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abstract
BACKGROUND AND OBJECTIVE: Streptococcus pneumoniae is a major
cause of pneumonia and sinusitis. Pneumonia kills .1 million children annually, and sinusitis is a potentially serious pediatric disease
that increases the risk of orbital and intracranial complications.
Although pneumococcal conjugate vaccine (PCV) is effective against
invasive pneumococcal disease, its effectiveness against pneumonia
is less consistent, and its effect on sinusitis is not known. We compared hospitalization rates due to sinusitis, pneumonia, and empyema
before 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 to
2012 were included in a population-based study of hospital registry
data on hospitalizations due to sinusitis, pneumonia, or empyema.
Trend analysis, incidence rates, and rate ratios (RRs) were calculated
comparing July 2003 to June 2007 with July 2008 to June 2012, excluding the year of PCV7 introduction.
RESULTS: Hospitalizations for sinusitis decreased signicantly in children aged 0 to ,2 years, from 70 to 24 cases per 100 000 population
(RR = 0.34, P , .001). Hospitalizations for pneumonia decreased signicantly in children aged 0 to ,2 years, from 450 to 366 per 100 000
population (RR = 0.81, P , .001) and in those aged 2 to ,5 years from
250 to 212 per 100 000 population (RR = 0.85, P = .002). Hospitalization
for empyema increased nonsignicantly. Trend analyses showed increasing hospitalization for pneumonia in children 0 to ,2 years before
intervention and conrmed a decrease in hospitalizations for sinusitis
and pneumonia in children aged 0 to ,5 years after intervention.
KEY WORDS
Streptococcus pneumoniae, sinusitis, pneumonia, pneumococcal
conjugated vaccine
ABBREVIATIONS
CIcondence interval
ICD-10International Classication of Diseases, 10th Revision
PCVpneumococcal conjugate vaccine
RRrate ratio
RSVrespiratory syncytial virus
Drs rtqvist and Alfvn made equal contributions to this article.
Dr Lindstrand conceptualized and designed the study, carried
out data collection and analyzed the data, and drafted and
revised the manuscript; Dr Bennet conceptualized and designed
the study, carried out data collection, and reviewed and revised
the manuscript; Mr Galanis performed statistical analysis and
reviewed and revised the manuscript; Drs Blennow, Rinder,
Eriksson, Henriques-Normark, rtqvist, and Alfvn
conceptualized and designed the study and reviewed and
revised the manuscript; Drs Ask and Dennison revised medical
records of the sinusitis patients and reviewed and revised the
manuscript; and all authors approved the nal manuscript as
submitted.
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, Public
Health Agency of Sweden, Nobels vg 18, 171 82 Stockholm,
Sweden. E-mail: ann.lindstrand@folkhalsomyndigheten.se
e1528
LINDSTRAND et al
ARTICLE
METHODS
A retrospective population-based study
was performed using International
Classication of Diseases, 10th Revision
(ICD-10) coded hospital registries to
identify all children hospitalized with
sinusitis, pneumonia, and empyema in
Stockholm County between July 2003 and
June 2012. The year of introduction of
PCV7, from July 1, 2007 to June 30, 2008,
was excluded from the analysis. The
study years included cases from July 1
through June 30, to keep winters higher
infection rates within 1 study year.
Study Population and Data
Collection
In 2012 Stockholm County had a population of 2 million, of whom 22% were
e1529
e1530
Ethical Permission
Ethical approval was obtained from the
Stockholm Regional Ethics Committee.
RESULTS
Sinusitis
Between July 2003 and June 2012,
678 children ,18 years old were
discharged from the hospital with
a diagnosis of sinusitis. Validation of
medical records using preset criteria
led to exclusion of 76 cases because of
incorrect diagnosis without signs of
concomitant sinusitis, such as skin infection, conjunctivitis, or insect bite
(n = 46), or because there were no
clinical signs of sinusitis (n = 30). Of
the 602 remaining validated sinusitis
cases, 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 sinusitis in children ,2 years of age
decreased signicantly from the prevaccination to the postvaccination
period, from 70 to 24 per 100 000 personyears (RR = 0.34; 95% CI, 0.250.47,
P , .001). A decrease, although not
signicant, was also seen in children
2 to ,5 years of age (RR = 0.72; 95%
CI, 0.511.02; P = .06), whereas the
incidence remained stable in older
children (Table 1).
