Helen Sumner

A comparison of objective and subjective measures of cough in asthma.

BACKGROUND Cough is widely recognized as a key symptom in the diagnosis and the monitoring of asthma, but little is known about how best to assess cough in asthma. OBJECTIVE To determine how objective cough rates correlate with subjective measures of cough in asthma. METHODS We studied 56 subjects, median age 42.0 years (range, 28.5-71), 34 (60.7%) female, with asthma. Subjects performed cough reflex sensitivity testing (concentration of citric acid causing 2 and 5 coughs [C2 and C5]), 24-hour fully ambulatory cough recordings, subjectively scored the severity of their cough (visual analog scales and 0-5 score) and completed a cough-related quality of life questionnaire (Leicester Cough Questionnaire). Ambulatory cough recordings were manually counted and reported in cough seconds per hour (cs/h). RESULTS The median time spent coughing was 2.6 cs/h (range, 0.0-14.2), with subjects spending more time coughing by day (median, 3.9 cs/h [0.0-18.5]) than by night (median, 0.3 cs/h [0.0-8.7]; P < .001). A weak inverse relationship was seen between day cough rates and log(10)C2 (r = -0.39; P = .03) but not log(10)C5 (r = -0.08; P = .65). Objective time spent coughing was also weak-moderately associated with subjective cough scores and visual analog scales, and most strongly correlated with cough-related quality of life (r = -0.54; P < .001). CONCLUSION Subjective measures of cough and cough reflex sensitivity are poor surrogates for objective cough frequency in asthma. When designing studies to assess interventions for cough in asthma, we advocate a combination of both objective measures of cough and cough-related quality of life.

Predictors of objective cough frequency in chronic obstructive pulmonary disease.

RATIONALE Cough is one of the principal symptoms of chronic obstructive pulmonary disease (COPD) but the potential drivers of cough are likely to be multifactorial and poorly understood. OBJECTIVES To quantify cough frequency in an unselected group of subjects with COPD and investigate the relationships between cough, reported sputum production, smoking, pulmonary function, and cellular airway inflammation. METHODS We studied 68 subjects with COPD (mean age, 65.6 ± 6.7 yr; 67.6% male; 23 smokers; 45 ex-smokers) and 24 healthy volunteers (mean age, 57.5 ± 8.9 yr; 37.5% male; 12 smokers; 12 nonsmokers). Subjects reported cough severity, cough-specific quality of life, and sputum expectoration and performed spirometry, sputum induction, cough reflex sensitivity to capsaicin, and 24-hour ambulatory cough monitoring. MEASUREMENTS AND MAIN RESULTS COPD current smokers had the highest cough rates (median, 9 coughs/h [interquartile range, 4.3-15.6 coughs/h]), almost double that of COPD ex-smokers (4.9 [2.3-8.7] coughs/h; P = 0.018) and healthy smokers (5.3 [1.2-8.3] coughs/h; P = 0.03), whereas healthy volunteers coughed the least (0.7 [0.2-1.4] coughs/h). Cough frequency was not influenced by age or sex and only weakly correlated with cough reflex sensitivity to capsaicin (log C5 r = -0.36; P = 0.004). Reported sputum production, smoking history, and current cigarette consumption strongly predicted cough frequency, explaining 45.1% variance in a general linear model (P < 0.001). In subjects producing a sputum sample, cough frequency was related to current cigarette consumption and percentage of sputum neutrophils (P = 0.002). CONCLUSIONS Ambulatory objective monitoring provides novel insights into the determinants of cough in COPD, suggesting sputum production, smoking, and airway inflammation may be more important than sensitivity of the cough reflex.

Preventing Severe Asthma Exacerbations in Children: A Randomised Trial of Mite Impermeable Bedcovers

