Change in Pneumococcus Serotypes but not Mortality or Morbidity in Pre- and Post-13-Valent Polysaccharide Conjugate Vaccine Era: Epidemiology in a Pediatric Intensive Care Unit over 10 Years

Change in Pneumococcus Serotypes but not Mortality or Morbidity in Pre- and Post-13-Valent... Abstract Aim Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally cause severe pneumococcal disease with high mortality and morbidity. We reviewed all pneumococcal serotypes and mortality/morbidity in a pediatric intensive care unit (PICU) following universal pneumococcal conjugate vaccine (PCV) immunization. Methods A 13-valent PCV was introduced in the universal immunization program in late 2011 in Hong Kong. We retrospectively reviewed all pneumococcal serotypes in the pre-(2007–11) and post-(2012–16) 13-valent PCV era. Results There were 29 (1.9%) PICU patients with pneumococcal isolation, of which 6 died (20% motality). Serogroups 6 and 19 predominated before and Serogroup 3 after 2012. In the post-13-valent PCV era, the prevalence of pneumococcus isolation in PICU was increased from 1 to 2% (p = 0.04); Serogroup 3 was the major serotype of morbidity, despite supposedly under vaccine coverage. The majority of pneumococcus were penicillin-sensitive (94%) in the post 13-valent PCV era. All pneumococcus specimens were sensitive to cefotaxime and vancomycin. Binary logistic regression showed that there were reductions in Serogroup 6 (odds ratio [OR], 0.050; 95% confidence interval [CI], 0.004–0.574; p = 0.016) and Serogroup 19 (odds ratio [OR], 0.105; 95% confidence interval [CI], 0.014–0.786; p = 0.028) but not mortality or morbidity for patients admitted after 2012. Conclusions SPD is associated with significant morbidity and mortality, despite treatment with systemic antibiotics and ICU support. The expanded coverage of 13-valent PCV results in the reduction of Serotypes 6 and 19 but not mortality/morbidity associated with SPD in the setting of a PICU. pneumococcus, serotypes, pleural effusion, immunizations, mortality, PICU INTRODUCTION Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally are responsible for severe pneumococcal disease (SPD) requiring intensive care support with high mortality and morbidity [1–3]. The World Health Organization (WHO) reports that pneumococcal disease is the world’s number one vaccine-preventable cause of death among infants and children <5 years of age [4]. A 13-valent polysaccharide vaccine was introduced in the universal immunization program in late 2011 in Hong Kong [5, 6]. This study investigated morbidity and mortality associated with pneumococcal infections in patients admitted to the pediatric intensive care unit (PICU). METHODS All children admitted to PICU of a university-affiliated teaching hospital (Prince of Wales Hospital [PWH]) in the pre-(2007–11) and post-(2012–16) 13-valent era with a laboratory isolation of pneumococcus were included. PWH provides tertiary PICU service for children aged up to 14 years in the Eastern New Territories cluster of Hong Kong with a catchment population of over 1.1 million (∼25% were children <12 years of age) [7]. Children with confirmed pneumococcal disease (culture of Streptococcus pneumoniae (SP) from blood, CSF or sterile body fluid) were identified by using the principal author’s database, which registered every PICU admission. Demographic data, mortality, length of PICU stay, hospital stay (till discharge or death), complications, pneumococcal serotype, specimen site and co-infection were compared with Mann–Whitney U test (for continuous data) or Fisher’s exact test (for categorical data). Binary logistic regression was performed using IBM SPSS 20.0 to ascertain the association of patients' admission year and the outcome of SP serotypes. All comparisons were made two-tailed, and p-values <0.05 were considered statistically significant. Ethics approval for this review was obtained from the hospital Clinical Research Ethics Committee. SP was identified using conventional diagnostic methodology from blood cultures, cerebrospinal fluids, pleural aspirates, tracheal aspirates (via endotracheal tube in intubated patients), urine or deep wound swabs (e.g. retropharyngeal abscess, peritoneum, post-mortem specimens). Specimens were processed in the same microbiology laboratory with standardized procedures and equipment. The antibiotic susceptibilities of SP against erythromycin, co-trimoxazole and vancomycin were performed by disc testing, whilst the minimum inhibitory concentrations (MICs) of penicillin and cefotaxime were determined using E-test