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Original Article
DOI: 10.1016/j.anpede.2021.06.005
Open Access
Available online 7 July 2021
Invasive pneumococcal disease in children under 60 months before and after availability of 13-valent conjugate vaccine
Enfermedad neumocócica invasiva en niños menores de 60 meses, antes y después de la introducción de la vacuna conjugada 13-valente
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Johanna Martínez-Osorioa,
Corresponding author
, Juan José García-Garcíab,c, Fernando Moraga-Llopd, Alvaro Díaze, Sergi Hernándezf, Anna Solé-Ribaltaa, Sebastià González-Perisd, Conchita Izquierdof, Cristina Estevab,c, Gemma Codinad, Ana María Planesd, Sonia Urionad, Magda Campinsd, Pilar Ciruelaf, Luis Sallerasg, Ángela Domínguezc,g, Carmen Muñoz-Almagrob,c,h, Mariona F. de Sevillab,c
a Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
b Malalties Prevenibles amb Vacunes, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
c Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
d Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
e Hospital de Nens, Barcelona, Spain
f Agència de Salut Pública de Catalunya, Generalitat de Catalunya, Barcelona, Spain
g Departament de Medicina, Universitat de Barcelona, Barcelona, Spain
h Departament de Medicina, Universitat Internacional de Catalunya, Barcelona, Spain
Received 18 February 2021. Accepted 20 May 2021
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Tables (5)
Table 1. Baseline characteristics, microbiological diagnosis and outcomes.
Table 2. Incidence by clinical presentation.
Table 3. Distribution of cases of IPD by serotype.
Table 4. Distribution of the most prevalent serotypes by clinical outcome.
Table 5. Antimicrobial susceptibility in 208 invasive pneumococcal strains.
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Additional material (1)
Abstract
Background

Invasive pneumococcal disease (IPD) is the most important bacterial infection in young children, and the introduction of pneumococcal conjugate vaccines has changed its presentation. This study compared the incidence, characteristics and serotype distribution of IPD before and after the introduction of the pneumococcal conjugate vaccine (PCV13).

Methods

Prospective enrolment of patients with IPD aged less than 60 months and admitted to either of 2 tertiary care hospitals between January 2007 and December 2009 (pre-PCV13 period) and January 2012 and June-2016 (PCV13 period).

Results

We identified 493 cases, 319 in the pre-PCV13 period and 174 in the PCV13 period. The incidence of IPD decreased from 89.7 to 34.4 casos per 100 000 habitantes ( −62%; P < .001). This decrease was observed in all forms of disease except necrotising pneumonia (increase from 0.8 to 3.7 casos/100 000 population). There was a significant reduction in all serotypes included in the PCV13 and not included in the PCV7. We did not find significant differences in length of stay, mortality or the frequency of sequelae between both periods, but in the PCV13 period, the length of stay in the paediatric intensive care unit and the duration of mechanical ventilation were longer (P = .00). The incidence of serotype 3 decreased from 10.4 to 6.9 casos per 100 000 population, although it was the serotype involved most frequently in patients with severe disease.

Conclusions

After the introduction of the PCV13, there has been a significant decrease in IPD cases. Serotype 3 continues to be an important cause of severe IPD.

Keywords:
Pneumococcal conjugate vaccine
Invasive pneumococcal disease
Streptococcus pneumoniae
Resumen
Introducción

La enfermedad neumocócica invasiva (ENI) es la infección bacteriana más relevante en niños pequeños y la introducción de las vacunas antineumocócicas conjugadas (VNC) ha cambiado su presentación clínica. En este estudio se analizaron los cambios en la incidencia, características clínicas y distribución de serotipos en los casos de ENI antes y después de la disponibilidad de la VNC13.

Métodos

Se incluyeron prospectivamente pacientes con ENI menores de 60 meses ingresados en dos hospitales pediátricos terciarios desde enero de 2007 a diciembre de 2009 (periodo pre-VNC13) y de enero de 2012 a junio de 2016 (período VNC13).

Resultados

Se identificaron 493 casos, 319 en el período pre-VNC13 y 174 en el período VNC13. La incidencia de ENI disminuyó de 89,7 a 34,4 casos por 100 000 habitantes (−62%, p < 0,001). Esta disminución de la incidencia se dio por igual en todas las presentaciones clínicas de la enfermedad excepto en la neumonía necrotizante (aumentó de 0,8 a 3,7 casos x 100 000 habitantes). Todos los serotipos incluidos en la VNC13 pero no incluidos en la VNC7 disminuyeron significativamente. No se encontraron diferencias significativas en la estancia hospitalaria, muerte y/o secuelas entre ambos períodos, aunque durante el período VNC13, los pacientes requirieron más días en la unidad de cuidados intensivos pediátricos y de ventilación mecánica (p = 0,00). La incidencia del serotipo 3 disminuyó de 10,4 a 6,9 casos x 100 000 habitantes, aunque fue el serotipo más frecuente en los pacientes con un cuadro clínico grave.

Conclusiones

luego de la introducción de la VNC13 se ha producido una disminución significativa de los casos de ENI. El serotipo 3 sigue siendo una causa importante de casos graves de enfermedad neumocócica invasiva.

Palabras clave:
Vacuna antineumocócica conjugada VNC
Enfermedad neumocócica invasiva
Streptococcus pneumoniae
Full Text
Introduction

Streptococcus pneumoniae is a gram-positive bacterium with more than 95 identified capsular serotypes1. Infection with this pathogen is a major cause of morbidity and mortality in both adults and children worldwide, with a wide clinical spectrum that ranges from asymptomatic colonization to mucosal disease, and invasive infection (involving previously sterile sites)2,3. Before the introduction of the pneumococcal conjugate vaccine, S. pneumoniae caused between 8% and 12% of all deaths in children under 5 years, amounting to an estimated 1 million deaths per year worldwide. In 2008, the mortality was estimated at 500 000 deaths per year worldwide4–6.

