Association of throat sensation severity with quality of life in patients with chronic cough

Introduction

Cough is a defensive reflex that involves complex interactions between peripheral sensory inputs, central nervous system processing, and cognitive regulatory mechanisms (1). While the cough reflex serves an essential protective function in healthy individuals, it can become dysregulated, leading to excessive and persistent coughing, which is marked by several characteristic features: increased cough sensitivity to normally harmless stimuli (allotussia), enhanced responses to tussive stimuli (hypertussia), and unusual sensations in the throat (laryngeal paresthesia) (2).

Chronic cough affects approximately 5–10% of the general adult population (3). It poses a significant socioeconomic burden by impairing quality of life (QoL) and is associated with healthcare burden (4-12). Abnormal throat sensation, such as throat tickling, itching, or irritation, is a frequent symptom that patients with chronic cough experience (9,13-17). These sensations are often attributed to laryngeal paresthesia or hypersensitivity (18), and they are frequent and relevant particularly in patients with refractory chronic cough (19,20). The identification of laryngeal sensations might have potential implications for treatment decisions, such as speech-language therapy (21). Central sensitization underlies urge-to-cough sensations (throat sensations evoked by tussigenic stimuli), and the impact of such sensations on activating motor arms of the cough reflex is likely to be enhanced in patients with chronic cough, compared to healthy controls (22). In a recent international Delphi study of expert clinicians involved in chronic cough practice, 84.9% of respondents indicated that measurement of throat sensations is important as a part of routine assessment at specialist cough clinics (23). However, the impact of abnormal throat sensations on health outcomes in chronic cough patients remains unknown.

This study was conducted to examine the clinical relevance of abnormal throat sensation, by measuring its severity and evaluating its association with QoL in a prospective registry of patients with chronic cough. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1994/rc).

Methods

Study participants

We used baseline data collected between July 2020 and February 2024 from the Korean Chronic Cough Registry, which is an ongoing multicenter, prospective, observational cohort study conducted at 18 allergy and pulmonology referral centers (24). Korean adult participants aged ≥19 years (based on domestic criteria in South Korea) with chronic cough (≥8 weeks) were enrolled. Exclusion criteria comprised: red-flag signs such as hemoptysis, severe dyspnea, fever, weight loss, peripheral edema, dysphagia, vomiting, or a history of recurrent pneumonia; abnormal findings on physical examination or chest X-ray suggesting other active medical conditions other than chronic cough which may affect cough or health status, such as severe asthma, active malignancy, heart failure, stroke, or other severe respiratory disease (24). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocols were approved by Institutional Review Board (IRB) of Asan Medical Center (IRB No. 2019-0754). All participating institutions were informed and agreed to the study. Informed consent was obtained from all study participants.

Baseline measurements

Throat sensation and cough severity were assessed with self-reported VAS scores [“How would you rate the severity of throat sensation discomfort (or the severity of cough) in the past week?”; 0= not at all to 100= worst ever] (24). The Cough Hypersensitivity Questionnaire (CHQ) was developed to measure cough-related laryngeal sensations and cough triggers, using a validated methodology (25). The CHQ comprised 22 questions (six on cough-related laryngeal sensation, and 16 on cough triggers). The number of items answered “yes” totaled the score on each domain (laryngeal sensation: 0–6; cough triggers: 0–16; total 0–22) (26). Cough-specific QoL was assessed using the Korean version of the Leicester Cough Questionnaire (LCQ), which comprises 19 questions evaluating the impact of cough across physical, psychologic, and social domains over the prior 2 weeks (27,28). General health-related QoL was assessed using the standardized EuroQoL 5-Dimension 5-Level (EQ-5D-5L) instrument (29), which consists of five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (30,31). All these questionnaires are available in the Korean language (24).

Baseline demographic data included age, sex, body mass index (BMI), and smoking history. Concomitant symptoms, such as sputum production, rhinorrhea, nasal obstruction, dyspnea, wheezing, regurgitation, heartburn, or snoring, and cough-induced complications, including fatigue, urinary incontinence, headache, or chest pain, were collected using structured yes/no questions.

History of physician-diagnosed conditions were recorded based on medical records. The diagnostic tests reviewed at baseline included spirometry, fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts.

