Invasive Pneumococcal Disease in High-risk Children: A 10-Year Retrospective Study : The Pediatric Infectious Disease Journal

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Invasive Pneumococcal Disease in High-risk Children: A 10-Year Retrospective Study

van Warmerdam, Jacqui MSc*; Campigotto, Aaron MD, MSc†,††; Bitnun, Ari MD, MSc†,§; MacDougall, Georgina RN§; Kirby-Allen, Melanie MD†,¶,‖; Papsin, Blake MD, MSc†,¶; McGeer, Allison MD, MSc*,**; Allen, Upton MBBS, MSc†,§,††; Morris, Shaun K. MD, MPH†,§,††,‡‡

Author Information
The Pediatric Infectious Disease Journal 42(1):p 74-81, January 2023. | DOI: 10.1097/INF.0000000000003748

Abstract

Streptococcus pneumoniae is one of the most common bacterial pathogens of childhood.1 Health Canada reported an average incidence rate of 10.0 invasive pneumococcal disease (IPD) cases per 100,000 individuals of all ages annually between 2009 and 2019.2 The risk and severity of IPD are higher in persons with underlying immune deficiency.3–8 A key determinant for IPD and disease severity is its serotype, defined by its capsular polysaccharide. S. pneumoniae has >90 serotypes differing in incidence, virulence and antimicrobial resistance patterns.9 Ongoing population serotype-specific surveillance is important to inform optimal immunization approaches.

Multivalent pneumococcal vaccines are included in routine Canadian child immunization schedules. Pneumococcal polysaccharide vaccine 23 (PPSV23) was authorized in Canada in 1983, received public funding in 1995 and has since been recommended for adults >65 years of age and patients 2–64 years old with high-risk conditions that predispose to IPD.10 Pneumococcal conjugate vaccine 7 (PCV7) was authorized in June 2001, followed by PCV10 in November 2009 and PCV13 in November 2010. For children with high-risk conditions, the US Advisory Committee on Immunization Practices and Canadian National Advisory Committee on Immunization (NACI) currently recommend 4 doses of PCV13 in infancy (at 2, 4, 6 and 12–15 months of age) and 1 dose of PPSV23 ≥2 years of age (with an additional booster at 5 years of age for children with immunocompromising conditions or asplenia).11,12 Healthy, non-high-risk children are recommended to receive 3 doses of PCV13 and no PPSV23 vaccination.9 The primary objective of this study was to describe the IPD case numbers and clinical outcomes in pediatric patients with underlying high-risk conditions. Secondary objectives included determining risk factors for IPD, isolating serotype patterns and vaccination trends in high-risk pediatric patients.

METHODS

A retrospective chart review identified all high-risk pediatric patients <18 years of age admitted to the Hospital for Sick Children (SickKids) for IPD from January 1, 2009, to December 31, 2018, inclusive. IPD was defined as the detection of S. pneumoniae in culture or by molecular test from a normally sterile body site [eg, blood, cerebral spinal fluid (CSF), peritoneal fluid, synovial fluid and bone]. Pneumonia was defined by the detection of S. pneumoniae in bronchoalveolar lavage or blood culture with evidence of infiltrates on chest radiograph. IPD diagnoses were identified using both a search of microbiology records by a microbiologist for culture/molecular confirmation, and International Classification of Disease-10 discharge diagnostic codes related to IPD to ensure complete capture (Table, Supplemental Digital Content 1, https://links.lww.com/INF/E867).

High-Risk Patient Definition

All identified IPD cases were assessed for eligibility as a high-risk pediatric patients through a medical chart review. High-risk conditions included: transplant (solid organ and hematopoietic stem cell), malignancy, primary immunodeficiency, asplenia, sickle cell disease (SCD), cochlear implant, nephrotic syndrome, chronic lung disease, CSF leak, HIV and use of immunosuppressive therapy (chemotherapy, biologic drugs or immune-suppressing medications) in the 90 days preceding IPD. Although SCD patients have limited spleen function, we described SCD and asplenia from other causes separately.

