1. 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
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 < % 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 ( ) 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
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