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.

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.

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.

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.

Comparison of mannitol and citric acid cough provocation tests.

RATIONALE: Citric acid has been used as a cough provocation test for decades. However, the methods of administration have not been standardized. Inhaled mannitol is a novel cough provocation test, which has regulatory approval and can be performed utilizing a simple disposable inhaler in a standardized manner. OBJECTIVE: To compare the mannitol and citric acid cough provocation tests with respect to their ability to identify subjects with chronic cough and their tolerability. METHODS: Subjects with chronic cough (n = 36) and controls (n = 25) performed provocation tests with mannitol and citric acid. Both tests were video recorded. Cough sensitivity was expressed as coughs-to-dose ratios (CDR) and the cumulative doses to mannitol or concentration to citric acid evoking 5 coughs (C5). Forced expiratory volume in 1 s (FEV1), visual analogue scales (VAS), test completion rates and the total cough frequencies were analysed. RESULTS: Mannitol and citric acid CDR both effectively separated those with cough and the control subjects (AUC 0.847 and 0.803, respectively) as did C5 (AUC 0.823 and 0.763, respectively). There was a good correlation between the cough sensitivity provoked by the two stimuli, either expressed as CDR (r = 0.65, p < 0.001) or C5 (r = 0.53, p = 0.001). Both tests were similarly tolerated in terms of VAS, although more patients discontinued the mannitol test early, primarily due to cough. CONCLUSIONS: Mannitol and citric acid tests correlated well, equally identified subjects with chronic cough and their tolerability was similar. The feasibility issues, strict standardisation and regulatory approval may favour mannitol to be used in clinical cough research.

Predictors of prolongation in recent-onset cough.

Chronic cough greatly decreases the quality of life and is often refractory to treatment. Interventions at an early stage could prevent cough from becoming chronic. To this end, the patients at high risk of cough prolongation would need to be identified. In this study, we investigated the factors that predicted cough at 12 months among subjects with a recent-onset cough. This was a prospective, observational follow-up study in a community-based population consisting of working-age subjects. The first e-mail survey in 2017 included a comprehensive questionnaire about current cough and its risk factors. The 259 subjects who reported a recent-onset (<8 weeks) cough were sent a follow-up questionnaire 12 months later. The response rate was 72.6% (188 subjects). There were 99 subjects (52.7%) with cough in 2018. The following baseline factors predicted the presence of any cough at 12 months in the multivariable analysis: wheezing (adjusted odds ratio (aOR 2.80, 95% CI 1.3-5.27), dog ownership (aOR 2.56, 95% CI 1.21-5.44), cough duration >3 weeks (aOR 2.29, 95% CI 1.11-4.76), family history of chronic cough (aOR 2.20, 95% CI 1.13-4.30), body mass index >25 kg·m-2 (aOR 2.06, 95% CI 1.02-4.15) and frequent somatic symptoms (aOR 1.36, 95% CI 1.13--1.64). There were 29 subjects (15.4%) with continuous cough and 66 subjects (35.1%) with recurrent cough. The risk factors were completely different between recurrent and continuous cough. It may be possible to identify the risk factors of cough prolongation among subjects with recent-onset cough. Early interventions should be targeted to these kinds of patients.

Risk factors for repetitive doctor's consultations due to cough: a cross-sectional study in a Finnish employed population.

