Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome Canadian Immunization Monitoring Program ACTive National Pediatric Surveillance (1991-2019)

doi:10.21203/rs.3.rs-3097836/v1

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Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome Canadian Immunization Monitoring Program ACTive National Pediatric Surveillance (1991-2019)

https://doi.org/10.21203/rs.3.rs-3097836/v1

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Background: Streptococcus pneumoniae-associated hemolytic uremic syndrome (SP-HUS) is an underreported cause of pediatric non-diarrheal HUS. This study describes the epidemiology of the largest Canadian case series of SP-HUS in comparison with non-HUS invasive pneumococcal disease (IPD).

Methods: The Canadian Immunization Monitoring Program, ACTive (IMPACT) is a national surveillance network for vaccine-preventable diseases. All confirmed IPD cases between 1991-2019 were included in the analysis. IPD cases with new HUS diagnoses were identified as SP-HUS cases, and the rest as non-HUS IPD cases.

Results: There were 30 (0.4%) cases of SP-HUS amongst 6,757 IPD cases. The median age of SP-HUS cases was 27.5 months, with no significant differences between SP-HUS and non-HUS cases in age or sex. S. pneumoniae serotypes 3 (30%) and 19A (26.7%) were more common in SP-HUS compared to non-HUS cases (P<0.0001). Pneumonia was more frequently observed in SP-HUS (67% vs. cases 26%; P<0.0001). All SP-HUS cases were hospitalized, compared with 71% non-HUS IPD cases (P=0.0004). SP-HUS cases had a longer median hospital length of stay (23.5 vs. 7 days; P<0.0001) and a higher proportion required ICU admission (70 vs 15.5%; P<0.0001). Moreover, ICU stays were longer in HUS cases compared with non-HUS cases (9 vs. 3 days; P<0.0001). All 30 SP-HUS patients survived while 3% of non-HUS cases died (P=0.33).

Conclusion: SP-HUS was usually seen in IPD cases with pneumonia and was most commonly caused by serotypes 3 and 19A. Mortality was rare, but ICU care with lengthy hospital stay was common.

invasive pneumococcal disease

atypical hemolytic uremic syndrome

non-diarrheal hemolytic uremic syndrome

Canada

IMPACT

Hemolytic uremic syndrome (HUS) is most commonly caused by Shiga-toxin producing Escherichia coli (STEC) enterocolitis. However, it is estimated that 40% of pediatric non-diarrheal HUS cases are Streptococcus pneumoniae-associated HUS (SP-HUS).¹ SP-HUS is a severe complication of invasive pneumococcal disease (IPD), frequently requiring renal replacement therapy, and could result in kidney failure associated transplant, prolonged dialysis, and death.^{1 2}

Despite its clinical significance, SP-HUS may be under-reported due to its similarities with pneumococcal sepsis³ and its variation in clinical presentations across geographies. There are wide differences in SP-HUS prevalence, and clinical presentation globally.^{4 5} Thus, geographic-specific SP-HUS data are necessary to identify, treat and prevent SP-HUS. Limited Canada-wide SP-HUS epidemiological data exist in the literature⁶, with only one Canada-wide surveillance study of HUS (with four SP-HUS cases) over a 24-month period.⁷ Additionally, to the best of our knowledge, no previous studies provide a detailed epidemiological comparison between SP-HUS and non-HUS IPD from the same surveillance system.

In this retrospective multi-center analysis, we describe the epidemiology of pediatric SP-HUS cases, in comparison to non-HUS IPD cases, using the Canadian Immunization Monitoring Program, ACTive (IMPACT) national pediatric IPD surveillance data from 1991–2019.

IMPACT is an active, national, sentinel surveillance network for vaccine-preventable diseases. The surveillance network involves 12 tertiary care pediatric hospitals and approximately 90% of tertiary care pediatric beds across Canada in the provinces of British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, Prince Edward Island, and Newfoundland. All centers used the same IPD case finding strategies, case definition, and report form. Inclusion in the surveillance required isolation of S. pneumoniae from a sterile site – such as bacterial culture and/or PCR from blood, cerebrospinal fluid, pleural fluid – in children 0 to 16 years of age⁸. Cases were identified at inpatient care, outpatient care, short stay/holding unit, emergency department at an IMPACT centre. Pneumococcal isolates were submitted to the National Centre for Streptococcus (1991–2009) and the National Microbiology Laboratory (2010–2019) for serotyping.

The case definition for SP-HUS was a diagnosis of HUS based on American society of nephrology guidelines⁹ - as a clinical manifestation of IPD. The rest of the IPD cases were identified as non-HUS IPD.

