The objective of this study was to analyze the incidence, clinical presentation, and severity of invasive pneumococcal disease (IPD)-causing serotypes and the impact of the 13-valent pneumococcal conjugate vaccination during epidemic and nonepidemic influenza periods in Catalonia, Spain. This was a prospective study in persons aged <18 years diagnosed with IPD between 2012 and 2015 in three Catalan pediatric hospitals.
KEYWORDS: 13-valent pneumococcal conjugate vaccine, invasive pneumococcal disease, highly invasive serotypes, influenza virus, seasonality
ABSTRACT
The objective of this study was to analyze the incidence, clinical presentation, and severity of invasive pneumococcal disease (IPD)-causing serotypes and the impact of the 13-valent pneumococcal conjugate vaccination during epidemic and nonepidemic influenza periods in Catalonia, Spain. This was a prospective study in persons aged <18 years diagnosed with IPD between 2012 and 2015 in three Catalan pediatric hospitals. IPD was defined as clinical infection together with isolation of Streptococcus pneumoniae by culture and/or detection by reverse transcription-PCR in a normally sterile sample. Incidence rate ratios (IRRs) and the fraction of IPD prevented associated with 13-valent pneumococcal conjugate vaccine (PCV13) were calculated. The bivariate analysis used the χ2 test and the multivariate analysis nonconditional logistic regression. A total of 229 cases of IPD were recorded. The incidence was higher during influenza epidemic periods (IRR, 2.7; 95% confidence interval [CI], 2.05 to 3.55; P < 0.001), especially for pneumonia (IRR, 3.25; 95% CI, 2.36 to 4.47; P < 0.001), with no differences in the distribution of pneumococcal serotypes. Complications during admission and sequel at discharge were greater during epidemic periods (adjusted odds ratio [aOR], 2.00; 95% CI, 1.06 to 3.77; P = 0.03) than at nonepidemic periods (aOR, 3.38; 95% CI, 1.37 to 8.29; P = 0.01). The prevented fraction for the population (PFp) of IPD in children aged 7 to 59 months was 48% to 49.4%. The PFp was higher in influenza epidemic than nonepidemic periods and increased when ≥2 doses of PCV13 or ≥1 after 24 months were administered. Influenza virus circulation increases the incidence of IPD in persons aged <18 years. In influenza epidemic periods, IPD cases were more severe. Increased PCV13 coverage might increase the fraction of IPD prevented in epidemic and nonepidemic periods.
INTRODUCTION
Invasive pneumococcal disease (IPD) is a major cause of morbidity and mortality in adults and children and fluctuates seasonally during the winter months in temperate countries (1, 2). Seasonality affects both the disease incidence and the clinical presentation. Reports have described an increased incidence of bacteremic pneumonia but not of other clinical presentations during the winter months (3–5).
Environmental factors, such as temperature, humidity, pollution, and hours of daylight, help explain the seasonality (2, 6). Likewise, the circulation of respiratory viruses during the winter months, especially the influenza virus, respiratory syncytial virus (RSV), and metapneumovirus, have been associated with an increased incidence of IPD, especially in children (2, 7). Although the mechanisms of interaction between respiratory viruses and Streptococcus pneumoniae at the host level have been widely described (8–11), the proportion of episodes of IPD attributable to the circulation of respiratory viruses is not clear (12, 13).
After the 2009 influenza pandemic, many studies showed that the influenza virus not only increases the incidence of invasive pneumococcal pneumonia but also may be a factor influencing severity (4, 14–16).
Influenza virus infection favors the nasopharyngeal colonization of S. pneumoniae in children (3), which is a critical step in the subsequent development of IPD. However, the relationship between influenza virus and IPD-causing S. pneumoniae serotypes is unclear. Some reports have linked prior influenza virus infection with a subsequent episode of IPD caused by highly invasive serotypes (7), while other authors link it with IPD produced by less invasive serotypes (17–19). Influenza epidemics have been shown to affect the distribution of IPD-causing serotypes (20).
The introduction of the pneumococcal conjugated heptavalent vaccine (PCV7) in 2001 (21), the 10-valent conjugate vaccine (PCV10) in 2009 (22), and the 13-valent conjugate vaccine (PCV13) in 2010 (23) was associated with a significant reduction in IPD and a change in the distribution of the main disease-causing S. pneumoniae serotypes (24). (25). In Catalonia, Spain, the PCV13 was not included in the childhood vaccination schedule financed by the public health system until July 2016. In the 2012 to 2015 study period, the estimated PCV13 coverage in children aged 7 to 59 months in Catalonia was 63% (26).
The aim of this study was to analyze variations in the incidence, clinical presentation, severity, and serotypes associated with IPD in Catalonia after the introduction of the 13-valent conjugate vaccine and the impact of vaccination, measured as the fraction of IPD prevented in the population, during epidemic and nonepidemic influenza periods.
MATERIALS AND METHODS
Data confidentiality and ethical aspects.
No diagnostic tests were made or samples taken from any participant in addition to those required by routine care. The study complies with the principles of the Declaration of Helsinki and the legal structure in respect to international human rights and biomedicine and protection of personal data laws.
The Ethics Committee of Hospital Sant Joan de Déu approved the study. Informed consent signed by parents or legal guardians was given for all participants. All data were treated as confidential, and records were accessed anonymously.
Study design.
A prospective study was conducted in persons aged <18 years diagnosed with IPD between 1 January 2012 and 31 December 2015 attended in three pediatric hospitals in Catalonia, Spain, namely, Hospital Sant Joan de Déu, Hospital Maternoinfantil Vall d'Hebrón, and Hospital de Nens de Barcelona. These hospitals are responsible for 20%, 8.5%, and 3%, respectively, of total hospital discharges in Catalonia of children aged <18 years, according to data from the Minimum Basic Data Set of Hospital Discharges (CMBDAH) (27), and the estimated reference population in this age group of the three hospitals was from 422,666 in 2012 to 452,927 in 2015.
Selection of cases.
Patients aged <18 years hospitalized due to IPD during the study period in the participating centers were included. IPD was defined as clinical infection together with the isolation by culture and/or detection of LytA gene DNA and an additional capsular gene of S. pneumoniae by reverse transcription-PCR (RT-PCR) in a normally sterile sample.
RT-PCR was carried out according to a standardized work protocol. Pediatricians requested RT-PCR in cases of clinical suspicion in a patient with clinical and hospital admission criteria. RT-PCR was performed in the most appropriate sterile sample, namely, cerebrospinal fluid, pleural fluid, or plasma (never in whole blood or in blood culture bottles), according to the clinical signs.