Patient chart review was used to collect data on each patient’s underlying high-risk condition, demographic information, pneumococcal vaccination status, disease severity, clinical course and patient outcomes. If a patient experienced multiple IPD episodes, the most recent episode was analyzed in this study.

Serotype Analysis, Antimicrobial Susceptibility and Vaccine Status

Since January 1, 1995, pneumococcal isolates from sterile sites from patients at the Hospital for Sick Children have been routinely submitted to the Toronto Invasive Bacterial Disease Network (TIBDN). TIBDN performs active, population-based surveillance for IPD in the greater Toronto area. Isolates received are confirmed as S. pneumoniae and serotyped using latex agglutination and Quellung reaction.13–15 Antimicrobial susceptibility of pneumococcal isolates was performed using broth microdilution (Trek Sensititre STP6F) and interpreted to Clinical and Laboratory Standards Institute standards.16 Only isolates collected from sterile sites and with complete antibiotic susceptibility data were included. Nonmeningitis resistance breakpoints for penicillin and ceftriaxone were used unless the isolate was from a CSF sample and then meningitis breakpoints were used. As part of a well-established and long-running network, TIBDN collects vaccination data by contacting the patient’s parent/guardian and relevant primary care physicians. Patient chart data was used to identify vaccine status, vaccine type, and date of vaccine receipt. Children who received mixed conjugate vaccine programs (ie, PCV7, then PCV13) were considered fully vaccinated based on the total number of conjugate vaccines received.

Data Management and Statistical Analysis

Baseline and demographic characteristics were summarized using descriptive statistics. A two-tailed Fisher exact test was used to test the significance of the decrease in the proportion of IPD hospitalizations caused by conjugate vaccine-contained serotypes, comparing the pre to post-PCV13 periods. Vaccine effectiveness analysis was used to assess the proportion of children with IPD due to PCV-contained serotypes in vaccinated and unvaccinated children.17 Significance was defined as P = 0.05. Ethics approval was obtained from The Hospital for Sick Children (REB: 1000063186).

RESULTS

Over 10 years, 94 high-risk pediatric patients were hospitalized for IPD. The median age at diagnosis was 5.5 years (IQR: 3.6–7.9) and 55% of patients were female (Table 1). The number of IPD cases decreased over time. Six children had a previously documented hospitalization for IPD, of which 4 (67%) had active leukemia, the others received a transplant or were on immunosuppressive therapy. The first episode of IPD requiring hospitalization occurred a median of 224 days before the second episode (IQR: 70–239). Children with active malignancy accounted for the most cases (n = 33, 35%), followed by transplant recipients (n = 17, 18%) and SCD (n = 14, 15%). Of the children with active malignancy, the mean time after a cancer diagnosis to IPD hospitalization was 2.6 years. Chemotherapy was received within 3 months before IPD among 23 children, 6 received hematopoietic stem cell transplant, 4 were on other immune suppressive medications and none were on biologic treatments. Among the children with acute lymphoblastic leukemia (n = 17), 1 was receiving induction treatment, 13 were receiving maintenance and 3 had completed treatment. Of the children who received transplants, the mean time from transplant to IPD hospitalization was 3.3 years. One child experienced graft rejection, and all 17 received an immunosuppressant within 3 months of the IPD event (Table, Supplemental Digital Content 1, https://links.lww.com/INF/E867). Of the children with SCD, 9 (64%) were older than 5 years at the time of IPD. The median age of IPD among patients receiving antibiotic prophylaxis was 4.0 years, and 9.5 years among those who were off antibiotic prophylaxis.

