Is fractional exhaled nitric oxide a treatable trait in chronic cough: a narrative review.

Background and Objective: Current management of chronic cough is largely based on sequential therapeutic trials. The concept of treatable traits was first introduced for individualized treatment of chronic airway diseases; however, it has emerged as a potentially useful strategy in revising the management of chronic cough. This narrative review aimed to analyze the literature to determine if fractional exhaled nitric oxide (FeNO) is a treatable trait in chronic cough, compared to other type 2 biomarkers, and to summarize current knowledge and gaps in the clinical application. Methods: An online electronic search was performed on PubMed, Web of Science, and Scopus of English-language literature with following keywords: cough, nitric oxide (NO), eosinophils, biomarker, and treatable trait. Relevance and eligibility of each article were assessed by one or more of the authors and a narrative review was composed. Key Content and Findings: Eosinophilic or type 2 airway inflammation is a major treatable trait in patients with chronic cough. Induced sputum tests are regarded as the gold standard for defining inflammatory phenotype, however, technically demanding and cannot be widely applied in clinical practice. FeNO, a practical biomarker, has emerged as an alternative to induced sputum analyses. Mechanistic and clinical evidence indicated that FeNO had a potential for diagnostic utility and treatment response predictability. Conclusions: FeNO measurement may help to identify patients with chronic cough that will benefit from corticosteroid treatment. Further studies are warranted to determine the diagnostic roles of FeNO in the management of patients with chronic cough.

Recurrent Cough in the Elderly: A Forgotten Entity.

INTRODUCTION: Recurrent cough is little researched in adults. We investigated the prevalence, risk factors, and consequences of recurrent cough, and compared the results to those of isolated chronic cough. METHODS: Cross-sectional email survey in an elderly community-based population. Recurrent cough was defined as ≥ 3 cough episodes within one year (each lasting ≥ 1 week) and no current chronic cough. Isolated chronic cough was defined as current cough lasting ≥ 8 weeks and no recurrent cough. RESULTS: The prevalence of recurrent cough was 3.8% among all respondents (n = 5983). Recurrent cough was associated with asthma (aOR 3.32 (95% CI 2.13-5.18)), chronic rhinosinusitis (2.91 (1.89-4.46)), family history of chronic cough (2.59 (1.88-3.56)), analgesic intolerance (2.13 (1.27-3.57)), male gender (1.92 (1.39-2.66)), gastro-esophageal reflux disease (1.73 (1.21-2.47)), obstructive sleep apnoea (1.69 (1.23-2.32)), symptom sum (1.12 per symptom (1.03-1.22)), and younger age (0.96 per year (0.93-1.00)). Isolated chronic cough was associated with chronic rhinosinusitis (3.45 (2.39-4.97)), asthma (2.17 (1.38-3.41), gastro-esophageal reflux disease (1.80 (1.32-2.47)), family history of chronic cough (1.80 (1.35-2.41)), obstructive sleep apnoea (1.49 (1.12-2.00)), symptom sum (1.18 per symptom (1.10-1.27)), and body mass index (0.96 per unit (0.93-1.00)). Among subjects with recurrent and isolated chronic cough, the prevalence of depressive symptoms were 7.7% and 4.2%, p = 0.11, the Leicester Cough Questionnaire total scores 15.2 (14.6-15.8) and 16.3 (16.0-16.6), P = 0.001, and the mean number of yearly cough-related doctor`s visits 0.58 (0.45-0.71) and 0.36 (0.19-0.53), P = 0.007, respectively. CONCLUSION: The risk factors and consequences of recurrent and isolated chronic cough were comparable. Recurrent cough seems beneficial to address in cough evaluation.

ß2-Adrenoceptor Agonists in Asthma or Chronic Obstructive Pulmonary Disease and Risk of Parkinson's Disease: Nested Case-Control Study.

