IgE indicates immunoglobulin E; KNHANES V, Korea National Health and Nutrition Examination Survey, fifth edition.
eTable 1. Baseline characteristics of participants with chronic laryngitis and control participants, according to KNHANES 2010-2012
eTable 2. Risk difference for association between sinonasal factors and allergic etiology of laryngitis in KNHANES 2010
eFigure. Schematic diagram showing the association between the participants’ rhinitis symptoms and laryngitis
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Lee K, Young Kang C, Lee H, Choi IH, Lee SH, Kim TH. Association of Sinonasal Factors With Chronic Laryngitis in Korean Adults. JAMA Otolaryngol Head Neck Surg. 2019;145(10):919–925. doi:10.1001/jamaoto.2019.2134
How are various sinonasal factors associated with chronic laryngitis and allergic cause of chronic laryngitis?
In this cross-sectional study of 11 283 participants, among various sinonasal factors associated with prevalence of chronic laryngitis, only the presence of rhinitis symptoms was associated with allergic causes in participants younger than 50 years.
The results of this study suggest that coexistence of rhinitis symptoms could be used as a factor for considering allergic cause of chronic laryngitis in young adults.
Allergic laryngitis is underdiagnosed owing to overlapping clinical manifestations that arise from other causes of laryngitis. Sinonasal conditions associated with chronic laryngitis, including allergic laryngitis, have not been reported using population-based epidemiologic data.
To estimate the association of the prevalence of chronic laryngitis with various sinonasal symptoms and endoscopic findings, and to identify which of the sinonasal factors are particularly associated with allergic cause of chronic laryngitis.
Design, Setting, and Participants
This cross-sectional, population-based study of 11 283 participants 18 years and older who had undergone laryngoscopic and nasal endoscopic examination used data from 2010 through 2012 in the fifth edition of the Korea National Health and Nutrition Examination Survey, a nationwide survey of South Korea. Participants were extracted by stratified, multistage, clustered sampling to comprise a nationally representative sample. Data were analyzed in September 2017.
Sociodemographic characteristics, smoking status, alcohol use, questionnaires for voice change and sinonasal symptoms, and nasal endoscopic examinations before and after shrinkage of the nasal mucosa.
Main Outcomes and Measures
Chronic laryngitis diagnosed by laryngoscopic examination, and allergic cause of laryngitis determined by specific serum immunoglobulin E tests.
Of the 11 283 participants included in the study, the mean (SD) age was 50.1 (16.6) years, and 6365 (56.4%) were women. In total, 343 participants (3.0%) were diagnosed with chronic laryngitis through results of laryngoscopic examination. Chronic laryngitis was associated with a higher rate of rhinitis symptoms (odds ratio [OR], 1.54; 95% CI, 1.21-1.96), anterior/posterior nasal drip (OR, 2.03; 95% CI, 1.38-2.98), nasal congestion (OR, 1.49; 95% CI, 0.99-2.25), endoscopic findings of pale mucosa (OR, 1.74; 95% CI, 1.33-2.28), mucous or puslike discharge (OR, 1.53; 95% CI, 1.08-2.18), and puslike discharge in the middle meatus (OR, 1.85; 95% CI, 1.19-2.88), especially in female participants and participants older than 50 years. Subgroup analysis revealed that all participants with allergic laryngitis showed sensitization to Dermatophagoides farinae, and the allergic laryngitis group (n = 9) had a higher presence of rhinitis symptoms (n = 5; 56%) than did the nonallergic laryngitis group (n = 1 of 12; 8%) among participants younger than 50 years (risk difference, 47%; 95% CI, 4%-78%).
Conclusions and Relevance
The association of various sinonasal factors with chronic laryngitis were prominent in female participants, as well as those 50 years and older. Nevertheless, the presence of rhinitis symptoms in patients with chronic laryngitis was associated with allergic cause of laryngitis solely in participants younger than 50 years. In young adults, presence of rhinitis symptoms might aid in considering allergic laryngitis.
