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Home , Pneumonia, Sinusitis

Sinusitis and Hospitalization After Introduction of Pneumococcal Conjugate

WHAT’S KNOWN ON THIS SUBJECT: Pneumococcal conjugated AUTHORS: Ann Lindstrand, MD, MPH,a,b Rutger Bennet, MD, (PCVs) are known to decrease invasive pneumococcal PhD,c Ilias Galanis, MSc,a Margareta Blennow, MD, PhD,d,e in children, but their effect on pneumonia necessitating Lina Schollin Ask, MD,d Sofia Hultman Dennison, MD,f hospitalization is more variable across study sites, and effects on Malin Ryd Rinder, MD, PhD,d Margareta Eriksson, MD, c a,g,h hospitalization for have not been shown previously. PhD, Birgitta Henriques-Normark, MD, PhD, Åke Örtqvist, MD, PhD,i, j and Tobias Alfvén, MD, PhDb,d WHAT THIS STUDY ADDS: There was a significant decrease in aPublic Health Agency of Sweden, Solna, Sweden; Departments of b , Public Health Sciences, Division of , eClinical hospitalizations for sinusitis in children 2 years of age, and Sciences and Education, and gMicrobiology, Tumor and Cell hospitalization for pneumonia decreased in children aged ,5 Biology, Karolinska Institutet, Stockholm, Sweden; cAstrid years after sequential introduction of PCV7 and PCV13. Lindgren Children’s Hospital, and hDepartment of Laboratory Medicine, Division of Clinical Microbiology, Karolinska University Hospital, Solna, Sweden; dSachs’ Children and Youth Hospital, South General Hospital, Stockholm, Sweden; fDepartment of , Karolinska University Hospital, Stockholm, Sweden; iDepartment of Communicable Disease Control and abstract Prevention, Stockholm County Council, Sweden; and jDepartment of Medicine, Unit of Infectious , Karolinska Institutet, BACKGROUND AND OBJECTIVE: pneumoniae is a major Karolinska, Solna, Sweden cause of pneumonia and sinusitis. Pneumonia kills .1 million chil- KEY WORDS dren annually, and sinusitis is a potentially serious pediatric disease , sinusitis, pneumonia, pneumococcal that increases the risk of orbital and intracranial complications. conjugated vaccine Although pneumococcal conjugate vaccine (PCV) is effective against ABBREVIATIONS CI—confidence interval invasive pneumococcal disease, its effectiveness against pneumonia ICD-10—International Classification of Diseases, 10th Revision is less consistent, and its effect on sinusitis is not known. We com- PCV—pneumococcal conjugate vaccine pared hospitalization rates due to sinusitis, pneumonia, and RR—rate ratio before and after sequential