Sinusitis and Pneumonia Hospitalization AfterIntroduction of Pneumococcal Conjugate Vaccine

WHAT’S KNOWN ON THIS SUBJECT: Pneumococcal conjugatedvaccines (PCVs) are known to decrease invasive pneumococcaldisease in children, but their effect on pneumonia necessitatinghospitalization is more variable across study sites, and effects onhospitalization for sinusitis have not been shown previously.

WHAT THIS STUDY ADDS: There was a significant decrease inhospitalizations for sinusitis in children ,2 years of age, andhospitalization for pneumonia decreased in children aged ,5years after sequential introduction of PCV7 and PCV13.

abstractBACKGROUND AND OBJECTIVE: Streptococcus pneumoniae is a majorcause of pneumonia and sinusitis. Pneumonia kills .1 million chil-dren annually, and sinusitis is a potentially serious pediatric diseasethat increases the risk of orbital and intracranial complications.Although pneumococcal conjugate vaccine (PCV) is effective againstinvasive pneumococcal disease, its effectiveness against pneumoniais less consistent, and its effect on sinusitis is not known. We com-pared hospitalization rates due to sinusitis, pneumonia, and empyemabefore and after sequential introduction of PCV7 and PCV13.

METHOD: All children 0 to ,18 years old hospitalized for sinusitis,pneumonia, or empyema in Stockholm County, Sweden, from 2003 to2012 were included in a population-based study of hospital registrydata on hospitalizations due to sinusitis, pneumonia, or empyema.Trend analysis, incidence rates, and rate ratios (RRs) were calculatedcomparing July 2003 to June 2007 with July 2008 to June 2012, ex-cluding the year of PCV7 introduction.

RESULTS: Hospitalizations for sinusitis decreased significantly in chil-dren aged 0 to ,2 years, from 70 to 24 cases per 100 000 population(RR = 0.34, P , .001). Hospitalizations for pneumonia decreased sig-nificantly in children aged 0 to ,2 years, from 450 to 366 per 100 000population (RR = 0.81, P , .001) and in those aged 2 to ,5 years from250 to 212 per 100 000 population (RR = 0.85, P = .002). Hospitalizationfor empyema increased nonsignificantly. Trend analyses showed in-creasing hospitalization for pneumonia in children 0 to,2 years beforeintervention and confirmed a decrease in hospitalizations for sinusitisand pneumonia in children aged 0 to ,5 years after intervention.

CONCLUSIONS: PCV7 and PCV13 vaccination led to a 66% lower risk ofhospitalization for sinusitis and 19% lower risk of hospitalization for pneu-monia in children aged 0 to,2 years, in a comparison of 4 years beforeand 4 years after vaccine introduction. Pediatrics 2014;134:e1528–e1536

AUTHORS: Ann Lindstrand, MD, MPH,a,b Rutger Bennet, MD,PhD,c Ilias Galanis, MSc,a Margareta Blennow, MD, PhD,d,e

Lina Schollin Ask, MD,d Sofia Hultman Dennison, MD,f

Malin Ryd Rinder, MD, PhD,d Margareta Eriksson, MD,PhD,c Birgitta Henriques-Normark, MD, PhD,a,g,h ÅkeÖrtqvist, MD, PhD,i, j and Tobias Alfvén, MD, PhDb,d

aPublic Health Agency of Sweden, Solna, Sweden; Departments ofbPublic Health Sciences, Division of Global Health, eClinicalSciences and Education, and gMicrobiology, Tumor and CellBiology, Karolinska Institutet, Stockholm, Sweden; cAstridLindgren Children’s Hospital, and hDepartment of LaboratoryMedicine, Division of Clinical Microbiology, Karolinska UniversityHospital, Solna, Sweden; dSachs’ Children and Youth Hospital,South General Hospital, Stockholm, Sweden; fDepartment ofOtorhinolaryngology, Karolinska University Hospital, Stockholm,Sweden; iDepartment of Communicable Disease Control andPrevention, Stockholm County Council, Sweden; and jDepartmentof Medicine, Unit of Infectious Diseases, Karolinska Institutet,Karolinska, Solna, Sweden