Chronic laryngitis is a condition of laryngeal inflammation with a lifetime incidence of up to 21%.1 The most common presenting symptoms of chronic laryngitis include dysphonia, throat clearing, cough, sore throat, and globus sensation. Various medical conditions, including laryngopharyngeal reflux (LPR), poor laryngeal hygiene, infections, or allergen sensitization, can induce chronic inflammation of the larynx; however, it is difficult to distinguish among the primary causes because their clinical manifestations are similar.2,3
Allergic laryngitis, an inflammatory condition of the larynx caused by sensitized allergens, was initially described in 1971, but its importance and underdiagnosis have recently been emphasized.3-5 Randhawa and colleagues6 suggested that allergic laryngitis is misdiagnosed as LPR because the number of patients with chronic laryngitis with positive skin prick test (SPT) was more than 3 times higher than patients with positive results based on the reflux symptom index/reflux finding score. A retrospective study7 that included a medical record review of 998 patients indicated that the laryngitis group showed similar odds ratios (ORs) of allergen sensitization compared with the rhinitis or chronic sinusitis groups, indicating the importance of allergen sensitivity test for laryngitis. A study8 that included animal models of allergen-induced chronic laryngitis indicated that the combination of iron soot and Dermatophagoides farinae resulted in eosinophilia of the glottis, subglottic, and tracheal epithelium.
Moreover, the association between chronic laryngitis and sinonasal diseases has been demonstrated with the unified airway concept.9,10 Indeed, patients with either allergic rhinitis or nonallergic rhinitis had higher prevalence of dysphonia and more severe laryngeal symptoms than participants without rhinitis.11 A study12 investigating the interrater variability of assessment of laryngeal findings for reflux and allergic rhinitis based on SPT indicated that the presence of thick endolaryngeal mucous was a significant predictor of allergic rhinitis or laryngitis. Nevertheless, none of those studies investigated the correlation between various nasal symptoms or findings through nasal endoscopic examination and chronic laryngitis, including allergic laryngitis diagnosed based on the laryngoscopy findings and specific serum immunoglobulin E (IgE) level.
The objectives of this nationwide study are to investigate the association between the prevalence of subjective/objective nasal manifestations and chronic laryngitis, as well as to reveal possible sinonasal indicators for allergic cause of laryngitis.
This cross-sectional study includes data from the fifth Korea National Health and Nutrition Examination Survey (KNHANES V) from 2010 through 2012. The KNHANES is a nationwide survey conducted by the Korea Centers for Disease Control and Prevention; includes a health interview, nutritional survey, and physical examination; and is representative of the nonindustrialized South Korean population. The survey data were extracted by stratified, multistage clustered sampling based on national census data. The Korean Society of Otorhinolaryngology–Head and Neck Surgery participated in KNHANES V. Endoscopic ear, nose, and throat examination and medical interview were conducted by 150 otorhinolaryngology residents from 47 institutions who underwent training in a standard manner. The study was approved by the institutional review board of the Korea Centers for Disease Control and Prevention, and all participants provided written informed consent.
Among the 25 534 participants, participants younger than 18 years, without nasal endoscopic or laryngoscopic examinations, having a lesion suspected for cancer after endoscopic or laryngoscopic examination, or with incomplete data were excluded. In total, 11 283 participants were enrolled (Figure).
Data regarding the participants’ age, sex, household income, residency, education level, smoking status, and alcohol consumption were collected. Household income was categorized by quartile (<25%, 25%-50%, 51%-75%, >75%). Residency was classified into urban and rural areas according to the official addresses of the participants. Education level was classified into 4 groups (less than elementary, less than high school, less than college, more than college). Smoking history was categorized into 2 groups: current smoker or exsmoker and nonsmoker. Alcohol consumption was categorized into 2 groups: drinking 4 or more times a week and drinking fewer than 4 times a week or nondrinker.