TABLE 1. - Cohort Demographics and Clinical Course
Demographic Information n (%)
Sex
 Female 51 (54)
 Male 43 (46)
Age at onset of first episode of IPD (years)
 Mean 6.3
 Median (IQR) 5.4 (3.6–7.7)
High-risk group n (%) *
Malignancy 33 (35)
 Hematologic 23 (25)
 Solid organ 10 (11)
Solid organ transplant 17 (18)
 Liver 9 (10)
 Heart 4 (4)
 Multi-visceral 3 (3)
 Kidney 1 (1)
Sickle cell disease 14 (15)
Asplenia 9 (10)
Hematopoietic stem cell transplant 8 (9)
Nephrotic syndrome 8 (9)
Chronic lung disease 7 (7)
Use of immune suppressing medications 32 (34)
 Chemotherapy 23 (25)
 Tacrolimus 14 (15)
 Corticosteroids 12 (13)
 Mycophenolate mofetil 3 (3)
 Sirolimus 3 (3)
Primary immunodeficiency 4 (4)
HIV 2 (2)
Cochlear implant 1 (1)
CSF leak 1 (1)
Preventative measures n (%)
Pneumococcal conjugate vaccination
 Full conjugate vaccine pneumococcal immunization 34 (36)
 High-risk child recommendation: 4 doses 20 (21)
 General healthy child recommendation: 3 doses 14 (15)
 Partial conjugate vaccine pneumococcal immunization 5 (5)
 2 doses 4 (4)
 1 dose 1 (1)
 Unknown number of pneumococcal conjugate vaccine dDoses 12 (13)
PPSV23 vaccination (age eligible, N = 82) 3 (4)
No pneumococcal vaccination 15 (16)
Unknown vaccine status 28 (30)
Vaccine received §
 PCV7 22 (23)
 PCV10 2 (2)
 PCV13 15 (16)
 PPSV23 & PCV7 1 (1)
 PPSV23 & PCV13 2 (2)
 Unknown vaccine type 9 (10)
Prophylactic pneumococcal antibiotic use 11 (12)
 Penicillin 6 (6)
 Amoxicillin 5 (5)
No prophylactic pneumococcal antibiotic use documented 83 (88)
Immunoglobulin use (within the past 30 days) 2 (2)
Clinical course n (%)
Site of first positive test
 Blood 81 (86)
 Bronchiolar fluid 4 (4)
 CSF 4 (4)
 Joint fluid 1 (1)
 Middle ear 0 (0)
 Pleural fluid 0 (0)
 Peritoneal fluid 1 (1)
 Other 2 (2)
Duration of IPD admission (days)
 Mean 11
 Median (IQR) 5 (3.3, 10.8)
ICU admission 15 (16)
Duration of ICU admission (days)
 Mean 7.5
 Median (IQR) 2 (1,9.5)
Assisted ventilation 10 (11)
Duration of assisted ventilation (days)
 Mean 9.8
 Median (IQR) 5 (2, 11)
ECMO use 0 (0)
Vasopressor use 1 (1)
Hemodynamic instability 5 (5)
Acute respiratory distress syndrome 3 (3)
Surgical procedure 7 (7)
End organ dysfunction 10 (11)
 Neurologic sequelae 5 (5)
 Renal failure 4 (4)
 Myocarditis 1 (1)
Permanent disabilities 1 (1)
Death 0 (0)
Full recovery 93 (99)
CSF indicates cerebral spinal fluid; ECMO, Extracorporeal membrane oxygenation; ICU, Intensive Care Unit; IPD, invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine; PPSV, pneumococcal polysaccharide vaccine.
*Patients with multiple risk factors were included in each respective subcategory, thus the total number exceeds the total study population.
Two of these children were <15 months of age, and thus vaccinated appropriate to age.
Serotypes in unvaccinated individuals: 15B (n = 4), 7F (n = 2), 19A (n = 2), 22F (n = 2), 23B (n = 2), 35B (n = 2) and 21 (n = 1).
§Recorded based on highest level of vaccine coverage (ie, if received PCV7 and then PCV13, they were classified as PCV13 recipients).

