Risk of acute epiglottitis in patients with preexisting diabetes mellitus: A population-based case–control study
Risk of acute epiglottitis in patients with preexisting diabetes mellitus: A population- based case±control study
Yao-Te Tsai 0 1
Ethan I. Huang 0 1
Geng-He Chang 0 1
Ming-Shao Tsai 0 1
Cheng- Ming Hsu 0 1
Yao-Hsu Yang 0
Meng-Hung Lin 0
Chia-Yen Liu 0
Hsueh-Yu Li 0
0 Editor: Yu Ru Kou, National Yang-Ming University , TAIWAN
1 Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital , Chiayi, Taiwan , 2 College of Medicine, Chang Gung University , Taoyuan, Taiwan , 3 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital , Chiayi, Taiwan , 4 Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health , Taipei, Taiwan , 5 School of Traditional Chinese Medicine, College of Medicine, Chang Gung University , Taoyuan, Taiwan , 6 Health Information and Epidemiology Laboratory, Chang Gung Memorial Hospital , Chiayi, Taiwan , 7 Department of Otolaryngology±Head and Neck Surgery, Linkou Chang Gung Memorial Hospital , Taoyuan , Taiwan
Data Availability Statement: The data underlying
this study is from the National Health Insurance
Research Database (NHIRD), which has been
transferred to the Health and Welfare Data Science
Center (HWDC). Interested researchers can obtain
the data through formal application to the HWDC,
Department of Statistics, Ministry of Health and
Funding: The authors received no specific funding
for this work.
Of the 2,393 patients, 180 (7.5%) had preexisting DM, whereas only 530 (5.5%) of the 9,572
controls had preexisting DM. Multivariate logistic regression analyses indicated that
preexisting DM was significantly associated with acute epiglottitis (adjusted odds ratio [aOR] =
1.42, 95% confidence interval [CI] = 1.15±1.75, P = 0.004). Subgroup analysis showed that
the association between DM and epiglottitis remained significant for men (aOR = 1.57, 95%
CI: 1.19±2.08, p = 0.002) but not for women. Age-stratified analysis revealed a significant
association between DM and acute epiglottitis in patients aged 35±64 years. Use of
anti-diabetic agents was not significantly associated with the development of acute epiglottitis
Competing interests: The authors have declared
that no competing interests exist.
among diabetic patients, including oral hypoglycemic agents (OHA) alone (aOR = 0.88,
95% CI = 0.53±1.46, p = 0.616), and OHA combined with insulin/ insulin alone (aOR = 1.30,
95% CI = 0.76±2.22, p = 0.339). The association between presence of diabetes
complications and the occurrence of acute epiglottitis was also not significant among diabetic patients
in this study setting (aOR = 0.86, 95% CI = 0.59±1.26, p = 0.439).
The results of our large-scale population-based case±control study indicate that preexisting
DM is one of the possible factors associated with the development of acute epiglottitis.
Physicians should pay attention to the symptoms and signs of acute epiglottitis in DM patients,
particularly in men aged 35±64 years.
Epiglottitis is the acute inflammation of the supraglottic region, including the epiglottis,
arytenoids, and aryepiglottic folds. It is a true airway emergency, and without timely intervention,
the supraglottic swelling may lead to life-threatening airway obstruction[
] and severe
complications such as sepsis, meningitis,[
] necrotizing fasciitis, and mediastinitis.[5±8] The
risk factors for epiglottitis include old age, the male sex, obesity, a preexisting epiglottic cyst,
and an impaired host immune system.[9±11] Infected epiglottic cysts and impaired immunity
have also been reported to increase the risk of recurrent episodes.[
] The most common
pathogens implicated in acute epiglottitis are bacteria such as type-b Haemophilus influenzae,
alpha- and beta-hemolytic streptococci, Staphylococcus aureus, Escherichia coli, Enterobacter,
Klebsiella pneumoniae, and other H. influenzae species. Other reported causes include viral
infections, fungal infections, trauma by a foreign body, inhalation burns, and chemical
] However, despite detailed investigation, a specific pathogen can be identified from
blood or throat cultures in only 10%±25% of patients with epiglottitis.[
] The incidence of
pediatric epiglottitis dropped dramatically after routine use of the H. influenzae type-b (Hib)
vaccine in childhood vaccination programs.[16±20] However, the incidence of acute
epiglottitis in adults has been either increasing[
2, 12, 16, 21
] or remaining constant.[
] Shah et al.