The results of the questionnaires and physical examinations of the participants’ nasal cavities and larynges in this study are summarized in Table 1. The diagnoses of rhinitis, nasal septal deviation, chronic sinusitis, and chronic laryngitis were made based on these findings. Participants with rhinitis were defined as those who reported to have rhinorrhea, sneezing, and itching sensation of the nose. Septal deviation was defined based on the nasal endoscopic findings of asymmetrical deviation of the nasal septum after shrinkage of the nasal mucosa. The diagnosis of chronic rhinosinusitis was based on the epidemiological section of the European study on rhinosinusitis and nasal polyp.13 Questions related to chronic rhinosinusitis addressed the following 4 symptoms of at least 12 weeks’ duration: anterior/posterior nasal drip, nasal obstruction, facial pain or pressure, and olfactory dysfunction. Chronic rhinosinusitis was diagnosed when more than 2 of these symptoms with at least 1 of either anterior/posterior nasal drip or nasal obstruction being present, or if the nasal polyp was identified by endoscopic findings.
Laryngoscopic examination using a 4-mm, 70-degree–angled rigid endoscope by trained otorhinolaryngology residents was performed, and recorded images using a charge-coupled device camera were further reviewed by otorhinolaryngology specialists. Chronic laryngitis was defined as a positive finding for chronic laryngeal inflammation with erythema, edema, pseudosulcus, Reinke edema, or thick endolaryngeal mucous under laryngoscopic examination, as described previously.14,15 Each participant was asked if they experienced voice problems, and those who provided affirmative responses were asked if the duration of voice change was fewer than 3 weeks or 3 weeks or more.
In 2010, 10% of total participants underwent ImmunoCAP 100 (Thermo Scientific; Uppsala, Sweden) testing in which the levels of specific IgEs for 3 common indoor allergens (D farinae, cockroaches, and dogs) were measured with a cutoff value of 0.35 kU/L. Among participants with laryngoscopic findings of chronic inflammation indicating chronic laryngitis, participants who were positive for at least 1 of the 3 specific IgEs were defined to have allergic laryngitis, while the others were defined to have nonallergic laryngitis. Although only a small subpopulation met the inclusion criteria, the data were used for further evaluation of the association between nasal findings and allergic laryngitis.
Statistical analyses were performed using Statistical Package for the Social Sciences, version 20 (IBM). Participants’ characteristics were described using the mean and standard deviation for continuous variables, and number and percentage for categorical variables. For the differences of general characteristics between participants with chronic laryngitis and control participants, continuous variables were analyzed by t test, and categorical variables were analyzed by χ2 test. To calculate the effect size, we used Cohen d for t test and Cramer V statistic for χ2 test with bootstrap CIs using the R software, version 3.5.1 (R Foundation for Statistical Computing). Univariable and multivariable logistic regression analyses were used to evaluate the associations between chronic laryngitis and sinonasal factors. Odds ratios with 95% CIs for each sinonasal factor were calculated. According to the adjusted confounding factors, 3 models were established: univariable analysis was conducted in model 1, adjustment for variables with age and sex was completed in model 2, and final adjustment for variables with sex, age, residency, household income, educational level, smoking status, and alcohol consumption was performed in model 3. Subsequently, the interaction of the participants’ sex and age to the association between chronic laryngitis and sinonasal factors was evaluated. The χ2 test and Fisher exact test were used to compare the presence of sinonasal factors between the allergic laryngitis and nonallergic laryngitis groups, and risk difference with 95% CIs were calculated using SAS software, version 9.4 (SAS Institute Inc).
Among the 11 283 participants analyzed in this study, 345 participants were diagnosed with chronic laryngitis. Participants with chronic laryngitis (mean [SD] age, 53.9 [14.4] years) were 4 years older than the controls (mean [SD] age, 49.9 [16.6] years) with strong association (Cramer V, 0.23; 95% CI, 0.13-0.34). With regard to sinonasal disease, the chronic laryngitis group had 7.6% (95% CI, 3.1%-13.9%) greater prevalence of chronic rhinitis (n = 111; 32.2%) (Cramer V, 0.02; 95% CI, 0.01-0.05) and 8.5% (95% CI, 3.2%-13.9%) higher prevalence of nasal septal deviation (n = 197;57.1%) (Cramer V, 0.03; 95% CI, 0.01-0.05) compared with the control group. Chronic rhinosinusitis had similar prevalence between the 2 groups. Participants with chronic laryngitis had higher prevalence of voice change for either fewer than 3 weeks (9.0%) or 3 weeks or more (2.8%) than the controls (eTable 1 in the Supplement).
