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Journal of Infection and Public Health 11 (2018) 270–274

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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


system expression and the risk of inflammation-related disease [8].
Insomnia is a common sleep disorder. In Taiwan, more than 25% Insomnia has affects both sleep quality and duration. Previ-
of adults have experienced insomnia symptoms [9]. The association ous studies have mostly focused on the association between short
between insomnia and chronic disease, such as type 2 diabetes [25], sleep durations and respiratory infection. For example, Prather et al.
hypertension (HT) [24], and acute myocardial infarction [14], has demonstrated that a shorter sleep duration (measured behaviorally
been extensively investigated. Despite the support for this associa- using an actigraphy) was associated with a greater risk of cold fol-
tion, the association between insomnia and infectious diseases has lowing experimental exposure to rhinovirus [19]. An observational
been relatively less studied. study revealed that sleep duration exhibited a U-shaped associa-
Sleep plays major role in the regulation of the immune sys- tion with pneumonia development risk in the female population
tem function in humans. Previous studies have demonstrated that [17]. A recent study demonstrated that short sleep duration, sleep
acute sleep deprivation is associated with the decrease in killer disorder, and sleep disturbances were associated with a higher
cell, monocyte and neutrophil, and phagocytic cell counts [8,22]. probability of developing a cold or respiratory infection [20].
One study identified nuclear factor-kappa B activation as a molec- 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
∗ Corresponding author. by using the Taiwan National Health Insurance Database (NHIRD).
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.

https://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/).
C.-L. Lin et al. / Journal of Infection and Public Health 11 (2018) 270–274 271

Fig. 1. The flowchart of study sample selection from National Health Insurance Research Database in Taiwan.

Materials and methods sex, urbanization level, season of diagnosis outcome, and comor-
bidity. Cox proportional hazards regression models were used to
Participants determine the risk of pneumonia, and the results are presented as
hazard ratios (HRs) with a 95% confidence interval (CI). The same
Taiwan’s National Health Insurance (NHI) program was variables were used in a multivariable analysis. All analyses were
launched as a single-payer system on March 1, 1995. As of 2014, performed using SPSS version 21 (SPSS, Inc., Chicago, IL, USA).
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. Results
The LHID2005 comprises 1 million people randomly selected from
the NHIRD. To protect patient privacy, the National Health Research Demographic data
Institutes encrypted all personal identification numbers before
releasing the LHID2005. In the LHID2005 dossier, the disease diag- Demographic data of the study participants are presented in
nosis codes are based on the International Classification of Diseases, Table 1. The insomnia and control cohorts comprised 8061 and
Ninth Revision, Clinical Modification (ICD-9-CM). This study was 16,112 patients, respectively. Most patients were older than 65
approved by the Ethics Review Board of National Taiwan University years (46.8% and 48.5% in the insomnia and control cohorts, respec-
(IRB No. 201412130W). tively) and male. The main comorbidity in the insomnia cohort was
The present study applied a retrospective cohort study design. COPD (23.2%) and that in the control cohort was HT (17.5%). In both
The study cohort comprised patients aged ≥20 years who had cohorts, most patients were classified as living in a medium urban-
received a diagnosis of insomnia between 2000 and 2005. They ization level (41.5% vs. 44.5%). The average follow-up duration was
were identified according to the corresponding ICD-9 code (780.52; 3.5 (SD 2.9) years for the insomnia cohort and 3.7 (SD 3.6) years for
insomnia, unspecified). For the control cohort, we randomly the control cohort.
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).
Incidence rates and adjusted HR of pneumonia by age, sex,
urbanization level, and comorbidities
Outcome measures

