High-Dimensional Immunophenotyping Identifies Circulating Immune Signatures Associated with FeNO-Defined Asthma Phenotypes
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Background
Asthma is a heterogeneous inflammatory airway disease traditionally classified into T2-high (eosinophilic) and T2-low inflammatory phenotypes. Fractional exhaled nitric oxide (FeNO) is commonly used as a biomarker of T2 inflammation, although nitric oxide also regulates monocyte maturation and T-cell polarization. We hypothesized that FeNO identifies distinct systemic immune phenotypes in asthma.
Methods
Peripheral immune-cell subsets were characterized using OMIP-69, a 40-color high-dimensional immunophenotyping panel encompassing innate and adaptive immune populations. Adults with asthma and healthy controls underwent peripheral blood immunophenotyping. FeNO was dichotomized at 25 ppb (FeNO-high ≥25 vs FeNO-low <25). Immune-cell subset proportions were summarized as medians (IQRs) and compared using the Wilcoxon rank-sum test. Logistic regression was used to evaluate associations between immune subsets and FeNO status.
Results
Eighteen participants with asthma and seven healthy controls were enrolled. Asthmatic participants had higher BMI than healthy controls (median [IQR] asthma: 35.1 [28.9– 37.7] vs healthy: 25.4 [22.6–26.7] kg/m²; p=0.003), although demographics were otherwise similar. Among asthmatics, 10 participants had FeNO-low asthma, and eight had FeNO-high asthma. FeNO-high asthma demonstrated increased classical monocytes (CD14++CD16−) and compared with healthy controls (p=0.027), whereas FeNO-low asthma more closely resembled healthy controls. Intermediate monocytes (CD14++CD16+) were increased in FeNO-high versus FeNO-low (p= 0.08); a similar association was noted for classical monocytes (p = 0.13). In contrast, CCR7+ γδ T cells were significantly enriched in FeNO-low asthma (p=0.002). Logistic regression demonstrated positive associations between high FeNO and classical monocytes (OR 16.06, 95% CI 1.56–1304.69; p=0.007) and intermediate monocytes (OR 4.19, 1.22–132.30; p=0.017), whereas CCR7+ γδ T cells were negatively associated with high FeNO (OR 0.06, 0.00–0.47; p=0.001).
Conclusions
Distinct systemic immune signatures identified by high-dimensional cytometry support the existence of biologically divergent FeNO-defined asthma endotypes and may inform future biomarker-driven approaches to patient stratification and precision therapy.
