Philip G. Bardin

Infection by influenza A virus (IAV) and other viruses causes disease exacerbations in chronic obstructive pulmonary disease (COPD). Immune responses are blunted in COPD, a deficit compounded by current standard-of-care glucocorticosteroids (GCS) to further predispose patients to life-threatening infections. The immunosuppressive effects of elevated transforming growth factor-beta (TGF-β) in COPD may amplify lung inflammation during infections whilst advancing fibrosis. In the current study, we investigated potential repurposing of pirfenidone, currently used as an anti-fibrotic for idiopathic pulmonary fibrosis, as a non-steroidal treatment for viral exacerbations of COPD. Murine models of lung-specific TGF-β overexpression or chronic cigarette smoke exposure with IAV infection were used. Pirfenidone was administered daily by oral gavage commencing pre-or post-infection, while inhaled pirfenidone and GCS treatment pre-infection were also compared. Tissue and bronchoalveolar lavage were assessed for viral replication, inflammation and immune responses. Overexpression of TGF-β enhanced severity of IAV infection contributing to unrestrained airway inflammation. Mechanistically, TGF-β reduced innate immune responses to IAV by blunting interferon regulated gene (IRG) expression and suppressing production of anti-viral proteins. Prophylactic pirfenidone administration opposed these actions of TGF-β, curbing IAV infection and airway inflammation associated with TGF-β overexpression and cigarette smoke-induced COPD. Notably, inhaled pirfenidone caused greater inhibition of viral loads and inflammation than inhaled GCS. These proof-of-concept studies demonstrate that repurposing pirfenidone and employing a preventative strategy may yield substantial benefit over anti-inflammatory GCS in COPD. Pirfenidone can mitigate damaging virus exacerbations without attendant immunosuppressive actions and merits further investigation, particularly as an inhaled formulation.

Transforming growth factor β1 (TGFβ1) is a pleiotropic cytokine implicated in the pathophysiology of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. Epithelial TGFβ1 is released in response to injury, inflammatory stimuli, and during bronchoconstriction to induce fibrosis. We hypothesized that elevated expression of endogenous TGFβ1, localized to the lung, would elicit autocrine effects to alter airway responsiveness. We utilized a transgenic mouse model of doxycycline (Dox)-induced, lung-specific overexpression of active TGFβ1 by giving Dox (0.25 mg/mL in drinking water, 8 wk), or normal water as a control. Comparing Dox with control groups, levels of TGFβ1 were ∼30-fold higher in bronchoalveolar lavage fluid (BALF), but not in serum, as measured by ELISA. BALF cells, predominantly macrophages, were ∼3.5-fold higher, with no evidence of tissue inflammation in hematoxylin and eosin (H&E)-stained sections from Dox mice. Higher collagen deposition was evident around the airways in Masson's trichrome-stained sections [subepithelial thickness (µm): control 10.4 ± 10.9, n = 9; Dox 25.8 ± 1.5, n = 13, P < 0.0001]. TGFβ1 overexpression increased baseline airway resistance and induced airway hyperresponsiveness (AHR) to methacholine (MCh) in vivo, as measured using in vivo plethysmography. Comparing precision-cut lung slices (PCLS) from separate Dox-treated and control mice, maximum contraction of intrapulmonary airways to MCh was increased ex vivo. Overall, elevated lung TGFβ1 levels resulted in localized airway fibrosis associated with increased airway contraction to MCh. These autocrine effects of endogenous TGFβ1 implicate its potential contribution to AHR, suggesting that targeting TGFβ1 may provide a novel approach to oppose excessive airway contraction in chronic lung diseases.NEW & NOTEWORTHY TGFβ upregulation is common in respiratory diseases. Here, the authors have utilized for the first time a mouse model of lung-specific overexpression of active TGFβ to demonstrate the dual role of TGFβ1 in structural remodeling and dysregulation of airway contractility. Given these pathologies are common to asthma and COPD, this model provides a unique opportunity to identify essential novel therapeutics for the treatment of chronic lung diseases.

Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) commonly co-exists with asthma and can start after viral infections. In this setting evidence suggests that dysfunctional breathing may induce the disorder but this possibility has not been researched. We therefore postulated that dysfunctional breathing can induce VCD/ILO, more so in people with asthma and after viral infections. Eight healthy control subjects, 16 people with asthma and eight people who had recent COVID-19 infection (three with asthma) were recruited. Video-recorded laryngoscopy was performed at tidal breathing and during controlled hyperventilation (used as a proxy for dysfunctional breathing). VCD/ILO was diagnosed by laryngoscopy using accepted criteria and correlated with study cohorts, clinical attributes, asthma severity and spirometry. Overall, 32 subjects were studied. Hyperventilation was verified in all subjects. None of the healthy control group or people with mild asthma developed VCD/ILO during or after hyperventilation but one person with moderate/severe asthma had clear evidence of VCD/ILO. In contrast, in people who had COVID-19 infection, hyperventilation induced VCD/ILO in 3/8 people (38%). These proof-of-concept studies suggest that hyperventilation can provoke VCD/ILO in asthma and after a recent viral infection. How and why VCD/ILO develops is not known and these preliminary findings should prompt further studies of links between dysfunctional breathing, asthma, and viral infections.

Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) commonly co-exists with asthma and can start after viral infections. In this setting evidence suggests that dysfunctional breathing may induce the disorder but this possibility has not been researched. We therefore postulated that dysfunctional breathing can induce VCD/ILO, more so in people with asthma and after viral infections. Eight healthy control subjects, 16 people with asthma and eight people who had recent COVID-19 infection (three with asthma) were recruited. Video-recorded laryngoscopy was performed at tidal breathing and during controlled hyperventilation (used as a proxy for dysfunctional breathing). VCD/ILO was diagnosed by laryngoscopy using accepted criteria and correlated with study cohorts, clinical attributes, asthma severity and spirometry. Overall, 32 subjects were studied. Hyperventilation was verified in all subjects. None of the healthy control group or people with mild asthma developed VCD/ILO during or after hyperventilation but one person with moderate/severe asthma had clear evidence of VCD/ILO. In contrast, in people who had COVID-19 infection, hyperventilation induced VCD/ILO in 3/8 people (38%). These proof-of-concept studies suggest that hyperventilation can provoke VCD/ILO in asthma and after a recent viral infection. How and why VCD/ILO develops is not known and these preliminary findings should prompt further studies of links between dysfunctional breathing, asthma, and viral infections.

Treatment targets in severe asthma have evolved towards a remission-focused paradigm guided by precision medicine. This novel concept requires a shift from evaluating the efficacy of therapies based on a single outcome at a single time point to an outcome that captures the complexity of asthma remission involving several domains assessed over a sustained period. Since the concept is still emerging, multiple definitions have been proposed, ranging from symptom control and exacerbation-free to resolution of underlying pathobiology, with varying rigour in each parameter. Understanding the strengths and weaknesses of the current construct is needed to progress further. We conducted a roundtable discussion with 27 asthma experts to address this issue, and discussions were narratively synthesised and summarised. The participants observed that between one in three and one in five people treated with targeted biological therapies or macrolides experience low disease activity over a sustained period. They unanimously agreed that labelling the attained clinical state as clinical remission is useful as a clinical (e.g., facilitating a treat-to-target approach), policy (e.g., widening eligibility criteria for biologics), and scientific (e.g., a path to understanding cure) tool. Current remission rates vary significantly due to definition variability. When assessing remission, it is essential to consider confounding factors (e.g., steroid use for adrenal insufficiency). More research is required to reach an acceptable definition, and including the patient's voice in such research is essential. In conclusion, the concept of treatment-induced clinical remission is possible and valuable in asthma. However, further refinement of the definition is required.

A Multi-center, Randomized, Double-blind, Parallel-group, Placebo-controlled Study of Mepolizumab 100 mg SC as add-on Treatment in Participants With COPD Experiencing Frequent Exacerbations and Characterized by Eosinophil Levels (Study 208657)