Introduction Patients with chronic obstructive pulmonary disease (COPD) are often hospitalised due to severe acute exacerbation (AE) or community-acquired pneumonia (CAP). Previous studies revealed the association of cough reflex sensitivity with the pathophysiology of COPD and pneumonia. We hypothesised that cough reflex sensitivity may be associated with severe AE or CAP requiring hospitalisation in patients with COPD.
Methods We prospectively recruited 68 patients with COPD between June 2018 and January 2020. Patient characteristics, lung and cardiac functions, and biomarkers, including capsaicin cough reflex sensitivity and blood eosinophil count, were evaluated at enrolment. All participants were monitored for AE or CAP requiring hospitalisation for 12 months. We determined the risk factors and ORs for hospitalisation in patients with COPD using a multivariate analysis.
Results Eight patients experienced AE (n=3) or CAP (n=5) and required hospitalisation during follow-up. Patients in the hospitalisation+ group had higher modified Medical Research Council scores and blood eosinophil counts (≥300 µL) than those in the hospitalisation− group. Capsaicin cough reflex sensitivity tended to decrease in the hospitalisation+ group compared with that in the hospitalisation− group. Multivariate analysis revealed that a decreased capsaicin cough reflex and high eosinophil count (≥300 µL) were predictive risk factors for future hospitalisation due to AE-COPD or CAP.
Conclusion In addition to eosinophils, decreased capsaicin cough reflex sensitivity was associated with hospitalisation due to AE-COPD or CAP. Capsaicin cough reflex sensitivity in patients with COPD may play a role in the prevention of severe AE or pneumonia requiring hospitalisation.
Trial registration number UMIN000032497.
- COPD exacerbations
Data availability statement
Data are available upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC?
Acute exacerbations (AE) and pneumonia are major causes of hospitalisation in chronic obstructive pulmonary disease (COPD). Increased capsaicin cough reflex sensitivity is associated with AE. Meanwhile, it rather decreases in patients who experience frequent pneumonia.
WHAT THIS STUDY ADDS?
Decreased capsaicin cough reflex sensitivity is an important risk factor for severe AE or community-acquired pneumonia (CAP) requiring hospitalisation in patients with COPD in addition to higher blood eosinophil counts.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY?
Decreased capsaicin cough reflex sensitivity was associated with hospitalisation due to AE-COPD or CAP. Cough reflex sensitivity in COPD may play a role in the prevention of severe AE or pneumonia requiring hospitalisation.
The incidence of chronic obstructive pulmonary disease (COPD) mainly caused by cigarette smoke exposure is increasing1 and is the third leading cause of death worldwide (https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death). Mortality due to COPD in all age groups increased by 11.6% between 1990 and 2015.2 The number of deaths due to COPD was eight times higher than that due to asthma. Acute exacerbation (AE) of COPD (AE-COPD), defined by worsening of respiratory symptoms such as dyspnoea, cough and/or sputum beyond ordinary day-to-day variations and requiring changes in medication,3 is one of the major causes of death from COPD, along with pneumonia, cardiovascular disorders and cancer.4 5 Community-acquired pneumonia (CAP) often coexists with AE-COPD, resulting in hospitalisation.5–9 CAP is associated with severe clinical manifestations during hospitalisation such as higher rates of ICU admission,6 assisted ventilation6 7 and mortality7–10 in patients with COPD. Thus, preventing hospitalisation due to AE-COPD or CAP is important in the management of COPD.
Cough, sputum and dyspnoea are some of the most prevalent symptoms of COPD.11 Both cough and sputum are associated with bronchial colonisation by pathogenic bacteria and frequent exacerbations and hospitalisation,11–13 leading to the deterioration of COPD and death.13 Altered cough reflex sensitivity is associated with COPD pathophysiology.14 The capsaicin cough reflex sensitivity was more heightened in patients with COPD than in healthy subjects. In addition, it is associated with cough frequency in the daytime15 and frequent exacerbations.16 17 Meanwhile, cough plays a role in protecting the lower airways from particles in the external field and aspiration of the oral and gastro-oesophageal contents. Indeed, capsaicin cough reflex sensitivity declines in patients who experience recurrent pneumonia compared with healthy subjects.18 We hypothesised that capsaicin cough reflex sensitivity may not increase but decrease in patients with COPD with severe AE or CAP requiring hospitalisation.