introduction of PCV7 and PCV13. RSV—respiratory syncytial , Drs Örtqvist and Alfvén made equal contributions to this article. METHOD: All children 0 to 18 years old hospitalized for sinusitis, Dr Lindstrand conceptualized and designed the study, carried pneumonia, or empyema in Stockholm County, Sweden, from 2003 to out data collection and analyzed the data, and drafted and 2012 were included in a population-based study of hospital registry revised the manuscript; Dr Bennet conceptualized and designed the study, carried out data collection, and reviewed and revised data on hospitalizations due to sinusitis, pneumonia, or empyema. the manuscript; Mr Galanis performed statistical analysis and Trend analysis, incidence rates, and rate ratios (RRs) were calculated reviewed and revised the manuscript; Drs Blennow, Rinder, comparing July 2003 to June 2007 with July 2008 to June 2012, ex- Eriksson, Henriques-Normark, Örtqvist, and Alfvén cluding the year of PCV7 introduction. conceptualized and designed the study and reviewed and revised the manuscript; Drs Ask and Dennison revised medical RESULTS: Hospitalizations for sinusitis decreased significantly in chil- records of the sinusitis patients and reviewed and revised the dren aged 0 to ,2 years, from 70 to 24 cases per 100 000 population manuscript; and all authors approved the final manuscript as submitted. (RR = 0.34, P , .001). Hospitalizations for pneumonia decreased sig- nificantly in children aged 0 to ,2 years, from 450 to 366 per 100 000 www.pediatrics.org/cgi/doi/10.1542/peds.2013-4177 population (RR = 0.81, P , .001) and in those aged 2 to ,5 years from doi:10.1542/peds.2013-4177 250 to 212 per 100 000 population (RR = 0.85, P = .002). Hospitalization Accepted for publication Sep 2, 2014 for empyema increased nonsignificantly. Trend analyses showed in- Address correspondence to Ann Lindstrand, MD, MPH, Public , Health Agency of Sweden, Nobels väg 18, 171 82 Stockholm, creasing hospitalization for pneumonia in children 0 to 2yearsbefore Sweden. E-mail: [email protected] intervention and confirmed a decrease in hospitalizations for sinusitis and pneumonia in children aged 0 to ,5 years after intervention. (Continued on last page) CONCLUSIONS: PCV7 and PCV13 led to a 66% lower risk of hospitalization for sinusitis and 19% lower risk of hospitalization for pneu- moniainchildrenaged0to,2 years, in a comparison of 4 years before and 4 years after vaccine introduction. Pediatrics 2014;134:e1528–e1536