according to criteria set by the Clinical Laboratory Standards Institute [1]. Capsular typing was performed using Pneumotest antisera (Statens Seruminstitut, Copenhagen) according to the manufacturer’s instruction. Specific serogroups typing has become available since 2007, using factor sera and multiplex PCR that targeted serotypes of the 13-valent vaccine [8]. Laboratory-proven co-infections were also evaluated. RESULTS Over the 10-year period, SP was isolated in 29 patients (Table 1). There were six deaths (20% motality). Serotyping was available in all but two of them. The majority of SP were sensitive to penicillin (MICs (0.06–2.0 μg/ml). All SP specimens were sensitive to cefotaxime and vancomycin. Bacterial, viral and fungal co-infections were occasionally found. Table 1 Pneumococcal disease as a percentage of the annual PICU admissions Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) N/A: not available; PCV: pneumococcal conjugate vaccine; PICU: pediatric intensive care unit. Table 1 Pneumococcal disease as a percentage of the annual PICU admissions Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) N/A: not available; PCV: pneumococcal conjugate vaccine; PICU: pediatric intensive care unit. Demographics and pneumococcal serotypes in the pre- (2007–2011) and post-(2012–16) 13-valent eras were compared (Table 2). Most patients were healthy young children with no premorbid conditions such as malignancy, mental retardation/cerebral palsy (MRCP)+/-seizure disorders, chromosomal or genetic disorders. In the post 13-valent PCV era, the proportion of PICU patients admitted for SPD was increased from 1% to 2% (p = 0.04), serogroup 3 was the major serogroup despite supposedly under vaccine coverage. Binary logistic regression showed that there were reductions of serogroup 6 (odds ratio [OR], 0.050; 95% confidence interval [CI], 0.004–0.574; p = 0.016) and serogroup 19 (odds ratio [OR], 0.105; 95% confidence interval [CI], 0.014–0.786; p = 0.028), but not mortality or morbidity for patients admitted after 2012. Table 2 Comparisons of demographics and clinical variables between PICU patients admitted before and after 2012 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 CRP: C-reactive protein; CSF: cerebrospinal fluid; IQR: interquartile range; MRCP: mental retardation/cerebral palsy; NPA: nasopharyngeal aspirate; N/A: not applicable. Bacterial and viral co-infection is defined here as infection incurred and results obtained from patient samples between the start of admission and discharge. Bacterial infections here included haemophilus influenza, mycoplasma pneumonia and staphylococcus. Viral infections here included Adenovirus, Enterovirus, Rhinovirus, RSV and Influenza A. a Analyzed by Mann–Whitney U test for continuous variables, and Fisher’s exact test for categorical variables. Note: Significant p-values were highlighted in bold. Table 2 Comparisons of demographics and clinical variables between PICU patients admitted before and after 2012 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 CRP: C-reactive protein; CSF: cerebrospinal fluid; IQR: interquartile range; MRCP: mental retardation/cerebral palsy; NPA: nasopharyngeal aspirate; N/A: not applicable. Bacterial and viral co-infection is defined here as infection incurred and results obtained from patient samples between the start of admission and discharge. Bacterial infections here included haemophilus influenza, mycoplasma pneumonia and staphylococcus. Viral infections here included Adenovirus, Enterovirus, Rhinovirus, RSV and Influenza A. a Analyzed by Mann–Whitney U test for continuous variables, and Fisher’s exact test for categorical variables. Note: Significant p-values were highlighted in bold. DISCUSSION Mortality and morbidity of severe pneumococcal disease SPD could result in death, septicemia or lung injury and permanent disabilities despite treatment with systemic antibiotics and intensive care support. Our study showed that pneumococcus were isolated in 1.6% of PICU patients, associated with a 20% mortality. The universal immunization and introduction of 13-valent PCV (PCV-13) in late 2011 provides an important opportunity to study the effects of vaccination on mortality, morbidity and serotypic changes of SPD in a PICU setting. This 10-year study demonstrates that confirmed SPD is uncommon in the PICU. However, the proportion of PICU patients admitted for SPD in our PICU has doubled despite universal childhood immunization with 13-valent PCV from late 2011. The true incidence of invasive pneumococcal disease (IPD) may never be