Imperial College London

ProfessorWisiaWedzicha

Faculty of MedicineNational Heart & Lung Institute

Clinical Chair in Respiratory Medicine
 
 
 
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Contact

 

j.wedzicha

 
 
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Location

 

B142Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

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261 results found

Wang Z, Locantore N, Haldar K, Ramsheh MY, Beech AS, Ma W, Brown JR, Tal-Singer R, Barer MR, Bafadhel M, Donaldson GC, Wedzicha JA, Singh D, Wilkinson TMA, Miller BE, Brightling CEet al., 2020, Inflammatory Endotype Associated Airway Microbiome in COPD Clinical Stability and Exacerbations - A Multi-Cohort Longitudinal Analysis., Am J Respir Crit Care Med

RATIONALE: Understanding the role of airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches. OBJECTIVES: To understand the association of airway microbiome with neutrophilic and eosinophilic COPD at stability and exacerbations. METHODS: An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 COPD patients recruited at four UK sites in BEAT-COPD, COPDMAP and AERIS cohorts. The microbiome was analyzed using COPDMAP and AERIS as discovery dataset and BEAT-COPD as validation dataset. RESULTS: The airway microbiome in neutrophilic COPD was heterogeneous with two primary community types differentiated by the predominance of Haemophilus. The Haemophilus-predominant subgroup had elevated sputum IL-1b and TNFa and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic-Haemophilus-predominant and eosinophilic states which were otherwise mutually exclusive. Time-series analysis on the microbiome showed the temporal trajectories of Campylobacter and Granulicatella were indicative of intra-patient switches from neutrophilic to eosinophilic inflammation, and in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns between neutrophilic-Haemophilus-predominant, neutrophilic-balanced-microbiome and eosinophilic subgroups. CONCLUSIONS: The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are inter-changeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status ov

Journal article

Wiseman DJ, Thwaites RS, Drysdale SB, Janet S, Donaldson GC, Wedzicha JA, Openshaw PJ, RESCEU Investigatorset al., 2020, Immunological and inflammatory biomarkers of susceptibility and severity in adult respiratory syncytial virus infections, Journal of Infectious Diseases, Vol: 222, Pages: S584-S591, ISSN: 0022-1899

BACKGROUND: . Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults. METHODS: A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946-October 2016. Nine articles were identified plus 9 from other sources. RESULTS: From observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection. CONCLUSIONS: Factors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.

Journal article

Shi T, Arnott A, Semogas I, Falsey AR, Openshaw P, Wedzicha JA, Campbell H, Nair H, RESCEU Investigatorset al., 2020, The etiological role of common respiratory viruses in acute respiratory infections in older adults: a systematic review and meta-analysis, Journal of Infectious Diseases, Vol: 222, Pages: S563-S569, ISSN: 0022-1899

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9-18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4-15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3-41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7-13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0-4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report.

Journal article

Ritchie A, Wedzicha JA, 2020, Definition, Causes, Pathogenesis, and Consequences of Chronic Obstructive Pulmonary Disease Exacerbations, CLINICS IN CHEST MEDICINE, Vol: 41, Pages: 421-438, ISSN: 0272-5231

Journal article

Barker RE, Jones SE, Banya W, Fleming S, Kon SSC, Clarke SF, Nolan CM, Patel S, Walsh JA, Maddocks M, Farquhar M, Bell D, Wedzicha JA, Man WD-Cet al., 2020, Reply to: one step at a time: a phased approach to behavioral treatment development in pulmonary rehabilitation, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 775-777, ISSN: 1073-449X

Journal article

Ritchie AI, Brill SE, Vlies BH, Finney LJ, Allinson JP, Alves-Moreira L, Wiseman DJ, Walker PP, Baker E, Elkin SL, Mallia P, Law M, Donaldson GC, Calverley PMA, Wedzicha JAet al., 2020, Targeted retreatment of incompletely recovered COPD exacerbations with ciprofloxacin: a double-blind, randomised, placebo-controlled, multicentre phase III trial, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 549-557, ISSN: 1073-449X