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Streptococcus pneumoniae is a com- less consistent, with a decrease rang- ,18 years (458 000) and 7% (144 000) mon cause of invasive in ing from 13% to 65% in all-cause were ,5 years old.17 Data on hospi- children, such as bacteremic pneumo- pneumonia hospitalizations in chil- talizations were collected from the 3 nia, septicemia, and , but dren.8,9 However, some studies show children’s hospitals in the county. For also of noninvasive infections such as decreased risk only in and in- the diagnosis of sinusitis, data were nonbacteremic pneumonia, sinusitis, creasing risk in older children.10–12 also included from the only otorhinophar- and otitis. Pneumococcal disease is To our knowledge PCV effectiveness yngeal clinic where children are treated the vaccine-preventable disease that against hospitalizations due to - as inpatients in Stockholm. Children currently causes most child deaths itis in children has not been clarified 0to,18 years with the diagnoses be- worldwide. Every year 826 000 deaths previously.13–15 ing studied were hospitalized exclu- in children 1 to 59 months old are caused In Stockholm County, Sweden, PCV7 was sively in these 4 places. All children with by S. pneumoniae, corresponding to offered on a 2+1 schedule at 3, 5, and 12 ICD-10 discharge diagnosis codes J13– 7% of all deaths in this age group.1 months of age to all children born since J18 (pneumonia coded as makes up 90% of these July1,2007. PCV7was changedtoPCV13 pneumonia, or pneumonia unspecified), deaths.2–4 in January 2010, even for children who J86 (empyema), and J01 (sinusitis) Sinusitis in preschool children is a po- had received 1 or 2 doses of PCV7. No were included. In Sweden children with tentially serious disease because of catch-up program was implemented. sinusitis are treated as inpatients only anatomic closeness to the orbita and High coverage with the vaccine was when they have complications, either the brain. Complications include peri- reached early on, and by 2 years of age with orbital or periorbital , or orbital and , , 96% of children born in 2008 and 98% of are in need of drainage or other surgical and meningitis. The most commonly those born in 2010 had received 3 doses procedures. isolated in pediatric sinusi- of PCV.16 We used pyelonephritis as a control tis are S. pneumoniae (30%), Haemo- The aim of this study was to evaluate the for the effect of PCV on number of philus influenzae (30%), and impact of PCV7 and PCV13 on the in- admissions (N10.9). To control for catarrhalis (10%).5 The disease is cidence of hospitalization due to pedi- possible changes in diagnosis rou- more severe in patients infected with atric sinusitis, pneumonia coded as tines we also recorded the number of pneumococci than in those infected bacterial pneumonia, and empyema. children admitted with and with H. influenzae.6 We compared hospital discharge di- obstructive (J45.1, J20.9), Pneumococci may be divided into .90 agnoses during the 4-year periods be- respiratory syncytial virus (RSV) (J21, serotypes, depending on the structure fore and after introduction of PCV7. J20.5, J12.1), and – of their polysaccharide capsules. Ef- (J09 12, except for J12.1 respiratory fl fective pneumococcal conjugate vac- METHODS syncytial pneumonia, J10.1 in uenza, cines (PCVs) targeting an increasing A retrospective population-based study and J09 H1N1) during the same time number of serotypes (PCV7, PCV10, and was performed using International period. PCV13) have been developed for chil- Classification of Diseases, 10th Revision Data on age, gender, and date of ad- dren ,2 years of age. Meta-analyses of (ICD-10) coded hospital registries to mission were recorded for all children. randomized -controlled clinical identify all children hospitalized with Patients readmitted with the same di- trials in children ,2 years show that sinusitis, pneumonia, and empyema in agnoses within 30 days of discharge PCVs have a vaccine efficacy against Stockholm County between July 2003 and were excluded. The children were di- vaccine-type invasive pneumococcal June 2012. The year of introduction of vided into the age groups 0 to ,2, 2 to disease (80% [58%–90%]), radiologi- PCV7, from July 1, 2007 to June 30, 2008, ,5, and 5 to ,18 years for analysis. cally verified pneumonia (27% [15% to was excluded from the analysis. The To validate the ICD-10 diagnoses we 36%]), and clinical pneumonia (6% study years included cases from July 1 reviewed the medical records of all [2%–9%]).7 Since 2000 global use of through June 30, to keep winter’shigher children with a discharge diagnosis of PCVs has increased and has consis- rates within 1 study year. sinusitis (N = 678) and 100 children tently led to reductions of 79% to with pneumonia coded as bacterial 100% in the incidence of vaccine- Study Population and Data pneumonia (50 before and 50 after type invasive pneumococcal disease. Collection vaccination). Information on signs Effectiveness of PCVs in reducing hos- In 2012 Stockholm County had a popu- and symptoms, radiographic findings, pitalization rates for pneumonia seems lation of ∼2 million, of whom 22% were treatment, risk factors, and outcome