accurately estimated in any population. Therefore it is important to assess the disease burden by studying patients with more severe disease or patients with one or more organ dysfunction (such as respiratory failure or septic shock). In Hong Kong, most of these children with organ system dysfunction are cared for in the PICU. Furthermore, the chances of isolation of pneumococcus may be higher in the PICU. Pneumococcus in the deeper sites may be yielded by such investiagations as pleural tap, deep tracheal aspiration or brochoalveolar lavage in a PICU setting. Hence, PICU is the ideal setting in studying the impact of SPD. Serotypes of pneumococcus Another key observation in our study is that shortly after universal immunization with PCV-13, there was a surge of SPD due to serogroup 3, which initially led to some fatality in our long series despite its small sample size. The increase in serotype 3 following PCV-13 immunization may be due to selection or a cyclic increase of a serotype. Serogroup 3 was supposed to be covered by the 13-valent PCV [9]. However due to the unique structure of the capsule of serogroup 3, protection against this serotype by PCV-13 was low [9]. Further literature review shows reduction of serotype 3 disease demonstrated in one European study, [10] but no evidence of protection or disease reduction in several large studies in Ireland, UK, Australia and Israel, respectively [11–14]. In contrast serogroups 6 and 19 were well covered by PCV-13, resulting in their low prevalences in the post-2012 era. Serogroups 6 and 19 include 6B and 6C, and 19A and 19F respectively. We have noted one case of serotype 6C. There is some cross coverage of 6C by other serotypes 6A and 6B [15]. Evolving non-susceptible serotypes have been reported since PCV-13 immunization [16]. Therefore, serotypes of SPD must be closely monitored [4, 10]. In an early local study, the prevalence of penicillin-nonsusceptible pneumococcus isolated in a Hong Kong hospital ranged from 46.7–63.6% each year [17]. In a respiratory surveillance study in 2005–6 from the same hospital, the penicillin and cefotaxime non-susceptibilities of pneumococcus isolated in this pediatric cohort were 64.9% and 37.2% respectively [18]. Among isolates from young children aged <5 years, dual penicillin/erythromycin resistance has increased from 44.1% to 64.2% (p = 0.01) [19]. Local antimicrobial sensitivity in PICU patients has also been reported [1]. These new clones of penicillin-nonsusceptible, multi-drug-resistant pneumococcus have led to the recommendation of the inclusion of vancomycin in patients with suspected invasive pneumococcal infection pending sensitivity evaluation [17, 18, 20, 21]. Our study of SPD in a PICU setting showed that pneumococcus is generally susceptible to high doses of penicillin. The Hong Kong Government introduced the PCV-7 vaccine in September 2009. In 2010, the vaccine was changed to the 10-valent vaccine and in 2011 recommendation was made to switch to a 13-valent vaccine. Serotype replacement has been observed [5]. Locally, the coverage of the 7-valent or 10-valent and 13-valent vaccines was 65% and 90%, respectively [19]. The serotype 19A is especially virulent and may be difficult to isolate in patients who have already been started on antibiotics. The pathogen has been reported to be associated with the hemolytic uremic syndrome [22–24]. Five of the 29 patients in our series developed hemolytic uremic syndrome. Ongoing surveillance in the post-vaccination era will be important to monitor the evolution and distribution of serotypes [4, 10]. The PCV-13 potentially prevents the 3 and 19A serotypes [8, 25, 26]. Nevertheless, we found serogroups 19 and 6 were reduced but not serogroup 3. Severe versus invasive pneumococcal disease Terminology on invasiveness or severity of streptococcal disease can be confusing in that invasive disease may not be severe and severe disease may not be invasive. There were children in the community with “invasive” occult pneumococcal bacteremia or pneumonia but not sick enough to deserve ICU support. They are often treated by their general practitioners or pediatricians. Our series arbitrarily define disease severity by the necessity of PICU admission/support and the term SPD was used instead of IPD. A recent community-based, cross-sectional surveillance study between 2013 and 2014 showed the rate of pneumococcal carriage was low in young children in Hong Kong and there appeared to have been an overall reduction in the carriage rate after introduction of PCV immunisation [16]. Also, serotype