IPD Prevention and Vaccination

Of the 66 (70%) patients with known pneumococcal vaccination status at the time of IPD, 34 (36%) received age-appropriate pneumococcal conjugate vaccinations as per NACI guidelines for high-risk children (Table 1).12 Five patients were partially immunized (1–2 doses) based on their age and general pediatric recommendations and 15 (23%) were unvaccinated. Of the unvaccinated children, many had an active malignancy at the time of IPD (n = 7, 47%), or were taking an immunosuppressant medication (n = 5, 33%). However, all unvaccinated children with cancer were diagnosed with a malignancy after 1 year of age. The median age of IPD in the unvaccinated children was 9.0 years (IQR: 4.7–9.7), older than the vaccinated cohort where the median age was 5.8 years (IQR: 4.0–9.0). A higher proportion of unvaccinated children were born between 1995 and 2004 (83%). PCV7 was the most common pneumococcal vaccine received (n = 22, 43%), followed by PCV13 (n = 15, 29%). Only 3 of the 84 age-eligible children (4%) received both a conjugate vaccine and PPSV23 and all were born after 2007 (Table, Supplemental Digital Content 2, https://links.lww.com/INF/E868). No children received only PPSV23 vaccination.

In unvaccinated/partially vaccinated children and fully vaccinated children, 14/20 (70%) and 2/34 (6%) cases were due to PCV13-contained serotypes, respectively (Table, Supplemental Digital Content 3, https://links.lww.com/INF/E869). Therefore, an unadjusted estimate of vaccine effectiveness for PCV13 against PCV13 serotypes is 97.3%.17

Prophylactic antibiotics were used by 12 patients (13%). Patients with SCD (n = 8) and transplant patients with asplenia (n = 3) composed 92% of patients using prophylactic antibiotics (Table 1).

Clinical Course and Patient Outcomes

The most common presentation was bacteremia (n = 81, 86%), followed by pneumonia (n = 23, 25%) (Table 2). Of the 23 patients with pneumonia, 19 (83%) were also bacteremic. In total 9 (10%) patients presented with meningitis, 8 of whom had SCD or asplenia. Of the 14 SCD patients and 9 asplenic patients with IPD, 43% (n = 6) and 22% (n = 2), respectively presented with pneumococcal meningitis. Three of the meningitis cases were receiving prophylactic antibiotics (penicillin n = 1 and amoxicillin n = 2).

TABLE 2. - Type of invasive pneumococcal disease Episode by High-Risk Group
Bacteremia n (%) Pneumonia n (%) * Meningitis n (%) Joint n (%) Endocarditis n (%)
Solid organ transplant (n = 17) 15 (88) 6 (35) 1 (7) 0 (0) 0 (0)
 Heart (n = 4) 3 (75) 3 (75) 0 (0) 0 (0) 0 (0)
 Kidney (n = 2) 1 (50) 0 (0) 0 (0) 0 (0) 0 (0)
 Liver (n = 12) 11 (92) 3 (25) 1 (8) 0 (0) 0 (0)
 Multi-visceral (n = 1) 1 (100) 0 (0) 0 (0) 0 (0) 0 (0)
Malignancy (n = 33) 30 (91) 4 (12) 1 (3) 1 (3) 1 (3)
 Hematologic (n = 23) 21 (91) 4 (17) 1 (4) 1 (4) 1 (4)
 Solid tumour (n = 10) 9 (90) 0 (0) 0 (0) 0 (0) 0 (0)
Hematopoietic stem cell transplant (n = 8) 7 (88) 0 (0) 1 (13) 1 (13) 1 (13)
Use of other immune suppressing medications (n = 32) 29 (91) 9 (28) 1 (3) 0 (0) 0 (0)
Primary immunodeficiency (n = 4) 4 (100) 2 (50) 0 (0) 0 (0) 0 (0)
Asplenia (n = 9) 8 (89) 0 (0) 2 (22) 1 (11) 1 (11)
Sickle cell disease (n = 14) 9 (64) 2 (14) 6 (43) 0 (0) 0 (0)
Cochlear implant (n = 1) 1 (100) 1 (100) 0 (0) 0 (0) 0 (0)
Nephrotic syndrome (n = 8) 8 (100) 0 (0) 0 (0) 0 (0) 0 (0)
Chronic lung disease (n = 7) 5 (71) 6 (86) 0 (0) 0 (0) 0 (0)
CSF leak (n = 1) 1 (100) 0 (0) 0 (0) 0 (0) 0 (0)
HIV (n = 2) 2 (100) 1 (50) 0 (0) 0 (0) 0 (0)
Total 81 (86) 23 (25) 9 (10) 2 (2) 1 (1)
CSF indicates cerebral spinal fluid.
*Pneumonia was defined by detection of S. pneumoniae in bronchoalveolar lavage or blood culture with evidence of infiltrates on chest radiograph. Most cases (n = 22) had a secondary bacteremia, 1 case had non-bacteremic pneumonia.
Patients with multiple risk factors were included in each respective subcategory, thus the total number exceeds the total study population.

