The identification of sputum eosinophilia indicating corticosteroid responsiveness in subjects with severe asthma heralded the beginning of phenotyping asthmatic subjects based on airways inflammation. Since then, the heterogeneity of severe asthma has been explored and the importance of immunobiology has come sharply into focus with the identification of the key type‐2 cytokine pathways driving eosinophilic inflammation. The development of molecules targeting these type‐2 pathways has transformed severe asthma treatment, but necessitates robust clinical evaluation, biomarker profiling and assessment of comorbid factors to identify subjects most likely to benefit from these therapies. It has also become clear that targeting these pathways does not eradicate asthma symptoms and exacerbation risk; further work is needed to clarify underlying non‐type‐2 mechanisms in severe asthma pathways and possible therapeutic targets. This review addresses progress to date in clinical assessment and management of severe asthma and some of the challenges and unmet needs in severe asthma to achieve the goal of delivering individualized patient care.

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Reduction in glucocorticoid exposure is the primary benefit of new biologic treatments in severe asthma, but there is currently no evidence that reduction in glucocorticoid exposure corresponds to a proportionate reduction in associated toxicity.ObjectivesTo use the validated Glucocorticoid Toxicity Index (GTI) to assess change in glucocorticoid toxicity after 12 months treatment with mepolizumab, and compare toxicity change to glucocorticoid reduction and change in patient reported outcome measures (PROMs).MethodsA longitudinal, real world prospective cohort of 101 consecutive patients with severe asthma commenced on mepolizumab in a Specialist UK Regional Severe Asthma clinic. GTI toxicity assessment, cumulative glucocorticoid exposure and PROMs were recorded on commencing mepolizumab (V1), and after 12 months treatment (V2).ResultsThere was significant reduction in oral glucocorticoid exposure (V1 4280 mg prednisolone/year [interquartile range (IQR) 3083, 5475] versus V2 2450 mg prednisolone/year [1243, 3360], p<0.001). Substantial improvements in individual toxicities were observed but did not correlate with oral glucocorticoid reduction. Mean GTI Aggregate Improvement Score (AIS) was −35.7 (sd 57.8) with a wide range in toxicity change at individual patient level (AIS range −165 to +130); 70% (71/101) had a reduction in toxicity (AIS <0), 3% (3/101) had no change (AIS=0) and 27% (27/101) an increase in overall toxicity. Sixty-two (62/101) patients met the AIS minimally clinically important difference of ≤−10, but AIS did not correlate with glucocorticoid reduction or change in PROMs.ConclusionMepolizumab resulted in substantial oral glucocorticoid reduction but this did not correlate with reduction in oral glucocorticoid toxicity, which varies widely at the individual patient level. Oral glucocorticoid reduction is not a comprehensive measure of response to mepolizumab.

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Airway remodelling rather than cellular infiltration characterizes both type2 cytokine biomarker-high and -low severe asthma. Allergy.