replacement was noted with a predominance of non-vaccine serotypes in pneumococcal carriage with the emergence of serogroup/type 15 and 6 C. However, findings of community surveillance studies in healthy children may not reflect prevalence of IPD or SPD. Hospitalization and especially in intensive care setting may be a more relevant venue to study SPD or IPD. With time, we might see emergence of non-vaccine serotypes. Continuous surveillance of the serotypes is necessary, while development of novel, non-capsular targeted vaccines are sought. SPD is associated with significant morbidity and mortality despite treatment with systemic antibiotics and ICU support. The expanded coverage of the PCV-13 results in the reduction of serogroups 6 and 19 but not mortality/morbidity associated with SPD in the setting of a local PICU. There were some limitations to this study. Our findings may not represent the complete spectrum of clinical pattern and outcome of SPD due to its small sample size and retrospective nature. A significant issue is that some patients have already received empirical antibiotics prior to hospital presentation, rendering false negative culture results despite genuine infections. We have witnessed a number of cases with typical lobar pneumonia± positive urine streptococcus antigen but cultures did no yield any organism. In two of the reported cases, pneumococcus was yielded but serotyping not obtained. Serotyping was not routinely performed in some of the local units rendering study of serotyping difficult in population studies. Despite these limitations, our meticulous attempts in SP isolation and serotyping enable important epidemiology of SPD to be characterized. FUNDING KL Hon has received travel and conference sponsorships from Pfizer (Wyeth). MI has received funds for sponsored studies from Pfizer (Wyeth), Novartis, Belpharma (Luxembourg) and Consultancy service for MSD. TF Leung has involved in influenza and viral immunization studies. REFERENCES 1 Hon KL , Ip M , Lee K , et al. Childhood pneumococcal diseases and serotypes: can vaccines protect? . Indian J Pediatr 2010 ; 77 : 1387 – 91 . 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Genetic analyses of penicillin binding protein determinants in multidrug-resistant Streptococcus pneumoniae serogroup 19 CC320/271 clone with high-level resistance to third-generation cephalosporins . Antimicrob Agents Chemother 2015 ; 59 : 4040 – 5 . Google Scholar CrossRef Search ADS PubMed 22 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 : 736 – 9 . Google Scholar CrossRef Search ADS PubMed 23 Copelovitch L , Kaplan BS. Streptococcus pneumoniae–associated hemolytic uremic syndrome: classification and the emergence of serotype 19A . Pediatrics 2010 ; 125 : e174 – 82 . Google Scholar CrossRef Search ADS PubMed 24 Hon KL , Ip M , Chu WC , Wong W. Megapneumonia coinfection: Pneumococcus, Mycoplasma pneumoniae, and Metapneumovirus . Case Report Med 2012 ; 2012 : 310104. Google Scholar CrossRef Search ADS 25 Giebink GS. The prevention of pneumococcal disease in children . N Engl J Med 2001 ; 345 : 1177 – 83 . Google Scholar CrossRef Search ADS PubMed 26 Kyaw MH , Lynfield R , Schaffner W , et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae . N Engl J Med 2006 ; 354 : 1455 – 63 . Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Change in Pneumococcus Serotypes but not Mortality or Morbidity in Pre- and Post-13-Valent Polysaccharide Conjugate Vaccine Era: Epidemiology in a Pediatric Intensive Care Unit over 10 Years

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Oxford University Press
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© The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0142-6338
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10.1093/tropej/fmx084
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Abstract

Abstract Aim Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally cause severe pneumococcal disease with high mortality and morbidity. We reviewed all pneumococcal serotypes and mortality/morbidity in a pediatric intensive care unit (PICU) following universal pneumococcal conjugate vaccine (PCV) immunization. Methods A 13-valent PCV was introduced in the universal immunization program in late 2011 in Hong Kong. We retrospectively reviewed all pneumococcal serotypes in the pre-(2007–11) and post-(2012–16) 13-valent PCV era. Results There were 29 (1.9%) PICU patients with pneumococcal isolation, of which 6 died (20% motality). Serogroups 6 and 19 predominated before and Serogroup 3 after 2012. In the