ERS 2022: Chronic Airway Diseases from Phenotypes to Severity
In this session, experts discussed various abstracts on the phenotypes and predictors of exacerbations in patients with chronic airway diseases.
The global mortality of asthma is 400,000 every year. Severe asthma is complex and immunologically heterogeneous. Severe asthma affects <10% of asthmatics. Airway infection and dysregulation of innate immunity may confer inhaled corticosteroid resistance. In this study, the authors hypothesized that marked airway microbiome compositional shifts in severe asthma represent a 'treatable trait' with the dominance of pathogenic species, necessitating targeted therapy.
Furthermore, these changes are considered distinct in the paucibacillary lower airway compared to the heavily colonized nasopharynx. The dominance of a single pathogenic organism (H.influenzae, S.pneumoniae, M.catarrhalis) was identified in the sputum of 21% of patients with severe asthma. Airway infection is associated with neutrophilia and elevated type-1 cytokines in the sputum supernatant. Metagenomic analysis of the nasal lavage showed a distinct microbiome. The presence of pathogenic organisms in the upper airways did not predict the concurrent presence in sputum of patients with severe asthma. The study concluded that airway infection in stable severe asthma is marked by a significant shift in the airway microbiome leading to the dominance of pathogenic organisms and is associated with sputum neutrophilia and elevated type-1 cytokines. The microbiome in the upper and lower airways is distinct, and research is ongoing to determine its impact on mucosal immune responses at these sites.
Non-invasive measures of airway remodelling are critical for better understanding the pathophysiology of severe asthma. A study evaluated chest high resolution computed tomography (CT) for asthma phenotyping and endotyping in 105 adults from the severe asthma European U-BIOPRED study. Three clusters were identified. Cluster 1 had higher levels of serum leptin and complement factor I. The expression of 43 serum proteins varied between clusters 2 (higher NOTCH signalling) and 3 (higher Insulin-like Growth Factor 1 Receptor signalling). Integrating radiomics and serum proteomics datasets can enable severe asthma endotyping. Radiomultiomics may contribute to clarifying the pathogenetic mechanisms underlying severe asthma heterogeneity and pave the way for a new approach to personalized medicine.
In real life, asthma attacks are often treated with antibiotics; however, little is known about these attacks and what predicts them. Risk factors for asthma attacks requiring corticosteroid treatment include elevated biomarkers of type-2 airway inflammation, e.g., eosinophils (EOS) and fractional exhaled nitric oxide (FeNO). A study aimed to explore the predictors for corticosteroid-treated/antibiotic-only attacks in the multi-country, prospective, observational NOVELTY cohort. From 4,753 patients with asthma, 961 with total predictors and outcome data were included in the study. Female sex increased symptoms, and previous corticosteroid-treated attacks were significant predictors for corticosteroid-treated attacks, while EOS and FeNO were not. Low FEV1%, comorbid rhinosinusitis and a previous antibiotic-only treated attack were predictors for antibiotic-only treated attacks. Thus, the risk factors for corticosteroid-treated asthma attacks differed from those for antibiotic-only attacks. Contrary to previous clinical trial reports, type-2 inflammation biomarkers did not predict asthma attacks in this subset of patients.
Mucociliary clearance (MCC) results from an effective interaction between the mucus layer and normal coordinated ciliary beating. An abnormal ciliary beat frequency (CBF) or ciliary beat pattern is called ciliary dyskinesia (CBP). Recent evidence demonstrates ciliary dyskinesia in moderate and severe asthma, but it is unknown whether this is primary or secondary to chronic inflammation. A study was conducted to determine whether ciliary dyskinesia is primary or secondary in severe asthma. The results confirmed that ciliary dyskinesia is increased in adults with severe asthma than in healthy subjects, with a lower CBF (11.52±0.67Hz vs 14.79±0.58Hz, p=0.001), and a higher percentage of dyskinetic CBP (%DK, 29.3±4.23% vs 17.28±2.04%, p=0.010). There is no significant difference in CBF (11.44+2.91Hz vs 12.88+1.75Hz, p=0.269) or %DK (32.7+15.79% vs 24.43+13.24%, p=0.378) when comparing CFA before and after air-liquid interface (ALI) cell culture. The study concluded that ciliary function is impaired in patients with severe asthma and may play a role in impaired MCC. Furthermore, the results indicate that ciliary dyskinesia may be primary and not secondary to chronic inflammation in severe asthma.
