Pulmonology — Weekly Evidence Brief

Recent studies highlight critical insights into the management and phenotyping of chronic respiratory diseases. For instance, appropriate inhaled corticosteroid (ICS) use during pregnancy in asthmatic mothers can diminish the association between maternal asthma and impaired infant lung function, supporting current management guidelines for pregnant patients 1. In severe asthma, quantitative CT (qCT) clustering reveals distinct phenotypes characterized by varying airway remodeling, air trapping, and lung density, each linked to specific molecular pathways, potentially guiding personalized treatment 2. Similarly, in pediatric asthma, exacerbation-prone children exhibit greater rhinovirus replication and exaggerated inflammatory responses, partly due to lower pre-infection interferon-stimulated gene expression, suggesting a modifiable causal determinant 3. For Chronic Obstructive Pulmonary Disease (COPD), achieving 'disease stability'—defined by no exacerbations, no FEV1 decline, and no worsening in symptom score—is associated with reduced exacerbations and mortality, making it a clinically meaningful treatment target despite potentially greater annual FEV1 decline 4.

Innovative diagnostic approaches are improving risk stratification across various lung conditions. A longitudinal radiomics-based approach, integrating time-varying CT features, significantly enhances lung cancer risk prediction in USPSTF-ineligible patients (non-smokers and light-smokers), outperforming existing models and supporting personalized screening 5. For non-small cell lung cancer (NSCLC), ultrasensitive, whole-genome, tumor-informed circulating tumor DNA (ctDNA) detection provides highly prognostic information both pre- and postoperatively, refining disease stratification and guiding adjuvant therapy by monitoring ctDNA kinetics for relapse insights 6. In COPD complicated by pulmonary aspergillosis, immune biomarkers like bronchoalveolar-lavage galactomannan, serum galactomannan, Aspergillus-specific IgG, and pentraxin-3 offer valuable tools for diagnosis, monitoring, and prognosis, complementing traditional microbiology and imaging 7. Furthermore, in Obstructive Sleep Apnea (OSA), specific exosome-related biomarkers (PRCP, UCHL1, BTG2) have been identified as central to immune-metabolic dysregulation, presenting potential diagnostic and therapeutic targets 8.

Understanding underlying mechanisms is paving the way for novel therapeutic strategies. In pulmonary fibrosis, mechanobiology, specifically the feedback loops between cells, the extracellular matrix, and the mechanical environment, drives disease progression, highlighting targeting these interactions as a promising approach for resolution and lung function restoration 9. Pulmonary hypertension (PH) pathogenesis involves significant endothelial cell dysfunction, with emerging evidence revealing unique heterogeneity among endothelial cell subpopulations that contribute to vascular remodeling, offering new therapeutic opportunities 10. For chronic thromboembolic pulmonary hypertension (CTEPH), elevated pre-operative activin-A levels are associated with an increased risk of residual PH or mortality after pulmonary endarterectomy, suggesting its potential as a predictive biomarker and a target for managing vascular remodeling 11. In COPD, non-coding RNAs have emerged as critical regulators of macrophage function and inflammatory responses, with pro-inflammatory microRNAs promoting pathological M1 polarization and offering therapeutic targets for personalized management 12.

Several studies elucidate persistent dysfunctions and external factors impacting lung health. Post-COVID-19 patients exhibit sustained endothelial dysfunction and inflammation for up to 6 months, characterized by dysregulated genes crucial for endothelial homeostasis and upregulation of inflammatory and oxidative stress markers, providing a biological basis for Long COVID symptoms 13. In cystic fibrosis (CF), CFTR modulator therapy (elexacaftor/tezacaftor/ivacaftor) leads to improvements in inflammation, epithelial remodeling, and bacterial infection, but a resurgence of inflammatory gene expression at 2 years suggests ongoing inflammation may presage disease progression with long-term therapy 14. Cystic fibrosis-related diabetes (CFRD) is independently associated with lower lung function and distinct inflammatory and proteomic changes, including higher sputum neutrophil elastase and IL-1β, even after matching for lung function, indicating unique pathophysiological pathways 15. Furthermore, long-term exposure to various air pollutants (PM2.5, PM10, SO2, NO2, CO) significantly increases the risk of active tuberculosis development from latent infection in rural China, underscoring the importance of air pollution control in LTBI management 16.

New research also addresses diverse challenges in pulmonary health, from exercise physiology to acute respiratory syndromes. Patients with myelofibrosis undergoing hematopoietic cell transplantation face a greater than 50% likelihood of developing pulmonary impairment, with a higher-than-expected incidence of bronchiolitis obliterans syndrome, necessitating increased post-HCT pulmonary monitoring 17. In COPD, impaired extracellular matrix (ECM) remodeling appears to be a key mechanism behind reduced muscle adaptation to exercise training, with distinct ECM protein expression patterns observed compared to healthy individuals 18. For Acute Respiratory Distress Syndrome (ARDS), SMARCD3 and TCN1 have been identified as critical biomarkers associated with immune cell and metabolic reprogramming, influencing mitochondrial function, oxidative stress, and inflammatory responses, offering valuable insights into ARDS pathogenesis 19. A randomized, placebo-controlled crossover trial is underway to determine if inhaled bronchodilators improve small airway function, gas exchange, lung mechanics, and exertional dyspnoea in hyperinflated COPD patients, which could refine treatment strategies targeting small airways 20.