post-13-valent PCV era, the prevalence of pneumococcus isolation in PICU was increased from 1 to 2% (p = 0.04); Serogroup 3 was the major serotype of morbidity, despite supposedly under vaccine coverage. The majority of pneumococcus were penicillin-sensitive (94%) in the post 13-valent PCV era. All pneumococcus specimens were sensitive to cefotaxime and vancomycin. Binary logistic regression showed that there were reductions in Serogroup 6 (odds ratio [OR], 0.050; 95% confidence interval [CI], 0.004–0.574; p = 0.016) and Serogroup 19 (odds ratio [OR], 0.105; 95% confidence interval [CI], 0.014–0.786; p = 0.028) but not mortality or morbidity for patients admitted after 2012. Conclusions SPD is associated with significant morbidity and mortality, despite treatment with systemic antibiotics and ICU support. The expanded coverage of 13-valent PCV results in the reduction of Serotypes 6 and 19 but not mortality/morbidity associated with SPD in the setting of a PICU. pneumococcus, serotypes, pleural effusion, immunizations, mortality, PICU INTRODUCTION Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally are responsible for severe pneumococcal disease (SPD) requiring intensive care support with high mortality and morbidity [1–3]. The World Health Organization (WHO) reports that pneumococcal disease is the world’s number one vaccine-preventable cause of death among infants and children <5 years of age [4]. A 13-valent polysaccharide vaccine was introduced in the universal immunization program in late 2011 in Hong Kong [5, 6]. This study investigated morbidity and mortality associated with pneumococcal infections in patients admitted to the pediatric intensive care unit (PICU). METHODS All children admitted to PICU of a university-affiliated teaching hospital (Prince of Wales Hospital [PWH]) in the pre-(2007–11) and post-(2012–16) 13-valent era with a laboratory isolation of pneumococcus were included. PWH provides tertiary PICU service for children aged up to 14 years in the Eastern New Territories cluster of Hong Kong with a catchment population of over 1.1 million (∼25% were children <12 years of age) [7]. Children with confirmed pneumococcal disease (culture of Streptococcus pneumoniae (SP) from blood, CSF or sterile body fluid) were identified by using the principal author’s database, which registered every PICU admission. Demographic data, mortality, length of PICU stay, hospital stay (till discharge or death), complications, pneumococcal serotype, specimen site and co-infection were compared with Mann–Whitney U test (for continuous data) or Fisher’s exact test (for categorical data). Binary logistic regression was performed using IBM SPSS 20.0 to ascertain the association of patients' admission year and the outcome of SP serotypes. All comparisons were made two-tailed, and p-values <0.05 were considered statistically significant. Ethics approval for this review was obtained from the hospital Clinical Research Ethics Committee. SP was identified using conventional diagnostic methodology from blood cultures, cerebrospinal fluids, pleural aspirates, tracheal aspirates (via endotracheal tube in intubated patients), urine or deep wound swabs (e.g. retropharyngeal abscess, peritoneum, post-mortem specimens). Specimens were processed in the same microbiology laboratory with standardized procedures and equipment. The antibiotic susceptibilities of SP against erythromycin, co-trimoxazole and vancomycin were performed by disc testing, whilst the minimum inhibitory concentrations (MICs) of penicillin and cefotaxime were determined using E-test according to criteria set by the Clinical Laboratory Standards Institute [1]. Capsular typing was performed using Pneumotest antisera (Statens Seruminstitut, Copenhagen) according to the manufacturer’s instruction. Specific serogroups typing has become available since 2007, using factor sera and multiplex PCR that targeted serotypes of the 13-valent vaccine [8]. Laboratory-proven co-infections were also evaluated. RESULTS Over the 10-year period, SP was isolated in 29 patients (Table 1). There were six deaths (20% motality). Serotyping was available in all but two of them. The majority of SP were sensitive to penicillin (MICs (0.06–2.0 μg/ml). All SP specimens were sensitive to cefotaxime and vancomycin. Bacterial, viral and fungal co-infections were occasionally found. Table 1 Pneumococcal disease as a percentage of the annual PICU admissions Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) N/A: not available; PCV: pneumococcal conjugate vaccine; PICU: pediatric intensive care