KEY WORDSStreptococcus pneumoniae, sinusitis, pneumonia, pneumococcalconjugated vaccine

ABBREVIATIONSCI—confidence intervalICD-10—International Classification of Diseases, 10th RevisionPCV—pneumococcal conjugate vaccineRR—rate ratioRSV—respiratory syncytial virus

Drs Örtqvist and Alfvén made equal contributions to this article.Dr Lindstrand conceptualized and designed the study, carriedout data collection and analyzed the data, and drafted andrevised the manuscript; Dr Bennet conceptualized and designedthe study, carried out data collection, and reviewed and revisedthe manuscript; Mr Galanis performed statistical analysis andreviewed and revised the manuscript; Drs Blennow, Rinder,Eriksson, Henriques-Normark, Örtqvist, and Alfvénconceptualized and designed the study and reviewed andrevised the manuscript; Drs Ask and Dennison revised medicalrecords of the sinusitis patients and reviewed and revised themanuscript; and all authors approved the final manuscript assubmitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-4177

doi:10.1542/peds.2013-4177

Accepted for publication Sep 2, 2014

Address correspondence to Ann Lindstrand, MD, MPH, PublicHealth Agency of Sweden, Nobels väg 18, 171 82 Stockholm,Sweden. E-mail: ann.lindstrand@folkhalsomyndigheten.se

(Continued on last page)

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Streptococcus pneumoniae is a com-mon cause of invasive infections inchildren, such as bacteremic pneumo-nia, septicemia, and meningitis, butalso of noninvasive infections such asnonbacteremic pneumonia, sinusitis,and otitis. Pneumococcal disease isthe vaccine-preventable disease thatcurrently causes most child deathsworldwide. Every year 826 000 deathsin children 1 to 59months old are causedby S. pneumoniae, corresponding to7% of all deaths in this age group.1

Pneumonia makes up 90% of thesedeaths.2–4

Sinusitis in preschool children is a po-tentially serious disease because ofanatomic closeness to the orbita andthe brain. Complications include peri-orbital and orbital cellulitis, abscesses,and meningitis. The most commonlyisolated pathogens in pediatric sinusi-tis are S. pneumoniae (30%), Haemo-philus influenzae (30%), and Moraxellacatarrhalis (10%).5 The disease ismore severe in patients infected withpneumococci than in those infectedwith H. influenzae.6

Pneumococci may be divided into.90serotypes, depending on the structureof their polysaccharide capsules. Ef-fective pneumococcal conjugate vac-cines (PCVs) targeting an increasingnumber of serotypes (PCV7, PCV10, andPCV13) have been developed for chil-dren,2 years of age. Meta-analyses ofrandomized placebo-controlled clinicaltrials in children ,2 years show thatPCVs have a vaccine efficacy againstvaccine-type invasive pneumococcaldisease (80% [58%–90%]), radiologi-cally verified pneumonia (27% [15% to36%]), and clinical pneumonia (6%[2%–9%]).7 Since 2000 global use ofPCVs has increased and has consis-tently led to reductions of 79% to100% in the incidence of vaccine-type invasive pneumococcal disease.Effectiveness of PCVs in reducing hos-pitalization rates for pneumonia seems

less consistent, with a decrease rang-ing from 13% to 65% in all-causepneumonia hospitalizations in chil-dren.8,9 However, some studies showdecreased risk only in infants and in-creasing risk in older children.10–12

To our knowledge PCV effectivenessagainst hospitalizations due to sinus-itis in children has not been clarifiedpreviously.13–15

