Faculty Bibliography

BACKGROUND:In lung cancer, upregulation of the PI3K pathway is an early event that contributes to cell proliferation, survival, and tissue invasion. Upregulation of this pathway was recently described as associated with enrichment of the lower airways with bacteria identified as oral commensals. We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways. METHODS:Airway brushes were collected prospectively from subjects with lung nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung cancer diagnoses and 36 subjects with non-cancer diagnosis. Additionally, samples from 10 healthy control subjects were included. 16S rRNA gene amplicon sequencing and paired transcriptome sequencing (RNAseq) were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed. RESULTS:The composition of the lower airway transcriptome in the cancer patients was significantly different from the controls, which included upregulation of ERK and PI3K signaling pathways. The lower airways of lung cancer patients were enriched for oral taxa (Streptococcus and Veillonella), which was associated with upregulation of the ERK and PI3K signaling pathways. In vitro exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus led to upregulation of these same signaling pathways. CONCLUSIONS:The data presented here shows that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.

INTRODUCTION:Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes. METHODS AND ANALYSIS:This prospective, randomised, multicentre study will compare the impact of using information on adherence to influence asthma treatment. Patients with severe uncontrolled asthma will be included. Data on adherence, inhaler technique and electronically recorded peak expiratory flow rate will be used to promote adherence and guide a clinical decision protocol to guide management in the active group. The control group will receive standard inhaler and adherence education. Medications will be adjusted using a protocol based on Global Initiativefor Asthma (GINA) recommendations. The primary outcome is the between-group difference in the proportion of patients who have refractory disease and are prescribed appropriate medications at the end of 32 weeks. A co-primary outcome is the difference between groups in the rate of adherence to salmeterol/fluticasone inhaler over the last 12 weeks. Secondary outcomes include changes in symptoms, lung function, type-2 cytokine biomarkers and clinical outcomes between both groups. Cost-effectiveness and cost-utility analyses of the INCA device intervention will be performed. The economic impact of a national implementation of the INCA-SUN programme will be evaluated. ETHICS AND DISSEMINATION:The results of the study will be published as a manuscript in peer-reviewed journals. The study has been approved by the ethics committees in the five participating hospitals. TRIAL REGISTRATION:NCT02307669; Pre-results.

OBJECTIVES/OBJECTIVE:among patients with chronic obstructive pulmonary disease (COPD) who currently receive the 23-valent pneumococcal polysaccharide vaccine (PPV-23) according to vaccination status, use of antibiotics and steroids. To investigate the prevalence of PPV-23 and 13-valent pneumococcal conjugate vaccine (PCV-13) serotypes within the study cohort. DESIGN/METHODS:A non-interventional, observational, prospective cohort study with a 12 -month follow-up period inclusive of quarterly study visits. SETTING/METHODS:Beaumont Hospital and The Royal College of Surgeons in Ireland Clinical Research Centre, Dublin, Ireland. PARTICIPANTS/METHODS:Patients with an established diagnosis of COPD attending a tertiary medical centre. PRIMARY OUTCOME MEASURE/METHODS:. SECONDARY OUTCOME MEASURE/UNASSIGNED:and its relationship with the incidence of exacerbations of COPD. RESULTS:fluctuated over the four seasons with a peak of 6.6% in spring and the lowest rate of 2.2% occurring during winter. Antibiotic use was highest during periods of low colonisation. CONCLUSIONS:colonisation among patients with COPD which may reflect antibiotic use in autumn and winter. The predominance of non-vaccine types suggests that PCV-13 may have limited impact among patients with COPD in Ireland who currently receive PPV-23. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT02535546; post-results.

OBJECTIVE:), a novel audio-recording device objectively measuring timing and proficiency of inhaler use, against established adherence measures, and explore its discriminant and predictive validity. DESIGN/METHODS:-enabled salmeterol/fluticasone inhaler for one-month post-hospital discharge. MAIN OUTCOME MEASURES/METHODS:(Attempted, Attempted Interval, Actual) adherence correlated with Doses Used Rate, self-reported adherence and prescription refill for concurrent validity. Discriminant validity for reason for admission, cognition and lung function; predictive validity for health status and quality-of-life. RESULTS:adherence. Attempted and Attempted Interval predicted health status, while Doses Used Rate predicted quality-of-life. CONCLUSION/CONCLUSIONS:as a method to identify intentional and unintentional adherence to inhaled medication and facilitate targeted intervention.

