Vaccine 31 (2013) 14261430

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Effectiveness of the inuenza vaccine at preventing hospitalization due to acute

lower respiratory infection and exacerbation of chronic cardiopulmonary
disease in Korea during 20102011
Yu Bin Seo a , Kyoung-wook Hong a , In Seon Kim a , Won Suk Choi a , Ji Hyeon Baek b , Jacob Lee c ,
Joon Young Song a , Jin Soo Lee b , Hee Jin Cheong a, , Woo Joo Kim a,d
a
Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
b
Division of Infectious Diseases, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea
c
Division of Infectious Diseases, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea
d
Division of Infectious Diseases, Department of Internal Medicine, Transgovernmental Enterprise for Pandemic Inuenza in Korea, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Background: Inuenza epidemics are accompanied by a considerable increase in hospitalization due
Received 1 June 2012 to acute lower respiratory infection and exacerbation of underlying medical conditions. We estimated
Received in revised form 31 August 2012 the effectiveness of the inuenza vaccine at preventing hospitalization due to acute lower respiratory
Accepted 4 October 2012
infection and new onset or acute exacerbation of chronic cardiopulmonary disease.
Available online 19 October 2012
Method: During the peak inuenza period in 20102011, we performed a multicenter, casecontrol, retro-
spective cohort study of patients who were hospitalized due to newly developed pneumonia, bronchitis,
Keywords:
and bronchiolitis, or new onset or acute exacerbation of asthma, COPD, ischemic heart disease, and CHF.
Inuenza vaccine
Effectiveness
Controls were selected from outpatients who visited study hospitals but who were not hospitalized dur-
Chronic cardiovascular disease ing the same study period. Controls were matched 1:1 to cases based on age, gender, and date of hospital
Chronic respiratory disease visit. Univariate and multivariate logistic regression analyses were used to determine the effectiveness
Casecontrol study of the inuenza vaccine at decreasing hospitalization.
Korea Results: Between December 2010 and February 2011, 556 hospitalized subjects were identied. Age, gen-
der, and body mass index (BMI) were similar between case and control groups. The inuenza vaccination
rate of the hospitalized and non-hospitalized patients was 42.4% and 52.2%, respectively (p < 0.001). The
overall vaccine effectiveness for preventing hospitalization was 32.5% (odds ratio 0.675, 95% condence
interval [CI] 0.4860.937; p = 0.019). Multivariate logistic analysis showed that inuenza vaccination
signicantly reduced the risk of hospitalization, especially due to new onset or acute exacerbation of
ischemic heart disease and CHF in patients aged 65 years and older (OR 0.274, 95% CI 0.1140.658,
p = 0.004). The estimated vaccine effectiveness in these patients was 72.6%.
Conclusion: Inuenza vaccination reduced the rate of hospitalization among patients with underlying
chronic heart disease, particularly those patients 65 years old and greater.
2012 Elsevier Ltd. All rights reserved.

1. Introduction cardiopulmonary disease in particular are at high risk for serious

Inuenza epidemics are accompanied by a considerable increase
in morbidity and mortality resulting from inuenza itself and
complications, which include both lower respiratory infection and
exacerbation of underlying medical conditions [14]. Patients with
Corresponding author at: Division of Infectious Disease, Department of Internal
Medicine, Korea University Guro Hospital, Korea University College of Medicine,
Guro-dong, Guro-gu, Seoul 152-703, Republic of Korea. Tel.: +82 2 2626 3050;
fax: +82 2 2626 1105.
E-mail address: heejinmd@korea.ac.kr (H.J. Cheong).
complications and are frequently admitted to hospital.
Since 2003, the Korea Centers for Disease Control and Preven-
tion have advocated annual vaccination in the elderly and patients
with chronic illnesses such as chronic cardiopulmonary disease,
diabetes, chronic liver disease, and malignancy, as well as residents
of long term care facilities, health-care personnel, and pregnant
women, to prevent inuenza. Despite the high vaccination rate
(77.2%) among the elderly, inuenza vaccination rates in the gen-
eral population and in high-risk groups were only 34.3% and 61.3%,
respectively, in the season of 20042005 [5]. Moreover, few studies
have investigated whether inuenza vaccination decreases hospi-
talization in Korea.