PEDIATRICS Volume 134, Number 6, December 2014 e1529 Downloaded from www.aappublications.org/news by guest on September 28, 2021 was collected. Sinusitis cases were Ethical Permission was observed for those aged 5 to 18 considered valid if there was a pre- Ethical approval was obtained from the years. There were no changes in gen- vious or ongoing respiratory infection, Stockholm Regional Ethics Committee. der distribution or in proportion of signs of orbital or periorbital swelling children with risk factors or chronic or redness, or a positive computed to- illnesses after introduction of PCVs mography scan. Pneumonia cases were RESULTS (data not shown). considered valid if there was ongoing Sinusitis respiratory infection or radiographic Pneumonia Between July 2003 and June 2012, verification, or they were judged by the 678 children ,18 years old were From July 2003 to June 2012, 5018 attending pediatrician to be of bacterial discharged from the hospital with children ,18 years of age with a dis- origin and were given. a diagnosis of sinusitis. Validation of charge diagnosis of pneumonia coded medical records using preset criteria as bacterial pneumonia were included; Statistical Analysis led to exclusion of 76 cases because of 2034 (41%) were ,2 years of age, and 1555 (31%) were 2 to ,5 years of age. Segmented regression analysis was incorrect diagnosis without signs of Of the 3589 children ,5 years of age, appliedtoevaluatetheeffectofthePCV7 concomitant sinusitis, such as skin in- 54% were boys. vaccination program on monthly hos- fection, conjunctivitis, or insect bite pital admission rates of sinusitis and (n = 46), or because there were no The incidence of hospitalization for pneumonia, comparing the periods clinical signs of sinusitis (n = 30). Of pneumonia in children ,2 years of age before and after vaccination, excluding the 602 remaining validated sinusitis decreased significantly, from 450 to the in-between year.18,19 Generalized cases, 234 (39%) patients were aged 366 per 100 000 person-years (P , linear models assuming a Poisson ,2 years and 159 (26%) 2 to ,5 years. .001), in a comparison of the pre- distribution for the monthly admission Of the 393 children ,5 years of age, vaccination and postvaccination peri- rates were fitted, and negative bi- 62% were boys. ods (Table 1). A significant decrease in nomial distribution was preferred in The incidence of hospitalization for si- incidence (P = .002) was also seen in the presence of overdispersion. Gen- nusitis in children ,2 years of age the age group 2 to ,5 years, whereas eralized additive models were used decreased significantly from the pre- the incidence remained stable in older instead of generalized linear models to vaccination to the postvaccination children. adjust for a seasonal effect when nec- period, from 70 to 24 per 100 000 person- Trend analysis showed that beforePCV7 essary. All models contained 3 basic years (RR = 0.34; 95% CI, 0.25–0.47, introduction there was a significant parameters accounting for the pre- P , .001). A decrease, although not increase in month-to-month hospital- intervention trend, the change in level significant, was also seen in children izations for pneumonia in children aged from the last preintervention point to 2to,5 years of age (RR = 0.72; 95% 0to,2 years (P = .001), but there was the first postintervention point, and the CI, 0.51–1.02; P = .06), whereas the no significant change in children aged difference in trend between the 2 incidence remained stable in older 2to,5 years. Soon after the first year periods. The postintervention trend children (Table 1). of vaccination (July 2008) there was and its SE were derived from a combi- Trend analysis showed that before a significant decrease in hospital- nation of the first and third parame- PCV7 introduction there was no signif- izations in children aged 0 to ,2 years ters. Correlograms were used to check icant month-to-month change in the (P = .002). However, a significant for autocorrelation in the residuals, incidence of hospitalization due to si- month-to-month decrease in the post- and the models were adjusted for first- nusitis in children ,5 years old (Fig 1 vaccination period was seen only in order autocorrelation when necessary. and Table 2). Immediately after the first those aged 2 to ,5 years (P = .02). For Rate ratios (RRs) and their respective year of vaccination (July 2008) there the age group 5 to 18 years there was 95% confidence intervals (CIs) were was a decrease in hospitalization in the an increasing trend in month-to-month calculated to compare the prevaccina- younger age group (0 to ,2 years); hospitalization both before and after tion and postvaccine periods. We con- however, this was not significant (P = vaccination, but there was no differ- ducted all analyses by using the .055). For this age group and for those ence in the incidence RR (Fig 1, Tables 1 statistical software R, version 3.0.1 aged 2 to ,5 years, a significant and 2). (R Foundation for Statistical Computing, month-to-month decrease in incidence When we compared the 50 validated Vienna, Austria), and P values,.05 were was observed after vaccination (P = pneumonia cases coded as bacterial considered statistically significant. .018 and .004, respectively). No change pneumonia before PCV7 introduction

