Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects

Abstract

Background: Sputum eosinophil percentages are a strong predictor of airway inflammation and exacerbations and aid asthma management, whereas sputum neutrophil percentages indicate a different severe asthma phenotype that is potentially less responsive to TH2-targeted therapy. Variables, such as blood eosinophil counts, total IgE levels, fraction of exhaled nitric oxide (Feno) levels, or FEV1 percent predicted, might predict airway eosinophil percentages, whereas age, FEV1 percent predicted, or blood neutrophil counts might predict sputum neutrophil percentages. Availability and ease of measurement are useful characteristics, but accuracy in predicting airway eosinophil and neutrophil percentages either individually or combined is not established.

Objectives: We sought to determine whether blood eosinophil counts, Feno levels, and IgE levels accurately predict sputum eosinophil percentages and whether age, FEV1 percent predicted, and blood neutrophil counts accurately predict sputum neutrophil percentages.

Methods: Subjects in the Wake Forest Severe Asthma Research Program (n = 328) were characterized by blood and sputum cell counts, health care use, lung function, Feno levels, and IgE levels. Multiple analytic techniques were used.

Results: Despite significant association with sputum eosinophil percentages, blood eosinophil counts, Feno levels, and total IgE levels did not accurately predict sputum eosinophil percentages, and combinations of these variables did not improve prediction. Age, FEV1 percent predicted, and blood neutrophil counts were similarly unsatisfactory for the prediction of sputum neutrophil percentages. Factor analysis and stepwise selection found Feno levels, IgE levels, and FEV1 percent predicted, but not blood eosinophil counts, correctly predicted 69% of sputum eosinophil percentages of less than 2% or 2% and greater. Likewise, age, asthma duration, and blood neutrophil counts correctly predicted 64% of sputum neutrophil percentages of less than 40% or 40% and greater. A model to predict both sputum eosinophil and neutrophil percentages accurately assigned only 41% of samples.

Conclusion: Despite statistically significant associations, Feno levels, IgE levels, blood eosinophil and neutrophil counts, FEV1 percent predicted, and age are poor surrogates, both separately and combined, for accurately predicting sputum eosinophil and neutrophil percentages.

Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Figures

Figure 1A nd 1B

Subject Distribution by Sputum Eos% and Blood Eos count/μl (1A) or FeNO ppb (1B) for mild, moderate and severe asthma. Sputum Eos>2% and blood Eos2% and FeNO300/ml (1A) or sputum Eos30ppb (1B) are false positive predictions indicated by shaded areas.

Figure 2A nd 2B

Subject Distribution by Sputum Neu%, 1%predicted (2B) for subjects with mild, moderate and severe asthma. Sputum Neu≥40% are indicated by crosshatched area for false negative prediction by age<40yr and by FEV1%predicted>90%. Sputum Neu<40% are indicated by shaded area for false positive prediction by age>40yr and by FEV1%predicted<90%.

Figure 3A nd 3B

ROC curves for blood Eos, FeNO or IgE individually to predict sputum Eos 2% (3A), or for age, FEV1%predicted or blood Neu to predict sputum Neu <or≥40% (3B). Areas under the curves were similar for all (Table III).

Figure 4

Three dimensional distribution of subjects’ FeNO, IgE, and FEV1%predicted levels for those with <2% sputum Eos (filled circles) or ≥2% sputum Eos (open circles). Subjects with <2% sputum Eos are shifted to the left with lower FeNO and higher FEV1%predicted levels, whereas subjects with ≥2% sputum Eos are shifted to the right with higher FeNO levels although not necessarily lower FEV1%predicted.

Figure 5

Three dimensional distribution of subjects’ age, asthma duration and blood Neu levels for subjects with sputum Neu