INEXAS: A Phase 2 Randomized Trial of On‐demand Inhaled Interferon Beta‐1a in Severe Asthmatics

McCrae, Christopher; Olsson, Marita; Gustafson, Per; Malmgren, Anna; Aurell, Malin; Fagerås, Malin; Silva, Carla A. Da; Cavallin, Anders; Paraskos, Jonathan; Karlsson, Karin; Wingren, Cecilia; Monk, Phillip; Marsden, Richard; Harrison, Tim

doi:10.1111/cea.13765

Cited by 15 publications

(11 citation statements)

References 29 publications

(51 reference statements)

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“…A randomized controlled trial investigating the effect of inhaled IFN-β did not meet its primary endpoint of assessing asthma symptoms, but did find improvements in morning peak flow and enhanced innate immunity, specifically ISG expression (235). The INEXAS (A Study in Asthma Patients to Evaluate Efficacy, Safety, and Tolerability of 14 Days Once Daily Inhaled Interferon Beta-1a after the Onset of Symptoms of an Upper Respiratory Tract Infection for the Prevention of Severe Exacerbations) trial also found small improvements in morning peak flow following use of inhaled IFN-β, but again, the primary endpoint was not met and the impact of inhaled IFN-β on the rate of severe asthma exacerbations was unable to be assessed (236). In contrast, inhaled IFN-β therapy was found to increase the odds of improvement in clinical status as well as time to recovery for hospitalized COVID-19 patients (237).…”

Section: Restoring the Balance Of Host Immunitymentioning

confidence: 99%

Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway

et al. 2021

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Asthma is a heterogeneous, chronic respiratory disease affecting 300 million people and is thought to be driven by different inflammatory endotypes influenced by a myriad of genetic and environmental factors. The complexity of asthma has rendered it challenging to develop preventative and disease modifying therapies and it remains an unmet clinical need. Whilst many factors have been implicated in asthma pathogenesis and exacerbations, evidence indicates a prominent role for respiratory viruses. However, advances in culture-independent detection methods and extensive microbial profiling of the lung, have also demonstrated a role for respiratory bacteria in asthma. In particular, airway colonization by the Proteobacteria species Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) is associated with increased risk of developing recurrent wheeze and asthma in early life, poor clinical outcomes in established adult asthma and the development of more severe inflammatory phenotypes. Furthermore, emerging evidence indicates that bacterial-viral interactions may influence exacerbation risk and disease severity, highlighting the need to consider the impact chronic airway colonization by respiratory bacteria has on influencing host responses to viral infection. In this review, we first outline the currently understood role of viral and bacterial infections in precipitating asthma exacerbations and discuss the underappreciated potential impact of bacteria-virus crosstalk in modulating host responses. We discuss the mechanisms by which early life infection may predispose to asthma development. Finally, we consider how infection and persistent airway colonization may drive different asthma phenotypes, with a view to identifying pathophysiological mechanisms that may prove tractable to new treatment modalities.

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Section: Restoring the Balance Of Host Immunitymentioning

confidence: 99%

Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway

et al. 2021

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“…Similar studies report that IFN deficiency is implicated in increased chronic obstructive pulmonary disease (COPD) exacerbation frequency (Singanayagam et al, 2019). These studies led to a clinical development program to study the effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections (Djukanovic et al, 2014;McCrae et al, 2021). These studies reported encouraging improvements in symptom severity and lung function in people with moderate/severe asthma, but neither study met its primary endpoint as insufficient numbers of volunteers suffered virus-induced worsening of their asthma of sufficient severity for the treatment to have an impact.…”

Section: Therapeutic Potential Of Modulating Type 1 Responsesmentioning

confidence: 85%

Airway Epithelial Innate Immunity

et al. 2021

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Besides providing an essential protective barrier, airway epithelial cells directly sense pathogens and respond defensively. This is a frontline component of the innate immune system with specificity for different pathogen classes. It occurs in the context of numerous interactions with leukocytes, but here we focus on intrinsic epithelial mechanisms. Type 1 immune responses are directed primarily at intracellular pathogens, particularly viruses. Prominent stimuli include microbial nucleic acids and interferons released from neighboring epithelial cells. Epithelial responses revolve around changes in the expression of interferon-sensitive genes (ISGs) that interfere with viral replication, as well as the further induction of interferons that signal in autocrine and paracrine manners. Type 2 immune responses are directed primarily at helminths and fungi. Prominent pathogen stimuli include proteases and chitin, and important responses include mucin hypersecretion and chitinase release. Type 3 immune responses are directed primarily at extracellular microbial pathogens, including bacteria and fungi, as well as viruses during their extracellular phase of infection. Prominent microbial stimuli include bacterial wall components, such as lipopeptides and endotoxin, as well as microbial nucleic acids. Key responses are the release of reactive oxygen species (ROS) and antimicrobial peptides (AMPs). For all three types of response, paracrine signaling to neighboring epithelial cells induces resistance to infection over a wide field. Often, the epithelial effector molecules themselves also have signaling properties, in addition to the release of inflammatory cytokines that boost local innate immunity. Together, these epithelial mechanisms provide a powerful first line of pathogen defense, recruit leukocytes, and instruct adaptive immune responses.

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“…However, giving IFN-β as a prophylactic before infection significantly improved antiviral efficiency in both COPD macrophages and epithelium, indicating that the timing of IFN admission may be critical in clinical trial design. Data from a Phase II randomized trial of on-demand inhaled interferon beta-1a in severe asthmatics subjects with upper respiratory tract infection indicated that inhaled interferon beta-1a treatment did not reduce the severe exacerbation rate, but improved lung function [148].…”

Section: Therapeutic Implications Of Ifn Signalling Cascades In Copd ...mentioning

confidence: 99%

Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium

et al. 2022

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COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract. COPD patients are more susceptible to viral infections and associated severe disease, leading to accelerated lung function deterioration, hospitalization, and an increased risk of mortality. The airway epithelium plays an essential role in maintaining immune homeostasis, and orchestrates the innate and adaptive responses of the lung against inhaled and pathogen insults. A healthy airway epithelium acts as the first line of host defense by maintaining barrier integrity and the mucociliary escalator, secreting an array of inflammatory mediators, and initiating an antiviral state through the interferon (IFN) response. The airway epithelium is a major site of viral infection, and the interaction between respiratory viruses and airway epithelial cells activates host defense mechanisms, resulting in rapid virus clearance. As such, the production of IFNs and the activation of IFN signaling cascades directly contributes to host defense against viral infections and subsequent innate and adaptive immunity. However, the COPD airway epithelium exhibits an altered antiviral response, leading to enhanced susceptibility to severe disease and impaired IFN signaling. Despite decades of research, there is no effective antiviral therapy for COPD patients. Herein, we review current insights into understanding the mechanisms of viral evasion and host IFN antiviral defense signaling impairment in COPD airway epithelium. Understanding how antiviral mechanisms operate in COPD exacerbations will facilitate the discovery of potential therapeutic interventions to reduce COPD hospitalization and disease severity.

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INEXAS: A Phase 2 Randomized Trial of On‐demand Inhaled Interferon Beta‐1a in Severe Asthmatics

Cited by 15 publications

References 29 publications

Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway

Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway

Airway Epithelial Innate Immunity

Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium

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