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Christopher Duckworth,1 Michael J Boniface,1 Adam Kirk,2 Thomas MA Wilkinson2– 4 1IT Innovation Centre, Digital Health and Biomedical Engineering, University of Southampton, Southampton, UK; 2 My mHealth Limited, London, UK; 3National Institute for Health Research Biomedical Research Centre, University of Southampton, Southampton, UK; 4Faculty of Medicine, University of Southampton, Southampton, UKCorrespondence: Christopher Duckworth, School of Engineering, University of Southampton, University Road, Southampton, SO17 1BJ, UK, Tel/Fax +44 23 8059 8866, Email C.J.Duckworth@soton.ac.ukIntroduction: The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2023 guidelines proposed important changes to the stratification of disease severity using the “ABCD” assessment tool. The highest risk groups “C” and “D” were combined into a single category “E” based on exacerbation history, no longer considering symptomology.Purpose: We quantify the differential disease progression of individuals initially stratified by the GOLD 2022 “ABCD” scheme to evaluate these proposed changes.Patients and Methods: We utilise data collected from 1529 users of the myCOPD mobile app, a widely used and clinically validated app supporting people living with COPD in the UK. For patients in each GOLD group, we quantify symptoms using COPD Assessment Tests (CAT) and rate of exacerbation over a 12-month period post classification.Results: CAT scores for users initially classified into GOLD C and GOLD D remain significantly different after 12 months (Kolmogorov–Smirnov statistic = 0.59, P = 8.2 × 10− 23). Users initially classified into GOLD C demonstrate a significantly lower exacerbation rate over the 12 months post classification than those initially in GOLD D (Kolmogorov–Smirnov statistic = 0.26; P = 3.1 × 10− 2; all exacerbations). Further, those initially classified as GOLD B have higher CAT scores and exacerbation rates than GOLD C in the following 12 months.Conclusion: CAT scores remain important for stratifying disease progression both in-terms of symptomology and future exacerbation risk. Based on this evidence, the merger of GOLD C and GOLD D should be reconsidered.Keywords: Global Initiative for Chronic Obstructive Lung Disease, differential disease progression, exacerbation rate

Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV1 and mean annual exacerbation rate. [ABSTRACT FROM AUTHOR]

RationaleSome COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.ObjectiveTo define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.MethodsWe analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).MeasurementsWe defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire 60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index)

Background Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients. Objectives We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D–deficient patients with COPD. Methods We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15–50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life. Results The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15–25 nmol/L (n  = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes. Conclusions Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency. This trial was registered at clinicaltrials.gov as NCT02122627. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, the University of Virginia adult cystic fibrosis (CF) center transitioned from in-person clinical encounters to a model that included interdisciplinary telemedicine. The pandemic presented an unprecedented opportunity to assess the impact of the interdisciplinary telemedicine model on clinical CF outcomes.Research Question: What are the clinical outcomes of a care model that includes interdisciplinary telemedicine (IDC-TM) compared with in-person clinical care for patients with CF during the COVID-19 pandemic?Study Design and Methods: Adults with CF were included. The prepandemic year was defined as March 17, 2019, through March 16, 2020, and the pandemic year (PY) was defined as March 17, 2020, through March 16, 2021. Patients were enrolled starting in the PY. Prepandemic data were gathered retrospectively. Telemedicine visits were defined as clinical encounters via secured video communication. Hybrid visits were in-person evaluations by physician, with in-clinic video communication by other team members. In-person visits were encounters with in-person providers only. All encounters included previsit screening. Outcomes were lung function, BMI, exacerbations, and antibiotic use. FEV1 percent predicted, exacerbations, and antibiotic use were adjusted for the effect of elexacaftor/tezacaftor/ivacaftor treatment.Results: One hundred twenty-four patients participated. One hundred ten patients were analyzed (mean age, 35 years; range, 18-69 years). Ninety-five percent had access to telemedicine (n = 105). Telemedicine visits accounted for 64% of encounters (n = 260), hybrid visits with telemedicine support accounted for 28% of encounters (n = 114), and in-person visits accounted for 7% of encounters (n = 30). No difference in lung function or exacerbation rate during the PY was found. BMI increased from 25 to 26 kg/m2 (t100 = -4.72; P < .001). Antibiotic use decreased from 316 to 124 episodes (z = 8.81; P < .0001).Interpretation: This CF care model, which includes IDC-TM, successfully monitored lung function and BMI, identified exacerbations, and followed guidelines-based care during the pandemic. A significant decrease in antibiotic use suggests that social mitigation strategies were protective.Trial Registry: ClinicalTrials.gov; No.: NCT04402801; URL: www.Clinicaltrials: gov. [ABSTRACT FROM AUTHOR]