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TABLE 1 Number of Hospitalizations and Incidence of Pneumonia, Sinusitis, Empyema, Pyelonephritis, Asthma and Obstructive Bronchitis, RSV Infection, and Viral Pneumonia in Children 0 to ,18 y Before and After Sequential PCV7 and PCV13 Introduction in Stockholm Diagnosis No. of Cases IncidenceRateper100 000Person-Years RR (95% CI) P

Before July After July Before July After July 2003–June 2007 2008–June 2012 2003–June 2007 2008–June 2012 Pneumonia 0–,2 y 914 836 450 366 0.81 (0.74–0.89) ,.001 2–,5 y 687 694 250 212 0.85 (0.76–0.94) .002 5–,18 y 604 683 51 56 1.10 (0.99–1.23) .09 Sinusitis 0–,2 y 142 55 70 24 0.34 (0.25–0.47) ,.001 2–,5 y 70 60 25 18 0.72 (0.51–1.02) .06 5–,18 y 82 98 7 8 1.16 (0.87–1.56) .31 Empyema 0–,2 y 5 10 2.5 4.4 1.78 (0.55–6.63) .42 2–,5 y 5 10 1.8 3.1 1.68 (0.52–6.26) .49 5–,18 y 11 19 0.9 1.6 1.68 (0.80–3.53) .17 Pyelonephritis 0–,2 y 598 757 294 331 1.13 (1.01–1.25) .03 2–,5 y 123 156 45 48 1.06 (0.84–1.35) .61 5–,18 y 167 233 14 19 1.36 (1.11–1.66) .002 Asthma and obstructive bronchitis 0–,y 2 2136 2493 1051 1090 1.04 (0.98–1.10) .21 2–,5 y 709 902 258 275 1.07 (0.97–1.18) .20 5–,18 y 334 323 28 27 0.94 (0.81–1.10) .44 RSV infection 0–,2 y 1711 2647 842 1158 1.37 (1.29–1.46) ,.001 2–,5 y 58 137 21 42 1.98 (1.46–2.69) ,.001 5–,18 y 7 28 0.6 2.3 3.89 (1.66–10.56) ,.001 Viral pneumonia 0–,2 y 70 115 34 50 1.46 (1.08–1.97) .01 2–,5 y 42 60 15 18 1.20 (0.81–1.78) .37 5–,18 y 24 58 2.0 4.8 2.35 (1.46–3.78) ,.001

(in 2005) with 50 cases after vaccine RR = 1.78; 95% CI, 0.55–6.63; P = .42) and viral pneumonia increased sig- introduction (in 2009), no differences (Table 1). nificantly in children ,2yearsold were observed in frequency of chest between the prevaccination and post- radiographs on admission (100% in Hospitalization for Control vaccination periods (RR = 1.37; 95% 2005, 98% in 2009). Chronic conditions Diagnosis CI, 1.29–1.46; P , .001 and RR = 1.46; (mainly asthma, prematurity, or neu- Pyelonephritis was used as an indica- 95% CI, 1.08–1.97; P = .01, respectively) rologic disease) were found in 36% of tor disease for general hospitalization (Table 1). children in 2005 and 31% in 2009 (P = trends during the study period. There .82). The clinical severity of pneumonia, wasaslightincreaseinhospitalizations DISCUSSION measured using mean C-reactive pro- duringthestudyperiodintheagegroup To our knowledge this is the first study tein, saturation, and need for 0to,2 years but not among children showing that introduction of PCV7 and oxygen or intensive care, was compa- aged 2 to ,5 years (Table 1). However, PCV13 in the childhood vaccination rable in 2005 and in 2009 (data not in the time trend analysis (Fig 1) the program significantly reduces hospi- shown). month-to-month incidence remained talizations for sinusitis in children ,5 stable in the prevaccination and post- years of age. We also found a signifi- Empyema vaccination period for both age groups cant reduction in hospitalization rates For children ,2 years old there was (Fig 1 and Table 2). for pneumonia in children ,5 years a nonsignificant increased incidence of The incidence of hospitalizations for old. However, there was an increase in hospitalization for empyema in the asthma and obstructive bronchitis empyema in children ,2 years of age period after compared with the period remained stable during the study pe- in the postvaccination compared with before PCV7 and PCV13 vaccination riod (Table 1). However, the incidence the prevaccination period, but this was (4.4 vs 2.5 per 100 000 person-years; of hospitalization for RSV infections not statistically significant.

PEDIATRICS Volume 134, Number 6, December 2014 e1531 Downloaded from www.aappublications.org/news by guest on September 28, 2021 FIGURE 1 Trend analysis of hospitalizations by discharge diagnosis per 100 000 population, by age groups 0 to ,2 years, 2 to ,5 years, and 5 to ,18 years in Stockholm County, Sweden, 2003–2012.