conducted an 8-year retrospective review of epiglottitis admissions from 1998 to 2006 and
concluded that epiglottitis continues to be a significant clinical entity in the United States and that
the incidence of adult epiglottitis is increasing in two groups: those 45±64 years of age and
those older than 85 years. A common perception is that in the Hib vaccine era, acute
epiglottitis has become a disease of adults and that the pathogens of epiglottitis have shifted to
those other than Hib.[
] A considerable number of adult patients with epiglottitis have
preexisting medical conditions at diagnosis, such as diabetes mellitus (DM), hypertension, and
alcohol abuse, which may weaken their immunity and increase their susceptibility to
12, 15, 22, 25
Studies has revealed that 3.5%±26.6% of patients with epiglottitis have comorbid DM,[
] and some have life-threatening complications with a fulminant clinical course [
Moreover, studies have indicated that the severity of epiglottitis is higher in patients with DM
due to the higher 2-day mortality and the elevated risk of airway obstruction necessitating
intervention in such patients than in those without DM.[
9, 11, 21, 22, 30
] Nevertheless, a
quantitative relationship between DM and acute epiglottitis has not been established in pediatric or
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adult patients due to the disease rarity. In the present population-based study, our aim was to
explore the relationship between preexisting DM and acute epiglottitis in different age and sex
groups by using data from the National Health Insurance Research Database (NHIRD) in
Material and methods
The study protocol was reviewed and approved by the Institutional Review Board (IRB) of
Chang Gung Memorial Hospital (approval no. 201701635B1). Since the NHIRD contains only
de-identified secondary data, the IRB waived the requirement of informed consent.
The Taiwanese government implemented a compulsory National Health Insurance (NHI)
program in March 1995, which is a nationwide health care system and provides medical
services for the country's 23.5 million residents. It covers over 99% of the population in Taiwan
and records clinical diagnosis according to the International Classification of Diseases, Ninth
Revision, Clinical Modification (ICD-9-CM) codes.[
] All claims data are collected in the
NHIRD, which contains encrypted personal information and provides various medical data
including records of registration, ambulatory and inpatient care, catastrophic illness, surgical
procedure, and medication.
The data used in this study originated from the Longitudinal Health Insurance Database
2005 (LHID2005), which is a representative database of the NHIRD. The LHID2005 includes
all the medical claims (1996±2013) of 1 million individuals randomly selected from the 2005
Registry of Beneficiaries of the NHIRD by using a systematic sampling method, representing
approximately 5% of all people in Taiwan. According to the Taiwan National Health Research
Institutes reports, no statistically significant differences exist in age, sex, or health care costs
between the sample group and all enrollees in the LHID2005.[
Study design and participants
We categorized patients into an acute epiglottitis (case) group and a nonepiglottitis (control)
group. Patients who met the following criteria were selected into the case group: (1) diagnosed
as having acute epiglottitis based on the ICD-9-CM code 464.3, 464.30, or 464.31 by an
otolaryngologist; (2) had two or more ambulatory visits or at least one inpatient visit for acute
epiglottitis; and (3) had no concomitant deep neck infectionÐthat is, ICD-9 code 528.3 (cellulitis
and abscess of oral soft tissues), 478.22 (parapharyngeal abscess), 478.24 (retropharyngeal
abscess), or 682.11 (cellulitis and abscess of neck) (Fig 1).[
] For each of these patients, the
date of initial epiglottitis diagnosis was assigned as the index date. To increase statistical
power, for each case identified on the index date, we randomly selected four individuals
without acute epiglottitis as controls on the same day. Both cases and controls were identified from
the LHID2005 with records between January 1, 2000, and December 31, 2013. The groups
were frequency matched for sex, age, urbanization level, and income.
