Cough Rates Research Articles

Longitudinal Cough Frequency Monitoring in Persistent Coughers: Daily Variability and Predictability

PurposeWe determined the cough counts and their variability in subjects with persistent cough for 30 days.MethodsThe Hyfe cough tracker app uses the mobile phone microphone to monitor sounds and recognizes cough with artificial intelligence-enabled algorithms. We analyzed the daily cough counts including the daily predictability rates of 97 individuals who monitored their coughs over 30 days and had a daily cough rate of at least 5 coughs per hour.ResultsThe mean (median) daily cough rates varied from 6.5 to 182 (6.2 to 160) coughs per hour, with standard deviations (interquartile ranges) varying from 0.99 to 124 (1.30 to 207) coughs per hour among all subjects. There was a positive association between cough rate and variability, as subjects with higher mean cough rates (OLS) have larger standard deviations. The accuracy of any given day for predicting all 30 days is the One Day Predictability for that day, defined as the percentage of days when cough frequencies fall within that day’s 95% confidence interval. Overall Predictability was the mean of the 30-One Day Predictability percentages and ranged from 95% (best predictability) to 30% (least predictability).ConclusionThere is substantial within-day and day-to-day variability for each subject with persistent cough recorded over 30 days. If confirmed in future studies, the clinical significance and the impact on the use of cough counts as a primary end-point of cough interventions of this variability need to be assessed.

Evaluating the protective effectiveness and risk factors of ursodeoxycholic acid on COVID-19 among outpatients.

Objective: This study aimed to assess the chemopreventive effect of ursodeoxycholic acid (UDCA) against COVID-19 and to analyze infection risk factors, symptoms, and recovery in outpatients with UDCA exposure. Methods: The study enrolled outpatients prescribed UDCA from the Second Affiliated Hospital of Chongqing Medical University, China, between 01 July 2022, and 31 December 2022. Data on demographics, comorbidities, and drug combinations were collected using electronic medical records. COVID-19 infection, symptoms, severity, prognosis, vaccinations, and UDCA administration were surveyed by telephone interviews. UDCA non-users served as controls and were matched in a 1:2 ratio with UDCA users using propensity score matching with the nearest neighbor algorithm. Infection rates, symptomatology, severity, and prognosis were compared between matched and control cohorts, and risk factors and infection and recovery symptoms were analyzed in UDCA-exposed outpatients. Results: UDCA-exposed outpatients (n = 778, 74.8%) and matched UDCA users (n = 95, 74.2%) showed significantly lower SARS-CoV-2 infection rates than control patients (n = 59, 92.2%) (p < 0.05). The matched UDCA group exhibited substantially lower fever, cough, sore throat, and fatigue rates than controls (p < 0.05). Participants with UDCA exposure generally experienced mild symptoms, while those without UDCA had moderate symptoms. The matched UDCA group also had significantly shorter durations of fever and cough (p < 0.05). Risk factors such as age over 60, less than 1month of UDCA administration, diabetes mellitus, and coronary artery disease significantly increased SARS-CoV-2 infection rates (p < 0.05), while smoking led to a decrease (p < 0.05). Hypertension was associated with a prolonged COVID-19 recovery (p < 0.05), while smoking, vaccination, and fatty liver disease were associated with shorter recovery periods (p < 0.05). The main symptoms in the full UDCA cohort were fever, cough, and sore throat, with fatigue, cough, and hyposthenia being the most persistent. Conclusion: UDCA demonstrated chemopreventive effect against SARS-CoV-2 in outpatients by significantly reducing infection incidence and mitigating COVID-19 symptoms, severity, and recovery duration. Old age, short UDCA course, and comorbidities such as diabetes mellitus and CAD increased infection rates, while hypertension prolonged recovery. Smoking, vaccination, and fatty liver disease reduced infection rates and shortened recovery. UDCA had minimal impact on symptom types. Larger and longer-term clinical studies are needed further to assess UDCA's effectiveness in COVID-19 prevention or treatment.

Inhaled alkaline hypertonic divalent salts reduce refractory chronic cough frequency.

Treatment of chronic cough remains a challenge. We hypothesised that inhaled alkaline hypertonic divalent salts (alkaline HDS) might provide relief for refractory chronic cough by laryngeal and tracheal hydration. We conducted an exploratory, single-blinded, nasal saline-controlled study in 12 refractory chronic cough patients to examine cough suppression efficacy of an alkaline HDS composition (SC001) at pH 8 or pH 9 administered by nasal inhalation. As control, we used nasal saline with the same hand-held pump spray aerosol device. Each subject was monitored continuously using a digital cough monitor watch for 1 week of baseline, 1 week of control treatment and 1 week of active treatment. Baseline daily cough rates ranged from 4 to 34 coughs·h-1 with mean visual analogue score 65±17 pre- and post-baseline testing. Control-adjusted efficacy of cough rate reduction ranged from 15% (p=0.015) (from Day 1) to 23% (p=0.002) (from Day 3). Control-adjusted efficacy was highest with SC001 pH 9 (n=5), ranging from 25% (p=0.03) (from Day 1) to 35% (p=0.02) (from Day 3), and lowest for SC001 pH 8 (n=7), ranging from 9% (p=0.08) (from Day 1) to 16% (p=0.02) (from Day 3). Hourly cough counts and visual analogue score correlated for baseline (r=0.254, p=0.02) and control (r=0.299, p=0.007) monitoring weeks. Treatment improved this correlation (r=0.434, p=0.00006). No adverse events were reported. Alkaline (pH 9) HDS aerosol is a promising treatment for refractory chronic cough and should be further evaluated.