All IMPACT IPD cases from 1991-2019 were analyzed in SAS Version 9.1. Data were collected from each IMPACT network hospital’s medical records by nurse monitors and analyzed for sex, age, clinical presentations, hospital and ICU admission and length of stay, morbidity, mortality, and pneumococcal serotypes.

SP-HUS and non-HUS cases were compared using the Wilcoxon signed rank for numerical data (i.e. age at admission), and categorical data were assessed using chi square or the Fisher exact test. A two-tailed 95% confidence interval for P value <0.05 was used as a threshold for statistical significance. Individual-level data used in this study are unavailable for public access.

Thirty children with SP-HUS were identified amongst all 6,757 IPD cases from 1991-2019, representing 0.4% of IPD cases. SP-HUS annual cases across study period ranged from 0 to 3 with a median of 1. Among SP-HUS cases, 19/30 (63%) were male and median age at admission was 27.5 months (16, 40 months IQR) as presented in Table 1. When compared with non-HUS data, there were no significant differences in sex (P=0.53) or age at admission (P=0.68).

The most common clinical manifestation in SP-HUS cases was pneumonia (20/30, 67%), with 43% (13/30) having complicated pneumonia (empyema / pleural effusion). Pneumonia was significantly more frequent in presentations of IPD leading to SP-HUS (67%) compared to non-HUS (26.4%; P<0.0001) and in presentations with empyema/pleural effusion 46.7% versus 7.6%; (P<0.0001).

Overall, the proportion of SP-HUS cases requiring hospitalization (30/30, 100%) was significantly higher compared with non-HUS IPD patients (4746/6727, 70.5%; P=0.004). SP-HUS cases stayed in hospital for a median of 23.5 days (17, 31 days IQR), significantly longer compared to the non-HUS median of 7 days (3, 12 days IQR; P<0.0001). Similarly, significantly more SP-HUS cases required ICU care (21/30, 70%) compared to non-HUS (1049/6727, 15.6%, P<0.0001). Moreover, SP-HUS cases had significantly longer ICU stay (median 9 days, 6-10 days IQR vs. median 3 days, 2-6 IQR, P<0.0001) compared with non-HUS cases. Despite the increased severity (longer hospital stay and higher level of care) observed in HUS cases, survival was similar between the two groups (100% SP-HUS vs. 97% non-HUS, P=0.33).

Among the cases with a known serotype, serotypes from the 13-valent pneumococcal conjugate vaccine (PCV13) occurred in 88% (22/25) of SP-HUS cases, compared to 70.2% (4,409/6,278) of non-HUS IPD cases. The majority of PCV13 serotype cases occurred prior to the implementation of PCV13 vaccine programs in Canada in 2011 for both HUS and non-HUS cases (63.6% (14/22) SP-HUS and 91.6% 4,042/4,409 non-HUS prior to 2011). Serotypes 3 (9/25, 36%) and 19A (8/25, 32%) were the most frequent serotypes in SP-HUS. On the other hand, the most frequent serotypes in non-HUS IPD were serotypes 14 (1036/6278, 16.5%), 6B (595/6278, 9.5%), 19F (527/6278, 8.4%), and 19A (507/6278, 8.1%). Serotypes 3 and 19A were more prevalent in SP-HUS cases than in non-HUS IPD (P<0.0001).

This is the largest Canada-wide case-series describing the epidemiology of pediatric SP-HUS cases from 1991 to 2019. In comparison to other SP-HUS case series, our SP-HUS cases had a higher median age of 27.5 months, but similar to other studies a higher proportion of male cases.²^,⁵^,¹⁰^,¹¹ For SP-HUS clinical presentations, our data support existing literature, with the most common manifestation being pneumonia, specifically pneumonia complicated by empyema or pleural effusion.⁵

Literature indicates SP-HUS is associated with substantial renal morbidity .²^,⁵ A 2011 SP-HUS North American series examined 30 children and showed after a median 6 months of follow-up, 23% remained on dialysis and 10% required kidney transplant.² Similarly, a 2008 literature review of all pediatric SP-HUS cases (n=73) found that 10% of children progressed to end-stage renal failure and 16% developed chronic kidney disease or hypertension.⁵ As such, monitoring long-term health sequelae of SP-HUS patients is important.