Identification, serotyping, and classification of S. pneumoniae.
All strains isolated by culture were serotyped using the Quellung reaction or dot blot by the National Centre for Microbiology, Majadahonda, Madrid, which allows 97 serotypes to be identified.
Capsular typing of all culture-negative and PCR-positive samples was performed using two methods depending on the amount of S. pneumoniae DNA available. If the amount was low (detection of LytA gene DNA and an additional capsular gene of S. pneumoniae by RT-PCR with the cycle threshold [CT] of >30 cycles), a previously described, real-time multiplex PCR technique that detects all pneumococcal capsular types and differentiates 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 was used (28). If the amount of S. pneumoniae DNA was high (PCR-positive samples with CT of ≤30 cycles), sequential multiplex PCR combined with fragment analysis and automated fluorescent capillary electrophoresis to differentiate serotypes [1, 2, 3, 4, 5, 6A/6B, 6C, 6,7C/(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, and 39] was used (29).
Since PCR does not differentiate between serotypes 6A and 6C; 7F and 7A; 9V, 9A, and 9N; and 19F, 19B, and 19C, these serotypes were considered vaccine serotypes 6A, 7F, 9V, and 19F, respectively. PCR-positive samples that were negative for the serotypes included in the sequential multiplex PCR (including all vaccine serotypes) were classified as other nonvaccine serotypes (ONVS).
The serotypes found were classified into two groups according to their invasiveness, namely, highly invasive serotypes (HIS; serotypes 1, 3, 4, 5, 7F, 8, 9N, 9V, 12F, 14, 18C, 19A, and 22F) and the remaining serotypes (non-HIS), as described by various authors (30–34).
Demographic, clinical, and epidemiological variables.
The following demographic, clinical, and epidemiological variables were recorded for each case: age, sex, date of birth, date of onset of symptoms, date of hospitalization, clinical form of IPD (meningitis, septic shock, pneumonia, complicated pneumonia, musculoskeletal infection, occult bacteremia, and others), in-hospital complications, mechanical ventilation, intensive care unit (ICU) admission and length of stay, risk medical conditions (sickle cell anemia; congenital or acquired asplenia; human immunodeficiency virus; cochlear implant; congenital immunodeficiency; chronic heart disease; chronic lung diseases, including asthma if treated with a risk dose of oral corticosteroids; cerebrospinal fluid fistula; chronic renal failure, including nephrotic syndrome; immunosuppressive treatment or radiotherapy; solid organ transplant; transplantation of hematopoietic progenitors; and diabetes mellitus), date and evolution at discharge (discharge without sequelae, sequelae, and death), and the history of vaccination with any pneumococcal conjugate vaccine.
Definition of influenza epidemic periods.
Influenza epidemic periods were established according to the data provided by the Pla d'Informació de les Infeccions Respiratòries Agudes a Catalunya (PIDIRAC) which, during the winter season (weeks 40 to 20) obtains daily information on morbidity due to acute respiratory infections through the population registry, including data from sentinel doctors throughout Catalonia (35). The epidemic threshold for influenza virus is established as >100 cases/105 inhabitants, and influenza epidemic periods were defined as weeks in which this incidence was reached and the two subsequent weeks (7).
Reference population and estimated vaccination coverage.
The reference population of the three hospitals used to measure weekly incidence rates (IRs) during the epidemic and nonepidemic influenza periods was calculated according to population data from the Statistical Institute of Catalonia and determined by calculating the percentage of discharges of each hospital and each age group of the study in relation to the total number of hospital discharges in Catalonia for these age groups (27) and extrapolating the data to the entire population. The estimated reference population aged <18 years of the three hospitals was stable during the study period and varied from 422,666 (31.5% of the Catalan population aged <18 years) in 2012, to 442,032 (31.8% of the Catalan population aged <18 years) in 2013, to 453,419 (32.6% of the Catalan population aged <18 years) in 2014, and 452,927 (32.5% of the Catalan population aged <18 years) in 2015. No other pediatric hospitals in the region were growing or contracting during the study period.
The vaccination coverage of the reference population aged 7 to 59 months was estimated yearly according to the vaccination data obtained in children aged 7 to 59 months treated for causes other than IPD in the study hospitals, as described elsewere (26). The vaccinated population was defined as children who had received ≥1 dose of PCV13 or as children who had received ≥2 doses of PCV13 or ≥1 dose after 24 months in order to evaluate the possible differences related to the number of PCV13 doses received.
Statistical analysis.
The incidence rate ratios (IRRs) of IPD were calculated between epidemic and nonepidemic periods. For categorical variables, differences between periods were analyzed using Pearson’s chi-square test or Fisher’s exact test, and for continuous variables the Student’s t test was used. The 95% confidence intervals (CIs) were calculated, and P values of ≤0.05 were considered statistically significant. A bilateral distribution was assumed for all P values.
Multivariate analysis was performed using nonconditional logistic regression to estimate the association between the severity of cases in epidemic and nonepidemic periods. The following variables were introduced into the model: ICU admission, complications, mechanical ventilation, sequelae at discharge, death, and age. The lack of collinearity of the independent variables was verified using the variance inflation factor (36).
To analyze the impact of PCV13 on the incidence of IPD in children aged 7 to 59 months during influenza epidemic periods, the fraction of IPD prevented in the total period and in the epidemic and nonepidemic periods was calculated using the formula: prevented fraction in the population = (IR in unvaccinated − IR in total population)/IR in unvaccinated (37).
The IR in the unvaccinated population was calculated by dividing the number of unvaccinated IPD cases caused by PCV13 serotypes in children aged 7 to 59 months by the estimated unvaccinated population according to the estimated vaccine coverage published (27) and the reference estimated population in the same age group.
The IR in the total population was calculated by dividing the number of all IPD cases caused by PCV13 serotypes in children aged 7 to 59 months by the estimated population according to the reference estimated population in the same age group.
The analysis was performed using the SPSS v.24 statistical package.
RESULTS
During the study period, 229 cases of IPD were recorded in persons aged <18 years, of which 71 cases (31.0%) were collected in 2012, 58 (25.3%) in 2013, 44 (19.2%) in 2014, and 56 (24.5%) in 2015; 137 (59.8%) patients were attended by Hospital Sant Joan de Déu, 66 (28.8%) by Hospital Maternoinfantil Vall d'Hebrón, and 26 (11.4%) by Hospital de Nens de Barcelona; 135 (59%) patients were male and 94 (41%) female; and 36.7% (84) of patients were aged <2 years, 38.0% (87) 2 to 4 years, and 25.3% (58) 5 to 17 years (Table 1). The clinical manifestations were the following: pneumonia, 165 cases (72.0%); occult bacteremia, 22 (9.6%); meningitis, 19 (8.3%); musculoskeletal infection, 7 (3.1%); bacteremic mastoiditis, 7 (3.1%); sepsis, 6 (2.6%); bacteremic orbital cellulitis, 2 (0.9%); and pancreatitis, 1 (0.4%). A total of 48.1% of cases (110) were diagnosed by PCR alone and 26.6% (61 cases) by culture alone, and in 25.3% of cases (58), both techniques were positive.