Comparative Analysis of Patient Satisfaction and Sedation Outcomes in Bronchoscopy: Fentanyl/Chlorpheniramine vs. Ketamine/Chlorpheniramine

This randomized clinical trial aimed to assess and compare patient satisfaction and sedation outcomes in bronchoscopy procedures using two distinct sedation protocols: fentanyl/chlorpheniramine (FC) and ketamine/chlorpheniramine (KC). Ninety patients undergoing simple bronchoscopy and bronchoalveolar lavage were randomly assigned to receive either FC (1 µg/kg fentanyl and 10 mg chlorpheniramine) or KC (0.5 mg/kg ketamine and 10 mg chlorpheniramine). Lidocaine was also administered during bronchoscopy. Primary outcomes included patient satisfaction scores, while secondary outcomes encompassed sedation levels, bronchoscopist satisfaction, cough rates, lidocaine usage, and physiological parameters. Patients in the FC group exhibited significantly higher satisfaction levels compared to the KC group (P=0.002). Bronchoscopist satisfaction was also superior in the FC group (P=0.001). Although cough rates did not differ significantly, severe persistent coughs were more prevalent in the KC group. Physiological parameters such as oxygen saturation were comparable, but the KC group demonstrated higher increases in systolic blood pressure and heart rate. The use of fentanyl/chlorpheniramine resulted in higher patient and bronchoscopist satisfaction during simple bronchoscopy and bronchoalveolar lavage compared to ketamine/chlorpheniramine. This study suggests that the combination of fentanyl and chlorpheniramine may be a preferable sedation choice for bronchoscopy procedures.

Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis. The PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40-90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed. Between Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82% (17·3), and mean predicted diffusion capacity of carbon monoxide was 48% (10·9). Of the 44 patients who were randomised, 43 completed morphine treatment and 41 completed placebo treatment. In the intention-to-treat analysis, morphine reduced objective awake cough frequency by 39·4% (95% CI -54·4 to -19·4; p=0·0005) compared with placebo. Mean daytime cough frequency reduced from 21·6 (SE 1·2) coughs per h at baseline to 12·8 (1·2) coughs per h with morphine, whereas cough rates did not change with placebo (21·5 [SE 1·2] coughs per h to 20·6 [1·2] coughs per h). Overall treatment adherence was 98% in the morphine group and 98% in the placebo group. Adverse events were observed in 17 (40%) of 43 participants in the morphine group and six (14%) of 42 patients in the placebo group. The main side-effects of morphine were nausea (six [14%] of 43 participants) and constipation (nine [21%] of 43). One serious adverse event (death) occurred in the placebo group. In patients with cough related to idiopathic pulmonary fibrosis, low dose controlled-release morphine significantly reduced objective cough counts over 14 days compared with placebo. Morphine shows promise as an effective treatment to palliate cough in patients with idiopathic pulmonary fibrosis, and longer term studies should be the focus of future research. The Jon Moulton Charity Trust.

Objective and self-reported evidence of dextromethorphan antitussive efficacy in children, aged 6-11 years, with acute cough due to the common cold.

To determine objective and subjective endpoints most suitable for evaluating antitussive efficacy of dextromethorphan hydrobromide (DXM) in children. Spontaneous resolution of acute cough and large placebo effects are impediments to evaluating antitussive efficacy. Another impediment is paucity of age-appropriate, validated cough assessment tools. This was a multiple-dose, double-blind, placebo-controlled, randomized, pilot clinical study in children, aged 6-11 years, with cough due to the common cold. Eligible subjects met entry criteria and qualified by completing a run-in period where coughs were recorded with a cough monitor after they were dosed with sweet syrup. They were subsequently randomized to receive DXM or placebo over 4 days. Coughs were recorded during the initial 24 h; subjective assessments of cough severity and frequency were self-reported daily during treatment. Data from 128 evaluable subjects (67 DXM; 61 placebo) were analyzed. Total coughs over 24-hours (primary endpoint) and cough frequency during daytime were reduced by 21.0% and 25.5%, respectively, with DXM relative to placebo. Also, greater reductions in cough severity and frequency were self-reported with DXM. These findings were statistically significant and medically relevant. No effects were detected between treatments for nighttime cough rates or impact of cough on sleep. Multiple doses of DXM and placebo were generally well-tolerated. Evidence of DXM antitussive efficacy was shown in children using objective and subjective assessment tools validated in pediatric populations. Diurnal variation of cough frequency over 24 h reduced the assay sensitivity needed to detect treatment differences at nighttime, as coughs/hour decreased during sleep for both groups.