unit. Table 1 Pneumococcal disease as a percentage of the annual PICU admissions Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) Year PICU admissions Pneumococcus (serotype) Remarks 2007 144 1 (19F) 2008 138 1 (19F) 2009 140 3 (6B, 6B, 19A) Universal immunization program PCV7 2010 149 1 (6B) Changed to PCV10 2011 198 2 (6C, 19A) Changed to PCV13 2012 187 3 (3, 3, 23A) 2013 226 4 (3, 3, 19A, 23F) 2014 190 4 (6C, 15A/F, 19A, 23F) 2015 216 6 (all 3) 2016 212 4 (3, 3, N/A, N/A) Total 1800 29 (1.6%) N/A: not available; PCV: pneumococcal conjugate vaccine; PICU: pediatric intensive care unit. Demographics and pneumococcal serotypes in the pre- (2007–2011) and post-(2012–16) 13-valent eras were compared (Table 2). Most patients were healthy young children with no premorbid conditions such as malignancy, mental retardation/cerebral palsy (MRCP)+/-seizure disorders, chromosomal or genetic disorders. In the post 13-valent PCV era, the proportion of PICU patients admitted for SPD was increased from 1% to 2% (p = 0.04), serogroup 3 was the major serogroup despite supposedly under vaccine coverage. Binary logistic regression showed that there were reductions of serogroup 6 (odds ratio [OR], 0.050; 95% confidence interval [CI], 0.004–0.574; p = 0.016) and serogroup 19 (odds ratio [OR], 0.105; 95% confidence interval [CI], 0.014–0.786; p = 0.028), but not mortality or morbidity for patients admitted after 2012. Table 2 Comparisons of demographics and clinical variables between PICU patients admitted before and after 2012 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 CRP: C-reactive protein; CSF: cerebrospinal fluid; IQR: interquartile range; MRCP: mental retardation/cerebral palsy; NPA: nasopharyngeal aspirate; N/A: not applicable. Bacterial and viral co-infection is defined here as infection incurred and results obtained from patient samples between the start of admission and discharge. Bacterial infections here included haemophilus influenza, mycoplasma pneumonia and staphylococcus. Viral infections here included Adenovirus, Enterovirus, Rhinovirus, RSV and Influenza A. a Analyzed by Mann–Whitney U test for continuous variables, and Fisher’s exact test for categorical variables. Note: Significant p-values were highlighted in bold. Table 2 Comparisons of demographics and clinical variables between PICU patients admitted before and after 2012 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 Demographics and clinical variables Admitted before 2012 (n = 8) Admitted after 2012 (n = 21) p-valuea Incidence (%) 8/769 (1%) 21/1031 (2%) 0.040 Median (IQR) age, year 3.4 (6.0) 2.8 (3.8) 0.770 Female, n (%) 4 (50.0) 13 (61.9) 0.683 Premorbidity (malignancy, MRCP, chromosomal or genetic disorders), n (%) (n = 26) 2 (25.0) (n = 8) 1 (5.6) (n = 18) 0.215 Lung tissue/Pleural fluid (NPA/tracheal aspirate/sputum), n (%) (n = 27) 6 (75.0) (n = 8) 13 (68.4) (n = 19) >0.999 Blood culture, n (%) (n = 27) 3 (37.5) (n = 8) 5 (26.3) (n = 19) 0.658 Other miscellaneous sites (wound, CSF samples, abscesses, peritoneal swab), n (%) (n = 27) 2 (25.0) (n = 8) 6 (31.6) (n = 19) >0.999 Serotype 3, n (%) 0 (0) 12 (57.1) 0.009 Serotype 6, n (%) 4 (50.0) 1 (4.8) 0.013 Serotype 19, n (%) 4 (50.0) 2 (9.5) 0.033 Miscellaneous/untypeable (not serotype 3,6 or 19), n (%) 0 (0) 6 (28.6; 1 type 15, 3 type 23, 2 untypable) 0.148 Mechanical ventilation, n (%) 4 (50.0) 16 (76.2) 0.209 Inotrope, n (%) 2 (25.0) 10 (47.6) 0.408 Dialysis, n (%) 1 (12.5) 4 (19.0) >0.999 Prematurity (Less than 37 weeks), n (%) (n = 24) 0 (0) (n = 6) 0 (0) (n = 18) N/A Prior pneumococcal vaccination, n (%) (n = 27) 4 (66.7) (n = 6) 15 (71.4) (n = 21) >0.999 Median (IQR) CRP, g/dL (n = 27) 182.8 (338.8) (n = 7) 111.7 (204.4) (n = 20) 0.934 Death, n (%) 1 (12.5) 5 (23.8) 0.647 Median (IQR) ICU stay, day 3.0 (2.0) 4.0 (8.0) 0.403 Median (IQR) hospital stay, day 15.0 (31.0) 15.0 (16.0) 0.558 Bacterial co-infection, n (%) 4 (50.0) 2 (9.5) 0.033 Viral co-infection, n (%) 2 (25.0) 7 (33.3) >0.999 Penicillin sensitive, n (%) (n = 25) 5 (62.5) (n = 8) 16 (94.1) (n  =  17) 0.081 PCV 13 serotpye 7 (88%) 16 (76%) 0.460 CRP: C-reactive protein; CSF: cerebrospinal fluid; IQR: interquartile range; MRCP: mental retardation/cerebral palsy; NPA: nasopharyngeal aspirate; N/A: not applicable. Bacterial and viral co-infection is defined here as infection incurred and results obtained from patient samples between the start of admission and discharge. Bacterial infections here included haemophilus influenza, mycoplasma pneumonia and staphylococcus. Viral infections here included Adenovirus, Enterovirus, Rhinovirus, RSV