Our finding of a decreased incidence of when PCV7 was used in the United tionhasvariedbetweenstudies.Ameta- sinusitis after introduction of PCV7 and States, 50% of the pneumococcal iso- analysis by Fitzwater et al8 showed PCV13 is supported by a recent study by lates recovered from children with a 13% to 65% reduction in hospital- Peña et al20 showing that S. pneumo- chronic sinusitis were serotype 19A, izations for pneumonia in children. In niae was nearly eliminated as an etio- probably because of serotype re- Norway, Magnus et al25 showed a logical agent of complicated sinusitis placement. So an overall decline in 22% decrease in pneumonia among in children after PCV introduction in the sinusitis after PCV7 and PCV13 vac- PCV7-vaccinated children of 12 to 18 United States. Moreover, they observed cination in children may be followed months of age. This is comparable to asignificant increase in S. aureus by both serotype replacement and the 19% decrease in hospitalization for as a cause of complicated sinusitis. expansion of other , similar pneumonia in children aged ,2 years Benninger21 described a change in to the experience with invasive and the 15% decreased risk of pneu- serotype distribution in both pneumococcal disease and otitis me- monia hospitalization in children 2 to and acute rhinosinusitis dia.8,23,24 ,5 years that we observed in this study. in children after PCV7 introduction. The effect of PCV on the incidence of Nelson et al10 observed an effect on McNeil et al22 showed that in the period pneumonia necessitating hospitaliza- pneumonia rates in outpatients in the

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United States but only a nonsig- P .001 .001 , , nificant reduction in confirmed hos- pitalization events in children aged ,1 year. In contrast, a recent study from the United States showed a sus- 1.029) .13 1.561) .47 1.014) .96 1.022) 0.70) 1.019) .001 1.014) .64 1.849) .65 1.013) .52 – – – – – – – – – tained decrease in hospitalizations

rst postintervention month to the for pneumonia in children and a de- fi . 0.77 (0.381 0.50 (0.357 crease in people 65 years old, pos- 1.123 (0.681 sibly a herd effect.26 Our use of a discharge diagnosis of pneumonia coded as bacterial pneumonia as an

18 y) fi 2012 endpoint was motivated by the dif - – – 18 y)

– culty of establishing an etiological 18 y) – diagnosis of pneumonia, especially in small children. Disease (Age Group) RR (95% CI) Sinusitis (5 Pneumonia (5 Pyelonephritis (5 Interestingly, we observed an in- creasing incidence of admissions to the hospital for pneumonia among P children ,2 years and from 5 to ,18 years old before vaccine introduction, from 2003 to 2007 (Fig 1). The reason for this increase is unclear, but nat- 1.029) .32 Preintervention trend 1.01 (0.996 2.425) .95 Change in level 0.990) .004 Postintervention trend 1.00 (0.985 1.011) .29 Preintervention trend 1.01 (1.007 1.255) .54 Change in level 0.999) .02 Postintervention trend 1.01 (1.005 1.016) .67 Preintervention trend 1.003 (0.992 1.740) .93 Change in level 1.010) .82 Postintervention trend 1.003 (0.994 – – – – – – – – – ural fluctuations caused by expansion of certain pneumococcal serotypes or

0.90 (0.647 clones might have contributed. A 1.026 (0.434 0.974 (0.551 similar increase in 2004 to 2006 was seen in a national time trend (1997 to 2008) study on hospitalizations for

5 y) 9

– pneumonia among children in England. 5 y) –

5 y) This might have led to an underes- – timation of the real effect of the PCV vaccination, because we did not cal- Disease (Age Group) RR (95% CI) Sinusitis (2 Pneumonia (2 Pyelonephritis (2 culate expected rates assuming a continued increasing trend and com- paring those with the observed rates, P as was done in other studies.27 Previous influenza virus infection has been shown to increase the risk of a 1.017) .47 Preintervention trend 1.01 (0.991 1.014) .055 Change in level 0.996) .018 Postintervention trend 0.969 (0.949 1.017) .001 Preintervention trend 1.004 (0.997 0.856) .002 Change in level 1.001) .13 Postintervention trend 0.992 (0.985 1.007) .99 Preintervention trend 1.00 (0.990 1.474) .57 Change in level 1.006) .90 Postintervention trend 0.999 (0.987 developing pneumococcal pneumo- – – – – – – – – – nia.28,29 Recent data from the United States showed excess risk of pneu- RR (95% CI) 0.52 (0.265 0.65 (0.494 1.09 (0.809 mococcal pneumonia during the H1N1 influenza pandemic in 2009.30 In our study we observed only an increase in hospitalizations for pneumonia, 2 y)