TABLE 1.
Characteristics of cases of invasive pneumococcal disease in epidemic and nonepidemic influenza periods
| Variable | Valuesa
by period |
P Value | ||
|---|---|---|---|---|
| Epidemic influenza | Nonepidemic influenza | |||
| Sex | Female | 36 (39.6) | 58 (42.0) | 0.71 |
| Male | 55 (60.4) | 80 (58.0) | ||
| Age in months (mean and SD) | 52.02 (36.90) | 39.46 (36.97) | 0.012 | |
| Risk medical conditions | No | 89 (97.8) | 125 (90.6) | 0.032 |
| Yes | 2 (2.2) | 13 (9.4) | ||
| ≥1 dose of PCV13 (0–4 yr) | No | 40 (65.6) | 58 (52.7) | 0.104 |
| Yes | 21 (34.4) | 52 (47.3) | ||
| ≥2 dose of PCV13 or ≥1 dose after 24 months (0–4 yr) | No | 41 (67.2) | 60 (54.5) | 0.107 |
| Yes | 20 (32.8) | 50 (45.5) | ||
| PCV13 serotypes | No | 26 (29.5) | 51 (38.1) | 0.192 |
| Yes | 62 (70.5) | 83 (61.9) | ||
| PCV13 serotypes (unvaccinated cases) | No | 16 (23.9) | 19 (23.2) | 0.919 |
| Yes | 51 (76.1) | 63 (76.8) | ||
| PCV13 serotypes (≥1 dose of PCV13) | No | 10 (47.6) | 32 (62.7) | 0.236 |
| Yes | 11 (52.4) | 19 (37.7) | ||
| PCV13 serotypes (≥2 doses of PCV13 or ≥1 dose after 24 months) | No | 10 (47.6) | 31 (63.3) | 0.226 |
| Yes | 11 (52.4) | 18 (36.7) | ||
| HIS serotypes | No | 27 (30.7) | 55 (41.0) | 0.118 |
| Yes | 61 (69.3) | 79 (59.0) | ||
| Serotype 3 | No | 67 (76.1) | 110 (82.1) | 0.282 |
| Yes | 21 (23.9) | 24 (17.9) | ||
| Serotype 1 | No | 68 (77.3) | 110 (82.1) | 0.379 |
| Yes | 20 (22.7) | 24 (17.9) | ||
| Serotype 19A | No | 80 (90.9) | 125 (93.3) | 0.517 |
| Yes | 8 (9.1) | 9 (6.7) | ||
| Serotype 14 | No | 85 (96.6) | 126 (94.0) | 0.396 |
| Yes | 3 (3.4) | 8(6.0) | ||
Values are n (%) unless otherwise indicated. HIS, highly invasive serotypes.
Of the 229 cases recorded, 222 (96.9%) were serotyped; 145 (65.3%) were caused by PCV13-serotypes, of which 20.8% (30 cases) received ≥1 dose of PCV13 and 20% (29 cases) received ≥2 doses of PCV13 or ≥1 dose after 24 months. Of the 77 cases (34.7%) caused by non-PCV13 serotypes, 42 (54.5%) received ≥1 dose of PCV13 and 41 (53.2%) received ≥2 doses of PCV13 or ≥1 dose after 24 months.
A smaller proportion of cases with medical risk conditions were detected during epidemic influenza periods than in nonepidemic periods (2.2% versus 9.4%, P = 0.032).
There were no differences in the vaccination status of cases during influenza epidemic and nonepidemic periods according to cases who had received ≥1 dose of PCV13 (P = 0.104) and cases who had received ≥2 doses of PCV13 or ≥1 dose after 24 months (P = 0.107).
There were no differences in demographic or risk factors between vaccinated and unvaccinated cases in the same epidemic and nonepidemic influenza period, either in cases who had received ≥1 dose of PCV13 or in cases who had received ≥2 doses of PCV13 or ≥1 dose after 24 months (see Table S1 and S2 in the supplemental material).
Incidence of IPD in epidemic and nonepidemic influenza periods.
Of the 209 weeks of the study period, 41 weeks corresponded to influenza epidemic periods (weeks 4 to 13 in 2012, 3 to 12 in 2013, 2 to 10 in 2014, and 3 to 14 in 2015). The incidence of IPD per person-week was greater in influenza epidemic periods (0.13 cases/105 person-weeks) than in nonepidemic periods (0.05 cases/105 person-weeks; IRR, 2.7; 95% CI, 2.05 to 3.55; P < 0.001). Significant differences were found in the 2- to 4-year (IRR, 3.33; 95% CI, 2.12 to 5.19; P < 0.001) and 5- to 17-year (IRR, 4.39; 95% CI, 2.53 to 7.63; P < 0.001) age groups but not in the <2-year age group (Table 2).
TABLE 2.