SP-HUS severity and level of care shown in our study is also supported by the literature.² We did not observe any mortality associated with SP-HUS, in this long term surveillance study, similar to the 3.3% found in other studies.¹⁰^,¹¹ SP-HUS cases presenting with IPD meningitis have a higher mortality rate than other presentations (37% vs. 2%).⁵^,¹⁰ The UK SP-HUS cases had higher frequencies of meningitis (25-30%) with corresponding greater mortality rate (11-15%),¹⁰ ¹¹ compared to US cases with lower meningitis rates (11%) and lower mortality (3%)² in its cohort. The patients in our study had similar meningitis rates (13%) to the US cohort (11%)² which could explain the lower mortality in our patients compared to the UK. Additionally, overall declines in SP-HUS-related mortality globally is attributed to advancements in critical care, early diagnosis, and plasmapheresis, or transfusion with washed blood products, as SP-HUS management. ¹ ¹²

The advantage of IMPACT is its longstanding, multi-centre national surveillance program which can identify SP-HUS cases to compare with non-HUS IPD cases and gather consistent data. However, since these are surveillance data and the follow-up period is limited to the initial hospital encounter, we do not have long-term outcome data following discharge. Furthermore, our analysis and study design precluded the estimation of incidence or risk of SP-HUS as IMPACT is not population based. Another limitation is our lack of lab marker records to confirm the diagnoses of HUS. However, clinical diagnosis of HUS followed provincial HUS guidelines⁹ which was consistent with our cases. It is also noteworthy that microbiological confirmation of S. pneumoniae pneumonia is low¹³ and more likely to occur in cases of pneumonia with severe manifestations such as HUS. Thus, we may have a diagnosis bias of over-identifying the proportion of S. pneumoniae pneumonia with IPD leading to HUS.

In the future, ongoing review examining vaccination coverage and association with specific S. pneumoniae serotypes would be of value, in context of new higher-valent pneumococcal vaccines. Finally, continuing to collect Canadian data investigating the long-term sequelae and outcomes of SP-HUS cases would be clinically relevant.

Competing interests

MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo, and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. JAB: no competing interests. NKV reports consulting fees from Broadstreet Health Economics & Outcomes Research on unrelated projects. JDK has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, and Pfizer. All funds have been paid to his university, and he has not received any personal payments. SKM has received honoraria for lectures from GlaxoSmithKline, was a member of ad hoc advisory boards for Pfizer Canada, Sanofi Pasteur, and Merck and is a co-investigator on an investigator-led grant from Pfizer, all unrelated to this study. SAH as been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Entos, and VBI Vaccines, and has served on ad hoc advisory committees for many of those same entities.

Authors’ contributions

LDL: Conceptualized the analysis, conducted preliminary data analysis, interpreted the data and wrote the manuscript. NKV: Conducted final data analysis, contributed to interpretation of data, wrote parts of the manuscript, and provided critical review of manuscript. KY: Conducted preliminary data analysis, data interpretation, and wrote the manuscript. MS: Contributed to study design, collected data, contributed to data interpretation, and provided critical review of manuscript. JAB: supervised the project, conceptualized analysis, curated the data, interpreted the data, and provided critical review of manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors gratefully acknowledge the expert assistance of the IMPACT nurse monitors and coordinator, staff of the IMPACT Data Center (Hennady Shulha, Suzanne Liu, Kim Marty) and Melanie Laffin (Canadian Paediatric Society). The Canadian Immunization Monitoring Program, Active (IMPACT) is a national surveillance initiative managed by the Canadian Paediatric Society and conducted by the IMPACT network of pediatric investigators on behalf of the Public Health Agency of Canada’s Centre for Immunization and Respiratory Infectious Diseases. MS is supported via salary awards from the BC Children’s Hospital Foundation and Michael Smith Health Research BC.

Investigators and centres participating in IMPACT included: N. Bridger MD, Cheryl Foo MD, Janeway Children’s Health & Rehabilitation Centre, St. John’s, NL;S.A. Halperin MD, K.A. Top MD, IWK Health Centre, Halifax, NS; R. Thibeault MD, Centre Mère-Enfant de Québec, CHUL, Quebec City, PQ; J. Papenburg MD, The Montreal Children’s Hospital, Montreal, PQ; M. Lebel MD, CHU Ste-Justine, Montreal, PQ; N. Le Saux MD, Children’s Hospital of Eastern Ontario, Ottawa, ON; S. Morris MD, The Hospital for Sick Children, Toronto, ON; J. Embree MD, Winnipeg Children’s Hospital, Winnipeg, MB; B. Tan MD, Athena McConnell MD, Jim Pattison Children’s Hospital, Saskatoon, SK; T. Jadavji MD, C. Constantinescu MD, Alberta Children’s Hospital, Calgary, AB; W. Vaudry MD, Stollery Children’s Hospital, Edmonton, AB; D. Scheifele MD, M. Sadarangani BM BCh DPhil, J. Bettinger PhD, L. Sauvé MD, BC Children’s Hospital, Vancouver, BC.

Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis Off J Natl Kidney Found. 2004;43(6):976-982. doi:10.1053/j.ajkd.2004.02.010
Banerjee R, Hersh AL, Newland J, et al. Streptococcus pneumoniae-associated Hemolytic Uremic Syndrome Among Children in North America. Pediatr Infect Dis J. 2011;30(9):736-739. doi:10.1097/INF.0b013e3182191c58
Loupiac A, Elayan A, Cailliez M, et al. Diagnosis of Streptococcus pneumoniae–associated Hemolytic Uremic Syndrome. Pediatr Infect Dis J. 2013;32(10):1045-1049. doi:10.1097/INF.0b013e31829ee872
Chen SY, Wu CY, Tsai IJ, Tsau YK, Su YT. Nonenteropathic hemolytic uremic syndrome: the experience of a medical center. Pediatr Neonatol. 2011;52(2):73-77. doi:10.1016/j.pedneo.2011.02.002
Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol. 2008;23(11):1951-1956. doi:10.1007/s00467-007-0518-y
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 J Can Mal Infect. 2003;14(6):339-343. doi:10.1155/2003/219027
Proulx F, Sockett P. Prospective surveillance of Canadian children with the haemolytic uraemic syndrome. Pediatr Nephrol Berl Ger. 2005;20(6):786-790. doi:10.1007/s00467-005-1843-7
Bettinger JA, Scheifele DW, Kellner JD, et al. The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000–2007. Vaccine. 2010;28(9):2130-2136. doi:10.1016/j.vaccine.2009.12.026
Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005 Apr;16(4):1035-50
Makwana A, Sheppard C, Fry NK, Ladhani SN. Pneumococcal-related Hemolytic Uremic Syndrome in the United Kingdom: National Surveillance, 2006–2016. Pediatr Infect Dis J. 2019;38(10):e254-e259. doi:10.1097/INF.0000000000002368
Waters AM, Kerecuk L, Luk D, et al. Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United kingdom experience. J Pediatr. 2007;151(2):140-144. doi:10.1016/j.jpeds.2007.03.055
Cochran JB, Panzarino VM, Maes LY, Tecklenburg FW. Pneumococcus-induced T-antigen activation in hemolytic uremic syndrome and anemia. Pediatr Nephrol Berl Ger. 2004;19(3):317-321. doi:10.1007/s00467-003-1382-z
Neuman MI, Hall M, Lipsett SC, et al. Utility of Blood Culture Among Children Hospitalized With Community-Acquired Pneumonia. Pediatrics. 2017;140(3):e20171013. doi:10.1542/peds.2017-1013

Table 1. Demographics and outcomes of SP-HUS and non-HUS IPD cases

Characteristic	SP-HUS (n=30)	Non-HUS IPD (n=6727)	P-value
Age at admission, Median months (IQR)	27.5 (16,40)	22.0 (11,53)	0.68
Sex, Count (%) Male Female	19 (63.3) 11 (36.7)	3877 (57.6) 2850 (42.4)	0.53
Most frequent serotypes in SP-HUS, Count (%) 3 19A	9 (30.0) 8 (26.7)	234 (3.5) 514 (7.5)	<0.0001 <0.0001
Clinical manifestation of IPD, Count (%) Pneumonia Pneumonia complicated by empyema/pleural effusion Meningitis Bacteremia only Pericarditis Central nervous system infarct	20 (67.0) 14 (46.7) <5 <5 <5 <5	1778 (26.4) 515 (7.6) 984 (14.6%) 1943 (28.9%) 17 (0.3%) <5	<0.0001 <0.0001 0.47 <0.0001 0.07 0.004
Hospital admission, Count (%)	30 (100)	4746 (70.5)	0.0004
Duration of hospital stay, Median days (IQR)	23.5 (17,31)	7 (3,12)	<0.0001
ICU admission, Count (%)	21 (70.0)	1049 (15.5)	<0.0001
Duration of ICU stay, Median days (IQR)	9 (6,10)	3 (2,6)	<0.0001
Outcome, Count (%) Survived Mortality	30 (100) <5	6521 (96.9) 206 (3.2)	0.33

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Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome Canadian Immunization Monitoring Program ACTive National Pediatric Surveillance (1991-2019)

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