In StockholmCounty, Sweden, PCV7wasoffered on a 2+1 schedule at 3, 5, and 12months of age to all children born sinceJuly 1, 2007. PCV7was changed toPCV13in January 2010, even for children whohad received 1 or 2 doses of PCV7. Nocatch-up program was implemented.High coverage with the vaccine wasreached early on, and by 2 years of age96% of children born in 2008 and 98% ofthose born in 2010 had received 3 dosesof PCV.16

Theaimof this studywas to evaluate theimpact of PCV7 and PCV13 on the in-cidence of hospitalization due to pedi-atric sinusitis, pneumonia coded asbacterial pneumonia, and empyema.We compared hospital discharge di-agnoses during the 4-year periods be-fore and after introduction of PCV7.

METHODS

A retrospective population-based studywas performed using InternationalClassification of Diseases, 10th Revision(ICD-10) coded hospital registries toidentify all children hospitalized withsinusitis, pneumonia, and empyema inStockholm County between July 2003 andJune 2012. The year of introduction ofPCV7, from July 1, 2007 to June 30, 2008,was excluded from the analysis. Thestudy years included cases from July 1through June 30, to keep winter’s higherinfection rates within 1 study year.

Study Population and DataCollection

In 2012 Stockholm County had a popu-lation of ∼2 million, of whom 22% were

,18 years (458 000) and 7% (144 000)were ,5 years old.17 Data on hospi-talizations were collected from the 3children’s hospitals in the county. Forthe diagnosis of sinusitis, data werealso included from the only otorhinophar-yngeal clinic where children are treatedas inpatients in Stockholm. Children0 to ,18 years with the diagnoses be-ing studied were hospitalized exclu-sively in these 4 places. All childrenwithICD-10 discharge diagnosis codes J13–J18 (pneumonia coded as bacterialpneumonia, or pneumonia unspecified),J86 (empyema), and J01 (sinusitis)were included. In Sweden children withsinusitis are treated as inpatients onlywhen they have complications, eitherwith orbital or periorbital cellulitis, orare in need of drainage or other surgicalprocedures.

We used pyelonephritis as a controlfor the effect of PCV on number ofadmissions (N10.9). To control forpossible changes in diagnosis rou-tines we also recorded the number ofchildren admitted with asthma andobstructive bronchitis (J45.1, J20.9),respiratory syncytial virus (RSV) (J21,J20.5, J12.1), and viral pneumonia(J09–12, except for J12.1 respiratorysyncytial pneumonia, J10.1 influenza,and J09 H1N1) during the same timeperiod.

Data on age, gender, and date of ad-mission were recorded for all children.Patients readmitted with the same di-agnoses within 30 days of dischargewere excluded. The children were di-vided into the age groups 0 to,2, 2 to,5, and 5 to ,18 years for analysis.

To validate the ICD-10 diagnoses wereviewed the medical records of allchildren with a discharge diagnosis ofsinusitis (N = 678) and 100 childrenwith pneumonia coded as bacterialpneumonia (50 before and 50 aftervaccination). Information on signsand symptoms, radiographic findings,treatment, risk factors, and outcome

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was collected. Sinusitis cases wereconsidered valid if there was a pre-vious or ongoing respiratory infection,signs of orbital or periorbital swellingor redness, or a positive computed to-mography scan. Pneumonia cases wereconsidered valid if there was ongoingrespiratory infection or radiographicverification, or they were judged by theattending pediatrician to be of bacterialorigin and antibiotics were given.

Statistical Analysis

Segmented regression analysis wasapplied toevaluate theeffect of thePCV7vaccination program on monthly hos-pital admission rates of sinusitis andpneumonia, comparing the periodsbefore and after vaccination, excludingthe in-between year.18,19 Generalizedlinear models assuming a Poissondistribution for the monthly admissionrates were fitted, and negative bi-nomial distribution was preferred inthe presence of overdispersion. Gen-eralized additive models were usedinstead of generalized linear models toadjust for a seasonal effect when nec-essary. All models contained 3 basicparameters accounting for the pre-intervention trend, the change in levelfrom the last preintervention point tothe first postintervention point, and thedifference in trend between the 2periods. The postintervention trendand its SE were derived from a combi-nation of the first and third parame-ters. Correlograms were used to checkfor autocorrelation in the residuals,and the models were adjusted for first-order autocorrelation when necessary.

