The first step is to confirm the asthma diagnosis by demonstrating airway obstruction with bronchodilation or bronchial hyperresponsiveness. Second, for patients with peripheral blood eosinophils (typically <200/μL) that fall in the NEA spectrum, it is important to determine that it is not secondary to a systemic corticosteroid effect, as frequently steroid-dependent asthmatics have profound eosinopenia. Carefully supervised steroid taper and/or focusing on phenotypic characteristics that are often associated with high eosinophil counts (severe early-onset allergic asthma or late-onset asthma associated with nasal polyposis and complex sinonasal disease, with or without aspirin sensitivity) can be useful in helping determine whether NEA status is secondary to the effect of these drugs. It is also important to rule out potential occupational or environmental exposures that could worsen non-eosinophilic airway inflammation (i.e., tobacco use, biomass exposure, diesel exhaust, etc.).

The use of short- and long-acting bronchodilators, such as LAMA or LABA, is effective regardless of eosinophil counts and can be used as first-line therapy in NEA patients. For patients with mild persistent disease, LAMA monotherapy with as needed SABA could be tried as an initial option, as these patients are less likely to respond to ICS. For patients with moderate persistent asthma, LABA (in combination with ICS) + LAMA would be a reasonable approach. If recurrent exacerbations are a significant consideration, long-term macrolides could be tried as an option, with the caveat that its effects on lung function and quality of life are relatively small. Unfortunately there is limited information on the effectiveness of other therapeutic approaches in NEA patients with more severe disease. Any additional treatment selection should be piloted and monitored closely for effectiveness and potential toxicity or side effects. Anti-TSLP is a promising biologic treatment that should be effective in NEA.