In the present study, we prospectively investigated the association between capsaicin cough reflex sensitivity and hospitalisation in patients with COPD. We thought that decreased capsaicin cough reflex sensitivity was associated with future hospitalisation due to severe AE-COPD or CAP.
Subjects and the definition of COPD and comorbid asthma
We prospectively recruited patients with COPD who visited the Nagoya City University Hospital and Shizuoka General Hospital between June 2018 and January 2020. We enrolled patients in this study if their condition was stable at the time of their outpatient department visit. COPD was diagnosed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018 as follows: (1) a postbronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of less than 0.70 (fixed airflow limitation); (2) persistent respiratory symptoms such as dyspnoea, cough, sputum production or wheezing and (3) significant exposure to noxious stimuli such as tobacco smoke or other environmental particles. We permitted to include patients with comorbid asthma, called ‘asthma-COPD overlap’ in the present study. Patients were diagnosed with comorbid asthma if they had some clinical features of asthma, such as (1) variable or paroxysmal clinical symptoms, (2) a diagnosis of asthma before the age of 40 years, (3) elevated levels of fractional nitric oxide (FeNO) of 35 ppb or higher and (4) a history of perennial allergic rhinitis, airway hyperresponsiveness, elevated peripheral blood eosinophils and total or allergen-specific immunoglobulin E levels, in addition to fixed airflow limitation.19 Conversely, patients were not recruited to the present study when they denied participation in the study, had chronic respiratory diseases other than asthma or had a postbronchodilator FEV1/FVC ratio of 0.7 or higher. Patients were not eligible for this study if they were in a nursing care home, were bedridden at home, had a history of aspiration pneumonia or underwent tubal feeding. Patients who had a respiratory infection within 4 weeks of enrolment or hospitalisation due to AE-COPD or CAP within 12 weeks before enrolment were also excluded because they could influence the results of the capsaicin cough challenge test. This study was approved by the ethics committee of Nagoya City University (60-18-0012) and registered in the UMIN Clinical Trials Registry. Written informed consent was obtained from all the participants.
Patient and public involvement statement
Patients were not involved in the development of study design or recruitment of participants.
All patients underwent blood biomarker analyses (blood neutrophil and eosinophil counts, serum total IgE, albumin, lactate dehydrogenase, C reactive protein (CRP), haemoglobin A1c and plasma brain natriuretic peptide), echocardiography (ejection fraction), FeNO measurement, lung function test, CT of the chest and capsaicin cough challenge test at enrolment. They also completed the Leicester Cough Questionnaire, COPD Assessment Test and modified Medical Research Council (mMRC) dyspnoea scale at that time. Clinical information (pneumococcal vaccinations, smoking history (current or ex-smoking and pack-years), the use of inhaled corticosteroids or home oxygen therapy, a history of asthma, perennial allergic rhinitis, AE-COPD or CAP and hospitalisations due to AE-COPD or CAP) was also assessed. The number of AE-COPD, CAP and hospitalisations due to AE-COPD or CAP was prospectively counted for 1 year after enrolment in the study. Detailed information on the measurements, except for the capsaicin cough challenge test, is provided in online supplemental manuscript.