Rate ratios (RRs) and their respective95% confidence intervals (CIs) werecalculated to compare the prevaccina-tion and postvaccine periods. We con-ducted all analyses by using thestatistical software R, version 3.0.1(R Foundation for Statistical Computing,Vienna, Austria), andP values,.05wereconsidered statistically significant.

Ethical Permission

Ethical approval was obtained from theStockholm Regional Ethics Committee.

RESULTS

Sinusitis

Between July 2003 and June 2012,678 children ,18 years old weredischarged from the hospital witha diagnosis of sinusitis. Validation ofmedical records using preset criterialed to exclusion of 76 cases because ofincorrect diagnosis without signs ofconcomitant sinusitis, such as skin in-fection, conjunctivitis, or insect bite(n = 46), or because there were noclinical signs of sinusitis (n = 30). Ofthe 602 remaining validated sinusitiscases, 234 (39%) patients were aged,2 years and 159 (26%) 2 to,5 years.Of the 393 children ,5 years of age,62% were boys.

The incidence of hospitalization for si-nusitis in children ,2 years of agedecreased significantly from the pre-vaccination to the postvaccinationperiod, from 70 to 24 per 100 000 person-years (RR = 0.34; 95% CI, 0.25–0.47,P , .001). A decrease, although notsignificant, was also seen in children2 to ,5 years of age (RR = 0.72; 95%CI, 0.51–1.02; P = .06), whereas theincidence remained stable in olderchildren (Table 1).

Trend analysis showed that beforePCV7 introduction there was no signif-icant month-to-month change in theincidence of hospitalization due to si-nusitis in children ,5 years old (Fig 1and Table 2). Immediately after the firstyear of vaccination (July 2008) therewas a decrease in hospitalization in theyounger age group (0 to ,2 years);however, this was not significant (P =.055). For this age group and for thoseaged 2 to ,5 years, a significantmonth-to-month decrease in incidencewas observed after vaccination (P =.018 and .004, respectively). No change

was observed for those aged 5 to 18years. There were no changes in gen-der distribution or in proportion ofchildren with risk factors or chronicillnesses after introduction of PCVs(data not shown).

Pneumonia

From July 2003 to June 2012, 5018children ,18 years of age with a dis-charge diagnosis of pneumonia codedas bacterial pneumonia were included;2034 (41%) were,2 years of age, and1555 (31%) were 2 to,5 years of age.Of the 3589 children ,5 years of age,54% were boys.

The incidence of hospitalization forpneumonia in children,2 years of agedecreased significantly, from 450 to366 per 100 000 person-years (P ,.001), in a comparison of the pre-vaccination and postvaccination peri-ods (Table 1). A significant decrease inincidence (P = .002) was also seen inthe age group 2 to ,5 years, whereasthe incidence remained stable in olderchildren.

Trend analysis showed that beforePCV7introduction there was a significantincrease in month-to-month hospital-izations for pneumonia in children aged0 to,2 years (P = .001), but there wasno significant change in children aged2 to,5 years. Soon after the first yearof vaccination (July 2008) there wasa significant decrease in hospital-izations in children aged 0 to,2 years(P = .002). However, a significantmonth-to-month decrease in the post-vaccination period was seen only inthose aged 2 to,5 years (P = .02). Forthe age group 5 to 18 years there wasan increasing trend in month-to-monthhospitalization both before and aftervaccination, but there was no differ-ence in the incidence RR (Fig 1, Tables 1and 2).

