Exhaled nitric oxide (<scp>FeNO</scp>): Bridging a knowledge gap in asthma diagnosis and treatment

Fractional exhaled nitric oxide (FeNO) testing has emerged as a valuable tool in assessing people with asthma, offering an objective measure of ongoing type 2 cytokine, chemokine and alarmin signalling in the airways.1 As a non-invasive and easily accessible biomarker, incorporating FeNO testing into asthma management may improve diagnostic accuracy by complementing clinical symptoms and spirometry measures. Raised values have been shown to predict response to inhaled corticosteroid (ICS) therapy, allowing for monitoring of treatment adherence by suppressing FeNO levels. Moreover, as a potential predictor of future risk, elevated FeNO levels are associated with increased asthma exacerbation rates and accelerated decline in lung function. FeNO testing also helps identify patients with severe asthma and type 2 inflammation who may benefit from specific biologic therapies and monitor the response to treatment2 (Figure 1). Since 2021, the American Thoracic Society (ATS) has provided a conditional recommendation for using FeNO testing in addition to usual care for individuals with asthma, specifically when treatment is being considered. This recommendation is based on evidence that suggests a reduction in asthma exacerbations with FeNO-based care.3 For its part, in 2018, the Global Initiative for Asthma (GINA) conducted a comprehensive review of FeNO testing. The focus was mainly on reducing exacerbations based on the evidence of a Cochrane review conducted by Petsky et al.4 GINA expanded its recommendations regarding using FeNO testing and emphasized its potential role in informing treatment decisions and improving asthma management, highlighting the need for further research. In the 2023 update, GINA mentions the anticipation of updates to the Cochrane review on this topic.5 In this Clinical & Experimental Allergy issue, Korevaar et al. published the much-awaited update of a Cochrane systematic review with meta-analysis on the FeNO-guided management of asthma.6 This update included studies published from the last Cochrane review in 2016 until March 2023. It included 12 randomized controlled trials (RCTs) covering 2116 adult participants—an additional 809 patients from 5 studies. The meta-analysis showed that FeNO-guided treatment significantly reduced the odds of experiencing at least one exacerbation compared to usual therapy (6 studies; odds ratio 0.61 (95% confidence intervals (CI) 0.44–0.83); GRADE moderate level of evidence) and resulted in a lower exacerbation rate (6 studies; relative risk 0.67 (95%CI 0.54–0.82); GRADE moderate level of evidence). A statistically significant lower Asthma Control Questionnaire (ACQ) score, indicating improved asthma control, was reported (9 studies; −0.10 points (95%CI −0.18 to −0.02); GRADE low level of evidence), although it did not reach the clinically important difference (0.5 points).6 No significant difference was found for the number of exacerbations requiring oral corticosteroids nor hospitalization, quality of life, lung function (FEV1% predicted), medication use (ICS dosage), or FeNO values. Pre-defined subgroup analyses, based on factors such as asthma severity, asthma control, allergy/atopy, obesity and pregnancy, did not reveal any indications that the effectiveness of FeNO-guided treatment varied among these factors. However, it is essential to note that evidence for most subgroups was limited.6 Interpreting the findings of the systematic review requires careful consideration of various factors. One significant limitation was the substantial variation in outcome measures reported across the RCTs. This variability posed a challenge when conducting comprehensive meta-analyses, hindering the ability to draw conclusive results. Moreover, the studies exhibited differing definitions of asthma exacerbation, often encompassing mild and severe events. However, the infrequency of severe exacerbations in the included studies limited our understanding of the impact of FeNO-guided treatment on these specific outcomes.6 While the results generally demonstrated consistency across most outcomes, there was imprecision in the estimated effect size for many of them. The FeNO-guided treatment protocols employed across included studies differed significantly, particularly regarding FeNO cut-offs and selected asthma control measures. Consequently, the optimal protocol for FeNO-guided treatment remains to be determined. As a result, providing definitive recommendations for using FeNO in specific asthma subgroups becomes challenging due to the need for firm evidence and precise effect estimates.6 The findings of this systematic review confirm that FeNO