Statistical analyses

Continuous variables are presented as mean ± standard deviation (SD) or median [interquartile range (IQR)]. Categorical variables are expressed as numbers with percentages. Correlations between symptom severity VAS and patient-reported outcome (PRO) scores were evaluated using Spearman rank correlation analysis. As both throat sensation and cough severity VAS scores followed a non-normal distribution, they were categorized into three groups based on tertile (T) ranges: T1 (throat sensation: 0≤ VAS <30; cough: 0≤ VAS <50), T2 (throat sensation: 30≤ VAS <60; cough: 50≤ VAS <70), and T3 (throat sensation: 60≤ VAS ≤100; cough: 70≤ VAS ≤100) (Figure S1). Comparisons of clinical characteristics, laboratory results, and PRO scores according to symptom severity tertiles were conducted using Student’s t-test or the Mann-Whitney U test for continuous variables, and the χ² or Fisher’s exact test for categorical variables. Multivariable linear regression analysis was performed to estimate associations of symptom severity tertiles with QoL scores. Baseline demographics, comorbidities, and clinical variables that were statistically significant (P<0.10) in the univariate analysis were included for adjustment. All tests were two-sided and a P value <0.05 was considered statistically significant. All statistical analyses were performed using Stata 18 statistical software (StataCorp; College Station, TX, USA) and GraphPad Prism 8 software (GraphPad Software; San Diego, CA, USA).

Results

Baseline characteristics

A total of 649 patients (age 54.7±15.3 years; females 68.1%) were enrolled (Table 1). Median cough duration was 72.0 (IQR, 36.0–132.5) months. At the initial visit, patients had a median number of 2.0 (IQR, 1.0–3.0) concomitant symptoms and 1.0 (IQR, 0.0–2.0) cough-induced complications. Sputum (60.4%) and rhinorrhea (39.0%) were the most frequent concomitant symptoms, while fatigue (36.2%), urinary incontinence (29.3%), and headache (28.9%) were the most frequent cough-induced complications.

Median throat sensation VAS score was lower than cough VAS score [40.0 (IQR, 17.5–70.0) vs. 60.0 (IQR, 40.0–75.0); P<0.001; Figure 1A]. The median total CHQ score was 8.0 (IQR, 6.0–11.0). The median LCQ score was 11.0 (IQR, 8.7–13.9), and the median EQ-5D index was 0.9 (IQR, 0.8–1.0).

Figure 1 Comparison of symptom severity VAS scores. (A) Box plot; and (B) scatter plot for correlations between throat sensation and cough severity VAS scores. VAS, visual analog scale.

Clinical correlations of throat sensation severity

Throat sensation VAS scores moderately correlated with cough severity VAS (r=0.47; P<0.001; Figure 1B), CHQ (r=0.35; P<0.001; Figure 2A), and LCQ scores (r=−0.41; P<0.001; Figure 2B). The correlation between throat sensation VAS score and the EQ-5D index was relatively weak (r=−0.25; P<0.001; Figure 2C). Correlations of each CHQ domain score with throat VAS were stronger than those with cough VAS [with CHQ laryngeal sensation domain score: (throat VAS, r=0.41 vs. cough VAS, r=0.27); and with CHQ cough trigger domain score: (throat r=0.25 vs. cough r=0.17), all P<0.001; Figure 3].

Figure 2 Scatter plots presenting correlations between throat sensation severity VAS and patient-reported outcome scores. (A) CHQ; (B) LCQ, and (C) EQ-5D index. CHQ, Cough Hypersensitivity Questionnaire; EQ-5D, EuroQoL 5-Dimension; LCQ, Leicester Cough Questionnaire; VAS, visual analog scale.

Figure 3 Correlation matrix between symptom VAS and CHQ scores. CHQ, Cough Hypersensitivity Questionnaire; VAS, visual analog scale.

Regression analyses

To analyze the association of throat sensation symptom severity with QoL scores, we first performed univariate regression analyses between throat sensation severity VAS tertiles and clinical characteristics, laboratory results, and PRO scores (Table 2). The severity of abnormal throat sensation VAS scores (T3 vs. T1) was associated with younger age (51.0±15.4 vs. 56.4±14.4 years; P<0.001), more allergic rhinitis (17.7% vs. 10.0%; P=0.028), more concomitant symptoms (mean 2.5±1.6 vs. 1.7±1.5; P<0.001), and more cough-induced complications (1.4±1.2 vs. 1.0±1.1; P<0.001).

Patients with higher throat sensation severity (T3) presented with more sputum, fatigue, headache, chest pain, reflux, and wheezing, compared to patients with lower throat sensation severity (T1) (all P<0.05) (Table S1). Throat symptoms of greater severity also showed dose-response relationships with higher CHQ, lower LCQ, and EQ-5D index scores (all P<0.001). However, cough duration, sex, lung function, blood eosinophil count, and FeNO values were not related to throat sensation in severity tertile. Additionally, duration of sputum production, and sputum color and amount were not significantly associated with throat sensation severity (Table S2).

In multivariate regression analyses (Table 3), abnormal throat sensation severity was significantly associated with LCQ score {T3 vs. T1: coefficient −1.63 [95% confidence interval (CI): −2.23 to −1.02]; P<0.001}, after adjusting for cough severity, baseline demographics (age, sex, smoking history, BMI), comorbidities (asthma and allergic rhinitis), and number of concomitant symptoms and cough-induced complications. The association between throat symptom severity and EQ-5D index was also significant [T3 vs. T1: coefficient −0.06 (95% CI: −0.09 to −0.02); P=0.005] after adjustment for confounders, including cough severity.