When we compared the 50 validatedpneumonia cases coded as bacterialpneumonia before PCV7 introduction

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(in 2005) with 50 cases after vaccineintroduction (in 2009), no differenceswere observed in frequency of chestradiographs on admission (100% in2005, 98% in 2009). Chronic conditions(mainly asthma, prematurity, or neu-rologic disease) were found in 36% ofchildren in 2005 and 31% in 2009 (P =.82). The clinical severity of pneumonia,measured using mean C-reactive pro-tein, oxygen saturation, and need foroxygen or intensive care, was compa-rable in 2005 and in 2009 (data notshown).

Empyema

For children ,2 years old there wasa nonsignificant increased incidence ofhospitalization for empyema in theperiod after compared with the periodbefore PCV7 and PCV13 vaccination(4.4 vs 2.5 per 100 000 person-years;

RR = 1.78; 95% CI, 0.55–6.63; P = .42)(Table 1).

Hospitalization for ControlDiagnosis

Pyelonephritis was used as an indica-tor disease for general hospitalizationtrends during the study period. Therewasaslight increase inhospitalizationsduring thestudyperiod in theagegroup0 to ,2 years but not among childrenaged 2 to,5 years (Table 1). However,in the time trend analysis (Fig 1) themonth-to-month incidence remainedstable in the prevaccination and post-vaccination period for both age groups(Fig 1 and Table 2).

The incidence of hospitalizations forasthma and obstructive bronchitisremained stable during the study pe-riod (Table 1). However, the incidenceof hospitalization for RSV infections

and viral pneumonia increased sig-nificantly in children ,2 years oldbetween the prevaccination and post-vaccination periods (RR = 1.37; 95%CI, 1.29–1.46; P , .001 and RR = 1.46;95% CI, 1.08–1.97; P = .01, respectively)(Table 1).

DISCUSSION

To our knowledge this is the first studyshowing that introduction of PCV7 andPCV13 in the childhood vaccinationprogram significantly reduces hospi-talizations for sinusitis in children ,5years of age. We also found a signifi-cant reduction in hospitalization ratesfor pneumonia in children ,5 yearsold. However, there was an increase inempyema in children ,2 years of agein the postvaccination compared withthe prevaccination period, but this wasnot statistically significant.

TABLE 1 Number of Hospitalizations and Incidence of Pneumonia, Sinusitis, Empyema, Pyelonephritis, Asthma and Obstructive Bronchitis, RSVInfection, 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 July2003–June 2007

After July2008–June 2012

Before July2003–June 2007

After July2008–June 2012

Pneumonia0–,2 y 914 836 450 366 0.81 (0.74–0.89) ,.0012–,5 y 687 694 250 212 0.85 (0.76–0.94) .0025–,18 y 604 683 51 56 1.10 (0.99–1.23) .09

Sinusitis0–,2 y 142 55 70 24 0.34 (0.25–0.47) ,.0012–,5 y 70 60 25 18 0.72 (0.51–1.02) .065–,18 y 82 98 7 8 1.16 (0.87–1.56) .31

Empyema0–,2 y 5 10 2.5 4.4 1.78 (0.55–6.63) .422–,5 y 5 10 1.8 3.1 1.68 (0.52–6.26) .495–,18 y 11 19 0.9 1.6 1.68 (0.80–3.53) .17

Pyelonephritis0–,2 y 598 757 294 331 1.13 (1.01–1.25) .032–,5 y 123 156 45 48 1.06 (0.84–1.35) .615–,18 y 167 233 14 19 1.36 (1.11–1.66) .002

Asthma and obstructive bronchitis0–,2 y 2136 2493 1051 1090 1.04 (0.98–1.10) .212–,5 y 709 902 258 275 1.07 (0.97–1.18) .205–,18 y 334 323 28 27 0.94 (0.81–1.10) .44