DM in both cases and controls was assessed on the basis of at least three outpatient claims or
at least one inpatient claim of ICD-9 Code 250.xx. Other medical conditions potentially
associated with acute epiglottitis, including asthma (ICD-9-CM code: 493.xx), chronic liver disease
and cirrhosis (ICD-9-CM code: 571.xx), coronary artery disease (ICD-9-CM codes: 410±414),
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Fig 1. Flow diagram of the study. ICD-9-CM. International Classification of Diseases, Ninth Revision, Clinical
hypertension (ICD-9-CM codes: 401±405), and pneumonia and influenza (ICD-9-CM codes:
480±488), upper digestive tract cancer (ICD-9-CM codes: 141±151), autoimmune diseases
(ICD-9-CM codes: 714.0, 720, 720.0, 710.0, 370.33, 710.2, 710.1), chronic obstructive
pulmonary disease (COPD, ICD-9-CM codes: 490±496), alcohol dependence and abuse
(ICD-9CM codes: 303, 303.xx, 305.0, 305.0x), corrosive injury of upper digestive tract (ICD-9-CM
codes: 947.0±947.3), and gastroesophageal reflux disease (GERD, ICD-9-CM codes: 530.11,
530.81,530.85) were also assessed from the claims data[11, 13, 15, 26, 27, 33±37]. We included
these comorbidities if they occurred either in the inpatient setting or in more than three
ambulatory care claims. Comorbidities of each individual were all identified before the index date or
matched index date, and each comorbidity was analyzed as a binomial variable.
In addition, adapted Diabetes Complications Severity Index (aDCSI) was computed to
represent the presence of diabetes complications[
]. The aDCSI includes following
seven categories of diabetes complications: cardiovascular disease, nephropathy, retinopathy,
peripheral vascular disease, cerebrovascular disease, neuropathy, and metabolic disease.
Events were identified by using ICD-9-CM codes from both inpatient and outpatient records.
Complications severity index was categorized into 2 or 3 levels (no abnormality = 0, some
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abnormality = 1, severe abnormality = 2), and neuropathy is the only complication with 2
levels (not present = 0, abnormal = 1). A total score of 0~13 was possible for the aDCSI score
The distributional properties of continuous variables are presented as mean and standard
deviation, and categorical variables are presented as frequency and percentage. We evaluated the
distributions of sex, age, urbanization level of patient's residence, insured amount, and
comorbidities between cases and controls by using the chi-squared test. The prevalence of diabetes
was the main outcome of interest of this study. To reduce potential confounders, a logistic
regression analysis was performed to evaluate the risk of epiglottitis associated with DM and
various comorbidities (after adjustment for age, sex, urbanization level, insured amount, and
comorbidities). All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC),
and statistical significance was set at a two-sided P value of < 0.05.
Between 2000 and 2013, 2,393 newly coded patients with acute epiglottitis met the criteria for
cases, and 9,572 individuals were matched as controls. Table 1 presents the intergroup
demographic characteristics. No significant differences in sex, age, urbanization level, or income
were observed between the groups because of frequency matching on these variables. The
mean age for the total 11,965 patients was 33.6 years (standard deviation = 23.3 years). Half of
the individuals were under 34 years old, and only 10.2% of the patients were over 65 years old.
