The McMaster Cough Severity Questionnaire (MCSQ): a cough severity instrument for patients with refractory chronic cough.

BACKGROUND: Cough severity represents an important endpoint to assess the impact of therapies for patients with refractory chronic cough (RCC). OBJECTIVE: To develop a new patient-reported outcome measure addressing cough severity in patients with RCC. METHODS: Phase 1 (item generation): A systematic survey, focus groups, and expert consultation generated 51 items. Phase 2 (item reduction): From a list of 51 items, 100 patients identified those they had experienced in the previous year and rated their importance on a 5-point scale. The MCSQ included items reported to occur most frequently and that had the highest importance scores. Patient feedback on the MCSQ led to elimination of redundant items. Another 100 patients completed the MCSQ, from which we performed an exploratory factor analysis and a Rasch analysis to further refine items on the MCSQ. RESULTS: Phase 2 led to selection of 15 items from the initial 51. Patient feedback on the 15 items led to elimination of 5 redundant items. An exploratory factor analysis of the 10-item MCSQ led to selection of two domains, elimination of one item that demonstrated cross-loading, and another that had high inter-item correlations. A Rasch analysis of the 8-item MCSQ confirmed that the response options functioned in a logically progressive manner and that no items exhibited differential item functioning. The final 8-item MCSQ has a one-week recall period and includes two domains (intensity and frequency). The 8-item MCSQ had high internal consistency (Cronbach's alpha, 0.89), proved able to distinguish different levels of cough severity (Pearson separation index, 0.89), and demonstrated high cross-sectional convergent validity (Pearson's correlation, 0.76 [95% CI 0.66 to 0.83]) with the 100-mm cough severity visual analogue scale. CONCLUSION: Initial evidence supports the validity of the MCSQ, an 8-item instrument measuring cough severity in patients with RCC. Future studies should evaluate its properties in measuring change over time.

The Effects of Diabetes on Gas Transfer Capacity, Lung Volumes, Muscle Strength, and Cardio-pulmonary Responses During Exercise.

BACKGROUND: Diabetes is a risk factor for the development of vascular disease, chronic kidney disease, retinopathy, and neuropathy. Diabetes is a co-morbid condition commonly present in patients with respiratory disorders but the extent to which it influences ventilatory capacity, gas exchange, and functional capacity is not well known. Research question Does the presence of diabetes contribute to impairment in spirometry, gas transfer, and exercise capacity? METHODS: Retrospective analysis of all subjects who performed incremental cardio-pulmonary exercise testing (CPET) between 1988 and 2012 at McMaster University Medical Centre. The impact of diabetes on physiological outcomes and maximum power output (MPO) was assessed using stepwise multiple additive linear regression models including age, height, weight, sex, muscle strength, and previous myocardial infarct as co-variates, and was also stratified based on BMI categories. RESULTS: 40,776 subjects were included in the analysis; 1938 (5%, 66% male) had diabetes. Diabetics were older (59 vs. 53 years), heavier (88.3 vs.78.0 kg), and had a higher BMI (31 vs. 27 kg/m2). The presence of diabetes was independently associated with a reduction in FEV1 (- 130 ml), FVC (- 220 ml), DLCO (- 1.52 ml/min/mmHg), and VA (- 340ml) but not KCO. Patients with diabetes achieved a lower % predicted MPO[diabetic subjects 70% predicted (670 kpm/min ± 95% CI 284) vs. 80% in non-diabetics (786 kpm/min ± 342), p < 0.001]. With the exception of KCO, these differences persisted across BMI categories and after adjusting for MI. CONCLUSION: The presence of diabetes is independently associated with weaker muscles, lower ventilatory and gas transfer capacity and translates to a lower exercise capacity. These differences are independent of age, height, weight, sex, and previous MI.

Patient satisfaction with the management of refractory and unexplained chronic cough in Canada: Results from a national survey.