DIGITAL ACOUSTIC SURVEILLANCE OF COUGH FOR THE DETECTION OF RESPIRATORY DISEASE

TYPE: Abstract TOPIC: Biotechnology PURPOSE: To evaluate the potential of AI-enabled syndromic surveillance tools for the detection of outbreaks of respiratory disease. METHODS: We carried out a prospective observational study (NCT04762693) between November 2020 and August 2021 in the province of Navarra, Spain. Participants recruited from the campus of the University of Navarra, in Pamplona, and neighboring towns were instructed to download a publicly available smartphone application that automatically detects and records episodes of cough, with their time and location. Clinical records from consenting participants were reviewed regularly. Aggregated cough data was compared with local incidence of covid-19, and the time of medical consultation due to respiratory symptoms, using a randomization routine. Focused group discussions were carried out to determine barriers and facilitators for the usage of the application. RESULTS: Cough rates of participants who consulted medical services were higher in the five-day period around the date of consultation, compared to the baseline (p = 0.012), suggesting that longitudinal cough records reflected changes in symptomatology. In contrast, no clear relationship between aggregated cough frequency and covid-19 incidence in the study area was observed. Interface simplicity and the possibility of observing changes of cough frequency in real time were appreciated by participants. The possibility of programming the application so it automatically starts and stops at certain times was the most common recommendation. CONCLUSIONS: Acoustic cough monitoring can capture changes in symptomatology. Adequate uptake and usage remain challenging. CLINICAL IMPLICATIONS: Upon further development, AI-enabled cough detection could offer an attractive complementary tool to traditional respiratory epidemiological surveillance. DISCLOSURE: JB is the CEO of Hyfe Inc. EK is a Hyfe employee. CCh discloses consultancy fees and equity from Hyfe. All other authors declare no conflict of interests. KEYWORD: cough

Cough and cold medicine prescription rates can be significantly reduced by active intervention

Our aim was to construct and test an intervention programme to eradicate cough and cold medicine (CCM) prescriptions for children treated in a nationwide healthcare service company. The study was carried out in the largest private healthcare service company in Finland with a centralised electronic health record system allowing for real-time, doctor-specific practice monitoring. The step-by-step intervention consisted of company-level dissemination of educational materials to doctors and families, educational staff meetings, continuous monitoring of prescriptions, and targeted feedback. Outreach visits were held in noncompliant units. Finally, those physicians who most often prescribed CCM were directly contacted. During the intervention period (2017–2020), there were more than one million paediatric visits. Prescriptions of CCMs to children were completely eradicated in 41% of units and the total number of CCM prescriptions decreased from 6738 to 744 (89%). During the fourth intervention year, CCMs containing opioid derivatives were prescribed for only 0.2% of children aged < 2 years. The decrease in prescriptions was greatest in general practitioners (5.2 to 1.1%). In paediatricians, the prescription rates decreased from 1.5 to 0.2%. The annual costs of CCMs decreased from €183,996 to €18,899 (89.7%). For the intervention, the developers used 343 h and the attended doctors used 684 h of work time during the 4-year intervention. The costs used for developing, implementing, reporting, evaluating, communicating, and data managing formed approximately 11% of total intervention costs.Conclusion: The study showed that a nationwide systematic intervention to change cough medicine prescription practices is feasible and requires only modest financial investments.What is Known:• Cough and cold medicines (CCM) are not effective or safe, especially for children aged 6 years.• Although the use of CCMs has been declining, caregivers continue to administer CCMs to children, and some physicians still prescribe them even for preschool children.What is New:• A nationwide systematic intervention can significantly and cost effectively change CCM prescription habits of paediatricians, general practitioners, and other specialists.• Electronic health records provide additional tools for operative guideline implementation and real-time quality monitoring, including recommendations of useless or harmful treatments.

The impact of topical lidocaine and timing of LMA removal on the incidence of airway events during the recovery period in children: a randomized controlled trial

BackgroundThe timing of laryngeal mask airway (LMA) removal remains undefined. This study aimed to assess the optimal timing for LMA removal and whether topical anesthesia with lidocaine could reduce airway adverse events.MethodsThis randomized controlled trial assessed one-to-six-year-old children with ASA I-II scheduled for squint correction surgery under general anesthesia. The children were randomized into the LA (lidocaine cream smeared to the cuff of the LMA before insertion, with mask removal in the awake state), LD (lidocaine application and LMA removal under deep anesthesia), NLA (hydrosoluble lubricant application and LMA removal in the awake state) and NLD (hydrosoluble lubricant application and LMA removal in deep anesthesia) groups. The primary endpoint was a composite of irritating cough, laryngeal spasm, SpO2 < 96%, and glossocoma in the recovery period in the PACU. The secondary endpoints included the incidence of pharyngalgia and hoarseness within 24 h after the operation, duration of PACU stay, and incidence of agitation in the recovery period. The assessor was unblinded.ResultsEach group included 98 children. The overall incidence of adverse airway events was significantly lower in the LA group (9.4%) compared with the LD (23.7%), NLA (32.6%), and NLD (28.7%) groups (P=0.001). Cough and laryngeal spasm rates were significantly higher in the NLA group (20.0 and 9.5%, respectively) than the LA (5.2 and 0%, respectively), LD (4.1 and 1.0%, respectively), and NLD (9.6 and 2.1%, respectively) groups (P=0.001). Glossocoma incidence was significantly lower in the LA and NLA groups (0%) than in the LD (19.6%) and NLD (20.2%) groups (P< 0.001). At 24 h post-operation, pharyngalgia incidence was significantly higher in the NLA group (15.8%) than the LA (3.1%), LD (1.0%), and NLD (3.2%) groups (P< 0.001).ConclusionsLMA removal in the awake state after topical lidocaine anesthesia reduces the incidence of postoperative airway events.Trial registrationChiCTR, ChiCTR-IPR-17012347. Registered August 12, 2017.