Introduction: Although ß2-adrenoceptor (ß2AR) agonists have been associated with a lower risk of Parkinson's disease (PD), the findings are inconclusive and may reflect confounding by indication. We studied the association between inhaled ß2AR agonists and risk of PD in persons with asthma or chronic obstructive pulmonary disease (COPD). Methods: The nested case-control study was conducted within a register-based Finnish Parkinson's disease study (FINPARK) and included 1406 clinically verified PD cases diagnosed during 1999-2015, who also had asthma/COPD >3 years before PD. PD cases were matched with up to seven controls by age, sex, duration of asthma/COPD, pulmonary diagnosis, and region (N = 8630). Cumulative and average annual exposure to short- and long-acting ß2AR agonists before a 3-year lag period was assessed with quartiles of defined daily doses (DDDs). Adjusted odds ratios (aORs) were calculated with 95% confidence intervals (CIs) using conditional logistic regression. Results: Cumulative exposure to either short- or long-acting ß2AR agonists was not associated with a risk of PD. With average annual exposure, a decreased risk was observed only for the highest quartile of long-acting ß2AR agonists (aOR 0.75; 95% CI 0.58-0.97). In the stratified analysis the lowest risk estimates were observed among those with both asthma and COPD diagnoses. The suggestion of an inverse association was seen for the highest quartile of long-acting ß2AR agonists in asthma. Discussion: Higher levels of exposure to ß2AR agonists were not consistently associated with a reduced risk of PD. The inverse association in the highest category of average annual exposure to long-acting ß2AR agonists may be explained by unmeasured confounding, such as disease severity or smoking.

Cross-country skiers often experience respiratory symptoms during and after exercise but have a low prevalence of prolonged cough.

Background: Cross-country skiers train and compete during the winter for long periods of time in subfreezing conditions, which strains the airways and provokes respiratory symptoms. This study aimed to compare the prevalence of exercise-related symptoms and prolonged cough in competitive cross-country skiers versus the general population and to investigate the association between these symptoms and asthma. Methods: A questionnaire was sent to Finnish cross-country skiers (n=1282) and a random sample of the general population (n=1754), with response rates of 26.9% and 19.0%, respectively. Results: Both groups were mostly asymptomatic at rest, but symptoms were increased in both groups during and after exercise. Cough was more prevalent after exercise in skiers and phlegm production was more common during and after exercise in skiers. Asthma did not provoke specific symptoms, but symptom prevalence was higher in asthmatic individuals. Skiers had a higher prevalence of cough after exercise (60.6% vs 22.8%, p<0.001) compared with controls, but controls had a higher prevalence of prolonged cough (4.1% vs 9.6%, p=0.004). In participants without asthma, cold air triggered symptoms more often in skiers than controls, while strong odours triggered symptoms more often in asthmatic controls than skiers. Chronic cough lasting more than 8 weeks was rare, reported by 4.8% of controls and 2.0% of skiers. Conclusion: Cross-country skiers, especially those with asthma, experience a higher burden of exercise-related respiratory symptoms compared with controls. However, repeated exposure to cold air does not appear to result in long-term hypersensitivity of the cough reflex arc.

Characteristics of idiopathic pulmonary fibrosis -associated cough. a case-control study.

BACKGROUND: Most patients with idiopathic pulmonary fibrosis (IPF) complain of cough. IPF-associated cough is widely characterized as dry or non-productive. The aim of this study was to compare chronic cough in early stage IPF patients to cough in subjects with chronic cough from a community-based sample and, especially, to investigate whether cough in IPF is less productive than chronic cough in a community-based sample. METHODS: The IPF cough population consisted of 46 biopsy-confirmed patients who complained of chronic cough. Control population consisted of subjects with chronic cough, gathered by a community-based email survey sent to public service employees and the Finnish Pensioners' Federation. A case-control setting was applied by having four age, gender, and smoking-status matched subjects from the community sample for each IPF cough patient. A cough specific quality of life questionnaire (Leicester Cough Questionnaire (LCQ)) was filled in by all subjects. The LCQ questionnaire contains 19 questions, each question is scored from 1 to 7 and total score from 3 to 21 with a smaller value indicating more severe impairment. RESULTS: The sputum production frequency, as assessed by LCQ question 2, was 5.0 (3.0-6.0) in the IPF chronic cough population and 5.0 (3.0-6.0) in the community-based chronic cough population (median and interquartile range p= 0.72). The LCQ total score was 14.8 (11.5-18.1) in the IPF chronic cough population and 15.4 (13.0-17.5) in the community-based chronic cough population (p=0.76). The domain impact scores were physical, 4.9 (3.9-6.1) vs. 5.1 (4.5-5.6) (p=0.80); psychological, 4.6 (3.7-5.9) vs. 4.7 (3.9-5.7) (p=0.90); and social, 5.5 (3.7-6.5) vs. 5.5 (4.5-6.3) (p=0.84), respectively. Furthermore, cough response to paint or fumes, cough disturbing sleep, and cough frequency per day did not differ between the groups. CONCLUSION: Cough in early stage IPF patients was not distinguishable from chronic cough in the community-based population by LCQ. Especially, there was no difference in the self-reported frequency of cough-associated sputum production.