&NA; Rationale: Allergen exposure in sensitized individuals with asthma interacts with viruses to increase the risk of asthma exacerbation. Objectives: To evaluate the use of house dust mite‐impermeable bedding and its impact on severe asthma exacerbations in children. Methods: We randomized mite‐sensitized children with asthma (ages 3‐17 yr) after an emergency hospital attendance with an asthma exacerbation to receive mite‐impermeable (active group) or control (placebo group) bed encasings. Measurements and Main Results: Over a 12‐month intervention period, the occurrence of severe asthma exacerbations was investigated. Of 434 children with asthma who consented, 286 (mean age, 7.7 yr; male sex, 65.8%) were mite sensitized, and 284 were randomized (146 to the active group and 138 to the placebo group). At 12 months, significantly fewer children in the active group than in the placebo group had attended the hospital with an exacerbation (36 [29.3%] of 123 vs. 49 [41.5%] of 118; P = 0.047). In the multivariable analysis, the risk of emergency hospital attendance was 45% lower in the active group (hazard ratio, 0.55; 95% confidence interval [CI], 0.36‐0.85; P = 0.006) than in the placebo group. The annual rate of emergency hospital attendance with exacerbations was 27% lower in the active group than in the placebo group, but this did not reach significance (estimated marginal mean [95% CI], active, 0.38 [0.26‐0.56] vs. placebo, 0.52 [0.35‐0.76]; P = 0.18). No difference between the groups in the risk of prednisolone use for exacerbation was found (hazard ratio, 0.82; 95% CI, 0.58‐1.17; P = 0.28). Conclusions: Mite‐impermeable encasings are effective in reducing the number of mite‐sensitized children with asthma attending the hospital with asthma exacerbations but not the number requiring oral prednisolone. This simple measure may reduce the health care burden of asthma exacerbations in children. Clinical trial registered with www.isrctn.com (ISRCTN 69543196).

Objective measurement of cough in otherwise healthy volunteers with acute cough

Cough is one of the commonest reasons for medical consultation and acute cough associated with upper respiratory tract infections (URTIs) is a global problem. In otherwise healthy volunteers complaining of cough associated with symptoms of URTI, we aimed to assess objective and subjective measures of cough and their repeatability and perform power calculations for the design of future studies to test therapies. We studied 54 otherwise healthy volunteers with acute cough (<3 weeks) (median age 22 yrs (interquartile range 21–26 yrs), 64% female, mean forced expiratory volume in 1 s 97.6±10.5% predicted). All subjects performed 24-h ambulatory cough monitoring and reported cough frequency and severity using visual analogue scales (VAS) on 2 consecutive days. Sample size calculations were performed for crossover and parallel group study designs. Objective cough frequency was high (session 1: geometric mean 12.1 coughs·h−1 (95%CI 9.7–15.2)) and fell significantly (session 2: 9.0 coughs·h−1 (95%CI 6.9–11.6); p<0.001). Repeatability was higher for objective cough frequency (intra-class correlation coefficient (ICC)=0.94, p<0.001) than reported cough frequency (daytime VAS ICC=0.784, p<0.001). Crossover/parallel studies require <15 and <41 subjects per arm to detect a 50% reduction in cough frequency with 90% power, respectively. Acute cough frequency is highly repeatable over any 48-h period, allowing small sample sizes to be used when investigating the effectiveness of novel anti-tussives.

S139 Cough responses to tussive agents in health and disease

Introduction Capsaicin or citric acid cough challenges have been used as an objective measure of cough reflex sensitivity for many decades. It remains unclear how the response to these agents differs in different diseases and how the response to one cough challenge agent differs from that to another. Prostaglandin E2 is known to result in cough when given as an inhalational agent, but has not been used as inhalational cough challenge agent. Objectives To assess the ability of individual challenges and combined challenge responses to discriminate between diagnostic groups and healthy volunteers. Methods We studied 102 subjects, median age 60.0 years (IQR 51.0–65.0) and 50% female (healthy volunteers n=21, healthy smokers n= 20, COPD n=18, asthma n=22 and chronic cough n=21). A doubling-dose, single inhalation method was used to measure the concentration of capsaicin (CAP), citric acid (CA) and prostaglandin E2 (PGE2) evoking at least 5 coughs (C5) within 15 s of administration, performed at weekly intervals. The operator was blinded to the challenge agent and each challenge contained 3 randomly interspersed placebo inhalations (saline). Data was analysed by multinomial logistic regression with healthy volunteers used as the reference category. Results Smokers (p=0.03) and COPD patients (p=0.003) had a significantly higher PGE2 logC5 than healthy volunteers. CA logC5 however was significantly lower in asthma (p=0.013), and chronic cough (p=0.001) compared with healthy volunteers. CAP logC5 was also significantly lower in chronic cough (p<0.001) but also in COPD (p=0.035) compared with healthy volunteers. Combining responses to all challenge agents suggested each individual challenge independently predicted the differences between disease groups and healthy volunteers (PGE2 p<0.001, CA p=0.018 and CAP p=0.015). Conclusions Cough responses to inhalational cough challenges can discriminate healthy controls from airway diseases. Furthermore, cough challenge agents differ in their ability to distinguish health from disease implying different underlying mechanisms drive coughing in these diagnoses. A combination of cough challenge tests appears to be better at discriminating diagnostic groups compared with any individual test in isolation.