BACKGROUND: Chronic cough (persisting for ≥8 weeks) is a common disorder affecting approximately 5 to 10% of adults worldwide that is sometimes refractory to treatment (refractory chronic cough [RCC]) or has no identifiable cause (unexplained chronic cough [UCC]). There is minimal information on the patient's experience of RCC/UCC in Canada. The aim of this study was to evaluate the patient journey and perceptions related to RCC/UCC management in Canada. METHODS: Our exploratory study included Canadians in the Leger Opinion Panel and focused on individuals with RCC or UCC. Key entry criteria were: age ≥18 years, cough on most days for ≥8 weeks, no smoking within 1 year, no serious respiratory disease or lung cancer, and not taking angiotensin-converting enzyme inhibitors. Individuals who met entry criteria were invited to complete an approximately 30-minute online survey with questions on demographic characteristics, healthcare professional (HCP) interactions, diagnosis of underlying conditions, current treatments, and satisfaction with HCPs and chronic cough therapies. RESULTS: A total of 49,076 individuals completed the chronic cough screening questionnaire (July 30, 2021 to September 1, 2021): 1,620 (3.3%) met entry criteria for RCC or UCC, and 1,046 (2.1%) completed the online survey (mean age of 45 years, 61% female). Most respondents (58%) reported their chronic cough was managed by a general practitioner (GP). Forty-four percent of respondents did not have a diagnosis of an underlying condition for their cough. Breathing tests (39%) and chest imaging (34%) were the most common diagnostic tests. Cough suppressants (18%) were the most frequent current treatment. Respondents were moderately satisfied with their HCPs, but more than half considered their treatment ineffective and 34% had considered no longer seeking medical attention because of a lack of treatment success. CONCLUSIONS: Individuals with RCC/UCC in Canada are largely unsatisfied with the effectiveness of treatment. Additional HCP education and new treatment options are needed to improve patient satisfaction.

Benralizumab for allergic asthma: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate the allergen-induced late asthmatic response (LAR) in participants with allergic asthma. METHODS: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed. RESULTS: 46 participants (mean age 30.9 years) were randomised to benralizumab (n=23) or placebo (n=23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7 h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81%, 95% CI -10.69- -0.94%; p=0.021); however, the LAR was not significantly different (least squares mean difference 2.54%, 95% CI 3.05-8.12%; p=0.363). Adverse events were reported for seven (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively. CONCLUSION: Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction.

Burden of Disease Associated with Refractory and Unexplained Chronic Cough in Canada: Results from a National Survey.

INTRODUCTION: Chronic cough (persisting for ≥ 8 weeks) is a common disorder that includes refractory chronic cough (RCC; cough that persists despite treatment of underlying disease) and unexplained chronic cough (UCC; cough with no identifiable cause). We evaluated self-reported health-related quality of life (HR-QoL) and work/activity impairment associated with RCC/UCC in Canada. METHODS: Our exploratory study included Canadians in the Leger Opinion Panel with RCC or UCC. Key entry criteria were ≥ 18 years of age, cough for ≥ 8 weeks, not currently smoking/quit ≥ 1 year ago, no serious respiratory disease or lung cancer, and not taking angiotensin-converting enzyme inhibitors. Respondents completed a 30-min online survey with general and cough-specific HR-QoL questionnaires, including the EuroQol (EQ) visual analogue scale (VAS), EQ-5-dimension 5-level (EQ-5D-5L), cough severity VAS, Leicester Cough Questionnaire (LCQ), and Work Productivity and Activity Impairment-Specific Health Problem (WPAI-SPH). RESULTS: Of 49,076 individuals who completed the chronic cough screening questionnaire (July 30-September 1, 2021), 1,620 (3.3%) met entry criteria for RCC/UCC and 1,046 (2.1%) completed the survey. The mean age of respondents was 45 years and 61% were female. Respondents reported impairments in global HR-QoL (EQ-VAS 73.8, 61% with anxiety/depression on the EQ-5D-5L) and cough-specific HR-QoL (mean cough severity VAS score 29.7, LCQ index 15.2). Work and non-work activities were reduced by 34% and 30%, respectively, on the WPAI-SPH. CONCLUSION: RCC/UCC is prevalent in Canada and associated with impaired HR-QoL, particularly in mental health domains. Additional support and management options may be required to fully address this burden.

Neuromedin-U Mediates Rapid Activation of Airway Group 2 Innate Lymphoid Cells in Mild Asthma.

