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).
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.
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.
1. Janahi IA, Fakhouri KPost TWIn: Epidemiology; clinical presentation; and evaluation of parapneumonic effusion and empyema
in children. 2016.Waltham, MA: Uptodate Inc.,
2. Janahi IA, Fakhouri KPost TWIn: Management and prognosis of parapneumonic effusion and empyema
in children. 2016.Waltham, MA: Uptodate Inc.,
3. Clark JE, Hammal D, Spencer D, et alChildren with pneumonia: how do they present and how are they managed? Arch Dis Child. 2007;92:394–398.
4. Byington CL, Spencer LY, Johnson TA, et alAn epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema
: risk factors and microbiological associations. Clin Infect Dis. 2002;34:434–440.
5. Hernández-Bou S, García-García JJ, Esteva C, et alPediatric parapneumonic pleural effusion
: epidemiology, clinical characteristics, and microbiological diagnosis. Pediatr Pulmonol. 2009;44:1192–1200.
6. Pernica JM, Moldovan I, Chan F, et alReal-time polymerase chain reaction for microbiological diagnosis of parapneumonic effusions in Canadian children. Can J Infect Dis Med Microbiol. 2014;25:151–154.
7. Strachan RE, Cornelius A, Gilbert GL, et alAustralian Research Network in Empyema
. Bacterial causes of empyema
in children, Australia, 2007-2009. Emerg Infect Dis. 2011;17:1839–1845.
8. Blaschke AJ, Heyrend C, Byington CL, et alMolecular analysis improves pathogen identification and epidemiologic study of pediatric parapneumonic empyema
. Pediatr Infect Dis J. 2011;30:289–294.
9. Lin TY, Hwang KP, Liu CC, et alEtiology of empyema
thoracis and parapneumonic pleural effusion
in Taiwanese children and adolescents younger than 18 years of age. Pediatr Infect Dis J. 2013;32:419–421.
10. Li ST, Tancredi DJEmpyema hospitalizations increased in US children despite pneumococcal conjugate vaccine. Pediatrics. 2010;125:26–33.
11. Ampofo K, Pavia AT, Chris S, et alThe changing epidemiology of invasive pneumococcal disease at a tertiary children’s hospital through the 7-valent pneumococcal conjugate vaccine era: a case for continuous surveillance. Pediatr Infect Dis J. 2012;31:228–234.
12. Yu D, Buchvald F, Brandt B, et alSeventeen-year study shows rise in parapneumonic effusion and empyema
with higher treatment failure after chest tube drainage. Acta Paediatr. 2014;103:93–99.
13. Muñoz-Almagro C, Jordan I, Gene A, et alEmergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of 7-valent conjugate vaccine. Clin Infect Dis. 2008;46:174–182.
14. Koshy E, Murray J, Bottle A, et alImpact of the seven-valent pneumococcal conjugate vaccination (PCV7) programme on childhood hospital admissions for bacterial pneumonia and empyema
in England: national time-trends study, 1997-2008. Thorax. 2010;65:770–774.
15. Strachan RE, Snelling TL, Jaffé AIncreased paediatric hospitalizations for empyema
in Australia after introduction of the 7-valent pneumococcal conjugate vaccine. Bull World Health Organ. 2013;91:167–173.
16. François P, Desrumaux A, Cans C, et alPrevalence and risk factors of suppurative complications in children with pneumonia. Acta Paediatr. 2010;99:861–866.
17. Van Ackere T, Proesmans M, Vermeulen F, et alComplicated parapneumonic effusion in Belgian children: increased occurrence before routine pneumococcal vaccine implementation. Eur J Pediatr. 2009;168:51–58.
18. Niemi E, Korppi MParapneumonic empyema
in children before the era of pneumococcal vaccination
. Acta Paediatr. 2011;100:1230–1233.
19. Walker W, Wheeler R, Legg JUpdate on the causes, investigation and management of empyema
in childhood. Arch Dis Child. 2011;96:482–488.
20. Moreno-Pérez D, Andrés Martín A, Tagarro García A, et al[Community acquired pneumonia in children: Treatment of complicated cases and risk patients. Consensus statement by the Spanish Society of Paediatric Infectious Diseases (SEIP) and the Spanish Society of Paediatric Chest Diseases (SENP)]. An Pediatr (Barc). 2015;83:217.e1–217.11.
21. Slinger R, Hyde L, Moldovan I, et alDirect Streptococcus pneumoniae real-time PCR serotyping from pediatric parapneumonic effusions. BMC Pediatr. 2014;14:189.
22. Obando I, Camacho-Lovillo MS, Porras A, et alSustained high prevalence of pneumococcal serotype 1 in paediatric parapneumonic empyema
in southern Spain from 2005 to 2009. Clin Microbiol Infect. 2012;18:763–768.