Cough Sensitivity to Several External Triggers is Associated with Multiple Non-respiratory Symptoms.

PURPOSE: Enhanced responsiveness to external triggers is thought to reflect hypersensitivity of the cough reflex. It may involve an enhanced sensitivity of the afferent nerves in the airways and/or an abnormal processing of the afferent information by the central nervous system (CNS). The CNS processing of cough has been shown to involve the same regions as those in symptom amplification, a phenomenon that often manifests as multiple symptoms. The main purpose of the present study was to define whether the presence of several cough triggers is associated with multiple symptoms. METHODS: 2131 subjects with current cough responding to two email surveys filled in a comprehensive questionnaire about social background, lifestyle, general health, doctors' diagnoses and visits, symptoms, and medication. Multiple symptoms was defined as three or more non-respiratory, non-mental symptoms. RESULTS: A carefully controlled multiple regression analysis revealed that the number of cough triggers was the only cough characteristic associating with multiple non-respiratory, non-mental symptoms [aOR 1.15 (1.12-1.19) per one trigger, p < 0.001]. Among the 268 subjects with current cough both in the first survey and in the follow-up survey 12 months later, the repeatability of the trigger sum was good with an intraclass correlation coefficient of 0.80 (0.75-0.84). CONCLUSION: The association between the number of the cough triggers and multiple symptoms suggests that the CNS component of cough hypersensitivity may be a manifestation of non-specific alteration in the CNS interpretation of various body sensations. The number of cough triggers is a repeatable measure of cough sensitivity.

Inflammatory myositis-associated interstitial lung disease can be distinguished from that associated with other connective tissue diseases.

Background: Acute onset of interstitial lung disease (ILD) has been described in patients with idiopathic inflammatory myositis (IIM), but controlled studies about this issue are sparse. The aim of this study was to compare disease onset, demographics, and high-resolution computed tomography (HRCT) patterns in IIM-ILD and other connective tissue disease (CTD)-ILDs. Methods: Clinical and radiological data of 22 IIM-ILD and 132 other CTD-ILD patients was retrospectively gathered from hospital registries between January 2000 and November 2019. Data was re-assessed and compared using a multivariate analysis. Results: Compared to other CTD-ILDs, the patients with IIM-ILD were younger (59.7 vs. 68.0 years, P=0.023), more often non-smokers (71.4% vs. 45.7%, P=0.029) and displayed radiological nonspecific interstitial pneumonia/organizing pneumonia (NSIP/OP) overlap pattern more frequently (27.3% vs. 1.5%, P<0.001). The onset of ILD was acute with patients needing intensive care significantly more often in IIM-ILD than in other CTD-ILDs (22.7% vs. 2.3%, P<0.001). In most patients ILD was diagnosed before or simultaneously with IIM presentation unlike in other CTD-ILDs (90.9% vs. 47.7%, P<0.001). In multivariate analysis, NSIP/OP overlap pattern, acute onset disease treated in intensive care unit and ILD preceding or being diagnosed simultaneously with CTD were significantly associated with IIM-ILD. The multivariate model, supplemented with age, had excellent diagnostic performance identifying IIM-ILD [area under curve (AUC) 0.845]. Conclusions: Unlike other CTD-ILDs, IIM-ILD often develops acutely, simultaneously with the systemic disease. Therefore, clinicians should consider IIM-ILD as an option of differential diagnosis in patients with acute ILD and promptly test muscle enzymes as well as comprehensive autoantibody tests.