0264-410X/$ see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2012.10.024
 Y.B. Seo et al. / Vaccine 31 (2013) 14261430
We performed a multicenter, retrospective cohort study to esti-
mate the effectiveness of inuenza vaccination at preventing hos-
pitalization due to acute lower respiratory infection and new onset
or acute exacerbation of underlying cardiopulmonary disease.
2. Methods
Fiver hundred fty-six patients were enrolled at four univer-
sity hospitals in Seoul, Incheon and Ansan city, Korea. Approval
was obtained from the Institutional Review Board of each hospi-
tal and this study was performed in accordance with the Helsinki
Declaration and Good Clinical Practice.
2.1. Study design and population
We performed a multicenter, casecontrol, retrospective cohort
study. We reviewed the medical records of patients who attended
cardiovascular and pulmonary clinics during the peak inuenza
period from December 2010 to February 2011. Based on ICD
10 diagnostic codes, we identied patients who had pneumonia,
bronchitis, bronchiolitis, asthma, chronic obstructive lung disease,
ischemic heart disease, and congestive heart failure (CHD). These
cases comprised all patients who were hospitalized due to newly
developed pneumonia, bronchitis, bronchiolitis, or the new onset or
acute exacerbation of asthma, chronic obstructive pulmonary dis-
ease (COPD), ischemic heart disease, or CHF. Subjects aged 18 years
or older were considered eligible for this study. For subgroup anal-
ysis, subjects were grouped into the age groups of <49 years, 5064
years, and >65 years. Controls for statistical analysis were selected
from outpatients who visited hospitals but who were not hospital-
ized during the same study period. The controls were matched 1:1
to the cases based on age, gender, and date of hospital visit. If there
was not an exactly matched control, 5 days difference from the
visit date or nearest age were allowed.
2.2. Study period
The Korea Centers for Disease Control (KCDC) provides weekly
numbers of total respiratory specimens tested for inuenza virus
by antigen detection and viral isolation methods and the num-
ber of positive result among the inuenza-like illness patients.
Study period was dened using weekly inuenza surveillance data.
We dened peak inuenza period as weeks during which more
than 20% of specimens tested positive for inuenza (week 49,
2010week 6, 2011).
During study periods, type A(H1N1)pdm09 and A(H3N2)
inuenza viruses circulated in Korea, which were well matched
to the corresponding strains of 20102011 seasonal vaccine
(A/California/07/2009 or A/Perth/16/2009). In the case of type B
strain, B/Brisbane/60/2008 (vaccine strain) and B/Florida/4/2006
circulated at the same time in the 2010/2011 season, and only 38.5%
of the inuenza B stains isolated were antigenically similar to the
vaccine strain. However, inuenza B strains were isolated sporad-
ically, and circulated mainly from March 2011 to May 2011. The
study period above may not be affected by the mismatch type B
inuenza.
2.3. Data collection
We obtained the following baseline variables from the elec-
tronic healthcare records: age, hospital visit date, gender, body
mass index, smoking history, co-existing chronic disease, inuenza
vaccination status in the 20102011 season before admission event
or outpatient visit, and admission to a ward or ICU. Because vacci-
nation status and hospitalization events were important variables
in this study, trained interviewers administered a standardized
1427
telephone questionnaire to case subjects and controls to conrm
the records after receiving verbal consent. Those who received the
20102011 seasonal inuenza vaccine were considered to be vac-
cinated if they received the vaccine 14 or more days before disease
exacerbation or new onset disease.
2.4. Statistical analyses
Categorical variables were compared by a two-sided Fishers
exact test, the chi-square test, or Students t-test. Continu-
ous variables were analyzed as means and compared by the
MannWhitney test. Vaccine effectiveness was estimated as
1 odds ratio (OR) 100. A protective effect was assumed when
the ORs were less than 1 and the 95% condence interval did not
include 1. To evaluate vaccine effectiveness, an adjusted OR and its
95% CI were calculated by multivariate logistic regression. A bilat-
eral p-value of <0.05 was considered signicant. These analyses
were conducted using SPSS 18.0 (SPSS Inc., Chicago, IL, USA).
3. Results
3.1. Overall cohort analysis
Between December 2010 and February 2011, 556 hospitalized
subjects were identied. The characteristics of case subjects and
their matched controls are shown in Table 1. Age, gender and
body mass index (BMI) were similar between the two groups.
Current smokers had a higher risk of hospitalization (p = 0.002).
Pneumonia and ischemic heart disease were more common among
the hospitalized cases. Inuenza vaccination rates of hospitalized
and non-hospitalized patients were 42.4% and 52.2%, respectively
(p < 0.001). The overall vaccine effectiveness at preventing hospi-
talization was 32.5% [odds ratio 0.675, 95% condence interval (CI)
0.4860.937; p = 0.019] after adjusting for age, gender, BMI, smok-
ing status, and underlying cardiopulmonary disease. During the
study period, 165 cases were admitted to the ICU. We compared
these cases with the others (391 general ward-admitted cases).
The inuenza vaccination rate was 37.0% in the ICU-admitted cases
and 44.8% in the general ward-admitted cases, a non-signicant
difference (p = 0.092, data not shown).
3.2. Subgroup analysis according to the cause of hospitalization
We performed subgroup analysis to evaluate the vaccine effec-
tiveness for each cause of hospitalization, namely acute lower
respiratory infection (pneumonia, bronchitis, bronchiolitis), new
onset or acute exacerbation of ischemic heart disease and CHF, and
new onset or acute exacerbation of asthma and COPD (Table 2).
Multivariate logistic analysis was performed for each cause of
hospitalization, and the variables of age, gender, smoking habits,
underlying cardiopulmonary disease, and vaccination status were
included. Inuenza vaccination signicantly reduced the risk of
hospitalization, especially due to new onset or acute exacerbation
of ischemic heart disease and CHF in patients aged 65 years and
older (OR 0.274, 95% CI 0.1140.658, p = 0.004). The estimated vac-
cine effectiveness in these patients was 72.6%. The preventative
effect of the vaccine against hospitalization was not statistically
signicant between subjects with lower respiratory infection and
those with chronic pulmonary disease.
4. Discussion
There is a general agreement that the inuenza vaccine should
be recommended to elderly and high-risk patients. However, the
clinical effectiveness and benets of the vaccine are controversial.
1428 Y.B. Seo et al. / Vaccine 31 (2013) 14261430