Clinical and Laboratory Comparison of Covid-19 and Influenza A/B in Children.

The clinical picture of COVID-19 shows significant similarity with influenza. In this study, it was aimed to compare the clinical and laboratory findings between pediatric patients diagnosed with COVID-19 and those with influenza A or B, and to obtain data on the differential diagnosis of COVID-19 from influenza in children. The study included 104 patients with COVID-19, 140 patients with influenza A and 135 patients with in-fluenza B (379 patients in total) who were admitted to our tertiary hospital with symptoms of acute respiratory tract infection. Fever, cough, runny nose, and pharyngeal hyperemia rates were significantly lower in patients with COVID-19 than in those with influenza A/B. The highest leukocytosis and lymphocytosis rates were seen in influenza A patients. Eosinophil levels were found significantly lower in the influenza A/B patients compared to the COVID-19 group. C-reactive protein levels were significantly higher in the influenza A/B group when compared with the COVID-19 group. The mean PDW value was significantly higher in the COVID-19 patients compared to influenza A/B. Our study data show that low body temperature and loss of taste and smell support the diagnosis of COVID-19, and fever, cough, pharyngeal hyperemia, and runny nose support the diagnosis of influenza. While leukocytosis and increased C-reactive protein suggest influenza, high PDW and eosinophil levels support COVID-19.

Characteristics of Asthma-related Nocturnal Cough: A Potential New Digital Biomarker.

IntroductionThe nature of nocturnal cough is largely unknown. It might be a valid marker for asthma control but very few studies characterized it as a basis for better defining its role and its use as clinical marker. This study investigated prevalence and characteristics of nocturnal cough in asthmatics over the course of four weeks.MethodsIn two centers, 94 adult patients with physician-diagnosed asthma were recruited. Patient-reported outcomes and nocturnal sensor data were collected by a smartphone with a chat-based study app.ResultsPatients coughed in 53% of 2212 nights (range: 0–345 coughs/night). Median coughs per hour were 0 (IQR 0–1). Nocturnal cough rates showed considerable inter-individual variance. The highest counts were measured in the first 30 min in bed (4.5-fold higher than rest of night). Eighty-six percent of coughs were part of a cough cluster. Clusters consisted of a median of two coughs (IQR 2–4). Nocturnal cough was persistent within patient.ConclusionTo the best of the authors’ knowledge, this study is the first to describe prevalence and characteristics of nocturnal cough in asthma over a period of one month, demonstrating that it was a prevalent symptom with large variance between patients and high persistence within patients. Cough events in asthmatics were 4.5 times more frequent within the first 30 min in bed indicating a potential role of positional change, and not more frequent during the early morning hours. An important next step will investigate the association between nocturnal cough and asthma control.

Dual Tasking Influences Cough Sensorimotor Outcomes in Healthy Young Adults.

Purpose Reflex cough is an essential airway protective mechanism that often occurs in the context of divided attention. The effect of divided attention on measures of reflexive cough airflow and sensitivity remains unknown. We present findings from a study testing the effects of divided attention (via a dual-task paradigm) on measures of reflex cough in healthy young adults. Method Volunteers (N = 20, age = 20-40 years) underwent 4 blocks of capsaicin-induced cough challenges. Within each block, capsaicin ranging from 0 to 200 μM was presented in a randomized order. Two blocks consisted of cough testing only (single task). During the other 2 blocks, participants counted tones while simultaneously undergoing cough testing (dual task). Measures of cough motor response, self-reported urge-to-cough, cough frequency, and cough airflow were collected. Results Participants coughed more in the single-task condition compared to the dual-task condition (p ≤ .001). Participants' urge-to-cough ratings were lower in the dual-task condition (x̅ = 2, "slight") compared to the single-task condition (x̅ = 3, "moderate"; p = .007). Participants' cough reflex sensitivity thresholds were significantly increased in the dual-task condition (p = .002). Cough peak expiratory flow rates did not change between the 2 conditions (p = .34). Conclusions Somatosensation of tussive stimuli changes during dual tasking. Abnormal cortical resource allocation may be a mechanism involved in silent aspiration.

Clinical evaluation of the use of an mhealth intervention on quality of care provided by Community Health Workers in southwest Niger.

