Pediatric Infectious Disease Journal:
Epidemiology of Streptococcus pneumoniae-Induced Hemolytic Uremic Syndrome in Utah Children
Bender, Jeffrey M. MD*; Ampofo, Krow MD*; Byington, Carrie L. MD*; Grinsell, Matthew MD, PhD†; Korgenski, Kent MT‡; Daly, Judy A. PhD‡; Mason, Edward O. PhD§; Pavia, Andrew T. MD*
From the *Department of Pediatrics, Pediatric Infectious Diseases and †Pediatric Nephrology, University of Utah, Salt Lake City; ‡Primary Children's Medical Center, Salt Lake City, UT; and §Baylor College of Medicine, Houston, TX.
Accepted for publication February 4, 2010.
Supported by NIH Rocky Mountain Regional Center for Excellence in Biodefense and Emerging Diseases young investigator award U54 AI065357 (to J.M.B.); Public Health Services research grant UL1-RR025764 from the National Center for Research Resources as well as, NIH/NIAID 1 U01 AI074419 and U01-A1061611, CDC 1 PO1 CD000284, and the NIH/Eunice Kennedy Shriver NICHD K24-HD047249 (to C.L.B.); and Children's Health Research Center at the University of Utah.
Potential conflicts of interest: C.L.B. and E.O.M. received support from Wyeth in 2007 for molecular typing of empyema isolates. All other authors: None.
Address for correspondence: Jeffrey M. Bender, MD, Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Utah School of Medicine, PO Box 581289, Salt Lake City, Utah 84158. E-mail: Jeffrey.Bender@hsc.utah.edu.
Background: Hemolytic uremic syndrome (HUS) is an uncommon complication of invasive pneumococcal disease (IPD) in children. Few studies examine the Streptococcus pneumoniae serotypes associated with HUS. Our objective was to describe the epidemiology of S. pneumoniae-related HUS (SP-HUS) and the serotypes associated with HUS in Utah children.
Methods: We reviewed separate longitudinal databases of HUS and IPD. These included all children <18 years cared for at Primary Children's Medical Center, Salt Lake City, UT, with IPD from 1997 to 2008 and all children in Utah with HUS since 1971.
Results: We identified 435 Utah children with culture-confirmed IPD (1997–2008) and 460 with HUS (1971–2008). There were no reported cases of SP-HUS before 1997. With the introduction of pneumococcal conjugate vaccine (PCV-7) in 2000, the percentage of IPD complicated by SP-HUS has increased from 0.3% to 5.6% (P < 0.001). Pneumonia (P = 0.051) and empyema (P = 0.012) were associated with the development of SP-HUS compared with IPD without SP-HUS. Children with SP-HUS also required ICU care and had longer stays than those with IPD alone. Only serotype 3 appeared associated with SP-HUS (P = 0.067).
Conclusions: 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.
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.
1. Boyce TG, Swerdlow DL, Griffin PM. Escherichia coli
O157:H7 and the hemolytic-uremic syndrome. N Engl J Med
2. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli
and haemolytic uraemic syndrome. Lancet
3. Klein PJ, Bulla M, Newman RA, et al. Thomsen-Friedenreich antigen in haemolytic-uraemic syndrome. Lancet
4. Moorthy B, Makker SP. Hemolytic-uremic syndrome associated with pneumococcal sepsis. J Pediatr
5. Cabrera GR, Fortenberry JD, Warshaw BL, Chambliss CR, Butler JC, Cooperstone BG. Hemolytic uremic syndrome associated with invasive Streptococcus pneumoniae
6. Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis
7. Copelovitch L, Kaplan BS. Streptococcus pneumoniae
-associated hemolytic uremic syndrome. Pediatr Nephrol
8. Erickson LC, Smith WS, Biswas AK, Camarca MA, Waecker NJ Jr. Streptococcus pneumoniae
-induced hemolytic uremic syndrome: a case for early diagnosis. Pediatr Nephrol
9. Geary DF. Hemolytic uremic syndrome and Streptococcus pneumoniae
: improving our understanding. J Pediatr
10. Gilbert RD, Argent AC. Streptococcus pneumoniae
-associated hemolytic uremic syndrome. Pediatr Infect Dis J
11. Proulx F, Liet JM, David M, et al. Hemolytic uremic syndrome associated with invasive Streptococcus pneumoniae
12. Waters AM, Kerecuk L, Luk D, et al. Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United kingdom experience. J Pediatr
13. Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol
14. Huang YH, Lin TY, Wong KS, et al. Hemolytic uremic syndrome associated with pneumococcal pneumonia in Taiwan. Eur J Pediatr
