Jaclyn A. Smith

ERS guidelines on the assessment of cough

### Cough 1) All basic scientific articles should refer to cough as a three-phase motor act. For the purposes of acoustic recordings in clinical studies, however, cough should be described as a forced expulsive manoeuvre or manoeuvres against a closed glottis that are associated with a characteristic sound or sounds. 2) All scientific articles should include a clear definition of what the authors have used as their definition of cough. ### Capsaicin and citric acid inhalation cough challenge 1) The methodology for the performance of inhalation cough challenge should be standardised so as to facilitate universal interpretation and comparison of data generated by different laboratories. 2) Comprehensive normal ranges need to be developed using the standardised methodology advocated in the present document. 3) The single-breath concentration–response method using a flow-limited dosimeter is recommended for most experimental protocols. 4) Both C2 and C5 should be recorded. 5) Since there is wide inter-individual variation, cough challenge data have no intrinsic significance, but may usefully be used to follow change in cough reflex sensitivity in an individual. ### Cough induced by inhalation of aqueous solutions 1) Aerosolised aqueous solutions represent a useful experimental tool in cough research. 2) The cough challenge with ultrasonic distilled water (fog) is difficult to standardise since it is highly dependent upon nebuliser output. 3) Consideration should be given to potential adverse events, such as bronchoconstriction and cross-infection. ### Cough monitors 1) No cough monitor is currently the gold standard. 2) Monitors should be developed that are ambulatory, are capable of being digitally processed and permit prolonged (24-h) recording. 3) There is little to commend any particular method of quantifying cough over any other. ### Assessment of quality of life of patients with chronic cough 1) Cough can have profound effects on health status, which can be assessed by cough-specific health status questionnaires. 2) Cough visual analogue scale (VAS, 0–100 mm) should be used to assess cough severity in patients with chronic cough. 3) Patients with chronic cough should be assessed with cough-specific quality-of-life questionnaires in clinical studies. ### Animal models of cough 1) The most useful animal model of cough is …

High-frequency Triazole Resistance Found In Nonculturable Aspergillus fumigatus from Lungs of Patients with Chronic Fungal Disease

BACKGROUND Oral triazole therapy is well established for the treatment of invasive (IPA), allergic (ABPA), and chronic pulmonary (CPA) aspergillosis, and is often long-term. Triazole resistance rates are rising internationally. Microbiological diagnosis of aspergillosis is limited by poor culture yield, leading to uncertainty about the frequency of triazole resistance. METHODS Using an ultrasensitive real-time polymerase chain reaction (PCR) assay for Aspergillus spp., we assessed respiratory fungal load in bronchoalveolar lavage (BAL) and sputum specimens. In a subset of PCR-positive, culture negative samples, we further amplified the CYP51A gene to detect key single-nucleotide polymorphisms (SNPs) associated with triazole resistance. RESULTS Aspergillus DNA was detected in BAL from normal volunteers (4/11, 36.4%) and patients with culture or microscopy confirmed IPA (21/22, 95%). Aspergillus DNA was detected in sputum in 15 of 19 (78.9%) and 30 of 42 (71.4%) patients with ABPA and CPA, compared with 0% and 16.7% by culture, respectively. In culture-negative, PCR-positive samples, we detected triazole-resistance mutations (L98H with tandem repeat [TR] and M220) within the drug target CYP51A in 55.1% of samples. Six of 8 (75%) of those with ABPA and 12 of 24 (50%) with CPA had resistance markers present, some without prior triazole treatment, and in most despite adequate plasma drug concentrations around the time of sampling. CONCLUSIONS The very low organism burdens of fungi causing infection have previously prevented direct culture and detection of antifungal resistance in clinical samples. These findings have major implications for the sustainability of triazoles for human antifungal therapy.

P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. METHODS We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730. FINDINGS Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. INTERPRETATION P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. FUNDING Afferent Pharmaceuticals.

Acoustic Cough?Reflux Associations in Chronic Cough: Potential Triggers and Mechanisms

