Respiratory tract infections (RTIs), in particular in the upper respiratory tract are common, with about 2 infections per year in adults and 6–8 per year in young children.1,2 RTIs, especially acute otitis media (AOM), are the most common indications for antibiotic prescriptions in children. The society’s health cost due to RTI is high.2,3
AOM is the most common cause of health care visits in children,2,4–74–74–74–7 and it is claimed that more than half of all children experience at least 1 episode during their first year of life and 60%–70% before 3 years of age.1,2,8 The most common bacteria are Streptococcus pneumonia (pneumococcus), nontypeable Haemophilus influenzae (H. influenzae) and Moraxella catarrhalis (M. catarrhalis).4–74–74–74–7,9,10 AOM is the most common cause of antibiotic usage in this age group,2,6,7 which consequently increases the risk of antibacterial resistance.11 Lower respiratory tract infections (LRTIs) are also common, especially in young children and the elderly. Viral infections including the seasonal influenza virus are the most common cause of LRTI, sometimes followed by bacterial infections.12–1512–1512–1512–15 Bronchiolitis may be the most common LRTI in children as the majority of children have had at least 1 episode of bronchiolitis before the age of 2, respiratory syncytial virus (RSV) being the most common cause.16–1916–1916–1916–19 Worldwide, it is estimated that one fifth of under-5 mortality is caused by pneumonia, mainly in developing countries, pneumococcus being the most common organism in those cases.6,12,14
Pneumococcus is often carried in the nasopharynx, especially in children6,20–2220–2220–22 and can cause various infections, especially in children and the elderly, including RTIs and severe invasive pneumococcal disease.12,20 Invasive pneumococcal disease in children younger than under 2 years before the start of pneumococcal vaccination was described in a European review to be as high as 27 per 100,000 children and even higher in US.23,24 Reducing pneumococcal infections is an important goal.
After introduction of the pneumococcal protein-conjugated vaccines (PCV), a reduction in the incidence of pneumococcal infections in children has been firmly established in various studies.9,25–2925–2925–2925–2925–29 Emerging results are also being published on the herd effect achieved by these immunizations.4,22
In April 2011, a pneumococcal H. influenzae protein D conjugate vaccine (PHiD-CV10/PCV-10) was introduced into the national childhood vaccination program in Iceland, a population not earlier vaccinated against pneumococcus. Thus, all children born after January 1, 2011 were eligible for the vaccination. It is important to study the effect of this intervention on children and the whole population. The aim of this was to investigate the impact of PCV-10 on RTIs diagnosed in children younger than 18 years at the Children’s Hospital Iceland after the introduction of this immunization.
MATERIALS AND METHODS
A retrospective, epidemiologic survey was conducted, where all visits because of RTI for children younger than 18 years to the Children’s Hospital Iceland Landspitali University Hospital, in the period January 1, 2008 to December 31, 2013 were recorded including both those admitted to the hospital and those treated as outpatients. The Children’s Hospital serves as a primary hospital for the capital-area with approximately 50,000 children (<18 years old; www.statice.is), as well as serving as tertiary hospital for all children in Iceland.
An RTI-associated visit was defined if a patient’s record listed any RTI diagnosis code anywhere in the record. All children with any International Classification of Diseases (ICD)-10 diagnostic number of any respiratory diseases possibly associated with infections were identified in the hospital records (Table 1) and included. No exclusion criteria were applied, and demographic information were collected from all children in the study. This approach detected all emergency ward visits and hospital admissions for RTI. When a patient’s chart contained more than 1 ICD-10 diagnosis, an algorithm was created to reliably identify the most relevant diagnoses for the study [in this order: (1) pneumonia or AOM, (2) complications of pneumonia or AOM and (3) other RTI]. Only one diagnosis was used for each visit. For recurrent visits of the same patient, a new case was defined if the patient had previously been discharged. The patients were stratified according to age group, sex and diagnosis. The age stratification were <1, 1 to <2, 2 to <3, 3 to <7 and 7 to <18 years.
The mean incidence rate (IR) in a 3-year period before the immunization (2008–2010) was compared with the mean IR in a 3-year period after the initiation of the vaccination (2011–2013). IR was calculated as number of cases per 10,000 children each year in the area using population data from Statistics Iceland (www.statice.is). Each group was studied separately, and age matched comparison made.