S115 Magnitude of cough response to inhaled capsaicin differentiates between health and disease

Background Patients with chronic cough (CC) have substantially higher 24-h cough rates compared to patients with asthma (A) or healthy controls (HC). CC patients also have a more sensitive cough reflex, when measured as the ‘threshold’ dose of a tussive agent (eg, capsaicin) inducing at least two or five coughs (C2/C5), although there is substantial overlap between CC and HC. We aimed to investigate if the ‘magnitude’ of cough response to inhaled capsaicin would better differentiate CC patients from A and HC subjects. Methods We devised a cough challenge technique, with increasing doubling concentrations of capsaicin (0.48–1000 μMol) extended beyond the C5 threshold, up to the maximum tolerated dose. At each capsaicin concentration four single-breath inhalations were administered from a dosimeter 30 s apart. After each inhalation, the number of coughs in the first 15 s was counted. Using Generalised Estimating Equations (GEE), we explored the effect of group and gender on average cough response to increasing concentrations of capsaicin. Results We studied 20 treatment resistant CC, 18 stable mild/moderate A and 20 HC subjects, matched for age and gender; (M:F 10:10, 9:9,10:10, respectively), age [mean (±SD) 57.1 years (±15.7), 51.7 years (±13.5), 58.8 years (±13.5); p=0.17], and lung function  [3.02L (±0.98), 2.96L (±1.10), 3.20L (±0.99); p=0.72]. CC (vs HC p<0.001) and females (vs males, p<0.001) cough significantly more after capsaicin (see Abstract S115 Figure 1). There was no significant difference between A and HC (p=0.407).Abstract S115 Figure 1 Average cough frequency with increasing doubling doses of capsaicin (log 10 scale) according to group. Adjusted means and 95% CI from GEE model shown. Conclusions Magnitude of cough responses to inhaled capsaicin, beyond the standard endpoints: clearly discriminates chronic cough from healthy controls, demonstrates gender differences, may be valuable for investigation of physiological mechanisms and anti-tussive agents. In addition to a reduced cough threshold, these findings are consistent with a failure of inhibitory mechanisms to prevent coughing to repetitive and potent stimuli in chronic cough.

P241 The feasibility and validity of objective cough monitoring in children using an adult cough detection system

Background In young children the evaluation of symptoms is almost wholly reliant upon parental reporting. Cough is extremely common in childhood and a tool to objectively measure cough frequency would be clinically beneficial. To date paediatric cough monitoring systems have relied on manual cough counting which is time consuming and costly. The VitaloJAK™ (Vitalograph, UK) is a custom built 24 hr semi-automated cough monitoring device that has been used successfully to quantify cough in adults. Using the VitaloJAK™ we tested the feasibility of 24 hr cough recordings in children and tested existing compression software for cough quantification. Methods Children (age 2–14 years) with acute or chronic cough were asked to wear VitaloJAK™ cough monitor for a maximum of 24 h. Feedback about the device was obtained from the child/carer were appropriate. All recordings were manually counted and also processed through the compression software. Results 40 children (21 male; mean age 8 yrs) wore the monitor for a median of 22.25 h (0.38 – 24 hrs). Children who wore the monitor as out-patients with chronic cough generally wore the monitor for longer (median 23.07 hrs) than those who were in-patients with acute symptoms (median 12.59 hrs; p = 0.06). Twenty-nine children (73%) wore the monitor for >12 h and 22 for >22 hrs including during the night. Eighteen (45%) children reported the monitor was heavy/bulky and eleven (28%) said at times it restricted some normal daily tasks (bending/stooping/using the toilet). Neither length of time the monitor was worn for, nor complaints about the size or restricting nature of the monitor, were age dependent. No serious adverse events were reported. One recording was excluded due to technical problems. Recordings demonstrated wide variability in frequency from 2 to 2712 coughs per recording (median 72). Following compression a median of 98.5% (85.7–100) of coughs were retained. Conclusions VitaloJAK™ semi-automated cough monitor can be used in children to accurately measure cough frequency. As with many medical interventions, it was not tolerated by all children for long periods, however the majority of children were able to wear it for >12 h.