Forced expiratory volume in one second (FEV1), FEV1/ forced vital capacity (FVC) and the rate of annual decline in FEV1 are the most widely used outcome measures for clinical trials and observational studies of COPD. According to lung function decline, COPD patients can be stratified into no decliners, slow decliners, and rapid decliners. The study aimed to quantify and compare the expression of inflammatory cells and markers of humoral immune response in bronchial biopsies of COPD patients with rapid as compared to slow or no functional decline. The expression of secretory IgA was significantly reduced in bronchial epithelium. In addition, the plasma cell numbers were significantly reduced in the bronchial lamina propria of rapid decliners compared to no decliners. "In vitro" stimulation of human bronchial epithelial cells (16HBE) cells with lipopolysaccharide (LPS, 10?g/ml) and IL-8 (10ng/ml) induced a significant increase while H2O2 (100?M) significantly decreased polymeric immunoglobulin receptor (pIgR) epithelial expression. The data showed an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria.
Parental factors like allergic diseases and smoking can influence respiratory disease in the offspring. However, it is unclear how parental factors influence fractional exhaled nitric oxide (FeNO) levels in the offspring, a known clinical biomarker of type-2 airway inflammation commonly elevated in patients with asthma. The study aimed to investigate if parental allergic diseases, smoking, and higher FeNO levels in parents are associated with higher FeNO levels in their offspring. Parental allergic rhinitis (AR) was significantly related to higher FeNO in the offspring, even into adulthood. In addition, parental FeNO is significantly associated with offspring FeNO. For every 1% increase in parental FeNO, offspring FeNO increased by 0.12% in models adjusted for offspring age, sex, height, smoking, current asthma, AR, allergic sensitization, parental smoking, asthma, and AR. The study concluded that parental AR and higher parental FeNO values were related to higher FeNO levels in the offspring.
Several studies have suggested that eosinophils (EOS) in the blood can be used to identify patients with COPD at increased risk for exacerbations. Others, including biologic therapy trials, report different results, possibly due to enrichment for those with a history of exacerbations. In a previous cross-sectional study of the SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort, a significant association between greater retrospective exacerbation frequency and high sputum EOS was observed, but not with high blood EOS. This study assessed whether EOS levels predict future exacerbations in patients with COPD... In adjusted multivariate models, neither blood nor sputum EOS was significantly associated with greater longitudinal exacerbation rates or with exacerbation counts. The study concluded that in the SPIROMICS cohort, neither higher blood nor sputum EOS is predictive of increased future exacerbations.
Lower blood eosinophil counts (<100cells/µL) in COPD show greater stability over time. This has not been investigated in sputum samples. A study investigated whether low sputum eosinophil counts are more stable over time. Most eosLOW remained in the same category after repeat sampling (67.6%), while eosINT and eosHIGH remained in different categories (25.7 and 59.1%, respectively). Repeatability coefficient analysis (RCA) revealed that 95% of repeat sputum eosinophil counts were within 2.07%, 21.79% and 14.84% at repeat visits for eosLOW, eosINT and eosHIGH groups, respectively. The mean within-patient difference in the eosLOW group was lower than in other groups, although it was not statistically significant. Sputum EOS counts in COPD show excellent repeatability at measurements taken 6 months apart. This stability appears to be driven by those with low sputum EOS counts (< 1%). Those with higher sputum EOS counts (> 1%) exhibit more temporal variation.
Mucus plugging (MP) contributes to airway obstruction and symptoms in patients with persistent asthma. The study aimed to find clinical predictors and phenotypic associations of mucus plugging in patients with moderate-to-severe asthma in a real-world clinic setting. Asthma patients with MP had significantly worse FEV1%, FEF25-75% and FEV1/FVC. In addition, higher levels of peripheral blood eosinophils, fractional exhaled nitric oxide, total IgE and A. fumigatus IgE titers were related to more frequent severe exacerbations. The adjusted odds ratios for MP prediction were as follows: FEV1/FVC 3.01; ≥ 2 exacerbations/year 5.00; blood eosinophils 3.23; total IgE 3.20; and IgE titers to A. fumigatus 9.37. In addition, patients with poorly controlled asthma with MP had significantly worse airflow obstruction and more significant T2 inflammation associated with more frequent severe exacerbations. The real-life clinical predictors of MP include spirometry, exacerbations, blood eosinophils, total IgE and A. fumigatus IgE.
European Respiratory Society (ERS) International Congress 2022, 3rd-6th Sept. 2022, Barcelona
