Nebulised interferon beta-1a (SNG001) in the treatment of viral exacerbations of COPD.

BACKGROUND: Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-ß is naturally produced in response to viral infection, limiting replication. This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-ß1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance. METHODS: In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]). RESULTS: In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001-placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments. CONCLUSIONS: Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study. TRIAL REGISTRATION: EU clinical trials register (2017-003679-75), 6 October 2017.

Digitally monitored inhaled therapy: a 'smart' way to manage severe asthma?

INTRODUCTION: One of the fundamental challenges of managing patients with severe asthma is treatment adherence, particularly with inhaled corticosteroids. Adherence is difficult to measure objectively and poor adherence is associated with worse outcomes. In this study, assess the ability of a 'smart' inhaler to record adherence in severe asthma patients and measure the impact of this on asthma control. METHODS: Consecutive consenting patients meeting criteria for biologics had their existing high-dose ICS/LABA//LAMA combination inhaler/s switched to mometasone/indacaterol/glycopyrronium (114/46/136). Routine clinical data, including blood eosinophils, FeNO, and ACQ-6 scores were collected at baseline and at 4 wk. Adherence was then checked on the Propeller Health app, and good adherence was defined as >80% of prescribed usage. Participants were then followed-up at 12 months to record the proportion of patients who were initiated on biologics. RESULTS: 77 patients (mean [SD] age = 50.4 [15.7] years, 67.5% female [n = 52]) participated. 71 participants were able to use the device and 65% (n = 46) of these attained good asthma control and were not initiated on biologics at 12-month follow-up. Both groups demonstrated a significant reduction in ACQ6 score at follow-up (2.81 vs. 1.92, p < 0.001 and 3.05 vs. 2.60, p < 0.001, respectively), but there was no statistically significant difference in improvement between groups. Patients with optimal adherence also demonstrated a significant reduction in median FeNO at follow-up (47 ppb vs. 40 ppb, p = 0.003). CONCLUSIONS: In severe asthma patients, 'smart' inhalers may represent an effective management tool to improve adherence and asthma control, therefore avoiding the need for patients to commence biological therapies.

Post-COVID-19 Symptom Burden: What is Long-COVID and How Should We Manage It?

The enduring impact of COVID-19 on patients has been examined in recent studies, leading to the description of Long-COVID. We report the lasting symptom burden of COVID-19 patients from the first wave of the pandemic. All patients with COVID-19 pneumonia discharged from a large teaching hospital trust were offered follow-up. We assessed symptom burden at follow-up using a standardised data collection technique during virtual outpatient clinic appointments. Eighty-six percent of patients reported at least one residual symptom at follow-up. No patients had persistent radiographic abnormalities. The presence of symptoms at follow-up was not associated with the severity of the acute COVID-19 illness. Females were significantly more likely to report residual symptoms including anxiety (p = 0.001), fatigue (p = 0.004), and myalgia (p = 0.022). The presence of long-lasting symptoms is common in COVID-19 patients. We suggest that the phenomenon of Long-COVID may not be directly attributable to the effect of SARS-CoV-2, and believe the biopsychosocial effects of COVID-19 may play a greater role in its aetiology.

Domiciliary Cough Monitoring for the Prediction of COPD Exacerbations.

INTRODUCTION: Acute exacerbations of COPD (AE-COPD) are a leading cause of health service utilisation and are associated with morbidity and mortality. Identifying the prodrome of AE-COPD by monitoring symptoms and physiological parameters (telemonitoring) has proven disappointing and false alerts limit clinical utility. We report objective monitoring of cough counts around AE-COPD and the performance of a novel alert system identifying meaningful change in cough frequency. METHODS: This prospective longitudinal study of cough monitoring included chronic obstructive pulmonary disease (COPD) patients experienced in telemonitoring that had two or more AE-COPD in the past year. Participants underwent cough monitoring and completed a daily questionnaire for 90 days. The automated system identified deteriorating trends in cough and this was compared with alerts generated by an established telemonitoring questionnaire. RESULTS: 28 patients [median age 66 (range 46-86), mean FEV-1% predicted 36% (SD 18%)] completed the study and had a total of 58 exacerbations (43 moderate and 15 severe). Alerts based on cough monitoring were generated mean 3.4 days before 45% of AE-COPD with one false alert every 100 days. In contrast, questionnaire-based alerts occurred in the prodrome of 88% of AE-COPD with one false alert every 10 days. CONCLUSION: An alert system based on cough frequency alone predicted 45% AE-COPD; the low false alert rate with cough monitoring suggests it is a practical and clinically relevant tool. In contrast, the utility of questionnaire-based symptom monitoring is limited by frequent false alerts.