23. Picazo J, Ruiz-Contreras J, Casado-Flores J, et alHeracles Study Group. Impact of introduction of conjugate vaccines in the vaccination schedule on the incidence of pediatric invasive pneumococcal disease requiring hospitalization in Madrid 2007 to 2011. Pediatr Infect Dis J. 2013;32:656–661.
24. Angoulvant F, Levy C, Grimprel E, et alEarly impact of 13-valent pneumococcal conjugate vaccine on community-acquired pneumonia in children. Clin Infect Dis. 2014;58:918–924.
25. Saxena S, Atchison C, Cecil E, et alAdditive impact of pneumococcal conjugate vaccines on pneumonia and empyema
hospital admissions in England. J Infect. 2015;71:428–436.
26. Simonsen L, Taylor RJ, Schuck-Paim C, et alEffect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: a time series analysis. Lancet Respir Med. 2014;2:387–394.
27. Farrington CPEstimation of vaccine effectiveness using the screening method. Int J Epidemiol. 1993;22:742–746.
28. Centers for Disease Control and Prevention (CDC). Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction–eight states, 1998–2005. MMWR Morb Mortal Wkly Rep. 2008;57(6):144–148.
29. Kellner JD, Vanderkooi OG, MacDonald J, et alChanging epidemiology of invasive pneumococcal disease in Canada, 1998-2007: update from the Calgary-area Streptococcus pneumoniae research (CASPER) study. Clin Infect Dis. 2009;49:205–212.
30. Miller E, Andrews NJ, Waight PA, et alHerd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study. Lancet Infect Dis. 2011;11:760–768.
31. Pavia M, Bianco A, Nobile CG, et alEfficacy of pneumococcal vaccination
in children younger than 24 months: a meta-analysis. Pediatrics. 2009;123:e1103–e1110.
32. Feikin DR, Kagucia EW, Loo JD, et alSerotype Replacement Study Group. Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites. PLoS Med. 2013;10:e1001517.
33. Aristegui J, Bernaola E, Pocheville I, et alReduction in pediatric invasive pneumococcal disease in the Basque Country and Navarre, Spain, after introduction of the heptavalent pneumococcal conjugate vaccine. Eur J Clin Microbiol Infect Dis. 2007;26:303–310.
34. Fletcher MA, Schmitt HJ, Syrochkina M, et alPneumococcal empyema
and complicated pneumonias: global trends in incidence, prevalence, and serotype epidemiology. Eur J Clin Microbiol Infect Dis. 2014;33:879–910.
35. Grijalva CG, Nuorti JP, Zhu Y, et alIncreasing incidence of empyema
complicating childhood community-acquired pneumonia in the United States. Clin Infect Dis. 2010;50:805–813.
36. Byington CL, Korgenski K, Daly J, et alImpact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema
. Pediatr Infect Dis J. 2006;25:250–254.
37. Steens A, Bergsaker MA, Aaberge IS, et alPrompt effect of replacing the 7-valent pneumococcal conjugate vaccine with the 13-valent vaccine on the epidemiology of invasive pneumococcal disease in Norway. Vaccine. 2013;31:6232–6238.
38. Hortal M, Estevan M, Meny M, et alImpact of pneumococcal conjugate vaccines on the incidence of pneumonia in hospitalized children after five years of its introduction in Uruguay. PLoS One. 2014;9:e98567.
39. Greenberg D, Givon-Lavi N, Ben-Shimol S, et alImpact of PCV7/PCV13 introduction on community-acquired alveolar pneumonia in children <5 years. Vaccine. 2015;33:4623–4629.
40. Sgambatti S, Minamisava R, Bierrenbach AL, et alEarly impact of 10-valent pneumococcal conjugate vaccine in childhood pneumonia hospitalizations using primary data from an active population-based surveillance. Vaccine. 2016;34:663–670.
41. Nath S, Thomas M, Spencer D, et alHas the incidence of empyema
in Scottish children continued to increase beyond 2005? Arch Dis Child. 2015;100:255–258.
42. Wiese AD, Griffin MR, Zhu Y, et alChanges in empyema
among U.S. children in the pneumococcal conjugate vaccine era. Vaccine. 2016;34:6243–6249.
43. Boccalini S, Azzari C, Resti M, et alEconomic and clinical evaluation of a catch-up dose of 13-valent pneumococcal conjugate vaccine in children already immunized with three doses of the 7-valent vaccine in Italy. Vaccine. 2011;29:9521–9528.
44. Guevara M, Barricarte A, Torroba L, Herranz M, Gil-Setas A, Gil F, et alDirect, indirect and total effects of 13-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in children in Navarra, Spain, 2001 to 2014: cohort and case–control study. Euro Surveill. 2016;21(14):pii=30186.