The duration of hospitalization was less than 7 days in 59% of cases, with a median of 5 days (IQR: 3.3–10.8) (Table 1). The hospitalization course was complicated by end-organ dysfunction (n = 10, 11%), Intensive Care Unit admission (n = 15, 16%) or the need for surgery (n = 7, 7%). Of the 10 patients with end-organ dysfunction, half (n = 5) were children with SCD who had a vaso-occlusive crisis. Of the 15 patients requiring Intensive Care Unit-level care, a large proportion had underlying chronic lung disease (n = 6, 40%) or SCD (n = 4, 27%). Surgical procedures included cardiac valve replacement and chest tube placement. One patient with meningitis experienced permanent neurologic sequelae. No patients died. A full recovery was made by 99% of patients (n = 93).

Isolate Serotypes

IPD isolates serotype data was retrieved for 66 patients. The 6 most common serotypes were 15B, 22F, 19A, 23A, 23B and 9N (Fig. 1). From 2016 to 2018, the most recent 3 years of the study, there was no IPD caused by PCV13-contained serotypes, despite PCV13-contained serotypes composing 27% (n = 7) in the first 3 years (2009–2011). IPD caused by PPSV23 persisted over the study period and composed 50% (n = 7) of the 14 cases of IPD from 2016 to2018 (Fig. 2). Of the 6 children with IPD caused by PPSV23-contained serotypes between 2016 and 2018, none received PPSV23 vaccination, and 1 was completely unvaccinated against S. pneumoniae. However, before 2016, 1 child who received the PPSV23 vaccine had IPD due to a serotype contained within PPSV23. The proportion of hospitalizations caused by PCV13-contained serotypes was significantly lower after PCV13 introduction when comparing pre-PCV13 (2009/2010; n = 8 of 22 total IPD cases) to post-PCV13 (2011–2018; n = 6 of 43 total IPD cases) time periods (P = 0.04).

F1
FIGURE 1.:
Yearly IPD serotype data from 2009 to 2018, grouped by vaccine coverage. IPD, invasive pneumococcal disease.
F2
FIGURE 2.:
Proportion of IPD serotype vaccine-coverage groups in pre-PCV13, early PCV13 and late PCV13 time periods, stratified by vaccination status. (Vaccine Coverage Groups: PCV7 represents IPD serotypes contained within PCV7, PCV13 represents serotypes uniquely covered by PCV13 and not PCV7, PPSV23 represents serotypes unique to PPSV23 and not contained within PCV13, and Non-vaccine type represents serotypes not included in current pneumococcal vaccines). IPD indicates invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine; PPSV, pneumococcal polysaccharide vaccine.

Of the 20 children with no vaccine or partial immunization (≤2 doses), 14 IPD episodes were due to serotypes included in vaccines (PPSV23-contained n = 10, PCV13-contained n = 3 and PCV-7-contained n = 1). IPD caused by a vaccine-contained serotype occurred in 2 immunized patients. Both had bacteremia without a focus of infection, 1 due to serotype 3 in a fully vaccinated transplant recipient, and 1 due to serotype 22F in a child using immune-suppressive medications who received 2 doses of PCV13.