The capsaicin cough challenge test
The capsaicin cough challenge test was performed using an Astograph (Chest, Tokyo, Japan) after blood collection, echocardiography, FeNO measurement and spirometry. Detailed information on this method has been previously reported.20 Briefly, 10 doubling concentrations of capsaicin (0.61 to 312.5 µM) were inhaled for 15 s per concentration at 1 min intervals in increasing order, following inhalation of physiological saline for 1 min. Saline was inhaled for 45 s until the initiation of the next inhalation of capsaicin to increase patient blindness. When patients coughed five or more times, the challenge ended at the end of the following saline inhalation for 45 s. The test ended when patients finished inhaling short-acting β2 agonists for 2 min after the capsaicin cough challenge. The concentrations required to induce at least two (C2) and five (C5) coughs were recorded. Lower C2 and C5 values indicate heightened capsaicin cough reflex sensitivity.20 21 We planned to perform a capsaicin cough challenge test 1 year after enrolment in the study, but we evaluated capsaicin cough reflex sensitivity 1 year after enrolment in only 22 patients because of the restriction of measurements due to the coronavirus disease 2019 pandemic.
Definition of AE-COPD and pneumonia
AE-COPD was defined as an acute worsening of respiratory symptoms that resulted in additional treatments such as bronchodilators, antibiotics and systemic corticosteroids. CAP was diagnosed when new infiltration was observed on chest radiography and/or CT with two or more of the following findings: (1) fever (body temperature >37.5°C or <36.0°C), (2) leukocytosis or leucopenia (white blood cells >10 000/mm3 or <4000/mm3) and (3) purulent tracheal aspirate and/or sputum.22
Statistical analysis was performed using the JMP V.14.3 software (SAS Institute Japan, Tokyo, Japan). Values are expressed as mean (SD) for continuous variables and n (%) for categorical variables. We categorised patients into the hospitalisation+ group (AE-COPD or patients with CAP requiring hospitalisation during 1 years after enrolment) and the hospitalisation− group. Two group comparisons were performed using unpaired t-test or Fisher’s exact test, as appropriate. The values of C2 and C5 were expressed as the number of doubling concentrations. The number of doubling concentrations ranges from 1 to 10, with a high number indicating a decreased cough sensitivity of inhaled capsaicin. Corresponding inhalation concentration of capsaicin to the number of doubling concentration is noted in online supplemental manuscript. They reflect base2 logarithmic values of C5. Multivariate analysis was performed to determine the OR for hospitalisation. A sensitivity analysis confined to patients who were hospitalised before enrolment was also performed to clarify the association between capsaicin cough reflex sensitivity and hospitalisation in patients with COPD. Longitudinal data on capsaicin cough reflex sensitivity were compared using paired t tests. A variable was considered significant if the p value was ≤0.05. Some data were missing (n=64 for total IgE, and n=66 for CRP and ejection fraction). We handled missing data as a blank because these did not affect main results of this study.
A diagram of patient recruitment flow is shown in figure 1. We recruited 80 patients, and 11 were not eligible for this study (11 showed a post-bronchodilator FEV1/FVC ratio≥0.7, and one had pneumonia on chest radiography at enrolment). We traced 68 of 69 patients with COPD for 12 months after enrolment (one patient died of an unknown cause during the follow-up period). Table 1 shows the characteristics of the 68 patients with COPD at enrolment in this study. Fifty-eight patients were men, and the median age was 75 years. All patients had a history of smoking, and 14 were current smokers. Thirty-four patients (50%) were hospitalised due to AE-COPD or CAP, and 27 (39.7%) were hospitalised within 2 years prior to enrolment. Ten patients (14.7%) had a history of frequent hospitalisation (≥2) and nine of whom experienced hospitalisation within 2 years prior to enrolment. Twenty and 19 patients had a history of CAP and AE within 2 years prior to enrolment, respectively. Seven patients had a history of cerebrovascular disease (including one with silent cerebral infarction), and none had neuromuscular diseases. During the 12-month follow-up period, no patients with cerebrovascular diseases were hospitalised due to AE-COPD or CAP. Only 19 patients (27.9%) were categorised into group A according to the GOLD guidelines, indicating that this cohort included many patients with severe COPD. Ten patients met criteria of ‘asthma–COPD overlap’. The biomarkers that were used are listed in table 1. The median doubling concentration of C5 was 5.8 (SD 2.5). Capsaicin cough reflex sensitivity was unaffected by current smoking or cerebrovascular diseases (data not shown).