Distribution of cases and incidence rates of invasive pneumococcal disease in epidemic and nonepidemic influenza periods according to clinical presentation and age groupa
| Clinical presentation | Age group (yrs) | Values by period |
Incidence rate ratio(95% CI) | P value | |||
|---|---|---|---|---|---|---|---|
| Epidemic influenza |
Nonepidemic influenza |
||||||
| n | IR | n | IR | ||||
| Meningitis | <2 | 6 | 0.09 | 8 | 0.03 | 3.07 (0.88–10.10) | 0.051 |
| 2–4 | 0 | 0.00 | 4 | 0.01 | NC | NC | |
| 5–17 | 0 | 0.00 | 1 | 0.00 | NC | NC | |
| Total | 6 | 0.01 | 13 | 0.00 | 1.891 (0.589–5.333) | 0.214 | |
| Pneumonia | <2 | 13 | 0.20 | 31 | 0.11 | 1.72 (0.825–3.38) | 0.113 |
| 2–4 | 34 | 0.24 | 39 | 0.07 | 3.572 (2.187–5.808) | <0.001 | |
| 5–17 | 26 | 0.05 | 22 | 0.01 | 4.843 (2.639–8.964) | <0.001 | |
| Total | 73 | 0.10 | 92 | 0.03 | 3.251 (2.358–4.469) | <0.001 | |
| Occult bacteremia | <2 | 1 | 0.02 | 13 | 0.05 | 0.315 (0.007–2.099) | 0.255 |
| 2–4 | 2 | 0.01 | 3 | 0.01 | 2.732 (0.228–23.847) | 0.31 | |
| 5–17 | 1 | 0.00 | 2 | 0.00 | 2.049 (0.035–39.355) | 0.581 | |
| Total | 4 | 0.01 | 18 | 0.01 | 0.911 (0.224–2.764) | 0.909 | |
| Other forms | <2 | 2 | 0.03 | 10 | 0.04 | 0.820 (0.087–3.846) | 0.858 |
| 2–4 | 3 | 0.02 | 2 | 0.00 | 6.146 (0.704–73.589) | 0.061 | |
| 5–17 | 3 | 0.01 | 3 | 0.00 | 4.098 (0.549–30.593) | 0.11 | |
| Total | 8 | 0.01 | 15 | 0.01 | 2.185 (0.802–5.491) | 0.089 | |
| Total | <2 | 22 | 0.33 | 62 | 0.23 | 1.454 (0.851–2.399) | 0.14 |
| 2–4 | 39 | 0.27 | 48 | 0.08 | 3.329 (2.125–5.188) | <0.001 | |
| 5–17 | 30 | 0.05 | 28 | 0.01 | 4.390 (2.535–7.626) | <0.001 | |
| Total | 91 | 0.13 | 138 | 0.05 | 2.702 (2.050–3.546) | <0.001 | |
NC, not calculable; IR, incidence rate (per 105 person-weeks).
The IR of pneumonia increased during influenza epidemic periods, both globally (IRR, 3.25; 95% CI, 2.36 to 4.47; P < 0.001) and in the 2- to 4-year (IRR, 3.57; 95% CI, 2.19 to 5.80; P < 0.001) and 5- to 17-year (IRR, 4.84; 95% CI, 2.64 to 8.86; P < 0.001) age groups.
Distribution of serotypes in epidemic and nonepidemic influenza periods.
The most frequently found serotypes were serotype 3 (45 cases, 19.7%), serotype 1 (44 cases 19.2%), serotype 19A (17 cases, 7.4%), and serotype 14 (11 cases, 4.8%) (Fig. 1). The distribution of these serotypes was similar in both periods (Table 1).
FIG 1.
Distribution of HIS and non-HIS serotypes causing invasive pneumococcal disease in epidemic and nonepidemic influenza periods. HIS, n = 222; “Others,” nonepidemic influenza period: 24 (2), 27 (1), 31 (2), 12F/A/44/46 (2), 16F (2), 24A (2), 33F (2), 6A/C (2), 6B (2), 38 (1), 15B (1), 25F (1), 35B (1), 35F (1), and 6A (1); Other nonvaccine serotypes (14); Others epidemic influenza period: 27 (1), 13 (1), 19B/F/C (1), 23A (1), and 23F (1); Other nonvaccine serotypes (13).
There were no significant differences in the distribution of vaccine and nonvaccine serotypes between epidemic and nonepidemic periods in the total cases (odds ratio [OR], 1.46; 95% CI, 0.82 to 2.60; P = 0.192), in unvaccinated cases (OR, 0.96; 95% CI, 0.45 to 2.06; P = 0.919), in cases with ≥1 doses of PCV13 (OR, 1.85; 95% CI, 0.66 to 5.17; P = 0.236), and in cases with ≥2 doses of PCV13 or ≥1 dose after 24 months (OR, 1.89; 95% CI, 0.67 to 5.33; P = 0.226) (Table 1). In 2015, the proportion of IPD cases caused by nonvaccine serotypes increased with respect to 2012 (54.7% versus 22.9%; OR, 4.08; 95% CI, 1.87 to 8.87; P = 0.001) in influenza epidemic periods (50.0% versus 20.6%; OR, 3.86; 95% CI, 1.15 to 12.91; P = 0.025) and nonepidemic periods (75.6% versus 25%; OR, 4.07; 95% CI, 1.46 to 11.32; P = 0.006) (Fig. 2).
FIG 2.
Distribution of vaccine and nonvaccine serotypes causing invasive pneumococcal disease according to year and nonepidemic and epidemic influenza periods.
The proportion of IPD-causing HIS-serotypes was slightly higher in epidemic influenza periods (69.3% versus 59.0%; OR, 1.57; 95% CI, 0.89 to 2.77; P = 0.118) (Table 1). The increase in the incidence of IPD per person/week during epidemic and nonepidemic periods was observed in both HIS and non-HIS serotypes (IRR, 3.164; 95% CI, 2.227 to 4.475; P < 0.001 and IRR, 2.012; 95% CI, 1.220 to 3.244; P = 0.005, respectively) (Table 3). There were no variations in the proportion of cases caused by HIS serotypes during influenza and noninfluenza epidemic periods in the following different age groups <2 years (42.4% versus 55.0%; OR, 1.62; 95% CI, 0.54 to 4.61; P = 0.471), 2 to 4 years (71.8% versus 68.1%; OR, 1.19; 95% CI, 0.47 to 3.02; P = 0.89), and 5 to 17 years (75.9% versus 78.6%; OR, 0.85; 95% CI, 0.25 to 2.96; P = 0.94).
TABLE 3.
Distribution of HIS and non-HIS serotypes causing invasive pneumococcal disease in epidemic and nonepidemic influenza periods according to clinical presentationa
| Serotype | Clinical presentation | Values by period |
Incidence rate ratio(95% CI) | P value | |||
|---|---|---|---|---|---|---|---|
| Epidemic influenza |
Nonepidemic influenza |
||||||
| n | IR | n | IR | ||||
| HIS | Meningitis | 1 | 0.001 | 3 | 0.001 | 1.366 (0.026–17.11) | 0.757 |
| Pneumonia | 56 | 0.078 | 65 | 0.022 | 3.530 (2.425–5.126) | <0.001 | |
| Occult bacteremia | 1 | 0.001 | 6 | 0.002 | 0.683 (0.015–5.629) | 0.804 | |
| Other | 3 | 0.004 | 5 | 0.002 | 2.459 (0.382–12.637) | 0.248 | |
| Total | 61 | 0.085 | 79 | 0.027 | 3.164 (2.227–4.475) | <0.001 | |
| Non-HIS | Meningitis | 4 | 0.006 | 10 | 0.007 | 1.639 (0.375–5.683) | 0.410 |
| Pneumonia | 15 | 0.021 | 24 | 0.008 | 2.561 (1.249–5,086) | 0.007 | |
| Occult bacteremia | 3 | 0.004 | 12 | 0.004 | 1,024 (0.186–3.796) | 0.925 | |
| Other | 5 | 0.007 | 9 | 0.003 | 2.276 (0.599–7.564) | 0.162 | |
| Total | 27 | 0.037 | 55 | 0.019 | 2.012 (1.220–3.244) | 0.005 | |
HIS, highly invasive serotypes; IR, incidence rate (per 105 person-weeks).
