Blood eosinophils as a biomarker in alpha 1 antitrypsin deficiency S Zaffarullah, R . Edgar, D Kantas, RA Stockley, AM Turner BACKGROUND N=760 Median (range) or n(%) Male 443 (58.0) Age 50.1 (17-84) Pack years 12 (0-132) Eosinophil count 0.16 (0-1) FEV1 % predicted 59 (10-161) FVC % predicted 100 (17-180) TLC % predicted 113 (81-186) DLCO % predicted 72 (5-187) Emphysema 277 (63.7) Chronic bronchitis 263 (34.6) Bronchodilator reversibility 321 (49.5) Death during follow up 119 (15.7) Blood eosinophils have been proposed as a useful biomarker in usual COPD Eosinophil counts >2% associate with better response to oral corticosteroids (CS) during exacerbations in usual COPD1 better response to inhaled corticosteroids (ICS) in post hoc analyses of several clinical trials2 AATD is a risk factor for COPD, with the classical clinical phenotype being lower zone dominant emphysema. However a range of phenotypes are seen and the influences on these appear similar to usual COPD3 Eosinophilia is typically seen more in asthma than COPD4 If eosinophilia is reflective of asthmatic features we might see differences in COPD sub-phenotype according to eosinophil count If blood eosinophilia is a driver of response to treatment in usual COPD we might see similar associations in AATD Figure 1: Frequency of categories of blood eosinophil count in AATD AIM & HYPOTHESIS To assess the clinical relevance of blood eosinophils >0.2 in patients with AATD. The hypothesis was that eosinophilia at this level would associate with features of asthma and better long term outcome if given ICS 58% of patients were taking ICS,at baseline. These individuals were more likely to be eosinophilic (p=0.002), with lower FEV1 and DLCO (both p<0.001) and had a greater pack year smoke exposure (16.5 v 7.8, p<0.001) When the multivariate analyses were stratified for baseline ICS use the relationship of persistent eosinophilia to slower FEV1 decline persisted in those on ICS, but not those who were not METHODS Retrospective analysis of UK AATD regiistry data 1996-2014 Examined associations of eosinophils>0.2 at baseline in both univariate and multivariate analyses, with clinical phenotype, lung function decline and mortality Classification of patients into always, intermittent or never eosinophils>0.2, and the relationship of this to disease progression & mortality Comparison of blood and sputum eosinophils, and sputum eosinophils to clinical features in a subset of patients Figure 2: FEV1 decline according to blood eosinophil count & ICS use 23 patients had sputum cytospins available, of whom 39% always had blood eosinophils >0.2 Figure 3 shows some representative slides from patients with and without airway eosinophilia Sputum & blood eosinophil count did not relate to one another (p=0.67) Sputum eosinophil count did not relate to any clinical feature in this small cohort, but the small numbers and population heterogeneity limit the conclusions that can be drawn from this observation RESULTS Characteristics of the whole cohort are shown in table 1. 41.5% of patients had an eosinophil count >0.2 at their first visit. In this group the mean% eosinophils was 3.9, compared to 1.2% in those with count <0.2. 91% of patients with a count >0.2 had >2% blood eosinophils. A count of >0.2 was termed ‘eosinophilic’ Patients eosinophilic at baseline appeared slightly less likely to have bronchodilator reversibility (p=0.037) from those who were not eosinophilic in univariate analysis, but this was not maintained after adjustment in multivariate for covariates such as FEV1 (p=0.064) During follow up (range 1-18 years), 35% of patients exhibited an eosinophil count >0.2 on at least one occasion (intermittent), and 24% always exhibited a value in this range (figure 1) Patients who were always eosinophilic had more gas trapping (RV 2.4l v 2.01 in those never eosinopjhilic, p=0.035), but declined more slowly than other patients (FEV1 p=0.001(figure 2) KCO p=0.006) In multivariate analyses assessing FEV1 decline , adjusting for age, baseline FEV1, Pi phenotype, bronchodilator reversibility and smoke exposure, blood eosinophil count associated with decline (p=0.036), such that those always eosinophilic exhibited decline 9.2ml/year less than those never eosinophilic. If only the baseline count was used this relationship was not detected. The odds ratio of declining more rapidly than normal aging (i.e. ↓≥1% predicted pa) was 2.5 (1.5-4.4) in patients who were never eosinophilic compared to those always eosinophilic (p=0.001). There were no differences in mortality between the categories of eosinophilia in similar univariate or multivariate analyses Figure 3: Sputum eosinophils in AATD CONCLUSIONS Eosinophil counts are a useful biomarker in AATD, but they require measurement on more than one occasion before results become reliable with respect to clinical phenotype and outcome Patients who are eosinophilic appear to have slower decline in lung function if given ICS, implying that blood eosinophilia could be used to help select AATD patients more likely to benefit from this treatment. Further work is required to assess whether sputum eosinophil count adds any further value over the blood; the preliminary data suggests it does not Bafadhel et al, AJRCCM (2012) 186: 48-55 4 Gibson & Simpson, Thorax (2009) 64: 728-35 Pascoe et al, Lanect Resp Med (2015) 3: 435-42. Stockley & Turner, Trends Mol Med (2014) 20: 105-15