Rationale: In asthma, sputum group 2 innate lymphoid cells (ILC2s) are activated within 7 hours after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2s colocalize to sensory neuronal termini expressing the neuropeptide neuromedin U (NMU), which stimulates type 2 (T2) cytokine secretion by ILC2s, with additive effects to alarmins in vitro. Objectives: To investigate the effect of the NMU/NMUR1 (NMU receptor 1) axis on early activation of ILC2s in asthma. Methods: Subjects with mild asthma (n = 8) were enrolled in a diluent-controlled allergen inhalation challenge study. Sputum ILC2 expression of NMUR1 and T2 cytokines was enumerated by flow cytometry, and airway NMU levels were assessed by ELISA. This was compared with samples from subjects with moderate to severe asthma (n = 9). Flow sort-purified and ex vivo-expanded ILC2s were used for functional assays and transcriptomic analyses. Measurements and Main Results: Significant increases in sputum ILC2s expressing NMUR1 were detected 7 hours after allergen versus diluent challenge whereby the majority of NMUR1+ ILC2s expressed IL-5/IL-13. Sputum NMUR1+ ILC2 counts were significantly greater in mild versus moderate to severe asthma, and NMUR1+ ILC2s correlated inversely with the dose of inhaled corticosteroid in the latter group. Coculturing with alarmins upregulated NMUR1 in ILC2s, which was attenuated by dexamethasone. NMU-stimulated T2 cytokine expression by ILC2s, maximal at 6 hours, was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase 1/2 and phosphoinositol 3-kinase but not the IL-33 signaling moiety MyD88 in vitro. Conclusions: The NMU/NMUR1 axis stimulates rapid effects on ILC2s and may be an important early activator of these cells in eosinophilic inflammatory responses in asthma.

Acuity of asthma exacerbations in Alberta, Canada is increasing: a population-based study.

BACKGROUND: Asthma is a common respiratory illness affecting 2.8 million Canadians, including 9.7% of Albertans. Prior studies showed a substantial decrease in ED visits for asthma in the decade preceding 2010, followed by a stabilization. This was attributed to improvements in the pharmacologic and non-pharmacologic treatments for asthma during that period followed by a balance between epidemiologic drivers and protective factors in the population. METHODS: We assessed whether this trend continued in Alberta from 2010 to 2022 using population level data for the volume of daily ED visits, acuity of asthma exacerbations in the ED, and hospitalization rate. RESULTS: The mean number of ED visits decreased from 4.5 to 2.2 per million persons per day, but the acuity of exacerbations and the proportion requiring hospitalization increased. The number of patients presenting with the highest level of acuity increased by over 300%, and the percentage of patients requiring hospitalization increased from 6.8 to 11.3%. CONCLUSION: Total ED visits for asthma exacerbations continues to decline in Alberta. The reasons for an increase in more severe exacerbations requires further attention.

Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study.

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics. Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus. Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted. Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages.

Burden of chronic cough on social participation, healthcare resource utilisation and activities of daily living in the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Chronic cough is a common troublesome condition, but it is unclear whether dry or productive chronic cough and sex, impacts the burden of cough differently. METHODS: The Canadian Longitudinal Study on Aging is a nationally generalizable, stratified random sample of adults aged 45-85 years. Chronic cough was identified based on a self-reported daily cough in the last 12 months assessed at baseline (2011-2015) and follow-up (2015-2018). Odds ratios (95 % CI) for cough status and change in social participation activities (SPA), healthcare resource utilisation (HCRU), basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs) were estimated using a weighted generalised estimating equation (WGEE). Results were stratified by sex, and adjusted for age, sex, smoking, body mass index, education, respiratory diseases and retirement status. RESULTS: Overall, chronic cough was associated with less SPA, greater HCRU and impaired ADL/IADLs. Productive chronic cough in males was associated with SPA limited by health, ED visits and hospitalisation. Females with productive chronic cough was associated with reduced frequency of SPA and ED visit. Dry chronic cough in females was associated with SPA limited by health and ED visits. Both types of cough was associated with at least 1 impaired basic ADL, but only in females with productive chronic cough was there an association with any impairment in IADLs. CONCLUSION: Chronic cough is associated with a greater burden on social participation, healthcare use and personal care.

Evaluation of the reproducibility of responses to nasal allergen challenge and effects of inhaled nasal corticosteroids.

