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Key Points: Question: What are the operating characteristics of the CAPTURE ([chronic obstructive pulmonary disease] COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening tool (composed of 5 questions and selective use of peak expiratory flow rate) to identify undiagnosed, clinically significant COPD among US primary care patients? Findings: In this cross-sectional study of 4325 patients from US primary care settings, the CAPTURE tool demonstrated a sensitivity of 48.2% and a specificity of 88.6% for detecting clinically significant COPD, which was defined by spirometry results showing airflow obstruction of moderate severity or accompanied by a history of acute respiratory illness. Meaning: In US primary care, the CAPTURE screening tool did not perform well identifying undiagnosed, clinically significant COPD. Importance: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in primary care. Objective: To evaluate the operating characteristics of the CAPTURE (COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening tool for identifying US primary care patients with undiagnosed, clinically significant COPD. Design, Setting, and Participants: In this cross-sectional study, 4679 primary care patients aged 45 years to 80 years without a prior COPD diagnosis were enrolled by 7 primary care practice–based research networks across the US between October 12, 2018, and April 1, 2022. The CAPTURE questionnaire responses, peak expiratory flow rate, COPD Assessment Test scores, history of acute respiratory illnesses, demographics, and spirometry results were collected. Exposure: Undiagnosed COPD. Main Outcomes and Measures: The primary outcome was the CAPTURE tool's sensitivity and specificity for identifying patients with undiagnosed, clinically significant COPD. The secondary outcomes included the analyses of varying thresholds for defining a positive screening result for clinically significant COPD. A positive screening result was defined as (1) a CAPTURE questionnaire score of 5 or 6 or (2) a questionnaire score of 2, 3, or 4 together with a peak expiratory flow rate of less than 250 L/min for females or less than 350 L/min for males. Clinically significant COPD was defined as spirometry-defined COPD (postbronchodilator ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity [FEV1:FVC] <0.70 or prebronchodilator FEV1:FVC <0.65 if postbronchodilator spirometry was not completed) combined with either an FEV1 less than 60% of the predicted value or a self-reported history of an acute respiratory illness within the past 12 months. Results: Of the 4325 patients who had adequate data for analysis (63.0% were women; the mean age was 61.6 years [SD, 9.1 years]), 44.6% had ever smoked cigarettes, 18.3% reported a prior asthma diagnosis or use of inhaled respiratory medications, 13.2% currently smoked cigarettes, and 10.0% reported at least 1 cardiovascular comorbidity. Among the 110 patients (2.5% of 4325) with undiagnosed, clinically significant COPD, 53 had a positive screening result with a sensitivity of 48.2% (95% CI, 38.6%-57.9%) and a specificity of 88.6% (95% CI, 87.6%-89.6%). The area under the receiver operating curve for varying positive screening thresholds was 0.81 (95% CI, 0.77-0.85). Conclusions and Relevance: Within this US primary care population, the CAPTURE screening tool had a low sensitivity but a high specificity for identifying clinically significant COPD defined by presence of airflow obstruction that is of moderate severity or accompanied by a history of acute respiratory illness. Further research is needed to optimize performance of the screening tool and to understand whether its use affects clinical outcomes. This cross-sectional study evaluates the operating characteristics of the CAPTURE screening tool by identifying US primary care patients with undiagnosed, clinically significant COPD. [ABSTRACT FROM AUTHOR]

Background: In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib.Methods: Patients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial.Results: A total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients.Conclusions: The adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy. Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178 A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety . [ABSTRACT FROM AUTHOR]

Introduction: Chronic cough is a highly problematic symptom for patients with idiopathic pulmonary fibrosis (IPF); limited therapeutic options are available. We evaluated gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough in IPF. Methods: This randomized, double-blind, placebo-controlled, crossover study included subjects with IPF. Sequence A included gefapixant 50 mg BID (period 1; 14 days) followed by placebo (period 2; 14 days); sequence B had the opposite sequence of treatments. This regimen was specified in a protocol amendment that modified the original active treatment regimen of gefapixant 50 mg BID for 10 days and 150 mg BID for 4 days. Patients randomized to the original treatment regimen were excluded from efficacy analyses but included in safety assessments. The primary efficacy endpoint was change from baseline in awake cough frequency (coughs/hour) from periods 1 and 2 combined. Adverse events (AEs) were monitored throughout the study. Results: A total of 51 subjects were randomized, 44 of whom were randomized to treatment sequences evaluated in the primary efficacy analysis (i.e., 22 subjects in sequence A and 22 subjects in sequence B); seven subjects received the treatment assigned before the protocol amendment and were excluded from efficacy analyses. The change from baseline in awake cough frequency from periods 1 and 2 combined (mixed model for repeated measures analysis) did not demonstrate a significant reduction versus placebo in cough at day 14 (p = 0.90); in a post hoc analysis of log-transformed data p value for reduction versus placebo at day 14 was 0.07. The most common AEs were related to taste (dysgeusia and ageusia). Conclusions: Gefapixant was generally well tolerated but was not associated with a significant improvement in chronic cough in subjects with IPF as defined by the primary endpoint in this study. Trial Registration: NCT02502097. [ABSTRACT FROM AUTHOR]