Table 1
Baseline characteristics of the hospitalized cases and non-hospitalized controls.

Characteristic Hospitalized subjects (n = 556) Non-hospitalized subjects (n = 556) p-Value

Male, n (%) 333 (59.9) 333 (59.9) 1.000

Age, years median 61.1 15.4 60.5 14.6 0.555
BMI, kg/m2 23.7 4.2 23.9 3.8 0.470
Current smoker, n (%) 147 (26.4) 104 (18.7) 0.002
Cause of hospital visit
Respiratory infectiona 208 28
Pneumonia, n (%) 201 (96.6) 15 (53.6) <0.001
Bronchitis, n (%) 7 (3.4) 12 (42.8) 0.355
Bronchiolitis, n (%) 0 (0) 1 (3.6) NA
Cardiovascular diseasea 258 281
Ischemic heart disease, n (%) 218 (84.5) 125 (44.5) <0.001
Congestive heart failure, n (%) 40 (15.5) 32 (11.4) 0.394
Others, n (%) 0 (0) 124 (44.1) NA
Pulmonary diseasea 120 296
Asthma, n (%) 60 (50.0) 61 (20.6) 1.000
COPD, n (%) 60 (50.0) 55 (18.6) 0.694
Others, n (%) 0 (0) 180 (60.8) NA
Inuenza vaccination, n (%) 236 (42.4) 290 (52.2) 0.001
a
Some patients had one or more conditions.

In this study, we analyzed the effects of the inuenza vaccine on
the prevention of hospitalization due to acute lower respiratory
infection and new onset or acute exacerbation of chronic cardiopul-
monary disease. This retrospective cohort study demonstrated that
inuenza vaccination reduced the risk of hospitalization due to new
onset or acute exacerbation in ischemic and CHF patients, especially
in elderly patients aged 65 years and older.
This study supports the effectiveness of vaccination at reducing
hospital admissions in patients with heart disease, consistent with
previous studies. In a large observational cohort study of 140,055
subjects during the 19981999 inuenza season and 146,328 sub-
jects during the 19992000 inuenza season, inuenza vaccination
was associated with a 19% reduction in the risk of hospitalization
due to heart disease [6]. In another observational cohort study of
147,551 person-periods during six seasons, vaccination was asso-
ciated with a 27% decrease in hospitalization for congestive heart
failure (p < 0.001) [3]. The vaccine effectiveness for the prevention
of hospitalization due to heart disease was higher in the present
study than those reported previously. In contrast to the previous
studies, our study conducted based on the inuenza surveillance
data during the peak inuenza epidemic, not including the entire
inuenza season. Moreover, the vaccine strain matched well with
the epidemic strain, which may explain why the estimated effec-
tiveness of the vaccine was higher in the present study.
Previous experimental studies have suggested that inuenza
may trigger ischemic heart disease [7]. Furthermore, it was found
that inuenza infection promotes inammation, smooth muscle
cell proliferation, and brin deposition in atherosclerotic plaques
in a mouse model [8]. Inuenza might alter endothelial function,
inhibit vasodilation, cause atheroma instability, and subsequently
initiate further progression of atherosclerosis and congestive heart
failure.
In the present study, we identied vaccine-associated reduc-
tions in hospitalization due to heart disease only in elderly patients
aged 65 years and older. Even though annual inuenza vaccination
is usually recommended for any age group with underlying heart
disease, there are few data to support this recommendation in adult
patients aged 1849 or 5064 years. A large population-based study
that compared inuenza and RSV-associated hospitalization during
four seasons found no excess in hospitalization among adults 1864
years of age, regardless of underlying heart disease [9]. Although
a prospective randomized study showed that hospitalization from

Table 2
Subgroup analysis of the effectiveness of the 20102011 seasonal inuenza vaccine at preventing hospitalization stratied by patient age and cause of hospitalization.