RSV infection0–,2 y 1711 2647 842 1158 1.37 (1.29–1.46) ,.0012–,5 y 58 137 21 42 1.98 (1.46–2.69) ,.0015–,18 y 7 28 0.6 2.3 3.89 (1.66–10.56) ,.001

Viral pneumonia0–,2 y 70 115 34 50 1.46 (1.08–1.97) .012–,5 y 42 60 15 18 1.20 (0.81–1.78) .375–,18 y 24 58 2.0 4.8 2.35 (1.46–3.78) ,.001

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Our finding of a decreased incidence ofsinusitis after introduction of PCV7 andPCV13 is supported by a recent study byPeña et al20 showing that S. pneumo-niae was nearly eliminated as an etio-logical agent of complicated sinusitisin children after PCV introduction in theUnited States. Moreover, they observeda significant increase in S. aureusas a cause of complicated sinusitis.Benninger21 described a change inserotype distribution in both acuteotitis media and acute rhinosinusitisin children after PCV7 introduction.McNeil et al22 showed that in the period

when PCV7 was used in the UnitedStates, 50% of the pneumococcal iso-lates recovered from children withchronic sinusitis were serotype 19A,probably because of serotype re-placement. So an overall decline insinusitis after PCV7 and PCV13 vac-cination in children may be followedby both serotype replacement andexpansion of other bacteria, similarto the experience with invasivepneumococcal disease and otitis me-dia.8,23,24

The effect of PCV on the incidence ofpneumonia necessitating hospitaliza-

tionhasvariedbetweenstudies. Ameta-analysis by Fitzwater et al8 showeda 13% to 65% reduction in hospital-izations for pneumonia in children. InNorway, Magnus et al25 showed a22% decrease in pneumonia amongPCV7-vaccinated children of 12 to 18months of age. This is comparable tothe 19% decrease in hospitalization forpneumonia in children aged ,2 yearsand the 15% decreased risk of pneu-monia hospitalization in children 2 to,5 years that we observed in this study.

Nelson et al10 observed an effect onpneumonia rates in outpatients in the

FIGURE 1Trend 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 StockholmCounty, Sweden, 2003–2012.

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United States but only a nonsig-nificant reduction in confirmed hos-pitalization events in children aged,1 year. In contrast, a recent studyfrom the United States showed a sus-tained decrease in hospitalizationsfor pneumonia in children and a de-crease in people .65 years old, pos-sibly a herd effect.26 Our use ofa discharge diagnosis of pneumoniacoded as bacterial pneumonia as anendpoint was motivated by the diffi-culty of establishing an etiologicaldiagnosis of pneumonia, especially insmall children.

Interestingly, we observed an in-creasing incidence of admissions tothe hospital for pneumonia amongchildren,2 years and from 5 to,18years old before vaccine introduction,from 2003 to 2007 (Fig 1). The reasonfor this increase is unclear, but nat-ural fluctuations caused by expansionof certain pneumococcal serotypes orclones might have contributed. Asimilar increase in 2004 to 2006 wasseen in a national time trend (1997 to2008) study on hospitalizations forpneumonia among children in England.9

This might have led to an underes-timation of the real effect of the PCVvaccination, because we did not cal-culate expected rates assuming acontinued increasing trend and com-paring those with the observed rates,as was done in other studies.27

Previous influenza virus infection hasbeen shown to increase the risk ofdeveloping pneumococcal pneumo-nia.28,29 Recent data from the UnitedStates showed excess risk of pneu-mococcal pneumonia during the H1N1influenza pandemic in 2009.30 In ourstudy we observed only an increasein hospitalizations for pneumonia,coded as bacterial pneumonia, inchildren aged 2 to ,5 years duringthis pandemic. There was a high cov-erage rate (50% of children aged 6months to 2 years, 70% of childrenTA

BLE2

TrendAnalysisof

MonthlyHospitalizations

byDischargeDiagnosisper100000Person-Years

byAgeGroupin

Stockholm

County,Sweden,2003–2012

Disease(Age

Group)