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis.Objective: To assess the effect of antimicrobial therapy on clinical outcomes.Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020).Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group.Main Outcomes and Measures: The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality.Results: Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%).Conclusions and Relevance: Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease.Trial Registration: ClinicalTrials.gov Identifier: NCT02759120. [ABSTRACT FROM AUTHOR]

Background: Triple 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.Methods: In 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.Results: The 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-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group.Conclusions: Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.). [ABSTRACT FROM AUTHOR]

Background: The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4.Methods: PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed.Results: The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals.Conclusions: This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history.Trial Registration: ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458). [ABSTRACT FROM AUTHOR]

Background: Many patients with chronic obstructive pulmonary disease (COPD) still experience daily symptoms, exacerbations, and accelerated lung function decline, even when receiving maximal combined treatment with inhaled long-acting bronchodilators and corticosteroids. Novel treatment options are needed for these patients. Phosphodiesterases (PDEs) are enzymes that impact a range of cellular functions by modulating levels of cyclic nucleotides, and there is evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive (or perhaps synergistic) effects. This study investigated the efficacy and safety of ensifentrine, a first-in-class dual inhibitor of PDE 3 and 4, in patients with COPD.Methods: This randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 40-80% predicted and FEV1/forced vital capacity ratio ≤ 0.7. Patients were randomised equally to inhale nebulised ensifentrine 0.75, 1.5, 3 or 6 mg or placebo, all twice daily.Primary Outcome: placebo-adjusted difference in peak FEV1 (assessed over 3 h) at Week 4.Results: The study took place between July 2017 and February 2018. Of 405 patients randomly assigned to medication, 375 (92.6%) completed the study. For peak FEV1 at Week 4, all four ensifentrine doses were superior to placebo (p ≤ 0.0001) with least squares mean differences of 146 (95% CI 75-216), 153 (83-222), 200 (131-270) and 139 (69-210) mL for ensifentrine 0.75, 1.5, 3 and 6 mg, respectively. Respiratory symptoms (assessed using the Evaluating Respiratory Symptoms questionnaire) were also significantly improved with all ensifentrine doses at Week 4. Adverse events were reported by 33.3, 44.4, 35.4 and 36.3% patients with ensifentrine 0.75, 1.5, 3 and 6 mg, respectively, and 39.2% with placebo.Conclusions: In this four-week Phase IIb study, all four ensifentrine doses significantly improved bronchodilation and symptoms, with a dose-ranging effect from 0.75 to 3 mg twice daily, and all doses well tolerated. The study supports the continuing development of ensifentrine in COPD.Trial Registration: EudraCT 2016-005205-40, registered 30 May 2017. [ABSTRACT FROM AUTHOR]

The article offers information on Idiopathic Pulmonary Fibrosis. It mentions that clinicians should consider interstitial lung disease in the differential diagnosis for adults presenting with unexplained exertional dyspnea, chronic dry cough, or Velcrolike crackles on examination. It states that shortened telomeres, oxidative injury and endoplasmic reticulum stress, and mitochondrial dysfunction lead to decreased alveolar epithelial-cell proliferation and secretion of profibrotic mediators.

Background: The clinical severity of COPD is currently categorized by symptom burden and exacerbation risk. Previous 24-week phase III trials (NCT01854645 and NCT01854658) that demonstrated better improvement of lung function with glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) (an MDI fixed-dose of GFF 18/9.6 μg) over individual monocomponent MDIs included a cross-section of patients with moderate to very severe airflow limitation and a broad range of COPD symptoms.Methods: These post hoc analyses of pooled data investigated whether baseline symptom burden, assessed using the COPD Assessment Test (CAT) score, impacted GFF MDI-associated improvements in lung function, health status, rescue medication use, and exacerbation risk.Results: In 3,699 patients, improvement in FEV1 at week 24 between the GFF MDI and monocomponent MDIs and a placebo MDI was similar in magnitude regardless of baseline CAT score. In contrast, the magnitude of mean difference in the St. George's Respiratory Questionnaire total score for GFF MDI vs monocomponent MDIs and the placebo MDI increased with increasing baseline CAT scores. Likewise, reduced rescue medication use and lower exacerbation risk were more pronounced in GFF MDI groups with a higher baseline symptom burden.Conclusions: Beneficial effects of GFF MDI on health status, rescue medication use, and exacerbation risk in symptomatic patients with COPD increased as a function of baseline symptom burden, whereas lung function benefits were independent. These data suggest a greater clinical benefit from dual bronchodilators in symptomatic patients than in patients without symptoms.Trial Registry: ClinicalTrials.gov; No.: NCT01854645 and NCT01854658; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Discriminative Accuracy of the CAPTURE Tool for Identifying COPD - Reply Discriminative accuracy of the CAPTURE tool for identifying chronic obstructive pulmonary disease in US primary care settings. Comment & Response B In Reply b We appreciate the key observations provided by Dr Hsu and colleagues about our article describing the operating characteristics of the CAPTURE strategy to identify previously undiagnosed patients with clinically significant COPD.[1] The Letter authors are correct in noting differences in sensitivity and specificity of the CAPTURE approach in this primary care population compared with the COPD-enriched specialty population used for the original derivation and validation study.[2] There was also a substantial effect of the COVID-19 pandemic on the operating characteristics of the CAPTURE screening tool, which performed much better before the pandemic than during the pandemic. [Extracted from the article]

