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Pneumococcal Vaccination and Pneumonia Associated With Pleural Effusion in a Pediatric Population

Bernaola, Enrique MD*; Gil, Francisco MD, PhD; Herranz, Mercedes MD*; Gil-Setas, Alberto MD; Guevara, Marcela MD, PhD§¶; Castilla, Jesus MD, PhD§¶

The Pediatric Infectious Disease Journal: April 2018 - Volume 37 - Issue 4 - p e87–e92
doi: 10.1097/INF.0000000000001798
Vaccine Reports

Objective: The aim was to assess the effect of the nonsystematic pneumococcal conjugate vaccine (PCV) on incidence of pneumonia associated with parapneumonic pleural effusion (PPE) in vaccinated and unvaccinated children.

Methods: Cases were patients <15 years of age who had been diagnosed with pneumonia associated with PPE in a tertiary hospital in Navarra (Spain) between 1995 and 2014. The population <15 years of age and covered by the public health service was used as reference. The vaccination status of the cases and population was obtained from computerized medical records. Logistic regression analyses included vaccination status, age group and time periods: prevaccine (1995–2001) and vaccination with PCV7 (2002–2010) and PCV13 (2011–2014).

Results: A total of 321 cases of PPE were included. The risk of PPE increased between the prevaccine and PCV7 period (adjusted odds ratio [OR], 3.34; 95% confidence interval [CI]: 2.37–4.71), while vaccination with PCV7 was found to be an independent risk factor (OR, 1.44; 95% CI: 1.09–1.89) in the same analysis. In the PCV13 period, the risk of PPE returned to the prevaccination incidence level among children vaccinated with PCV13 (OR, 1.07; 95% CI: 0.56–2.04), while unvaccinated children (OR, 1.69; 95% CI: 0.96–2.98) and overall those vaccinated with PCV7 (OR, 3.64; 95% CI: 2.15–6.17) maintained an increased risk of PPE.

Conclusion: The nonsystematic introduction of PCV7 was followed by an increased incidence of PPE. The subsequent introduction of PCV13 was associated with a return to the incidence level in the prevaccine period, mainly in children vaccinated with PCV13.

From the *Department of Pediatrics, and Department of Microbiology, Navarra Hospital Complex, Pamplona, Spain; Department of Pediatrics, Estella Hospital, Spain; §Instituto de Salud Pública de Navarra, IdiSNA, Pamplona, Spain; and CIBER Epidemiología y Salud Pública, Spain.

Accepted for publication April 24, 2017.

This work was partially supported by SpIDnet, a network funded by the European Centre for Disease Prevention and Control (ECDC/2012/038).

The authors have no financial relationships relevant to this article to disclose.

Enrique Bernaola has collaborated as a researcher in a clinical trial of PCV13 for Pfizer Inc. The other authors report no conflicts of interest.

Address for correspondence: Francisco Gil, MD, PhD, Department of Pediatrics, Estella Hospital, 22 Santa Soria Street, Estella 31200, Spain. E-mail:

Parapneumonic pleural effusion (PPE) is defined as pleural effusion associated with lung infection.1 According to its clinical presentation, it can be divided into 3 distinct stages: simple PPE (initial stage where the exudate is usually sterile), complicated PPE (the effusion has partitions or fibrin septa, which can be detected by ultrasound) and empyema (final stage defined by the presence of bacteria and/or purulent fluid in the pleural cavity).2 It is estimated that approximately 10% of pneumonias in pediatric patients may be complicated by PPE or empyema,3 the percentage rises to approximately 30% of hospitalized patients.4 , 5 Streptococcus pneumoniae is the most common etiologic agent in PPE,1 accounting for 50% to 75% of PPE in the pediatric population.6–9

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) coincided with significant epidemiologic changes in the incidence of PPE in America,10 , 11 in Europe12–14 and in other regions of the world.15 However, similar increases were reported before the introduction of the vaccine,4 , 16–18 and so it is possible that the origin of these increases in incidence is multifactorial.8 , 19 , 20 Some etiologic studies of PPE cases using polymerase chain reaction (PCR) techniques found that most of the pneumococcal serotypes involved in causing PPE are included in the 13-valent pneumococcal conjugate vaccine (PCV13).21 , 22 Few published studies have demonstrated the protective effect of this new vaccine against PPE.23–26 Furthermore, most of these studies have been performed in countries where pneumococcal vaccination was integrated systematically in childhood immunization programs and address its effect from the perspectives of the impact on the population. The purpose of this study was to assess the direct and indirect effect of pneumococcal conjugated vaccination on the risk of PPE in children under 15 years old in a region where these vaccines were used, but not included in the official vaccination program and, thus, where vaccination coverage was relatively low.