Association of symptoms positive for rhinitis or chronic sinusitis with chronic laryngitis was analyzed (Table 2). Univariable analysis revealed that symptoms of rhinitis (OR, 1.44; 95% CI, 1.16-1.83), anterior/posterior nasal drip over 3 months (OR, 2.13; 95% CI, 1.48-3.06), and nasal congestion (OR, 1.51; 95% CI, 1.02-2.24) showed positive association with chronic laryngitis. After adjusting for confounding factors (in models 2 and 3), symptoms of rhinitis, anterior/posterior nasal drip, and nasal congestion showed association with chronic laryngitis. For nasal endoscopic findings, pale mucosa (OR, 1.68; 95% CI, 1.30-2.18), mucous or puslike discharge (OR, 1.72; 95% CI, 1.23-2.40), nasal septal deviation (OR, 2.07, 95% CI, 1.35-3.17), and puslike discharge in the middle meatus (OR, 1.41; 95% CI, 1.14-1.75) were shown to have association with chronic laryngitis in model 1. After adjustment for confounding factors, including the baseline characteristics (in models 2 and 3), endoscopic findings of pale mucosa, watery discharge, and mucous or puslike discharge before shrinkage, as well as nasal septal deviation and puslike discharge in the middle meatus after shrinkage, showed association with higher prevalence of chronic laryngitis.
Among the nasal symptoms and findings, the 8 clinically meaningful factors identified through multivariable analysis (model 3) shown in Table 2 were analyzed for their effect on chronic laryngitis according to the participants’ sex and age (Table 3). After the adjustment for confounding factors, the following factors showed association with higher prevalence of chronic laryngitis in female participants and participants 50 years and older: subjective symptoms of rhinitis (female participants: OR, 1.65 [95% CI, 1.16-2.35]; participants ≥50 years old: OR, 2.00 [95% CI, 1.48-2.70]), anterior/posterior nasal drip (female participants: OR, 3.41 [95% CI, 2.13-5.46]; participants ≥50 years old: OR, 2.42 [95% CI, 1.54-3.82]), and nasal congestion (female participants: OR, 2.56 [95% CI, 1.50-4.37]; participants ≥50 years old: OR, 1.81 [95% CI, 1.08-3.04]), as well as endoscopic findings of pale mucosa (female participants: OR, 2.04 [95% CI, 1.40-2.96]; participants ≥50 years old: OR, 2.00 [95% CI, 1.42-2.82]), mucous or puslike discharge (female participants: OR, 1.75 [95% CI, 1.00-3.07]; participants ≥50 years old: OR, 2.05 [95% CI, 1.37-3.06]), and puslike discharge in the middle meatus (female participants: OR, 2.46 [95% CI, 1.30-4.66]; participants ≥50 years old: OR, 1.93 [95% CI, 1.17-3.20]). In male participants, only rhinitis symptom (OR, 1.46; 95% CI, 1.05-2.02) was associated with higher prevalence of chronic laryngitis, and none of 8 sinonasal factors had clinically meaningful association with chronic laryngitis in participants younger than 50 years.
Further analysis of the ImmunoCAP data of 2010 was completed to evaluate the utility of the coexistence of nasal symptoms or findings in patients with chronic laryngitis as an indicator for allergic cause of laryngitis. Among 1415 participants who underwent ImmunoCAP in 2010, 47 participants were diagnosed with chronic laryngitis. In the laryngitis group, 17 were classified as having allergic laryngitis, and all participants with allergic laryngitis had positive results for IgE against D farinae. The presence of rhinitis symptoms, anterior/posterior nasal drip, and endoscopic findings of pale mucosa showed no clinically meaningful differences between the allergic laryngitis and nonallergic laryngitis subgroups when all participants’ data were analyzed (Table 4).
Further subgroup analysis according to the participants’ sex and age revealed that only participants younger than 50 years showed positive association between the presence of rhinitis symptoms and allergic laryngitis (risk difference, 47.20; 95% CI, 3.50-79.37) (Table 4; eTable 2 in the Supplement).