BACKGROUND:Researchers, using checklists, have identified that 30%-90% of patients make errors in inhaler use. It is not certain whether these errors affect the delivery of medication. We have developed an electronic monitor (INCAâ„¢) that records audio each time an inhaler is used, providing objective information on inhaler technique. The aim of this study was to assess the effect that correctly identified inhaler errors, with the INCA device, have on drug delivery. METHODS:This was a prospective study of healthy volunteers using a salbutamol Diskusâ„¢. The inclusion criteria allowed for the recruitment of healthy participants who were nonfrequent users of Salbutamol. Each participant was assigned to one control "phase" first and two/three subsequent error "phases." Each phase consisted of six doses of the drug taken 6 hours apart, and the participants' blood was drawn before and 25 minutes after doses one and six. This allowed us to sample their trough and peak serum salbutamol levels. RESULTS:Fourteen healthy volunteers were studied. The inhaler technique errors simulated in this study included exhaling into the device after drug priming but before inhalation, low inspiratory flow, multiple inhalations, low breath hold, missed doses, and wrong inhaler position. Only the exhalation error, low inspiratory flow, and missed doses led to a significant reduction in serum salbutamol levels. After six doses of the exhalation error, there was a 62% reduction in peak salbutamol levels. Low inspiratory flow led to a 52% reduction in peak salbutamol levels and a 78% reduction in trough levels. Missed doses led to a 37% reduction in trough salbutamol levels. CONCLUSIONS:These findings confirm that technique errors affect drug delivery. Furthermore, we were able to identify that the most critical technique errors with the Diskus inhaler are exhalation into the device before inhalation, poor inspiratory flow, and missing doses.

RATIONALE:Objective adherence to inhaled therapy by patients with chronic obstructive pulmonary disease (COPD) has not been reported. OBJECTIVES:To objectively quantify adherence to preventer Diskus inhaler therapy by patients with COPD with an electronic audio recording device (INCA). METHODS:This was a prospective observational study. On discharge from hospital patients were given a salmeterol/fluticasone inhaler with an INCA device attached. Analysis of this audio quantified the frequency and proficiency of inhaler use. MEASUREMENTS AND MAIN RESULTS:was 1.3 L, and 59% had evidence of mild/moderate cognitive impairment. By combining time of use, interval between doses, and critical technique errors, thus incorporating both intentional and unintentional nonadherence, a measure "actual adherence" was calculated. Mean actual adherence was 22.6% of that expected if the doses were taken correctly and on time. Six percent had an actual adherence greater than 80%. Hierarchical clustering found three equally sized well-separated clusters corresponding to distinct patterns. Cluster 1 (34%) had low inhaler use and high error rates. Cluster 2 (25%) had high inhaler use and high error rates. Cluster 3 (36%) had overall good adherence. Poor lung function and comorbidities were predictive of poor technique, whereas age and cognition with poor lung function distinguished those with poor adherence and frequent errors in technique. CONCLUSIONS:These data may inform clinicians in understanding why a prescribed inhaler is not effective and to devise strategies to promote adherence in COPD.

RATIONALE:Currently, studies on adherence to inhaled medications report average adherence over time. This measure does not account for variations in the interval between doses, nor for errors in inhaler use. OBJECTIVES:To investigate whether adherence calculated as a single area under the (concentration-time) curve (AUC) measure, incorporating the interval between doses and inhaler technique, was more reflective of patient outcomes than were current methods of assessing adherence. METHODS:We attached a digital audio device (INhaler Compliance Assessment) to a dry powder inhaler. This recorded when the inhaler was used, and analysis of the audio data indicated if the inhaler had been used correctly. These aspects of inhaler use were combined to calculate adherence over time, as an AUC measure. Over a 3-month period, a cohort of patients with asthma was studied. Adherence to a twice-daily inhaler preventer therapy using this device and clinical measures were assessed. MEASUREMENTS AND MAIN RESULTS:Recordings from 239 patients with severe asthma were analyzed. Average adherence that was based on the dose counter was 84.4%, whereas the ratio of expected to observed accumulated AUC, actual adherence, was 61.8% (P < 0.01). Of all the adherence measures, only adherence calculated as AUC reflected changes in asthma quality of life, β-agonist reliever use, and peak expiratory flow over the 3 months (P < 0.05 compared with other measures of adherence). CONCLUSIONS:Adherence that incorporates the interval between doses and inhaler technique, and calculated as AUC, is more reflective of changes in quality of life and lung function than are the currently used measures of adherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01529697).