There were no differences in the proportion of cases with medical conditions and HIS/non-HIS serotypes globally (5.0% versus 9.8%; P = 0.173) in epidemic influenza periods (1.6% versus 3.7%; P = 0.522) and in nonepidemic influenza periods (7.6% versus 12.7%; P = 0.323).
IPD severity in epidemic and nonepidemic influenza periods.
ICU admission was required by 15.4% of cases during influenza epidemic periods and 22.5% in nonepidemic periods (aOR, 0.31; 95% CI, 0.12 to 0.80; P = 0.02) (Table 4). However, the proportions of cases with in-hospital complications and sequelae at discharge/death were higher during epidemic than nonepidemic periods, namely, 75.8% versus 55.8% (aOR, 2.00; 95% CI, 1.06 to 3.77; P = 0.03) and 22% versus 8.7% (aOR, 3.38; 95% CI, 1.37 to 8.29; P = 0.01), respectively. Cases of pneumonia with sequelae at discharge/death were associated with influenza epidemic periods (aOR, 3.70; 95% CI, 1.26 to 10.86; P = 0.02).
TABLE 4.
Severity of invasive pneumococcal disease in persons aged <18 years in epidemic and nonepidemic influenza periods according to clinical presentation and invasive power of serotypesa
| Severity according to category | No. (%) of cases by period |
Crude OR(95% CI) | P value | Adjusted OR(95% CI) | P value | |
|---|---|---|---|---|---|---|
| Epidemic influenza | Nonepidemic influenza | |||||
| Total cases | 91 | 138 | ||||
| ICU | 14 (15.4) | 31 (22.5) | 0.63 (0.31–1.26) | 0.19 | 0.31 (0.12–0.80) | 0.02 |
| Complication | 69 (75.8) | 77 (55.8) | 2.48 (1.38–4.46) | 0.002 | 2.00 (1.06–3.77) | 0.03 |
| Mechanical ventilation | 5 (5.5) | 5 (3.6) | 1.55 (0.43–5.50) | 0.50 | 3.24 (0.68–15.37) | 0.14 |
| Sequelae at discharge/deathb | 20 (22.0) | 12 (8.7) | 2.96 (1.37–6.40) | 0.006 | 3.38 (1.37–8.29) | 0.01 |
| Pneumonia | 73 | 92 | ||||
| ICU | 8 (11.0) | 13 (14.1) | 0.75 (0.29–1.91) | 0.54 | 0.33 (0.09–1.27) | 0.16 |
| Complications | 62 (84.9) | 66 (71.7) | 2.22 (1.01–4.87) | 0.047 | 1.91 (0.84–4.36) | 0.08 |
| Mechanical ventilation | 4 (5.5) | 3 (3.3) | 1.72 (0.37–7.94) | 0.49 | 4.44 (0.58–33.92) | 0.15 |
| Sequelae at discharge/death | 15 (20.5) | 6 (6.5) | 3.71 (1.36–10.11) | 0.01 | 3.70 (1.26–10.86) | 0.02 |
| Other nonpneumonia | 18 | 46 | ||||
| ICU | 6 (33.3) | 18 (39.1) | 0.78 (0.25–2.44) | 0.67 | 0.26 (0.04–1.59) | 0.14 |
| Complications | 7 (38.9) | 11 (23.9) | 2.02 (0.63–6.49) | 0.23 | 2.96 (0.40–21.89) | 0.29 |
| Mechanical ventilation | 1 (5.6) | 2 (4.3) | 1.29 (0.11–15.22) | 0.84 | 1.27 (0.08–20.18) | 0.86 |
| Sequelae at discharge/death | 5 (27.8) | 6 (13.0) | 2.56 (0.67–9.81) | 0.17 | 2.46 (0.38–16.01) | 0.34 |
| HIS serotypes | 61 | 79 | ||||
| ICU | 7 (11.5) | 15 (19.0) | 0.55 (0.21–1.45) | 0.55 | 0.25 (0.06–0.98) | 0.05 |
| Complications | 53 (86.9) | 55 (69.6) | 2.89 (1.19–7.00) | 0.02 | 2.20 (0.87–5.57) | 0.09 |
| Mechanical ventilation | 3 (4.9) | 3 (3.8) | 1.31 (0.25–6.73) | 0.75 | 3.56 (0.41–31.13) | 0.25 |
| Sequelae at discharge/death | 16 (26.2) | 6 (7.6) | 4.33 (1.58–11.87) | 0.004 | 4.88 (1.57–15.18) | 0.006 |
| Non-HIS serotypes | 27 | 55 | ||||
| ICU | 6 (22.2) | 16 (29.1) | 0.70 (0.27–2.05) | 0.70 | 0.46 (0.11–2.01) | 0.30 |
| Complications | 15 (55.6) | 21 (38.2) | 2.02 (0.79–5.15) | 0.14 | 2.12 (0.73–6.20) | 0.17 |
| Mechanical ventilation | 2 (7.4) | 2 (3.6) | 2.12 (0.28–15.93) | 0.46 | 2.84 (0.28–28.79) | 0.38 |
| Sequelae at discharge/death | 3 (11.1) | 6 (10.9) | 1.02 (0.24–4.44) | 0.98 | 0.98 (0.17–5.60) | 0.98 |
HIS, highly invasive serotypes; ICU, intensive care unit.
Pulmonary (19), neurological (6), hearing loss (2), deaths (2), venous thrombosis (1), and hypertension (1).
There was an association between IPD cases due to HIS serotypes and sequelae at discharge/death during influenza epidemic periods (aOR, 4.88; 95% CI, 1.57 to 15.18; P = 0.006).
The severity of IPD caused by non-HIS serotypes showed no significant differences between epidemic and nonepidemic influenza periods.
Impact of PCV13 on the incidence of IPD during epidemic influenza periods.