Discussion

In this cross-sectional analysis, we examined the severity of throat sensation and investigated the relationships with cough severity, comorbidities, concomitant symptoms, and PRO scores in patients with chronic cough. Although the VAS score of abnormal throat sensation was lower than that of cough, the sensation severity was significantly associated with cough-specific (LCQ) and general health-related QoL (EQ-5D index) scores in multivariate regression analyses, after adjustment for confounders including cough severity. These findings suggest that abnormal throat sensation is an important symptom domain of chronic cough syndromes.

Chronic cough can widely affect patients’ QoL, including social activities, work productivity, and psychologic domains (7,8,32). Several demographic factors, including older age, female sex, comorbidities, and cough severity are associated with worse QoL (8,33). However, to our knowledge, the impact of throat sensation on health outcomes in patients with chronic cough has been under-investigated. In a recent study, patients rated throat sensation as an important component in the disease control of chronic cough, whereas physicians were primarily focused on the cough itself (34). Previous studies on the relationships between throat sensation severity VAS and QoL reported their insignificant correlations, but they were limited to small samples (8,35). Thus, our study is a valuable addition to the literature, reporting significant associations of throat sensation severity with both cough-specific and general health-related QoL in a large sample of well-characterized patients (n=649).

The present study found positive associations between throat sensation severity and younger age, allergic rhinitis, and concomitant symptoms, such as sputum, fatigue, headache, chest pain, acid reflux, and wheezing. These findings suggest that multiple factors may underlie abnormal throat sensation, and they provide potential clues to identify determinants of abnormal sensation in further studies. Interestingly, throat sensation severity was not significantly related to lung function, FeNO, blood eosinophil count, or sputum characters. These results suggest that abnormal throat sensation may be driven by a distinct sensory mechanism, rather than by airway inflammation or airflow obstruction.

We observed positive dose-responsive relationships between throat sensation VAS severity and CHQ score, particularly its laryngeal sensation domain score (Table 2 and Figure 3). These findings suggest that the VAS severity scoring can be a simple practical tool for assessing laryngeal hypersensitivity. However, the VAS scale utilized in this study had descriptors only at the extreme ends [e.g., 0 (no throat sensation) to 100 (worst possible throat sensation)]. The severity measurement could be refined in further studies by using descriptive anchors for categories (such as mild, moderate, or severe) (36).

This study has some limitations. First, it was a cross-sectional study, and we could not determine the impact of throat sensation severity and its causal relationship with QoL impairment. Second, patients were recruited from secondary and tertiary clinics; thus, the generalizability of our study may be limited. However, the demographic profile of a middle-aged female predominance is typical for patients with chronic cough in different countries (37). Third, we only utilized a simple subjective VAS scoring to measure throat sensation severity. Indeed, there is currently no practically available objective tool available for measuring laryngeal sensory dysfunction (35). In this regard, our findings should be interpreted within the context of a pragmatic study that employed a simple scoring method. However, in a previous study by Despite these limitations, this is the largest clinical study to investigate the severity and potential impact of abnormal throat sensation in patients with chronic cough, and the study provides important baseline data for incorporating throat sensation severity into future longitudinal studies.

Conclusions

Throat sensation severity may independently contribute to impaired QoL in patients with chronic cough. While longitudinal studies are needed to clarify the impact and determinants of abnormal throat sensation, our findings suggest that throat sensation is a clinically relevant symptom of chronic cough syndromes.

Acknowledgments

Collaborators from the Korean Chronic Cough Registry who contributed to this study, but are not listed as co-authors, include (in alphabetical order): Yoon-Seok Chang, Seoul National University Bundang Hospital, Seongnam, Korea; Ji-Ho Lee, Yonsei University Wonju College of Medicine, Wonju, Korea; and So-Young Park, Chung-Ang University College of Medicine, Seoul, Korea

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1994/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1994/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1994/prf

Funding: The study was supported in part by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme LLC. The grantor had no role in the study design, data collection, analysis, results’ interpretation, decision to publish, or manuscript preparation. The opinions expressed in this paper are entirely those of the authors.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1994/coif). W.J.S. serves as an unpaid editorial board member of Journal of Thoracic Disease. W.J.S. declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, Bellus, AstraZeneca, Shionogi, and GSK, and lecture fees from Merck, AstraZeneca, GSK, Sanofi, and Novartis. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocols were approved by Institutional Review Board (IRB) of Asan Medical Center (IRB No. 2019-0754). All participating institutions were informed and agreed to the study. Informed consent was obtained from all study participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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