Antimicrobial Susceptibility

Complete antimicrobial susceptibility results were available for 64 isolates (68%) (Table 3). Erythromycin had the highest proportion of resistant (36% of isolates resistant), followed by trimethoprim-sulfamethoxazole (11%), cefuroxime (11%), meropenem (8%) and penicillin (5%) based on nonmeningitis resistance breakpoints. Of the 6 patients on penicillin prophylaxis, all IPD isolates were sensitive to penicillin. All isolates were susceptible to vancomycin and levofloxacin. Serotype 19A had the highest proportion of resistant with 100% of isolates resistant to erythromycin, 67% resistant to cefuroxime and meropenem, 50% resistant to penicillin, 33% resistant to trimethoprim-sulfamethoxazole and 17% resistant to ceftriaxone. High proportions of resistance were also seen in serotypes 15B and 19F (Table 3). Over the study period, meropenem and penicillin proportions of resistance decreased from 12% to 8%, respectively in 2009–2011 and to 0% in 2016–2018.

TABLE 3. - Antibiotic Sensitivities of Invasive Pneumococcal Disease Isolates by Serotype and Time Period, Using Non-Meningitis Resistance Breakpoints
Serotype n = % Resistant
TMP-SMX Penicillin * Erythromycin Cefuroxime Ceftriaxone Meropenem Vancomycin Levofloxacin ≥1 Antibiotic ≥2 Antibiotics
15B 10 10 0 20 10 10 0 0 0 20 10
22F 9 0 0 11 0 0 0 0 0 11 0
19A 6 33 33 100 67 0 67 0 0 100 67
23A 5 20 0 40 0 0 0 0 0 60 0
23B 4 0 0 25 0 0 0 0 0 25 0
9N 3 0 0 0 0 0 0 0 0 0 0
7F 2 0 0 50 0 0 0 0 0 50 0
35F 2 0 0 0 0 0 0 0 0 0 0
19F 2 50 0 50 50 50 50 0 0 50 50
16F 2 0 0 0 0 0 0 0 0 0 0
15C 2 50 0 50 0 0 0 0 0 100 0
21 2 0 0 50 0 0 0 0 0 50 0
Others 15 7 0 47 7 0 0 0 0 47 13
Total 64 11 5 36 11 2 8 0 0 39 12
Time Period n = N Cases per Year TMP-SMX Penicillin * Erythromycin Cefuroxime Ceftriaxone Meropenem Vancomycin Levofloxacin ≥1 Antibiotic ≥2 Antibiotic
2009–2011 25 8.3 8 8 40 12 0 12 0 0 40 16
2012–2015 27 6.8 15 4 30 11 4 7 0 0 37 11
2016–2018 12 4 8 0 42 8 0 0 0 0 42 8
*If using meningitis breakpoints, 19% are resistant to penicillin.
If using meningitis breakpoints, 11% are resistant to ceftriaxone.

Antimicrobial susceptibility data were available for extraction from 4 patients with meningitis. Using meningitis breakpoints, 2 were resistant to trimethoprim-sulfamethoxazole, and 1 was resistant to erythromycin, but all were sensitive to penicillin, ceftriaxone, cefuroxime, vancomycin, levofloxacin and meropenem.

DISCUSSION

This study illustrates that IPD continues to impact children with underlying medical conditions despite vaccine implementation. In a previously published Toronto study, 28% of all IPD (adult and child) between 1995 and 2012 occurred in immunocompromised individuals, despite this group making up only 2.8% of the population.15 The highest proportion of hospitalized IPD patients in our study was children with active malignancy, followed by transplant recipients, and SCD. This may be due to the many children with malignancy treated at SickKids (approximately n = 275 new cases annually) compared with other immunocompromised patients: transplant recipients (n = 61/year), HIV (n = 16/year) or cochlear implants (n = 85/year).18,19 B. Papsin, personal communication, October 201920 and A. Bitnun, personal communication, November 2019.21 Prior studies report similar findings with the highest proportion of IPD in patients with active malignancy, SCD and transplant recipients.6,15,22 These data suggest additional efforts should be made to ensure optimal implementation of preventive measures in these patient subgroups.