During the study period, there was an increase both in vaccination coverage in children aged 7 to 59 months and in the prevented fraction for the population (PFp) of IPD in children aged 7 to 59 months (Fig. 3). When the vaccinated population was considered children who had received ≥1 dose of PCV13, the vaccination coverage was 48.3% in 2012, 64.0% in 2013, 68.5% in 2014, and 74.6% in 2015 (63.6% vaccination coverage for all the study period), and the PFp was 30.5% in 2012, 44.6% in 2013, 53.1% in 2014, and 55.0% in 2015 (49.4% for all the study period). When the vaccinated population was considered children who had received ≥2 doses of PCV13 or ≥1 after 24 months, the vaccination coverage was 47.6% in 2012, 59.6% in 2013, 66.9% in 2014, and 70.3% in 2015 (63.1% vaccination for all the study period), and the PFp was 31.9% in 2012, 37.8% in 2013, 50.7% in 2014, and 55.5% in 2015 (48.0% for all the study period) (Fig. 3).
FIG 3.
Evolution of estimated vaccination coverage and prevented fraction in the population during the study period in children aged 7 to 59 months.
Considering the vaccinated population as children who had received ≥1 dose of PCV13, the PFp of IPD associated with PCV13 vaccination in children was higher during influenza epidemic periods, both globally (3.47% more in epidemic periods than in nonepidemic periods) and in the 7- to 23-month and the 24- to 59-month age groups (4.18% and 3.79%, respectively).
Pneumonia showed the greatest difference between epidemic and nonepidemic periods; the PFp during epidemic periods compared with nonepidemic periods was 7.20% higher in children aged 7 to 59 months, 5.03% higher in children aged 7 to 23 months, and 8.91% higher in children aged 24 to 59 months (Table 5).
TABLE 5.
Prevented fraction of invasive pneumococcal disease caused by serotypes included in the PCV13 in epidemic and nonepidemic influenza periods according to clinical presentation and age in children aged 7 to 59 monthsa
| Clinical presentation | Age group (months) | Values by total period |
Values by epidemic influenza periods |
Values by nonepidemic influenza periods |
Difference in PFp in epidemic and nonepidemic periods (%) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| IR in unvaccinated population | IR in total population | Prevented fraction in the population (%) | IR in unvaccinated population | IR total population | Prevented fraction in the population (%) | IR in unvaccinated population | IR total population | Prevented fraction in the population (%) | |||
| Meningitis | 7–23 | 0.031 | 0.009 | 71.4 | 0.053 | 0.015 | 71.4 | 0.026 | 0.007 | 71.4 | 0.00 |
| 24–59 | 0.000 | 0.000 | NC | 0.000 | 0.000 | NC | 0.000 | 0.000 | NC | NC | |
| Total | 0.008 | 0.003 | 63.6 | 0.013 | 0.005 | 63.6 | 0.006 | 0.002 | 63.6 | 0.00 | |
| Pneumonia | 7–23 | 0.207 | 0.083 | 60.0 | 0.369 | 0.136 | 63.2 | 0.167 | 0.070 | 58.2 | 5.03 |
| 24–59 | 0.137 | 0.078 | 43.1 | 0.358 | 0.188 | 47.5 | 0.083 | 0.051 | 38.6 | 8.91 | |
| Total | 0.152 | 0.080 | 47.6 | 0.354 | 0.172 | 51.5 | 0.102 | 0.057 | 44.3 | 7.20 | |
| Occult bacteremia | 7–23 | 0.031 | 0.009 | 71.4 | 0.000 | 0.000 | NC | 0.039 | 0.011 | 71.4 | NC |
| 24–59 | 0.014 | 0.005 | 61.1 | 0.018 | 0.007 | 61.1 | 0.013 | 0.005 | 61.1 | 0.00 | |
| Total | 0.018 | 0.007 | 63.6 | 0.013 | 0.005 | 63.6 | 0.019 | 0.007 | 63.6 | 0.00 | |
| Other forms | 7–23 | 0.021 | 0.009 | 57.1 | 0.053 | 0.015 | 71.4 | 0.013 | 0.007 | 42.8 | 28.60 |
| 24–59 | 0.004 | 0.003 | 22.2 | 0.000 | 0.007 | NC | 0.004 | 0.002 | 61.1 | NC | |
| Total | 0.008 | 0.005 | 39.3 | 0.013 | 0.010 | 27.2 | 0.006 | 0.003 | 45.4 | −18.20 | |
| Total | 7–23 | 0.290 | 0.110 | 62.2 | 0.475 | 0.166 | 65.0 | 0.245 | 0.096 | 60.9 | 4.18 |
| 24–59 | 0.155 | 0.086 | 44.3 | 0.376 | 0.202 | 46.3 | 0.101 | 0.058 | 42.5 | 3.79 | |
| Total | 0.185 | 0.094 | 49.4 | 0.393 | 0.191 | 51.5 | 0.134 | 0.070 | 48.0 | 3.47 | |
Children were considered vaccinated if they had received ≥1 dose of PCV13. NC, not calculable; IR, incidence rate (per 105 person-weeks); PFp, prevented fraction in the population.
Considering the vaccinated population as children who had received ≥2 doses of PCV13 or ≥1 after 24 months, the PFp of IPD in children aged 7 to 59 months associated with PCV13 vaccination was higher during influenza epidemic periods (9.17% more in epidemic periods than in nonepidemic periods) and in the 7- to 23-month and the 24- to 59-month age groups (10.59% and 9.64%, respectively).
Meningitis only showed differences in the PFp between epidemic and nonepidemic periods in the 7- to 59-month group (22.62% more in epidemic periods than in nonepidemic periods).
Pneumonia showed differences between epidemic and nonepidemic periods; the PFp during epidemic periods compared with nonepidemic periods was 17% higher globally, 10.17% higher in children aged 7 to 23 months, and 25.20% higher in children aged 24 to 59 months (Table 6).
TABLE 6.
