ACE2, TMPRSS2 AND FURIN GENE EXPRESSION IN THE AIRWAYS OF PEOPLE WITH ASTHMA - IMPLICATIONS FOR COVID-19.

To-date, there has not been a clear signal suggesting that asthma or treatment with inhaled steroids are a risk factor for severe COVID-19 disease. We have therefore explored ACE2 receptor mRNA expression, and co-factors for Sars-CoV-2 infectivity (TMPRSS2 and furin) in bronchial brushes and biopsies from people with asthma and healthy controls, and looked for relationships between asthma severity, Th2- and IL-17 dependent gene signatures, and clinical demographics (age, sex). We have looked at a cohort of 356 research participants from previously described studies. The only significant association was a positive correlation between ACE2 and IL-17-dependent gene expression, and an inverse correlation between ACE2 and Th2-cytokine-dependent gene expression. These data suggest that differences in ACE2, TMPRSS2 and furin epithelial and airway gene expression are unlikely to confer enhanced COVID-19 pneumonia risk in patients with asthma across all treatment intensities and severity

Fractional Exhaled Nitric Oxide Nonsuppression Identifies Corticosteroid-Resistant Type 2 Signaling in Severe Asthma.

Recently, two post-hoc analyses of clinical trials in moderate to severe asthma showed that fractional exhaled nitric oxide (FeNO) and the blood eosinophil (Eos) count provide additive prognostic information on the occurrence of severe asthma attacks (1, 2). The effect is large, with a three-fold increased risk in attacks seen in patients with FeNO ≥50 ppb and blood Eos ≥0.3×109/L compared to those with a FeNO Although raised FeNO classically identifies corticosteroid responsiveness, the advent of FeNOsuppression testing for uncontrolled type-2 high asthma has proven that a third of patients have corticosteroid-resistant elevations in FeNO – and disease burden – despite objective evidence of treatment adherence (7, 8). FeNO non-suppression provides a convenient model to control for nonadherence and independently study corticosteroid resistance in severe asthma.We tested the hypothesis that FeNO and blood Eos relate differently to inflammation observed in the sputum (reflecting airway) and blood (reflecting systemic) compartments. An important feature of our approach was to study patients in whom we had a high degree of confidence in treatment adherence to high-dose inhaled corticosteroids (ICS) and/or systemic corticosteroids.</div

Airway remodelling rather than cellular infiltration characterises both type2 cytokine biomarker-high and -low severe asthma

The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type-2 (T2) cytokine biology which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood. To explore airway pathology in T2 biomarker-high and -low severe asthma. T2 biomarker-high severe asthma (T2-high, n=17) was compared to biomarker-intermediate (T2-intermediate, n=21) and biomarker-low (T2-low, n=20) severe asthma, and healthy controls (n=28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD2 and LTE4 measurements. Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodeling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared to health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5, and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD2 and LTE4 , were increased in T2-high and T2-intermediate asthma compared to healthy controls. Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodeling persists, and may be important for residual disease expression beyond eosinophilic exacerbations.</p

Airway remodelling rather than cellular infiltration characterizes both type2 cytokine biomarker‐high and ‐low severe asthma

BACKGROUND The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type-2 (T2) cytokine biology which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood. OBJECTIVES To explore airway pathology in T2 biomarker-high and -low severe asthma. METHODS T2 biomarker-high severe asthma (T2-high, n=17) was compared to biomarker-intermediate (T2-intermediate, n=21) and biomarker-low (T2-low, n=20) severe asthma, and healthy controls (n=28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD and LTE measurements. RESULTS Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodeling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared to health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5, and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD and LTE , were increased in T2-high and T2-intermediate asthma compared to healthy controls. CONCLUSIONS Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodeling persists, and may be important for residual disease expression beyond eosinophilic exacerbations