BACKGROUND:The efficacy of drug delivery from inhalers is very much dependent on the user's peak inspiratory flow rate (PIFR). Current methods to measure PIFR in inhalers are based on subjective checklists. There is a lack of methods currently available to objectively remotely monitor PIFR in pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). In this study, for the first time, non-contact acoustic methods were employed to estimate PIFR through three commonly used inhalers (Diskus™ DPI, Turbuhaler™ DPI, and Evohaler™ pMDI) with the aim of applying these methods to remotely monitor inhaler inhalation technique in future clinical applications. METHODS:Each inhaler was placed inside an airtight container connected to a spirometer to measure PIFR. A high quality microphone was placed 5 cm from the mouthpiece of the inhalers to record inhalation sounds. Over 2000 inhaler inhalation sounds were recorded from 11 healthy participants. A range of temporal and spectral acoustic features from the inhalation sounds were correlated with PIFR. The variation of acoustic features and the repeatability of the inhalation acoustic spectral profile were investigated to further characterize inhaler inhalation sounds and to determine the reliability of acoustics to estimate PIFR. RESULTS: = 0.75 (Evohaler™)]. Acoustic features generated low variation and the spectral profile of inhalation sounds was repeatable regardless of flow rate, suggesting that acoustic methods are a reliable method of estimating PIFR. CONCLUSIONS:The methods presented in this study may be employed in a wearable monitoring device in future applications to measure inhaler PIFR. Objective monitoring of PIFR in inhalers may help patients improve their inhaler inhalation technique and therefore may be of significant clinical benefit to both patients and clinicians.

BACKGROUND:Mortality rates within the Irish farming community are increasing, whilst that of the general population falls. The aim of this cross-sectional study was to determine the prevalence of respiratory disease amongst Irish farmers. METHODS:All study participants were farming volunteers attending an agricultural exhibition. Data collected by questionnaire included baseline demographics, respiratory history, presence of respiratory symptoms and occupational exposures. Spirometry was performed on all participants. RESULTS:Data from 372 farmers was analysed. The majority were male (76%) with median age of 55 years. 61% were never smokers. 13% were previously diagnosed with airway disease (Chronic Obstructive Pulmonary Disease(COPD)/Asthma/Inhaler use) with 14% reporting hayfever/allergies. Almost two-thirds reported one or more chronic respiratory symptom. Forty-four (12%) had obstructive spirometry using fixed FEV1/FVC < 0.70 criterion and 29 (7.8%) using FEV1/FVC < 5% lower limit of normal. The majority, two-thirds, were never smokers. Amongst never smokers with obstruction (13%), there was a significantly higher proportion with a prior diagnosis of airway disease and hayfever/allergies. There was no significant association between specific occupational exposures and obstruction. CONCLUSION:The majority of Irish farmers are never smokers. They have a high prevalence of respiratory symptoms. 13% of never smokers have airflow obstruction (FEV1/FVC < 0.70). The presence of airflow obstruction is significantly associated with self-reported allergy history and prior airway disease. Further studies are needed to identify the workplace factors accounting for these findings.

This Letter investigated the efficacy of a decision-support system, designed for respiratory medicine, at predicting asthma exacerbations in a multi-site longitudinal randomised control trial. Adherence to inhaler medication was acquired over 3 months from patients with asthma employing a dose counter and a remote monitoring adherence device which recorded participant's inhaler use: n = 184 (23,656 audio files), 61% women, age (mean ± sd) 49.3 ± 16.4. Data on occurrence of exacerbations was collected at three clinical visits, 1 month apart. The relative risk of an asthma exacerbation for those with good and poor adherence was examined employing a univariate and multivariate modified Poisson regression approach; adjusting for age, gender and body mass index. For all months dose counter adherence was significantly (p < 0.01) higher than remote monitoring adherence. Overall, those with poor adherence had a 1.38 ± 0.34 and 1.42 ± 0.39 (remotely monitored) and 1.25 ± 0.32 and 1.18 ± 0.31 (dose counter) higher relative risk of an exacerbation in model 1 and model 2, respectively. However, this was not found to be statistically significantly different. Remotely monitored adherence holds important clinical information and future research should focus on refining adherence and exacerbation measures. Decision-support systems based on remote monitoring may enhance patient-physician communication, possibly reducing preventable adverse events.