BackgroundUnder the World Health Organization’s (WHO) integrated community case management (iCCM) Rapid Access Expansion Program (RAcE), World Vision Niger and Canada supported the Niger Ministry of Public Health to implement iCCM in four health districts in Niger in 2013. Community health workers (CHWs), known as Relais Communautaire (RCom), were deployed in their communities to diagnose and treat children under five years of age presenting with diarrhea, malaria and pneumonia and refer children with severe illness to the higher-level facilities. Two of the districts in southwest Niger piloted RCom using smartphones equipped with an application to support quality case management and provide good timely clinical data. A two-arm cluster randomized trial assessed the impact of use of the mHealth application mainly on quality of care (QoC), but also on motivation, retention and supervision.MethodsA two-arm cluster randomized trial was conducted from March to October 2016 in Dosso and Doutchi districts. The intervention arm comprised 66 RCom equipped with a smartphone and 64 in the paper-based control arm. Trained expert clinicians observed each RCom assessing sick children presenting to them (264 in intervention group; 256 in control group), re-assessed each child on the same set of parameters, and made further observations regarding perceptions of motivation, retention, supervision, drug management and caregiver satisfaction. The primary outcome was a QoC score composed of diagnostic and treatment variables. Other factors were assessed by questionnaires.ResultsOn average, the mHealth equipped RCom showed a 3.4% higher QoC score (mean difference of 0.83 points). They were more likely to ask about the main danger signs: convulsions (69.7% vs 50.4%, P < 0.001); incapacity to drink or eat (79.2% vs 59.4%, P < 0.001); vomiting (81.4% vs 69.9%, P < 0.01); and lethargy or unconsciousness (92.4% vs 84.8%, P < 0.01). Specifically, they consistently asked one more screening question. They were also significantly better at examining for swelling feet (40.2% vs 13.3%, P < 0.01) and advising caretakers on diarrhea, drug dosage and administration, and performed (though non-significantly) better when examining cough and breathing rates, referring all conditions, getting children to take prescribed treatments immediately and having caregivers understand treatment continuation. The control group was significantly better at diagnosing fast breathing, bloody diarrhea and severe acute malnutrition; and was somewhat better (non-significant) at treating fever and malaria. With treatment in general of the three diseases, there was no significant difference between the groups. On further inspection, 83% of the intervention group had a QoC score greater than 80% (25 out of 31), whereas only 67% of the control group had comparable performance. With respect to referrals, the intervention group performed better, mostly based on their better assessment of danger signs, with more correct (85% vs 29%) and fewer missed, plus a lower proportion of incorrect referrals, with the reverse being true for the controls (P = 0.012). There were no statistically significant differences in motivation, retention and supervision between the two groups, yet intervention RCom reported double the rate of no supervision in the last three months (31.8% vs 15.6%).ConclusionsResults suggest that use of the mHealth application led to modestly improved QoC through better assessment of the sick children and better referral decisions by RCom, but not to improvement in the actual treatment of malaria, pneumonia and diarrhea. Considering mHealth’s additional costs and logistics, questions around its viability remain. Further implementation could be improved by investing in RCom capacity building, building organization culture and strengthened supervision, all essential areas for improving any CHW program. In this real-world setting, in poor and remote communities in rural Niger, this study did not support the overall value of the mHealth intervention. Much was learned for any future mHealth interventions and scale-up.

Cardiovascular Safety and Efficacy of Nebulized Glycopyrrolate/eFlow CS in Phase 3 Trials of Patients With Moderate to Very Severe COPD