RATIONALE: COPD exacerbations are prone to non-recovery but there are no data about the effectiveness of retreatment on these prolonged events. We examined whether further therapy with ciprofloxacin for incompletely resolved COPD exacerbations prolonged the time until the next event. METHODS: This multi-centre randomised double-blind placebo-controlled trial studied retreatment with oral ciprofloxacin 500mg or matched placebo twice daily for 7 days in patients with GOLD stage II - IV COPD with persistent symptoms and/or serum C-reactive protein (CRP) ≥8mg/L initiated 14 (+/- 3) days after an index COPD exacerbation. The primary outcome was the time to the next exacerbation within a 90-day period. RESULTS: Of 826 patients screened at 4 centres, 144 eligible participants with incomplete recovery were randomised to receive ciprofloxacin (n=72) or placebo (n=72). 57% of patients in the ciprofloxacin group had experienced 1 or more exacerbations, compared to 53% in the placebo group. The median time to the next exacerbation was 32.5 days (IQR 13-50) in the placebo arm and 34 days (IQR 17-62) in the ciprofloxacin arm, which was not significantly different (adjusted hazard ratio = 1.07, 95% CI 0.68-1.68; p=0.76). No significant differences were seen in quality of life scores or lung function between treatment groups. CONCLUSION: In patients with persistent symptoms and/or raised CRP 14 days following a COPD exacerbation, an additional course of ciprofloxacin resulted in no additional benefit compared to placebo. This suggests that non-recovered exacerbations are not driven by ongoing bacterial infection and may potentially be targeted with anti-inflammatory therapy.

Journal article

Wedzicha JA, Buhl R, Singh D, Vogelmeier CF, de la Hoz A, Xue W, Anzueto A, Calverley PMAet al., 2020, Tiotropium/Olodaterol Decreases Exacerbation Rates Compared with Tiotropium in a Range of Patients with COPD: Pooled Analysis of the TONADO(R)/DYNAGITO(R) Trials, ADVANCES IN THERAPY, Vol: 37, Pages: 4266-4279, ISSN: 0741-238X

Journal article

Haldar K, George L, Wang Z, Mistry V, Ramsheh MY, Free RC, John C, Reeve NF, Miller BE, Tal-Singer R, Webb AJ, Brookes AJ, Tobin MD, Singh D, Donaldson GC, Wedzicha JA, Brown JR, Barer MR, Brightling CEet al., 2020, The sputum microbiome is distinct between COPD and health, independent of smoking history, Respiratory Research, Vol: 21, Pages: 1-12, ISSN: 1465-9921

BackgroundAirway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD.MethodsWe compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium.ResultsIn healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001).ConclusionThe healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.

Journal article

Rabe KF, Martinez FJ, Ferguson GT, Wang C, Singh D, Wedzicha JA, Trivedi R, St Rose E, Ballal S, McLaren J, Darken P, Aurivillius M, Reisner C, Dorinsky Pet al., 2020, Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD, New England Journal of Medicine, Vol: 383, Pages: 35-48, ISSN: 0028-4793

BACKGROUNDTriple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking.METHODSIn a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only.RESULTSThe modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg–budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg–budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate–formoterol group (2120 patients), and 1.24 in the budesonide–formoterol group (2131 patients). The rate was significantly lower with 320-μg–budesonide triple therapy than with glycopyrrolate–formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide–formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P=0.003). Similarly, the rate was significantly lower with 160-μg–budesonide triple therapy than with glycopyrrolate&nda

Journal article

Barker RE, Jones SE, Banya W, Fleming S, Kon SSC, Clarke SF, Nolan CM, Patel S, Walsh JA, Maddocks M, Farquhar M, Bell D, Wedzicha JA, Man WD-Cet al., 2020, The effects of a video intervention on post-hospitalization pulmonary rehabilitation uptake: a randomized controlled trial., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1517-1524, ISSN: 1073-449X