and Influenza A. a Analyzed by Mann–Whitney U test for continuous variables, and Fisher’s exact test for categorical variables. Note: Significant p-values were highlighted in bold. DISCUSSION Mortality and morbidity of severe pneumococcal disease SPD could result in death, septicemia or lung injury and permanent disabilities despite treatment with systemic antibiotics and intensive care support. Our study showed that pneumococcus were isolated in 1.6% of PICU patients, associated with a 20% mortality. The universal immunization and introduction of 13-valent PCV (PCV-13) in late 2011 provides an important opportunity to study the effects of vaccination on mortality, morbidity and serotypic changes of SPD in a PICU setting. This 10-year study demonstrates that confirmed SPD is uncommon in the PICU. However, the proportion of PICU patients admitted for SPD in our PICU has doubled despite universal childhood immunization with 13-valent PCV from late 2011. The true incidence of invasive pneumococcal disease (IPD) may never be accurately estimated in any population. Therefore it is important to assess the disease burden by studying patients with more severe disease or patients with one or more organ dysfunction (such as respiratory failure or septic shock). In Hong Kong, most of these children with organ system dysfunction are cared for in the PICU. Furthermore, the chances of isolation of pneumococcus may be higher in the PICU. Pneumococcus in the deeper sites may be yielded by such investiagations as pleural tap, deep tracheal aspiration or brochoalveolar lavage in a PICU setting. Hence, PICU is the ideal setting in studying the impact of SPD. Serotypes of pneumococcus Another key observation in our study is that shortly after universal immunization with PCV-13, there was a surge of SPD due to serogroup 3, which initially led to some fatality in our long series despite its small sample size. The increase in serotype 3 following PCV-13 immunization may be due to selection or a cyclic increase of a serotype. Serogroup 3 was supposed to be covered by the 13-valent PCV [9]. However due to the unique structure of the capsule of serogroup 3, protection against this serotype by PCV-13 was low [9]. Further literature review shows reduction of serotype 3 disease demonstrated in one European study, [10] but no evidence of protection or disease reduction in several large studies in Ireland, UK, Australia and Israel, respectively [11–14]. In contrast serogroups 6 and 19 were well covered by PCV-13, resulting in their low prevalences in the post-2012 era. Serogroups 6 and 19 include 6B and 6C, and 19A and 19F respectively. We have noted one case of serotype 6C. There is some cross coverage of 6C by other serotypes 6A and 6B [15]. Evolving non-susceptible serotypes have been reported since PCV-13 immunization [16]. Therefore, serotypes of SPD must be closely monitored [4, 10]. In an early local study, the prevalence of penicillin-nonsusceptible pneumococcus isolated in a Hong Kong hospital ranged from 46.7–63.6% each year [17]. In a respiratory surveillance study in 2005–6 from the same hospital, the penicillin and cefotaxime non-susceptibilities of pneumococcus isolated in this pediatric cohort were 64.9% and 37.2% respectively [18]. Among isolates from young children aged <5 years, dual penicillin/erythromycin resistance has increased from 44.1% to 64.2% (p = 0.01) [19]. Local antimicrobial sensitivity in PICU patients has also been reported [1]. These new clones of penicillin-nonsusceptible, multi-drug-resistant pneumococcus have led to the recommendation of the inclusion of vancomycin in patients with suspected invasive pneumococcal infection pending sensitivity evaluation [17, 18, 20, 21]. Our study of SPD in a PICU setting showed that pneumococcus is generally susceptible to high doses of penicillin. The Hong Kong Government introduced the PCV-7 vaccine in September 2009. In 2010, the vaccine was changed to the 10-valent vaccine and in 2011 recommendation was made to switch to a 13-valent vaccine. Serotype replacement has been observed [5]. Locally, the coverage of the 7-valent or 10-valent and 13-valent vaccines was 65% and 90%, respectively [19]. The serotype 19A is especially virulent and may be difficult to isolate in patients who have already been started on antibiotics. The pathogen has been reported to be associated with the hemolytic uremic syndrome [22–24]. Five of the 29 patients in our series developed hemolytic uremic syndrome. Ongoing surveillance in the post-vaccination era will be important to monitor