– coded as bacterial pneumonia, in 2 y)

– ,

2 y) children aged 2 to 5 years during – Trend Analysis of Monthly Hospitalizations by Discharge Diagnosis per 100 000 Person-Years by Age Group in Stockholm County, Sweden, 2003 this pandemic. There was a high cov- erage rate (50% of children aged 6 Preintervention trend 1.00 (0.992 Change in level Postintervention trend 0.976 (0.957 Preintervention trend 1.01 (1.004 Change in level Postintervention trend 0.996 (0.990 Preintervention trend 1.00 (0.994 Change in level Postintervention trend 1.00 (0.994 Disease (Age Group) When referring to the preintervention and postintervention trend, the RR expresses the month-to-month change in hospitalization rates. For the change in level it expresses comparison of the hospitalization rate of the TABLE 2 a last preintervention one. Sinusitis (0 Pneumonia (0 Pyelonephritis (0 months to 2 years, 70% of children

PEDIATRICS Volume 134, Number 6, December 2014 e1533 Downloaded from www.aappublications.org/news by guest on September 28, 2021 aged 3–18 years) of AS03-adjuvanted from 3.7 cases per 100 000 children to pyelonephritis were stable during the monovalent vaccine against influenza 10.3 after vaccine introduction in the postvaccination period. However, a clear A(H1N1)pdm09 in Sweden. This vaccine United States.35–37 As was found in limitation is that data on outpatient care was about 90% effective in preventing earlier studies, we found a nearly are not available. the need for hospitalization for pan- twofold increase in hospitalizations for OurdatacomefromSweden,acoun- demic influenza,31 which may have empyema in children aged ,2 years; try with 98% PCV coverage, .80% lowered the excess risk for pneumo- this was nonsignificant, probably be- day care attendance, very low levels coccal pneumonia. cause of low numbers. The highest in- of HIV infection and , AdecreaseinRSVinfectionswasseenin cidence of empyema was observed in and low consumption com- South Africa during a PCV trial, and an 2007 to 2009, immediately after in- pared with most countries, all of increase in RSV activity was associated troduction of PCV7, indicating that which play a role in the results. with an increased incidence of pneu- factors other than the vaccine may Therefore, it is not only pneumococcal monia in children in Israel, indicating have contributed. vaccines that affect the rate of hos- mixed infections with RSV and pneu- A major strength of this population- pitalization for pneumonia and si- mococci.32,33 In contrast, we noted an based study is inclusion of 100% of nusitis in children; fluctuations in increase in RSV after PCV introduction, the relevant hospitalizations registered other bacterial and viral pathogens, which may be explained by 3 consecu- in the area. This is also the main socioeconomic status, hygiene in day tive seasons with unusually high cir- , because the result depends care centers, and antibiotic pressure culations of RSV and increasing use of on doctors assigning the correct ICD in society may also affect pneumococcal viral respiratory polymerase chain re- diagnosis and not changing coding transmission. action diagnostics on nasopharyngeal practices over time. However, we vali- samples in the last 10 years. Thus, the dated all cases of sinusitis and a se- CONCLUSIONS higher burden of influenza and RSV lection of cases of pneumonia, finding after PCV may have lowered the effect no major changes in ICD coding. An- Pneumococcal disease is the most im- of the vaccine on pneumonia, as we other weakness is that we could not link portant vaccine-preventable disease in found. clinical cases to bacterial strains or children, because it causes most child deaths. Many low- and middle-income Empyema is a rare of serotypes of pneumococci with this countries are implementing PCV vac- pneumonia. Grijalva et al34,35 showed study design. However, in prospective cination programs. This study adds a twofold increase in hospitalizations studies it is also difficult to isolate the evidence that PCV vaccine (PCV7 and for parapneumonic empyema after causative microbe in children with PCV13) prevents severe sinusitis and vaccine introduction in children in the pneumonia, sinusitis, or empyema. pneumonia,withimplicationsforglobal United States. Serotypes 1 and 3 have Except for introduction of PCV in the child survival.38–40 Specifically, we are been associated with empyema, and vaccination programs, there were no the first to show great effectiveness because they are not included in PCV7, changes or interventions that should against sinusitis in children aged ,5 serotype replacement may cause in- have affected pneumonia or sinusitis years. creased rates of empyema after vac- case management or hospital care or cine introduction.36 An increase in that could have explained the decrease ACKNOWLEDGMENTS staphylococcal empyema or empyema in hospitalizations for sinusitis and of unknown etiology has been de- pneumonia.Thisfindingissupportedby We gratefully acknowledge Anna Granath scribed, as well as an increase in thefactthatthehospitalizationratesfor for her scientific contribution to the si- pneumonia complicated by empyema, asthma or obstructive bronchitis and nusitis part of the study.