Among the 2,393 patients with acute epiglottitis, 180 (7.5%) had underlying DM, whereas 530
(5.5%) of the 9,572 controls had DM (p < .001). Most DM patients in both case and control
groups were type 2 DM. Compared with the control group, the epiglottitis group had a higher
incidence of asthma, chronic liver disease, coronary artery disease, and pneumonia and
influenza, chronic obstructive pulmonary disease (COPD), autoimmune diseases, alcohol
dependence and abuse, gastroesophageal reflux disease (GERD), and upper digestive tract cancer.
Table 2 presents the results of the multivariate logistic regression analyses. After adjustment
for age, sex, urbanization level, income, and comorbidities, results from the multivariable
logistic regression analyses indicated that underlying DM was associated with acute epiglottitis
(adjusted odds ratio [aOR] = 1.42, 95% confidence interval [CI] = 1.15±1.75, p = 0.004). Other
comorbidities including pneumonia and influenza, COPD, autoimmune diseases, GERD, and
upper digestive tract cancer also showed significant associations with acute epiglottitis. The
subgroup analysis showed that the association between DM and epiglottitis remained
significant for men (aOR = 1.57, 95% CI: 1.19±2.08, p = 0.002) but not for women (aOR = 1.23, 95%
CI = 0.91±1.68, p = 0.181). Age-stratified analysis revealed remarkable associations between
DM and epiglottitis among those aged 35±49 years (aOR = 2.12, 95% CI = 1.29±3.48, p =
0.003) and 50±64 years (aOR = 1.52, 95% CI = 1.10±2.09, p = 0.011).
Table 3 lists the stratified analysis for the association between acute epiglottitis and DM
with different definition of preexisting DM duration before the index date. After adjusting for
the demographic factors and comorbidities, the association remained significant and constant
when the underlying DM was diagnosed at least 3 months, 6 months, 1 year, and 3 years before
the occurrence of acute epiglottitis (aOR = 1.28, 1.28, 1.27, 1.23; p = 0.023, 0.026, 0.032, and
Table 4 lists the Odds ratios for acute epiglottitis with regards to anti-diabetic agents and
diabetes related complications among diabetic patients in this study setting. Compared to the
diabetic patients who did not receive anti-diabetic agents before the index date, the adjusted
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Abbreviations: NTD, New Taiwan dollar. COPD indicates chronic obstructive pulmonary disease; GERD,
gastroesophageal reflux disease.
OR of epiglottitis was 1.02 (95% CI = 0.63±1.65. p = 0.929) for those who did take anti-diabetic
agents before the index date. Use of anti-diabetic agents was not significantly associated with
the development of acute epiglottitis among diabetic patients, including oral hypoglycemic
agents (OHA) alone (aOR = 0.88, 95% CI = 0.53±1.46, p = 0.616), and OHA combined with
insulin/ insulin alone (aOR = 1.30, 95% CI = 0.76±2.22, p = 0.339). The association between
presence of diabetes complications and the occurrence of acute epiglottitis was also not
significant among diabetic patients in this study setting (aOR = 0.86, 95% CI = 0.59±1.26,
p = 0.439).
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Abbreviations: OR, odds ratio; CI, confidence interval
The model was adjusted for sex, age, urbanization level, income, and comorbidities.
PLOS ONE | https://doi.org/10.1371/journal.pone.0199036
To the best of our knowledge, this population-based case±control study is the first to elucidate
the quantitative relationship between DM and acute epiglottitis. By using the nationwide
population-based database, we overcame the difficulty of recruiting patients with a disease of low
incidence and identified adequate numbers of epiglottitis cases with minimal selection bias,
and this is because all health care services are covered by the NHI program in Taiwan. Based
Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; OHA, oral hypoglycemic agents; DM, diabetes mellitus; aDCSI, adapted Diabetes Complications
²Data were adjusted for sex, age, urbanization level, income, and comorbidities.
p value of chi-squared test.