RATIONALE: Pulmonary rehabilitation following hospitalizations for exacerbations of chronic obstructive pulmonary disease (COPD) improves exercise capacity and health-related quality of life, and reduces readmissions. However, post-hospitalization pulmonary rehabilitation uptake is low. To date, no trials of interventions to increase uptake have been conducted. OBJECTIVE: Effect of a co-designed education video as an adjunct to usual care on post-hospitalization pulmonary rehabilitation uptake. METHODS: An assessor- and statistician-blinded randomized controlled trial with nested qualitative interviews of participants in the intervention group. Participants hospitalized with COPD exacerbations were assigned 1:1 to receive either usual care (COPD discharge bundle including pulmonary rehabilitation information leaflet) or usual care plus the co-designed education video delivered via a handheld tablet device at discharge. Randomization used minimization to balance age, sex, forced expiratory volume in 1 second (FEV1) % predicted, frailty, transport availability and previous pulmonary rehabilitation experience. MEASUREMENTS AND MAIN RESULTS: The primary outcome was pulmonary rehabilitation uptake within 28 days of hospital discharge. 200 patients were recruited with 196 randomized (51% female, median (interquartile range) FEV1 % predicted 36(27, 48)). Pulmonary rehabilitation uptake was 41% and 34% in the usual care and intervention groups respectively (p=0.37), with no differences in secondary (pulmonary rehabilitation referral and completion) or safety (readmissions and death) endpoints. Six of the fifteen participants interviewed could not recall receiving the video. CONCLUSION: A co-designed education video delivered at hospital discharge did not improve post-hospitalization pulmonary rehabilitation uptake, referral or completion. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0

Journal article

Chotirmall SH, Martinez FJ, Schumacker PT, Cooke CR, Seam N, Brochard L, Tighe RM, Levy BD, Gern D, Wedzicha JAet al., 2020, Life at the Editorial "COVID Frontline" The American Thoracic Society Journal Family, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 201, Pages: 1457-1459, ISSN: 1073-449X

Journal article

Leisman DE, Harhay MO, Lederer DJ, Abramson M, Adjei AA, Bakker J, Ballas ZK, Barreiro E, Bell SC, Bellomo R, Bernstein JA, Branson RD, Brusasco V, Chalmers JD, Chokroverty S, Citerio G, Collop NA, Cooke CR, Crapo JD, Donaldson G, Fitzgerald DA, Grainger E, Hale L, Herth FJ, Kochanek PM, Marks G, Moorman JR, Ost DE, Schatz M, Sheikh A, Smyth AR, Stewart I, Stewart PW, Swenson ER, Szymusiak R, Teboul J-L, Vincent J-L, Wedzicha JA, Maslove DMet al., 2020, Development and reporting of prediction models: guidance for authors from editors of respiratory, sleep, and critical care journals, Critical Care Medicine, Vol: 48, Pages: 623-633, ISSN: 0090-3493

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of “modifiable risk factors”, measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.

Journal article

Mackay AJ, Kostikas K, Roche N, Frent S-M, Olsson P, Pfister P, Gupta P, Patalano F, Banerji D, Wedzicha JAet al., 2020, Impact of baseline symptoms and health status on COPD exacerbations in the FLAME study, RESPIRATORY RESEARCH, Vol: 21

Journal article

Sundaram V, Rothnie K, Bloom C, Zakeri R, Sahadevan J, Singh A, Nagai T, Potts J, Wedzicha J, Smeeth L, Simon D, Timmis A, Rajagopalan S, Quint JKet al., 2020, Impact of comorbidities on peak troponin levels and mortality in acute myocardial infarction, Heart, Vol: 106, Pages: 677-685, ISSN: 1355-6037