The main finding of this study was that the presence of rhinitis symptoms showed positive association with allergic cause of laryngitis in participants younger than 50 years, despite stronger association of chronic laryngitis with various sinonasal factors from questionnaires and endoscopic findings in female participants and participants 50 years and older (eFigure in the Supplement). To our knowledge, this is the first study to investigate the association between the subjective/objective factors of sinonasal disease and chronic laryngitis and to determine the utility of sinonasal finding of patients with chronic laryngitis as a factor for considering allergic cause of chronic laryngitis.
In this study, the prevalence of chronic laryngitis was 3.1% for the overall population, and more than a third of the patients with laryngitis (1.2%) had a positive result on the serum specific IgE test, which suggests the importance of distinguishing the allergic cause among patients with chronic laryngitis. It has been reported that 67% of patients with primary voice disorder demonstrated allergy, while only 20% of patients had reflux, which emphasizes the possibility of overtreatment with proton pump inhibitors (PPIs) in cases of laryngitis.6 Stein and colleagues1 conducted a population-based study and reported that among a total of 40 317 patients, 79% with a voice problem received PPIs at their first visit to the clinic. A prospective, double-blind, placebo-controlled study16 for laryngeal inhalant allergen challenge revealed that greater phonatory threshold pressure was required after allergen challenge, indicating a primary association between allergen exposure and vocal function impairment. Although these studies emphasized the probable misdiagnosis or mismanagement of allergic laryngitis, it is generally accepted that the differential diagnosis between allergic laryngitis and LPR is difficult owing to similar clinical manifestations.4,17 Therefore, we evaluated the differences in the coexistence of various sinonasal factors according to allergic condition in participants with chronic laryngitis in order to reveal possible indicators for allergic laryngitis.
This study indicated that the subjects of the chronic laryngitis group had higher prevalence of chronic rhinitis and nasal septal deviation, while prevalence of CRS showed no meaningful difference. The multivariable logistic analysis revealed that among various sinonasal symptoms, presence of rhinitis symptoms, anterior/posterior nasal drip, and nasal congestion were associated with chronic laryngitis. In the case of nasal endoscopic examination, findings of pale mucosa, watery rhinorrhea, nasal septal deviation, and mucous or puslike discharge either in front of the nasal cavity or the middle meatus showed association with chronic laryngitis. Subgroup analysis revealed that the association between nasal findings and prevalence of chronic laryngitis was prominent in female participants and participants 50 years and older; however, the coexistence of nasal findings in the participants with chronic laryngitis was not related to the allergic cause of chronic laryngitis. Age-related changes in the upper airways might affect the comorbidity of rhinitis and laryngitis; several structural changes that occur with the normal aging process, including decreased mucosal blood flow, viscoelastic change of mucus, and increased cholinergic activity, could influence the increased prevalence of chronic laryngitis associated with rhinitis.10,18 In female individuals, estrogen may play a role in the coexistence of rhinitis and laryngitis. Elevation in the estrogen level aggravated the conditions of rhinitis, including nasal conditions or impaired mucociliary clearance, as well as gastric acid secretion, which could influence chronic laryngitis.19,20 In addition, the hypersecretion of airway mucous was increased by administration of estradiol through the estrogen receptor beta, supporting the effect of estrogen on posterior nasal drip, which showed a dominant relationship with chronic laryngitis in the female participants in this study.21
In contrast, patients with chronic laryngitis with rhinitis symptoms in the group of participants younger than 50 years showed an association of these symptoms with allergic cause. The presence of rhinitis symptoms alone had high-risk difference with clinical importance, while endoscopic findings of rhinitis, including pale mucosa and watery rhinorrhea, showed a wide range of 95% CIs despite high-risk difference, which could be because of the much lower proportion of participants with those findings in the chronic laryngitis group compared with that in the participants with rhinitis symptoms. Findings of the laryngoscopic examination suggesting allergic laryngitis could not be investigated because we could not assess from the data collected which specific findings among various factors indicating chronic laryngitis were presented under laryngoscopic examination in each individual. In addition to the previous literature reporting thick endolaryngeal mucous as an indicator of allergic laryngitis, the results of the present study indicate that in patients younger than 50 years with chronic laryngitis consideration for the possibility of allergic laryngitis based on the presence of rhinitis symptoms could prevent the overprescription of PPIs.12
In this study, all patients with allergic laryngitis had a positive result in the D farinae sensitization test. Several previous studies have investigated the association between chronic laryngitis and sensitization to specific allergens. Notably, subjects with dust-mite allergen sensitization on SPT showed a higher voice handicap index score than did nonallergic subjects despite the absence of differences in acoustic data or stroboscopic parameters.5 Brook and collagues7 analyzed the OR for the association between positive results on various specific allergen tests and presenting symptoms, including rhinitis, laryngitis, otitis, and sinusitis; 51.9% of participants in their study with primary laryngeal symptoms showed a positive result for allergen sensitivity test, and dust mite was the most common allergen. The findings from the present study were consistent with those from the above studies indicating that dust mite is the major allergen; however, the proportion of allergic participants among the chronic laryngitis group was lower than that reported by Brook and colleagues, which could be explained by the fact that KNHANES V focused on the inclusion of data regarding sensitization to only indoor allergens.