Trend analysis showed that before
PCV7 introduction there was no significant month-to-month change in the
incidence of hospitalization due to sinusitis in children ,5 years old (Fig 1
and Table 2). Immediately after the rst
year of vaccination (July 2008) there
was a decrease in hospitalization in the
younger age group (0 to ,2 years);
however, this was not signicant (P =
.055). For this age group and for those
aged 2 to ,5 years, a signicant
month-to-month decrease in incidence
was observed after vaccination (P =
.018 and .004, respectively). No change
Pneumonia
From July 2003 to June 2012, 5018
children ,18 years of age with a discharge diagnosis of pneumonia coded
as bacterial pneumonia were included;
2034 (41%) were ,2 years of age, and
1555 (31%) were 2 to ,5 years of age.
Of the 3589 children ,5 years of age,
54% were boys.
The incidence of hospitalization for
pneumonia in children ,2 years of age
decreased signicantly, from 450 to
366 per 100 000 person-years (P ,
.001), in a comparison of the prevaccination and postvaccination periods (Table 1). A signicant decrease in
incidence (P = .002) was also seen in
the age group 2 to ,5 years, whereas
the incidence remained stable in older
children.
Trend analysis showed that before PCV7
introduction there was a signicant
increase in month-to-month hospitalizations for pneumonia in children aged
0 to ,2 years (P = .001), but there was
no signicant change in children aged
2 to ,5 years. Soon after the rst year
of vaccination (July 2008) there was
a signicant decrease in hospitalizations in children aged 0 to ,2 years
(P = .002). However, a signicant
month-to-month decrease in the postvaccination period was seen only in
those aged 2 to ,5 years (P = .02). For
the age group 5 to 18 years there was
an increasing trend in month-to-month
hospitalization both before and after
vaccination, but there was no difference in the incidence RR (Fig 1, Tables 1
and 2).
When we compared the 50 validated
pneumonia cases coded as bacterial
pneumonia before PCV7 introduction
LINDSTRAND et al
ARTICLE
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
Pneumonia
0,2 y
2,5 y
5,18 y
Sinusitis
0,2 y
2,5 y
5,18 y
Empyema
0,2 y
2,5 y
5,18 y
Pyelonephritis
0,2 y
2,5 y
5,18 y
Asthma and obstructive bronchitis
0,2 y
2,5 y
5,18 y
RSV infection
0,2 y
2,5 y
5,18 y
Viral pneumonia
0,2 y
2,5 y
5,18 y
No. of Cases
RR (95% CI)
Before July
2003June 2007
After July
2008June 2012
Before July
2003June 2007
After July
2008June 2012
914
687
604
836
694
683
450
250
51
366
212
56
0.81 (0.740.89)
0.85 (0.760.94)
1.10 (0.991.23)
,.001
.002
.09
142
70
82
55
60
98
70
25
7
24
18
8
0.34 (0.250.47)
0.72 (0.511.02)
1.16 (0.871.56)
,.001
.06
.31
5
5
11
10
10
19
2.5
1.8
0.9
4.4
3.1
1.6
1.78 (0.556.63)
1.68 (0.526.26)
1.68 (0.803.53)
.42
.49
.17
598
123
167
757
156
233
294
45
14
331
48
19
1.13 (1.011.25)
1.06 (0.841.35)
1.36 (1.111.66)
.03
.61
.002
2136
709
334
2493
902
323
1051
258
28
1090
275
27
1.04 (0.981.10)
1.07 (0.971.18)
0.94 (0.811.10)
.21
.20
.44
1711
58
7
2647
137
28
842
21
0.6
1158
42
2.3
1.37 (1.291.46)
1.98 (1.462.69)
3.89 (1.6610.56)
,.001
,.001
,.001
70
42
24
115
60
58
34
15
2.0
50
18
4.8
1.46 (1.081.97)
1.20 (0.811.78)
2.35 (1.463.78)
.01
.37
,.001
DISCUSSION
To our knowledge this is the rst study
showing that introduction of PCV7 and
PCV13 in the childhood vaccination
program signicantly reduces hospitalizations for sinusitis in children ,5
years of age. We also found a signicant reduction in hospitalization rates
for pneumonia in children ,5 years
old. However, there was an increase in
empyema in children ,2 years of age
in the postvaccination compared with
the prevaccination period, but this was
not statistically signicant.
e1531
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, 20032012.
