The Relationship Between Cough Reflex Sensitivity and Exacerbation Frequency in Chronic Obstructive Pulmonary Disease

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Abstract

Background

Cough is predictive of exacerbations of chronic obstructive pulmonary disease (COPD). Little is known about cough reflex sensitivity during exacerbation of COPD and whether it is associated with exacerbation frequency. This pilot study aimed to investigate cough reflex sensitivity during and following recovery from exacerbation of COPD, and its association with the frequency of future exacerbations. In addition, the repeatability of cough reflex sensitivity in stable COPD was investigated.

Methods

Twenty participants hospitalised with exacerbation of COPD underwent inhaled capsaicin challenge during exacerbation and after 6 weeks of recovery. The frequency of future exacerbations was monitored for 12 months. The repeatability of cough reflex sensitivity was assessed in separate participants with stable COPD, who underwent 2 capsaicin challenge tests, 6 weeks apart.

Results

Cough reflex sensitivity was heightened during exacerbation of COPD. Geometric mean (SD) capsaicin concentration thresholds to elicit 5 coughs (C5) during exacerbation and after 6 weeks of recovery were 1.76 (3.73) vs. 8.09 (6.25) μmol L ⁻¹, respectively ( p < 0.001). The change in C5 from exacerbation to 6-week recovery was associated with the frequency of future exacerbations ( ρ = − 0.687, p = 0.003). C5 was highly repeatable over 6 weeks in stable COPD, and intraclass correlation coefficient was 0.85.

Conclusion

Cough reflex sensitivity is heightened during exacerbation of COPD and reduces after recovery. The persistence of cough reflex hypersensitivity at recovery was associated with the frequency of future exacerbations.

Electronic supplementary material

The online version of this article (10.1007/s00408-020-00366-x) contains supplementary material, which is available to authorised users.

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Most cited references 26

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Susceptibility to exacerbation in chronic obstructive pulmonary disease.

John R. Hurst, Jørgen Vestbo, Antonio Anzueto … (2010)

Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)

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The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough.

S S Birring, T. Fleming, S. Matos … (2008)

Chronic cough is a common condition that presents to both primary and secondary care. Assessment and management are hampered by the absence of well-validated outcome measures. The present study comprises the validation of the Leicester Cough Monitor (LCM), an automated sound-based ambulatory cough monitor. Cough frequency was measured with the LCM and compared with coughs and other sounds counted manually over 2 h of a 6-h recording by two observers in nine patients with chronic cough in order to determine the sensitivity and specificity of the LCM. Automated cough frequency was also compared with manual counts from one observer in 15 patients with chronic cough and eight healthy subjects. All subjects underwent 6-h recordings. A subgroup consisting of six control and five patients with stable chronic cough underwent repeat automated measurements > or = 3 months apart. A further 50 patients with chronic cough underwent 24-h automated cough monitoring. The LCM had a sensitivity and specificity of 91 and 99%, respectively, for detecting cough and a false-positive rate of 2.5 events x h(-1). Mean+/-SEM automated cough counts x patient x h(-1) was 48+/-9 in patients with chronic cough and 2+/-1 in the control group (mean difference 46 counts x patient x h(-1); 95% confidence interval (CI) 20-71). The automated cough counts were repeatable (intra-subject SD 11.4 coughs x patient x h(-1); intra-class correlation coefficient 0.9). The cough frequency in patients undergoing 24-h automated monitoring was 19 coughs x patient x h(-1); daytime (08:00-22:00 h) cough frequency was significantly greater than overnight cough frequency (25 versus 10 coughs x patient x h(-1); mean difference 15 coughs x patient x h(-1), 95% CI 8-22). The Leicester Cough Monitor is a valid and reliable tool that can be used to assess 24-h cough frequency in patients with cough. It should be a useful tool to assess patients with cough in clinical trials and longitudinal studies.