Predictive factors of hospitalisation in patients with COPD
Fifteen patients (22.1%) experienced an acute worsening of respiratory symptoms during the 12-month follow-up period. Of these, eight (11.8%) experienced AE-COPD (n=3) or CAP (n=5) requiring hospitalisation. When patients were stratified according to the presence or absence of hospitalisation during the 12-month follow-up (table 2), all eight patients had a history of AE-COPD or CAP requiring hospitalisation within 2 years prior to enrolment. Half of the patients (n=4) had a history of hospitalisation two times or more owing to AE-COPD or CAP. Furthermore, patients in the hospitalisation+ group frequently experienced AE-COPD and hospitalisation within 2 years prior to enrolment more as those in the hospitalisation− group (table 2). Meanwhile, the proportion of patients who experienced CAP within 2 years prior to enrolment was similar between the two groups. The mMRC scores were higher, but lung function was lower in the hospitalisation+ group than in the hospitalisation− group. Accordingly, GOLD classification was more severe in the hospitalisation+ group than in the hospitalisation− group. Patients in the hospitalisation+ group tended to have decreased capsaicin cough reflex sensitivity compared with those in the hospitalisation− group (table 2). Although blood eosinophil counts were similar between the two group, the proportion of patients with higher blood eosinophil counts of ≥300/µL was significantly higher in the hospitalisation+ group than in the hospitalisation− group (50% vs 13.3%, p=0.028). A similar result was obtained when comparing patients with CAP requiring hospitalisation (n=5) and those not requiring hospitalisation (blood eosinophil counts ≥300/µL: 60% vs 13.3%, p=0.03). Meanwhile, comorbid asthma and levels of FeNO and serum IgE were not related to hospitalisation. Cough-specific quality of life (QoL) assessed using the Leicester Cough Questionnaire, cardiac function assessed using echocardiography and other biomarkers were also comparable between the two groups.
Multivariate logistic regression analysis was performed to determine OR for hospitalisation in patients with COPD (table 3). Decreased capsaicin cough reflex sensitivity and higher absolute eosinophil counts (≥300/µL) were associated with future hospitalisations due to AE-COPD or CAP. If the number of doubling concentrations of C5 rose to the next number (eg, from 7 to 8), OR for hospitalisation increased by 2.19 times.
Association of decreased cough reflex sensitivity with repeated hospitalisation in patients with COPD
To further clarify the association between capsaicin cough reflex sensitivity and hospitalisation in patients with COPD, a sensitivity analysis confined to patients who experienced hospitalisation before enrolment was performed (table 4). Although the mMRC scores and lung function were similar between patients who were hospitalised during the follow-up period (n=8) and those who did not (n=26), there were significant differences in capsaicin cough reflex sensitivity and the proportion of patients with blood eosinophil counts ≥300/µL between the two groups (table 4). This suggests that decreased capsaicin cough reflex sensitivity may be a risk factor for repeated hospitalisation due to severe AE and CAP in patients with COPD, along with a higher blood eosinophil count.
Longitudinal changes of capsaicin cough reflex sensitivity in patients with COPD
We assessed the changes in capsaicin cough reflex sensitivity in 22 patients with COPD. The capsaicin cough reflex sensitivity did not change during the 12-month follow-up period (data not shown).
Several reports have described an association between altered cough reflex sensitivity and COPD pathophysiology. However, the clinical implications of altered cough reflex sensitivity on its pathophysiology are poorly understood. We showed for the first time that decreased capsaicin cough reflex sensitivity is an important risk factor for severe AE or CAP requiring hospitalisation in patients with COPD, particularly when they had a history of recent hospitalisation (≤2 years) due to AE-COPD or CAP.