OBJECTIVES: Cough is the most common symptom prompting people to consult a doctor, thus representing a huge cost to the healthcare. This burden could be reduced by decreasing the number of repetitive consultations by the same individuals. Therefore, it would be valuable to recognise the factors that associate with repetitive doctor's consultations due to cough. DESIGN: A cross-sectional, email survey. SETTING: Public service employees in two Finnish towns. PARTICIPANTS: The questionnaire was sent to 13 980 subjects; 3695 (26.4 %) participated. INTERVENTIONS: The questionnaire sought detailed information about participant characteristics, all disorders diagnosed by a doctor, various symptoms and doctor's consultations. Those with current cough were inquired about cough characteristics and filled in the Leicester Cough Questionnaire (LCQ). PRIMARY OUTCOME: Repetitive (≥3) doctor's consultations due to cough during the previous 12 months. RESULTS: There were 205 participants (5.5% of the participants) with repetitive consultations. They accounted for 848 out of the 1681 doctor's consultations (50.4%) due to cough. Among all participants, repetitive consultations were mainly related to the presence of asthma (adjusted OR (aOR) 2.90 (2.01 to 4.19)) and chronic rhinosinusitis (aOR 2.40 (1.74 to 3.32)). Among the 975 participants with current cough, repetitive consultations were mainly related to a low LCQ total score (aOR 3.84 (2.76 to 5.34) per tertile). Comorbidity, depressive symptoms and smoking were also associated with repetitive consultations. CONCLUSIONS: A modest proportion of subjects with repetitive consultations is responsible for every second doctor's consultation due to cough. The typical features of these subjects could be identified. These findings can help to focus on certain subpopulations in order to plan interventions to reduce the healthcare burden attributable to cough.

Subfreezing air as a cough trigger and multiple triggers are strongly associated with the presence of asthma in chronic cough.

BACKGROUND: Management of chronic cough relies on the recognition of cough background disorders. It is not known whether certain cough triggers are associated with specific background disorders. METHODS: This was an e-mail study to public service employees of two towns in Finland. The questionnaire included twelve triggers. Current asthma was defined as doctor's diagnosis of asthma and current wheezing. Chronic rhinosinusitis was defined as either nasal blockage or nasal discharge and either facial pain/pressure or reduction/loss of smell for more than three months. Gastroesophageal reflux disease was defined as heartburn and/or regurgitation on at least one day a week during the last three months. Idiopathic cough was defined as absence of any of them. RESULTS: There were 421 subjects with current cough that had lasted at least eight weeks. Subfreezing air as a cough trigger was associated with an adjusted odds ratio (aOR) of 7.27 (4.09-12.9), (p < 0.001), for current asthma. The number of cough triggers was largest in asthma, followed by chronic rhinosinusitis, gastroesophageal reflux, and idiopathic cough (7.05 (6.14-7.96), 4.94 (4.35-5.54), 4.60 (3.77-5.43), and 3.44 (3.02-3.86), respectively, p < 0.001). Presence of five or more triggers was associated with an aOR of 7.49 (3.96-14.2), (p < 0.001) for current asthma. Absence of any cough triggers increased the probability of idiopathic cough (aOR 2.71 (1.54-4.77), p = 0.001). CONCLUSIONS: Subfreezing air as a cough trigger and multiple triggers are strongly associated with the presence of current asthma in chronic cough. Absence of any cough triggers increases the probability of idiopathic cough.

The impacts of cough: a cross-sectional study in a Finnish adult employee population.

Given the very high prevalence of cough, little is known about its impacts. A questionnaire was sent via e-mail to all public service employees in two towns in Finland. There were 373 subjects with acute cough, 174 with subacute cough and 421 with chronic cough. Cough-related quality of life was assessed with the Leicester Cough Questionnaire (LCQ) and depressive symptoms with Patient Health Questionnaire-2. In addition, data on doctor's visits and sick leave days were collected. Mean LCQ (95% CI) total scores were 16.2 (15.9-16.5), 14.5 (14.1-15.0) and 14.6 (14.3-14.9) among subjects with acute, subacute and chronic cough, respectively (p<0.001). The prevalence of depressive symptoms was 5.4%, 7.5% and 4.8%, respectively, and 5.0% among subjects without current cough (p=0.50). The respective proportions of subjects with at least one doctor's visit due to cough during the previous year were 27.6%, 44.8%, 49.6% and 16.1% (p<0.001). The respective proportions of subjects with at least one sick leave day due to cough during the previous year were 28.9%, 39.1%, 36.3% and 15.3% (p<0.001). Any current cough was associated with an increased the risk of several (three or more) yearly doctor's visit due to any reason (adjusted odds ratio (aOR) 1.49, 95% CI 1.27-1.76) and several (seven or more) yearly sick leave days due to any reason (aOR 1.43, 95% CI 1.22-1.68). Cough decreases quality of life, and has a large socioeconomic impact by increasing doctor's visits and sick leave days. However, it is not associated with depressive symptoms. The impacts of subacute and chronic cough are comparable, and larger than those of acute cough.