Cause of hospitalization Hospitalization, n (%) Non-hospitalization, n (%) Univariate analysis Multivariate analysis

Vaccinated Unvaccinated Vaccinated Unvaccinated OR (95% CI) P-value OR (95% CI) P-value
Number of subjects (percent)

Overall Hospitalization
<50 years 20 (8.7) 94 (41.0) 30 (13.1) 85 (37.1) 0.603 (0.3191.140) 0.120 0.821 (0.3391.993) 0.664
5064 years 69 (18.0) 123 (32.1) 78 (20.4) 113 (29.5) 0.813 (0.5381.228) 0.324 1.093 (0.5862.039) 0.780
65 years 147 (29.4) 103 (20.6) 182 (36.4) 68 (13.6) 0.486 (0.3660.776) 0.001 0.480 (0.2960.781) 0.003
All ages 236 (21.2) 320 (28.8) 290 (26.1) 266 (23.9) 0.677 (0.5340.857) 0.001 0.675 (0.4860.937) 0.019
Acute lower respiratory infection
<50 years 13 (21.7) 47 (70.1) 2 (3.0) 5 (7.5) 0.692 (0.1203.984) 0.649 2.054 (0.040106.001) 0.721
5064 years 23 (33.8) 39 (57.4) 6 (8.8) 0 (0) 0.046 (0.0030.850) 0.039 NA NA
65 years 44 (44.4) 42 (42.4) 6 (6.1) 7 (7.1) 1.222 (0.3803.936) 0.148 2.262 (0.12441.355) 0.582
All ages 80 (34.2) 128 (54.7) 14 (6.0) 12 (5.1) 0.536 (0.2361.217) 0.136 0.986 (0.1915.103) 0.987
New onset or acute exacerbation of chronic heart disease
<50 years 2 (3.6) 34 (60.7) 3 (5.4) 17 (30.4) 0.333 (0.0512.188) 0.253 0.223 (0.0163.104) 0.264
5064 years 24 (15.9) 77 (51.0) 14 (9.3) 36 (23.8) 0.802 (0.3721.723) 0.573 0.919 (0.2972.841) 0.883
65 years 69 (35.0) 49 (24.9) 62 (31.5) 17 (8.6) 0.386 (0.2020.739) 0.004 0.274 (0.1140.658) 0.004
All ages 95 (23.5) 160 (39.6) 79 (19.6) 70 (17.3) 0.526 (0.3490.793) 0.002 0.444 (0.2480.796) 0.006
New onset or acute exacerbation of chronic pulmonary disease
<50 years 5 (12.5) 16 (40.0) 8 (20.2) 11 (27.5) 0.430 (0.1111.667) 0.222 0.525 (0.0713.879) 0.528
5064 years 21 (32.3) 12 (18.5) 22 (33.8) 10 (15.4) 0.800 (0.2842.229) 0.663 1.220 (0.2795.344) 0.792
65 years 43 (35.2) 19 (15.6) 47 (38.5) 13 (10.7) 0.626 (0.2761.418) 0.262 0.918 (0.3332.528) 0.868
All ages 69 (30.5) 46 (20.4) 77 (34.1) 34 (15.0) 0.662 (0.3821.148) 0.142 0.830 (0.4031.708) 0.612
 Y.B. Seo et al. / Vaccine 31 (2013) 14261430
acute coronary syndrome and heart failure occurred less frequently
in the vaccinated group than the unvaccinated group, no preventive
effect of vaccination was found in the age group <65 years by sub-
group analysis [10]. Age-stratied, randomized, controlled studies
are required to better clarify the real benets of inuenza vaccina-
tion in preventing hospitalization due to acute heart disease.
Various observational studies have found that inuenza vac-
cination is associated with a 2040% reduction in the risk of
hospitalization for pneumonia [3,11,12]. However, in our study,
we did not nd a reduction in hospitalization due to pneumonia in
the vaccinated subjects. Caution is needed when interpreting these
results. Previous studies investigated whether or not inuenza vac-
cination had a protective effect against pneumonia. In contrast
to previous studies, we investigated whether inuenza vaccina-
tion could prevent hospitalization in patients already suffering
from pneumonia, and demonstrated that vaccination did not seem
to affect the severity of lower respiratory tract infection. Only
a few reports have investigated the impact of inuenza vacci-
nation on the severity of pneumonia. Interestingly, two studies
with opposing results based on the same network study have
been reported (the German competence network for community
acquired pneumonia, CAPNETZ). One study reported that prior
vaccination was associated with a less severe clinical course and
improved overall long-term survival in patients with pneumonia
[13]. The other study found no excess mortality in patients with
inuenza-associated pneumonia [14]. These conicting results may
be due to the limitations of each study. In addition, early antivi-
ral and antibiotic therapy might mitigate the effectiveness of the
inuenza vaccine on pneumonia severity. The causative pathogens
of pneumonia were not identied in the former study and the num-
bers of cases were too small in the latter study. A large longitudinal
cohort study is needed to clarify the effect of the inuenza vaccine
on the severity of inuenza-conrmed pneumonia.
Annual vaccination is universally recommended in patients with