OBJECTIVES: To characterise peak cardiac troponin levels, in patients presenting with acute myocardial infarction (AMI), according to their comorbid condition and determine the influence of peak cardiac troponin (cTn) levels on mortality. METHODS: We included patients with the first admission for AMI in the UK. We used linear regression to estimate the association between eight common comorbidities (diabetes mellitus, previous angina, peripheral arterial disease, previous myocardial infarction (MI), chronic kidney disease (CKD), cerebrovascular disease, chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD)) and peak cTn. Peak cTn levels were adjusted for age, sex, smoking status and comorbidities. Logistic regression and restricted cubic spline models were employed to investigate the association between peak cTn and 180-day mortality for each comorbidity. RESULTS: 330 367 patients with ST elevation myocardial infarction and non-ST elevation myocardial infarction were identified. Adjusted peak cTn levels were significantly higher in patients with CKD (adjusted % difference in peak cTnT for CKD=42%, 95% CI 13.1 to 78.4) and significantly lower for patients with COPD, previous angina, previous MI and CHF when compared with patients without the respective comorbidities (reference group) (cTnI; COPD=-21.7%, 95% CI -29.1 to -13.4; previous angina=-24.2%, 95% CI -29.6 to -8.3; previous MI=-13.5%, 95% CI -20.6 to -5.9; CHF=-28%, 95% CI -37.2 to -17.6). Risk of 180-day mortality in most of the comorbidities did not change substantially after adjusting for peak cTn. In general, cTnI had a stronger association with mortality than cTnT. CONCLUSIONS: In this nationwide analysis of patients presenting with AMI, comorbidities substantially influenced systemic concentrations of peak cTn. Comorbid illness is a significant predictor of mortality regardless of peak cTn levels and should be taken into consideration while interpr

Journal article

Nici L, Mammen MJ, Charbek E, Alexander PE, Au DH, Boyd CM, Criner GJ, Donaldson GC, Dreher M, Fan VS, Gershon AS, Han MK, Krishnan JA, Martinez FJ, Meek PM, Morgan M, Polkey MI, Puhan MA, Sadatsafavi M, Sin DD, Washko GR, Wedzicha JA, Aaron SD, American Thoracic Society Assembly on Clinical Problemset al., 2020, Pharmacologic management of COPD: an official American Thoracic Society clinical practice guideline., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1-14, ISSN: 1073-449X

BACKGROUND: This document provides clinical recommendations for the pharmacologic treatment of COPD. It represents a collaborative effort on the part of a panel of expert COPD clinicians and researchers along with a team of methodologists under the guidance of the ATS. METHODS: Comprehensive evidence syntheses were performed on all relevant studies which addressed the clinical questions and critical patient-centered outcomes agreed upon by the panel of experts. The evidence was appraised, rated, and graded, and recommendations were formulated using GRADE. RESULTS: After weighing the quality of evidence and balancing the desirable and undesirable effects, the guideline panel made six recommendations, listed in full in the document. CONCLUSIONS: The task force made recommendations on the pharmacologic treatment of COPD based on currently available evidence. Additional research in populations that are under-represented in clinical trials is needed, including studies in COPD patients 80 years of age and older, those with multiple chronic health conditions, and those with a co-diagnosis of COPD and asthma.

Journal article

Muro S, Yoshisue H, Kostikas K, Olsson P, Gupta P, Wedzicha JAet al., 2020, Indacaterol/glycopyrronium versus tiotropium or glycopyrronium in long-acting bronchodilator-naïve COPD patients: a pooled analysis, Respirology, Vol: 25, Pages: 393-400, ISSN: 1323-7799