This study has several limitations. Owing to the cross-sectional study design, a causal relationship could not be defined. In addition, KNHANES V provided data of only 3 specific IgEs for common indoor allergens, and hence, we were unable to assess the association between allergic airway conditions and seasonal allergens. Finally, because questionnaires or examinations related with acid reflux were not included in these nationwide data, the clinical features of allergic laryngitis isolated from the effects of LPR could not be analyzed. However, even in practice, examinations for objective acid reflux verification, such as 24-hour pH monitoring, cannot be performed in all suspected patients, and the majority of LPR cases are diagnosed through reactivity to PPIs. From the present study, various sinonasal factors were associated with chronic laryngitis, especially in female participants and participants 50 years and older, and the possibility of allergic cause could be verified if rhinitis symptoms were present in patients younger than 50 years with chronic laryngitis. This result could be useful for suspecting other causes of chronic laryngitis before testing on reflux or prescribing PPIs. The present study has strength in that, to our knowledge, this is the first nationwide study to evaluate the association between sinonasal factors and chronic laryngitis, including allergic laryngitis, in participants who represent the entire South Korean population. In addition, the reliability of this study is supported by the fact that the laryngoscopic and nasal endoscopic examinations were conducted in a large population by trained otolaryngologists using a standardized protocol.
The current study included nationwide data and showed that the association of sinonasal factors, including rhinitis symptoms, anterior/posterior nasal drip, endoscopic findings of pale mucosa, and mucous or puslike discharge, with chronic laryngitis was dominant in female individuals and older adults. Nevertheless, the presence of rhinitis symptoms in patients with chronic laryngitis was associated with the allergic cause of laryngitis only in participants younger than 50 years. The identification of this association may enable distinguishing allergic laryngitis from other causes of chronic laryngitis in young adults.
Accepted for Publication: June 11, 2019.
Corresponding Author: Tae Hoon Kim, MD, PhD, Department of Otorhinolaryngology–Head & Neck Surgery, College of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, South Korea (firstname.lastname@example.org).
Published Online: August 15, 2019. doi:10.1001/jamaoto.2019.2134
Author Contributions: Drs Kim and K. Lee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs K. Lee and Young Kang contributed equally to this work.
Study concept and design: K. Lee, S. Lee, Kim.
Acquisition, analysis, or interpretation of data: K. Lee, Young Kang, H. Lee, Choi.
Drafting of the manuscript: K. Lee, Young Kang, H. Lee, Choi.
Critical revision of the manuscript for important intellectual content: S. Lee, Kim.
Statistical analysis: K. Lee, Young Kang, Choi.
Obtained funding: Kim.
Administrative, technical, or material support: K. Lee.
Study supervision: S. Lee, Kim.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by the Korea Health Industry Development Institute through the Ministry of Health & Welfare (HI17C0387).
Role of the Funder/Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the 150 residents of the otorhinolaryngology departments of 47 training hospitals in South Korea and members of the Division of Chronic Disease Surveillance in Korea Centers for Disease Control & Prevention for participating in this survey and for their dedicated work. They were not compensated for their contributions beyond their regular salaries.
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