can play a role in treating adult asthma patients; however, adopting and interpreting research findings related to FeNO's clinical utility must be guided by implementing standardized cut-off values among different guidelines and accounting for the influence of additional factors.2 Recently, FeNO testing has emerged as a biomarker that requires the crucial complementary mechanistic information provided by the blood eosinophil count. These two biomarkers inform us about distinct immune compartments and components of asthma pathogenesis. While blood eosinophilia primarily reflects systemic type-2 inflammation driven by interleukin (IL)-5 activity, elevated FeNO levels indicate the airway epithelial component of the disease driven by type-2 cytokines (IL-4, IL-5 and Il-13), chemokines and alarmins.7 Regarding asthma diagnosis, a retrospective study conducted on 2349 patients with suspected asthma demonstrated that combining FeNO levels above 40 ppb and blood eosinophils above 300 cells/μL slightly improved diagnostic efficacy and supported the asthma diagnosis. These biomarkers exhibited a high specificity of over 95% and a positive likelihood ratio of over 10.8 Furthermore, in controlled trials involving mild to severe asthma, the combination of blood eosinophils and FeNO proved valuable in predicting severe asthma attacks and treatment responses. Elevated levels of these biomarkers were associated with more significant benefits from anti-inflammatory therapies, such as higher dose ICS in moderate asthma or type-2/alarmin-targeted biologics in moderate-to-severe asthma. To enhance risk assessment and clinical decision-making in asthma, the prototype Oxford Asthma Attack Risk Scale (ORACLE) incorporates both biomarkers in conjunction with current GINA asthma treatment intensity and other important clinical risk factors.9 In moderate-to-severe asthma, high levels of FeNO and blood eosinophils can predict treatment response to medications like dupilumab and tezepelumab. Additionally, their reduction could be one crucial milestone criterion for achieving complete remission in asthma when using biological therapies.2 To summarize, FeNO can play a role in treating adult asthma patients, leading to a reduction in asthma exacerbations. The ease of use, cost-effectiveness, noninvasive nature and point-of-care availability of FeNO testing contribute to its growing applicability in clinical practice. The updated Cochrane review published in this edition of the Journal is marginally incremental in its results but highlights the remaining knowledge gaps. Does FeNO gain additional prognostic and theragnostic value when combined with a blood eosinophil count? Could clinically accessible biomarkers be helpful in the assessment of asthma attacks? Tackling these questions may lead to substantial progress in the diagnostic and therapeutic journey of people with asthma of all severities. Carlos Andrés Celis-Preciado, Philippe Lachapelle and Simon Couillard contributed to manuscript writing and figure development. All authors reviewed and approved the final version. Supported by the Association Pulmonaire du Québec and the Fonds de Recherche du Québec. Carlos Andrés Celis-Preciado: reports speaker honoraria from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron; he received consultancy fees from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. Philippe Lachapelle reports speaker honoraria from AstraZeneca, Sanofi-Regeneron, GlaxoSmithKline, Boehringer Ingelheim and Novartis outside of the submitted work; he received consultancy fees from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. Simon Couillard reports non-restricted research grants from the NIHR Oxford BRC, the Quebec Respiratory Health Research Network, the Fondation Québècoise en Santé Respiratoire, AstraZeneca, bioMérieux and Sanofi-Genyme-Regeneron; he is the holder of the Association Pulmonaire du Québec's Research Chair in Respiratory medicine and is a Clinical research scholar of the Fonds de recherche du Québec; he received speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron and Valeo Pharma; he received consultancy fees for FirstThought, AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron; he has received sponsorship to attend/speak at international scientific meetings by/for AstraZeneca and Sanofi-Regeneron. He is an advisory board member and will have stock options for Biometry Inc—a company developing a FeNO device (myBiometry). He advised the Institut national d'excellence en santé et services sociaux (INESSS) for an update of the asthma general practice information booklet for general practitioners. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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