the evolution and distribution of serotypes [4, 10]. The PCV-13 potentially prevents the 3 and 19A serotypes [8, 25, 26]. Nevertheless, we found serogroups 19 and 6 were reduced but not serogroup 3. Severe versus invasive pneumococcal disease Terminology on invasiveness or severity of streptococcal disease can be confusing in that invasive disease may not be severe and severe disease may not be invasive. There were children in the community with “invasive” occult pneumococcal bacteremia or pneumonia but not sick enough to deserve ICU support. They are often treated by their general practitioners or pediatricians. Our series arbitrarily define disease severity by the necessity of PICU admission/support and the term SPD was used instead of IPD. A recent community-based, cross-sectional surveillance study between 2013 and 2014 showed the rate of pneumococcal carriage was low in young children in Hong Kong and there appeared to have been an overall reduction in the carriage rate after introduction of PCV immunisation [16]. Also, serotype replacement was noted with a predominance of non-vaccine serotypes in pneumococcal carriage with the emergence of serogroup/type 15 and 6 C. However, findings of community surveillance studies in healthy children may not reflect prevalence of IPD or SPD. Hospitalization and especially in intensive care setting may be a more relevant venue to study SPD or IPD. With time, we might see emergence of non-vaccine serotypes. Continuous surveillance of the serotypes is necessary, while development of novel, non-capsular targeted vaccines are sought. SPD is associated with significant morbidity and mortality despite treatment with systemic antibiotics and ICU support. The expanded coverage of the PCV-13 results in the reduction of serogroups 6 and 19 but not mortality/morbidity associated with SPD in the setting of a local PICU. There were some limitations to this study. Our findings may not represent the complete spectrum of clinical pattern and outcome of SPD due to its small sample size and retrospective nature. A significant issue is that some patients have already received empirical antibiotics prior to hospital presentation, rendering false negative culture results despite genuine infections. We have witnessed a number of cases with typical lobar pneumonia± positive urine streptococcus antigen but cultures did no yield any organism. In two of the reported cases, pneumococcus was yielded but serotyping not obtained. Serotyping was not routinely performed in some of the local units rendering study of serotyping difficult in population studies. Despite these limitations, our meticulous attempts in SP isolation and serotyping enable important epidemiology of SPD to be characterized. FUNDING KL Hon has received travel and conference sponsorships from Pfizer (Wyeth). MI has received funds for sponsored studies from Pfizer (Wyeth), Novartis, Belpharma (Luxembourg) and Consultancy service for MSD. TF Leung has involved in influenza and viral immunization studies. REFERENCES 1 Hon KL , Ip M , Lee K , et al. Childhood pneumococcal diseases and serotypes: can vaccines protect? . Indian J Pediatr 2010 ; 77 : 1387 – 91 . 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Lancet Respir Med 2017 ; 5 : 648 – 56 . Google Scholar CrossRef Search ADS PubMed 11 Corcoran M , Vickers I , Mereckiene J , et al. The epidemiology of invasive pneumococcal disease in older adults in the post-PCV era. Has there been a herd effect? Epidemiol Infect 2017 ; 145 : 2390 – 9 . Google Scholar CrossRef Search ADS PubMed 12 Jayasinghe S , Menzies R , Chiu C , et al. Long-term impact of a “3 + 0” schedule for 7- and 13-valent pneumococcal conjugate vaccines on invasive pneumococcal disease in Australia, 2002-2014 . Clin Infect Dis 2017 ; 64 : 175 – 83 . Google Scholar CrossRef Search ADS PubMed 13 Waight PA , Andrews NJ , Ladhani SN , et al. Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study . Lancet Infect Dis 2015 ; 15 : 535 – 43 . Google Scholar CrossRef Search ADS PubMed 14 Dagan R , Juergens C , Trammel J , et al. 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The prevention of pneumococcal disease in children . N Engl J Med 2001 ; 345 : 1177 – 83 . Google Scholar CrossRef Search ADS PubMed 26 Kyaw MH , Lynfield R , Schaffner W , et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae . N Engl J Med 2006 ; 354 : 1455 – 63 . Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

Journal of Tropical PediatricsOxford University Press

Published: Nov 6, 2017

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