Healthcare-Seeking Behaviour Due to Cough in Finnish Elderly: Too Much and Too Little.

INTRODUCTION: Cough-related healthcare-seeking has not been studied specifically in the elderly, although chronic cough is most prevalent among them. We studied the frequencies and predictors of any (≥ 1) and repeated (≥ 3) doctor's visits due to any cough episode during the past year, and due to the current cough episode. METHODS: This was a cross-sectional email survey among a Finnish community-based elderly population. Participants with current cough and age ≥ 64 years were included in the analyses (n = 1109). RESULTS: The proportions of participants with ≥ 1 and ≥ 3 cough-related doctor's visits during the past year were 25.9% and 7.1%, respectively. Repeated visitors accounted for 55.9% of the visits during the past year. These visits first increased with cough duration but decreased after 5 years. In the multivariate analysis, bronchiectasis [aOR 3.22 (CI95% 1.08-9.58)], asthma [2.62 (1.56-4.40)], chronic sputum production [1.61 (0.94-2.76)], low self-assessed health status [1.40 (1.04-1.88)] and Leicester Cough Questionnaire total score [1.34 per tertile (1.10-1.62)] predicted repeated cough-related doctor's visits during the past year. The proportions of ≥ 1 and ≥ 3 doctor's visits due to current cough were 31.8% and 15.5%, respectively. Among participants with current chronic cough, 60.1% had not visited a doctor. CONCLUSION: A minority of participants accounted for most of the cough-related doctor's visits during the past year, whereas most participants with chronic cough had never sought medical help for it. The heavy healthcare users were not those with the longest cough episodes. Repeated visitors due to cough were characterised by chronic phlegmy respiratory conditions, and quality-of-life impairment.

Validation of the cough phenotype TBQ among elderly Finnish subjects.

Background: Phenotypes can be utilised in the clinical management of disorders. Approaches to phenotype disorders have evolved from subjective expert opinion to data-driven methodologies. A previous cluster analysis among working-age subjects with cough revealed a phenotype TBQ (triggers, background disorders, quality-of-life impairment), which included 38% of the subjects with cough. The present study was carried out to validate this phenotyping among elderly, retired subjects with cough. Methods: This was an observational cross-sectional study conducted via email among the members of the Finnish Pensioners' Federation (n=26 205, 23.6% responded). The analysis included 1109 subjects with current cough (mean±sd age 72.9±5.3 years; 67.7% female). All filled in a comprehensive 86-item questionnaire including the Leicester Cough Questionnaire. Phenotypes were identified utilising k-means partitional clustering. Results: Two clusters were identified. Cluster A included 75.2% of the subjects and cluster B 24.8% of the subjects. The three most important variables to separate the clusters were the number of cough triggers (mean±sd 2.47±2.34 versus 7.08±3.16, respectively; p<0.001), Leicester Cough Questionnaire physical domain (5.38±0.68 versus 4.21±0.81, respectively; p<0.001) and the number of cough background disorders (0.82±0.78 versus 1.99±0.89 respectively; p<0.001). Conclusion: The phenotype TBQ could be identified also among elderly, retired subjects with cough, thus validating the previous phenotyping among working-age subjects. The main underlying pathophysiological feature separating the phenotype TBQ from the common cough phenotype is probably hypersensitivity of the cough reflex arc.

Reticulation pattern without honeycombing on high-resolution CT is associated with the risk of disease progression in interstitial lung diseases.

