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Contents lists available at ScienceDirect

Journal of Infection and Public Health

journal homepage: http://www.elsevier.com/locate/jiph

Risk of pneumonia in patients with insomnia: A nationwide

population-based retrospective cohort study
Chia-Ling Lin a , Ta-Chun Liu b , Chi-Hsiang Chung c , Wu-Chien Chien d,e,∗,1
a
Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan
b
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
c
Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan
d
Department of Medical Research, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
e
School of Public Health, National Defense Medical Center, Taipei, Taiwan

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

Article history: Evidence is lacking regarding whether insomnia increases the risk of infectious disease. Accordingly, the
Received 13 April 2017 present study examined the risk of pneumonia in patients with insomnia.
Accepted 5 August 2017 This study was a population-based retrospective cohort study on a cohort of 8061 patients with insom-
nia and a control cohort of 16,112 patients (matched by age, sex, and year of diagnosis) from the Taiwan
Keywords: National Health Insurance Research Database for the 2000–2010 period.
Insomnia
Overall incidence of pneumonia was 50.6 per 1000 person-years in the insomnia cohort, which was
Pneumonia
significantly higher than that in the control cohort (30.9 per 1000 person-years). Overall, the insomnia
Retrospective cohort study
Infectious disease cohort exhibited a higher risk of pneumonia (HR = 2.43; CI, 2.24–2.62). By age group, the risk of pneumonia
was significantly higher in the insomnia cohort for those aged ≤40 years (HR = 3.23, CI: 1.38–7.57), 41–65
years (HR = 2.62, CI: 2.07–3.32), and >65 years (CI: 2.21–2.61).
Compared with the controls, the insomnia cohort exhibited a higher risk of pneumonia, particularly in
young adults.
© 2017 The Authors. Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University
for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction ular pathway by which sleep disturbance may influence immune

Insomnia is a common sleep disorder. In Taiwan, more than 25%
of adults have experienced insomnia symptoms [9]. The association
between insomnia and chronic disease, such as type 2 diabetes [25],
hypertension (HT) [24], and acute myocardial infarction [14], has
been extensively investigated. Despite the support for this associa-
tion, the association between insomnia and infectious diseases has
been relatively less studied.
Sleep plays major role in the regulation of the immune sys-
tem function in humans. Previous studies have demonstrated that
acute sleep deprivation is associated with the decrease in killer
cell, monocyte and neutrophil, and phagocytic cell counts [8,22].
One study identified nuclear factor-kappa B activation as a molec-
∗ Corresponding author.
E-mail address: chienwu@ndmctsgh.edu.tw (W.-C. Chien).
1
Address: No. 161, Sec. 6, Ming-Chuang E. Rd., Neihu Dist., Taipei City 114, Taiwan.
Fax: +886 2 87923147.
system expression and the risk of inflammation-related disease [8].
Insomnia has affects both sleep quality and duration. Previ-
ous studies have mostly focused on the association between short
sleep durations and respiratory infection. For example, Prather et al.
demonstrated that a shorter sleep duration (measured behaviorally
using an actigraphy) was associated with a greater risk of cold fol-
lowing experimental exposure to rhinovirus [19]. An observational
study revealed that sleep duration exhibited a U-shaped associa-
tion with pneumonia development risk in the female population
[17]. A recent study demonstrated that short sleep duration, sleep
disorder, and sleep disturbances were associated with a higher
probability of developing a cold or respiratory infection [20].
However, few studies have explored the long-term effects of
sleep disorders such as insomnia on pneumonia. Therefore, the
present study investigated this risk in a cohort of patients with
insomnia and compared it with that in a cohort of without insomnia
by using the Taiwan National Health Insurance Database (NHIRD).