SESSION TITLE: COPD 2 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: The GOLDEN Phase 3 studies in subjects with moderate-to-very-severe COPD assessed the efficacy and safety of a novel, nebulized glycopyrrolate (GLY) and were prospectively designed to include subjects with cardiovascular (CV) risk factors. METHODS: In two 12-week and one 48-week study, 2379 subjects were stratified by CV risk (high vs low) and randomized to placebo, GLY 25 or 50 mcg twice daily, or tiotropium (TIO; 18 mcg once daily). Safety, lung function, patient-reported outcomes and exacerbations were assessed by CV risk subgroup. RESULTS: Across studies, 1526 subjects were at high CV risk and 853 were at low CV risk. At week 12, the incidence of adverse events leading to discontinuation was similar in high and low CV risk subgroups and lower in GLY 25 and 50 mcg groups (high: 6.2% and 3.6%; low: 3.2% and 4.5%) than placebo (high: 9.0%; low: 9.9%). In the 48-week study, discontinuations were higher for GLY (high: 10.7%; low: 8.7%) vs TIO (3.7%; 1.2%, respectively), partly due to increased cough and COPD event rates. CV events of special interest were low in both CV risk subgroups, and generally similar between treatments at 12 weeks (high: placebo, 3.6%; GLY 25 mcg, 1.1%; GLY 50 mcg, 2.2%; low: 0.7%; 2.6%; 1.9%, respectively). Incidences at 48 weeks were similar in the high CV risk group and numerically higher for TIO than GLY in the low CV risk subgroup, particularly for arrhythmias (high: GLY, 5.0%; TIO, 5.1%; low: GLY, 2.3%; TIO, 4.1%). Major adverse cardiac events (MACE) occurred more frequently with placebo in the high CV risk subgroup at 12 weeks (incidence rate [IR] for high vs low: placebo, 25.1 vs 0; GLY 25 mcg, 0 vs 0; GLY 50 mcg, 24.3 vs 21.6). At 48 weeks, IR for MACE were higher for TIO than GLY (high vs low: GLY, 6.7 vs 6.0; TIO 24.3 vs 13.6). GLY led to statistically significant, clinically important improvements in trough forced expiratory volume in 1 second (FEV1) in high and low CV risk subgroups at week 12 vs placebo (25 mcg, 95 and 97 mL; 50 mcg, 99 and 113 mL, respectively, p<0.001). The overall change from baseline in trough FEV1 was similar across CV risk subgroups for GLY (100 and 94 mL) and TIO (84 and 107 mL) over 48 weeks’ treatment. At week 12, in both subgroups, GLY produced statistically significant improvements (p<0.05) vs placebo in St George’s Respiratory Questionnaire (SGRQ) and the proportion of GLY responders was consistently higher than placebo. Over 48 weeks, change from baseline in SGRQ was higher for GLY vs TIO in the high CV risk subgroup, as was the proportion of GLY SGRQ responders at 48 weeks (47% vs 39%). Change and response for the low risk group was numerically higher for TIO than GLY. Exacerbation rates were similar across all treatment groups and most exacerbations were moderate in severity in both subgroups after 12 and 48 weeks. CONCLUSIONS: Nebulized GLY had an acceptable safety/tolerability profile and improved lung function and patient-reported outcomes in subjects with COPD and CV risk factors for up to 48 weeks. CLINICAL IMPLICATIONS: Nebulized GLY is well tolerated and effective and provides a novel treatment option in patients who may require or benefit from nebulized long-acting muscarinic antagonist therapy. DISCLOSURE: Gary Ferguson: Grant monies (from industry related sources): Sunovion Pharmaceuticals Inc., Grant monies (from industry related sources): Boehringer Ingelheim, Other: Sunovion Pharmaceuticals Inc., Other: Boehringer Ingelheim Robert Tosiello: Employee: Sunovion Pharmaceuticals Inc. Thomas Goodin: Employee: Sunovion Pharmaceuticals Inc. Abstract describes analysis from Phase 3 trials of nebulized glycopyrrolate in COPD (not currently approved)

The Effect of Concurrent Bronchodilator Therapy on the Efficacy and Safety of a Novel, Nebulized Glycopyrrolate in Phase 3 Studies in Subjects With Moderate to Very Severe COPD

SESSION TITLE: COPD: Advances in Pharmacotherapy SESSION TYPE: Original Investigation Slide PRESENTED ON: Tuesday, October 31, 2017 at 11:00 AM - 12:15 PM PURPOSE: The GOLDEN Phase 3 studies assessed the efficacy and safety of a novel, nebulized glycopyrrolate (GLY) for up to 48 weeks, and included subjects on stable doses of long-acting β2-agonists (LABA) ± inhaled corticosteroids (ICS) who continued background therapy over the treatment period. METHODS: In two 12-week placebo-controlled studies and one 48-week active-controlled study, 2379 subjects were stratified by background LABA±ICS (LABA-yes [n=861] vs LABA-no [n=1518]) and randomized to placebo, GLY 25 or 50 mcg twice daily (BID) via an investigational eFlow Closed System nebulizer (PARI Pharma, Germany), or tiotropium (TIO; 18 mcg once daily). Lung function, patient-reported outcomes, exacerbations and safety were assessed in the LABA subgroups. Statistical methodology included mixed-model repeated measures, analysis of covariance and descriptive safety data. RESULTS: GLY 25 and 50 mcg BID produced statistically significant and clinically important improvements vs placebo in trough forced expiratory volume in 1 second (FEV1; 92-110 mL, p<0.001) in LABA subgroups at week 12. The overall change from baseline in trough FEV1 was similar for GLY 50 mcg BID and TIO (92-106 mL) in both LABA subgroups at week 48. At 12 weeks, GLY produced statistically significant improvements in SGRQ in LABA subgroups (-2.073 to -3.888 vs placebo, p<0.05), and the proportion of SGRQ responders was consistently higher with GLY 25 and 50 mcg BID (LABA-yes: 48.3%, 43.4%; LABA-no: 46.1%, 40.9%) than placebo (yes: 24.8%; no: 38.7%). Over 48 weeks, change from baseline SGRQ in the LABA-yes subgroup was -5.190 for GLY and -3.094 for TIO, and -4.368 and -4.821, respectively, in the LABA-no subgroup. The proportion of GLY SGRQ responders was higher in the LABA-yes (53.7% vs 41.1% TIO) and similar to TIO in the LABA-no (42.6% vs 48.8% TIO) subgroups after 48 weeks. Exacerbation rates were generally similar across treatments and most were moderate in severity in both LABA subgroups after 12 and 48 weeks. The incidence of adverse events leading to discontinuation was similar in the LABA subgroups and less frequent in the GLY groups compared to placebo at 12 weeks. There was a higher discontinuation rate in the GLY LABA subgroups, with higher overall cough and COPD incidence rates (IRs) vs TIO. Cardiovascular events of special interest were more frequent in the LABA-no subgroup with generally similar IRs between treatments in LABA subgroups at 12 and 48 weeks. At 12 weeks, there were two major adverse cardiac events (MACE; IR per thousand patient-years=23.6) in the placebo LABA-no group and three MACE (IR=33.9) in the GLY 50 mcg BID LABA-no group. The MACE IRs in the TIO group were numerically higher than GLY in both LABA subgroups at 48 weeks. CONCLUSIONS: Nebulized GLY improved lung function and patient-reported outcomes with an acceptable safety/tolerability profile in subjects with COPD, with and without background LABA±ICS, for up to 48 weeks. CLINICAL IMPLICATIONS: Nebulized GLY is well tolerated and effective when administered with or without concurrent bronchodilator therapy and provides a novel treatment option for patients who may require or benefit from nebulized LAMA therapy. DISCLOSURE: Edward Kerwin: Consultant fee, speaker bureau, advisory committee, etc.: Sunovion Robert Tosiello: Employee: Sunovion Pharmaceuticals Inc. Barry Price: Employee: Sunovion Pharmaceuticals Inc. Thomas Goodin: Employee: Sunovion Pharmaceuticals Inc. Abstract describes analysis from Phase 3 trials of nebulized glycopyrrolate in COPD (not currently approved)

