Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids: a mechanistic analysis

Baker, Jonathan; Mahdi, Mahdi; Nicolau, Dan V.; Ramakrishnan, Sanjay; Barnes, Peter J.; Simpson, Jodie L.; Cass, Steven P.; Russell, Richard; Donnelly, Louise; Bafadhel, Mona

doi:10.1016/s2213-2600(22)00002-9

The Lancet Respiratory Medicine

2022

DOI: 10.1016/s2213-2600(22)00002-9

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Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids: a mechanistic analysis

Jonathan Baker

Mahdi Mahdi

Dan V. Nicolau

et al.

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Cited by 35 publications

(46 citation statements)

References 36 publications

(41 reference statements)

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“…How might delivery of budesonide to the lower respiratory tract affect the nasal mucosa and the outcome of COVID-19? Although Baker and colleagues 5 show that type 2 inflammatory mediators are reduced after budesonide treatment, the differences in individual mediators were not large nor were they present in both the plasma and nasal samples. Notably, Baker and colleagues 5 did not assess the lower respiratory tract where we might expect to see greatest changes.…”

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confidence: 81%

“…Although Baker and colleagues 5 show that type 2 inflammatory mediators are reduced after budesonide treatment, the differences in individual mediators were not large nor were they present in both the plasma and nasal samples. Notably, Baker and colleagues 5 did not assess the lower respiratory tract where we might expect to see greatest changes. It is possible that the changes found by Baker and colleagues 5 in the nasal mucosa and plasma might represent only a small fraction of more distinct changes occurring in the lower respiratory tract, and that these changes in the lower respiratory tract affect the outcome of COVID-19.…”

mentioning

confidence: 81%

“…Notably, Baker and colleagues 5 did not assess the lower respiratory tract where we might expect to see greatest changes. It is possible that the changes found by Baker and colleagues 5 in the nasal mucosa and plasma might represent only a small fraction of more distinct changes occurring in the lower respiratory tract, and that these changes in the lower respiratory tract affect the outcome of COVID-19. Assessment of the lower airway is not always possible in clinical studies of this type but would be useful to bring clarity to these findings.…”

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confidence: 99%

“… 4 However, so far, in SARS-CoV-2 infection, there has been little focus on altering the condition of the respiratory mucosa. In this issue of The Lancet Respiratory Medicine , Jonathan R Baker and colleagues 5 provide an update on the outcomes of the STOIC study, 6 showing that there is a distinctive nasal inflammatory response during the initial phase of infection, which might be altered by early administration of inhaled budesonide. This is important, since corticosteroid inhalers are widely used for asthma and are cheap, safe, and readily available.…”

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confidence: 99%

“…The authors speculate that inhaled budesonide, taken within 7 days of symptom onset, alters disease outcome by modulating inflammation in the nasal mucosa. 5 …”

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confidence: 99%

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Inhaled corticosteroids: not just for asthma, but for COVID-19?

Liew

Openshaw

2022

The Lancet Respiratory Medicine

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mentioning

confidence: 81%

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confidence: 81%

mentioning

confidence: 99%

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confidence: 99%

“…The authors speculate that inhaled budesonide, taken within 7 days of symptom onset, alters disease outcome by modulating inflammation in the nasal mucosa. 5 …”

mentioning

confidence: 99%

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Inhaled corticosteroids: not just for asthma, but for COVID-19?

Liew

Openshaw

2022

The Lancet Respiratory Medicine

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Lung epithelial cells: Upstream targets in type 2‐high asthma

Lameire

Hammad

2023

Eur J Immunol

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Over the last years, technological advances in the field of asthma have led to the identification of two disease endotypes, namely, type 2‐high and type 2‐low asthma, characterized by different pathophysiologic mechanisms at a cellular and molecular level. Although specific immune cells are important contributors to each of the recognized asthma endotype, the lung epithelium is now regarded as a crucial player able to orchestrate responses to inhaled environmental triggers such as allergens and microbes. The impact of the epithelium goes beyond its physical barrier. It is nowadays considered as a part of the innate immune system that can actively respond to insults. Activated epithelial cells, by producing a specific set of cytokines, trigger innate and adaptive immune cells to cause pathology. Here, we review how the epithelium contributes to the development of Th2 sensitization to allergens and asthma with a “type 2‐high” signature, in both murine models and human studies of this asthma endotype. We also discuss epithelial responses to respiratory viruses, such as rhinovirus, respiratory syncytial virus, and SARS‐CoV‐2, and how these triggers influence not only asthma development but also asthma exacerbation. Finally, we also summarize the results of promising clinical trials using biologicals targeting epithelial‐derived cytokines in asthmatic patients.

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Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial

et al. 2023

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Purpose We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically ventilated patients. Methods In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 µg every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composite of hospital-acquired pneumonia or all-cause mortality on day 28. The planned sample size was 200 with interim safety analyses after enrolling 50 and 100 patients. Results The study was discontinued after the second safety analysis for potential harm with interferon gamma-1b, and the follow-up was completed in June 2022. Among 109 randomized patients (median age, 57 (41–66) years; 37 (33.9%) women; all included in France), 108 (99%) completed the trial. Twenty-eight days after inclusion, 26 of 55 participants (47.3%) in the interferon-gamma group and 16 of 53 (30.2%) in the placebo group had hospital-acquired pneumonia or died (adjusted hazard ratio (HR) 1.76, 95% confidence interval (CI) 0.94–3.29; P = 0.08). Serious adverse events were reported in 24 of 55 participants (43.6%) in the interferon-gamma group and 17 of 54 (31.5%) in the placebo group ( P = 0.19). In an exploratory analysis, we found that hospital-acquired pneumonia developed in a subgroup of patients with decreased CCL17 response to interferon-gamma treatment. Conclusions Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared with placebo did not significantly reduce the incidence of hospital-acquired pneumonia or death on day 28. Furthermore, the trial was discontinued early due to safety concerns about interferon gamma-1b treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-023-07065-0.

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Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids: a mechanistic analysis

Cited by 35 publications

References 36 publications

Inhaled corticosteroids: not just for asthma, but for COVID-19?

Inhaled corticosteroids: not just for asthma, but for COVID-19?

Lung epithelial cells: Upstream targets in type 2‐high asthma

Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial

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