Experience with tofacitinib in Canada: patient characteristics and treatment patterns in rheumatoid arthritis over 3 years.

OBJECTIVES: To describe characteristics, treatment patterns and persistence in patients with RA treated with tofacitinib, an oral Janus kinase inhibitor, in Canadian clinical practice between 1 June 2014 and 31 May 2017. METHODS: Data were obtained from the tofacitinib eXel support programme. Baseline demographics and medication history were collected via patient report/special authorization forms; reasons for discontinuation were captured by patient report. Treatment persistence was estimated using Kaplan-Meier methods, with data censored at last follow-up. Cox regression was applied to analyse baseline characteristics associated with treatment discontinuation. RESULTS: The number of patients with RA enrolled from 2014 to 2017 was 4276; tofacitinib utilization increased during that period, as did the proportion of biologic (b) DMARD-naïve patients prescribed tofacitinib. Of patients who initiated tofacitinib, 1226/3678 (33.3%) discontinued, mostly from lack of efficacy (35.7%) and adverse events (26.9%). Persistence was 62.7% and 49.6% after 1 and 2 years of treatment, respectively. Prior bDMARD experience predicted increased tofacitinib discontinuation (vs bDMARD-naïve, P < 0.001). Increased retention was associated with older age (56-65 years and >65 years vs ⩽45 years; P < 0.05), and time since diagnosis of 15 to <20 years (vs <5 years; P < 0.01). In bDMARD-naïve, post-1 bDMARD, post-2 bDMARD and post-⩾3 bDMARD patients, median survival was >730, 613, 667 and 592 days, respectively. CONCLUSION: Since 2014, tofacitinib use in Canadian patients with RA increased, especially among bDMARD-naïve/post-1 bDMARD patients. Median drug survival was ∼2 years. Likelihood of persistence increased for bDMARD-naïve (vs bDMARD-experienced) patients and those aged ⩾56 (vs ⩽45) years.

Objective Assessment of Cough: An Early Marker of Response to Biological Therapies in Asthma?

Cough is an important symptom of asthma. The objective assessment of chronic cough has been enhanced by the development of ambulatory cough monitoring systems. Mepolizumab has been demonstrated to reduce exacerbations in eosinophilic asthmatics long-term. We evaluate the utility of objective cough count as an outcome measure in severe eosinophilic asthma treated with mepolizumab. Consecutive, consenting patients initiated on treatment with mepolizumab had a 24-h cough count recorded at baseline; this was repeated at 1, 3 and 6 months. Asthma control questionnaire (ACQ) scores and exacerbation frequency were also recorded. The mean 24-h cough count in 11 subjects (8 females, mean age 53.6 years) was 172.4 at baseline; at 1, 3 and 6 months following initiation of treatment this decreased to 101.4, 92 and 70.8, respectively (p < 0.02). Significant improvements were also observed in mean ACQ score (3-1.6, p < 0.01) and exacerbation frequency (5.5 per year - 1.3, p < 0.01). Objective cough measurement could be used as an early, precise and clinically relevant endpoint in assessing response to asthma therapy.

Agreement between blood draw techniques for assessing platelet activation by flow cytometry.

It is widely believed that assays of platelet activation are susceptible to preanalytical variables related to blood draw technique. We assessed platelet activation by whole blood flow cytometry and investigated the effects of: (1) drawing blood into vacuum tubes or manually aspirated syringes, and (2) discarding the first drawn blood sample (discard tube). Platelet P-selectin expression and platelet-monocyte complexes were measured by flow cytometry under both basal conditions and following stimulation with 0.1, 1, or 10 µM ADP. Bland-Altman plots demonstrated agreement between results for vacuum tube and syringe-aspirated samples with an a priori-defined clinically relevant agreement limit of 5%. Agreement of results was also observed between discard tube and second draw samples for both vacuum-driven and manually aspirated blood. We conclude that a vacuum tube or a manually-aspirated syringe can be used when assessing platelet activation by flow cytometry and that there is no need for a discard tube.

Phenotyping patients with chronic cough: Evaluating the ability to predict the response to anti-inflammatory therapy.