Invasive pneumococcal disease (IPD) is most prevalent in the very young and the elderly, especially in children under 5 years. The most frequent presentations are pneumonia, meningitis and bacteraemia. The introduction of pneumococcal conjugate vaccines has had a significant impact on IPD in terms of disease incidence and the serotype distribution. After the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in the United States, there was a dramatic decline in the incidence of IPD. However, in our region there was a significant increase in the incidence of IPD caused by non-PCV7 serotypes, a slight reduction in the rate of IPD caused by PCV7 serotypes and emergence of previously stable virulent clones of non-PCV7 serotypes2,7–9. With the aim of improving vaccine coverage against non-PCV7 serotypes, the 13-valent pneumococcal conjugate vaccine (PCV13) was approved in 2010 for active immunization of children aged 6 weeks to 5 years. Although the Advisory Committee on Vaccines of the Asociación Española de Pediatría (Spanish Association of Pediatrics, AEP) has recommended routine administration of conjugate pneumococcal vaccines (PCV7 in the 2003–2010 period and PCV13 once it had been authorised/introduced), at the time of this writing these vaccines were not funded by the public health system of Catalonia except for children with selected risk factors, and therefore their administration depended on the judgment of the paediatrician and the willingness of families. The pneumococcal vaccine coverage in Catalonia in children under 60 months has been estimated at 50% in the pre-PCV13 period and 63% in the PCV13 period, based on previous studies conducted by our group9–11.

The aim of the present study was to compare the incidence and describe epidemiological variables, the clinical presentation, current trends and serotype distribution for IPD among children before and after the introduction of the PCV13 in Catalonia, Spain, a region where this vaccine was not included in the routine vaccination schedule.

MethodsSample and definitions

We conducted a prospective study in patients with IPD aged less than 60 months and admitted to either of 2 tertiary care hospitals in Barcelona (Catalonia, Spain) over 6 years. The study period was divided into a pre-PCV13 period (January 2007 to December 2009) and a PCV13 period (January 2012 to June 2016). The participating hospitals were the Hospital Sant Joan de Déu and the Hospital Vall d’Hebron, 2 referral children’s hospitals corresponding to more than 30% of the total paediatric admissions in Catalonia, a region with a population of 7 500 000 inhabitants of who more than 400 000 are children aged less than 5 years12. After the introduction of the PCV13 in 2010, the vaccine coverage in children under 60 months in Catalonia was estimated at 55% in the 2012–2013 period and 78% in 201512,13.

We defined case of IPD as the presence of clinical manifestations of infection with detection of S. pneumoniae in any normally sterile body fluid2,10,12. We defined microbiological detection as isolation of a S. pneumoniae strain in culture and/or detection by real-time polymerase chain reaction (RT-PCR) of ply and/or lyta genes and an additional capsular gene of S. pneumoniae.

We obtained the vaccination status from the personal vaccination card or primary care records of the patients. The PCV13-PCV7 vaccination schedule in Catalonia follows a 3 + 1 scheme, with administration of 3 doses in the first 6 months of life (at ages 2, 4 and 6 months) followed by a booster dose at age 12–15 months. We defined PCV vaccine failure as recommended by the Council for the International Organizations of Medical Sciences and the World Health Organization (WHO) Working Group as illness in a correctly vaccinated individual13–15.

Confidentiality and ethical considerations

The study did not involve performance of diagnostic tests or collection of samples in any participant besides those required by routine care. The protocol adhered to the principles of the Declaration of Helsinki and current legislation on international human rights, biomedicine and the protection of personal data and was approved by the Clinical Research Ethics Committee of the Fundació Sant Joan de Déu. We obtained signed informed consent from the parents or legal guardians of all participants (cases and controls). All data were kept confidential and data collection from records was anonymised.

Data collection

For each patient, we collected general and clinical data at hospital admission, discharge and 6 months post discharge. The epidemiological variables included age, sex, S. pneumoniae vaccination status (when documented), comorbidities (with categorization into 2 risk groups based on the criteria of the American Academy of Pediatrics13–15), attendance to childcare centre, antibiotic treatment and/or respiratory infection before the diagnosis of IPD, history of breastfeeding, clinical presentation of IPD and past medical history.

The clinical variables included the clinical presentation, length of stay, intensive care unit (ICU) admission, complications, antibiotherapy at admission and discharge, death and presence of sequelae at 180 days post discharge. We also collected microbiological data on the identified S. pneumoniae serotypes and antimicrobial susceptibility to penicillin/cefotaxime.