aP-value of multivariate logistic analyses
b include OHA combined with insulin and insulin alone
on the power of the large sample size, our study provides robust evidence for the higher odds
ratio of underlying DM in patients with epiglottitis than in those without. To consider the
effects of potential confounders, we used multivariate logistic regression after adjustment for
comorbidities, including asthma, chronic liver disease, coronary artery disease, hypertension,
and pneumonia/influenza, upper digestive tract cancer, autoimmune diseases, COPD, alcohol
dependence and abuse, corrosive injury of upper digestive tract, and GERD, to compare the
outcomes of the case and control groups. The association between DM and acute epiglottitis
remained significant even after adjustment for a variety of comorbidities, and remained
constant with different preexisting DM duration before the index date. Based on the results of this
case control study, several comorbidities, including pneumonia and influenza, COPD, GERD,
autoimmune diseases, and upper digestive tract cancer were also associated with the
development of acute epiglottitis (Table 2). Therefore, it must be cautious in the interpretation of
these results: although preexisting DM is a significant factor associated with the development
of acute epiglottitis, other factors can play a role in contributing to the acute epiglottitis due to
its multi-factorial characteristics. Subgroup analyses elucidated the significant associations
between DM and acute epiglottitis in men and patients aged 35±64 years. By analyzing the use
of anti-diabetic agents and aDCSI among diabetic patients in this study setting, we tried to
correlate the severity of DM with occurrence of acute epiglottis. We found that among diabetic
patients, taking anti-diabetic agents or not was not significantly associated with the
development of acute epiglottitis. Similarly, patients with diabetes-related complications were not
associated with increased occurrence of acute epiglottitis as compared to those without
complication. These findings suggested the importance of blood glucose control and active
management of diabetes complications regarding the occurrence of acute epiglottitis. In the future,
prospective clinical trials are mandatory to elucidate the causal relationship between severity
of DM and the development of acute epiglottitis.
Numerous studies have demonstrated epiglottitis to occur predominantly in men (54%±
1, 15, 22, 30, 35, 36, 41, 42
] In the present study, the subgroup analysis showed a
significant association between DM and epiglottitis in men but not in women, supporting the
malepredominant incidence in epiglottitis patients with DM as previously reported; however,
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the underlying mechanism remains unclear. Studies revealed that men are more susceptible
than women to most kinds of respiratory tract infections in adults and children[
of androgens in the regulation of the immune system and disease resistance genes may
contribute to the observed sex differences in the association between DM and epiglottitis[43±46].
Lifestyle, behavioral, and socioeconomic differences between men and women may also
explain the observed findings[
The present study identified a significant association between DM and epiglottitis in
patients aged 35±64 years, perhaps because patients in this age group tend to be relatively
healthy with fewer comorbidities. Notably, a large number of patients with epiglottitis were
younger than 34 years in this study (Table 2). However, patients with epiglottis in this age
group had DM less frequently, and no statistical significance was observed. In patients aged
older than 65 years, the weakened immune responses by aging and increased underlying
comorbidities may further attenuate the influence of DM on the risk of developing epiglottitis.
Studies have revealed that 3.5%±26.6% of patients with epiglottis have comorbid DM.[
15, 23, 25, 27, 30
] However, this association was never verified due to the disease rarity and the
lack of control subjects for testing the corresponding statistical significance. In this study, we
identified a significant association between DM and epiglottitis, which may be explained by
the altered immunity from depressed polymorphonuclear leukocyte function[48±50]and
decreased leukocyte adherence and phagocytic activity[
] that make the patient more
susceptible to acute epiglottitis. In addition, the most frequent respiratory tract infection
associated with DM is caused by S. pneumoniaeÐthe most important bacterial etiology of acute
epiglottitis in both adults[
] and vaccinated children.[
] Therefore, we assume that the
common respiratory infection in patients with DM and in epiglottitis shared the same
pathogen, which may lead to the increased risk of epiglottitis among patients with DM and must be
corroborated by future investigations. These findings suggest that underlying DM may play a
role in the pathogenesis or pathophysiology of acute epiglottitis, which makes patients with
DM more susceptible to acute epiglottitis.