Prevented fraction of invasive pneumococcal disease caused by serotypes included in the PCV13 in epidemic and nonepidemic influenza periods according to clinical presentation and age in children aged 7 to 59 monthsa
| Clinical presentation | Age group (months) | Values by total period |
Values by epidemic influenza periods |
Values by nonepidemic influenza periods |
Difference in PFp in epidemic and nonepidemic periods (%) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| IR in unvaccinated population | IR in total population | Prevented fraction in the population (%) | IR in unvaccinated population | IR in total population | Prevented fraction in the population (%) | IR in unvaccinated population | IR in total population | Prevented fraction in the population (%) | |||
| Meningitis | 7–23 | 0.009 | 0.003 | 67.9 | 0.000 | 0.000 | NC | 0.011 | 0.004 | 67.9 | NC |
| 24–59 | 0.000 | 0.000 | NC | 0.000 | 0.000 | NC | 0.000 | 0.000 | NC | NC | |
| Total | 0.008 | 0.001 | 87.7 | 0.013 | 0.000 | 100.0 | 0.006 | 0.001 | 81.6 | 22.62 | |
| Pneumonia | 7–23 | 0.166 | 0.074 | 55.4 | 0.329 | 0.136 | 58.7 | 0.126 | 0.059 | 53.3 | 10.17 |
| 24–59 | 0.133 | 0.078 | 41.2 | 0.347 | 0.188 | 45.7 | 0.080 | 0.051 | 36.5 | 25.20 | |
| Total | 0.144 | 0.077 | 46.9 | 0.349 | 0.172 | 50.8 | 0.095 | 0.054 | 43.4 | 17.00 | |
| Occult bacteremia | 7–23 | 0.018 | 0.006 | 67.9 | 0.000 | 0.000 | NC | 0.023 | 0.007 | 67.9 | NC |
| 24–59 | 0.014 | 0.005 | 59.8 | 0.017 | 0.007 | 59.8 | 0.013 | 0.005 | 59.8 | 0.00 | |
| Total | 0.015 | 0.006 | 63.1 | 0.013 | 0.005 | 63.1 | 0.016 | 0.006 | 63.1 | 0.00 | |
| Other forms | 7–23 | 0.009 | 0.006 | 35.8 | 0.047 | 0.015 | 67.9 | 0.000 | 0.004 | NC | NC |
| 24–59 | 0.003 | 0.003 | 19.6 | 0.000 | 0.007 | NC | 0.004 | 0.002 | 59.8 | NC | |
| Total | 0.005 | 0.004 | 26.2 | 0.013 | 0.010 | 26.2 | 0.003 | 0.002 | 26.2 | 0.00 | |
| Total | 7–23 | 0.203 | 0.089 | 56.2 | 0.376 | 0.151 | 59.9 | 0.161 | 0.074 | 54.1 | 10.59 |
| 24–59 | 0.150 | 0.086 | 42.4 | 0.364 | 0.202 | 44.5 | 0.097 | 0.058 | 40.6 | 9.64 | |
| Total | 0.167 | 0.087 | 48.0 | 0.375 | 0.186 | 50.4 | 0.117 | 0.063 | 46.1 | 9.17 | |
Children were considered vaccinated if they had received ≥2 doses of PCV13 or ≥1 dose after 24 months. NC, not calculable; IR, incidence rate (per 105 person-weeks); PFp, prevented fraction in the population.
The differences in the PFp of IPD in children aged 7 to 59 months associated with PCV13 vaccination between epidemic and nonepidemic periods were higher, both globally, in pneumonia and in all age groups, when the vaccinated population was considered children who had received ≥2 doses of PCV13 or ≥1 after 24 months.
DISCUSSION
This study highlights the increase in the incidence of IPD in persons aged <18 years in influenza epidemic periods. Stratification by age showed the association was strongest in children aged 2 to 4 years and especially in the 5- to 17-year age group, but there was no significant association in children aged <2 years. The annual PIDIRAC reports show that during all the years studied, the highest cumulative incidence of influenza infections was in the <4-year age group (35). Some reports have found an association between IPD and influenza (2, 13) but without having specifically analyzed children aged <2 years. Weinberger et al. (12) found a strong association between the circulation of the respiratory syncytial virus (RSV) and episodes of IPD in children aged <2 years. During the period 2012 to 2015, the reports published by the Microbiological Notification System of Catalonia (38) showed that 84.9% of cases of RSV infection recorded in Catalonia were in children aged <2 years and that the peak of RSV activity preceded the influenza epidemic. The temporal coincidence between RSV and IPD in children aged <2 years could explain the high IR observed during nonepidemic influenza periods, which was much higher than the total IR in that period (0.23 cases/105 person-weeks versus 0.05 cases/105 person-weeks), and why when considering epidemic influenza periods and nonepidemic periods in this age group we found no significant differences.
McCullers et al. (19) using animal models and Grijalva et al. (3) in a case-control study showed that the influenza virus increases the transmission of S. pneumoniae and, therefore, the risk of nasopharyngeal acquisition, a step prior to the development of IPD. However, although we found a higher IR of IPD in epidemic periods globally, the increase in the incidence during epidemic influenza periods compared with nonepidemic periods was only statistically significant for the clinical presentation of pneumonia. Weinberger et al. (39) and Ben-Shimol et al. (40) postulated that viral respiratory infection increases susceptibility to pneumonia, an approach that would coincide with our results.
The great variability in IPD-causing serotypes found in our study, with none being predominant during the epidemic or nonepidemic influenza periods, suggests there is no relationship between the influenza virus and a specific S. pneumoniae serotype. Likewise, during the study period, the subtypes of viruses that cause influenza epidemics have varied (35), although a specific relationship with certain viral subtypes cannot be ruled out. Launes et al. (20) found a significant decrease in the proportion of IPD caused by serotype 1 during the 2009 pandemic; however, in the subsequent seasonal influenza season, caused by the same influenza A subtype virus, S. pneumoniae serotype 1 was detected in the same proportion as before. The results of our study support the idea that the circulation of influenza viruses is not related to the incidence of vaccine or nonvaccine serotypes.
Some reports (17, 18) indicate that influenza virus infection has a greater effect on non-HIS serotypes. This would mean that the influenza virus increases the susceptibility of the host to bacterial infections. Thus, while HIS serotypes could cause IPD under any circumstances, non-HIS serotypes would increase the ability to produce IPD in the presence of the influenza virus. Weinberger et al. (18) found this same association only in adults without comorbidities. A Catalan study made before the introduction of the 13-valent vaccine found an association between IPD caused by non-HIS serotypes and coinfection with different respiratory viruses (17). Grijalva et al. (3) reported that the acquisition of a new S. pneumoniae serotype after influenza virus infection was observed in patients previously colonized by another serotype. In our study, although the proportion of IPD-causing HIS serotypes was higher in epidemic than in nonepidemic influenza periods, there was no statistically significant association and the increase in incidence during influenza epidemic periods was significant for both HIS and non-HIS serotypes. The fact that our study did not permit an analysis of the previous state of colonization or accurate determination of the antecedents of infection by the influenza virus or other respiratory viruses may have cushioned the specific effect of the influenza virus on IPD cases caused by non-HIS-serotypes. Likewise, serotype 3 was considered a non-HIS serotype, whereas we considered it as an HIS-serotype, as indicated by authors who evaluated the invasive capacity of the serotype, including episodes detected only by PCR with negative culture (33) and after the introduction of PCV13 (34). Other authors (14, 15) also found no differences between the serotypes causing IPD during the epidemic and nonepidemic influenza periods in children or adults, which suggests that the interaction between the influenza virus and the various pneumococcal serotypes is complex and depends on numerous factors and not only on the invasive capacity of the serotype.