Recording of Influenza-Like Illness in UK Primary Care 1995-2013: Cohort Study.

BackgroundThere is a lack of recent studies examining recording of influenza-like illness (ILI) in primary care in the UK over time and according to population characteristics. Our aim was to determine time trends and socio-demographic patterns of ILI recorded consultations in primary care.MethodsWe used The Health Improvement Network (THIN) UK primary care database and extracted data on all ILI consultations between 1995 and 2013. We estimated ILI recorded consultation rates per 100,000 person-weeks (pw) by age, gender, deprivation and winter season. Negative binomial regression models were used to examine time trends and the effect of socio-demographic characteristics. Trends in ILI recorded consultations were compared to trends in consultations with less specific symptoms (cough or fever) recorded.ResultsThe study involved 7,682,908 individuals in 542 general practices. The ILI consultation rate decreased from 32.5/100,000 pw (95% confidence interval (CI) 32.1, 32.9) in 1995–98 to 15.5/100,000 pw (95% CI 15.4, 15.7) by 2010–13. The decrease occurred prior to 2002/3, and rates have remained largely stable since then. Declines were evident in all age groups. In comparison, cough or fever consultation rates increased from 169.4/100,000 pw (95% CI 168.6, 170.3) in 1995–98 to 237.7/100,000 pw (95% CI 237.2, 238.2) in 2010–13. ILI consultation rates were highest among individuals aged 15–44 years, higher in women than men, and in individuals from deprived areas.ConclusionThere is substantial variation in ILI recorded consultations over time and by population socio-demographic characteristics, most likely reflecting changing recording behaviour by GPs. These results highlight the difficulties in using coded information from electronic primary care records to measure the severity of influenza epidemics across time and assess the relative burden of ILI in different population subgroups.

Historical Associations and Geographical Distributions of Childhood Epidemics in the United States: An Exploratory, Pre-1955, Analysis at the State Level

The analysis explores possible associations among epidemic childhood diseases over time and in their geographical distributions in the United States. Diseases include diphtheria, polio, measles, scarlet fever, and whooping cough (pertussis). Analysis of their incidence rates is cross-sectional and geographical at the state level using the latitude and longitude of state centroids. All five diseases are analyzed in 1950 controlling for socio-demographic factors. Polio and measles are given an extended historical analysis from 1930 to 1954 and whooping cough from 1940 to 1954. The results show a complex relationship between measles and whooping cough where none was expected. On average, over time, states with higher measles rates also had higher whooping cough rates, and the average weekly incidence of whooping cough lags measles by a delay of two to three weeks. These findings give tentative support for the hypothesis that because of its immune suppressing effects measles causes an increase in whooping cough. The analysis shows little support for disease interference between measles and whooping cough but a possible association between scarlet fever and whooping cough. Geographical distributions of polio, measles, and whooping cough are relatively stable over time, on average, despite great seasonal and annual variations in incidence rates. The method of spatial analysis used here complements conventional metapopulation epidemic models that start in the time domain.

