Hemolytic uremic syndrome (HUS) is a common cause of acute kidney injury in children. The majority of cases are associated with diarrheal illness caused by either Shiga toxin-producing Escherichia coli (STEC) or Shigella dysenteriae type I.1,2 Since the initial description of HUS in the late 1970s,3,4 Streptococcus pneumoniae has been recognized as a common cause of nonenteropathic HUS in children.5–12 Case series suggest that S. pneumoniae associated HUS (SP-HUS) develops most commonly in individuals with loculated infected fluid collections such as subdural and parapneumonic empyemas.7,13–16 Data on whether specific pneumococcal serotypes are associated with HUS are limited.
The epidemiology of invasive disease caused by S. pneumoniae has changed considerably in the last decade.17,18 The introduction of heptavalent pneumococcal conjugate vaccine (PCV-7) led to marked reductions in invasive pneumococcal disease (IPD) because of vaccine serotypes and the emergence of nonvaccine serotypes.17–21 The incidence of parapneumonic empyema has increased in many parts of the world, including Utah.17,19,22–26 We hypothesized that the changing patterns of S. pneumonia serotypes and disease may have influenced the epidemiology of SP-HUS in the years after licensure of PCV-7. We used 2 longitudinal databases from a single institution; one documenting 38 years of pediatric HUS, and another examining serotypes causing IPD over 12 years to examine the epidemiology of SP-HUS. Our objective was to describe the epidemiology and long-term outcomes of patients with SP-HUS and to identify S. pneumoniae serotypes specifically associated with SP-HUS.
MATERIALS AND METHODS
Human Subjects Protection
The institutional review boards for both the University of Utah and Intermountain Healthcare reviewed and approved this study. Informed consent was waived.
Study Design and Setting
We searched 2 longitudinal databases for children with SP-HUS, described in detail below. Pneumococcal isolates available for serotyping were from children with IPD cared for at Primary Children's Medical Center (PCMC) in Salt Lake City, Utah. PCMC is a 252-bed children's hospital that serves as both the community hospital for Salt Lake County, Utah, and as a tertiary referral center for 5 states in the Intermountain West (Utah, Idaho, Wyoming, Nevada, and Montana).
Identification of Children With HUS
A prospective registry of children with HUS younger than 18 years of age and cared for in Utah hospitals has been maintained since 1970.27–29 The registry includes all children referred to PCMC from throughout the 5 state intermountain region as well as Utah children diagnosed at other hospitals. Relevant demographic, clinical, and laboratory data including all culture results were collected. For this study we restricted our search to children, <18 years old, who were Utah residents. HUS was defined based on the Center for Disease Control and Prevention case definition criteria as: anemia (acute onset) with microangiopathic changes (ie, schistocytes, burr cells, or helmet cells) on peripheral blood smear; and renal injury (acute onset) evidenced by either hematuria, proteinuria, or elevated creatinine level (ie, ≥1.0 mg/dL in a child aged <13 years or ≥1.5 mg/dL in a person aged ≥13 years, or ≥50% increase over baseline).30
Identification of Children With Invasive Pneumococcal Disease
Since 1996, all isolates of S. pneumoniae recovered from normally sterile sites from children cared for at PCMC have been archived and serotyped,19,22,24 and a computerized database of all children hospitalized at PCMC with S. pneumoniae isolated from sterile sites is maintained. The database includes clinical, laboratory, and demographic information extracted from the Intermountain Healthcare electronic medical record. All S. pneumoniae isolates were typed by means of the capsular swelling method with the use of commercially available type specific antiserum samples. The investigator performing the analyses (EOM) was blinded to the source of (ie, blood, pleural fluid) and clinical information associated with the bacterial isolates.
Identification of Children With SP-HUS
We searched the 2 computerized databases for patients identified as having SP-HUS and joined these. A patient met our case definition of SP-HUS if they both met the clinical definition of HUS and had S. pneumoniae isolated from a sterile site. Demographic and clinical data were abstracted. Two investigators (J.M.B. and K.A.) reviewed the charts of all of the identified cases and confirmed abstracted data. We gathered follow-up data from pediatric nephrology records where HUS patients are routinely followed every 2–6 months postdischarge until return of normal renal function. To determine a crude estimate of incidence of SP-HUS in Utah, we divided the average number of cases seen per year (1997–2008) by the 2000 Utah census population of children <18 years old.31
Comparison of IPD With SP-HUS
To examine the outcomes and importance of serotype on SP-HUS we compared patients with SP-HUS with those patients with IPD without evidence of HUS. We analyzed the data using Fisher exact test for categorical outcomes and Mann-Whitney/Wilcoxon 2-sample test for continuous outcomes. For each demographic and outcome variable P values were calculated. Stata statistical software version 10.0 (StataCorp, College Station, TX), was used for the statistical analysis.