To better evaluate the vaccination effect, children born in 2011 (vaccine eligible cohort, VEC) were compared with children born 2008–2010 (nonvaccine eligible cohort, NVEC). Follow-up was from 3 months of age (first primary vaccination) until 2 years of age.
To evaluate the possible impact of misdiagnosis of pneumonia as acute bronchiolitis, the yearly incidence of both diagnoses was calculated separately and the trends analyzed. Acute bronchiolitis diagnosis was analyzed independently, for example, an algorithm was created to search for all visits where acute bronchiolitis was noted on the patients chart.
The possible impact of annual influenza was evaluated by calculating the incidence of RTI with and without influenza cases as primary diagnosis. The diagnostic and admission practices at the hospital did not change during the study period.
Statistical analysis was done in R. Difference between IRs of 2 populations was tested using a large sample Z test. Asymptotic confidence intervals (CIs) for IR and incidence rate ratio were constructed using large sample theory.
The study was approved by The National Bioethics Committee (VSNb2013010015/03.07), The National Data Protection Authority (2013010100VEL/--) and the University Hospital director. The study is a part of a larger study on vaccinations in Iceland (The VIce study).
The number of hospital visits for RTI during the study period was 11,752, by 7158 patients, thereof 643 admissions. Less than 15% of the patients had more than 2 visits because of RTI during the 6-year study period. The median age was 1.5 years, and males were 56%. Seasonal variation revealed the highest incidence of RTI during the winter months. The quarterly IR of RTI per 10,000 children during the study period is given in Figure 1.
Changes in Incidence Rate
IR for all-cause RTI before and after the commencement of the vaccination was highest in children 1–2 years of age, for whom the IR declined 15% (95% CI: 8%–22%, P < 0.0005) from 2322 to 1967 per 10,000 children-years in the period (Table 2; Fig. 2). A 15% reduction (95% CI: 0%–28%, P < 0.05) was also noted for children 7–18 years of age (Table 2). For children in their first year, a 13% increase (95% CI: 2%–24%, P < 0.05) was seen in overall IR for all-cause RTI. The IR was unchanged in other age groups (Table 2; Fig. 2).
For all-cause AOM, a 26% reduction in IR (95% CI: 17%–34% P < 0.001) from 1426 to 1058 per 10,000 children-years was noted for children 1–2 years of age. In other age groups, no significant change was noted (Table 2; Fig. 2). For all-cause pneumonia, a 30% reduction in IR (95% CI: 11%–45%, P < 0.01) from 245 to 172 per 10,000 children-years in children younger than 1 year, a 23% reduction in IR (95% CI: 10%–34%, P < 0.01) from 596 to 460 for children 1–2 years of age. In other age groups, no significant change was noted (Table 2; Fig. 2). For all-cause acute bronchiolitis, a 51% increase in IR (95% CI: 33%–85%, P < 0.001) from 423 to 637 per 10,000 children-years in children younger than 1 year was noted, a 96% increase in IR (95% CI: 63%–172%, P < 0.001) from 149 to 292 for children 1–2 years of age and a 94% increase in IR (95% CI: 46%–240%, P <0.001) from 54 to 105 for children 2–3 years of age. In other age groups, no significant change was noted (Table 2; Fig. 2).
Comparison of Vaccine Eligible and Nonvaccine Eligible Cohorts
When comparing the IR of children born in 2011 (VEC) with children born 2008–2010 (NVEC), a 24% reduction (95% CI: 13%–33%, P < 0.0001) for all-cause AOM was found from 1198 to 915 per 10,000 children-years. A 23% reduction (95% CI: 5%–36%, P < 0.01) for all-cause pneumonia was established and a 53% increase in all-cause acute bronchiolitis (95% CI: 24%–90%, P < 0.0005) from 223 to 342 (Fig. 3).
Lower Respiratory Infection IR, Influenza and Other Hospital Visits
For children <18 years of age, the incidence for bronchiolitis was 187, 425, 624, 671, 685 and 642 and for pneumonia 1218, 1160, 1214, 1205, 1041 and 855 for the years 2008–2013, respectively, per 100,000 children-years.
Incidence of influenza during each winter period was low for all the years except the winter of 2009–2010 during the H1N1 influenza epidemic. Excluding patient visits whose primary diagnosis was associated with influenza did only have a minor effect on the evaluation of RTI (Table 2).