Four parameters were taken into account to assess the severity of IPD, namely, ICU stay, in-hospital complications, mechanical ventilation, and sequelae at discharge/death. ICU stay was associated with nonepidemic influenza periods due to the greater number of episodes of meningitis and sepsis recorded, as opposed to epidemic periods, in which most cases were pneumonia. Cases with in-hospital complications and sequelae at discharge were much more frequent during epidemic periods. The low prevalence of medical risk conditions in cases during influenza epidemic periods and the fact that there were no significant differences between the serotypes causing IPD according to influenza activity suggest that the increase in severity in cases of IPD during epidemic periods could be due to a synergistic effect between S. pneumoniae and the influenza virus (41, 42). In the adjusted model, in cases of pneumonia, although an association between epidemic influenza periods and sequelae at discharge/death was found, no association was observed between complications and influenza epidemic periods. This could be due to the large increase in serotypes causing pneumonia with empyema or pleural effusion and necrotizing pneumonia recorded in recent years (7, 43), which have resulted in complicated pneumonia being the most frequent clinical presentation in both periods. The severity of cases of IPD caused by HIS serotypes was associated with influenza activity only in the proportion of cases with sequelae at discharge/death.
Our results show that the PFp of IPD in children aged 7 to 59 months associated with the PCV13 vaccine was higher during epidemic periods than in nonepidemic periods, with the greatest difference being in cases of pneumonia. These results seem logical because influenza virus infection may increase the incidence of pneumococcal pneumonia caused by both vaccine and nonvaccine serotypes. There are few studies on the impact of PCV13 in the influenza season. McGarry et al. (5) calculated, in a predictive model, that PCV13 would prevent 63% to 67% of cases of invasive pneumococcal pneumonia, depending on the incidence of the influenza virus during the epidemic period. This percentage is higher than our results suggest, which may be because our vaccination coverage for the entire study period was only around 63% in children aged 7 to 59 months since PCV13 was not administered systematically and was not financed by the Catalan health system until July 2016. The results shown in Fig. 3, although the number of cases analyzed separately each year was low, support this idea since they show that the PFp increases in tandem with the vaccination coverage. Another possible explanation would be the low effectiveness of PCV13 against serotype 3 (26), the most frequent serotype during influenza epidemic periods, together with the increase in the proportion of nonvaccine serotypes.
Domínguez et al. (26) found that the vaccination effectiveness of PCV13 in preventing IPD was higher when ≥2 doses of PCV13 or ≥1 after 24 months were administered than when ≥1 dose of PCV13 was administered (90.0% versus 75.8%). In our study, the differences in the PFp found between epidemic and nonepidemic periods were higher when the vaccinated population was considered children who had received ≥2 doses of PCV13 or ≥1 after 24 months compared with children who had received ≥1 dose of PCV13. It is plausible to assume that in epidemic influenza periods, when the incidence of IPD increases, the protective effect of PCV13 will be higher when administering a vaccine schedule that offers greater effectiveness than in nonepidemic influenza periods, when this environment factor that favors the acquisition of IPD does not exist.
Although vaccination coverages have increased throughout the study period, Loughlin et al. (44) postulate that evidence of indirect protection in unimmunized children was observed as vaccine uptake reached 75% in the target community. The estimated vaccination coverage in our study was <75% during the 4 years; therefore, we can assume that the PFp found is the result of direct protection but will also increase due to herd immunity after the introduction of the PCV13 vaccine into the Catalan vaccination schedule.
This study has some limitations. First, unlike other studies (3), the carrier status of S. pneumoniae before the development of IPD was not known. Likewise, there was no microbiological confirmation of prior infection by the influenza virus or other respiratory viruses. However, in the periods considered epidemic, there was evidence of an increase in the circulation of influenza viruses with respect to other respiratory viruses (33), so it seems plausible to assume that some IPD cases in the epidemic period appeared after influenza infection.
In conclusion, our results show that during influenza epidemic periods the incidence of all forms of IPD in persons aged <18 years increased, especially after the age of 2 years and in cases of pneumonia. No association was observed between the increase in incidence rates of IPD in influenza epidemic periods and any specific pneumococcal serotype. In influenza epidemic periods, increases were observed in complications and in sequelae at discharge in cases of IPD.
The PFp of cases of IPD caused by PCV13 serotypes was higher in influenza epidemic periods than in nonepidemic periods, and this difference increased when ≥2 doses of PCV13 or ≥1 after 24 months were administered. The increase in vaccination coverage after the addition of PCV13 to the vaccines financed by the Catalan health system will probably increase the PFp in both epidemic and nonepidemic influenza periods, although the increase could be limited by the large proportion of cases of IPD caused by serotype 3 and, possibly, by an increase in other nonvaccine serotypes. Therefore, it remains essential to monitor IPD in order to detect possible serotype replacement after PCV13 vaccination.
Supplementary Material
ACKNOWLEDGMENTS
Fernando Moraga-Llop reports participation in expert meetings and symposiums organized by Pfizer and GSK. Carmen Muñoz-Almagro reports grants from Pfizer laboratories and personal fees from GSK Laboratories, outside the submitted work. Magda Campins reports participation as an investigator in clinical trials from GSK and in expert meetings and symposiums organized by Pfizer and GSK. Juan José García-García reports personal fees from Pfizer. All other authors declare no competing interests.
This work was supported by the National Plan of R+D+I 2008 to 2011 and ISCIII Sub-Directorate General for Evaluation and Promotion of Research (projects PI11/02081 and PI11/2345) and cofunded by European Regional Development Fund (ERDF) and the Catalan Agency for the Management of Grants for University Research (AGAUR grants 2017/SGR 1342, 2014/SGR 505, and 2014/SGR 0742).
The members of the Working Group of Projects PI11/02081 and PI11/2345 are Conchita Izquierdo, Pilar Ciruela, Sergi Hernández (Public Health Agency of Catalonia), Àngela Dominguez, Luis Salleras, Nuria Soldevila (University of Barcelona), Anna Solé-Ribalta, Carmen Muñoz-Almagro, Cristina Esteva, Johanna Martínez-Osorio, Juan José García-García, Mariona F. de Sevilla, (Hospital Sant Joan de Déu Barcelona, University of Barcelona, Barcelona), Ana María Planes, Fernando Moraga-Llop, Gemma Codina, Magda Campins, Sebastià González-Peris, Sonia Uriona, (Vall d'Hebron University Hospital, Barcelona), and Alvaro Díaz (Hospital de Nens, Barcelona).
Footnotes
Supplemental material for this article may be found at https://doi.org/10.1128/JCM.00363-19.
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