BACKGROUND: Similar immune responses in the nasal and bronchial mucosa implies that nasal allergen challenge (NAC) is a suitable early phase experimental model for drug development targeting allergic rhinitis (AR) and asthma. We assessed NAC reproducibility and the effects of intranasal corticosteroids (INCS) on symptoms, physiology, and inflammatory mediators. METHODS: 20 participants with mild atopic asthma and AR underwent three single blinded nasal challenges each separated by three weeks (NCT03431961). Cohort A (n = 10) underwent a control saline challenge, followed by two allergen challenges. Cohort B (n = 10) underwent a NAC with no treatment intervention, followed by NAC with 14 days pre-treatment with saline nasal spray (placebo), then NAC with 14 days pre-treatment with INCS (220 µg triamcinolone acetonide twice daily). Nasosorption, nasal lavage, blood samples, forced expiratory volume 1 (FEV1), total nasal symptom score (TNSS), peak nasal inspiratory flow (PNIF) were collected up to 24 h after NAC. Total and active tryptase were measured as early-phase allergy biomarkers (≤30 min) and IL-13 and eosinophil cell counts as late-phase allergy biomarkers (3-7 h) in serum and nasal samples. Period-period reproducibility was assessed by intraclass correlation coefficients (ICC), and sample size estimates were performed using effect sizes measured after INCS. RESULTS: NAC significantly induced acute increases in nasosorption tryptase and TNSS and reduced PNIF, and induced late increases in nasosorption IL-13 with sustained reductions in PNIF. Reproducibility across NACs varied for symptoms and biomarkers, with total tryptase 5 min post NAC having the highest reproducibility (ICC = 0.91). Treatment with INCS inhibited NAC-induced IL-13 while blunting changes in TNSS and PNIF. For a similar crossover study, 7 participants per treatment arm are needed to detect treatment effects comparable to INCS for TNSS. CONCLUSION: NAC-induced biomarkers and symptoms are reproducible and responsive to INCS. NAC is suitable for assessing pharmacodynamic activity and proof of mechanism for drugs targeting allergic inflammation.

Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough: A Systematic Review and Dose-Response Meta-Analysis.

Importance: Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough. Objective: To evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023. Study Selection: Two reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo. Data Extraction and Synthesis: Two reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID). Main Outcomes and Measures: Cough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events. Results: Nine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, -6.2 mm [95% CI, -4.1 to -8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]). Conclusions and Relevance: Compared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

The added value of haemoglobin to height, age, and sex to predict DLCO in subjects with preserved exercise capacity.

BACKGROUND: The single breath diffusion capacity for carbon monoxide (DLCO) captures several aspects of the role of the lung in meeting the metabolic demands of the body. The magnitude of the independent contributors to the DLCO is unknown. The aim of this study was to investigate the factors that independently contribute to the DLCO. OBJECTIVES: The objective was to investigate the impact of height, age, sex and haemoglobin on DLCO, alveolar volume (VA) and carbon monoxide transfer coefficient (KCO). METHODS: Study participants were pre-screened based on normal exercise capacity achieved during an incremental cardio-pulmonary exercise testing (CPET) using cycle ergometry at McMaster University Medical Center between 1988-2012. Participants who had an FEV1>80% predicted, with an FEV1/FVC ≥0.7 and who achieved a maximum power output ≥80% were selected for analysis. In total, 16,298 subjects [61% male, mean height 1.70m (range 1.26-2.07), age 49 yrs (10-94), weight 79 kg (23-190) had DLCO measured while demonstrating normal spirometry and exercise capacity. RESULTS: The DLCO increased exponentially with height, was 15% greater in males, increased with age yearly until 20, then decreased yearly after the age of 35, and was 6% higher per gram of haemoglobin (5.58*Height(m)1.69*1.15 in Males*(1-0.006*Age>35)*(1+0.01*Age<20) *(1+0.06*Hb gm/dl), (r = 0.76). CONCLUSION: Height, age, sex, and haemoglobin all have independent influence on the DLCO in subjects with normal spirometry and preserved exercise capacity.

Cough and cough hypersensitivity as treatable traits of asthma.