Christopher B Cooper,1 Robert Paine,2 Jeffrey L Curtis,3,4 Richard E Kanner,2 Carlos H Martinez,3 Catherine A Meldrum,3 Russell Bowler,5 Wanda O’Neal,6 Eric A Hoffman,7 David Couper,6 Miguel Quibrera,6 Gerald Criner,8 Mark T Dransfield,9 MeiLan K Han,3 Nadia N Hansel,10 Jerry A Krishnan,11 Stephen C Lazarus,12 Stephen P Peters,13 R Graham Barr,14 Fernando J Martinez,15 Prescott G Woodruff12 On behalf of the SPIROMICS investigators1Departments of Medicine and Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Section of Pulmonary and Critical Care Medicine, Department of Veterans Affairs Medical Center, University of Utah, Salt Lake City, UT, USA; 3Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA; 4Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA; 5National Jewish Health, University of Colorado School of Medicine, Denver, CO, USA; 6University of North Carolina Marisco Lung Institute, Chapel Hill, NC, USA; 7Department of Radiology, University of Iowa, Iowa City, IA, USA; 8Department of Pulmonary and Critical Care Medicine, Temple University, Philadelphia, PA, USA; 9Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 10Johns Hopkins University School of Medicine, Baltimore, MD, USA; 11Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA; 12Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; 13Wake Forest School of Medicine, Winston-Salem, NC, USA; 14Department of Medicine, Columbia University Medical Center, New York, NY, USA; 15Joan and Sanford I Weill Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USACorrespondence: Christopher B CooperDepartments of Medicine and Physiology,David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, 37-131 CHS, Los Angeles, CA 90095, USAEmail ccooper@mednet.ucla.eduRationale: Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.Objective: To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.Methods: We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).Measurements: We defined respiratory disability by ≥ 4 of 7 criteria: mMRC dyspnea scale ≥ 3; Veterans Specific Activity Questionnaire < 5; 6-minute walking distance < 250 m; St George’s Respiratory Questionnaire activity domain > 60; COPD Assessment Test > 20; fatigue (FACIT-F Trial Outcome Index) < 50; SF-12 < 20.Results: Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P< 0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point − 1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability.Conclusion: Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.Keywords: disability, frailty, exacerbation rate, mortality, SPIROMICS

• Inhaling levofloxacin might increase the FEV 1 in people with CF. • Inhaling levofloxacin might reduce the exacerbation rate in people with CF. • Inhaling levofloxacin is well tolerated. Levofloxacin inhalation solution is the most recently approved inhaled antibiotic in Europe and Canada for adult cystic fibrosis patients. Its efficacy and safety have been assessed in randomized controlled trials. Our aim was to evaluate real life experience and outcomes in our treatment centre. We evaluated the efficacy of inhaled levofloxacin solution in 86 patients with cystic fibrosis in terms of the following outcome parameters: changes in %-predicted forced expiratory volume in one second (FEV 1), body-mass index (BMI), and exacerbation rate. We conducted an intraindividual analysis of patients who received levofloxacin inhalation solution twice daily 240 mg for at least 4 weeks. Change in FEV 1 % predicted for the treatment period was +2.27% (p=0.0027) after 4 weeks. There was no change in BMI for overall group, but exacerbation rate compared to one year before initiation of inhaled levofloxacin decreased significantly (p=0.0024) after 1 year of treatment (3.23 ± 1.39 versus 2.71 ± 1.58). In patients with cystic fibrosis, inhaled levofloxacin solution has the potential to improve FEV 1 and to reduce the number of bronchopulmonary exacerbations. [ABSTRACT FROM AUTHOR]