Defining the risk factors for acute, subacute and chronic cough: a cross-sectional study in a Finnish adult employee population.

OBJECTIVES: Chronic cough is linked to various long-standing risk factors like asthma, chronic rhinitis and oesophageal reflux disease. On the contrary, acute and subacute cough are usually considered to be caused by acute respiratory infections. Little is known about the possible long-standing risk factors for acute and subacute cough. In this study, we have identified the long-standing risk factors for acute, subacute and chronic cough in order to identify the risk factors specifically associated with chronic cough. DESIGN: A comprehensive 80-item questionnaire was sent via email to the participants. SETTING: A community-based study to all public service employees of two towns in central Finland. PARTICIPANTS: There were 13 980 employees, of them 3697 responded (26.4%). Among the responders, there were 199 subjects with current daily acute cough (duration <3 weeks, prevalence 5.4%), 126 subjects with current daily subacute cough (duration 3-8 weeks, prevalence 3.4%) and 267 subjects with current daily chronic cough (duration >8 weeks, prevalence 7.2%). PRIMARY OUTCOME MEASURES: The risk factors that associated with each cough subtype. The subjects without any cough formed the reference group. RESULTS: Several risk factors were associated with both short and long cough subtypes namely family history of chronic cough, moisture damage exposure and number of reported somatic symptoms. Furthermore, allergy was associated with acute and subacute cough. Current asthma and chronic rhinitis were associated with subacute and chronic cough. Oesophageal reflux disease and advanced age were associated with chronic cough. CONCLUSIONS: The specific risk factors for chronic cough were oesophageal reflux disease and advanced age. Acute and subacute cough should not be regarded merely as symptoms of acute respiratory infections but possible manifestations of long-standing risk factors. A new risk factor for all cough types was family history of chronic cough.

Long-term prognosis of chronic cough: a prospective, observational cohort study.

BACKGROUND: The long-term prognosis of chronic cough and its determinants need to be clarified. METHODS: This is a prospective, observational cohort study. Eighty-nine unselected subjects with chronic (> 8 weeks' duration) cough were carefully investigated: Clinical examination, symptom questionnaire, Leicester Cough Questionnaire (LCQ), skin prick tests, ambulatory peak expiratory flow monitoring, spirometry before and after 0.4 mgs of salbutamol, exhaled nitric oxide concentration measurement, hypertonic saline cough provocation test, and histamine bronchial provocation test. After five years, a letter was sent to the subjects containing questions about continuation of cough, smoking, indoor exposures, presence of co-morbidities, and current medication. It also contained LCQ and Cough Clinic diagnostic questionnaire. Sixty-eight subjects (76%) responded. RESULTS: At five years, continuing regular cough was present in 31 (46%) of the subjects and continuing impairment in cough-related quality of life (less than 1.3 points' improvement in LCQ) in 32 (47%). Continuing regular cough was associated with presence of chronic rhinitis or esophageal reflux disease, baseline mild airway responsiveness to histamine, and baseline strong cough responsiveness to hypertonic saline. Continuing impairment in cough-related quality of life was associated with high body mass index, absence of atopy, absence of pets, and high number of background disorders (esophageal reflux disease, asthma, or chronic rhinitis). CONCLUSIONS: Almost half of subjects with chronic cough suffered of the disorder at five years from initial assessment. Several possible determinants of poor prognosis could be identified.