Children With HUS
We identified 460 cases of HUS among Utah children from 1971 to 2008. The majority (85%) of the children had HUS associated with diarrheal illnesses. Thirty-four children (7.4%) had unspecified type HUS, including 7 (1.5%) identified as SP-HUS. No additional cases of SP-HUS not identified by the IPD database were identified from the HUS registry.
Children With IPD
From 1997 through 2008, we identified 435 children with culture-confirmed IPD. Of these children, 124 (29%) were bacteremic only, 91 (21%) had uncomplicated pneumonia, 106 (24%) developed parapneumonic empyema, and 67 (15%) developed meningitis. HUS was a complication in 7 (1.6%) of the IPD cases.
No children were identified with SP-HUS from 1971 to 1996.29 Seven children had culture confirmed SP-HUS from 1997 to 2008. The incidence of SP-HUS was 0.015/100,000 child years averaged over those 12 years. In comparison, the total HUS incidence in Utah was 1.4 cases/100,000 child years over the same period.28 Before 2000 and the introduction of the PCV-7, 1 (0.3%) of the 352 children with HUS had SP-HUS. After 2000, 6 of the 108 HUS patients were identified with associated S. pneumoniae infection accounting for 5.6% of all HUS cases (P < 0.001, odds ratio, 19.6, 95% confidence interval, 2–902).
SP-HUS Demographics and Clinical Features
The ages of children with culture confirmed SP-HUS ranged from 9 months to 7 years old; the median age was 16 months. Further demographic and clinical features are shown in Table 1. Although there were no deaths, 43% required dialysis and 33% had evidence of long-term renal sequelae.
Comparison of IPD With SP-HUS
Children with SP-HUS were more likely to have pneumonia and parapneumonic empyema, to require admission to the intensive care unit and to require ventilatory support than other children with IPD (Table 2). Hospital length of stay was significantly longer for children with SP-HUS (median 21 vs. 8 days; P = 0.007). Of the 5 different serotypes identified from patients with HUS, only serotype 3 appeared associated with SP-HUS (P = 0.067).
Postinfectious HUS remains a serious cause of renal failure in children. The overwhelming majority of HUS follows enteric infection, but S. pneumonia is an important cause of nonenteric HUS. Our study suggests that the frequency of SP-HUS is increasing. Further we demonstrated that SP-HUS was related to pneumonia and empyema. Serotype 3, a frequent cause of complicated pneumonia since the introduction of PCV-7 in 2000, was associated with SP-HUS.
The epidemiology of invasive disease because of S. pneumoniae has undergone complex changes since the introduction of PCV-7 in 2000. Significant declines in pediatric IPD have been reported in the United Sates and in all regions where the vaccine was introduced.17–21 Invasive disease because of nonvaccine serotypes has increased, but there are marked differences in regional epidemiology.18,19,24,25 Specifically, in many regions of the world, the incidence of pneumococcal parapneumonic empyema increased over the last decade.17,19,21,23–26,32–36 Similarly, the incidence of SP-HUS is increasing in Utah and in other parts of the United States, Canada, and the United Kingdom.5,12,37,38 Although SP-HUS in the past 9 years represents only 5.6% of the total HUS cases seen in Utah children, SP-HUS accounts for a significantly greater proportion of HUS than in the previous 3 decades. A recent population-based study in England and Ireland yielded remarkably similar rates of SP-HUS to those seen in Utah.39 The authors identified 413 cases of HUS between 1997 and 2001 with 8 of 413 (2%) having documented SP-HUS, an estimated incidence of 0.014/100,000 child years. During a similar time period, we documented an estimated incidence of SP-HUS of 0.015/100,000 child years in Utah.
It is possible that the increase in empyema has led to an increase in HUS associated with S. pneumoniae. Several authors have observed that SP-HUS is commonly associated with loculated fluid collections such as subdural and parapneumonic empyemas.7,13–15,40,41 In our study, 5 of 7 (71%) of children with SP-HUS had empyema and children with SP-HUS were significantly more likely to have empyema when compared with children with IPD. In a series of 12 patients seen from 1990 to 1999 at 4 pediatric referral centers, Brandt et al noted empyema in 75% of children with SP-HUS.41 In the largest series to date, which identified 43 children with SP-HUS in the UK between 1998 and 2005, 23 (53%) had empyema.12 Our data combined with these support the concept that pneumococcal empyema increases the risk of HUS.