RR(95%

CI)a

PDisease(Age

Group)

RR(95%

CI)

PDisease(Age

Group)

RR(95%

CI)

P

Sinusitis

(0–2y)

Sinusitis

(2–5y)

Sinusitis

(5–18

y)Preinterventiontrend

1.00

(0.992–1.017)

.47

Preinterventiontrend

1.01

(0.991–1.029)

.32

Preinterventiontrend

1.01

(0.996–1.029)

.13

Change

inlevel

0.52

(0.265–1.014)

.055

Change

inlevel

1.026(0.434–2.425)

.95

Change

inlevel

0.77

(0.381–1.561)

.47

Postinterventiontrend

0.976(0.957–0.996)

.018

Postinterventiontrend

0.969(0.949–0.990)

.004

Postinterventiontrend

1.00

(0.985–1.014)

.96

Pneumonia(0–2y)

Pneumonia(2–5y)

Pneumonia(5–18

y)Preinterventiontrend

1.01

(1.004–1.017)

.001

Preinterventiontrend

1.004(0.997–1.011)

.29

Preinterventiontrend

1.01

(1.007–1.022)

,.001

Change

inlevel

0.65

(0.494–0.856)

.002

Change

inlevel

0.90

(0.647–1.255)

.54

Change

inlevel

0.50

(0.357–0.70)

,.001

Postinterventiontrend

0.996(0.990–1.001)

.13

Postinterventiontrend

0.992(0.985–0.999)

.02

Postinterventiontrend

1.01

(1.005–1.019)

.001

Pyelonephritis(0–2y)

Pyelonephritis(2–5y)

Pyelonephritis(5–18

y)Preinterventiontrend

1.00

(0.994–1.007)

.99

Preinterventiontrend

1.00

(0.990–1.016)

.67

Preinterventiontrend

1.003(0.992–1.014)

.64

Change

inlevel

1.09

(0.809–1.474)

.57

Change

inlevel

0.974(0.551–1.740)

.93

Change

inlevel

1.123(0.681–1.849)

.65

Postinterventiontrend

1.00

(0.994–1.006)

.90

Postinterventiontrend

0.999(0.987–1.010)

.82

Postinterventiontrend

1.003(0.994–1.013)

.52

aWhenreferringtothepreinterventionandpostinterventiontrend,theRR

expressesthemonth-to-monthchange

inhospitalizationrates.Forthechange

inlevelitexpresses

comparisonofthehospitalizationrateofthefirstpostinterventionmonthtothe

lastpreinterventionone.

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aged 3–18 years) of AS03-adjuvantedmonovalent vaccine against influenzaA(H1N1)pdm09 in Sweden. This vaccinewas about 90% effective in preventingthe need for hospitalization for pan-demic influenza,31 which may havelowered the excess risk for pneumo-coccal pneumonia.

Adecrease inRSV infectionswasseen inSouth Africa during a PCV trial, and anincrease in RSV activity was associatedwith an increased incidence of pneu-monia in children in Israel, indicatingmixed infections with RSV and pneu-mococci.32,33 In contrast, we noted anincrease in RSV after PCV introduction,which may be explained by 3 consecu-tive seasons with unusually high cir-culations of RSV and increasing use ofviral respiratory polymerase chain re-action diagnostics on nasopharyngealsamples in the last 10 years. Thus, thehigher burden of influenza and RSVafter PCV may have lowered the effectof the vaccine on pneumonia, as wefound.