Takeo Ishii,1,2,* Masaharu Nishimura,3,* Asako Akimoto,1 Mark H James,4 Paul Jones4,5,* 1Respiratory Medical Affairs, Development and Medical Affairs, GSK K.K., Tokyo, Japan; 2Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 3Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 4Respiratory Franchise Medical, GSK House, Brentford, Middlesex, UK; 5Institute of Infection and Immunity, St George’s, University of London, London, UK *These authors contributed equally to this workAbstract: COPD is associated with significant morbidity and is one of the leading causes of death worldwide. Periods of exacerbation, the acute worsening of symptoms, are interspersed throughout the disease’s natural history and can result in increased treatment burden and hospitalization for patients with COPD. The frequency of exacerbations varies between countries, with both epidemiological studies and randomized controlled trials (RCTs) showing significant differences in observed prevalence rates. Differences in study design and the healthcare setting are likely to contribute to differences in exacerbation frequency, however the perceived rate of exacerbations in Japan is currently lower then the rest of the world. This review identified nine cohort studies and five RCTs that reported COPD annual exacerbation rates in Japan in the ranges of 0.1–2.1 and 0.33–1.79, respectively. The difference in exacerbation rate between studies appeared greater than the difference between Japan and Western countries, likely because of disparities between settings, design, and inclusion criteria. Of these, only one (Understanding the Long-Term Impacts of Tiotropium) had uniform inclusion criteria across different regions. This study found that the annual rate of exacerbation events per patient in Japan was 0.61, compared with 0.85 worldwide in the placebo groups. This review summarizes the published rates of COPD exacerbations in Japan and the rest of the world and explores the hypotheses as to why rates in Japan might be lower than other countries. These include access to medical care, variance in the associated morbidity profile, environmental factors, diagnostic crossover with related diseases, and differences in study design (including the underreporting of COPD exacerbations in Japan). Understanding the reasons why COPD exacerbation rates appear lower in Japan could help clinicians to recognize and modify treatment behaviors, which may lead to improved patient outcomes in all populations. Keywords: COPD, exacerbation rate, asthma-COPD overlap, Japan

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In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at-risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol. [ABSTRACT FROM AUTHOR]

Background: Reductions in asthma exacerbations during the coronavirus disease 2019 (COVID-19) pandemic may have an impact on clinical trial enrollment and outcomes., Objective: Our aim was to review clinical studies and reports evaluating asthma exacerbations before and during the COVID-19 pandemic., Methods: We reviewed clinical studies conducted with biologics over the past decade that evaluated asthma exacerbations as the primary end point. We also reviewed recent clinical reports evaluating asthma exacerbations during the COVID-19 pandemic., Results: We showed that studies requiring at least 2 exacerbations in the prior year resulted in a higher number of exacerbations on study in the placebo arm, and conversely, those studies in which exacerbations were not required for entering the study failed to meet the primary end point. This result confirmed that history of prior exacerbations is a good maker to predict future exacerbations. In addition, a review of the literature confirmed a reduction of asthma exacerbations during the COVID-19 pandemic. The data presented are descriptive; no formal statistics were used., Conclusion: Because of the COVID-19 pandemic, historical exacerbations may no longer be the best predictor for exacerbations in a clinical trial or clinical practice. Other clinical markers associated with exacerbations, such as blood eosinophil count and fractional exhaled nitric oxide level, should be considered for enrollment in clinical studies assessing asthma exacerbations., (© 2022 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.)

Objective – To investigate whether supplementation with fish oil given together with dietary advice and vitamin supplementation influenced the clinical outcome in newly diagnosed multiple sclerosis (MS) patients. Material and methods – Sixteen consecutive, newly diagnosed patients with multiple sclerosis were recruited to an open intervention study. They were given dietary advice and supplemented with 0.9 g/day of long‐chain marine fatty acids and vitamins. The patients were followed for 2 years with respect to dietary habits, blood parameters and neurological assessment including exacerbation rate. Results – There was a significant reduction in the mean annual exacerbation rate and the mean Expanded Disability Status Scale (EDSS) as compared to pre‐study values. The plasma total phospholipid n‐3 fatty acids increased and n‐6 fatty acids decreased significantly. Conclusions – The results suggest that fish oil supplementation given together with vitamins and dietary advice can improve clinical outcome in patients with newly diagnosed MS. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of changing anticholinergic therapy in patients with COPD from ipratropium to tiotropium on pulmonary function., Methods: We examined records of patients prescribed high-dose ipratropium, who were subsequently converted to tiotropium. Spirometric values were obtained within 2 days of the change in medication and after 56 to 224 days of the switch to tiotropium., Results: 15 subjects were documented to have filled a prescription for ipratropium-containing medications the month prior to the change. Medication compliance over the 6 months prior to the switch in these patients was 72% +/- 31% (mean +/- SD) for ipratropium compared to 87% +/- 14% for tiotropium over the 6-month period after the switch (P = 0.1). FEV(1) improved from 1.12 +/- 0.39 L at baseline to 1.37 +/- 0.49 L after the change to tiotropium (P = 0.01). FVC also improved from 2.45 +/- 0.73 L at baseline to 2.72 +/- 0.69 L after the change (P = 0.04). Maximal voluntary ventilation was also increased from 39.67 +/- 10.7 L/min to 45.13 +/- 15.8 L/min (P = 0.045)., Conclusions: We conclude that replacing high-dose ipratropium with tiotropium therapy significantly improves pulmonary function in a clinical setting.