The mechanism hypothesized for SP-HUS is that pneumococcal neuraminidase exposes the Thomsen-Freidenreich antigen (T-antigen) on red blood cells and glomerular endothelial cells,3,42 although, there are conflicting data on the association of the level of neuraminidase expression by S. pneumoniae associated with SP-HUS.37,38 It is possible that parapneumonic and subdural empyemas increase the risk of SP-HUS by increased systemic absorption of extracellular products of S. pneumoniae.
Relatively little is known about the serotypes associated with SP-HUS. Before the introduction of the PCV-7 vaccine, a review of SP-HUS in Atlanta reported serotype data for 5 cases. All were PCV-7 vaccine serotypes: 2 serotype 14, two 23F, and one 6B.5 In a 2007 report of SP-HUS from the United Kingdom, the predominant S. pneumoniae serotype identified was 19A.12
In our study, we found that 6 of 7 isolates were nonvaccine serotypes (1, 3, 7F, 22F). These serotypes are increasingly common in our region19,24 and are associated with complicated pneumonias (1, 3, and 7F) and meningitis (22F).22 We observed a correlation with serotype 3 and SP-HUS. Previously, we demonstrated that serotype 3 is more frequently associated with severe necrotic pneumonia and empyema in Utah.22 Thus, the virulence characteristics of this serotype might be associated with an increased risk of HUS. The pneumococcal conjugate vaccine-13 (PCV-13), currently being considered for approval by the Food and Drug Administration, contains antigen for serotypes 1, 3, and 7F. Once licensed, use of the PCV-13 may decrease the rates of empyema and SP-HUS in Utah and other regions with similar epidemiology.
It remains difficult to predict long-term outcomes in children with HUS. A meta-analysis examining diarrhea-associated HUS estimated that approximately 25% (range, 0%–65%) of patients will develop long term renal sequelae with 12% (range, 0%–30%) developing end-stage renal disease or progressing to death.43 Although prior studies suggested worse prognosis in patients with nonenteropathic HUS, 2 of the largest HUS databases showed no difference in outcomes between diarrheal and nondiarrheal-associated HUS.29,44 Few studies have specifically looked at the long-term sequelae in SP-HUS.16 One small case series reported 9 of 11 (82%) required dialysis, 3 of 11 (27%) developed ESRD, 2 of 11 (18%) had chronic renal insufficiency, and 4 of 11 (36%) died.16
This study has some limitations. It is a retrospective review of 2 longitudinal databases and computerized records. It is possible that ascertainment changed with time; however, HUS has been systemically studied at our institution for more than 35 years. Thrombocytopenia (<150,000/mm3) though present in most of cases, was not included in the definition of HUS in our study as the CDC case definition states that this finding maybe missed. It is possible that detection of pneumococcal infection increased as the prevalence of parapneumonic empyema increased beginning in the late 1990s. However, cultures of blood and pleural fluid were routinely obtained on critically ill patients throughout the period. As the association with S. pneumoniae was originally described in the 1970s, evidence of pneumococcal infection was likely to be documented from the beginning of the HUS database in 1971. We did not include cases of presumed pneumococcal infection detected by molecular or serologic diagnosis. Although our case definition of SP-HUS is based on the published literature, there is overlap between the findings of HUS and those of S. pneumoniae bacteremia with septic shock and disseminated intravascular coagulation. Renal biopsy was not performed to confirm thrombotic microangiopathy, which may provide a definitive diagnosis of HUS. We do not have long-term follow-up data on all patients, so our ability to predict long-term outcomes such as ESRD or transplant is limited.
We identified an increasing incidence of SP-HUS in Utah children. SP-HUS is a serious complication of IPD associated most frequently with pneumonia and empyema because of serotypes not included in the PCV-7, particularly serotype 3. SP-HUS requires increased levels of acute care when compared with other forms of IPD and is associated with chronic renal morbidity.
The authors are indebted to Dr. Richard Siegler for establishing the HUS registry in 1971 and Dr. Raoul Nelson for maintaining the database. The authors acknowledge the PCMC microbiology laboratory staff for their continued efforts in the identification and study of S. pneumoniae. Special thanks also to Linda Lamberth and the rest of the S. pneumoniae serotyping laboratory at Baylor College of Medicine.
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