http://dx.doi.org/10.1016/j.jiph.2017.08.002
1876-0341/© 2017 The Authors. Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Lin C-L, et al. Risk of pneumonia in patients with insomnia: A nationwide population-based retro-
spective cohort study. J Infect Public Health (2017), http://dx.doi.org/10.1016/j.jiph.2017.08.002
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Fig. 1. The flowchart of study sample selection from National Health Insurance Research Database in Taiwan.
Materials and methods
Participants
Taiwan’s National Health Insurance (NHI) program was
launched as a single-payer system on March 1, 1995. As of 2014,
the NHI program provides insurance for 99.9% of Taiwan’s popula-
tion. In the present study, data were collected from the Longitudinal
Health Insurance Database 2005 (LHID2005), a subset of the NHIRD.
The LHID2005 comprises 1 million people randomly selected from
the NHIRD. To protect patient privacy, the National Health Research
Institutes encrypted all personal identification numbers before
releasing the LHID2005. In the LHID2005 dossier, the disease diag-
nosis codes are based on the International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-CM). This study was
approved by the Ethics Review Board of National Taiwan University
(IRB No. 201412130W).
The present study applied a retrospective cohort study design.
The study cohort comprised patients aged ≥20 years who had
received a diagnosis of insomnia between 2000 and 2005. They
were identified according to the corresponding ICD-9 code (780.52;
insomnia, unspecified). For the control cohort, we randomly
selected patients without a history of insomnia. The insomnia and
control cohorts were frequency-matched by age (5-year spans), sex,
and year of diagnosis (Fig. 1).
Outcome measures
All study individuals were followed up from the index date until
the onset of pneumonia (ICD-9-CM 480–486) in the subset file from
the LHID2005, withdrawal from the NHI program, or the end of
2010, whichever occurred first.
Variable definitions
The individuals were grouped by sex, urbanization level (low,
medium, and high; according to their registered address with the
NHI) [15], and season of diagnosis outcome (spring, March–May;
summer, June–August; autumn, September–November; and win-
ter, December–February). The comorbidities considered in this
study were asthma (ICD-9-CM code 493), chronic kidney disease
(CKD; ICD-9-CM codes 585.3, 585.4, 585.5, and 585.9), chronic
obstructive pulmonary disease (COPD; ICD-9-CM codes 490–496),
cardiovascular disease (CVD; ICD-9-CM codes 410–414), depres-
Please cite this article in press as: Lin C-L, et al. Risk of pneumonia in patients with insomnia: A nationwide population-based retro-
spective cohort study. J Infect Public Health (2017), http://dx.doi.org/10.1016/j.jiph.2017.08.002
sion (ICD-9-CM codes 296.2, 296.3, 300.4, and 311), HT (ICD-9-CM
codes 401–405), and stroke (ICD-9-CM codes 430–438). Individu-
als with any of the aforementioned comorbidities were classified
as having a comorbidity.
Statistical analysis
Descriptive statistics were used for basic information, including
the percentage, mean, and standard deviation. Chi-squared and t
tests were used to evaluate the distributions of categorical and con-
tinuous variables between the insomnia and control cohorts. The
incidence densities of pneumonia were calculated according to age,
sex, urbanization level, season of diagnosis outcome, and comor-
bidity. Cox proportional hazards regression models were used to
determine the risk of pneumonia, and the results are presented as
hazard ratios (HRs) with a 95% confidence interval (CI). The same
variables were used in a multivariable analysis. All analyses were
performed using SPSS version 21 (SPSS, Inc., Chicago, IL, USA).
Results
Demographic data
Demographic data of the study participants are presented in
Table 1. The insomnia and control cohorts comprised 8061 and
16,112 patients, respectively. Most patients were older than 65
years (46.8% and 48.5% in the insomnia and control cohorts, respec-
tively) and male. The main comorbidity in the insomnia cohort was
COPD (23.2%) and that in the control cohort was HT (17.5%). In both
cohorts, most patients were classified as living in a medium urban-
ization level (41.5% vs. 44.5%). The average follow-up duration was
3.5 (SD 2.9) years for the insomnia cohort and 3.7 (SD 3.6) years for
the control cohort.
Incidence rates and adjusted HR of pneumonia by age, sex,
urbanization level, and comorbidities
The incidence rates and adjusted HRs of pneumonia by age,
sex, urbanization level, and comorbidities are presented in Table 2.
During the follow-up period, the pneumonia incidence rate in the
insomnia cohort was significantly higher than that in the control
cohort (50.6 vs. 30.9 per 1000 person-years), and the risk of pneu-
monia was 2.43 times higher in the insomnia cohort than in the
control cohort (adjusted HR, 2.43 [95% CI, 2.24–2.62]).
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Table 1
Demographic data for the study participants.

Insomnia

With (N=8 061) Without (N=16 122) P value

N % N %

Age (y) 0.011*

≤40 1,274 15.8 3,028 18.8
41-65 3,011 37.4 5,271 32.7
>65 3,776 46.8 7,823 48.5
Gender 0.999
Male 4,682 58.1 9,364 58.1
Female 3,379 41.9 6,758 41.9
Comorbidities
Asthma 220 2.7 286 1.8 <0.001***
CKD 184 2.3 535 3.3 <0.001***
COPD 1,872 23.2 1,852 11.5 <0.001***
CVD 782 9.7 1,437 8.9 0.024*
Depression 434 5.4 92 0.6 <0.001***
HT 1,564 19.4 2,821 17.5 <0.001***
Stroke 674 8.4 1,424 8.8 0.114
Urbanization level <0.001***
Low 2,938 36.4 3,758 23.3
Middle 3,347 41.5 7,173 44.5
High 1,776 22.0 5,191 32.2
Follow–up period (y) 3.5 ± 2.9 3.7 ± 3.6 0.051

Total follow-up period: 3.6 ± 3.4.