Microbiological testing

All pneumococcal isolates were identified by the same microbiological methods throughout the study period, including the optochin susceptibility test and an antigen test that targets the capsular polysaccharide (Slidex pneumo-kit, bioMérieux, Marcy-l’Étoile, France). Detection of S. pneumoniae DNA was performed by RT-PCR assays with previously described methods, including amplification of the pneumolysin gene (ply) or the autolysin gene (lyta)16,17. Serotyping of the strains isolated by culture was performed with the Quellung reaction at the Centro Nacional de Microbiología (Majadahonda, Spain). In cases diagnosed based solely on the RT-PCR test, previously validated methods were applied for detection of pneumococcal serotypes18,19. In the pre-PCV13 period, the PCR protocol included detection of DNA in the conserved wzg capsular gene and other genes of S. pneumoniae selected to distinguish 24 serotypes (1, 3, 4, 5, 6A/C, 6B/D, 7F/A, 8, 9V/A/N/L, 14, 15B/C, 18C/B, 19A, 19F/B/C, 23A and 23F). In the PCV13 period, the protocol had been improved and allowed identification of 40 serotypes in samples with a high bacterial DNA load, defined by a RT-PCR cycle threshold of 30 or less (1, 2, 3, 4, 5, 6A/6B, 6C, 7C/(7B/40), 7F/7A, 9N/9L, 9V/9A, 10A, 10F/(10C/33C), 11A/11D, 12F/(12A/44/46), 13, 16F, 17F, 18/(18A/18B/18C/18F), 19A, 19F, 20(20A/20B), 21, 22F/22A), 23A, 23B, 24/(24A/24B/24F), 31, 34, 35A/(35C/42), 35B, 35F/47F, 38/25F, 39)18,20. We defined susceptibility to penicillin and third generation cephalosporins applying the 2015 meningeal breakpoints of the Clinical Laboratory Standards Institute (CLSI) using American Type Culture Collection 49619 (serotype 19F) as the control. We defined resistance to penicillin as a minimum inhibitory concentration (MIC) of 0.12 µg/mL or greater and resistance to cefotaxime as a MIC of 2 µg/mL or greater21.

Statistical analysis

We summarised categorical variables as absolute frequencies and percentages and continuous variables as mean ± standard deviation (SD). To compare categorical variables between groups, we used the Pearson chi square or Fisher exact test as applicable, and we used the nonparametric Mann–Whitney U test to assess differences in continuous variables. We defined statistical significance as a p-value of 0.05 or less. The incidence of IPD, defined as the number of cases per 100 000 inhabitants, was calculated using the annual estimates in the paediatric population obtained from the Department of Statistics of Catalonia and the proportion of the total hospitalizations in children under 5 years managed by the 2 participating hospitals22. The statistical analysis was performed with the software packages SPSS version 18.0 (IBM Corp) and OpenEpi 3.023.

Results

During the study period, 493 cases of IPD were detected, 319 in the pre-PCV13 period and 174 in the PCV13 period. A serotype had been documented in 395 of the total cases (245 in the pre-PCV13 period and 150 in the PCV13 period). Table 1 presents the analysis of the baseline characteristics. We found differences in terms of breastfeeding, attendance to childcare centre or school, previous history of respiratory infection, risk factors for pneumococcal disease, microbiological diagnosis and the sites from which positive samples were obtained.

Table 1.

Baseline characteristics, microbiological diagnosis and outcomes.

  Pre-PCV13 period n = 319  PCV13 periodn = 174  P 
Baseline characteristics       
Age, mean ± SD (months)  29.6 ± 15.7  27.5 ± 16.2  .16 
≤24 months, n (%)  129 (40.5%)  82 (47.1%)  .31 
25–59 months, n (%)  190 (59.5%)  92 (52.8%)   
Sex      .06 
Male, n (%)  170 (53.3%)  108 (62.1%)   
Female, n (%)  149 (46.7%)  66 (37.9%)   
Place of birth, n (%)      .37 
Spain  298 (93.4%)  164 (94.3%)   
Outside Spain  21 (6.6%)  10 (5.7%)   
Time of hospitalization, n (%)       
January–March  106 (33.2%)  65 (38%)  .35 
April–June  63 (19.7%)  46 (26.4%)  .08 
July–September  24 (7.5%)  9 (5.2%)  .18 
October–December  126 (39.5%)  54 (31%)  .06 
Underlying disease, n (%)  18 (6.1%)  8 (5.3%)  .71 
Risk Group 2*  4 (1.3%)  10 (5.7%)  .00 
Risk Group 1  – 
Breastfeeding,n (%)  224 (73.4%)  142 (81.6%)  .01 
Attendance to childcare or school,n (%)  244 (79%)  111 (64.5%)  .00 
Respiratory infection in previous month,n (%)  142 (45.8%)  98 (56.3%)  .01 
Antibiotic treatment in previous month, n (%)  49 (15.8%)  25 (14.4%)  .15 
Microbiological diagnosis       
Identification of S. pneumoniae, n (%)       
Only through bacterial culture  54 (16.9%)  46 (26.4%)  .01 
Only through PCR  206 (64.6%)  84 (48.3%)  .00 
Through both culture + PCR  59 (18.5%)  44 (25.3%)  .07 
Site of positive samples, n (%)       
Blood  103 (32.3%)  86 (49.4%)  .00 
Pleural fluid  181 (56.7%)  66 (37.9%)  .00 
Cerebrospinal fluid  29 (9.1%)  15 (8.6%)  .46 
Joint fluid  5 (1.6%)  4 (2.3%)  .33 
Mastoid  0 (0%)  2 (1.1%)  .04 
Other  1 (0.2%)  1 (0.7%)  .26 
Clinical outcomes       
Length of stay, mean ± SD (days)  10.8 ± 7.5  12.2 ± 9.6  .07 
ICU admission,n (%)  43 (13.5%)  41 (23.7%)  .00 
ICU length of stay, mean ± SD (days)  5.5 ± 6  6.9 ± 9  .40 
Mechanical ventilation,n (%)  4 (1.3%)  10 (5.7%)  .00 
Death, n (%)  4 (1.3%)  2 (1.2%)  .93 
Sequelae post discharge, n (%)  33 (10.3%)  17 (9.9%)  .39 

ICU, intensive care unit; PCR, polymerase chain reaction; PCV13, 13-valent pneumococcal conjugate vaccine; SD, standard deviation.

*

Risk groups defined based on the criteria of the American Academy of Pediatrics15.

