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

Abstract

Background Sputum eosinophils (Eos) are a strong predictor of airway inflammation, exacerbations, and aid asthma management, whereas sputum neutrophils (Neu) indicate a different severe asthma phenotype, potentially less responsive to TH2-targeted therapy. Variables such as blood Eos, total IgE, fractional exhaled nitric oxide (FeNO) or FEV1% predicted, may predict airway Eos, while age, FEV1%predicted, or blood Neu may predict sputum Neu. Availability and ease of measurement are useful characteristics, but accuracy in predicting airway Eos and Neu, individually or combined, is not established. Objectives To determine whether blood Eos, FeNO, and IgE accurately predict sputum eosinophils, and age, FEV1% predicted, and blood Neu accurately predict sputum neutrophils (Neu). Methods Subjects in the Wake Forest Severe Asthma Research Program (N=328) were characterized by blood and sputum cells, healthcare utilization, lung function, FeNO, and IgE. Multiple analytical techniques were utilized. Results Despite significant association with sputum Eos, blood Eos, FeNO and total IgE did not accurately predict sputum Eos, and combinations of these variables failed to improve prediction. Age, FEV1%predicted and blood Neu were similarly unsatisfactory for prediction of sputum Neu. Factor analysis and stepwise selection found FeNO, IgE and FEV1% predicted, but not blood Eos, correctly predicted 69% of sputum Eos<or≥2%. Likewise, age, asthma duration and blood neutrophils correctly predicted 64% of sputum Neu<or≥40%. A model to predict both sputum Eos and Neu accurately assigned only 41% of samples. Conclusion Despite statistically significant associations FeNO, IgE, blood Eos and Neu, FEV1%predicted, and age are poor surrogates, separately and combined, for accurately predicting sputum eosinophils and neutrophils.

Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

“…The main finding of this study is the increased expression of IL-1R family members in distinguish between the various inflammatory profiles in sputum (24). FeNO levels and blood 428 eosinophil counts were similar and highest in the eosinophilic and mixed group but equally 429 low in the neutrophilic and pauci-granular groups, mirroring the findings of Hastie and 430 colleagues (24).…”

The association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma: subanalyses of the Phase III SIROCCO and CALIMA studies

“…Of a range of different biomarkers, blood eosinophil counts offer the greatest diagnostic accuracy for sputum eosinophilia, with increasing specificity as blood eosinophil counts increase 28,29 . However, given the natural variability of blood eosinophil counts (even within 24 hours) and their sensitivity to corticosteroids, low blood eosinophil counts may belie clinically significant eosinophilic airway inflammation 13,30,31 . The results of the current analyses underscore the potential limitations of defining probable responders to eosinophil depletion therapy, based on a blood eosinophil count of !300 cells/lL alone.…”

Improving the diagnosis of eosinophilic asthma

“…Therefore, eosinophil counts in peripheral blood have become popular in identifying asthma patients with airway eosinophilia, in particular in studies with anti-IL-5 therapies [5]. However, although there exists a significant association between eosinophils in blood and in sputum, the use of blood eosinophils to identify sputum eosinophilia is still debated because of the relatively high false-negative and false-positive rates [26]. This was illustrated in the 328 patients of the severe asthma research programme (SARP) showing that the accuracy of blood eosinophils to predict sputum eosinophilia was low, leading to considerable misclassification of patients with eosinophilic or non-eosinophilic asthma.…”

“…Many studies have shown a positive relationship between FeNO and the number of percentage sputum eosinophils [23,32,33], and one study showed that FeNO measurement could identify the subgroup of patients with severe eosinophilic asthma [34]. However, in the SARP study, a high rate of misdiagnosis was found when using FeNO for diagnosing eosinophilic asthma based on sputum eosinophils ≥2% [26]. One possible explanation for this discrepancy might be that FeNO values in severe asthma can be confounded by many factors [30].…”

“…Only few studies have specifically looked at the accuracy of a combination of two or more biomarkers to detect eosinophilic airway inflammation [26,46,50]. Unfortunately, the results of these studies are not fully conclusive.…”