The total number of visits to the emergency ward at the Children’s Hospital increased significantly during the study period from 12,229 in 2008 to 13,525 in 2013.
A statistically significant reduction in the incidence of AOM (1 to <2 years of age) and pneumonia (<2 years of age) was found in children visiting the Children’s Hospital Iceland after the introduction of the PCV-10 vaccine. This is in context with earlier reports.25–2825–2825–2825–28 However, this early effect of an abrupt and significant reduction of AOM is noteworthy.
The primary vaccinations with PCV-10 are given at age 3 and 5 months in Iceland, with an impressive >95% vaccination coverage in the first year of the vaccination (www.landlaeknir.is/english). One can expect the antipneumococcal antibodies to become protective after the primary vaccinations. We compared RTI in children in the VEC with RTI in children in NVEC with a follow-up time from 3 months to 2 years of age and found a significant difference in IR of AOM and pneumonia. The only major difference between the groups was the vaccination. We, therefore, assume that the main factor in the noted reduction in AOM and pneumonia is the impact of the vaccination.
In this context, it is important to compare these changes with the incidence of other infections. One RTI that should not be affected by the immunization is acute bronchiolitis,16–1816–1816–18 often caused by RSV causing yearly epidemics varying in severity.19,30,31 The annual bronchiolitis epidemics were unusually strong in Iceland in the postvaccination era (2011–2013) with a significant increase in the number of children infected. These severe epidemics were also observed in Ireland, where a 100% increase in bronchiolitis hospitalization was noted in 2011 and 2012 compared with the previous 4 years,31 perhaps fueled by a novel RSV-A strain first detected in Canada in December 2010 and had become prevalent in Europe in 2011–2012 epidemic season.32 Several studies have shown an increase in bacterial adherence on respiratory tract epithelium, especially in the URT, after respiratory tract viral infections, including RSV infections. Recent viral infection has also been shown to have a small but significant impact on incidence of AOM and pneumonia.13,15,16,33,34 Therefore, one would expect an increase in the incidence of AOM and pneumonia after this increase in bronchiolitis. In fact, the opposite was found.
Diagnosis of pneumonia in children can be difficult. In our study, we used all pneumonias, physician diagnosed as well as X-ray confirmed, and all possible complications thereof in a single centre. Mild pneumonias can be misdiagnosed as bronchiolitis. As all clinical diagnoses of pneumonia were included in this study, this represents a possible confounder. During the study period, no change in the diagnostic and admission practices at the hospital took place. It is, therefore, unlikely that changes in the incidence of pneumoniae or bronchiolitis are caused by misdiagnosis of these diseases. Moreover, the incidence of bronchiolitis was initially low, increased in period before the vaccination and plateaued in the postvaccination period. The incidence of pneumonia on the other hand was relatively stable in the prevaccination period but decreased after the initiation of the vaccine. This indicates that the decrease in pneumonia incidence is independent of the increase in bronchiolitis.
As the majority of RTI infections are of viral origin and only a proportion are caused by bacteria whereof only some are caused by pneumococcus,32 the significant reduction in the total number of children with pneumonia is noteworthy.
There are some possible explanations in addition to the direct vaccination impact, for this very clear decrease in the incidence of AOM and pneumonia. The most virulent bacteria in AOM are the pneumococci often resulting in recurrent AOM.10 Recurrent AOM are often the result of disrupted epithelium in the middle ear, mucosal damage and impaired clearing of mucus following bacterial otitis, paving the way for recurrent infections, often with other microbes such as nontypeable H. influenzae and M. catarrhalis.10 Preventing this first episode can interrupt this process. In addition, formations of biofilms may play a role in recurrent infections. In some studies, biofilms account for a considerable part of culture negative AOM.10,35 Although one Israeli study has shown reduction of 85% in vaccine-type serotype AOM,9 others have only shown a 0%–7% reduction of all-cause AOM.29 However, these studies used the PCV-7 vaccine, whereas in this study, the vaccinations were done with the PCV-10 vaccine. The more serotypes included in that vaccine may be important, but the protein D conjugate from H. influenzae may have added to this effect. Reports on the PCV-10 vaccine impact on H. Influenzae have been conflicting; a prelicense study of a 11 valent pneumococcal H. influenzae protein D vaccine showed up to 34% reduction in AOM caused by H. influenzae,36,37 a result that has not been replicated in later studies for the 10 valent vaccine, which studied vaccine efficacy for carriage of nontypeable H. influenza rather than vaccine efficacy against AOM.38,39 This warrants further attention.
