, and at least 3 percent of patients died. An undetermined number of children will develop long-term complications (e.g., hypertension) that may not become apparent until adulthood (1Go).

The epidemiologic profile of our patient cohort was comparable to that described in previous North American and European studies (3Go, 6Go, 10Go, 25Go, 28Go, 33GoGoGoGo–37Go). HUS incidence rates in California (0.67 per 100,000 children <=17 years of age and 0.74 per 100,000 children <=14 years of age) were similar to rates in Oregon (0.72 per 100,000 children <=17 years of age; L. V. Duke, Oregon Department of Human Services, unpublished data) and were lower than rates in Washington State (33Go) (1.74 per 100,000 children <=14 years of age) and Canada (35Go) (1.44 per 100,000 children <=14 years of age). The higher HUS rate among younger children in our study and other studies (3Go, 10Go, 28Go, 34GoGoGo–37Go) may reflect increased host susceptibility (3Go), although other exposure-related differences may also play a role (38Go). In our study and other studies (3Go, 10Go, 28Go, 34GoGoGo–37Go), the higher rate of HUS during summer and fall likely reflects the seasonality of E. coli O157:H7 infections (3Go, 4Go, 22Go). Unexplained are the higher rates of HUS among girls, White non-Hispanic children, and Hispanic children in northern California. Some studies have reported a higher proportion of girls (6Go, 25Go, 28Go, 34Go, 36Go) and White children (34Go, 36Go) among HUS cases, while other studies have reported no elevated risk for girls (10Go) or White children (28Go, 37Go).

We observed a significant regional variation in HUS rates in California. We also found that HUS rates seemed to decrease from north to south, as demonstrated by the rates in Washington State (1.74 per 100,000 children <=14 years of age), northern California (1.04 per 100,000 children <=14 years of age), and southern California (0.56 per 100,000 children <=14 years of age). The reasons for this apparent gradient are unclear. Other investigators have noted a striking geographic variability in rates of HUS (3Go, 35Go) and E. coli O157:H7 infections (22Go, 39Go); a recent US study found that the proportion of fecal specimens with E. coli O157:H7 isolates was significantly higher in northern states than in southern ones (22Go). Sporadic E. coli O157:H7 infections have been linked to various exposures (18Go, 39Go, 40Go), including direct farm contact and consumption of locally processed beef (39Go). Northern California children are 3.5 times more likely than those in southern California to reside in a rural area (13.8 percent vs. 3.9 percent). Further study is required to determine whether rural residence provides more opportunity for STEC exposures in northern California.

Population-based HUS trends may provide practical information to help assess the success of heightened STEC exposure control strategies introduced since 1996 (5Go, 19Go). HUS incidence rates decreased only modestly from 1997 through 1999 in California children. E. coli O157:H7 infection rates reported from sentinel sites in the United States were also relatively stable from 1996 through 2000 (2.7 vs. 2.9 per 100,000) (41Go). We did not have data to evaluate the many factors that can influence the risk of developing HUS after E. coli O157:H7 infection (3Go, 42Go), including the use of certain antibiotics (13Go, 42Go, 43Go). Therefore, our HUS rate trends may reflect cyclical fluctuations in exposure and disease, or they may reflect modest decreases in the risk of STEC infections, the risk of progression to HUS after STEC infection, or some combination of these factors. Continued monitoring of HUS rate trends is needed.

We detected a large reservoir of HUS cases that were not reported to public health authorities, and we suspect (based on our estimate of expected E. coli O157:H7 infections) that many E. coli O157:H7 infections were also unreported. Although some proportion of unreported HUS cases could have been attributable to non-STEC etiologies (2Go, 3Go), most were likely related to STEC infections, including E. coli O157:H7 (2GoGoGoGoGoGoGoGoGoGo–12Go). The low number of E. coli O157:H7 infections reported to public health authorities suggests that many such infections were either undetected or unreported or that other non-O157 STEC infections (which are not routinely sought by laboratories and not reported to public health authorities) may have occurred, or both. The apparently more complete HUS reporting in northern California could be related to enhanced federally funded surveillance efforts in that part of the state.

Underreporting of HUS cases, to the degree observed in our study and another (44Go), can delay time-critical public health action and distort disease burden and risk estimates. Clustering of HUS cases can be an indicator of unrecognized STEC O157 outbreaks (especially if cases are geographically dispersed) and the only indicator of non-O157 STEC outbreaks (15Go, 16Go). Early detection of STEC infections is important for the medical management of patients, and timely reporting is a cornerstone of outbreak detection and prevention efforts. Both the Centers for Disease Control and Prevention and the Infectious Diseases Society of America recommend that any illness characterized by acute bloody diarrhea should prompt laboratory evaluation for E. coli O157:H7 infection (22Go, 45Go). Early collection of cultures is particularly important (24Go). If early cultures or if sera do not yield evidence of O157, non-O157 STECs should be considered, especially if case clustering is suspected.

We found the California Patient Discharge Data Set to be a useful complement to HUS surveillance and, by proxy, STEC infection surveillance in California. Periodic review of local hospital discharge databases may be a helpful way to identify unreported HUS cases. Because HUS is a severe, distinct disease, case ascertainment may be fairly complete (5Go), and HUS may be well suited for this type of surveillance.

There are limitations to our study. First, we did not review medical charts to confirm each HUS diagnosis. If we had included children who did not have HUS, we would have overestimated HUS incidence rates. However, other investigators suggest that this bias would not be large (44Go), and our rate estimates were very comparable to those in previously published studies. Second, by defining individual children in the Patient Discharge Data Set as those with the same date of birth, sex, and county of residence, we may have excluded some children with HUS (e.g., twins or children who, by coincidence, had these three characteristics in common). Although excluding children with HUS would have caused us to underestimate HUS rates, we expect that this bias would have been small. Third, we used population projections rather than population estimates; projections adjusted by using 2000 US Census data were not available for this investigation. If these projections overestimated the California population toward the end of the decade, our rates (especially during 1997–1999) may have been underestimated. Finally, our estimates of charges should be interpreted cautiously, because charges can be higher than the actual cost of care; however, hospital-based physicians' fees were not included in listed charges.

In summary, we used a population-based data source, hospital discharges, to calculate HUS incidence rates in California children. Despite national efforts to heighten food safety, HUS incidence rates in California children declined only modestly from 1997 to 1999. Substantial underreporting of HUS and of E. coli O157:H7 infections to public health authorities can delay time-critical public health action. The association between HUS and non-O157 STEC infections in California remains unclear; further study is needed. California health care providers and laboratory staff play a key role in disease control efforts by coupling a high index of suspicion for STEC infections and HUS (including appropriate specimen collection and laboratory testing) with diligent public health notification practices. Use of hospital discharge summaries and enhanced active surveillance are important strategies to ensure complete ascertainment of cases.


    NOTES
 
Correspondence to Kate Cummings, California Department of Health Services, Disease Investigations and Surveillance Branch, Division of Communicable Disease Control, 2151 Berkeley Way, Room 708, Berkeley, CA 94704 (e-mail: kcumming{at}dhs.ca.gov).


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Received for publication July 2, 2001. Accepted for publication February 1, 2002.





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