BACKGROUND: Whether the fraction of exhaled nitric oxide (FeNO) measurement can predict the response to anti-inflammatory treatment in chronic cough is unknown. OBJECTIVE: To explore whether the effectiveness of treatment with 10 mg of montelukast or 20 mg of prednisolone in patients with chronic cough is predicted by FeNO level. METHODS: In this randomized, open-label, controlled pilot study conducted in the Clinical Trial Unit in Castle Hospital in the United Kingdom, 50 nonsmoking patients with a cough that lasted more than 8 weeks were sequentially enrolled in the study. Thirty patients with high FeNO levels (≥30 ppb) were randomized in a 1:1 ratio to receive 10 mg of montelukast or 20 mg of prednisolone for 2 weeks followed by 10 mg of montelukast for 2 weeks. Twenty patients with a low FeNO level (≤20 ppb) received 10 mg of montelukast. The primary objective was to determine the effectiveness of treatment on 24-hour cough counts. RESULTS: The 24-hour cough counts decreased in both groups by approximately 50% (P < .005), indicating that FeNO did not predict treatment response. However, it was a good marker for eosinophilic inflammation with a high degree of correlation with blood and sputum eosinophilia (P < .001). CONCLUSION: These results suggest that prior investigation may not predict response to anti-inflammatory treatment, which may be consequent on localized leukotriene-mediated inflammation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02479074.

Does FeNO Predict Clinical Characteristics in Chronic Cough?

PURPOSE: To evaluate whether exhaled nitric oxide measurement can facilitate in the assessment of chronic cough patients based on their airway inflammatory phenotype. METHODS: We have studied consecutive patients attending a specialist cough clinic. 30 patients with high FeNO (> 30 ppb) and 20 patients with low FeNO (< 20 ppb) were recruited. RESULTS: There was a significant correlation between FeNO, B-Eos and sputum eosinophil count (p < 0.001). The number of recorded coughs in 24 h and HARQ scores were significantly (p < 0.05) higher in patients with a low FeNO. In contrast to the high FeNO group (48%), the greater proportion of these patients were women (90%). LCQ scores were worse in the low FeNO group but it was not significant. CONCLUSION: A strong relationship between FeNO, blood eosinophils and sputum eosinophils confirming phenotypic identity was observed. Whether the observed gender disparity accounts for the different cough frequency characteristics is unknown.

Continuous Cough Monitoring Using Ambient Sound Recording During Convalescence from a COPD Exacerbation.

PURPOSE: Cough is common in chronic obstructive pulmonary disease (COPD) and is associated with frequent exacerbations and increased mortality. Cough increases during acute exacerbations (AE-COPD), representing a possible metric of clinical deterioration. Conventional cough monitors accurately report cough counts over short time periods. We describe a novel monitoring system which we used to record cough continuously for up to 45 days during AE-COPD convalescence. METHODS: This is a longitudinal, observational study of cough monitoring in AE-COPD patients discharged from a single teaching hospital. Ambient sound was recorded from two sites in the domestic environment and analysed using novel cough classifier software. For comparison, the validated hybrid HACC/LCM cough monitoring system was used on days 1, 5, 20 and 45. Patients were asked to record symptoms daily using diaries. RESULTS: Cough monitoring data were available for 16 subjects with a total of 568 monitored days. Daily cough count fell significantly from mean ± SEM 272.7 ± 54.5 on day 1 to 110.9 ± 26.3 on day 9 (p < 0.01) before plateauing. The absolute cough count detected by the continuous monitoring system was significantly lower than detected by the hybrid HACC/LCM system but normalised counts strongly correlated (r = 0.88, p < 0.01) demonstrating an ability to detect trends. Objective cough count and subjective cough scores modestly correlated (r = 0.46). CONCLUSIONS: Cough frequency declines significantly following AE-COPD and the reducing trend can be detected using continuous ambient sound recording and novel cough classifier software. Objective measurement of cough frequency has the potential to enhance our ability to monitor the clinical state in patients with COPD.

Bleomycin increases neutrophil adhesion to human vascular endothelial cells independently of upregulation of ICAM-1 and E-selectin.