15. Lee CF, Liu SC, Lue KH, Chen JP, Sheu JN. Pneumococcal pneumonia with empyema and hemolytic uremic syndrome in children: report of three cases. J Microbiol Immunol Infect
16. Nathanson S, Deschenes G. Prognosis of Streptococcus pneumoniae
-induced hemolytic uremic syndrome. Pediatr Nephrol
17. Centers for Disease Control and Prevention (CDC). Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction–eight states, 1998–2005. MMWR Morb Mortal Wkly Rep
18. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med
19. Byington CL, Korgenski K, Daly J, Ampofo K, Pavia A, Mason EO. Impact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema. Pediatr Infect Dis J
20. Lexau CA, Lynfield R, Danila R, et al. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA
21. Messina AF, Katz-Gaynor K, Barton T, et al. Impact of the pneumococcal conjugate vaccine on serotype distribution and antimicrobial resistance of invasive Streptococcus pneumoniae
isolates in Dallas, TX, children from 1999 through 2005. Pediatr Infect Dis J
22. Bender JM, Ampofo K, Korgenski K, et al. Pneumococcal necrotizing pneumonia in Utah: does serotype matter? Clin Infect Dis
23. Bender JM, Ampofo K, Sheng X, Pavia AT, Cannon-Albright L, Byington CL. Parapneumonic empyema deaths during past century, Utah. Emerg Infect Dis
24. Byington CL, Samore MH, Stoddard GJ, et al. Temporal trends of invasive disease due to Streptococcus pneumoniae
among children in the intermountain west: emergence of nonvaccine serogroups. Clin Infect Dis
25. Eastham KM, Freeman R, Kearns AM, et al. Clinical features, aetiology and outcome of empyema in children in the north east of England. Thorax
26. Rees JH SD, Parikh D, Weller P. Increase in incidence of childhood empyema in West Midlands, UK. Lancet
27. Siegler RL. The hemolytic uremic syndrome. Pediatr Clin North Am
28. Siegler RL, Pavia AT, Christofferson RD, Milligan MK. A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics
29. Siegler RL, Pavia AT, Hansen FL, Christofferson RD, Cook JB. Atypical hemolytic-uremic syndrome: a comparison with postdiarrheal disease. J Pediatr
30. Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. MMWR Recomm Rep
32. Li S. Empyema hospitalizations increasing in the U.S. despite decreasing invasive pneumococcal disease post-introduction of the pneumococcal conjugate vaccine. In: Pediatric Academic Society Meeting
; Honolulu; May 2–6, 2008; HI. 4055.4.
33. Pelton SI, Huot H, Finkelstein JA, et al. Emergence of 19A as virulent and multidrug resistant Pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine. Pediatr Infect Dis J
34. Singleton RJ, Hennessy TW, Bulkow LR, et al. Invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA
35. Lin CJ, Chen PY, Huang FL, Lee T, Chi CS, Lin CY. Radiographic, clinical, and prognostic features of complicated and uncomplicated community-acquired lobar pneumonia in children. J Microbiol Immunol Infect
36. Hendrickson DJ, Blumberg DA, Joad JP, Jhawar S, McDonald RJ. Five-fold increase in pediatric parapneumonic empyema since introduction of pneumococcal conjugate vaccine. Pediatr Infect Dis J
37. Cochran JB, Panzarino VM, Maes LY, Tecklenburg FW. Pneumococcus-induced T-antigen activation in hemolytic uremic syndrome and anemia. Pediatr Nephrol
38. Huang DT, Chi H, Lee HC, Chiu NC, Huang FY. T-antigen activation for prediction of pneumococcus-induced hemolytic uremic syndrome and hemolytic anemia. Pediatr Infect Dis J
39. Lynn RM, O'Brien SJ, Taylor CM, et al. Childhood hemolytic uremic syndrome, United Kingdom and Ireland. Emerg Infect Dis
40. Vanderkooi OG, Kellner JD, Wade AW, et al. Invasive Streptococcus pneumoniae
infection causing hemolytic uremic syndrome in children: two recent cases. Can J Infect Dis
41. Brandt J, Wong C, Mihm S, et al. Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics
42. Novak RW, Martin CR, Orsini EN. Hemolytic-uremic syndrome and T-cryptantigen exposure by neuraminidase-producing pneumococci: an emerging problem? Pediatr Pathol
43. Garg AX, Suri RS, Barrowman N, et al. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA
44. Spizzirri FD, Rahman RC, Bibiloni N, Ruscasso JD, Amoreo OR. Childhood hemolytic uremic syndrome in Argentina: long-term follow-up and prognostic features. Pediatr Nephrol
serotype; invasive pneumococcal disease; T-antigen; pneumococcal vaccine; serotype 3
© 2010 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read