Cough is a common and troublesome symptom in people with asthma and is often associated with poorer asthma control and exacerbations. Apart from asthma, other causes or comorbidities might underlie cough in asthma, such as rhinosinusitis and bronchiectasis. Eosinophilic inflammation and bronchoconstriction can lead to an acute episode of cough or worsen chronic cough. Cough hypersensitivity with laryngeal paraesthesia, allotussia, and hypertussia might underlie the cough of asthma through augmented sensory nerve excitability of upper-airway vagal sensory nerves. Cough associated with bronchoconstriction and type 2 inflammation should respond to inhaled corticosteroids and long-acting ß-adrenoceptor agonist therapy. For cough hypersensitivity in adults, speech and language therapy and neuromodulators (eg, gabapentin) could be considered. In children, there is no consistent association of asthma with cough sensitivity or between cough and asthma severity. Further research is needed to realise the potential of cough as a measure of asthma control, to understand the mechanisms of cough in asthma, and to develop safe, effective treatments and a precision-medicine approach to the management of cough in asthma in children and adults.

Emerging drugs in the treatment of chronic cough.

INTRODUCTION: Chronic cough is a debilitating condition that is among the most common reasons for seeking medical attention yet remains challenging to manage. Identifying an underlying respiratory, nasal, or upper gastrointestinal disease triggering cough is the first step in assessment, but once this has been ruled out or adequately treated, many patients remain troubled with chronic cough. AREAS COVERED: This narrative review discusses the role of existing treatments and describes the current research landscape for the development of new therapies for chronic cough greater than 8 weeks that is refractory (RCC) or unexplained (UCC). The literature search includes published studies found on pubmed and conference abstracts until 2023. EXPERT OPINION: RCC/UCC can occur due to neuronal dysregulation of the vagus nerve or central nervous system. Hence, novel anti-tussives have targeted ion channels involved in the neuronal signaling which triggers cough. Although some therapies targeting receptors such as TRPV1 have failed to show efficacy, P2X3 antagonists have emerged as the most promising therapy for patients impacted by chronic cough. Disease-specific therapies such as for idiopathic pulmonary fibrosis are in early development.

Canadian Health Care Professionals' Familiarity with Chronic Cough Guidelines and Experiences with Diagnosis and Management: A Cross-Sectional Survey.

INTRODUCTION: Educational programs on chronic cough may improve patient care, but little is known about how Canadian physicians manage this common debilitating condition. We aimed to investigate Canadian physicians' perceptions, attitudes, and knowledge of chronic cough. METHODS: We administered a 10-min anonymous, online, cross-sectional survey to 3321 Canadian physicians in the Leger Opinion Panel who managed adult patients with chronic cough and had been in practice for > 2 years. RESULTS: Between July 30 and September 22, 2021, 179 physicians (101 general practitioners [GPs] and 78 specialists [25 allergists, 28 respirologists, and 25 ear/nose/throat specialists]) completed the survey (response rate: 5.4%). In a month, GPs saw a mean of 27 patients with chronic cough, whereas specialists saw 46. About one-third of physicians appropriately identified a duration of > 8 weeks as the definition for chronic cough. Many physicians reported not using international chronic cough management guidelines. Patient referrals and care pathways varied considerably, and patients frequently experienced lost to follow-up. While physicians endorsed nasal and inhaled corticosteroids as common treatments for chronic cough, they rarely used other guideline-recommended treatments. Both GPs and specialists expressed high interest in education on chronic cough. CONCLUSION: This survey of Canadian physicians demonstrates low uptake of recent advances in chronic cough diagnosis, disease categorization, and pharmacologic management. Canadian physicians also report unfamiliarity with guideline-recommended therapies, including centrally acting neuromodulators for refractory or unexplained chronic cough. This data highlights the need for educational programs and collaborative care models on chronic cough in primary and specialist care.

Mini-review: Hypertussivity and allotussivity in chronic cough endotypes.

In recent years our understanding of the neurophysiological basis of cough has increased substantially. In conjunction, concepts around the drivers of chronic coughing in patients have also significantly evolved. Increasingly it is recognised that dysregulation of the neuronal pathways mediating cough play an important role in certain phenotypes of chronic cough and therefore pathological processes affecting the nervous system are likely to represent key endotypes in patients. Taking inspiration from the study of neuropathic pain, the term hypertussia has been employed to describe the phenomenon of abnormal excessive coughing in response to airway irritation and allotussia to describe coughing in response to stimuli not normally provoking cough. This review aims to summarise current clinical evidence supporting a role for the hyperexcitability of neuronal pathways contributing to chronic coughing and suggest how these might align with the clinical features observed in patients.