Exacerbations in asthma and chronic obstructive pulmonary disease (COPD) are associated with increased morbidity, mortality, and healthcare burden.^1,2 Blood eosinophils (EOS) and fractional exhaled nitric oxide (FeNO) have emerged as potential biomarkers for disease characterization, but their predictive value for future exacerbations across asthma and COPD in the real-world population remains incompletely understood.^3,4 New findings from the NOVELTY study demonstrate that elevated baseline EOS levels are associated with an increased risk of future exacerbations in asthma, while FeNO exhibits heterogeneous associations across exacerbation subtypes, suggesting potential for a more personalized approach to exacerbation risk assessment and management.⁴

Asthma and COPD are heterogeneous airway diseases characterized by airflow limitation and recurrent exacerbations that contribute substantially to morbidity, healthcare utilization, and disease progression.^1,2,4 Patients with asthma and/or COPD exhibiting a type 2-high phenotype are at increased risk of exacerbations.⁴ Blood EOS count has been established as a biomarker of type 2 airway inflammation and corticosteroid responsiveness, while FeNO is widely used as a marker of eosinophilic airway inflammation and may complement blood EOS assessment in characterizing chronic airway diseases.^4,5 Nevertheless, the relative utility of EOS and FeNO in predicting future exacerbations in real-life settings remains uncertain.⁴

To address this knowledge gap, the NOVELTY (NOVEL observational longiTudinal studY) cohort study was conducted, which assessed the association between baseline EOS and FeNO levels, and subsequent exacerbation risk across the spectrum of asthma, COPD, and asthma + COPD.⁴ NOVELTY enrolled >12,000 patients with physician-assigned or clinically suspected asthma, COPD, or asthma + COPD from routine primary and specialist clinical practice.⁴ The EOS analysis included 4,319 patients (asthma n=2,138; COPD n=1,541; asthma + COPD n=640), while the FeNO analysis included 7,770 patients (asthma n=4,166; COPD n=2,588; asthma + COPD n=1,016).⁴ Exacerbations were classified as all exacerbations, antibiotics-only treated exacerbations, or oral-corticosteroids (OCS)-only treated exacerbations, and their associations with baseline biomarker levels were assessed using regression analyses adjusted for age, sex, and smoking status after 1 year of follow-up.⁴

Higher baseline EOS levels were associated with a significantly increased risk of all exacerbations in patients with asthma, with each doubling of EOS corresponding to a 9% increase in exacerbation risk (incidence rate ratio [IRR]=1.09; 95% CI: 1.01-1.18; p=0.033).⁴ A similar trend was observed in COPD (IRR=1.09; 95% CI: 1.00-1.19; p=0.069), although statistical significance was not reached in the standalone analysis.⁴  In standalone FeNO analyses, higher baseline FeNO levels were associated with a lower risk of all exacerbations in COPD (IRR=0.91; 95% CI: 0.84-0.99; p=0.025), but were not associated with overall exacerbation risk in asthma (IRR=0.99; 95% CI: 0.93-1.04; p=0.683) or asthma + COPD (IRR=0.99; 95% CI: 0.90-1.09; p=0.877).⁴ However, when both biomarkers were evaluated together in a combined model, higher baseline EOS emerged as a significant independent predictor of overall exacerbations in both asthma (IRR=1.14; 95% CI: 1.05-1.24; p=0.003) and COPD (IRR=1.12; 95% CI: 1.02-1.24; p=0.033).⁴ Notably, within this same combined model for COPD, lower baseline FeNO also emerged as a significant independent predictor of all-cause exacerbations (IRR=0.87; 95% CI: 0.78-0.96; p=0.009).⁴ No independent EOS or FeNO associations for overall exacerbations were observed in patients with asthma + COPD.⁴

Distinct patterns emerged when investigators examined exacerbation subtypes according to treatment.⁴ Higher baseline FeNO levels were associated with a 16% higher odds of OCS-only exacerbations in asthma (odds ratio [OR]=1.16; 95% CI: 1.04-1.29; p=0.006) and asthma + COPD (OR=1.55; 95% CI: 1.22-1.97; p<0.001) in standalone assessments.⁴ In contrast, higher standalone baseline FeNO was also associated with a 25% lower odds of antibiotics-only exacerbations in asthma (OR=0.75; 95% CI: 0.64–0.89; p=0.001), but no significant association was observed in patients with asthma + COPD.⁴ Notably, baseline EOS levels were not associated with specific exacerbation subtypes in either asthma or asthma + COPD.⁴ Notably, while baseline EOS levels were not associated with specific exacerbation subtypes in standalone analyses, higher baseline EOS did emerge as a significant independent predictor of OCS-only exacerbations in asthma within the combined model (OR=1.18; 95% CI: 1.01-1.39; p=0.041).⁴ Furthermore, no significant associations were observed between baseline EOS or FeNO levels and OCS-only or antibiotics-only treated exacerbations in patients with COPD across either model.⁴ The findings suggested that distinct inflammatory mechanisms may underlie different exacerbation phenotypes, highlighting the importance of considering exacerbation subtype when evaluating future risk and selecting treatment strategies.⁴

In conclusion, the NOVELTY study demonstrated that elevated blood EOS levels are associated with an increased risk of future exacerbations in asthma and COPD, while FeNO identifies distinct exacerbation phenotypes, particularly OCS-treated exacerbations in asthma and asthma + COPD.⁴ These findings suggest that assessment of exacerbation subtype, together with biomarker profiling, may help improve personalized treatment management across the spectrum of obstructive airway diseases.⁴