A reassuring finding of our study was that no children died. In a Toronto-based study of IPD immunocompromised children between 1995 and 2012 and a nationwide Danish study of 18,858 non-high-risk children from 1977 to 2007, the mortality rate was 1.5% and 3%, respectively.15,23 End-organ dysfunction occurred in 11% of our patients, half of whom had SCD. In the latter cases, organ damage usually followed a vaso-occlusive crisis triggered by infection. It is also noteworthy that most meningitis episodes occurred in children with SCD.

Of children with known pneumococcal vaccination status, only 30% received the recommended 4 doses of conjugate vaccine. Despite Canadian recommendations to vaccinate high-risk children older than 2 years with PPSV23, only 3 patients had received PPSV23. A quarter of children were unvaccinated. These results are consistent with previous studies reporting suboptimal vaccination rates among high-risk children.24 In a study of transplant patients from 1995 to 2012, only 23.8% received PPV23 before to IPD.25 Among pediatric transplant recipients from 1990 to 2001 only 33% of eligible patients received PPSV23.26 Thus, our data, as well as that of others, suggest that most children and adults at high risk of IPD are incompletely vaccinated according to standard recommendations. Reasons for incomplete vaccination would be important to elucidate in future research.

Of the infections in children with incomplete or no vaccination in our study, 70% were associated with serotypes included in the PCV13 or PPSV23 vaccines. This is consistent with a previous study reporting that 50% of IPD serotypes in high-risk individuals were vaccine serotypes (19A, 22F, 7F, 23A, 6C and 3).15 Since PCV13’s introduction, our study identified a decrease in the number of high-risk children hospitalized for IPD caused by PCV13-contained serotypes. In fact, in the most recent 3 years of the study from, 2016 to 2018, there was no IPD caused by PCV13 serotypes. This reduction has been paralleled in studies of nonimmunocompromised children, as a study from England on children from 2000 to 2014 reports a 69% decline in PCV13 serotypes over the study period.27 However, IPD caused by PPSV23-contained serotypes persisted over the time period, and composed 50% (n = 7) of the 14 cases of IPD from 2016 to 2018. Thus, our data, as well as those of others, suggest a substantial proportion of IPD is potentially preventable with appropriate vaccination. This vaccine effect may be due to direct immunization or herd immunity. However, our data suggest serotype replacement with serotypes uniquely covered by PPSV23 or serotypes not covered by any vaccine over the years. This is consistent with national data demonstrating an overall increase in the proportion of PPSV23 serotypes from 24.7% to 38.0% between 2010 and 2014.28 With respect to serotypes contained in the PPSV23, but not PCV13, it is noteworthy that some of these more prevalent serotypes will be included in upcoming conjugate pneumococcal vaccines.29 PCV15 and PCV20 will contain the PCV13 serotypes, and an additional 2 or 7 conjugates respectively (PCV15: 22F, 33F; PCV20: 8, 10A, 11A, 12F, 15B, 22F and 33F). In our study, the number of IPD cases caused by serotypes not covered by PCV13 which will be included in PCV15 and PCV20 was 11/52 (21%) and 23/52 (44%), respectively. Although these serotypes are also contained within PPSV23, widespread use of the higher valency PCV’s in the general population could reduce circulation and indirectly protect these vulnerable patients. Vaccination of the general population and subsequent herd protection are important factors in IPD prevention, especially among high-risk individuals who may be ineligible or unable to be vaccinated during certain periods because of their condition.

