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Novel predictor of inhaled corticosteroid effectiveness in COPD patients

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Created On: 04/12/2025

For chronic obstructive pulmonary disease (COPD), inhaled corticosteroids (ICS) are a cornerstone therapy.

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Key take away

BALF-derived extracellular vesicle proteins, particularly CST1 from the cystatin family, correlate with improved lung function and predict inhaled corticosteroid responsiveness in COPD patients.

Background

For chronic obstructive pulmonary disease (COPD), inhaled corticosteroids (ICS) are a cornerstone therapy. Yet, patient responses to therapy vary extensively. The identification of reliable biomarkers that can clarify disease mechanisms and predict ICS responsiveness remains a major clinical need.

Extracellular vesicles (EVs)—crucial mediators of intercellular communication—are emerging as promising sources of novel biomarkers in respiratory diseases. This study explored EVs to provide insights into the ICS treatment response in COPD.

Method

In total, 34 COPD sufferers received either placebo or ICS (500 µg fluticasone ± 50 µg salmeterol) over a 6-month period. Lung function parameters, including forced expiratory volume in 1 second percent predicted (FEV1% predicted), forced expiratory volume in 1 second to forced vital capacity ratio (percent) (FEV1/FVC%), and residual volume to total lung capacity ratio (percent predicted) (RV/TLC% predicted), were evaluated at baseline and after treatment. Bronchoalveolar lavage fluid (BALF)-derived EV proteins were analyzed via label-free quantitative proteomics.

Using weighted gene co-expression network analysis, EV protein modules linked with baseline lung function were identified in 24 patients. Following ICS therapy, the baseline EV protein levels were then linked with lung function alteration. Statistical analysis was carried out in R (v4.3.2), applying non-parametric and correlation tests, with significance set at p < 0.05.

Result

In total, 13 distinct EV protein co-expression modules were detected. Among these, the red and salmon modules exhibited prominent links with baseline lung function—FEV1% predicted (r = –0.46, p = 0.02) and FEV1/FVC% (r = 0.43, p = 0.04), respectively. Within these modules, 25 and 11 proteins, respectively, illustrated significant correlations with post-ICS improvements in lung function. Notably, members of the cystatin (CST) superfamily—particularly CST1—were strongly related to positive changes in FEV1% predicted (r = 0.61, p = 0.003) and FEV1/FVC% (r = 0.46, p = 0.035). CST family proteins displayed distinct expression profiles between ICS responders and non-responders, indicating a mechanistic link to type 2 inflammation and corticosteroid sensitivity.

Conclusion

BALF-derived EVs can serve as valuable biomarker sources for predicting ICS treatment response in COPD. Specifically, cystatin family proteins, especially CST1, may act as potential predictors of corticosteroid responsiveness, offering novel insights into personalized COPD therapy.