BACKGROUND AND OBJECTIVE: Indacaterol/glycopyrronium (IND/GLY) 110/50 μg once daily (q.d.) has demonstrated greater improvements in lung function, patient-reported outcomes and lower exacerbation rates versus mono long-acting muscarinic antagonists (LAMA) in chronic obstructive pulmonary disease (COPD) patients. However, data are limited on initial treatment with IND/GLY 110/50 μg q.d. versus mono LAMA in COPD patients, not previously on maintenance treatment with long-acting bronchodilators (LABD). METHODS: A pooled analysis of ARISE, SHINE and SPARK trials was conducted to evaluate the efficacy of IND/GLY 110/50 μg q.d. versus open-label (OL) tiotropium (TIO) 18 μg q.d. and GLY 50 μg q.d. in COPD patients, not on maintenance treatment with LABD at study entry (LABD-naïve). Efficacy was assessed after 24/26 weeks of treatment. RESULTS: In total, 998 LABD-naïve patients were included (IND/GLY: 353; OL TIO: 328; GLY: 317). Patients treated with IND/GLY 110/50 μg q.d. experienced greater improvements in trough forced expiratory volume in 1 s (FEV1 ) versus OL TIO 18 μg q.d. (least squares mean treatment difference (Δ): 0.086 L) and GLY 50 μg q.d. (Δ: 0.080 L) after 24/26 weeks. Improvements in electronic diary (eDiary) symptom scores, transition dyspnoea index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score and rescue medication use were also greater with IND/GLY versus OL TIO and GLY. Greater proportion of patients achieved minimal clinically important difference in trough FEV1 , TDI and SGRQ with IND/GLY versus OL TIO and GLY. CONCLUSION: LABD-naïve patients treated with IND/GLY 110/50 μg q.d. achieved improvements in lung function, daily symptoms, dyspnoea, health-related quality of life and rescue medication use versus those who received single LAMA.

Journal article

Barrecheguren M, Kostikas K, Mezzi K, Shen S, Alcazar B, Soler-Cataluña JJ, Miravitlles M, Wedzicha JAet al., 2020, COPD clinical control as a predictor of future exacerbations: concept validation in the SPARK study population, Thorax, Vol: 75, Pages: 351-353, ISSN: 0040-6376

The concept of chronic obstructive pulmonary disease (COPD) control has been proposed to guide treatment decisions in COPD. In this study, we aimed to validate the prospective value of this concept in the SPARK study population. Control was assessed based on COPD stability and impact. Patients with low impact and stability during weeks 1-12 were classified as controlled, and exacerbations were measured during a 52-week follow-up. Of the 2044 patients included a majority were non-controlled (80%), frequently due to high impact. During the follow-up, the rate of moderate/severe exacerbations was significantly lower in controlled patients (rate ratio, 0.56, 95% CI 0.48 to 0.65 p<0.0001) and time-to-first moderate/severe exacerbation was significantly delayed. This study demonstrated an association between control status and risk of exacerbations.

Journal article

Long GH, Southworth T, Kolsum U, Donaldson GC, Wedzicha JA, Brightling CE, Singh Det al., 2020, The stability of blood Eosinophils in chronic obstructive pulmonary disease, Respiratory Research, Vol: 21, ISSN: 1465-9921

Blood eosinophils are a predictive biomarker of inhaled corticosteroid response in chronic obstructive pulmonary disease (COPD). We investigated blood eosinophil stability over 1 year using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 thresholds of < 100, 100- < 300 and ≥ 300 eosinophils/μL in 225 patients from the COPDMAP cohort. Blood eosinophils showed good stability (rho: 0.71, p < 0.001, ICC 0.84), and 69.3% of patients remained in the same eosinophil category at 1 year. 85.3% of patients with eosinophils < 100 cells/μL had stable counts. The majority of blood eosinophil counts remain stable over 1 year using the GOLD 2019 thresholds.