BACKGROUND: The disease course of idiopathic pulmonary fibrosis (IPF) is progressive and occasionally, other types of interstitial lung disease (ILD) may progress similarly to IPF. This study aimed to evaluate risk factors for disease progression within 24 months in patients with various ILDs. METHODS: This prospective study obtained 97 patients with a suspected ILD who underwent a transbronchial lung cryobiopsy. The extent of several high-resolution computed tomography (HRCT) patterns was assessed. Due to the inclusion criteria the study population presented a low extent of honeycombing and definite usual interstitial pneumonia (UIP) pattern on HRCT suggesting an early stage of ILD. Disease progression within 24 months despite treatment was defined as a relative decline of ≥ 10% in forced vital capacity (FVC), or a relative decline in FVC of ≥ 5% and one of the three additional criteria: (1) a decline in diffusion capacity to carbon monoxide (DLCO) ≥ 15%; (2) increased fibrosis on HRCT; (3) progressive symptoms, or progressive symptoms and increased fibrosis on HRCT. The same definition was utilized in patients with IPF and other ILDs. Risk factors for disease progression were evaluated in a multivariable logistic regression model. RESULTS: Disease progression was revealed in 52% of the patients with ILD, 51% of the patients with IPF, and 53% of the patients with other types of ILD. A high extent of reticulation on HRCT (Odds ratio [OR] 3.11, 95% Confidence interval [CI] 1.21-7.98, P = 0.019) and never smoking (OR 3.11, CI 1.12-8.63, P = 0.029) were associated with disease progression whereas platelet count (OR 2.06 per 100 units increase, CI 0.96-4.45, P = 0.065) did not quite reach statistical significance. CONCLUSION: Higher extent of reticulation on HRCT and never smoking appeared to associate with the risk of disease progression within 24 months in ILD patients without honeycombing. Approximately half of the patients with ILD revealed disease progression, and similar proportions were observed in patients with IPF and in other types of ILD.

Risk factors of clinically significant complications in transbronchial lung cryobiopsy: A prospective multi-center study.

BACKGROUND: The use of a transbronchial lung cryobiopsy (TBLC) is increasing as a diagnostic method of interstitial lung diseases (ILD). This study aimed to evaluate risk factors associated with clinically significant complications of TBLC in ILD patients. METHODS: Patients referred to Kuopio or Tampere university hospitals, in Finland, for a suspected ILD were included. The TBLC was performed in an outpatient setting for 100 patients. Patients were mechanically ventilated in general anesthesia. Fluoroscopy guidance and prophylactic bronchial balloon were used. Complications, such as bleeding, pneumothorax, infections, and mortality were recorded. Moderate or serious bleeding, pneumothorax, or death ≤90 days were defined as clinically significant complications. A multivariable model was created to assess clinically significant complications. RESULTS: The extent of traction bronchiectasis (Odds ratio [OR] 1.30, Confidence interval [CI] 1.03-1.65, p = 0.027) and young age (OR 7.96, CI 2.32-27.3, p = 0.001) were associated with the risk of clinically significant complications whereas the use of oral corticosteroids ≤30 days before the TBLC (OR 3.65, CI 0.911-14.6, p = 0.068) did not quite reach statistical significance. A history of serious cough was associated with the risk of pneumothorax (OR 4.18, CI 1.10-16.0, p = 0.036). Procedure associated mortality ≤90 days was 1%. CONCLUSION: The extent of traction bronchiectasis on HRCT and young age were associated with the risk of clinically significant complications whereas oral corticosteroid use did not quite reach statistical significance. A history of serious cough was associated with the risk of clinically significant pneumothorax.

Daily Inhaled Corticosteroids Treatment Abolishes Airway Hyperresponsiveness to Mannitol in Defence and Police Recruits.