AIM OF THE STUDY: Bleomycin-induced lung disease is a serious complication of therapy characterized by alveolar injury, cytokine release, inflammatory cell recruitment, and eventually pulmonary fibrosis. The mechanisms underlying bleomycin-induced pulmonary fibrosis may be relevant to other progressive scarring diseases of the lungs. Pulmonary vascular endothelial cells are critically involved in immune cell extravasation at sites of injury through adhesion molecule expression and cytokine release. We sought to determine the effects of bleomycin on adhesion molecule expression and cytokine release by pulmonary vascular endothelial cells, and their functional relevance to inflammatory cell recruitment. MATERIALS AND METHODS: The effects of pharmacologically relevant concentrations of bleomycin on adhesion molecule expression and cytokine release by human vascular endothelial cells in vitro were studied by flow cytometry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. A flow chamber model was used to assess the functional consequences on adhesion of flowing human neutrophils to endothelial cell monolayers. RESULTS: Bleomycin increased intercellular adhesion molecule 1 (ICAM-1; CD54), vascular cell adhesion molecule (VCAM-1; CD106), and E-selectin (CD62E) expression, and increased monocyte chemoattractant protein (MCP-1) and interleukin (IL-8) release by endothelial cells. Increases in protein expression were accompanied by increased mRNA transcription. In contrast, there was no direct effect of bleomycin on the profibrotic cytokines transforming growth factor-beta (TGF-ß), platelet-derived growth factor-BB (PDGF-BB), or endothelin-1. Under flow conditions, endothelial cells exposed to bleomycin supported increased neutrophil adhesion which was independent of ICAM-1 or E-selectin. CONCLUSION: Our findings demonstrate that bleomycin promotes endothelial-mediated inflammation and neutrophil adhesion. These mechanisms may contribute to the development of pulmonary fibrosis by supporting immune cell recruitment in the lungs.

Objective Measurement of Cough Frequency During COPD Exacerbation Convalescence.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Cough and sputum production are associated with adverse outcomes in COPD and are common during COPD exacerbation (AE-COPD). This study of objective cough monitoring using the Hull Automated Cough Counter and Leicester Cough Monitor software confirms that this system has the ability to detect a significant decrease in cough frequency during AE-COPD convalescence. The ability to detect clinically meaningful change indicates a potential role in home monitoring of COPD patients.

Increased platelet binding to circulating monocytes in idiopathic pulmonary fibrosis.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and its prognosis is poor. Epidemiological evidence suggests an association of IPF with vascular disease and thrombotic tendency, which may be related to platelet activation. METHODS: Platelet-monocyte adhesion in peripheral blood was examined by flow cytometry in patients with IPF (n = 19), interstitial lung disease (ILD) other than IPF (n = 9), and control subjects without pulmonary fibrosis (n = 14). Expression of platelet activation markers P-selectin (CD62P), PSGL-1 (CD162), and CD40 ligand (CD40L) on leukocytes and platelets were studied. Plasma concentrations of soluble P-selectin and CD40L were measured by ELISA. RESULTS: Significantly elevated levels of platelet-monocyte binding were found in patients with IPF (35.6 ± 4.34 % [mean ± SEM]) compared with patients with non-IPF ILD (23.5 ± 3.68 %) and non-ILD control subjects (16.5 ± 2.26 %; P < 0.01). There was a trend towards increased divalent cation-independent platelet-monocyte binding in IPF (6.0 ± 0.77 % [mean ± SEM]) compared with non-IPF ILD (4.3 ± 1.38 %) and control subjects without ILD (3.1 ± 1.75 %; P = 0.058). There was no differential surface expression of platelet activation markers on subsets of leukocytes or platelets. Plasma concentrations of CD40L and soluble P-selectin did not differ between IPF and control subjects. Platelet-monocyte binding had no significant correlation with percent predicted TLco or FVC. CONCLUSIONS: Platelet-monocyte binding is increased in IPF, suggesting increased platelet activation. This conjugation is predominantly calcium-dependent, but there may be more calcium-independent adhesion in IPF. These findings support further research into the role of platelet activation in IPF.

Telerehabilitation for patients who have been hospitalised with covid-19: a qualitative study.

PURPOSE: The aim of this qualitative study was to explore the views of participants of a group-based, supervised, telerehabilitation programme, following discharge from hospital with Covid-19. This study was part of a single-centre, fast-track (wait-list), randomised, mixed-methods, feasibility trial of telerehabilitation (Registration: Clinicaltrials.gov reference:285205). METHODS: Semi-structured interviews were conducted over a virtual teleconference platform with 10 participants who took part in a telerehabilitation programme following Covid-19 after discharge from an acute hospital. Data were transcribed verbatim and analysed using thematic analysis. RESULTS: Five themes were important from the participant perspective: telerehabilitation programme as part of the Covid-19 journey; the telerehabilitation programme design and delivery; peer aspects; the role of the instructor; and the role of technology and online delivery. CONCLUSIONS: Overall, the telerehabilitation programme was a positive experience for participants. The instructors were central to this positive view as was the group nature of the programme. The group aspect was particularly important in supporting the broader perceived wellbeing gains, such as the sense of enjoyment and reduced social isolation. Several participants would have liked to have continued with the exercises beyond the six-week intervention indicating that the programme could be a way to help people sustain a physically active lifestyle.IMPLICATIONS FOR REHABILITATIONParticipants who were recovering from Covid-19 following hospital admission perceived the telerehabilitation to be a positive experience overall.The group aspect of the telerehabilitation programme was important in supporting the broader perceived wellbeing gains such as the sense of enjoyment and reduced social isolation.Telerehabilitation programmes for Covid-19 may need to include pathways for participants to continue to engage in exercise beyond the time-limited six-week intervention to support ongoing self-management.