Vaccination status

In the first period, 131 cases (44.7%) occurred in patients correctly vaccinated with PCV7 for their age and 3 of the cases were caused by PCV7 serotypes (vaccine failure rate, 2.3%). In the second period, 49 cases (32%) occurred in patients correctly vaccinated with PCV13 for their age, 12 of the cases were caused by PCV13 serotypes (vaccine failure rate, 24%, with 10 cases [83.3%] caused by serotype 3). The supplemental table summarises the characteristics of fully vaccinated children with IPD.

Incidence

Table 2 shows the incidence of IPD overall and by clinical presentation. In the pre-PCV13 period, the incidence of IPD increased between 2007 and 2009: 76.2 cases per 100 000 inhabitants in 2007, 82.1 cases per 100 000 inhabitants in 2008 and 109.8 cases per 100 000 inhabitants in 2009. In the PCV13 period, the incidence decreased gradually from 39.6 cases per 100 000 inhabitants in 2012 to 29.7, 32.5, 36.2 and 33 cases per 100 000 inhabitants in 2013, 2014, 2015 and 2016, respectively.

Table 2.

Incidence by clinical presentation.

  Pre-PCV13 periodPCV13 period   
  Cases, n (%)  Incidence*  Cases, n (%)  Incidence*  Change, % (95% CI)  P 
Incidence of IPD*  319 (64.7%)  89.7  174 (35.3%)  34.4  −62% (−69% to −54%)  <.001 
Pneumonia  254 (79.6%)  71.3  120 (69%)  23.7  −67% (−74% to −59%)  <.001 
Pneumonia with empyema  170 (53.3%)  47.7  58 (33.3%)  11.4  −76% (−83% to −68%)  <.001 
Necrotising pneumonia  3 (0.9%)  0.8  19 (10.9%)  3.7  340% (30% to 1400%)  .004 
Meningitis  29 (9.1%)  8.1  18 (10.3%)  3.5  −57% (−76% to −22%)  .002 
Occult bacteraemia  25 (7.8%)  7.0  18 (10.3%)  3.5  −50% (−73% to −8%)  .012 
Septic shock  3 (0.9%)  0.8  6 (3.4%)  0.1  −40% (−65% to 3058%)  .313 
Osteoarticular infection  6 (1.9%)  1.6  7 (4%)  1.3  −18% (−73% to 140%)  .361 
Mastoiditis  0 (0%)  5 (2.9%)  0.9  –  .030 
Cellulitis  2 (0.7%)  0.56  0 (0%)  –  .004 

CI, confidence interval; IPD, invasive pneumococcal disease; PCV13, 13-valent pneumococcal conjugate vaccine.

*

Cases per 100 000 inhabitants.

The incidence of IPD after the introduction of the PCV13 vaccine decreased from 89.7 cases per 100 000 inhabitants to 34.4 cases per 100 000 inhabitants, corresponding to a −62% reduction (95% confidence interval [CI], −69% to ―54%; P < .001).

Table 3 summarises the changes in the frequency of PCV13 serotypes. The frequency of serotypes 3, 1, 19A, 7FA, 5, 6A/C and 19F decreased significantly while changes in the remaining PCV13 serotypes were not significant.

Table 3.

Distribution of cases of IPD by serotype.

Serotype  Pre-PCV13 periodPCV13 period   
  n (%)  Incidence*  n (%)  Incidence*  Change, % (95% CI)  P 
Serotypes included in the PCV13 vaccine,n (%)
37 (12.5%)  10.4  35 (20.7%)  6.9  −34% (−59% to 0%)  .041 
62 (20.9%)  17.4  19 (11.2%)  3.7  −79% (−88% to −64%)  <.001 
19A  47 (15.8%)  13.2  16 (9.5%)  3.1  −77% (−87% to −58%)  <.001 
7 FA  21 (7.1%)  5.9  3 (1.8%)  0.5  −90% (−98% to −67%)  <.001 
9 (3%)  2.5  0 (0%)  –  <.001 
6A/C  6 (2.0%)  1.6  2 (0.6%)  0.3  −77% (−96% to 10%)  .026 
19 F  9 (3%)  2.5  4 (2.4%)  0.7  −69% (−90% to 0%)  .020 
14  12 (4.0%)  3.3  14 (8.3%)  2.7  −18% (−63% to 70%)  .307 
6B/D  0 (0%)  2 (1.2%)  0.3  –  .118 
18C/B  1 (0.3%)  0.2  1 (0.6%)  0.1  −30% (−96% to 1000%)  .401 
9V/A  2 (0.7%)  0.5  2 (1.2%)  0.3  −30% (−91% to 390%)  .361 
23F  3 (1%)  0.8  1 (0.6%)  0.1  −77% (−98% to 120%)  .085 
0 (0%)  1 (0.6%)  0.1  –  .200 
Serotypes not included in the PCV13 vaccine,n (%)
10A  2 (0.7%)  0.5  6 (3.6%)  1.1  110% (−58% to 940%)  .17 
24F  1 (0.3%)  0.3  4 (2.4%)  0.8  180% (−70% to 2410%)  .17 
11A  0 (0%)  4 (2.4%)  0.8  –  .04 
33F  0 (0%)  2 (1.2%)  0.4  –  .11 
24A  1 (0.3%)  0.2  2 (1.2%)  0.4  40% −88% to 1452%)  .38 
23B  3 (1%)  0.8  3 (1.8%)  0.6  −30% (−86% to 248%)  .33 
15A  2 (0.7%)  0.5  2 (1.2%)  0.4  −30% (−91% to 399%)  .36 
15C  1 (0.3%)  0.3  1 (0.6%)  0.2  −30% (−96% to 1000%)  .40 
22F  1 (0.3%)  0.3  2 (1.2%)  0.4  40% (−88% to 1452%)  .38 
38  1 (0.3%)  0.3  2 (1.2%)  0.4  40% (88% to 1452%)  .38 
12F/A/44/46  0 (0%)  3 (1.8%)  0.6  –  .07 
6C  0 (0%)  1 (0.6%)  0.2  –  .20 
0 (0%)  1 (0.6%)  0.2  –  .20 
13  0 (0%)  1 (0.6%)  0.2  –  .20 
15B  0 (0%)  1 (0.6%)  0.2  –  .20 
16F  0 (0%)  1 (0.6%)  0.2  –  .20 
31  0 (0%)  2 (1.2%)  0.4  –  .11 
27  0 (0%)  1 (0.6%)  0.2  –  .20 
25F  0 (0%)  1 (0.6%)  0.2  –  .20 
35B  0 (0%)  1 (0.6%)  0.2  –  .20 
24  0 (0%)  2 (1.2%)  0.4  –  .11 
9V/A  0 (0%)  1 (0.6%)  0.2  –  .20 
6A/C  0 (0%)  1 (0.6%)  0.2  –  .20 
33AF/37  0 (0%)  1 (0.6%)  0.2  –  .20 
35F  0 (0%)  1 (0.6%)  0.2  –  .20 
24B  1 (0.3%)  0.3  0 (0%)  –  .11 
28  1 (0.3%)  0.3  0 (0%)  –  .11 
Serotypes not included in the assay,n (%)
SNIA  74 (24.9%)  20.7  24 (14.2%)  4.7  −78% (−86% to −64%)  .00 