Background Long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-μg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. Methods These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed. Results At week 24, differences in change from baseline in the morning predose trough FEV 1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). Conclusions We conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. Trial Registry ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658 ; URL: www.clinicaltrials.gov . [ABSTRACT FROM AUTHOR]

Summary HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1. Video Abstract [ABSTRACT FROM AUTHOR]

Background Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment. Methods For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3–4 trial, the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029. Findings Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753–1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740–0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1·8%) deaths occurred in the roflumilast group compared with 18 (1·9%) in the placebo group. Interpretation Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy, even in combination with tiotropium. [ABSTRACT FROM AUTHOR]

Culture-independent microbiological techniques have shown a previously unappreciated complexity to the bacterial microbiome of the respiratory tract that forces reconsideration of the interactions between host, bacteria, and the pathogenesis of exacerbations of chronic lung disease. The composition of the lung microbiome is determined by microbial immigration, elimination, and relative growth rates of its members. All these factors change dramatically in chronic lung disease and further during exacerbations. Exacerbations lack the features of bacterial infections, including increased bacterial burden and decreased diversity of microbial communities. We propose that exacerbations are occasions of respiratory tract dysbiosis--a disorder of the respiratory tract microbial ecosystem with negative effects on host biology. Respiratory tract dysbiosis provokes a dysregulated host immune response, which in turn alters growth conditions for microbes in airways, promoting further dysbiosis and perpetuating a cycle of inflammation and disordered microbiota. Differences in the composition of baseline respiratory tract microbiota might help to explain the so-called frequent-exacerbator phenotype observed in several disease states, and might provide novel targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Culture-independent microbiological techniques have shown a previously unappreciated complexity to the bacterial microbiome of the respiratory tract that forces reconsideration of the interactions between host, bacteria, and the pathogenesis of exacerbations of chronic lung disease. The composition of the lung microbiome is determined by microbial immigration, elimination, and relative growth rates of its members. All these factors change dramatically in chronic lung disease and further during exacerbations. Exacerbations lack the features of bacterial infections, including increased bacterial burden and decreased diversity of microbial communities. We propose that exacerbations are occasions of respiratory tract dysbiosis--a disorder of the respiratory tract microbial ecosystem with negative effects on host biology. Respiratory tract dysbiosis provokes a dysregulated host immune response, which in turn alters growth conditions for microbes in airways, promoting further dysbiosis and perpetuating a cycle of inflammation and disordered microbiota. Differences in the composition of baseline respiratory tract microbiota might help to explain the so-called frequent-exacerbator phenotype observed in several disease states, and might provide novel targets for therapeutic intervention. INSET: Search strategy and selection criteria. [ABSTRACT FROM AUTHOR]

Background: Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking.Methods: In our initial double-blind, placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period.Results: At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P=0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P=0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P>0.99).Conclusions: As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00650091.). [ABSTRACT FROM AUTHOR]

The article focuses on a randomized trial which evaluated the beneficial effects of acetylcysteine in patients with idiopathic pulmonary fibrosis (IPF). Topics discussed include the primary outcome measure which showed a change in forced vital capacity (FVC) over 60 weeks, the absence of a significant difference in the change in FVC at 60 weeks between the acetylcysteine group and the placebo group, and how the drug benefits patients with IPF by altering the oxidative state of the lung.

Abstract: Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients' fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modeling for drug screening. [Copyright &y& Elsevier]

Background: Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown. Methods: Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants. Results: All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD. In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells. Production of the Tc1 cytokines IFN-γ and TNF-.alpha; by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists. Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD. Conclusions: These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1. [ABSTRACT FROM AUTHOR]

The article focuses on the challenges of developing drugs for chronic obstructive pulmonary disease (COPD). It indicates that there are major challenges in the development of agents which are intended to modify the progression of COPD including high estimated costs, unvalidated biomarkers, and inadequate in-vitro and in-vivo models. It also cites novel therapeutic approaches and non-pharmacotherapies which are under development.