Previous study indicated that the severity of epiglottitis is higher in DM patients due to the
increased two days mortality and airway intervention rates.[
] A recent study reported that
the outcome of critical epiglottitis patients was favorable if early respiratory tract protection
could be adequately performed.[
] Therefore, identifying the risk factors for DM patients
with epiglottitis who will probably require airway intervention is imperative in clinical
decision-making to avoid fatal complications. Factors associated with an increased risk of airway
obstruction in patients with epiglottitis include DM, stridor, muffled voice, hypoxia, drooling,
rapid clinical course, a high pulse rate, and an epiglottic cyst or abscess.[
9, 11, 21, 22, 30
et al. analyzed 96 adult patients with epiglottitis and proposed that, under flexible
laryngoscopy, severely swollen epiglottis and arytenoid/aryepiglottic folds with less than half of the
posterior vocal folds visible were correlated with the requirement for airway intervention.[
Flexible endoscopy enables early detection of acute epiglottitis and identifies the need for
airway intervention. Those with precarious symptoms/signs and endoscopic findings should be
observed intensively, or the airway should be secured immediately.[
] With appropriate and
timely treatment, the prognosis of acute epiglottitis is usually favorable.[
The major strength of this study is its large population size. To investigate the significance
of underlying DM in the pathogenesis of acute epiglottitis, conducting a single-center study
with a sufficient sample size and adequate follow-up time may not be feasible. The nationwide
insurance claims database enabled us to investigate the risk factors for epiglottitis with a low
selection bias. The statistical power and the precision of risk appraisal were also increased by
the size of the study population. The NHIRD has been reported to be a valid source for
population-based research with regular examinations of the accuracy of medical coding and the
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] However, our study has limitations. First, innate information bias may
exist because all diagnoses of the clinical conditions of interest and other comorbidities were
based on ICD-9-CM codes in the claims records. Second, detailed information regarding the
severity of DM, such as blood glucose levels, HbA1c levels, or dosages of anti-diabetic drugs,
and epiglottitis related test/images were not available in the claims data. Therefore, the
relationship between the severity and treatment outcomes of acute epiglottitis and the level of DM
control could not be evaluated. Third, some suspected contributing risk factors for epiglottitis
were unavailable from the insurance data, such as the personal history of alcohol and cigarette
11, 12, 37
]Ða potential confounder that could not be adjusted for. Finally, we
did not explore the underlying mechanism of the association between DM and acute
epiglottitis. More research is warranted to validate our findings and to assess the association between
the level of DM control and the occurrence and severity of acute epiglottitis.
In conclusion, the findings of this population-based case±control study suggest that DM is
one of the possible factors associated with the development of acute epiglottitis. To achieve an
early diagnosis and avert life-threatening complications of acute epiglottitis, physicians should
always be aware of the symptoms/signs of acute epiglottitis in DM patients, particularly in
men aged 35±64 years.
The authors thank the Health Information and Epidemiology Laboratory (CLRPG6G0041)
and Center of Excellence for Chang Gung Research Datalink (CORPG6D0163) for the
comments and assistance in data analysis. This manuscript was edited by Wallace Academic
Conceptualization: Ethan I. Huang.
Data curation: Yao-Te Tsai, Ming-Shao Tsai, Meng-Hung Lin, Chia-Yen Liu.
Formal analysis: Ming-Shao Tsai, Cheng-Ming Hsu, Yao-Hsu Yang.
Investigation: Cheng-Ming Hsu, Yao-Hsu Yang.
Methodology: Geng-He Chang.
Software: Chia-Yen Liu.
Supervision: Ethan I. Huang, Hsueh-Yu Li.
Validation: Geng-He Chang, Meng-Hung Lin.
Visualization: Yao-Te Tsai.
Writing ± original draft: Yao-Te Tsai.
Writing ± review & editing: Hsueh-Yu Li.
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