A large N1H1 influenza epidemic was established in Iceland in the fall and winter of 2009 as opposed to mild influenza outbreaks the other years; this could be viewed as a possible confounder. However, excluding visits contributed by influenza did not change the results.
The study shows a clear reduction in hospital visits because of AOM and pneumonia in the VEC. This significant and early effect described is encouraging.
1. Gudnason T, Hrafnkelsson B, Laxdal B, et al. Does hygiene intervention at day care centres reduce infectious illnesses in children
? An intervention cohort study. Scand J Infect Dis. 2013;45:397–403
2. Ahmed S, Shapiro NL, Bhattacharyya N. Incremental health care utilization and costs for acute otitis media in children
. Laryngoscope. 2014;124:301–305
3. Yin JK, Salkeld G, Lambert SB, et al. Estimates and determinants of economic impacts from influenza-like illnesses caused by respiratory viruses in Australian children
attending childcare: a cohort study. Influenza Other Respir Viruses. 2013;7:1103–1112
4. Benninger MS. Acute bacterial rhinosinusitis and otitis media: changes in pathogenicity following widespread use of pneumococcal conjugate vaccine. Otolaryngol Head Neck Surg. 2008;138:274–278
5. Gene A, del Amo E, Inigo M, et al. Pneumococcal serotypes causing acute otitis media among children
in Barcelona (1992–2011): emergence of the multiresistant clone ST320 of serotype 19A. Pediatr Infect Dis J. 2013;32:e128–e133
6. Mehr S, Wood N. Streptococcus pneumoniae–
a review of carriage, infection, serotype replacement and vaccination. Paediatr Respir Rev. 2012;13:258–264
7. Wald ER. Acute otitis media and acute bacterial sinusitis. Clin Infect Dis. 2011;52(Suppl 4):S277–S283
8. Todberg T, Koch A, Andersson M, et al. Incidence of otitis media in a contemporary Danish National Birth Cohort. PLoS One. 2014;9:e111732
9. Ben-Shimol S, Givon-Lavi N, Leibovitz E, et al. Near-elimination of otitis media caused by 13-valent pneumococcal conjugate vaccine (PCV) serotypes in southern Israel shortly after sequential introduction of 7-valent/13-valent PCV. Clin Infect Dis. 2014;59:1724–1732
10. Dagan R, Leibovitz E, Greenberg D, et al. Mixed pneumococcal-nontypeable Haemophilus influenzae
otitis media is a distinct clinical entity with unique epidemiologic characteristics and pneumococcal serotype distribution. J Infect Dis. 2013;208:1152–1160
11. Arason VA, Sigurdsson JA, Erlendsdottir H, et al. The role of antimicrobial use in the epidemiology of resistant pneumococci: a 10-year follow up. Microb Drug Resist. 2006;12:169–176
12. Farha T, Thomson AH. The burden of pneumonia
in the developed world. Paediatr Respir Rev. 2005;6:76–82
13. Hament JM, Kimpen JL, Fleer A, et al. Respiratory viral infection predisposing for bacterial disease: a concise review. FEMS Immunol Med Microbiol. 1999;26:189–195
14. Madhi SA, De Wals P, Grijalva CG, et al. The burden of childhood pneumonia
in the developed world: a review of the literature. Pediatr Infect Dis J. 2013;32:e119–e127
15. Avadhanula V, Rodriguez CA, Devincenzo JP, et al. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner. J Virol. 2006;80:1629–1636
16. Borchers AT, Chang C, Gershwin ME, et al. Respiratory syncytial virus–a comprehensive review. Clin Rev Allergy Immunol. 2013;45:331–379
17. Hervás D, Reina J, Yañez A, et al. Epidemiology of hospitalization for acute bronchiolitis in children
: differences between RSV and non-RSV bronchiolitis. Eur J Clin Microbiol Infect Dis. 2012;31:1975–1981
18. Ogra PL. Respiratory syncytial virus: the virus, the disease and the immune response. Paediatr Respir Rev. 2004;5(Suppl A):S119–S126
19. Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children
, 1980–1996. JAMA. 1999;282:1440–1446