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The study included all cases of pneumonia associated with PPE in children under 15 years diagnosed between 1995 and 2014 at the Navarra Hospital Complex, tertiary referral hospital for a population of approximately 640,000 inhabitants, including ≈100,000 children under 15 years old. The design of the study, the obtaining and working of data, was done according to the ethical and confidentiality standards of our center.

The inclusion criteria were patients diagnosed with pneumonia who required hospitalization and also had significant amount of PPE evaluated by chest ultrasound performed by a radiologist (including simple, complicated and empyema PPE). Exclusion criteria were patients with pleural effusion secondary to other diseases, cancer, postsurgical patients or those who had been admitted with PPE less than 4 weeks ago. Information about age, microbiologic tests (blood culture, pleural fluid culture, antigen test or PCR for pneumococcus), surgical techniques (thoracocentesis, thoracostomy and video-assisted thoracoscopy), days of hospitalization and vaccination status (unvaccinated, vaccinated with PCV7 or vaccinated with PCV13) was collected. PPE was considered to have confirmed pneumococcal etiology in those who presented: blood culture and/or pleural fluid culture, and/or antigen or PCR pleural fluid positive to pneumococcal. PPE was considered to have a probable pneumococcal etiology in those with positive urine pneumococcal antigen who did not show confirmed pneumococcal etiology. Children considered vaccinated with PCV7 were those who had followed a correct vaccination schedule according to the technical specifications of the manufacturer, usually 3 doses in the first year and a booster dose in the second year of life. Children considered vaccinated with PCV13 were those who followed the correct schedule for PCV13 or a correct primary vaccination for PCV7 and PCV13 booster.

The study population was defined from the primary care computerized medical records, including all children less than 15 years of age and covered by the Navarra health service (universal public health care system that covers virtually the entire population). From this source, we obtained the PCV7 and PCV13 vaccination status for every age and year of the entire study period. PPE incidence rates were calculated for periods and age groups and compared using the mid-p exact test. The effectiveness of the vaccine was estimated by the screening method, which is based on the comparison between the proportion of vaccinated cases and the proportion of the vaccinated population (both obtained from official Navarre immunization records), using the approach described by Farrington.27

Logistic regression models were used to estimate odds ratios (OR), with their 95% confidence intervals (CI) adjusted for age group and period. Age was grouped into 3 categories: children under 2 years, from 2 to 4 years old and 5 to 14 years old. The study period was divided into a prevaccine period (1995–2001), a PCV7 vaccination period (2002–2010) and a PCV13 vaccination period (2011–2014). To separate the direct and indirect effects of each vaccine, a variable combining periods and vaccination status was included in certain models, taking the unvaccinated children in the 1995–2001 period as the reference category.

Analysis of variance test was used to compare days of hospitalization, and χ2 test was used to compare proportion of surgical treatment in cases.

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In total, 321 cases of PPE diagnosed between January 1995 and December 2014 were included. The mean age at diagnosis was 4.54 years, and 57.6% were male. In 47.7% (153/321) of the cases, a pleural fluid sample was obtained for microbiologic analysis. Of all cases included in the study, 23.7% (76/321) had a confirmed pneumococcal etiology, and this percentage rose to 49.0% (75/153) of patients whose pleural fluid was obtained. A determination of pneumococcal antigen in urine was performed in 54.5% (175/321) of the cases, and 47.7% (153/321) of all cases were of probable or confirmed pneumococcal etiology. This percentage rose to 68% (104/153) in patients from whom pleural fluid was obtained.