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PEDIATRICS Volume 134, Number 6, December 2014 e1535 Downloaded from www.aappublications.org/news by guest on September 28, 2021 38. Roca A, Sigaúque B, Quintó L, et al. Estimating Efficacy of nine-valent pneumococcal con- 40. Bhutta ZA, Das JK, Walker N, et al; Lancet the vaccine-preventable burden of hospital- jugate vaccine against pneumonia and in- Diarrhoea and Pneumonia Interventions ized pneumonia among young Mozambican vasive pneumococcal disease in The Study Group. Interventions to address children. Vaccine. 2010;28(30):4851–4857 Gambia: randomised, double-blind, placebo- deaths from childhood pneumonia and di- 39. Cutts FT, Zaman SM, Enwere G, et al; Gam- controlled trial. Lancet. 2005;365(9465): arrhoea equitably: what works and at what bian Pneumococcal Vaccine Trial Group. 1139–1146 cost? Lancet. 2013;381(9875):1417–1429

(Continued from first page) PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: In the tender for buying pneumococcal vaccine, Stockholm County Council included a demand that the company chosen to supply the vaccine was to give the county a 5% discount off the vaccine price for enabling an epidemiological follow-up. Money from this discount has been used for the current study. The money was not paid to an institution but directly to the Stockholm County Council. FUNDING: Supported by Stockholm County Council research funds, Foundation Samariten, Sachs’ Children’s Hospital, Swedish Research Council, Swedish Foundation for Strategic Research, Knut and Alice Wallenberg Foundation, and Sven Jerrings Foundation. POTENTIAL CONFLICT OF INTEREST: Dr Lindstrand received financial contributions for participation in 2 scientific conferences from GSK and Pfizer, and her employer financed the equivalent amount according to the national rules for pharmaceutical sponsorship for medical education, and she has participated in 1 clinical vaccine trial in collaboration with GSK.

e1536 LINDSTRAND et al Downloaded from www.aappublications.org/news by guest on September 28, 2021 Sinusitis and Pneumonia Hospitalization After Introduction of Pneumococcal Conjugate Vaccine Ann Lindstrand, Rutger Bennet, Ilias Galanis, Margareta Blennow, Lina Schollin Ask, Sofia Hultman Dennison, Malin Ryd Rinder, Margareta Eriksson, Birgitta Henriques-Normark, Åke Örtqvist and Tobias Alfvén Pediatrics 2014;134;e1528 DOI: 10.1542/peds.2013-4177 originally published online November 10, 2014;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/134/6/e1528 References This article cites 38 articles, 6 of which you can access for free at: http://pediatrics.aappublications.org/content/134/6/e1528#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Vaccine/ http://www.aappublications.org/cgi/collection/vaccine:immunization _sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 Sinusitis and Pneumonia Hospitalization After Introduction of Pneumococcal Conjugate Vaccine Ann Lindstrand, Rutger Bennet, Ilias Galanis, Margareta Blennow, Lina Schollin Ask, Sofia Hultman Dennison, Malin Ryd Rinder, Margareta Eriksson, Birgitta Henriques-Normark, Åke Örtqvist and Tobias Alfvén Pediatrics 2014;134;e1528 DOI: 10.1542/peds.2013-4177 originally published online November 10, 2014;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/134/6/e1528

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