20. Song JY, Nahm MH, Moseley MA. Clinical implications of pneumococcal serotypes: invasive disease potential, clinical presentations, and antibiotic resistance. J Korean Med Sci. 2013;28:4–15
21. Tomasson G, Gudnason T, Kristinsson KG. Dynamics of pneumococcal carriage among healthy Icelandic children
attending day-care centres. Scand J Infect Dis. 2005;37:422–428
22. van Hoek AJ, Sheppard CL, Andrews NJ, et al. Pneumococcal carriage in children
and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England. Vaccine. 2014;32:4349–4355
23. Hausdorff WP, Siber G, Paradiso PR. Geographical differences in invasive pneumococcal disease rates and serotype frequency in young children
. Lancet. 2001;357:950–952
24. Jefferson T, Ferroni E, Curtale F, et al. Streptococcus pneumoniae
in western Europe: serotype distribution and incidence in children
less than 2 years old. Lancet Infect Dis. 2006;6:405–410
25. Afonso ET, Minamisava R, Bierrenbach AL, et al. Effect of 10-valent pneumococcal vaccine on pneumonia
, Brazil. Emerg Infect Dis. 2013;19:589–597
26. De Wals P, Lefebvre B, Defay F, et al. Invasive pneumococcal diseases in birth cohorts vaccinated with PCV-7 and/or PHiD-CV in the province of Quebec, Canada. Vaccine. 2012;30:6416–6420
27. Picazo J, Ruiz-Contreras J, Casado-Flores J, et al.Heracles 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
28. Yildirim I, Stevenson A, Hsu KK, et al. Evolving picture of invasive pneumococcal disease in massachusetts children
: a comparison of disease in 2007-2009 with earlier periods. Pediatr Infect Dis J. 2012;31:1016–1021
29. Taylor S, Marchisio P, Vergison A, et al. Impact of pneumococcal conjugate vaccination on otitis media: a systematic review. Clin Infect Dis. 2012;54:1765–1773
30. Hasegawa K, Tsugawa Y, Brown DF, et al. Temporal trends in emergency department visits for bronchiolitis in the United States, 2006 to 2010. Pediatr Infect Dis J. 2014;33:11–18
31. O’Connor G, Tariq M, Greally P, et al. The changing epidemiology of the bronchiolitis epidemic in Tallaght Hospital. Ir Med J. 2013;106:314–315
32. Pierangeli A, Trotta D, Scagnolari C, et al. Rapid spread of the novel respiratory syncytial virus A ON1 genotype, central Italy, 2011 to 2013. Euro Surveill. 2014;19:1–10
33. Kristjánsson S, Skúladóttir HE, Sturludóttir M, et al. Increased prevalence of otitis media following respiratory syncytial virus infection. Acta Paediatr. 2010;99:867–870
34. Short KR, Diavatopoulos DA, Thornton R, et al. Influenza virus induces bacterial and nonbacterial otitis media. J Infect Dis. 2011;204:1857–1865
35. Thornton RB, Rigby PJ, Wiertsema SP, et al. Multi-species bacterial biofilm and intracellular infection in otitis media. BMC Pediatr. 2011;11:94
36. Prymula R, Kriz P, Kaliskova E, et al. Effect of vaccination with pneumococcal capsular polysaccharides conjugated to Haemophilus influenzae
-derived protein D on nasopharyngeal carriage of Streptococcus pneumoniae
and H. influenzae
under 2 years of age. Vaccine. 2009;28:71–78
37. Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae
and non-typable Haemophilus influenzae
: a randomised double-blind efficacy study. Lancet. 2006;367:740–748
38. Tregnaghi MW, Sáez-Llorens X, López P, et al.COMPAS Group. Efficacy of pneumococcal nontypable Haemophilus influenzae
protein D conjugate vaccine (PHiD-CV) in young Latin American children
: a double-blind randomized controlled trial. PLoS Med. 2014;11:e1001657
39. van den Bergh MR, Spijkerman J, Swinnen KM, et al. Effects of the 10-valent pneumococcal nontypeable Haemophilus influenzae
protein D-conjugate vaccine on nasopharyngeal bacterial colonization in young children
: a randomized controlled trial. Clin Infect Dis. 2013;56:e30–e39
Keywords:Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Respiratory infections; children; pneumococcal vaccination; Streptococcus pneumoniae; AOM; pneumonia