The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study

Background: Clinical trials with anti-IL5 therapies show a 50% reduction in severe asthma exacerbations. Exacerbations on mepolizumab appear different from placebo, questioning their inflammatory phenotype and physiological characteristics.

Methods: This prospective observationalSave study of 145 mepolizumab-treated participants was undertaken at four UK Severe Asthma Specialist clinics. Participants were aged between 18-80 years old, with eosinophilic asthma (GINA steps 4 and 5) and suitable for access to mepolizumab therapy as per national UK guidelines. All participants received mepolizumab 100mg sc every four weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment) and undertook daily peak flow and symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when their symptoms worsened outside of their normal daily variation and prior to commencing treatment; exacerbation assessment included detailed medical history, examination, FeNO, spirometry, peripheral blood eosinophil count, CRP, and sputum induction, as well as blood and urine samples for biobanking. Where a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment prior to study visit, clinical details of the missed exacerbation were collected by clinical staff. This study was exploratory with the end-point being 100 exacerbations assessed prior to treatment, and all measurements pre-determined to precisely define exacerbation phenotype as per the study aims. Study analysis included description of the cohort and comparisons of subgroups within the cohort, including comparison of the characteristics of those who proceeded to exacerbate on mepolizumab and those who did not, comparison of peak flow and symptoms diaries for assessed and missed exacerbations and comparisons of exacerbation phenotypes defined by sputum cell count. Negative and positive predictive values were used to assess the utility of both FeNO and CRP in determining exacerbation phenotype on mepolizumab treatment. (Clinicaltrials.gov NCT03324230).
 
Findings: Between 30th November 2017 and 29th May 2019, a total of 172 exacerbations occurred, with 96 assessed prior to commencing treatment. Daily peak flow and symptoms diaries showed no difference in assessed and non-assessed exacerbations. At first assessed exacerbation per participant, 45/69 (65%) produced sputum of whom 47% were sputum eosinophil high ≥2% (SEHIGH) and 53% were sputum eosinophil low <2% (SELOW). SEHIGH exacerbations were FeNO high (57ppb vs 24ppb, median difference 33; 95% CI 8,87; p<0.001), with low FEV1% predicted (55·6% vs 71·5%, mean difference -15·9; 95% CI –27·0,-4·8; p=0·0075), obstructive spirometry (FEV1 /FVC 57·5% vs 67·8%, mean difference -10·3; 95% CI -17·0,-3·6; p=0·0043) and higher blood eosinophils (70 vs 30cells/µL, median difference 40; 95% CI 20,70; p<0·001). In contrast, SELOW exacerbations were FeNO low, CRP high (15mg/L vs 2.3mg/L, median difference 12·7; 95% CI 3·5,18·5; p<0·001), sputum neutrophil high (89·8% vs 37·1%, median difference 52·7; 95% CI 34·5,59·2; p<0·001) and 50% received antibiotics (v 19% in SE≥2%, p0·031). FeNO (≤20 or ≥50ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 of 34 events), none of the adverse events were study procedure related.

Interpretation: Exacerbations on mepolizumab are two distinct entities which can largely be differentiated using FeNO; non-eosinophilic events are driven by infection with a low FeNO and high CRP, while eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of OCS for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. The results highlight clinically available tools to enable profiling of these residual exacerbations in mepolizumab treated patients.