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Galectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma

Melanie Erriah, Kavita Pabreja, Michael Fricker … (2019)

Background Galectin-3 is a 32 kDa protein secreted by macrophages involved in processes such as cell activation, chemotaxis and phagocytosis. Galectin-3 has previously been shown to improve the ability of airway macrophages to ingest apoptotic cells (efferocytosis) in chronic obstructive pulmonary disease (COPD) and may be of interest in non-eosinophilic asthma (NEA) which is also characterised by impaired efferocytosis. It was hypothesised that the addition of exogenous galectin-3 to monocyte-derived macrophages (MDMs) derived from donors with NEA would enhance their ability to engulf apoptotic granulocytes. Methods Eligible non-smoking adults with asthma (n = 19), including 7 with NEA and healthy controls (n = 10) underwent a clinical assessment, venepuncture and sputum induction. MDMs were co-cultured with apoptotic granulocytes isolated from healthy donors with or without exogenous recombinant galectin-3 (50 μg/mL) and efferocytosis was assessed by flow cytometry. Galectin-3 expression and localisation in MDMs was visualised by immunofluorescence staining and fluorescence microscopy. Galectin-3, interleukin (IL)-6 and CXCL8 secretion were measured in cell culture supernatants by ELISA and cytometric bead array. Results Baseline efferocytosis (mean (±standard deviation)) was lower in participants with asthma (33.2 (±17.7)%) compared with healthy controls (45.3 (±15.9)%; p = 0.081). Efferocytosis did not differ between the participants with eosinophilic asthma (EA) (31.4 (±19.2)%) and NEA (28.7 (±21.5)%; p = 0.748). Addition of galectin-3 significantly improved efferocytosis in asthma, particularly in NEA (37.8 (±18.1)%) compared with baseline (30.4 (±19.7)%; p = 0.012). Efferocytosis was not associated with any of the clinical outcomes but was negatively correlated with sputum macrophage numbers (Spearman r = − 0.671; p = 0.017). Galectin-3 was diffusely distributed in most MDMs but formed punctate structures in 5% of MDMs. MDM galectin-3 secretion was lower in asthma (9.99 (2.67, 15.48) ng/mL) compared with the healthy controls (20.72 (11.28, 27.89) ng/mL; p = 0.044) while IL-6 and CXCL8 levels were similar. Conclusions Galectin-3 modulates macrophage function in asthma, indicating a potential role for galectin-3 to reverse impaired efferocytosis in NEA. Electronic supplementary material The online version of this article (10.1186/s12931-018-0967-9) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Surinder S. Birring: surinder.birring@nhs.net

Journal

Journal ID (nlm-ta): Lung

Journal ID (iso-abbrev): Lung

Title: Lung

Publisher: Springer US (New York )

ISSN (Print): 0341-2040

ISSN (Electronic): 1432-1750

Publication date (Electronic): 19 June 2020

Publication date PMC-release: 19 June 2020

Publication date (Print): 2020

Volume: 198

Issue: 4

Pages: 617-628

Affiliations

[1 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, , King’s College London, ; London, UK

[2 ]GRID grid.429705.d, ISNI 0000 0004 0489 4320, Department of Respiratory Medicine, , King’s College Hospital NHS Foundation Trust, ; London, UK

[3 ]GRID grid.417895.6, ISNI 0000 0001 0693 2181, Department of Respiratory Medicine, Charing Cross Hospital, , Imperial College Healthcare Trust, ; London, UK

Author information

Peter S. P. Cho http://orcid.org/0000-0001-8689-8541

Article

Publisher ID: 366

DOI: 10.1007/s00408-020-00366-x

PMC ID: 7374441

PubMed ID: 32561993

SO-VID: 790ed032-1e92-4e10-addf-18a9d3aed424

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 March 2020

Date accepted : 1 June 2020

Custom metadata

ScienceOpen disciplines: Respiratory medicine

Keywords: cough reflex sensitivity,cough,chronic obstructive pulmonary disease,exacerbation of chronic obstructive pulmonary disease

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ScienceOpen disciplines: Respiratory medicine

Keywords: cough reflex sensitivity, cough, chronic obstructive pulmonary disease, exacerbation of chronic obstructive pulmonary disease

The Relationship Between Cough Reflex Sensitivity and Exacerbation Frequency in Chronic Obstructive Pulmonary Disease

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

Related collections

Biomarkers for Inflammatory Lung Disease

Most cited references 26

Susceptibility to exacerbation in chronic obstructive pulmonary disease.

The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough.

Galectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma

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