LINDSTRAND et al
,.001
,.001
.001
.64
.65
.52
1.01 (1.0071.022)
0.50 (0.3570.70)
1.01 (1.0051.019)
1.003 (0.9921.014)
1.123 (0.6811.849)
1.003 (0.9941.013)
.67
.93
.82
1.00 (0.9901.016)
0.974 (0.5511.740)
0.999 (0.9871.010)
.29
.54
.02
1.004 (0.9971.011)
0.90 (0.6471.255)
0.992 (0.9850.999)
.99
.57
.90
1.00 (0.9941.007)
1.09 (0.8091.474)
1.00 (0.9941.006)
.001
.002
.13
1.01 (1.0041.017)
0.65 (0.4940.856)
0.996 (0.9901.001)
a 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 rst postintervention month to the
last preintervention one.
.13
.47
.96
1.01 (0.9961.029)
0.77 (0.3811.561)
1.00 (0.9851.014)
.32
.95
.004
1.01 (0.9911.029)
1.026 (0.4342.425)
0.969 (0.9490.990)
.47
.055
.018
1.00 (0.9921.017)
0.52 (0.2651.014)
0.976 (0.9570.996)
RR (95% CI)
Disease (Age Group)
P
RR (95% CI)
Sinusitis (518 y)
Preintervention trend
Change in level
Postintervention trend
Pneumonia (518 y)
Preintervention trend
Change in level
Postintervention trend
Pyelonephritis (518 y)
Preintervention trend
Change in level
Postintervention trend
Sinusitis (25 y)
Preintervention trend
Change in level
Postintervention trend
Pneumonia (25 y)
Preintervention trend
Change in level
Postintervention trend
Pyelonephritis (25 y)
Preintervention trend
Change in level
Postintervention trend
TABLE 2 Trend Analysis of Monthly Hospitalizations by Discharge Diagnosis per 100 000 Person-Years by Age Group in Stockholm County, Sweden, 20032012
Sinusitis (02 y)
Preintervention trend
Change in level
Postintervention trend
Pneumonia (02 y)
Preintervention trend
Change in level
Postintervention trend
Pyelonephritis (02 y)
Preintervention trend
Change in level
Postintervention trend
ARTICLE
United States but only a nonsignicant reduction in conrmed hospitalization events in children aged
,1 year. In contrast, a recent study
from the United States showed a sustained decrease in hospitalizations
for pneumonia in children and a decrease in people .65 years old, possibly a herd effect.26 Our use of
a discharge diagnosis of pneumonia
coded as bacterial pneumonia as an
endpoint was motivated by the difculty of establishing an etiological
diagnosis of pneumonia, especially in
small children.
Interestingly, we observed an increasing incidence of admissions to
the hospital for pneumonia among
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 natural uctuations caused by expansion
of certain pneumococcal serotypes or
clones might have contributed. A
similar increase in 2004 to 2006 was
seen in a national time trend (1997 to
2008) study on hospitalizations for
pneumonia among children in England.9
This might have led to an underestimation of the real effect of the PCV
vaccination, because we did not calculate expected rates assuming a
continued increasing trend and comparing those with the observed rates,
as was done in other studies.27
Previous inuenza virus infection has
been shown to increase the risk of
developing pneumococcal pneumonia.28,29 Recent data from the United
States showed excess risk of pneumococcal pneumonia during the H1N1
inuenza pandemic in 2009.30 In our
study we observed only an increase
in hospitalizations for pneumonia,
coded as bacterial pneumonia, in
children aged 2 to ,5 years during
this pandemic. There was a high coverage rate (50% of children aged 6
months to 2 years, 70% of children
e1533
CONCLUSIONS
Pneumococcal disease is the most important vaccine-preventable disease in
children, because it causes most child
deaths. Many low- and middle-income
countries are implementing PCV vaccination programs. This study adds
evidence that PCV vaccine (PCV7 and
PCV13) prevents severe sinusitis and
pneumonia, with implications for global
child survival.3840 Specically, we are
the rst to show great effectiveness
against sinusitis in children aged ,5
years.
ACKNOWLEDGMENTS
We gratefully acknowledge Anna Granath
for her scientic contribution to the sinusitis part of the study.
REFERENCES
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LINDSTRAND et al
ARTICLE
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Efcacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The
Gambia: randomised, double-blind, placebocontrolled trial. Lancet. 2005;365(9465):
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LINDSTRAND et al
References
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