BACKGROUND & AIMS Central sensitization is thought to play a role in chronic cough and might explain the temporal association between cough and gastroesophageal reflux (GOR) in patients in whom non-GOR causes have been excluded. Using our novel simultaneous acoustic cough recording and impedance/pH monitoring technique, we aimed to explore this further by assessing such temporal associations and their relationship to the acidity, duration, and proximal extent of reflux and the presence of erosive disease and cough reflex sensitivity in unselected patients (ie, including non-GOR causes) with chronic cough. METHODS Twenty-four hour ambulatory acoustic cough monitoring with simultaneous impedance/pH recording was carried out in 71 unselected patients with chronic cough, aged 51-64 years (47 female). In addition, all patients underwent cough reflex sensitivity testing to citric acid, and 66 patients underwent gastroscopy. Temporal associations between cough and reflux were expressed using the symptom association probability. RESULTS Seventy percent of patients exhibited temporal associations, with 48% having a positive symptom association probability (SAP(R-C)) for cough preceded by reflux (mainly distal), 56% a positive symptom association probability (SAP(C-R (2 min))) for reflux preceded by cough, and 32% both. Moreover, SAP(R-C) positive patients had a more sensitive cough reflex (P = .03) but similar esophageal reflux exposure and erosive disease, together with similar prevalence of extraesophageal causes of cough compared with SAP(R-C) negative patients. Reflux immediately following cough was rare. CONCLUSIONS Cough temporally associates with reflux irrespective of proposed diagnoses, may be self-perpetuating in some patients, and is likely to be driven by central processes.

Expert opinion on the cough hypersensitivity syndrome in respiratory medicine

In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area. Cough hypersensitivity syndrome was clearly endorsed by opinion leaders as a valid and useful concept http://ow.ly/zxk83

Chronic cough: how do cough reflex sensitivity and subjective assessments correlate with objective cough counts during ambulatory monitoring?

Background: Cough reflex sensitivity, subjective estimates of cough frequency and cough-related quality of life have been used to assess cough and monitor treatment responses. The relationships between these measures and objective cough monitoring remain unclear and the usefulness of subjective assessments remains questionable. Subjects: 62 patients with chronic cough (39 women) were studied. Mean age of patients was 54.9 (SD 12.2) years, with a median duration of cough of 5.5 (range 1–30) years. Methods: Cough reflex sensitivity testing (C5; citric acid) was performed in all patients before fully ambulatory day-time and night-time cough recordings. Patients scored the frequency and severity of their cough (Visual Analogue Scales (VAS) and 0–5 score) for each recording period and completed a cough-related quality-of-life questionnaire, Leicester Cough Questionnaire (LCQ). Ambulatory cough recordings were manually counted and reported in terms of cough seconds per hour (cs/h). Cough rates were log10 transformed for analysis. Results: The median time spent coughing was 11.36 (range 1.06–46) cs/h with median day rates of 15.59 (range 2–74.8) cs/h and median night rates of 2.94 (range 0–26.67) cs/h. An inverse relationship was seen between day cough rates and log10 C5 (r = −0.452, p⩽0.001). Subjective cough scores and visual analogue scales were only moderately associated with objective time spent coughing, with night-time being scores more strongly associated than day-time scores. The strongest correlation with objective cough frequency was cough-related quality of life (LCQ), (r = −0.622, p⩽0.001), mediated through the psychological domain. Conclusions: Subjective measures of cough and cough reflex sensitivity are only moderately related to objective time spent coughing, and hence cannot be used as surrogate markers for objective cough-frequency measurements. Cough-related quality of life (LCQ) is most strongly related to objectively counted cough, and may be a useful adjunct to objective measures in the assessment of cough.

Sex differences and predictors of objective cough frequency in chronic cough

Background: Women are consistently over-represented in specialist cough clinics and known to have a more sensitive cough reflex than men. Whether female sex and other patient characteristics are associated with higher cough rates is not known. A study was conducted to determine the predictors of objective cough frequency in patients presenting to a tertiary referral clinic with chronic cough. Methods: 100 subjects (65 women) of mean (SD) age 55.8 (11.0) years and median cough duration 4 years (IQR 2.0–10.0) with unexplained chronic cough completed flow-volume loops (mean (SD) forced expiratory volume in 1 s 103 (15.2)% predicted; forced expiratory flow (FEF50) 68.8 (24.1)% predicted), methacholine challenge (42% positive), citric acid cough reflex sensitivity (C5; 0.12 M (IQR 0.06–0.50)) and the Leicester Cough Questionnaire. 24-h ambulatory cough monitoring was performed in 86 subjects; manually counted coughs were quantified as the number of explosive cough sounds per hour. Results: Women coughed significantly more than men (geometric mean 16.6 coughs/h (95% CI 13.1 to 21.0) vs 9.4 coughs/h (95% CI 6.4 to 13.9), p = 0.01)). The cough reflex was also more sensitive in women than in men (median logC5 −0.9 M vs −0.6 M, p = 0.002), but cough-related quality of life was similar in women and men (12.0 (3.6) and 12.2 (3.2), respectively, p = 0.76). Linear regression analysis showed that 38.6% of the variation in cough rate was predicted by sex (p = 0.01), logC5 (p<0.001) and age (p = 0.002) but not lung function or bronchial hyper-reactivity. Conclusions: Ambulatory objective cough monitoring provides novel insights into factors modulating chronic cough. These findings suggest that effects of sex and age must be taken into account in the study of cough and when designing clinical trials testing novel antitussive agents.