Emphysema is characterized by the destruction of alveolar parenchymal tissue and the concordant loss of lung epithelial cells, endothelial cells, and interstitial mesenchymal cells. Key features in the pathobiology of emphysema include inflammation, alveolar epithelial cell injury/apoptosis, and excessive activation of extracellular matrix (ECM) proteases. Mesenchymal cells are versatile connective tissue cells that are critical effectors of wound-repair. The excessive loss of connective tissue and the destruction of alveolar septae in emphysema suggest that the mesenchymal cell reparative response to epithelial injury is impaired. Yet, the mechanisms regulating mesenchymal cell (dys)function in emphysema remain poorly understood. We propose that mesenchymal cell fate, modulated by transforming growth factor beta-1 (TGF-β 1) and the balance of ECM proteases and antiproteases, is a critical determinant of the emphysema phenotype. We examine emphysema in the context of wound-repair responses, with a focus on the regulation of mesenchymal cell fate and phenotype. We discuss the emerging evidence supporting that genetic factors, inflammation and environmental factors, including cigarette smoke itself, collectively impair mesenchymal cell survival and function, thus contributing to the pathogenesis of emphysema. [ABSTRACT FROM AUTHOR]

COPD has a profound impact on daily life, yet remains underdiagnosed and undertreated. We set out to develop a brief, reliable, self-scored questionnaire to identify individuals likely to have COPD. COPD-PS™ development began with a list of concepts identified for inclusion using expert opinion from a clinician working group comprised of pulmonologists (n = 5) and primary care clinicians (n = 5). A national survey of 697 patients was conducted at 12 practitioner sites. Logistic regression identified items discriminating between patients with and without fixed airflow obstruction (AO, postbronchodilator FEV1/FVC < 70%). ROC analyses evaluated screening accuracy, compared scoring options, and assessed concurrent validity. Convergent and discriminant validity were assessed via COPD-PS and SF-12v2 score correlations. For known-groups validation, COPD-PS differences between clinical groups were tested. Test-retest reliability was evaluated in a 20% sample. Of 697 patients surveyed, 295 patients met expert review criteria for spirometry performance; 38% of these (n = 113) had results indicating AO. Five items positively predicted AO (p < 0.0001): breathlessness, productive cough, activity limitation, smoking history, and age. COPD-PS scores accurately classified AO status (area under ROC curve = 0.81) and reliable (r = 0.91). Patients with spirometry indicative of AO scored significantly higher (6.8, SD = 1.9; p< 0.0001) than patients without AO (4.0, SD = 2.3). Higher scores were associated with more severe AO, bronchodilator use, and overnight hospitalization for breathing problems. With the prevalence of COPD in the studied cohort, a score on the COPD-PS of greater than five was associated with a positive predictive value of 56.8% and negative predictive value of 86.4%. The COPD-PS accurately classified physicianreported COPD (AUC = 0.89). The COPD-PS is a brief, accurate questionnaire that can identify individuals likely to have COPD. [ABSTRACT FROM AUTHOR]

The article presents information on development in the methods of diagnosing idiopathic interstitial pneumonias, the most common of the idiopathic interstitial pneumonias. It is said that surgical biopsy can now be avoided with the help of new high-resolution CT (HRCT) scanning technologies. It may also help in prognosis and identifying disease progression.

Abstract: Antibiotic therapy is of clinical benefit in certain patients with acute exacerbations of chronic bronchitis (AECB). In this randomised, investigator-blinded, multicentre trial, azithromycin (500mg once a day (qd) for 3 days) was compared with moxifloxacin (400mg qd for 5 days) for the treatment of outpatients with AECB (forced expiratory volume in 1s (FEV1) >35%). Of 342 patients randomised to either treatment, 169 received azithromycin and 173 received moxifloxacin. The mean age in the azithromycin and moxifloxacin groups was 56.4 years and 55.5 years, respectively. In the intent-to-treat analysis, clinical success rates for azithromycin and moxifloxacin were comparable at Days 10–12 (90% versus 90%, respectively) and Days 22–26 (81% versus 82%, respectively). Among patients who were culture-positive at baseline for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis or Haemophilus parainfluenzae, clinical efficacy for azithromycin versus moxifloxacin at Days 10–12 was 93% versus 84%, respectively, and at Days 22–26 it was 89% versus 73%, respectively. The incidence of at least one treatment-related adverse event (AE) in the azithromycin and moxifloxacin groups was 18.3% and 19.1%, respectively. The most common AEs were diarrhoea, nausea, abdominal pain and vaginitis. Most treatment-related AEs were of mild or moderate severity, with no serious treatment-related AEs. One subject in the moxifloxacin group discontinued treatment owing to a treatment-related AE (precordial pain and dry throat). Compliance with both regimens was >90%. Three-day azithromycin and 5-day moxifloxacin demonstrate comparable efficacy and safety for the treatment of AECB in outpatients. [Copyright &y& Elsevier]

