Claudio Candia

The lower airways are a dynamic environment where physical, microbial, and molecular factors intersect to regulate respiratory health and disease. The muco-microbiotic (MuMi) layer, composed of mucus, resident microbes, and extracellular vesicles (EVs), is not just a passive barrier but also an active site for host–microbe communication. This layer integrates epithelial cell biology, microbial activity, and immune responses within the bronchial environment. New transcriptomic and metatranscriptomic technologies show that it is not only which microbes are present but also their gene activity that closely links to airway inflammation and disease. EV-associated RNAs from both host and microbial cells act as key messengers, influencing epithelial responses, immune activity, mucus properties, and microbial behaviour. This review highlights evidence that positions the MuMi layer as central to understanding lower airway disease, particularly asthma and chronic obstructive pulmonary disease (COPD). Distinct gene expression programs and biomarker profiles, such as exhaled nitric oxide, may reflect different disease mechanisms even in cases with similar clinical features, such as eosinophilia. Multi-omic approaches focused on the MuMi layer enable better disease classification, biomarker discovery, and therapy selection. By putting the MuMi interface at the core of precision pulmonology, we provide a framework for advancing personalised care in chronic respiratory diseases.

Arterial stiffness has traditionally been interpreted as a marker of vascular ageing and cumulative blood pressure exposure. Increasing evidence, however, indicates that it should be viewed as an active determinant of cardiovascular loading conditions rather than a passive epiphenomenon. By accelerating pulse wave velocity and altering the timing of wave reflection, large artery stiffening increases central systolic pressure, augments late systolic load, and facilitates the transmission of pulsatile energy to the microcirculation. These hemodynamic alterations shape ventricular remodeling, influence ventricular–vascular coupling, and contribute to organ vulnerability even when brachial blood pressure appears adequately controlled. In this review, population-based observations and mechanistic human studies are integrated to position arterial stiffness as a stage-dependent dimension of cardiovascular disease. Community data illustrate its association with different blood pressure phenotypes and early cardiac structural changes, whereas evidence from advanced heart failure settings helps contextualize arterial stiffness within states of marked autonomic activation. Taken together, this perspective suggests that arterial stiffness is not merely a marker of cumulative damage, but a mediator that contributes to disease progression across clinical stages and, in practical terms, a phenotyping dimension along the trajectory from hypertension to heart failure.

Chronic obstructive pulmonary disease (COPD) continues to be framed predominantly as a disorder of the lower airways, defined operationally by airflow limitation, and assessed through a combination of spirometry, symptom burden, and exacerbation history

Chronic obstructive pulmonary disease (COPD) is a complex, progressive inflammatory disorder characterized by airflow limitation and respiratory symptoms. Its heterogeneity is manifested at etiological, pathological and clinical levels, and leads to different phenotypes: chronic bronchitis, emphysema, asthma-COPD overlap, frequent exacerbator and eosinophilic phenotypes. COPD is also associated with systemic manifestations including cardiovascular diseases, muscle dysfunction, osteoporosis and mental-health issues, which require a comprehensive management approach. Key risk factors are tobacco smoke and air pollution, both of which induce oxidative stress and airway remodeling. Although there is still no definitive cure for COPD, an early diagnosis and a multidisciplinary treatment are essential to prevent or slow the disease progression and reduce the mortality rate. Molecular biomarkers, particularly those identified through metabolomics, show promise for early detection, phenotyping and precision therapies. Challenges in biomarker discovery include specimen variability and stability. Overall, metabolomics provides valuable insights into COPD’s molecular pathways, supporting improved diagnosis, prognosis and tailored treatments. In this tutorial, we will explore metabolomics findings from different COPD matrices and their clinical implications for diagnosis, treatment and prognosis.

Background: Mepolizumab improves asthma control in severe eosinophilic asthma (SEA). However, its multidimensional effects on airway and systemic biomarkers are still incompletely understood. Methods: In this prospective study, 15 SEA patients were evaluated at baseline (T₀), 6 (T₆), and 12 months (T₁₂) after starting mepolizumab. Lung function, FeNO values, asthma control, blood eosinophil count (BEC), cytokines, and metabolomic profiles (¹H-NMR) were evaluated in serum, nasal secretions, and exhaled breath condensate (EBC). Univariate and multivariate (PCA, OPLS-DA) analyses were performed. Results: Mepolizumab reduced exacerbations, from a median of 2 at T₀ to 0 at both T₆ (p = 0.001) and T₁₂ (p = 0.003). ACT improved from 18.7 ± 4.7 at baseline to 23.0 ± 2.8 at T₆ (p = 0.026) and 23.4 ± 3.3 at T₁₂ (p = 0.032), while FEV₁ increased by 270 mL at T₆ (p = 0.032) and remained stable at T₁₂. Median BEC decreased from 450.0 (350.0–560.0) to 65.0 (50.0–87.5) cells/μL at T₆ and to 50.0 (35.0–160.0) at T₁₂ (p < 0.001), while FeNO showed a non-significant downward trend. IL-13 significantly decreased in serum and nasal secretions at T₆ and T₁₂, while IL-5 increased in nasal secretions at both timepoints and remained unchanged in serum. IL-2 showed opposite trends in serum and nasal samples, whereas GM-CSF and IFN-γ increased in nasal secretions at T₁₂. Metabolomic profiling suggested compartment-specific changes, with decreased short-chain alcohols in EBC, increased amino acids in nasal secretions and serum at T₆, and elevated pyruvate in serum at T₁₂, although none reached statistical significance in univariate analysis. Conclusions: Mepolizumab induced consistent clinical, immunologic, and metabolic changes across compartments, supporting the use of integrated cytokine and ¹H-NMR metabolomic profiling as a complementary approach for response assessment in SEA.

Chronic obstructive pulmonary disease (COPD) constitutes a persistent and substantial global health challenge, characterized by pronounced clinical and biological heterogeneity