CI, confidence interval; IPD, invasive pneumococcal disease; PCV13, 13-valent pneumococcal conjugate vaccine; SNIA, serotype not included in the serotyping assay.

*

Number of cases per 100 000 inhabitants.

Cases of IPD in the pre-PCV13 period were mainly caused by PCV13 serotypes. After the introduction of the PCV13, we observed a significant reduction in IPD caused by PCV13 serotypes overall, with no evidence of serotype replacement.

Clinical presentation and outcomes

The clinical presentation was different in the 2 periods, with a decrease in the incidence of pneumonia (from 71.3–23.7 cases/100 000 inhabitants; P < .001), meningitis (from 8.1–3.5 cases/100 000 inhabitants; P = .002) and occult bacteraemia (from 7.0–3.5 cases/100 000 inhabitants; P = .012). The incidence of pneumonia with empyema decreased from 47.7–11.4 cases per 100 000 inhabitants (P < .001) of the total cases of pneumonia. There was an important increase in the incidence of necrotizing pneumonia during the study period (from 0.8 to 3.7 cases/100 000 inhabitants; P = .004), which corresponded to a 340% increase (95% CI, 30%–1400%) between the 2 periods. There were no significant changes in the incidence of septic shock and osteoarticular infection during the study period (Table 2).

We did not find statistically significant differences in the mean length of stay, mortality and frequency of sequelae between both periods, although in the PCV13 period patients had longer stays in the paediatric intensive care unit and required more days of mechanical ventilation (P = .00) (Table 1).

Serotypes, molecular testing and antibiotic susceptibility

Serotyping was performed in 466 (94.5%) of the total cases of IPD, 297 (94%) in the first period and 169 (97.1%) in the second period. The most frequently identified serotypes were 1 (62; 20.9%), 19A (47; 15.8%) and 3 (37; 12.5%) in the pre-PCV13 period and 3 (35; 20.7%), 1 (19; 11.2%) and 19A (16; 9.5%) in the PCV13 period. The PCV13 serotypes caused 209 (70.3%) of the 297 cases in the pre-PCV13 period, while in the PCV13 period these serotypes caused 98 (57.9%) of the 169 IPD cases (Table 3).

There was a reduction in the incidence of IPD caused by PCV13 serotypes. The largest decreases corresponded to serotypes 1, 19A, 7F/A and 5. The proportion of cases caused by the main pathogenic serotypes also changed significantly. The proportion of cases of IPD caused by serotype 1 decreased from 20.9%–11.2% in the PCV13 period (P < .001), while cases caused by serotype 3 increased from 11.5%–20.7% (P < .01).

When it came to severe IPD, serotype 3 was the most frequent serotype involved patients that required ICU admission (15.2%), required mechanical ventilation (33%) with prolonged lengths of stay (27.4%), that developed complications during the stay (20.7%) and with sequelae at discharge (20.8%) (Table 4).

Table 4.

Distribution of the most prevalent serotypes by clinical outcome.

Outcome  Serotype  Patients, n (%)  Outcome  Serotype  Patients, n (%) 
ICU admission n = 7919A  13 (16.4%)  No ICU admissionn = 38777 (19.8%) 
12 (15.1%)  60 (15.5%) 
7F  5 (6.3%)  19A  50 (12.9%) 
19F  4 (5.0%)  14  23 (5.9%) 
4 (5.0%)  7FA  9(2.3%) 
Mechanical ventilation n = 124 (33.3%)  No mechanical ventilationn = 45481 (17.8%) 
7F  1 (8.3%)  68 (15%) 
19A  1 (8.3%)  19A  62 (13.7%) 
11A  1 (8.3%)  14  25 (5.5%) 
14  1 (8.3%)  19F  12 (2.6%) 
Prolonged stay >14 daysn = 9526 (27.4%)  Length of stay <14 daysn = 37171 (19.1%) 
19A  16 (16.8%)  19A  47 (12.7%) 
10 (10.5%)  46 (12.4%) 
7F  5 (5.3%)  14  21 (5.7%) 
14  5 (5.3%)  19F  10 (2.7%) 
Complicationsn = 32466 (20.7%)  Without complicationsn = 14219A  20 (14.1%) 
66 (20.7%)  14 (9.9%) 
19A  43 (13.3%)  19F  10 (7.0%) 
14  19 (5.9%)  14  7 (4.9%) 
7FA  10 (3.1%)  10A  6 (4.2%) 
Sequelae post dischargen = 4810 (20.8%)  Free of sequelaen = 41879 (18.8%) 
19A  6 (12.5%)  62 (14.8%) 
7FA  3 (6.2%)  19A  56 (13.3%) 
14  3 (6.2%)  14  22 (5.2%) 
7F  3 (6.2%)  19F  12 (2.8%) 

ICU, intensive care unit.