Background: Airway hyperresponsiveness (AHR) is a key pathophysiological feature of asthma and causes exercise-induced bronchoconstriction (EIB). Indirect bronchial provocation tests (BPTs) (e.g., exercise, mannitol) aid to diagnose asthma and identify EIB. Daily inhaled corticosteroids (ICS) can abolish AHR caused by indirect stimuli. Where strenuous physical exertion is integral to an occupation, identification of those at risk of EIB is important and documentation of inhibition of AHR with ICS is required before recruitment. Methods/Objectives: A retrospective analysis was performed on 155 potential recruits with AHR to mannitol who underwent follow-up assessment after daily ICS treatment to determine the proportion that can abolish AHR using ICS and to determine any predictors of the persistence of AHR. Results: Airway hyperresponsiveness was abolished in the majority (84%, n = 130) over the treatment period (mean ± SD 143 ± 72days), and it was defined as the provoking dose of mannitol to cause a 15% fall in FEV1 (cumulative inhaled dose of mannitol to cause 15% fall in FEV1, PD15) improved from (GeoMean) 183 to 521 mg. Compared with recruits in whom AHR was abolished with daily ICS (i.e., no 15% fall in FEV1 to the maximum cumulative dose of mannitol of 635 mg), in those where AHR remained (16%, n = 25), baseline AHR was more severe (PD15: 85 mg vs. 213 mg, P < 0.001), baseline FEV1% was lower (89 vs. 96%; 95%CI:2-12, P=0.004), and they had a longer follow-up duration (180 vs. 136 days; 13-74, P = 0.006). Baseline FEV1% (adjusted odds ratio 0.85; 95%CI:0.77-0.93), FEV1/FVC (0.78; 0.67-0.90), FEF25-75% (1.15; 1.06-1.25), and airway reactivity to mannitol (%Fall/cumulative dose of mannitol multiplied by 100) (1.07; 1.03-1.11) predicted AHR remaining after daily ICS. Conclusion: Airway hyperresponsiveness to mannitol can be abolished after 20 weeks of daily treatment with ICS. Inhibition of AHR is likely due to attenuation of airway inflammation in response to ICS treatment. Increased airway reactivity and lower spirometry variables predicted the persistence of AHR. Thus, those with a slower response to daily ICS on AHR can potentially be identified at the commencement of monitoring ICS using inhaled mannitol.

Cough in the Elderly During the COVID-19 Pandemic.

INTRODUCTION: The prevalence of chronic cough increases with age. However, data on the prevalence and background disorders of cough subtypes in the elderly are scarce. The objective of this study was to identify the point prevalence and risk factors of acute, subacute, and chronic cough in an elderly community-based population. METHODS: This was a cross-sectional email survey amongst 26,205 members of the Finnish Pensioners' Federation during the COVID-19 pandemic in spring 2021. RESULTS: The response rate was 23.6% (6189). 5983 subjects aged at least 64 years were included in the analyses (mean 72.6 years, 66.3% female). The point prevalence of daily acute, subacute, and chronic cough were 1.4%, 0.7%, and 9.6%, respectively. Only 0.4% of the subjects had a COVID-19 infection. In the multivariate analyses, chronic rhinosinusitis, and obstructive sleep apnoea were common risk factors for all cough subtypes. Chronic cough had several risk factors; Bronchiectasis (OR 5.79 (CI95% 2.70-12.41)), current asthma (2.67 (2.02-3.54)), chronic rhinosinusitis (2.51 (1.94-3.24)), somatic symptom score (1.13 per symptom (1.07-1.19)), family history of chronic cough (1.88 (1.54-2.30)), gastro-oesophageal reflux disease (1.86 (1.50-2.32)), advanced age (1.20 per decade (1.02-1.40)), chronic obstructive pulmonary disease (1.74 (0.99-3.05)), dog ownership (1.42 (1.07-1.89)), and obstructive sleep apnoea (1.41 (1.16-1.73)). CONCLUSION: Acute and subacute cough, as well as previous COVID-19 infection, were uncommon in this Finnish elderly population. The prevalence of chronic cough was higher than that previously found in younger adults. Chronic cough is a multifactorial disorder in the elderly.

Utility of Cough Provocation Tests in Chronic Cough and Respiratory Diseases: A Comprehensive Review and Introduction of New Reference Ranges for the Capsaicin Test.