Journal article

Celli BR, Wedzicha JA, 2019, Update on Clinical Aspects of COPD. Reply., N Engl J Med, Vol: 381, Pages: 2485-2486

Journal article

Belchamber K, Singh R, Batista C, Moira W, Dockrell D, Kilty I, Matthew R, Wedzicha J, Barnes P, Donnelly Let al., 2019, Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages, European Respiratory Journal, Vol: 54, Pages: 1-14, ISSN: 0903-1936

Background: Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). Objective: This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD. Methods: Monocyte-derived macrophages (MDM) were generated from non-smoker, smoker and COPD subjects, differentiated in either GM-CSF (G-Mϕ) or M-CSF (M-Mϕ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage. Macrophages were incubated +/- 200M H2O2 for 24 hours, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 hours, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (m) were measured. Results: Phagocytosis of bacteria was significantly decreased in both G-Mϕ and M-Mϕ from COPD patients, compared to non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or m, however in COPD, phagocytosis increased early mROS and decreased m in both G-Mϕ and M-Mϕ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages, and non-smoker MDM, associated with reduced mROS production. Conclusion: COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.

Journal article

Wedzicha JA, Ritchie AI, Martinez FJ, 2019, Can macrolide antibiotics prevent hospital readmissions?, American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 796-798, ISSN: 1073-449X

Journal article

Rabe KF, Martinez FJ, Ferguson GT, Wang C, Singh D, Wedzicha JA, Trivedi R, St Rose E, Ballal S, McLaren J, Darken P, Reisner C, Dorinsky Pet al., 2019, A phase III study of triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 320/18/9.6 μg and 160/18/9.6 μg using co-suspension delivery technology in moderate-to-very severe COPD: The ETHOS study protocol, Respiratory Medicine, Vol: 158, Pages: 59-66, ISSN: 0954-6111

BACKGROUND: Single inhaler triple therapies providing an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting β2-agonist (ICS/LAMA/LABAs) are an emerging treatment option for chronic obstructive pulmonary disease (COPD). Nevertheless, questions remain regarding the optimal patient population for triple therapy as well as the benefit:risk ratio of ICS treatment. METHODS: ETHOS is an ongoing, randomized, double-blind, multicenter, parallel-group, 52-week study in symptomatic patients with moderate-to-very severe COPD and a history of exacerbation(s) in the previous year. Two doses of single inhaler triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI 320/18/9.6 μg and 160/18/9.6 μg) will be compared to glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg and budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, all formulated using co-suspension delivery technology. Outcomes include the rate of moderate/severe (primary endpoint) and severe COPD exacerbations, symptoms, quality of life, and all-cause mortality. Sub-studies will assess lung function and cardiovascular safety. STUDY POPULATION: From June 2015-July 2018, 16,044 patients were screened and 8572 were randomized. Preliminary baseline demographics show that 55.9% of patients had experienced ≥2 moderate/severe exacerbations in the previous year, 79.1% were receiving an ICS-containing treatment at study entry, and 59.9% had blood eosinophil counts ≥150 cells/mm3. CONCLUSIONS: ETHOS will provide data on exacerbations, patient-reported outcomes, mortality, and safety in 8572 patients with moderate-to-very severe COPD receiving triple and dual fixed-dose combinations. For the first time, ICS/LAMA/LABA triple therapy with two different doses of ICS will be compared to dual ICS/LABA and LAMA/LABA therapies. CLINICAL TRIAL REGISTRATION NUMBER: NCT02465567.

Journal article

Celli BR, Wedzicha JA, 2019, Update on clinical aspects of chronic obstructive pulmonary disease, New England Journal of Medicine, Vol: 381, Pages: 1257-1266, ISSN: 0028-4793

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; COPD led to 3.2 million deaths in 2017, a toll expected to reach 4.4 million yearly by 2040.1,2 With a worldwide prevalence of 10.1%, COPD afflicts many people in low-income, middle-income, and wealthy countries (Figure 1), and years of life lost prematurely increased 13.2% between 2007 and 2017.1 Although COPD has traditionally been considered a disease that affects men, in some countries, the prevalence and associated mortality are higher among women than among men. In this review, we update the clinical face of COPD, concentrating on the pulmonary aspects of the disease, which also affects many other organ systems. The pathogenesis of COPD is discussed in a companion article by Agustí and Hogg in this issue of the Journal,3 and the review of muco-obstructive lung diseases in a recent issue of the Journal4 complements this article.

