Sub‐stratification of type‐2 high airway disease for therapeutic decision‐making: A ‘bomb’ (blood eosinophils) meets ‘magnet’ (FeNO) framework

Biologic therapies targeting components of the type-2 inflammatory response seen in many patients with obstructive airways disease have had a dramatic impact in the clinic. In the severe asthma clinic, extraordinary outcomes are being achieved and the days when the severe asthma clinicians’ job was mainly about overseeing an orderly decline (much of it due to oral corticosteroid-related morbidity) have been confined to the history books. In 2023, it is projected that sales will top $10 billion, accounting for over 30% of total worldwide asthma drug sales. The success of biologics was not predicted by all and there was a view that targeting treatment to a biomarkerdefined subgroup of patients would result in a severely restricted market. In fact, we have seen the opposite. The ability to target treatment to a population who are most likely to benefit has incentivized clinicians to look for these patients, has increased the likelihood of a good response to treatment and has resulted in low rates of treatment failure. It has also made the job of jumping regulatory hurdles and making a compelling cost–benefit case for funding of treatment much more straightforward. We now have four monoclonal antibody targeting strategies inhibiting different aspects of the immune response driving asthma attacks (Figure 1). The target population is patients with persistent airway inflammation despite treatment with a reasonable dose of inhaled corticosteroids (ICS). The persistence of type-2 inflammation indicates that the airway mucosal mechanisms driving recruitment of eosinophils towards the airway epithelium are, or have become, corticosteroid-resistant. In this situation, effective treatment exploits other mechanisms to reduce eosinophilic airway inflammation: depletion of circulating eosinophils (oral corticosteroids and biologics targeting the IL-5 pathway: mepolizumab, benralizumab, reslizumab); prevention of eosinophils leaving the vascular compartment (targeting the IL-4 receptor and inhibiting IL-4/IL-13 responses: dupiliumab); or inhibition of the corticosteroid-resistant airway mucosal drivers of type-2 inflammation by other mechanisms (dupilumab again or targeting thymic stromal lymphopoietin [TSLP] with tezepelumab). A sixth biologic (omalizumab) targets the distal effector of the allergic reaction (IgE) with marginal effects on the type-2 immune response. The presence of multiple biologic options and the absence of any direct head-to-head comparisons mean that finding the right biologic for the right patient has become increasingly challenging. In this commentary article, we suggest that one way forward is to sub-stratify type-2 inflammatory airway disease according to the dominant driving mechanism. This concept is based on the demonstration that the two clinically accessible biomarkers of type-2 inflammation, fractional exhaled nitric oxide (FeNO) and the blood eosinophil count, provide independent prognostic (of exacerbations) and predictive (of corticosteroid response) information because they identify different aspects of type-2 inflammation. Mechanistic support for this idea comes from a recent cross-sectional analysis of induced sputum and serum markers of type-2 inflammation in patients with severe asthma who were confirmed to be adherent to high-dose ICS. We found that FeNO correlated with almost all of the assessed components of the airway type-2 immune response in sputum, whereas the blood eosinophil count correlated with serum IL-5 but not with any assessed measure of airway inflammation (Figure 2). FeNO and blood eosinophils therefore relate to different components and compartments of type-2 inflammation (Figure 2): FeNO reflects airway type-2 activity and the chemotactic pull to the airways (the magnet), whereas blood eosinophils reflect the systemic pool of available effector cells and circulating IL-5 (the bomb). The important clinical corollary of these mechanistic data is observable in randomized clinical trials, where raised values of baseline FeNO and blood eosinophils act synergistically to predict asthma attacks in the placebo arm—an excess risk which is entirely removed by appropriate type-2 targeting anti-inflammatory therapy. These findings imply that we might be in a position to choose the most appropriate biologic for an individual patient based on their biomarker profile and the primary The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Received: 27 April 2022 Accepted: 5 May 2022