Our antimicrobial resistance proportions were generally higher than the national average but lower than globally reported rates. Ceftriaxone resistance in our study (5%) was above the national average in 2017 (0.7%),28 but lower than the United States average from 1999 to 2011 (6%).30–32 The increased resistance proportions reported in our population may be due to a higher proportion of the generally resistant serotype 19A, increased use of prophylactic antibiotics or the higher likelihood of recent antibiotic use for other infections.33,34 However, penicillin breakpoint resistance was lower in our study (10%) than the Canadian average in 2017 (14.9%)28 and the United States average in 2011–2012 (28%).31 Reassuringly, all isolates were sensitive to vancomycin and levofloxacin, providing options for resistant IPD. Our study reported serotypes 19A, 19F and 15B to have the highest overall antimicrobial resistance proportion. This is consistent with global data suggesting serotype 19F has high penicillin and macrolide resistance,35,36 whereas 19A has high multidrug resistance.37,38 These isolates are among the 7 serotypes reported to account for 91% of all penicillin-resistant S. pneumoniae.39 However, our small number of isolates available for analysis limits any definitive conclusions on antimicrobial resistance. Additionally, the most multidrug-resistant serotype, serotype 19A, is contained within PCV13 and was not detected after 2015. This suggests a decrease in serotype 19A circulation following the implementation of PCV13, and the importance of vaccination in preventing IPD caused by resistant and thus, difficult-to-treat serotypes. Finally, of the 6 children receiving penicillin prophylaxis, all IPD serotypes were sensitive to penicillin. Potential contributors to prophylaxis failure include inconsistent prophylaxis use, and poor absorption in certain underlying comorbidities. Additionally, while prophylaxis reduces risk, it does not eliminate risk completely and breakthrough infections may still occur.

Our study has several limitations. First, as a single-center retrospective review, we describe patients of one geographic area, which may not be representative of other regions. Second, vaccine records were not available for approximately 30% of children. The TIBDN vaccine database contains validated vaccine data for 87.5% of IPD cases within the Greater Toronto Area. The remaining IPD cases with unknown vaccine status could not be validated (5%), were unreachable or refused participation in the study (7.6%). Similarly, our study was limited in our understanding of why these children were unvaccinated, their opinions on vaccines, and any vaccine education received. Factors related to low vaccine uptake within high-risk pediatric populations should be explored in future studies. Third, as a tertiary care center, our study is likely biased toward the sickest children. Fourth, previous studies have suggested that the increased risk of IPD in high-risk populations may be due to the lower threshold for hospital admission in such patients rather than the increased disease severity.3,40 However, in a Toronto study on IPD in all children, 92% of all children with IPD were hospitalized for their illness.15 Thus, the higher propensity to hospitalize high-risk children should have a marginal effect on our reported risk of IPD. Finally, laboratory values were not captured and thus we cannot comment on which patients were neutropenic or had low hemoglobin levels. Serotype data were not available for PCR-diagnosed cases, bronchiolar lavage samples or samples obtained outside the greater Toronto area. The CSF samples were more likely to be assessed by Polymerase chain reaction and thus we were unable to capture serotype data for many of these patients.

Conclusion

In conclusion, this study demonstrates that IPD among high-risk children continues to occur and that most cases are in children with malignancy, organ transplantation and SCD. Despite frequent contact with the medical system, most of these high-risk children were under-immunized and, in half of the cases, IPD was caused by serotypes contained within PPSV23 vaccines. Thus, targeted efforts should be implemented to immunize children >2 years of age with PPV23. Elimination of PCV13-contained serotypes, including the most multidrug-resistant serotype 19A, in our population over the last 3 years of our study suggests the positive impacts of PCV13 vaccination among high-risk children. Strategies to identify gaps in vaccine coverage and optimize immunization should be pursued. Future work should continue to assess barriers to complete vaccination of high-risk individuals, vaccination trends, serotype distribution and vaccine development for the most common IPD serotypes.

ACKNOWLEDGMENTS

Many thanks to the support from our research team. Zach Tanner provided guidance upon project design and data collection. Daniel Farrar provided RedCap training and data analysis guidance. Nadine Francis, Theresa Passanha, and Jenna Craig provided key administrative support throughout the project.

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Keywords:

IPD; vaccine; immunocompromised

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