We did not find statistically significant differences in the frequency of strains that were not susceptible to penicillin or cefotaxime (Table 5).

Table 5.

Antimicrobial susceptibility in 208 invasive pneumococcal strains.

  pre-PCV13 period  PCV13 period  P 
Antibiogram performed, n (%)  125 (39.2%)  83 (47.7%)  .08 
Antibiotic susceptibility*       
Penicillin MIC, mean ± SD (µg/mL)  0.42 ± 0.79  0.55 ± 1.15  .33 
Resistance to penicillin, n (%)  41 (34.5%)  41 (47.1%)  .06 
Cefotaxime MIC, mean ± SD (µg/mL)  0.26 ± 0.41  0.42 ± 1  .12 
Resistance to cefotaxime, n (%)  2 (1.7%)  5 (5.7%)  .11 

MIC, minimum inhibitory concentration; PCV13, 13-valent pneumococcal conjugate vaccine; SD, standard deviation.

*

Susceptibility defined applying CLSI 2015 breakpoints21.

Discussion

Although the vaccine coverage in our region is not high, the incidence of invasive pneumococcal disease in children under 60 months has decreased significantly after the introduction of PCV13. The general characteristics of the population in both periods were similar.

Pneumonia, meningitis and occult bacteraemia accounted for more than 90% of cases of IPD in both groups. We observed a significant decrease in the cases of pneumonia complicated with empyema associated with a shift in the distribution of serotypes that caused IPD in the PCV13 period (decline of serotype 1), which was consistent with the literature24–26, while cases of necrotising pneumonia increased substantially from 0.84 to 3.3 cases per 100 000 inhabitants. Although length of stay and mortality did not change with the introduction of the PCV13, we found a relative increase in severity reflected in an increase in the proportion of patients requiring admission to the ICU, requiring ventilation or presenting with septic shock. It is worth noting that there was also a significant increase in the proportion of children with risk factors. We assume that the changes in clinical presentation were due to the impact of vaccination with the PCV13, which was associated with an evident shift in the serotypes causing IPD. In the PCV13 period, opportunistic serotypes, or serotypes with low invasive disease potential, have caused disease with a significantly greater frequency in patients with a higher rate of comorbidities, which may in turn be associated with an increased risk of complications and mortality27,28. We believe that the increase in the proportion of cases caused by serotype 3 could have an important impact on the incidence of necrotising pneumonia, we observed an increase in both the absolute and relative frequency of this form of disease between the 2 periods (from 3 [0.8%] to 19 [10.9%]) despite a decrease in overall incidence, which suggests that there are other factors at play in the increase in necrotising pneumonia, such as an increased proportion of patients with comorbidities in the PCV13 period.

Overall, the use of pneumococcal DNA detection by PCR increased the frequency of cases of IPD with microbiological confirmation, as previously reported29. However, in the PCV13 period there was a lesser increase of cases with detection by PCR only. This was probably due to the decline in cases manifesting with empyema, as pneumococcal PCR is significantly more sensitive in samples of pleural fluid (where a high bacterial load is expected) compared to blood, where the bacterial load is lower.

There was an overall decrease in the incidence of IPD caused by PCV13 serotypes, with a decline in serotype 1 from being the most frequent (20.9%) in the pre-PCV13 period to accounting for only 11.2% of IPD cases in the PCV13 period. Although we observed a significant decrease in the incidence of IPD caused by serotype 3, this serotype became the most prevalent in the PCV13 period, causing 20.9% of IPD cases. This proportional increase can be explained by the failure rate of the PCV13 vaccine for serotype 3 in our study, a phenomenon previously reported by our group and other authors12,30,31. The causes of serotype 3 vaccine failure are not well understood, but are probably related to the low immunogenicity of the vaccine for this particular serotype12.

Serotype 3 is the most frequent serotype, especially in the most severe cases, such as those requiring ICU admission, mechanical ventilation or prolonged hospitalization and those with complications during the hospital stay or sequelae after discharge. This combination of high incidence and high proportion of severe cases was among the salient results of this study.

One of the limitations of the study was that the molecular techniques used to detect pneumococcal DNA and in serotyping changed during the study. In the first period, we used amplification of the ply gene, which has a high sensitivity, and a multiplex PCR assay for detection of 24 serotypes, while in the second period we used amplification of LytA gene for pneumococcal detection, which offers a better specificity, and a different molecular assay to detect 40 serotypes. This change in methodology could have played a role in the significant decrease of patients with IPD caused by serotypes not included in the assay.

In conclusion, in the PCV13 period there was a decrease in the incidence of IPD without serotype replacement. We observed changes in epidemiological variables and clinical manifestations, with a proportional increase in cases in children with risk factors and an increase in cases of necrotising pneumonia, with required admission to the ICU and mechanical ventilation in a greater proportion of patients.

We now need to see what happens in upcoming years following the inclusion of the PCV13 in the routine immunisation schedule of Catalonia in July 2016.