Journal article

Singanayagam A, Glanville N, Cuthbertson L, Bartlett NW, Finney LJ, Turek E, Bakhsoliani E, Calderazzo MA, Trujillo-Torralbo M-B, Footitt J, James PL, Fenwick P, Kemp SV, Clarke TB, Wedzicha JA, Edwards MR, Moffatt M, Cookson WO, Mallia P, Johnston SLet al., 2019, Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease, Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234

Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

Journal article

Finney LJ, Belchamber KBR, Fenwick PS, Kemp SV, Edwards MR, Mallia P, Donaldson G, Johnston SL, Donnelly LE, Wedzicha JAet al., 2019, Human rhinovirus impairs the innate immune response to bacteria in alveolar macrophages in chronic obstructive pulmonary disease, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 1496-1507, ISSN: 1073-449X

Rationale Human rhinovirus (HRV) is a common cause of COPD exacerbations. Secondary bacterial infection is associated with more severe symptoms and delayed recovery. Alveolar macrophages clear bacteria from the lung and maintain lung homeostasis through cytokine secretion. These processes are defective in COPD. The effect of HRV on macrophage function is unknown. Objectives To investigate the effect of HRV on phagocytosis and cytokine response to bacteria by alveolar macrophages and monocyte derived macrophages (MDM) in COPD and healthy controls. Methods Alveolar macrophages were obtained by bronchoscopy and MDM by adherence. Macrophages were exposed to HRV 16 (multiplicity of infection 5), polyI:C 30μg/ml, interferon (IFN)-β 10μg/ml, IFN-γ 10μg/ml or medium control for 24 hours. Phagocytosis of fluorescently-labelled Haemophilus influenzae or Streptococcus pneumoniae was assessed by fluorimetry. CXCL8, TNF and IL-10 release was measured by ELISA. Main Results HRV significantly impaired phagocytosis of H. influenzae by 23% in MDM (n=37) and 18% in alveolar macrophages (n=20) in COPD. HRV also significantly reduced phagocytosis of S. pneumoniae by 33% in COPD MDM. There was no effect in healthy controls. Phagocytosis of H. influenzae was impaired by polyI:C but not IFN-β or IFN-γ. HRV significantly reduced cytokine responses to H. influenzae. The IL-10 response to H. influenzae was significantly impaired by polyI:C, IFN-β and IFN-γ. Conclusions HRV impairs phagocytosis of bacteria in COPD which may lead to an outgrowth of bacteria. HRV also impairs cytokine responses to bacteria via the TLR3/IFN pathway which may prevent resolution of inflammation leading to prolonged exacerbations in COPD.

Journal article

Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Criner GJ, Frith P, Halpin DMG, Han M, López Varela MV, Martinez F, Montes de Oca M, Papi A, Pavord ID, Roche N, Sin DD, Stockley R, Vestbo J, Wedzicha JA, Vogelmeier Cet al., 2019, Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: The GOLD Science Committee Report 2019, European Respiratory Journal, Vol: 53, ISSN: 0903-1936

Precision medicine is a patient specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICS) in COPD patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment.The Global initiative for the management of chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment naïve individuals at initial presentation. However, their use is more problematic during follow up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow up.Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICS and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This paper explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations.