Acute exacerbations of chronic bronchitis (AECB), which are characteristic of chronic obstructive pulmonary disease (COPD), contribute to morbidity and decreased quality of life for patients with COPD. A significant proportion of these exacerbations are due to bacterial infections. The Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria provide guidance for choosing the optimal drug at its optimal dose and duration for antimicrobial treatment of AECB due to bacterial infection. Evidence-based guidelines recommend stratifying patients according to risk factors to improve selection of targeted antimicrobial therapy. With increasing rates of resistance to some antimicrobials, resistance is also an important consideration for reducing treatment failures and decreasing the need for further pharmacologic treatment. Fluoroquinolones are recommended as first-line therapy for patients with chronic bronchitis who have risk factors; gatifloxacin, gemifloxacin, and levofloxacin are highly active against commonly encountered pathogens. Safety profiles are an important consideration because adverse events and poor tolerability can reduce patient adherence rates, which in turn can lead to poorer outcomes. Safety profiles also become an important consideration as shorter-course, higher-dose therapies become more prevalent. First-line therapy with a well-tolerated antibiotic that is active against the predominant pathogens, combined with low resistance rates and a convenient once-a-day dosing regimen, may reduce overall costs. Fluoroquinolones exhibit low resistance, good activity levels, and high respiratory penetration, and they are particularly well suited for shorter-course, higher-dose regimens in selected patients. Shorter-course, higher dose regimens, in turn, may be more effective, cost-efficient, and appropriate for controlling the rise of resistance than standard regimens. [Copyright &y& Elsevier]

Background: Prospective data defining the clinical course in idiopathic pulmonary fibrosis (IPF) are sparse. Objective: To analyze the clinical course of patients with mild to moderate IPF. Design: Analysis of data from the placebo group of a randomized, controlled trial evaluating interferon γ1b. Setting: Academic and community medical centers. Patients: 168 patients in the placebo group of a trial evaluating interferon-γ1b. Measurements: Measures of physiology and dyspnea assessed at 12-week intervals; hospitalizations; and the pace of deterioration and cause of death over a median period of 76 weeks. Results: Physiologic variables changed minimally during the study. However, 23% of patients required hospitalization for a respiratory disorder and 21 % died. Idiopathic pulmonary fibrosis was the primary cause of death in 89% of patients who died, and an apparent acute clinical deterioration preceded death in 47% of these patients. Limitations: The instrument used to define the pace of deterioration and cause of death was applied retrospectively. Conclusions: Recognition of the common occurrence of acute fatal deterioration in patients with mild to moderate IPF has important implications for monitoring patients and supports early referral for lung transplantation. [ABSTRACT FROM AUTHOR]

Several medical-specialty professional societies have suggested that combination therapy with a β-lactam plus a macrolide or doxycycline or monotherapy with a "respiratory quinolone" (i.e., levofloxacin, gatifloxacin, moxifloxacin, or gemifloxacin) are optimal first-line therapy for patients hospitalized with community-acquired pneumonia. These recommendations are based predominantly on retrospective studies that suggest improved rates of morbidity and mortality and hospital length of stay among patients treated in such a fashion. Well- designed, prospective, randomized studies confirming this tenet of therapy have not been published, although numerous prospective studies have provided indirect confirmation. The biological rationale for such a differential response (i.e., favoring combination therapy or fluoroquinolone therapy) includes the immunomodulatory effects of macrolides or more-optimal treatment of primary infection or coinfection with atypical pathogens. Well-designed, prospective, randomized trials are required to best define the effectiveness of combination therapy with a β-lactam plus macrolide or doxycycline or with a respiratory quinolone in hospitalized patients with community-acquired pneumonia. [ABSTRACT FROM AUTHOR]

Discusses the prevalence of macrolide resistance among Streptococcus pneumoniae, risk factors and mechanisms responsible for resistance, therapeutic strategies and implications for the future. Impact of antimicrobial resistance on clinical outcomes; Clinical significance of in vitro macrolide resistance; Recommendations.

The authors reflect on the influence of pulmonary arterial hypertension (PAH) on idiopathic pulmonary fibrosis (IPF). They assert that the association of PAH with increased mortality in IPF patients has raised the possibility that therapy directed against PAH may be of benefit in IPF patients. They suggest that the development of PAH in IPF patients seems to portend a signal of mortality, and that phase 3 trials of therapy are needed to determine which agents can provide effective treatment.

