D1.180 - Hidden fragility behind optimal ACT score: identifying silent-risk phenotypes through clinical-biological dissociation

In asthma management, an ACT score ≥20 is often regarded as a milestone of stability, reflecting good symptomatic control from the patient’s perspective. However, clinical practice frequently reveals a discrepancy between perceived well-being and underlying airway inflammation or risk of future exacerbations. Subjective wellbeing can mask persistent functional fragility or ongoing Type 2 inflammation. So, the objective of our study was to identify factors capable of intercepting "apparently controlled" but clinically unstable patients, for whom a proactive review of therapy or monitoring is required.

We analyzed 80 asthmatic patients followed at the Asthma Clinic of the Policlinico Agostino Gemelli in Rome. All patients had an ACT ≥20 and were divided into two cohorts: Group 1 (n=41; FEV1 ≥80%, stable) and Group 2 (n=39; FEV1 <80% and/or at least one exacerbation per year). T2-biomarkers (blood eosinophils, total IgE, FeNO), allergic profile, and oral corticosteroid (OCS) use in the previous year were compared to determine predictors of clinical instability.

Despite a comparable perception of well-being (median ACT 24 vs 23, p=0.10), a deep dissociation between biology and lung function emerged. Group 2 showed significantly higher instability, with OCS use nearly four times higher than Group 1 (35.9% vs 9.8%, p=0.005). Biologically, the study revealed a paradox: stable patients (Group 1) presented numerically higher levels of eosinophils and IgE (median blood eosinophils: 380 vs 210 cells/μL; median IgE: 245 vs 130 IU/mL; p=NS). This higher T2-inflammatory load did not translate into an increase in exacerbations, suggesting a potential "organ adaptation" to T2-inflammation in the functionally preserved group. Conversely, instability in Group 2 appeared linked to differential organ sensitivity, with mold sensitization emerging as the only specific marker for this phenotype (12.8% vs 0%, p=0.02). This environmental trigger seems to act as a determinant of fragility even in the presence of a lower eosinophilic load.

Based on our findings, ACT score appears to be able to mask an underlying clinical vulnerability. The observed dissociation indicates that instability does not necessarily and linearly depend on T2 biomarkers—to which some patients appear to exhibit biological tolerance—but on different organ sensitivity and specific environmental triggers. Although these conclusions require validation on larger study populations, the study emphasizes the need to intercept these "silent" phenotypes early through constant spirometric and environmental monitoring, proactively optimizing the therapeutic strategy beyond mere symptomatic control.