Dimensions of respiratory symptoms in preschool children: Population-based birth cohort study

RATIONALE A focus on distinctive collections of symptoms may be more informative of the probability of respiratory disease than individual and possibly transient phenotypes. However, such collections or components of overall symptomatology need to be valid, and their relationship established with the known risk factors and physiologic measures. OBJECTIVES To analyze detailed parentally reported respiratory symptoms by principal components analysis and derive symptom components; to examine the relationship of such components with measures of lung physiology and atopy. METHODS An unselected, population-based birth cohort (n = 946). MEASUREMENTS AND MAIN RESULTS Interviewer-administered questionnaires, lung function (specific airway resistance [sRaw]), airway reactivity (dry air challenge), and atopic status were obtained at ages 3 and 5 years; principal components analysis and multivariate analysis of variance were used to analyze the data. The four-component solution (wheeze, cough, colds, chronic symptoms) explained 53.2% of the variance in symptoms at age 3, and the five-component solution (wheeze, wheeze with irritants, wheeze with allergens, cough, chest congestion) explained 49.8% of variance at age 5. The multivariate analysis revealed novel relationships between symptoms, risk factors for asthma, and measures of lung function. At age 3, sRaw and the interaction between maternal asthma and childs atopy were not only related to wheeze but also independently to the cough component. At age 5, overall wheeze and allergic wheeze were related to lung function and airway reactivity; childs atopy was only related to symptoms when considered as a continuous trait. CONCLUSIONS Our analysis supports the need to move beyond the presence or absence of individual symptoms. Syndromes of coexisting symptoms more likely reflect underlying pathophysiologic processes.

Objective measurement of cough during pulmonary exacerbations in adults with cystic fibrosis

Background: Little is known about cough frequency in adults with cystic fibrosis (CF). This study aimed to determine (1) daytime and overnight cough rates in patients with CF at the beginning and end of a course of antibiotics for treatment of an exacerbation; (2) the relationship between cough frequencies and standard clinical measures of disease; and (3) the relationship between objective cough rates and the subjective assessment of cough. Methods: Nineteen adult patients admitted with a pulmonary exacerbation performed daytime and overnight sound recordings on admission; 13 had repeat recordings prior to discharge. Coughs were manually quantified in cough seconds (time spent coughing). Patients subjectively scored their cough using a visual analogue scale (VAS) and numerical score. Lung function, C-reactive protein (CRP) levels, and sputum weights were recorded. Results: Cough rates fell substantially with treatment; median fall in cough rate was 51.3% (IQR 32.3–77.5) (p<0.001) for daytime and 72.2% (28.6–90.1) (p = 0.049) for overnight. Multivariate regression analyses showed that forced expiratory volume in 1 second and CRP levels predicted overnight cough rates on admission. On discharge, sputum volume predicted daytime cough rates. Only the change in overnight VAS correlated with the change in objective cough rates. Conclusions: The cough rate significantly decreases with treatment of a pulmonary exacerbation in adults with CF. Lung function, sputum volume, and CRP influences the cough rate, with the effects differing from day to night and between admission and discharge. Subjective reporting of a nocturnal cough may indicate a pulmonary exacerbation of CF in adults.

Objective cough frequency in Idiopathic Pulmonary Fibrosis

BackgroundCough is a common presenting symptom in patients with Idiopathic Pulmonary Fibrosis (IPF). This study measured cough rates in IPF patients and investigated the association between cough and measures of health related quality of life and subjective cough assessments. In addition, IPF cough rates were related to measures of physiological disease severity and compared to cough rates in health and other respiratory conditions.MethodsNineteen IPF patients, mean age 70.8 years ± 8.6, five female (26.3%) were studied. Subjects performed full pulmonary function testing, 24 hour ambulatory cough recordings, completed a cough related quality of life questionnaire (Leicester Cough Questionnaire) and subjectively scored cough severity with a visual analogue scale. Ambulatory cough recordings were manually counted and reported as number of coughs per hour.ResultsThe 24hr cough rates were high (median 9.4, range 1.5-39.4), with day time rates much higher than night time (median 14.6, range 1.9-56.6 compared to 1.9, range 0-19.2, p = 0.003). Strong correlations were found between objective cough frequency and both the VAS (day r = 0.80, p < 0.001, night r = 0.71, p = 0.001) and LCQ (r = -0.80, p < 0.001), but not with measures of pulmonary function. Cough rates in IPF were higher than healthy subjects (p < 0.001) and asthma patients (p < 0.001) but similar to patients with chronic cough (p = 0.33).ConclusionsThis study confirms objectively that cough is a major, very distressing and disabling symptom in IPF patients. The strong correlations between objective cough counts and cough related quality of life measures suggest that in IPF patients, perception of cough frequency is very accurate.