Lung transplantation remains the sole curative option for patients with idiopathic pulmonary fibrosis (IPF), but donor organs remain scarce, and many eligible patients die before transplant. Tools to optimize the timing of transplant referrals are urgently needed. Least absolute shrinkage and selection operator was applied to clinical and proteomic data generated as part of a prospective cohort study of interstitial lung disease (ILD) to derive clinical, proteomic, and multidimensional logit models of near-term death or lung transplant within 18 months of blood draw. Model-fitted values were dichotomized at the point of maximal sensitivity and specificity, and decision curve analysis was used to select the best-performing classifier. We then applied this classifier to independent IPF and non-IPF ILD cohorts to determine test performance characteristics. Cohorts were restricted to patients aged ≤72 years with body mass index 18 to 32 to increase the likelihood of transplant eligibility. IPF derivation, IPF validation, and non-IPF ILD validation cohorts consisted of 314, 105, and 295 patients, respectively. A multidimensional model comprising 2 clinical variables and 20 proteins outperformed stand-alone clinical and proteomic models. Following dichotomization, the multidimensional classifier predicted near-term outcome with 70% sensitivity and 92% specificity in the IPF validation cohort and 70% sensitivity and 80% specificity in the non-IPF ILD validation cohort. A multidimensional classifier of near-term outcomes accurately discriminated this end-point with good test performance across independent IPF and non-IPF ILD cohorts. These findings support refinement and prospective validation of this classifier in transplant-eligible individuals. [ABSTRACT FROM AUTHOR]

As seen in this CME online activity (available at http://courses.elseviercme.com/694), idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrotic lung disease of unknown cause that is associated with substantial health-care utilization and high rates of mortality. The clinical symptoms of IPF are nonspecific and overlap with many pulmonary and cardiac diseases making differential diagnosis challenging. The American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines strongly recommend a multidisciplinary approach to the diagnosis of interstitial lung diseases; however, there are several limitations to the feasibility of this approach in clinical practice. Although early diagnosis is relevant to any chronic, progressive, and irreversible disorder, it is crucially important that effective treatments for IPF are prescribed without delay. A window of opportunity may exist during which time treatment can have optimal outcomes. Evidence on the clinical management of IPF is rapidly evolving, and key updates were made to the most recent ATS/ERS/JRS/ALAT guidelines. The widely used combination of prednisone, azathioprine, and N-acetylcysteine has now been associated with increased risk of hospitalization and death compared with placebo in patients with IPF. These treatments and others for IPF have been mostly supportive, but recently pirfenidone and nintedanib have demonstrated efficacy in reducing functional decline and disease progression in IPF. A pooled analysis of three phase 3 studies of pirfenidone found a significant 48% reduction in all-cause mortality, and a pooled analysis of a phase 2 and two phase 3 studies of nintedanib found a significant 43% reduction in on-treatment mortality. As patient exposure to these two new drugs increases, data continue to emerge on how and when to use these medications and on how to manage their side effects. Finally, several medications targeting the fibrotic pathobiology of IPF are currently in development. Given the limited treatment options for IPF, enrollment in a clinical trial may be the best chance to delay or prevent progression of IPF. This CME-certified expert video roundtable from CHEST reviews the ATS/ERS/JRS/ALAT guidelines with a specific focus on accurate and timely diagnosis of IPF and the latest data on the treatment of IPF. [ABSTRACT FROM AUTHOR]

As seen in this CME online activity (available at http://courses.elseviercme.com/chest16/647e), idiopathic pulmonary fibrosis (IPF) is a specific form of chronic progressive fibrotic lung disease of unknown cause. It is the most common form of idiopathic interstitial pneumonia in adults. Its prevalence among US Medicare beneficiaries has more than doubled in the past 14 years. With the approval of two agents that reduce functional decline and disease progression, and the 2015 update of the American Thoracic Society guidelines on the treatment of IPF, the options for appropriate clinical management of the disease have become well defined. Early diagnosis and early initiation of treatment are of critical importance for long-term clinical outcomes. The diagnostic process, which may require a multidisciplinary team of experts, is centered on excluding systemic diseases and exposures and identifying a pattern of usual interstitial pneumonia on high-resolution CT or surgical lung biopsy results. Familiarity with the 2015 American Thoracic Society guidelines is critical with respect to both the treatments that the guidelines recommend and those that they advise against. Standard immunosuppressive therapy is no longer indicated, whereas pirfenidone, nintedanib, and antacid therapy are all conditionally recommended for use. Individualizing treatment is important in light of potential improved adherence to both drug therapy and health behaviors. An early referral to an interstitial lung disease center offers the advantages of comprehensive diagnostic and disease-management expertise, potential enrollment in a clinical trial, and evaluation for transplantation. [ABSTRACT FROM AUTHOR]