Pneumococcal serotype could be known in a low percentage of cases in the prevaccine period (14, 3 and 1) and in very few cases in PCV13 period (14, 19A and 24F). In the PCV7 period, serotypes found were 1 (60%), 19A (16.6%), 3 (10%), 7F (6.6%), 14 (3.3%), 6A (3.3%) and 10A (3.3%). In PCV7 period, only one of the cases corresponded with PVC7 vaccine serotypes, but 96.6% were serotypes included in PCV13 vaccine. In PCV13 period, only one case corresponding with PCV13 vaccine serotypes had been vaccinated.

The average of admission days was 11.91 (standard deviation, 6.28), and 47.7% of patients needed some surgical technique (thoracocentesis, thoracostomy or video-assisted thoracoscopy). Not significant differences were found because of vaccination status in length of hospitalization (not vaccinated 11.98, PCV7 vaccinated 11.63, and PCV13 vaccinated 13.58; p=0.578) or proportion of surgical treatment (not vaccinated 43.2%, PCV7 vaccinated 53.8%, PCV13 vaccinated 58.3%; p=0.146).

The average annual PPE incidence was 16.13 cases per 100,000 children under 15 years, although there were wide variations depending on the age group of patients and the year ( Figure 1).



Vaccination coverage increased over time in all age groups. In children younger than 2 years, the coverage rose from less than 15% in 2002 to over 70% in 2014, the year in which the vaccination coverage in all children under 15 years of age was slightly less than 60% (Figure 2).



Upon comparison of the prevaccine period and the PCV7 period, a significant increase in incidence was found in all age groups (Table 1). When comparing the incidence in the periods of use of PCV7 and PCV13, statistically significant decreases were observed in all age groups except in 5–14 years old (Table 2).





Upon comparison with the prevaccine period and adjusted for age and vaccination status, an increased risk of PPE was observed in the PCV7 period. In the same multivariate model, the risk of PPE was significantly higher for children vaccinated with PCV7 compared with those who had not been vaccinated and was much higher in children under 5 years than those 5 to 14 years of age (Table 2). A significant decrease in risk of PPE was observed when comparing the PCV13 and PCV7 periods. Regardless of the risk difference per period, children vaccinated with PCV13 showed a 45% (95% CI: −9 to 72) effectiveness in reducing the risk of PPE as compared with children who had not received this vaccine (Table 3).



Taking unvaccinated children in the prevaccine period (1995–2001) as the reference and adjusting for age, the risk of PPE was higher in children vaccinated with PCV7 in both the 2002–2010 period (OR, 4.78; 95% CI: 3.32–6.89) and the 2011–2014 period (OR, 3.64; 95% CI: 2.15–6.17). An increased risk of PPE was also seen in unvaccinated children during the PCV7 period (OR, 3.34; 95% CI: 2.37–4.72), but decreased and was no longer significant during the PCV13 period (OR, 1.69; 95% CI: 0.96–2.98). Children vaccinated with PCV13 recovered the PPE baseline risk (OR, 1.07; 95% CI: 0.56–2.04). These findings were consistent for all analyses stratified according to age group (Table 4).



These analyses were repeated in the subgroup of patients with PPE from confirmed pneumococcal etiology and also from confirmed or probable pneumococcal etiology with similar results, albeit with loss of statistical significance in certain comparisons because of a decrease of statistical power (data not shown).

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The introduction of PCVs has been followed by transcendental changes in the incidence of pneumonia associated with PPE in our study population. The introduction of PCV7 brought a significant decrease in invasive pneumococcal disease around the world, a fact that has been repeatedly reported in various countries,28–32 including Spain.33 However, at the same time, there was an increase in the incidence of PPE and empyema, which may have been related to the replacement of serotypes after the introduction of the vaccine.10–15 , 34–36 These studies were conducted in countries where the vaccine had been incorporated into the official systematic vaccinations programs. In Navarra, the vaccine was not introduced systematically, so vaccination coverage was lower than that of other countries. This circumstance made possible to estimate the direct effect in children vaccinated with PCV on the incidence of pneumonia associated with PPE and indirect effect in children unvaccinated living in a region with a part of the population vaccinated.

