| Summary: | <p><strong>Background:</strong> Factional exhaled nitric oxide (FeNO) and blood eosinophils are biomarkers of the higher risk type-2 inflammatory phenotype in asthma.</p>
<p><strong>Objectives:</strong> 1) To assess if patients who fail to suppress FeNO after monitored therapy exhibit corticosteroid resistance. 2) To translate non-suppression of type-2 biomarkers to inflammatory mediators in the airway and peripheral blood in severe asthma. 3) To develop a prototype risk scale predicting asthma attacks based on FeNO and blood eosinophils.</p>
<p><strong>Methods:</strong> 1) Induced sputum eosinophils and 11 sputum supernatant plus 9 serum inflammatory proteins were analysed in a paired before/after analysis of FeNO suppression tests conducted in Oxford, compared on the basis of a positive/negative test (i.e.: ≥42/% decrease in FeNO following monitored high-intensity corticosteroid therapy). 2) These inflammatory mediators were also correlated to the FeNO and blood eosinophil levels at the point of maximum treatment intensity in a cross-sectional study pooling the Oxford FeNO suppression cohort and the RASP-UK trial cohort. 3) Biomarker-stratified trial-level attack rates were extracted and pooled from the control arms of 8 randomised clinical trials. These were used to derive rate ratios and the predicted asthma attack rate for different patient groups.</p>
<p><strong>Results:</strong> 1) Thirty-four FeNO suppression tests were analysed. The 19 patients failing to suppress FeNO were older, more intensely treated, and had little or no trends for improvement in clinical nor sputum/serum measurements compared to those who suppressed. 2) In 74 patients with severe asthma, FeNO correlated with airway type-2 cytokine, chemokine, alarmin and eosinophilia, whilst blood eosinophils correlated with serum interleukin-5. 3) The trial-derived (n=3051) prototype risk scale showed feasibility and potential to predict asthma attacks which can be prevented by anti-inflammatory therapy.</p>
<p><strong>Conclusion:</strong> FeNO non-suppression carries significant translational, prognostic and theragnostic utility as a biomarker of type-2 airway inflammation in asthma – especially when used in combination with blood eosinophils.</p>
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