The incidence rates and adjusted HRs of pneumonia by age,


All study individuals were followed up from the index date until
sex, urbanization level, and comorbidities are presented in Table 2.
the onset of pneumonia (ICD-9-CM 480–486) in the subset file from
During the follow-up period, the pneumonia incidence rate in the
the LHID2005, withdrawal from the NHI program, or the end of
insomnia cohort was significantly higher than that in the control
2010, whichever occurred first.
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
Variable definitions
control cohort (adjusted HR, 2.43 [95% CI, 2.24–2.62]).
When the patients were divided into three age groups of ≤40,
The individuals were grouped by sex, urbanization level (low,
41–65, and >65 years, the risk of pneumonia in the insomnia cohort
medium, and high; according to their registered address with the
was significantly higher for all ages groups. By sex, both men and
NHI) [15], and season of diagnosis outcome (spring, March–May;
women in the insomnia cohort were at a significantly higher risk
summer, June–August; autumn, September–November; and win-
of pneumonia compared with the control cohort (adjusted HRs:
ter, December–February). The comorbidities considered in this
2.60 [95% CI, 2.38–2.84] and 1.86 [95% CI, 1.57–2.20]). By urbaniza-
study were asthma (ICD-9-CM code 493), chronic kidney disease
tion level and season of diagnosis, the risk of pneumonia was also
(CKD; ICD-9-CM codes 585.3, 585.4, 585.5, and 585.9), chronic
higher in the insomnia cohort. Furthermore, among patients with
obstructive pulmonary disease (COPD; ICD-9-CM codes 490–496),
comorbidities, the risk of pneumonia was significantly higher in the
cardiovascular disease (CVD; ICD-9-CM codes 410–414), depres-
insomnia cohort than in the control cohort (adjusted HR: 2.43 [95%
sion (ICD-9-CM codes 296.2, 296.3, 300.4, and 311), HT (ICD-9-CM
CI, 2.24–2.62]).
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.
Incidence rates and adjusted HRs of pneumonia by follow-up years
Statistical analysis
We conducted a Kaplan–Meier survival analysis to assess the
Descriptive statistics were used for basic information, including cumulative incidence. We observed that the differences in the
the percentage, mean, and standard deviation. Chi-squared and t cumulative incidence of pneumonia between the insomnia and
tests were used to evaluate the distributions of categorical and con- control cohorts were 5.8, 10.3, and 10.0% in the 1st, 5th, and 11th
tinuous variables between the insomnia and control cohorts. The year of follow-up (Table 3), and these differences were significant
incidence densities of pneumonia were calculated according to age, (log-rank test; P < 0.001; Fig. 2).
272 C.-L. Lin et al. / Journal of Infection and Public Health 11 (2018) 270–274

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
C.-L. Lin et al. / Journal of Infection and Public Health 11 (2018) 270–274 273

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
Fig. 2. Kaplan–Meier for cumulative risk of pneumonia among aged 20 and over population.
stratified by insomnia with log-rank test.
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
Discussion as lifestyle factors, physical activity, smoking, and alcohol use,
were not controlled in this analysis, which may have resulted
In the present study, we observed that the insomnia cohort was in residual confounding. Second, we could not control obesity or
associated with an increased risk of incident pneumonia compared sleep-disordered breathing in the present study, although a previ-
with those the controls. According to our review of relevant liter- ous study reported an association between sleep apnea syndrome
ature, no study has investigated the association between insomnia and C-reactive protein levels [4]. Third, the Taiwan NHI program
and pneumonia in an adult population. Previous studies have not provides free pneumonia and influenza vaccine to general pop-
reported that insomnia affects sleep quality and duration and that ulation and only selected groups, previous studies have reported
insomnia is associated with an increased probability of respiratory that receiving an influenza vaccine can reduce the risk of respi-
infections such as the common cold and pneumonia [17,3,19,20]. ratory infection [27,28]; however, we could not confirm whether
Moreover, one study suggested that a short sleep duration may the preventive vaccines for respiratory infections altered the effect
negatively influence antibody responses to novel antigens, and of sleep disturbances on pneumonia. Fourth, the present study did
inadequate sleep patterns increase the susceptibility to infectious not consider the subtypes of insomnia, which may have caused bias
diseases [18]. Because of growing evidence that sleep problems are in determining the association between insomnia and pneumonia.
associated with infectious diseases, insomnia has become a notable Fifth, because of growing evidence that benzodiazepines, which are
public health concern in modern societies. often prescribed to treat insomnia, are associated with an elevated
Although the main mechanism underlying the association infection risk [10], future studies should consider investigating the
between insomnia and pneumonia remains unclear, inferences hypnotics effect between sleep disturbance and infectious diseases.
from previous studies may provide some explanation. First, sleep In conclusion, the present study to indicate that insomnia is
deprivation has been reported to be associated with activated associated with an increased risk of pneumonia. When examining
proinflammatory processes, elevated C-reactive protein levels patients (particularly young adults), clinical practitioners should
[16], decreased natural killer cell activity [5], and suppressed pay more attention to the association between inadequate sleep
interleukin-2 response [26]. Second, previous studies have demon- and the risk of infectious disease.
strated that sleep plays a role in modulating immune system
responses [1,12]. For example, individuals with partial sleep restric- Funding
tion were shown to exhibit significantly decreased T cell cytokine
production [6]. Third, inadequate sleep duration can reduce the No funding sources.
release of immune-stimulating hormones, such as growth hor-
mone, prolactin, and dopamine, which may affect immune system
Competing interests
function [13] and the performance of pro-inflammatory cytokine
genes, IL-6 mRNA and TNF-␣ mRNA [7]. In addition, sleep depriva-
None declared.
tion may influence antibody titers following vaccination [13]. These
biological mechanisms evidence the crucial role of sleep in immune
Ethical approval
responses and the susceptibility to infectious diseases.
Several studies have demonstrated the association of sleep
Not required.
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 Acknowledgment
partial sleep restriction have a higher risk of metabolic disorders
and may present imbalances in the endocrine environment such as The authors thank the National Health Research Institute of
increased insulin resistance, decreased insulin sensitivity, orexin Taiwan for providing the insurance claims data.
imbalance, and inflammatory disorder; thus, sleep plays a vital role
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