In our study, the risk of PPE in the whole of the pediatric population was 3 times higher in the PCV7 period than in the prevaccine period, and the target population of this vaccine (under 5 years old) was the most affected. In addition, children vaccinated with PCV7 had a 40% higher risk of PPE compared with those who were not vaccinated. Previous studies had demonstrated increase in incidence of PPE after the introduction of PCV7,10–15 but this is the first study that describes the direct effect of PCV7 on the incidence of pneumonia associated with PPE. One possible reason of this finding could be direct effect of PCV7 preventing oropharyngeal colonization by serotypes included in vaccine. Colonization by other serotypes would be more viable in these children because of a lower bacteriologic pressure, so they could be the first to suffer the effects of this new colonization, before and more intensive than not vaccinated children.

The change of PCV7 to PCV13 was followed by the opposite effect, reducing the risk of PPE to prevaccination period levels. After changing PCV7 for PCV13, decreases in the incidence of invasive pneumococcal disease37 and in admission rates because of pneumonia have been reported.26 , 38 , 39 A decrease in admission rates has also been described because of pneumonia after the introduction of the 10-valent pneumococcal vaccine in Brazil,40 a country where there had previously been no systematic vaccination with PCV7. In populations where the PCV13 vaccination was introduced systematically, a reduction in the incidence of pneumonia associated with PPE and empyema has also been documented.23–25 , 41 A recent study conducted in the United States describes the same results as in our study: an increase in incidence of empyema after introducing PCV7 and posterior decrement to prevacunal incidence after introducing PCV13, although in this case, the vaccination was introduced systematically.42

A relevant finding of this study was that the risk of PPE is modified according to, not only vaccine type introduced in the population in the study period but also the vaccination status and type of vaccine at individual level. In children under 5 years old, the direct protective effect of the PCV13 in vaccinated children was statistically significant, and the incidence rate of PPE returned to that found in the prevaccination period. The excess risk of PPE observed in the PCV7 period also declined in the PCV13 period among unvaccinated children. This change suggests an indirect effect of PCV13 on the incidence of PPE.

In view of these results, a catch-up campaign with PCV13 could have been advisable for children who received PCV7 to reduce the risk of PPE. A study in Italy after the commercialization of the PCV13 supports the strategy of conducting a catch-up campaign with PCV13 in children under 5 years old, both from a clinical and economic perspective.43 The risk also appears to be higher in children older than 5 years who received PCV7 during this period; however, the lower frequency of the disease at this age, the high costs of catch-up in such a large population group and the decrease of the risk by indirect effect of vaccination results in the recommendation of a catch-up campaign in these patients not being so evident.

The most important limitation of this study was that clinical cases were analyzed, but a part of them were not confirmed in the laboratory for Streptococcus pneumoniae. We establish a relationship between the introduction of vaccines and changes in the incidence of PPE without entering into microbiologic etiology. However, in almost 70% of the patients studied in depth, S. pneumoniae was the most likely etiologic agent. Furthermore, in the subset of confirmed or probable pneumococcal etiology, results were similar, although statistical significance was lost because of the reduced sample size. Nor was an analysis of pneumococcal serotypes included, such that it cannot be categorically said that the changes in incidence are because of changes in serotypes, but descriptive data of serotypes from PVC7 period show that almost all serotypes recovered were included in PCV13 vaccine. Some studies indicate that reduction of PPE after introduction of PCV13 has been the consequence of reduction in serotypes that more frequently were causing PPE, like serotype 1, 19A, 3 and 7F,23 , 41 being these serotypes the most frequents in our study. However, a recent study of our context suggests a significant decrease in the incidence of invasive pneumococcal disease after the introduction of the PCV13, especially at the expense of a decrease in the serotypes included in the vaccine,44 so it is reasonable to assume that this change may be applicable to pneumonia associated with PPE.

These findings show the crucial importance of epidemiologic surveillance in the follow-up of pneumococcal vaccination programs to detect changes in serotype distribution that can guide the development of vaccines with broader serotypes coverage.

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In a population with intermediate coverage of PCV7, this vaccination was associated with an increased incidence of pneumonia associated with PPE. In this context, the further change of PCV7 by PCV13 in childhood vaccination has helped to restore PPE risk to that of prevaccination period levels. These effects have been seen mainly in vaccinated children but have also affected those unvaccinated, probably because of the indirect effect. A catch-up campaign using PCV13 for children previously vaccinated with PCV7 could prevent PPE.

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pleural effusion; pneumococcal vaccination; empyema

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