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Defining severe obstructive lung disease in the biologic era: an endotype-based approach.

ABSTRACT: Severe obstructive lung disease, which encompasses asthma, chronic obstructive pulmonary disease (COPD) or features of both, remains a considerable global health problem and burden on healthcare resources. However, the clinical definitions of severe asthma and COPD do not reflect the heterogeneity within these diagnoses or the potential for overlap between them, which may lead to inappropriate treatment decisions. Furthermore, most studies exclude patients with diagnoses of both asthma and COPD. Clinical definitions can influence clinical trial design and are both influenced by, and influence, regulatory indications and treatment recommendations. Therefore, to ensure its relevance in the era of targeted biologic therapies, the definition of severe obstructive lung disease must be updated so that it includes all patients who could benefit from novel treatments and for whom associated costs are justified. Here, we review evolving clinical definitions of severe obstructive lung disease and evaluate how these have influenced trial design by summarising eligibility criteria and primary outcomes of phase III randomised controlled trials of biologic therapies. Based on our findings, we discuss the advantages of a phenotype- and endotype-based approach to select appropriate populations for future trials that may influence regulatory approvals and clinical practice, allowing targeted biologic therapies to benefit a greater proportion and range of patients. This calls for co-ordinated efforts between investigators, pharmaceutical developers and regulators to ensure biologic therapies reach their full potential in the management of severe obstructive lung disease.

SUBMITTER: Martin RJ

PROVIDER: S-EPMC6917363 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Defining severe obstructive lung disease in the biologic era: an endotype-based approach.

Martin Richard J RJ Bel Elisabeth H EH Pavord Ian D ID Price David D Reddel Helen K HK

The European respiratory journal 20191121 5

Severe obstructive lung disease, which encompasses asthma, chronic obstructive pulmonary disease (COPD) or features of both, remains a considerable global health problem and burden on healthcare resources. However, the clinical definitions of severe asthma and COPD do not reflect the heterogeneity within these diagnoses or the potential for overlap between them, which may lead to inappropriate treatment decisions. Furthermore, most studies exclude patients with diagnoses of both asthma and COPD. ...[more]

PMID: 31515397

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Project description:PurposeObstructive lung disease is increasingly common among persons with HIV, both smokers and nonsmokers. We used aptamer proteomics to identify proteins and associated pathways in HIV-associated obstructive lung disease.MethodsBronchoalveolar lavage fluid (BALF) samples from 26 persons living with HIV with obstructive lung disease were matched to persons living with HIV without obstructive lung disease based on age, smoking status and antiretroviral treatment. 6414 proteins were measured using SomaScan® aptamer-based assay. We used sparse distance-weighted discrimination (sDWD) to test for a difference in protein expression and permutation tests to identify univariate associations between proteins and forced expiratory volume in 1 s % predicted (FEV1 % pred). Significant proteins were entered into a pathway over-representation analysis. We also constructed protein-driven endotypes using K-means clustering and performed over-representation analysis on the proteins that were significantly different between clusters. We compared protein-associated clusters to those obtained from BALF and plasma metabolomics data on the same patient cohort.ResultsAfter filtering, we retained 3872 proteins for further analysis. Based on sDWD, protein expression was able to separate cases and controls. We found 575 proteins that were significantly correlated with FEV1 % pred after multiple comparisons adjustment. We identified two protein-driven endotypes, one of which was associated with poor lung function, and found that insulin and apoptosis pathways were differentially represented. We found similar clusters driven by metabolomics in BALF but not plasma.ConclusionProtein expression differs in persons living with HIV with and without obstructive lung disease. We were not able to identify specific pathways differentially expressed among patients based on FEV1 % pred; however, we identified a unique protein endotype associated with insulin and apoptotic pathways.