The role of cough reflex sensitivity in the pathophysiology of respiratory diseases has been previously reported. In asthma, cough reflex sensitivity is a component of the pathophysiology of severe asthma.23 We showed that heightened capsaicin cough reflex sensitivity was associated with worse clinical outcomes of asthma, such as poor asthma control and frequent exacerbations,20 and that some treatments, such as tiotropium and bronchial thermoplasty, can reduce the capsaicin cough reflex sensitivity of asthma.24 25 Furthermore, tiotropium alleviates acute cough due to upper respiratory infections by improving heightened capsaicin cough reflex sensitivity,26 indicating that upper airway respiratory infections may increase capsaicin cough reflex sensitivity. In contrast, decreased capsaicin cough reflex sensitivity is a risk factor for recurrent pneumonia.18 Based on this evidence, we suggest that increased capsaicin cough sensitivity caused by infection prevents severe pneumonia that requires hospitalisation.
Previous studies have shown an association between increased capsaicin cough reflex sensitivity and AE-COPD,16 17 which were converse outcome to this study. The discrepancy between previous work and ours could be explained by the reason for hospitalisation. In our study, five of eight patients with COPD were admitted to the hospital with CAP. Additionally, wheezes and dyspnoea, rather than a cough, were the main symptoms of AE in the three patients who required hospitalisation. Therefore, differences in the causes of AE (eg, the worsening of cough) may result in contradictory outcomes between previous studies and ours. Furthermore, previous studies did not investigate whether increased capsaicin cough reflex sensitivity was associated with future hospitalisation for AE-COPD or CAP.16 17 The role of capsaicin cough reflex sensitivity may differ between severe and non-severe AE or CAP in patients with COPD. We speculate that cough reflex sensitivity is a biological defence response designed to prevent the development of severe AE and pneumonia requiring hospitalisation.
We found that blood eosinophil count (≥300/µL) was a potential biomarker for future hospitalisation in patients with COPD. Recently, eosinophils are important therapeutic target against COPD.27 The GOLD guidelines strongly recommend that the use of inhaled corticosteroids is beneficial in patients with eosinophil count of 300/µL or higher for the prevention of severe exacerbations requiring hospitalisation. In addition, the incidence of pneumonia requiring hospitalisation was 2.17-fold higher in patients with COPD with a high blood eosinophil count (≥0.34×109 cells/L) than in those with a normoeosinophil count.28 Thus, the presence of blood eosinophilia when analysed under stable conditions indicates a high risk of hospitalisation in patients with COPD. In contrast, in a retrospective study on the impact of blood eosinophilia on CAP in patients with COPD, those with blood eosinophilia determined by >2% at the time of the emergency department had higher lung function, less severe COPD, lower leucocyte counts and lower risk of prolonged length of respiratory intensive care unit stay (≥14 days) than those without (≤2%).29 However, the lower eosinophil counts observed in that study may be an epiphenomenon of more severe infections. Indeed, a subsequent study showed that lower blood eosinopenia (<50/µL) at the time of admission was associated with increased 18-month mortality and more severe infection in patients with AE-COPD and CAP requiring hospitalisation.30
The association between hospitalisation, lower lung function and severe dyspnoea has been well documented in previous studies. Worse lung function is associated with an increased risk of hospitalisation owing to severe exacerbation and subsequent mortality.31 32 It is also an independent risk factor for CAP that requires hospitalisation in patients with COPD together with older age.33 34 CAP is prone to develop in patients with severe COPD assigned to stage III or IV according to the GOLD classification.35 The mMRC scores are widely used to assess dyspnoea in clinical practice. A primary care population survey conducted in the United Kingdom revealed that higher mMRC scores are risk factors for frequent exacerbations (≥2) that require hospitalisation, along with severely impaired lung function, older age and osteoporosis.36 In addition, higher mMRC scores (≥2) and acute respiratory acidosis at admission were predictors of prolonged hospitalisation (>7 days) in AE-COPD.37 These results are consistent with those of the previous studies.