chronic lung disease. The effectiveness of the inuenza vaccine has
been evaluated from both observational studies and randomized
controlled studies based on various types of outcome measures,
such as the proportion of acute exacerbation of COPD, changes in
lung function, and days of disability. However, few studies have
evaluated the effect of the inuenza vaccine on hospitalization.
In a previous Cochrane analysis, vaccination did not have a sig-
nicantly greater effect on hospitalization than the placebo (OR
0.33, 95% CI 0.091.24, p = 0.52), but the number of studies ana-
lyzed was too small to be condent in the results [15]. Similarly
to COPD, there are too few published studies to assess the effec-
tiveness of the inuenza vaccine on asthma exacerbation. There is
no strong evidence from controlled clinical trials to support uni-
versal vaccination in patients with asthma [16]. This study has
the same limitation. It was difcult to demonstrate a clear bene-
t of inuenza vaccination because of the small number of patients
we evaluated. Despite the high vaccination rate in patients with
COPD and asthma, vaccination was not related to a reduction in
hospitalization. These ndings indicate that vaccination is not that
effective at reducing hospitalization in patients with asthma and
COPD.
All previous studies did not show the preventive effect of
inuenza vaccination [17]. Based on the limited randomized con-
trolled data, it is not possible to draw conclusions with respect
to the protective potential of inuenza vaccination. Some authors
have emphasized the importance of selection bias in cohort studies
[18]. To identify the potential biases, it has been recommended to
repeat analysis before and during the inuenza season, comparing
the results with the estimated effectiveness. However, consider-
ing the absence of cases before the inuenza season, this method
may not be applicable to the present study. Instead, we tried to
reduce the possibility of selection bias. Admission date-matched
1429
cases-controls were selected weekly without information about
vaccination status.
This study had several limitations. First, although we used mul-
tivariate logistic regression analysis, selection bias might have
occurred. Hospital visits may have been inuenced by the patients
health status, socioeconomic status, and accessibility to healthcare.
However, it is unlikely to affect patients requiring hospitalization
for acute serious illness. Second, we measured rates of hospitaliza-
tion without laboratory conrmation of inuenza virus infection.
Moreover, inuenza virus diagnostic testing was not undertaken
and for this reason the precise number of inuenza infections is
unknown. Therefore, we were not able to exclude the possibility
that other respiratory pathogens, such as respiratory syncytial virus
(RSV) and pneumococcus, were present during the same period.
However, surveillance data on the viral pathogen among patients
with acute respiratory infection showed 4 RSV versus 42 inuenza
infection during study period, so presumptive relative burden of
RSV might be much lower than inuenza (unpublished data). Third,
we analyzed the data without including other comorbidities that
may have inuenced hospitalization such as diabetes, renal disease,
and cancer. Fourth, the hospitalization criteria might have been dif-
ferent for each hospital. The decision to hospitalize a given patient
was at the discretion of the practitioner at each site.
In conclusion, inuenza vaccination reduced the rate of hospi-
talization among patients with underlying chronic heart disease,
particularly adults aged 65 years and over. The inuenza vacci-
nation did not appear to reduce the severity of lower respiratory
infection and hospitalization due to chronic pulmonary disease.
Further large longitudinal cohort studies are required to clarify the
effects of the inuenza vaccine.
Acknowledgement
This study was supported by a grant of the Korea Healthcare
technology R&D Project Ministry of Health & Welfare Republic of
Korea (Grant No. A103001).
Conict of interest: None to declare.
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