Conflicts of interest

Dr de Sevilla MF received grants from the Instituto de Salud Carlos III and fees from Pfizer Inc. while the study was underway. Dr Moraga-Llop has received fees from Pfizer Inc. outside the study period. Dr Campins received fees from Pfizer while the study was underway. Dr Muñoz-Almagro has received grants from Pfizer, bioMérieux, Stat DX and the Instituto de Salud Carlos III and fees from Roche and GSK outside the study period. Dr García-García received grants from Instituto de Salud Carlos III and fees from Pfizer Inc. while the study was underway. The remaining authors had no conflicts of interest to disclose.

Funding

This work was supported by the National Plan of Research, Development and Innovation of Spain (PI11/02081, PI11/02345 and PI13/01729 projects) through the Insituto de Salud Carlos III (General Vice Directorate of Health Research Evaluation and Promotion) and the European Regional Development Fund (ERDF).

Author contributions

Johanna (J) Martínez-Osorio, MD*: Design and methodology, data collection, writing and data analysis. Mariona (M) F de Sevilla, PhD*: Design and methodology, data collection, writing and data analysis. Fernando (F) Moraga-Llop, MD: Expertise, feedback and writing. Alvaro (A) Díaz, PhD: Expertise, feedback and writing. Sergi (S) Hernández MSc: Data analysis and writing. Anna (A) Solé-Ribalta, MD: Data collection and writing. Sebastià (S) González-Peris, MD: Data collection and writing. Conchita (C) Izquierdo, PhD: Expertise, feedback and writing. Cristina (C) Esteva, PhD: Laboratory sample processing and writing. Gemma (G) Codina, PhD: Laboratory sample processing and writing. Ana María (AM) Planes, PhD: Laboratory sample processing and writing. Sonia (S) Uriona, MD: Laboratory sample processing and writing. Magda (M) Campins, PhD: Expertise, feedback and writing. Pilar (P) Ciruela, PhD: Expertise, feedback and writing. Luis (L) Salleras, PhD: Expertise, feedback and writing. Ángela (Á) Domínguez, PhD: Expertise, feedback, writing and fundraising. Carmen (C) Muñoz-Almagro, PhD: Design and methodology, Expertise, feedback, laboratory sample processing, writing of the manuscript and fundraising. Juan José (JJ) García-García, PhD: Design and methodology, Expertise, feedback, writing and fundraising.

Acknowledgments

We thank Roberto Chalela for his advice in statistics.

Appendix A
Supplementary data

The following is Supplementary data to this article:

References
[1]
Z.B. Harboe, A Riis, P Valentiner-Branth, J.J. Christensen, L Lambertsen, et al.
Pneumococcal serotypes and mortality following invasive pneumococcal disease: a population-based cohort study.
PLoS Med., 6 (2009),
[2]
M.F. de Sevilla, C Esteva, F Moraga, S Hernández, L Selva, et al.
Clinical presentation of invasive pneumococcal disease in Spain in the era of heptavalent conjugate vaccine.
Pediatr Infect Dis J., 31 (2012), pp. 124-128
[3]
N. Janoff Eduard.
Streptococcus pneumoniae in Enfermedades infecciosas.
Principios y práctica (Mandell, Douglas y Bennett), Elsevier Inc., (2016), pp. 2434-2453
[4]
K.L. O’Brien, L.J. Wolfson, J.P. Watt, E Henkle, M Deloria-Knoll, N McCall, et al.
Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates.
Lancet., 374 (2009), pp. 893-902
[5]
J.K. Rajaratnam, J.R. Marcus, A.D Flaxman, H Wang, A Levin-Rector, L Dwyer, et al.
Neonatal, postneonatal, childhood, and under-5 mortality for 187 countries, 1970–2010: a systematic analysis of progress towards Millennium Development Goal 4.
Lancet., 375 (2010), pp. 1988-2008
[6]
World Health Organization.
Estimated Hib and pneumococcaldeaths for children under 5 years of age.
[7]
S.L. Kaplan, E.O. Mason, E.R. Wald, G.E. Schutze, J.S. Bradley, T.Q. Tan, et al.
Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine.
Pediatrics., 113 (2004), pp. 443-449
[8]
F. González Martínez, M.L. Navarro Gómez, J Saavedra Lozano, M.M Santos Sebastián, R Rodríguez Fernández, M González Sanchéz, et al.
Emergence of invasive pneumococcal disease caused by non-vaccine serotypes in the era of the 7-valent conjugate vaccine.
An Pediatr (Barc)., 80 (2014), pp. 173-180
[9]
C. Munoz-Almagro, I Jordan, A Gene, C Latorre, J.J. Garcia-Garcia, R Pallares, et al.
Emergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of 7-valent conjugate vaccine.
Clin Infect Dis., 15 (2008), pp. 174-182
[10]
A. Domínguez, J.J. García-García, F Moraga, M.F. de Sevilla, Selva L.
Effectiveness of 7-valent pneumococcal conjugate vaccine in the prevention of invasive pneumococcal disease in children aged 7-59 months. A matched case-control study.
Vaccine., 29 (2011), pp. 9020-9025
[11]
Á Domínguez, P Ciruela, S Hernández, J.J. García-García, N Soldevila, C Izquierdo, et al.
Effectiveness of the 13-valent pneumococcal conjugate vaccine in preventing invasive pneumococcal disease in children aged 7-59 months. A matched case-control study.
[12]
F. Moraga-Llop, J.J. Garcia-Garcia, A Díaz-Conradi, P Ciruela, J Martínez-Osorio, S González-Peris, et al.
Vaccine failures in patients properly vaccinated with 13-valent pneumococcal conjugate vaccine in Catalonia, a region with low vaccination coverage.
Pediatr Infect Dis J., 35 (2016), pp. 460-463
[13]
G. Hanquet, P Krizova, P Valentiner-Branth, S.N. Ladhani, J.P. Nuorti, A Lepoutre, et al.
Effect of childhood pneumococcal conju-gate vaccination on invasive disease in older adults of 10European countries: implications for adult vaccination.
[14]
D. Moreno-Pérez, F.J. Alvarez García, J Arístegui Fernández, M.J. Cilleruelo Ortega, J.M. Corretger Rauet, N García Sánchez, et al.
Immunization schedule of the SpanishAssociation of Paediatrics: 2014 recommendations.
An Pediatr (Barc)., 80 (2014), pp. 1-37
[15]
U. Heininger, N.S. Bachtiar, P Bahri, A Dana, A Dodoo, J Gidudu, et al.
The concept of vaccination failure.
Vaccine., 30 (2012), pp. 1265-1268
[16]
American Academy of Pediatrics, Committee on InfectiousDiseases.
Policy statement: recommendations for the pre-vention of pneumococcal infections, including the use ofpneumococcal conjugate vaccine (Prevnar), pneumococcalpolysaccharide vaccine, and antibiotic prophylaxis.
Pediatrics., 106 (2000), pp. 362-366
[17]
C. Muñoz-Almagro, S. Gala, L. Selva, I. Jordan, D. Tarragó, R. Pallares.
DNA bacterial load in children and adolescents with pneu-mococcal pneumonia and empyema.
Eur J Clin Microbiol Infect Dis., 30 (2011), pp. 327-335
[18]
Centers for Disease Control and Prevention. Chapter 10: PCR for Detection and characterization of bacterialmeningitis pathogens: Neisseria meningitidis, Haemop-hilus influenzae and S. pneumoniae. Available from: https://www.cdc.gov/meningitis/lab-manual/chpt10-pcr.html.
[19]
D. Tarragó, A Fenoll, D Sánchez-Tatay, L.A. Arroyo, C Muñoz-Almagro, C Esteva, et al.
Identification of pneumococcal serotypes fromculture-negative clinical specimens by novel real-time PCR.
Clin Microbiol Infect., 14 (2008), pp. 828-834
[20]
L. Selva, C. Berger, J.J. Garcia-Garcia, H. de Paz, D. Nadal, C. Muñoz-Almagro.
Direct identification of Streptococcus pneumoniaecapsular types in pleural fluids by using multiplex PCR combinedwith automated fluorescence-based capillary electrophoresis.
J Clin Microbiol., 52 (2014), pp. 2736-2737
[21]
L. Selva, E. del Amo, P. Brotons, C. Muñoz-Almagro.
Rapid and easy identification of capsular serotypes of Streptococcus pneumoniae by use of fragment analysis byautomated fluorescence-based capillary electrophoresis.
J Clin Microbiol., 50 (2012), pp. 3451-3457
[22]
Clinical and Laboratory Standards Institute.
Performance Stan-dards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. CLSI document M100-S25 (ISBN 1-56238-990-4).
Clinical and Laboratory Standards Institute, 950West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, (2015),
[23]
Estadística Oficial de Catalunya. Institut d’Estadística de Cata-lunya. Available from: http://www.idescat.net.
[24]
K.M. Sullivan, A. Dean, M.M. Soe.
OpenEpi: A Web-Based Epidemio-logic and Statistical Calculator for Public Health.
Public Health Rep., 124 (2009), pp. 471-474
[25]
A.D. Wiese, M.R. Griffin, Y. Zhu, E.F. Mitchel, C.G. Grijalva.
Changes inempyema among U.S. children in the pneumococcal conjugatevaccine era.
Vaccine., 34 (2016), pp. 6243-6249
[26]
C. Muñoz-Almagro, L. Selva, R. Pallares.
Influence of pneumococ-cal vaccine on the incidence of empyema.
Curr Opin Pulm Med., 16 (2010), pp. 394-398
[27]
K. Krenke, E. Sadowy, E. Podsiadły, W. Hryniewicz, U. Demkow, M. Kulus.
Etiology of parapneumonic effusion and pleural emp-yema in children. The role of conventional and molecularmicrobiological tests.
Respir Med., 116 (2016), pp. 28-33
[28]
I. Yildirim, K.M. Shea, B.A. Little, A.L. Silverio, S.I. Pelton.
Members of the Massachusetts Department of Public Health Vaccination, underlying comorbidities, and risk of invasive pneumococcaldisease.
Pediatrics., 135 (2015), pp. 495-503
[29]
L. Olarte, W.J. Barson, R.M. Barson, J.R. Romero, J.S. Bradley, T Tan, et al.
Pneumococcal pneumonia requiring hospitali-zation in US children in the 13-valent pneumococcal conjugatevaccine era.
Clin Infect Dis., 64 (2017), pp. 1699-1704
[30]
D. Novak, A. Lundgren, S. Westphal, S. Valdimarsson, M.L. Olsson, B. Trollfors.
Two cases of hemolytic uremic syndrome caused by Streptococcus pneumoniae serotype 3, one being a vaccine failure.
Scand J Infect Dis., 45 (2013), pp. 411-414
[31]
J. Poolman, P Kriz, C Feron, E Di-Paolo, I Henckaerts, A Miseur, et al.
Pneumococcal serotype 3 otitis media, limited effect of polysaccharide conjugate immunisation and strain characteristics.
Vaccine., 27 (2009), pp. 3213-3222

Please cite this article as: Martínez-Osorio J, García-García JJ, Moraga-Llop F, Díaz A, Hernández S, Solé-Ribalta A et al., Enfermedad neumocócica invasiva en niños menores de 60 meses, antes y después de la introducción de la vacuna conjugada 13-valente. Anales Pediatría. 2021. https://doi.org/10.1016/j.anpedi.2021.05.018

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