P93 The practicalities of using allergen-impermeable bed covers in children with mite allergic asthma

Objective As part of a randomised double-blind placebo-controlled study in children with mite-allergic asthma, mite-impermeable bedding encasings were evaluated in terms of reduction in allergen exposure and patient/parent acceptability. Methods Physician diagnosed asthmatic children (3–17 years) were recruited following an exacerbation of asthma. Mite-sensitised children were randomised to either mite-impermeable encasings for the mattress, pillow and duvet (Astex Pristine; ACP solutions, Gloucestershire, UK) or placebo encasings (100% polycotton; Musbury fabrics, Rossendale, UK), in a double-blind manner. Vacuumed dust samples were collected from the child’s mattress prior to fitting the encasings and at 12 months, stored at -20°C, then analysed for mite allergen content (Der p1) by enzyme-linked immunosorbent assay (Indoor Biotechnologies, Cardiff, UK). Questions aimed at assessing the practicalities of using the encasements were asked of parents by an interviewer blind to their allocation, 8–12 months later. Results 284 children (mean age 7.7 years; 65.8% male) were randomised (146 active; 136 placebo). There was an 84% decrease in Der p 1 levels in child’s mattress in those using the mite-impermeable encasings, which was not seen in the Placebo group (p < 0.001). Data on ‘use of bedding encasements’ were obtained from 232 participants. Significantly more families in the active group reported that the duvet slipped within its cover, compared to the placebo group (32.2% vs 5.3% respectively, p < 0.001) and that it was “noisy” (14.4% active vs 0.9% in placebo, p < 0.001). Some reported the extra covers made them too warm (3.4% active vs 1.8% placebo, p = 0.64). Overall 31(26.3%) using the mite-impermeable encasings rated them as “uncomfortable” compared with 2(1.8%) in the placebo group (p < 0.001). Furthermore, 30(25.4%) children in the mite-impermeable group said they would prefer to have the encasings removed, compared to 3(2.6%) in the placebo group (p < 0.001). There was no difference in the numbers of families who stated that they would continue to use the encasings if it were of benefit to the child, (87.3% mite-impermeable vs 89.35% placebo p = 0.68) Conclusions Mite-impermeable encasings can significantly reduce mite allergen levels in the bed. Despite some practical issues, most families are willing to use this intervention if it is of benefit to their child’s asthma.

S116 Urge-to-cough intensity in chronic cough patients compared to asthmatics and healthy controls

Background Healthy subjects inhaling increasing doses of capsaicin perceive an urge-to-cough (UTC) prior to initiating coughing. We compared subjective ratings of UTC intensity following inhalation of capsaicin in patients with chronic cough (CC), asthma (A) and healthy controls (HC). Methods A double-blind, randomised block design, capsaicin cough challenge was performed using single-breath inhalations, separated by 1 min, through a dosimeter (inspiratory flow rate limited). Seven individually pre-determined doses (0.48–1000 μMol; maximum dose inducing an average of at least five coughs) and one placebo dose were administered four times each, in four individually randomised blocks (Davenport et al), to reduce the bias associated with subjective UTC ratings. After each inhalation, UTC was rated on a modified Borg scale (0–10) and number of coughs in the first 15 s was recorded. Using Generalised Estimating Equations (GEE), we explored the effect of group and gender on average UTC intensity and average cough responses to increasing concentrations of capsaicin. Results We studied 20 treatment resistant CC, 18 stable mild/moderate A and 20 HC subjects, matched for gender (M:F 10:10, 9:9,10:10, respectively), age [mean (±SD) 57.1 years (±15.7), 51.7 years (±13.5), 58.8 years (±13.5); p=0.17], and lung function [3.02L (±0.98), 2.96L (±1.10), 3.20L (±0.99); p=0.72]. CC had significantly greater UTC intensity (p=0.006, see Abstract S116 Figure 1) and cough responses (p=0.002) compared to HC. Females had significantly greater UTC (p=0.001) and cough responses (p<0.001) compared to males. There was no significant difference in UTC intensity (p=0.449) or cough responses (p=0.997) between A and HC.Abstract S116 Figure 1 Average urge to cough frequency with increasing doubling doses of capsaicin (log 10 scale) according to group. Adjusted means extracted from GEE model shown. Conclusions In a randomised double-blind capsaicin cough challenge: Chronic cough patients perceive a more intense UTC sensation and also demonstrate a greater magnitude of cough response than healthy controls. Females perceive a more intense UTC sensation than males. These findings suggest both a heightened sensory experience in addition to an excessive motor response in patients with chronic cough. This data could be explained by sensitisation of afferent pathways (ie, peripheral and/or central sensitisation) but also by impaired inhibitory control mechanisms.