Cough provocation tests (CPTs) are an objective measurement of the sensitivity of the cough reflex arc. However, they are not established in clinical practice because a large variability of response in healthy subjects limits their diagnostic value. There is a paucity of studies that have investigated CPT reference ranges in healthy subjects. This systematic review describes the variability of the responses to CPTs in healthy subjects and factors that influence it. A new analysis of 134 healthy subjects was conducted to create reference ranges for single-breath capsaicin CPT by calculating the interquartile ranges for the provocative concentration of capsaicin to induce 2 and 5 coughs. Female subjects had a more sensitive cough reflex than male counterparts. The ability of CPTs to distinguish various respiratory diseases from healthy subjects was also reviewed. Cough sensitivity was consistently heightened in the following groups: unselected patients with chronic, refractory, or recurrent cough, unexplained chronic cough, gastro-esophageal reflux-associated cough, cough-variant asthma, lower airway symptoms induced by chemical irritants, and fibrotic interstitial lung diseases. In the following groups, hypersensitivity of the cough reflex was present in those individuals whose symptom profile was predominated by cough: asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and sarcoidosis. In the following conditions, patients usually cough in order to expectorate mucus from their airways, not because of a hypersensitive cough reflex arc: productive cough, asthma, upper airway cough syndrome, COPD, bronchiectasis, cystic fibrosis, and chronic respiratory infections. CPTs have the potential to identify patients with chronic respiratory symptoms due to cough reflex hypersensitivity, thereby providing a targeted approach for therapy.

Deep Inspiration-Provoked Cough: A Sign of Cough Reflex Arc Hypersensitivity.

Deep inspiration-provoked cough (DIPC) is a form of allotussia. Allotussia is thought to be a manifestation of cough reflex arc hypersensitivity but objective evidence about this is lacking. 36 subjects with chronic cough and 25 healthy subjects underwent mannitol and citric acid cough provocation tests. DIPC was defined as two or more coughs after deep inhalation of an empty mannitol capsule. Citric acid was administered utilizing a dosimetric nebulizer during controlled tidal breathing. Nine subjects demonstrated DIPC, 8/36 subjects with chronic cough and 1/25 healthy subjects (p = 0.048). The concentration of citric acid to provoke five or more coughs (C5) was 23.4 (63.8) mM among subjects with DIPC and 750 (2941) mM among the subjects without it (p = 0.006). The number of deep inspiration-provoked coughs correlated with the citric acid C5 (Rs -0.38, p = 0.002). In conclusion, DIPC, a form of allotussia, is associated with cough reflex arc hypersensitivity.Trial Registration Number.ClinicalTrials.gov database KUH5801136.

Sputum production in chronic cough increases the probability of asthma: a cross-sectional questionnaire study.

Sputum production may suggest asthma as the most probable background disorder maintaining the cough https://bit.ly/2Qk8aar.

Cluster analysis in 975 patients with current cough identifies a phenotype with several cough triggers, many background disorders, and low quality of life.

BACKGROUND: Recognition of disorder phenotypes may help to estimate prognosis and to guide the clinical management. Current cough management guidelines classify patients according to the duration of the cough episode. However, this classification is not based on phenotype analyses. The present study aimed to identify cough phenotypes by clustering. METHODS: An email survey among employed, working-age subjects identified 975 patients with current cough. All filled in a comprehensive 80-item questionnaire including the Leicester Cough Questionnaire. Phenotypes were identified utilizing K-means partitional clustering. A subgroup filled in a follow-up questionnaire 12 months later to investigate the possible differences in the prognosis between the phenotypes. RESULTS: Two clusters were found. The cluster A included 608 patients (62.4% of the population) and the cluster B 367 patients (37.6%). The three most important variables to separate the clusters were the number of the triggers of cough (mean 2.63 (SD 2.22) vs. 6.95 (2.30), respectively, p < 0.001), the number of the cough background disorders (chronic rhinosinusitis, current asthma, gastroesophageal reflux disease, 0.29 (0.50) vs. 1.28 (0.75), respectively, p < 0.001), and the Leicester Cough Questionnaire physical domain (5.33 (0.76) vs. 4.25 (0.84), respectively, p < 0.001). There were significant interrelationships between these three variables (each p < 0.001). Duration of the episode was not among the most important variables to separate the clusters. At 12 months, 27.0% of the patients of the cluster A and 46.1% of the patients of the cluster B suffered from cough that had continued without interruptions from the first survey (p < 0.001). CONCLUSIONS: Two cough phenotypes could be identified. Cluster A represents phenotype A, which includes the majority of patients and has a tendency to heal by itself. The authors propose that cluster B represents phenotype TBQ (Triggers, Background disorders, Quality of life impairment). Given the poor prognosis of this phenotype, it urges a prompt and comprehensive clinical evaluation regardless of the duration of the cough episode.