Project description:Antimicrobial resistance is a global concern in chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD). The collection of antibiotic resistance genes or resistome in human airways may underlie the resistance. COPD is heterogeneous, and understanding the airway resistome in relation to patient phenotype and endotype may inform precision antibiotic therapy. Here, we characterized the airway resistome for 94 COPD participants at stable disease. Among all demographic and clinical factors, patient inflammatory endotype was associated with the airway resistome. There were distinct resistome profiles between patients with neutrophilic or eosinophilic inflammation, two primary inflammatory endotypes in COPD. For neutrophil-predominant COPD, the resistome was dominated by multidrug resistance genes. For eosinophil-predominant COPD, the resistome was diverse, with an increased portion of patients showing a macrolide-high resistome. The differential antimicrobial resistance pattern was validated by sputum culture and in vitro antimicrobial susceptibility testing. Ralstonia and Pseudomonas were the top contributors to the neutrophil-associated resistome, whereas Campylobacter and Aggregatibacter contributed most to the eosinophil-associated resistome. Multiomic analyses revealed specific host pathways and inflammatory mediators associated with the resistome. The arachidonic acid metabolic pathway and matrix metallopeptidase 8 (MMP-8) exhibited the strongest associations with the neutrophil-associated resistome, whereas the eosinophil chemotaxis pathway and interleukin-13 (IL-13) showed the greatest associations with the eosinophil-associated resistome. These results highlight a previously unrecognized link between inflammation and the airway resistome and suggest the need for considering patient inflammatory subtype in decision-making about antibiotic use in COPD and broader chronic respiratory diseases. IMPORTANCE Antibiotics are commonly prescribed for both acute and long-term prophylactic treatment in chronic airway disorders, such as chronic obstructive pulmonary disease (COPD), and the rapid growth of antibiotic resistance is alarming globally. The airway harbors a diverse collection of microorganisms known as microbiota, which serve as a reservoir for antibiotic resistance genes or the resistome. A comprehensive understanding of the airway resistome in relation to patient clinical and biological factors may help inform decisions to select appropriate antibiotics for clinical therapies. By deep multiomic profiling and in vitro phenotypic testing, we showed that inflammatory endotype, the underlying pattern of airway inflammation, was most strongly associated with the airway resistome in COPD patients. There were distinct resistome profiles between neutrophil-predominant and eosinophil-predominant COPD that were associated with different bacterial species, host pathways, and inflammatory markers, highlighting the need of considering patient inflammatory status in COPD antibiotic management.

Project description:BackgroundThe UK Severe Asthma Registry (UKSAR) is the world's largest national severe asthma registry collecting standardised data on referrals to UK specialist services. Novel biologic therapies have transformed the management of type 2(T2)-high severe asthma but have highlighted unmet need in patients with persisting symptoms despite suppression of T2-cytokine pathways with corticosteroids.MethodsDemographic, clinical and treatments characteristics for patients meeting European Respiratory Society / American Thoracic Society severe asthma criteria were examined for 2225 patients attending 15 specialist severe asthma centres. We assessed differences in biomarker low patients (fractional exhaled nitric oxide (FeNO) <25?ppb, blood eosinophils <150/?L) compared with a biomarker high population (FeNO ?25?ppb, blood eosinophils ?150/µL).ResultsAge (mean 49.6 (14.3) y), age of asthma onset (24.2 (19.1) y) and female predominance (62.4%) were consistent with prior severe asthma cohorts. Poor symptom control (Asthma Control Questionnaire-6: 2.9 (1.4)) with high exacerbation rate (4 (IQR: 2, 7)) were common despite high-dose treatment (51.7% on maintenance oral corticosteroids (mOCS)). 68.9% were prescribed biologic therapies including mepolizumab (50.3%), benralizumab (26.1%) and omalizumab (22.6%). T2-low patients had higher body mass index (32.1 vs 30.2, p<0.001), depression/anxiety prevalence (12.3% vs 7.6%, p=0.04) and mOCS use (57.9% vs 42.1%, p<0.001). Many T2-low asthmatics had evidence of a historically elevated blood eosinophil count (0.35 (0.13, 0.60)).ConclusionsThe UKSAR describes the characteristics of a large cohort of asthmatics referred to UK specialist severe asthma services. It offers the prospect of providing novel insights across a range of research areas and highlights substantial unmet need with poor asthma control, impaired lung function and high exacerbation rates. T2-high phenotypes predominate with significant differences apparent from T2-low patients. However, T2-low patients frequently have prior blood eosinophilia consistent with possible excessive corticosteroid exposure.

Project description:Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease who have minimal or no airflow obstruction. Objectives: To develop a multidimensional definition of a lung-related "resilient smoker" that is useful in research studies and then identify a resilient smoker subgroup in the SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort using this definition. Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ⩾80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD. Results: Consensus was achieved on 6 of 12 diagnostic items, which include cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in forced expiratory volume in 1 second. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of CRP (C-reactive protein) and sTNFRSF1A (soluble tumor necrosis receptor factor1A) was lower in resilient than nonresilient smokers (P = 0.02 and P = 0.03). Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "nonresilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from nonresilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).

Dataset Information

Defining severe obstructive lung disease in the biologic era: an endotype-based approach.

Publications

Defining severe obstructive lung disease in the biologic era: an endotype-based approach.

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