Background: Chronic hypersensitivity pneumonitis (CHP) is an interstitial lung disease (ILD) caused by long term exposure to an offending antigen. Antigen avoidance is associated with improved outcomes. We are unable to identify the antigen source in approximately half of patients. When an antigen is successfully identified, patients have difficulty with avoidance.Methods: We conducted three structured group discussions with US based ILD specialists utilizing the nominal group technique (NGT). Participants listed barriers to antigen detection and avoidance in CHP. Each participant ranked what they perceived to be the top three barriers in the list in terms of importance. The master list of barriers was consolidated across the three groups into themes that were prioritized based on receiving the highest rankings by participants.Results: Twenty-five physicians participated; 56% had experience caring for CHP patients for ≥ 16 years. Sixty barriers to antigen detection were categorized into seven themes of which the top three were: 1. unclear significance of identified exposures; 2. gaps in clinical knowledge and testing capabilities; 3. there are many unknown and undiscovered antigens. Twenty-eight barriers to antigen avoidance were categorized into five themes of which the top three were: 1. patient limitations, financial barriers and lack of resources; 2. individual patient beliefs, emotions and attachments to the antigen source; and 3. gaps in clinical knowledge and testing capabilities.Conclusions: This study uncovered challenges at the individual patient, organizational, and societal levels and ranked them in terms of level of importance. These findings provide information to guide development and validation of multidisciplinary support and interventions geared towards antigen identification and avoidance in CHP. [ABSTRACT FROM AUTHOR]

Antifibrotics are effective in slowing FVC decline in idiopathic pulmonary fibrosis (IPF). However, whether antifibrotic type is differentially associated with FVC decline remains inconclusive. Are there significant differences in 12-month FVC decline between pirfenidone and nintedanib? A post hoc analysis was performed using the Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in IPF (CleanUP-IPF) trial (No. NCT02759120). Participants who reported using pirfenidone or nintedanib on enrollment into the trial were in the primary analysis. Spirometry was scheduled at baseline and the 12- and 24-month study visits. Linear mixed-effects models with random intercept and slope were used to examine changes in FVC over time. Models were adjusted for age, sex, smoking history, coronary artery disease history, baseline FVC, and 12-month spline term. Survival and nonelective respiratory hospitalization by antifibrotic type were determined using Cox regression models with adjustment for age, sex, smoking history, coronary artery disease history, and baseline FVC and diffusing capacity for carbon monoxide. Out of the 513 participants with IPF randomized in the CleanUP-IPF trial, 407 reported using pirfenidone (n = 264, 65%) or nintedanib (n = 143, 35%). The pirfenidone group had more participants with a history of coronary artery disease than the nintedanib group (34.1% vs 20.3%, respectively). Patients treated with nintedanib had a higher 12-month visit FVC than patients treated with pirfenidone (mean difference, 106 mL; 95% CI, 34-178). This difference was attenuated at the 24-month study visit. There were no significant differences in overall survival and nonelective respiratory hospitalization between the pirfenidone- and nintedanib-treated groups. Patients with IPF who used nintedanib had a slower 12-month FVC decline than pirfenidone in a post hoc analysis of a clinical trial. [Display omitted] [ABSTRACT FROM AUTHOR]

A case study of a 50-year-old is presented with 2 days of worsening dyspnea. Topics include chest radiography shows patchy bilateral opacities in the lung parenchyma, and reverse transcriptase-polymerase-chain-reaction assay detects the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in a nasopharyngeal swab.

Background: Small airways disease (SAD) is a major cause of airflow obstruction in COPD patients and has been identified as a precursor to emphysema. Although the amount of SAD in the lungs can be quantified using our Parametric Response Mapping (PRM) approach, the full breadth of this readout as a measure of emphysema and COPD progression has yet to be explored. We evaluated topological features of PRM-derived normal parenchyma and SAD as surrogates of emphysema and predictors of spirometric decline. Methods: PRM metrics of normal lung (PRMNorm) and functional SAD (PRMfSAD) were generated from CT scans collected as part of the COPDGene study (n = 8956). Volume density (V) and Euler-Poincaré Characteristic (χ) image maps, measures of the extent and coalescence of pocket formations (i.e., topologies), respectively, were determined for both PRMNorm and PRMfSAD. Association with COPD severity, emphysema, and spirometric measures were assessed via multivariable regression models. Readouts were evaluated as inputs for predicting FEV1 decline using a machine learning model. Results: Multivariable cross-sectional analysis of COPD subjects showed that V and χ measures for PRMfSAD and PRMNorm were independently associated with the amount of emphysema. Readouts χfSAD (β of 0.106, p < 0.001) and VfSAD (β of 0.065, p = 0.004) were also independently associated with FEV1% predicted. The machine learning model using PRM topologies as inputs predicted FEV1 decline over five years with an AUC of 0.69. Conclusions: We demonstrated that V and χ of fSAD and Norm have independent value when associated with lung function and emphysema. In addition, we demonstrated that these readouts are predictive of spirometric decline when used as inputs in a ML model. Our topological PRM approach using PRMfSAD and PRMNorm may show promise as an early indicator of emphysema onset and COPD progression. [ABSTRACT FROM AUTHOR]