The present study had some limitations. Although patients were recruited from two hospitals, the present cohort consisted of a small number of patients (n=68) with a 12-month follow-up period. Therefore, only eight patients experienced severe AE or pneumonia requiring hospitalisation. However, the capsaicin cough challenge test was only performed for research purposes. Because we focused on the association between capsaicin cough reflex sensitivity and hospitalisation in patients with COPD, we could not enrol a larger number of patients. It is extremely difficult to perform capsaicin cough challenge tests in many hospitals. Second, the concentration of inhaled capsaicin for C2 and C5 was marginally but not significantly higher in the hospitalisation group than in the non-hospitalisation group (table 2). Therefore, decreased capsaicin cough reflex sensitivity may have a minor impact on hospitalisation in patients with COPD when compared with other factors such as higher blood eosinophil counts and a history of AE-COPD or pneumonia. Last, we could not perform the capsaicin cough challenge test 12 months after enrolment due to the COVID-19 pandemic. We refrained from performing all the aerosol-generated measurements at that time. It remains unclear how changes in capsaicin cough reflex sensitivity affect future severe AE or pneumonia requiring hospitalisation. Further studies are needed to evaluate the association between longitudinal changes in capsaicin cough reflex sensitivity and hospitalisation due to COPD. Despite these limitations, we showed for the first time an association between capsaicin cough reflex sensitivity and hospitalisation due to COPD in the present study.
Although an association between heightened capsaicin cough reflex sensitivity and AE-COPD has been reported in previous studies, we speculate that increased capsaicin cough reflex sensitivity in patients with COPD may protect against the development of severe AE or pneumonia requiring hospitalisation. Meanwhile, other well-known risk factors for AE or CAP in patients with COPD include higher blood eosinophil counts and a history of AE-COPD or CAP. Therefore, targeting therapy for capsaicin cough reflex sensitivity may not necessarily reduce severe AE-COPD and pneumonia requiring hospitalisation. Larger studies are required to confirm these findings.
Data availability statement
Data are available upon reasonable request.
Patient consent for publication
This study was approved by the ethics committee of Nagoya City University (60-18-0012) and registered in the UMIN Clinical Trials Registry (Registry ID UMIN000032497). Written informed consent was obtained from all the participants.
YK and RK are joint first authors.
YK and RK contributed equally.
Contributors YK: established the conception of the study and contributed to the performance of diagnostic tests, the collection of data, the recruitment of patients, disease diagnosis and management, the acquisition and interpretation of data, and drafting the manuscript. RK contributed to the performance of the diagnostic tests, and data acquisition, analysis, and interpretation. TA, KF, SF and YI contributed to the patient recruitment, diagnostic tests, and data collection and interpretation. NT, TT, HN and KI contributed to the performance of diagnostic tests, data collection, and data acquisition and interpretation. YM, TU, HO, MT, KM and TO contributed to the diagnostic tests, data collection, and interpretation. TS and AN contributed to the patient recruitment, disease diagnosis and management, data interpretation, and manuscript revision. YK is responsible for the overall content as guarantor.
Funding This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government (20K17220).
Competing interests YK received research grants from Novartis Pharma, MSD, Sanofi, and Kyowa-Kirin Corporation and personal fees from GSK, Novartis Pharma, AstraZeneca, Sanofi, and Kyorin. KF received research grants from Novartis Pharma and GSK. SF received personal fees from AstraZeneca and Eli Lilly. HO received a research grant from Boehringer Ingelheim. KM received personal fees from Pfizer and Chugai Pharmaceutical. TO reports personal fees from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Pfizer, Chugai Pharmaceutical, MSD, Daiichi Sankyo, and Asahi Kasei Pharma, as well as research grants and personal fees from Kyowa Hakko Kirin, Boehringer Ingelheim, Ono Pharmaceutical, and Novartis. MT has received a research grant from Pfizer. AN reports personal fees from Astellas, AstraZeneca, Kyorin, GSK, MSD, Shionogi, Bayer, Sanofi, Taiho, and Boehringer Ingelheim, and research grants from Astellas, Kyorin, Boehringer Ingelheim, Novartis, MSD, Daiichi Sankyo, Taiho, Teijin, Ono, Takeda, and Sanofi Pharmaceutical. The other authors did not receive any grants or personal fees.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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