Abbreviations: y, years; CVD, cardiovascular disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary diseases; HT, hypertension.
*p < 0.05; ***< 0.001.

Table 2
Incidence rates and adjusted HR of pneumonia by age, gender, urbanization level and comorbidities.

Variable With insomnia Without insomnia

a
Event PY IR Event PY IRa Adjusted HR c , d (95% CI)

Overall 1447 28,572.0 50.6 1825 59,073.3 30.9 2.425*** (2.243–2.622).

Age (y)
≤40 28 4178.8 6.7 7 6800.7 1.0 3.228** (1.376–7.571)
41–65 206 11,952.6 17.2 110 18,724.8 5.9 2.620*** (2.067–3.321)
>65 1213 12,440.7 97.5 1168 33,547.8 34.8 2.403*** (2.211–2.612)

Gender
Male 1160 15,142.1 76.6 997 33,748.2 29.5 2.602*** (2.382–2.842)
Female 287 13,429.9 21.4 288 25,325.2 11.4 1.863*** (1.574–2.204)

Urbanization level
Low 641 10,561.6 60.7 308 15,067.6 20.4 3.130*** (2.719–3.602)
Middle 626 11,788.4 53.1 630 26,707.4 23.6 2.332*** (2.082–2.612)
High 180 6221.9 28.9 347 17,298.3 20.1 1.755*** (1.460–2.111)

Seasons
Spring 376 5829.1 64.5 345 13,356.5 25.8 2.416*** (2.075–2.813)
Summer 341 7168.4 47.6 285 14,992.6 19.0 2.544*** (2.516–3.002)
Autumn 358 9111.6 39.3 321 17,138.7 18.7 2.361*** (2.020–2.759)
Winter 372 6462.9 57.6 334 13,585.5 24.6 2.442*** (2.094–2.848)

Comorbiditiesb
No 0 15,201.9 0 0 32,752.6 0 –
Yes 1447 13,370.1 108.2 1285 26,320.7 48.8 2.425*** (2.243–2.622)

Abbreviations: PY, person-years; IR, incidence rate; HR, hazard ratio; CI, confidence interval; y, years.
**p < 0.01; ***< 0.001.
a
Indicates the IR per 1000 person-years.
b
Indicates a patient with any of the comorbidities that were classified as the comorbidities group.
c
Indicates adjustment for age, gender, urbanization level, period, and presence of comorbidities.
d
“With insomnia” compared with “Without insomnia (reference)”.

Table 3
Cumulative incidence rate of pneumonia in the follow-up period with and without insomnia.

Insomnia Follow-up time (y) 1 2 3 4 5 6 7 8 9 10 11

With n 653 916 1093 1214 1296 1351 1401 1433 1440 1446 1447
% 8.1 11.4 13.6 15.1 16.1 16.8 17.4 17.8 17.9 17.9 18.0

Without n 366 566 709 820 931 1024 1104 1179 1214 1249 1285
% 2.3 3.5 4.4 5.1 5.8 6.4 6.8 7.3 7.5 7.7 8.0