Objectives To explore prognostic and predictive markers of SSc-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART). Methods The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan–Meier estimation and Cox regression were used for time-to-event analyses. Results In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P   =  0.0001). FVC was 9.8% lower in patients with CRP >6 mg/ml vs those with CRP ≤6 mg/ml (P  = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease (<2 years duration), had IL-6 levels <10 pg/ml, or had anti-topoisomerase antibodies (ATA). In the SMART cohort, prognostic factors for ppFVC <70% were male sex, ATA, and low baseline FVC. Males had 3.3% lower FVC 1 year after disease onset (P  < 0.001) and 0.6% faster yearly decline (P  = 0.03) than females. Conclusion Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but IL-6 ≥10 pg/ml was not predictive of response to tocilizumab. Trial Registration ClinicalTrials.gov: NCT02453256. [ABSTRACT FROM AUTHOR]

Background and Objective: Surrogate endpoints enable determination of meaningful treatment effects more efficiently than applying the endpoint of ultimate interest. We used data from trials of nintedanib in subjects with pulmonary fibrosis to assess decline in forced vital capacity (FVC) as a surrogate for mortality. Methods: Data from the nintedanib and placebo groups of trials in subjects with idiopathic pulmonary fibrosis, other forms of progressive pulmonary fibrosis, and pulmonary fibrosis due to systemic sclerosis (NCT00514683, NCT01335464, NCT01335477, NCT01979952, NCT02999178, NCT02597933) were pooled. Using joint models for longitudinal and time‐to‐event data, we assessed the association between decline in FVC % predicted and time to death over 52 weeks. The rate of change in FVC % predicted and the current value of FVC % predicted were modelled longitudinally and estimates applied as predictors in time‐to‐event models. Results: Among 2583 subjects with pulmonary fibrosis, both a greater rate of decline in FVC % predicted and a lower current value of FVC % predicted were associated with an increased risk of death over 52 weeks (HR 1.79 [95% CI: 1.57, 2.03] and HR 1.24 [1.17, 1.32] per 5‐percentage point decrease, respectively). Associations between the rate of change in FVC % predicted and the risk of death were consistent between patients with IPF and other ILDs. Conclusion: Data from clinical trials in subjects with pulmonary fibrosis of diverse aetiology demonstrate a strong association between decline in FVC % predicted and mortality over 52 weeks, supporting FVC decline as a surrogate for mortality in these patients. We used data from clinical trials of nintedanib in subjects with pulmonary fibrosis of diverse aetiology to demonstrate a strong association between decline in FVC per cent predicted and mortality over 52 weeks, supporting the use of FVC decline as a surrogate for mortality in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-μg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD.Methods: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed.Results: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms).Conclusions: We conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD.Trial Registry: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Editorial Idiopathic pulmonary fibrosis (IPF) currently affects about 100 000 individuals in the US, and millions globally. A close examination of analyses stratified by background standard of care therapy reveals high rates of treatment-related, treatment-emergent adverse events among patients taking both nintedanib and ziritaxestat. The feasibility of using this outcome to evaluate the efficacy of antimicrobial therapy for the treatment of IPF was demonstrated in Clean-UP-IPF.[15] Moving forward with these lessons will be challenging, especially as IPF therapies improve and trials need to increase in size and duration to detect smaller treatment effects while patients are continuing to receive standard of care treatment. Effect of antimicrobial therapy on respiratory hospitalization or death in adults with idiopathic pulmonary fibrosis: the CleanUP-IPF randomized clinical trial. [Extracted from the article]

Introduction: Asthma‐chronic obstructive pulmonary disease (COPD) overlap (ACO) is a heterogenous condition with clinical features shared by both asthma and COPD. Objectives: This online global survey of respiratory/allergy specialists and primary care practitioners (PCPs) was performed to understand current clinical approaches to the differential diagnosis and management of asthma, COPD and ACO. Methods: Respondents were recruited through: (a) a global online physician respondent community (49,980 PCPs and 7205 specialists); (b) market research agents; (c) experts; (d) professional societies; (e) colleague invitation. Respondents were presented with a survey including hypothetical clinical scenarios of diagnostic uncertainty to identify management approaches. Results: 891 responses (447 PCPs and 444 specialists) were collected across 13 countries. Reported features used for diagnosis of asthma and COPD were consistent with practice guidelines, but there was variability in those selected for ACO diagnosis. Features typically selected by specialists focused on spirometry/history, while PCPs focused on previous treatment/symptoms. Most respondents could correctly diagnose patients with features of ACO; however, features selected for theoretical diagnosis were often different to those selected in the case scenarios. Additionally, treatment selection was often inconsistent with guidelines, with over half of respondents not recommending inhaled corticosteroids in a patient with ACO and dominant features of asthma. Conclusion: While most PCPs and respiratory/allergy specialists can reach a working diagnosis of ACO, there remains uncertainty around which diagnostic features are most important and what constitutes optimal management. It is imperative that clinical studies including patients with ACO are initiated, allowing the generation of evidence‐based management strategies. [ABSTRACT FROM AUTHOR]