Journal article

Smith JA, McGarvey L, Morice AH, Birring SS, Wedzicha JA, Notari M, Zapata A, Segarra R, Seoane B, Jarreta Det al., 2019, The Effect of Aclidinium on Symptoms Including Cough in COPD: A Phase IV, DoubleBlind, Placebo-Controlled, Parallel-Group Study., Am J Respir Crit Care Med

Journal article

Agusti A, Faner R, Donaldson G, Heuvelin E, Breyer-Kohansal R, Melén E, Maitland-van der Zee AH, Vestbo J, Allinson JP, Vanfleteren LEGW, van den Berge M, Adcock IM, Lahousse L, Brusselle G, Wedzicha JA, onbehalf of the CADSET Clinical Research Collaboration, Current members of the CADSET Clinical Research Collaborationet al., 2019, Chronic Airway Diseases Early Stratification (CADSET): a new ERS Clinical Research Collaboration, European Respiratory Journal, Vol: 53, ISSN: 0903-1936

A recent editorial in the European Respiratory Journal highlighted the strategic importance of the Clinical Research Collaborations (CRCs) launched in 2013 by the European Respiratory Society (ERS) [1]. These have the aim of 1) promoting the exchange of research ideas among clinicians and affiliated scientists in Europe and/or globally; 2) building an infrastructure for prospective clinical research; 3) securing additional funding through national and European Union funding streams; and 4) facilitating the planning, implementation, evaluation and publication of clinical and translational studies at pan-European level and beyond. So far, there are currently 17 ongoing CRCs that cover eight major respiratory disease domains (airway diseases, interstitial lung diseases, pulmonary vascular diseases, sleep and breathing disorders, respiratory critical care, paediatric respiratory diseases, respiratory infections and thoracic oncology), all of them linked to one or more ERS assemblies [2–12]. CADSET, an acronym that stands for “Chronic Airway Diseases Early Stratification”, is the latest addition to the list of ongoing CRCs (www.ersnet.org/research/clinical-research-collaborations). This editorial presents the rationale, goals and research strategy for CADSET.

Journal article

Pfeffer PE, Donaldson GC, Mackay AJ, Wedzicha JAet al., 2019, Increased COPD exacerbations of likely viral etiology follow elevated ambient nitrogen oxides, American Journal of Respiratory and Critical Care Medicine, Vol: 199, ISSN: 1073-449X

RATIONALE: Epidemiological research strongly supports an association between air pollution and COPD exacerbations. Numerous mechanisms may underlie any association as pollutants are toxic to pulmonary cells and may increase susceptibility to respiratory infections. The relationship between ambient pollution and exacerbation etiology has not been studied. OBJECTIVES: To evaluate the characteristics of pollution-associated exacerbations and whether the association is specific to exacerbations of infective or non-infective etiology. METHODS: We analyzed the effect of preceding ambient PM10, NOx and O3 on characterized COPD exacerbations in a regression model adjusted for temperature, seasonality and long-term trend. We specifically examined associations with exacerbations of suspected viral and/or bacterial, or non-infective etiology. For the associations identified we further examined the characteristics of pollution-associated exacerbations. MEASUREMENTS AND MAIN RESULTS: 4173 exacerbations occurred over the 20 year study period. Higher ambient NOx was consistently associated with increased viral-type exacerbations at 2-4 days lag (p=0.010). Recovery for viral-type exacerbations following higher ambient NOx was significantly prolonged. These findings were consistent in the subset of 2841 exacerbations treated with oral corticosteroids or antibiotics, with recovery 1.29 (95% CI 1-17-1.42; P<0.001) times longer with 'viral-type' exacerbations of onset 3 days after above versus below median ambient NOx. A likely bimodal association of PM10 with infective exacerbations was also evident, and supported by a daily time-series analysis. CONCLUSIONS: Higher levels of ambient NOx are associated with prolonged exacerbations of likely viral etiology, supporting toxicological effects of air pollution that increase susceptibility to, and severity of, infection.

Journal article

Chapman KR, Hurst JR, Fogel RB, Pfister P, Kostikas K, Wedzicha JA, SUNSET investigatorset al., 2019, Reply to: Different background, short duration, inappropriate participants may harm your conclusion, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 390-392, ISSN: 1073-449X

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