Difference 5.8 7.9 9.2 10.0 10.3 10.4 10.5 10.5 10.3 10.2 10.0

Please cite this article in press as: Lin C-L, et al. Risk of pneumonia in patients with insomnia: A nationwide population-based retro-
spective cohort study. J Infect Public Health (2017), http://dx.doi.org/10.1016/j.jiph.2017.08.002
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Fig. 2. Kaplan–Meier for cumulative risk of pneumonia among aged 20 and over
stratified by insomnia with log-rank test.
When the patients were divided into three age groups of ≤40,
41–65, and >65 years, the risk of pneumonia in the insomnia cohort
was significantly higher for all ages groups. By sex, both men and
women in the insomnia cohort were at a significantly higher risk
of pneumonia compared with the control cohort (adjusted HRs:
2.60 [95% CI, 2.38–2.84] and 1.86 [95% CI, 1.57–2.20]). By urbaniza-
tion level and season of diagnosis, the risk of pneumonia was also
higher in the insomnia cohort. Furthermore, among patients with
comorbidities, the risk of pneumonia was significantly higher in the
insomnia cohort than in the control cohort (adjusted HR: 2.43 [95%
CI, 2.24–2.62]).
Incidence rates and adjusted HRs of pneumonia by follow-up years
We conducted a Kaplan–Meier survival analysis to assess the
cumulative incidence. We observed that the differences in the
cumulative incidence of pneumonia between the insomnia and
control cohorts were 5.8, 10.3, and 10.0% in the 1st, 5th, and 11th
year of follow-up (Table 3), and these differences were significant
(log-rank test; P < 0.001; Fig. 2).
Discussion
In the present study, we observed that the insomnia cohort was
associated with an increased risk of incident pneumonia compared
with those the controls. According to our review of relevant liter-
ature, no study has investigated the association between insomnia
and pneumonia in an adult population. Previous studies have
reported that insomnia affects sleep quality and duration and that
insomnia is associated with an increased probability of respiratory
infections such as the common cold and pneumonia [17,3,19,20].
Moreover, one study suggested that a short sleep duration may
negatively influence antibody responses to novel antigens, and
inadequate sleep patterns increase the susceptibility to infectious
diseases [18]. Because of growing evidence that sleep problems are
associated with infectious diseases, insomnia has become a notable
public health concern in modern societies.
Although the main mechanism underlying the association
between insomnia and pneumonia remains unclear, inferences
from previous studies may provide some explanation. First, sleep
deprivation has been reported to be associated with activated
proinflammatory processes, elevated C-reactive protein levels
[16], decreased natural killer cell activity [5], and suppressed
Please cite this article in press as: Lin C-L, et al. Risk of pneumonia in patients with insomnia: A nationwide population-based retro-
spective cohort study. J Infect Public Health (2017), http://dx.doi.org/10.1016/j.jiph.2017.08.002
interleukin-2 response [26]. Second, previous studies have demon-
strated that sleep plays a role in modulating immune system
responses [1,12]. For example, individuals with partial sleep restric-
tion were shown to exhibit significantly decreased T cell cytokine
production [6]. Third, inadequate sleep duration can reduce the
release of immune-stimulating hormones, such as growth hor-
mone, prolactin, and dopamine, which may affect immune system
function [13] and the performance of pro-inflammatory cytokine
genes, IL-6 mRNA and TNF-␣ mRNA [7]. In addition, sleep depriva-
tion may influence antibody titers following vaccination [13]. These
biological mechanisms evidence the crucial role of sleep in immune
responses and the susceptibility to infectious diseases.
Several studies have demonstrated the association of sleep
problems with the risk of chronic diseases such as type 2 dia-
betes [11], obesity [2], and CVD [14]; all chronic diseases may
increase probability of developing pneumonia. Individuals with
partial sleep restriction have a higher risk of metabolic disorders
and may present imbalances in the endocrine environment such as
increased insulin resistance, decreased insulin sensitivity, orexin
imbalance, and inflammatory disorder; thus, sleep plays a vital role
in the pathophysiology of metabolic disorders [21,23]. The factors
contributing to infectious diseases involve complex risks. Addi-
tional studies are warranted to elucidate the direct and indirect
effects of sleep on infectious disease development.
The present study demonstrated that young adults (≤40 years)
with insomnia predominantly had a higher risk of pneumonia.
However, we could not confirm the actual mechanism and inferred
only potential explanations from previous studies. Young adults
with chronic sleep loss exhibit a higher risk of metabolic diseases,
such as type 2 diabetes [11], obesity [29], and HT [24], which may
increase the probability of pneumonia. However, because a previ-
ous study suggested that the impact of inadequate sleep patterns
on health outcomes has been underestimated, particularly in young
populations [23], this finding requires further investigation.
The strengths of the present study are its population-based
design, generalizability of the findings, and use of well-validated
cohort data with a large sample. This is the first study to propose
that chronic insomnia is associated with an increased risk of pneu-
monia. Although a previous study reported similar results [17], that
study was limited to females and not applicable to the general
population.
Several potential limitations of the present study must be dis-
cussed. First, the NHIRD does not provide detailed information
regarding patient factors and many potential confounders, such
as lifestyle factors, physical activity, smoking, and alcohol use,
were not controlled in this analysis, which may have resulted
in residual confounding. Second, we could not control obesity or
sleep-disordered breathing in the present study, although a previ-
ous study reported an association between sleep apnea syndrome
and C-reactive protein levels [4]. Third, the Taiwan NHI program
not provides free pneumonia and influenza vaccine to general pop-
ulation and only selected groups, previous studies have reported
that receiving an influenza vaccine can reduce the risk of respi-
ratory infection [27,28]; however, we could not confirm whether
the preventive vaccines for respiratory infections altered the effect
of sleep disturbances on pneumonia. Fourth, the present study did
not consider the subtypes of insomnia, which may have caused bias
in determining the association between insomnia and pneumonia.
Fifth, because of growing evidence that benzodiazepines, which are
often prescribed to treat insomnia, are associated with an elevated
infection risk [10], future studies should consider investigating the
hypnotics effect between sleep disturbance and infectious diseases.
In conclusion, the present study to indicate that insomnia is
associated with an increased risk of pneumonia. When examining
patients (particularly young adults), clinical practitioners should
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pay more attention to the association between inadequate sleep
and the risk of infectious disease.
Funding
No funding sources.
Competing interests
None declared.
Ethical approval
Not required.
Acknowledgment
The authors thank the National Health Research Institute of
Taiwan for providing the insurance claims data.
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