Integrated care policy recommendations for complex multisystem long term conditions and long COVID.

The importance of integrated care for complex, multiple long term conditions was acknowledged before the COVID pandemic but remained a challenge. The pandemic and consequent development of Long COVID required rapid adaptation of health services to address the population's needs, requiring service redesigns including integrated care. This Delphi consensus study was conducted in the UK and found similar integrated care priorities for Long COVID and complex, multiple long term conditions, provided by 480 patients and health care providers, with an 80% consensus rate. The resultant recommendations were based on more than 1400 responses from survey participants and were supported by patients, health care professionals, and by patient charities. Participants identified the need to allocate resources to: support integrated care, provide access to care and treatments that work, provide diagnostic procedures that support the personalization of treatment in an integrated care environment, and enable structural consultation between primary and specialist care settings including physical and mental health care. Based on the findings we propose a model for delivering integrated care by a multidisciplinary team to people with complex multisystem conditions. These recommendations can inform improvements to integrated care for complex, multiple long term conditions and Long COVID at international level.

Designing an intervention to help the quitters quit: A qualitative, intervention co-design study.

Objective: E-cigarettes are increasingly being provided by publicly funded stop smoking services. Our objectives were to understand the challenges and establish the means by which services could best support the use and subsequent discontinuation of e-cigarettes for this purpose. Methods: Semi-structured interviews and co-design workshops with service users and providers of a stop smoking service. Results: Thematic analysis was conducted. Interviews identified: 1. a reluctance to use e-cigarettes for cessation, 2. struggle to quit e-cigarettes (dependency, fear of relapse, compensatory "puffing") and 3. service development needs (consistency of approach). Co-design workshops suggested: 1. facilitation of e-cigarette use through understanding previous failed attempts, 2. offering a longer, two-staged approach to tobacco then e-cigarette cessation, careful timing of behavioural strategies and 3. enhanced communication between providers. Conclusions: Our study suggests additional modifications to smoking cessation support measures when e-cigarettes are used for smoking cessation to address the challenges posed by public health guidance: "smokers should switch to vaping and vapers should stop smoking completely". Innovation: Our study is the first to consider experiences of service users and providers about the challenges of using e-cigarettes for cessation; our co-design group of providers informed nine strategies needed to support this approach in practice.

Group-based pulmonary telerehabilitation is feasible, safe, beneficial and well-received in patients who have been hospitalised with COVID-19.

Introduction: Coronavirus disease 2019 (COVID-19) has caused worldwide mass hospitalisation. The need for multidisciplinary post-hospitalisation rehabilitation is becoming increasingly apparent, and telerehabilitation has been endorsed. The aim of study was to investigate the feasibility and efficacy of pulmonary telerehabilitation for COVID-19 survivors. Methods: This was a single-centre, mixed-methods, fast-track (wait-list), randomised controlled trial of telerehabilitation for patients who had been hospitalised with COVID-19. 40 patients discharged from two university teaching hospitals in the north of England were recruited. Telerehabilitation consisted of 12 exercise classes, six education events and opportunity for peer support. Patients commenced telerehabilitation 14 days after randomisation in the fast-track group and 56 days after randomisation in the wait-list group. Outcome measures and results: Descriptive and statistical improvements were noted in several clinical outcome measures. Exercise capacity increased from a median (interquartile range) 20 (14-24) sit-to-stand repetitions in 1 min at baseline to 25 (24-30) post-telerehabilitation. Breathlessness rated using the Medical Research Council dyspnoea scale changed from 3.5 (3-4) at baseline to 2 (1.5-3) post-telerehabilitation, with additional favourable outcomes noted in respiratory symptoms measured using numerical rating scales and visual analogue scales (VAS). Quality of life measured using the EuroQol VAS improved from 55 (60-70) units at baseline to 70 (55-80) units following telerehabilitation. Improvements in fatigue (modified Functional Assessment of Chronic Illness Therapy: Fatigue) and mood (Hospital Anxiety and Depression Scale - Depression) were also observed. Natural recovery was observed in the wait-list group prior to receiving telerehabilitation; however, improvements were accelerated by early telerehabilitation in the fast-track group. Conclusions: We have shown that group-based telerehabilitation is feasible, safe, beneficial and well-received in this population.