S79 Cough Prevalence And Frequency In Pulmonary Tuberculosis

Introduction Patterns of cough in tuberculosis influence transmission of disease yet have been little studied. We report the prevalence, duration, severity and frequency of coughing in tuberculosis. Method The first part was a retrospective review of the medical records of all individuals diagnosed with pulmonary tuberculosis (PTB) at our hospital during 2012–3. The reported presence and duration of coughing was noted. In the second part of the study, successive patients with an ultimate diagnosis of PTB wore the Leicester Cough Monitor for 24 h prior to commencing treatment. Controls had latent TB infection (LTBI). Participants rated their cough severity from 0–100 with a visual analogue scale (VAS). Cough characteristics were compared with other clinical variables. Results 108 cases of PTB from 2012–3 were included. 82 reported cough of median (IQR) duration 4 (1–8) weeks. There was a significant association of the presence of cough with TB sputum culture positivity (odds ratio, 11.0; 95% confidence interval, 2.5–50.0) but not gender, smoking, smear positivity, cavitary disease or extent of radiographic change. No clear predictor of the duration of cough was identified and there were too few patients to estimate the effect of TB strain. Cough frequency was measured in subjects with sputum smear positive PTB (S+; n = 20), smear negative PTB (S-; n = 10) and LTBI (n = 11). Variability was high: median (IQR) cough rates were 238 (121–701), 126 (15–395) and 11 (7–56) coughs/24 h, respectively, and not significantly different for S+ vs. S- (figure). For active TB, cough rates were reduced overnight (2.8 [0.2–12.4] vs. 12.7 [3.3–23.4] coughs/h for night vs. day, respectively; p = 0.01). No effect of smoking was detected, nor was there a correlation between cough frequency and radiographic extent of disease, cavities or time to sputum culture positivity. Cough severity was higher for S+ than S- but also variable and the difference not statistically significant (VAS: 60 [13–94] vs. 22 [1.5–70] respectively; p = 0.41). Severity correlated with cough frequency in active tuberculosis (Spearman’s r = 0.60, p = 0.001). Conclusion Cough in TB reduces overnight and is related to culture positivity. Bacterial burden and extent of disease may not be important. Other determinants of cough await characterisation.

P1 A Novel Capsaicin Cough Challenge In Healthy Adults; Beyond The C5

Introduction We have developed a novel cough challenge methodology and previously showed that evoked maximal cough responses, defined as E max , better discriminate health from disease than traditional endpoints. 1 It is unclear how other factors influence E max or how it relates to the low cough rates observed in health. We therefore aimed to investigate the variability, repeatability and influences on E max in a larger group of healthy volunteers. Objective To assess maximum cough responses to capsaicin in a group of healthy adults representing a wide range of ages. Method Doubling doses of capsaicin 0.49 to 1000[micro]M) were inhaled sequentially up to the maximum tolerated dose. Four inhalations of each dose were administered 30 seconds apart and the number of coughs evoked within 15 seconds was recorded. The maximum number of coughs evoked by any dose of capsaicin (E max ) and the dose that elicited half of the E max , defined as ED 50 , were calculated. General linear models were used to assess the influence of subject demographics on these endpoints. Results Forty seven healthy volunteers performed the capsaicin challenge; median age 38 years (range 20–74), 17 males, median FEV 1 103% predicted (97–115), median BMI 25.0 (22.2–28.6), and median total cough rate 0.2 c/h (0.0–0.1). The median E max was 11 coughs (IQR, 8–19) with an ED 50 of 15.6[micro]M (7.8–109.4). The intraclass correlation coefficients for E max and ED 50 were 0.89 and 0.96 respectively which were highly significant (p 1 and BMI had no significant influence on E max . In contrast, gender (p 50 explaining 41.7% of the variation. Those subjects with a higher BMI and females tended to have a lower ED 50 . Objective 24 h cough frequency did not correlate with either E max or ED 50 . Conclusion Data collected to date has demonstrated that in healthy volunteers, E max and ED 50 are stable measures over time however E max has the advantage of being independent of patient factors. Intere stingly, objective cough frequency in healthy volunteers seems to be unrelated to capsaicin evoked coughing. References J Allergy Clin Immunol . 2013 Oct;132(4):847–55

P7 Neuronal Dysfunction In Asthma; Insights From The Study Of The Cough Reflex

Introduction Cough in asthma is common, troublesome, predicts severity and poor prognosis, yet remarkably little is understood about the underlying neuronal mechanism. Currently available asthma medications are not designed to directly treat cough, the archetypal airway neuronal reflex. Previous studies have commonly used the dose of capsaicin that evokes two coughs (C 2 ) or five coughs (C 5 ) as the standard measure to assess the sensitivity of the cough reflex. These measures poorly discriminate between health and disease, and correlate only weakly with objective cough rates. 2 A novel challenge methodology that uses the maximum number of evoked coughs (E max ) as an end point better discriminates between health and disease and correlates strongly with subjective cough measures. 2 Objective To assess the differences in the maximum cough responses evoked by capsaicin (E max ) between asthmatics and healthy volunteers. Method A capsaicin inhalational challenge (doubling doses 0.49 to 1000[micro]M) was performed. Four inhalations 30 seconds apart were performed at each concentration and the total coughs evoked at each dose were recorded and verified using a cough monitor. The highest total number of coughs evoked at any dose of capsaicin is denoted E max . Results Fourty nine asthmatics were compared with 47 healthy volunteers. There was a significant difference in the median age between groups (asthmatics 22.9 (IQR 20–27) , healthy volunteers 38.0 (29–47) p max between asthmatics (mean coughs 20.5 (SD±10.1) and healthy volunteers 13.1 (±7.2) (p Conclusion Using this novel full dose response methodology, this data suggests that even during stability, asthmatics have an exaggerated cough response to capsaicin. This suggests that sub-groups of asthmatics have neuronal dysfunction which can identified by this capsaicin challenge. References J Allergy Clin Immunol . 2008 Nov;122(5):903–7 J Allergy Clin Immunol . 2013 Oct;132(4):847–55