Cough as an adverse effect on inhalation pharmaceutical products.

Cough is an adverse effect that may hinder the delivery of drugs into the lungs. Chemical or mechanical stimulants activate the transient receptor potential in some airway afferent nerves (C-fibres or A-fibres) to trigger cough. Types of inhaler device and drug, dose, excipients and formulation characteristics, including pH, tonicity, aerosol output and particle size may trigger cough by stimulating the cough receptors. Release of inflammatory mediators may increase the sensitivity of the cough receptors to stimulants. The cough-provoking effect of aerosols is enhanced by bronchoconstriction in diseased airways and reduces drug deposition in the target pulmonary regions. In this article, we review the factors by which inhalation products may cause cough.

Persistence of chronic cough in a community-based population.

Chronic cough causes significant impairment in the quality of life and is often immune to treatment. Previous studies about its persistence have focused on patients managed in special cough clinics. Little is known about the persistence of chronic cough in unselected populations. In this prospective follow-up study, we investigated factors that predict the persistence of cough at 12-month follow-up in a community-based study of subjects with chronic cough. The first e-mail survey in 2017 included a questionnaire about current cough and its risk factors. The 264 subjects who reported chronic cough were sent a follow-up questionnaire 12 months later. The response rate was 77.7% (205 subjects), of whom 165 subjects (80.5%) still had cough in 2018. In multivariate analysis, the following baseline factors predicted the persistence of cough at 12 months; gastro-oesophageal reflux disease (adjusted OR (aOR) 5.02 (95% CI 1.10-22.83)), presence of a chemical trigger (aOR 2.88 (95% CI (1.20-7.00)), duration of cough more than 1 year (aOR 2.80 (95% CI 1.27-6.22)), frequent somatic symptoms (aOR 1.31 (95% CI 1.07-1.59)), and low number of family members (aOR 0.71 (95% CI 0.52-0.98)). In conclusion, most patients with chronic cough still suffer from cough 1 year later. The presence of gastro-oesophageal reflux disease is the main predictor for the persistence of cough.

Cough-provocation tests with hypertonic aerosols.

Recent advances in cough research suggest a more widespread use of cough-provocation tests to demonstrate the hypersensitivity of the cough reflex arc. Cough-provocation tests with capsaicin or acidic aerosols have been used for decades in scientific studies. Several factors have hindered their use in everyday clinical work: i.e. lack of standardisation, the need for special equipment and the limited clinical importance of the response. Cough-provocation tests with hypertonic aerosols (CPTHAs) involve provocations with hypertonic saline, hypertonic histamine, mannitol and hyperpnoea. They probably act via different mechanisms than capsaicin and acidic aerosols. They are safe and well tolerated and the response is repeatable. CPTHAs can assess not only the sensitivity of the cough reflex arc but also the tendency of the airway smooth muscles to constrict (airway hyper-responsiveness). They can differentiate between subjects with asthma or chronic cough and healthy subjects. The responsiveness to CPTHAs correlates with the cough-related quality of life among asthmatic subjects. Furthermore, the responsiveness to them decreases during treatment of chronic cough. A severe response to CPTHAs may indicate poor long-term prognosis in chronic cough. The mannitol test has been stringently standardised, is easy to administer with simple equipment, and has regulatory approval for the assessment of airway hyper-responsiveness. Manual counting of coughs during a mannitol challenge would allow the measurement of the function of the cough reflex arc as a part of clinical routine.