Empyema is a rare complication ofpneumonia. Grijalva et al34,35 showeda twofold increase in hospitalizationsfor parapneumonic empyema aftervaccine introduction in children in theUnited States. Serotypes 1 and 3 havebeen associated with empyema, andbecause they are not included in PCV7,serotype replacement may cause in-creased rates of empyema after vac-cine introduction.36 An increase instaphylococcal empyema or empyemaof unknown etiology has been de-scribed, as well as an increase inpneumonia complicated by empyema,

from 3.7 cases per 100 000 children to10.3 after vaccine introduction in theUnited States.35–37 As was found inearlier studies, we found a nearlytwofold increase in hospitalizations forempyema in children aged ,2 years;this was nonsignificant, probably be-cause of low numbers. The highest in-cidence of empyema was observed in2007 to 2009, immediately after in-troduction of PCV7, indicating thatfactors other than the vaccine mayhave contributed.

A major strength of this population-based study is inclusion of 100% ofthe relevant hospitalizations registeredin the area. This is also the mainweakness, because the result dependson doctors assigning the correct ICDdiagnosis and not changing codingpractices over time. However, we vali-dated all cases of sinusitis and a se-lection of cases of pneumonia, findingno major changes in ICD coding. An-otherweakness is thatwe could not linkclinical cases to bacterial strains orserotypes of pneumococci with thisstudy design. However, in prospectivestudies it is also difficult to isolate thecausative microbe in children withpneumonia, sinusitis, or empyema.

Except for introduction of PCV in thevaccination programs, there were nochanges or interventions that shouldhave affected pneumonia or sinusitiscase management or hospital care orthat could have explained the decreasein hospitalizations for sinusitis andpneumonia. Thisfinding is supportedbythe fact that thehospitalizationrates forasthma or obstructive bronchitis and

pyelonephritis were stable during thepostvaccination period. However, a clearlimitation is that data on outpatient careare not available.

Our data come from Sweden, a coun-try with 98% PCV coverage, .80%day care attendance, very low levelsof HIV infection and tuberculosis,and low antibiotic consumption com-pared with most countries, all ofwhich play a role in the results.Therefore, it is not only pneumococcalvaccines that affect the rate of hos-pitalization for pneumonia and si-nusitis in children; fluctuations inother bacterial and viral pathogens,socioeconomic status, hygiene in daycare centers, and antibiotic pressurein societymay also affect pneumococcaltransmission.

CONCLUSIONS

Pneumococcal disease is the most im-portant vaccine-preventable disease inchildren, because it causes most childdeaths. Many low- and middle-incomecountries are implementing PCV vac-cination programs. This study addsevidence that PCV vaccine (PCV7 andPCV13) prevents severe sinusitis andpneumonia,with implications forglobalchild survival.38–40 Specifically, we arethe first to show great effectivenessagainst sinusitis in children aged ,5years.

ACKNOWLEDGMENTS

We gratefully acknowledge Anna Granathfor her scientific contribution to the si-nusitis part of the study.

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(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 thevaccine 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 thecurrent 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, SwedishFoundation 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 heremployer financed the equivalent amount according to the national rules for pharmaceutical sponsorship for medical education, and she has participated in1 clinical vaccine trial in collaboration with GSK.

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DOI: 10.1542/peds.2013-4177 originally published online November 10, 2014; 2014;134;e1528Pediatrics 

Henriques-Normark, Åke Örtqvist and Tobias AlfvénSofia Hultman Dennison, Malin Ryd Rinder, Margareta Eriksson, Birgitta

Ann Lindstrand, Rutger Bennet, Ilias Galanis, Margareta Blennow, Lina Schollin Ask,Conjugate Vaccine

Sinusitis and Pneumonia Hospitalization After Introduction of Pneumococcal

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DOI: 10.1542/peds.2013-4177 originally published online November 10, 2014; 2014;134;e1528Pediatrics 

Henriques-Normark, Åke Örtqvist and Tobias AlfvénSofia Hultman Dennison, Malin Ryd Rinder, Margareta Eriksson, Birgitta

Ann Lindstrand, Rutger Bennet, Ilias Galanis, Margareta Blennow, Lina Schollin Ask,Conjugate Vaccine

Sinusitis and Pneumonia Hospitalization After Introduction of Pneumococcal

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