Daily Respiratory Research Analysis

BACKGROUND: Among individuals with a history of smoking but preserved spirometry (tobacco exposed with preserved spirometry, or TEPS), lung volume-based stratification identifies two phenotypes at increased risk for COPD (pre-COPD): those with a relatively elevated total lung capacity ([TLC]high) and those with a relatively elevated functional residual capacity-to-TLC ratio ([FRC/TLC]high). These subgroups exhibit distinct respiratory symptoms, radiographic abnormalities, and clinical trajectories. OBJECTIVE: To determine whether these lung volume-based pre-COPD phenotypes have distinct biological features reflected in their circulating proteome. METHODS: We analyzed peripheral blood proteomic profiles (SomaScan v4.0; 4,979 aptamers) and computerized tomography scan-derived supine lung volumes from 1,959 TEPS participants at the 5-year follow-up visit (Visit 2) of the COPDGene cohort. Participants with [TLC]high and [FRC/TLC]high were compared with a low-COPD-risk reference group (without high TLC or high FRC/TLC). Analyses included covariate-adjusted regression, machine learning, and pathway enrichment modeling, adjusting for age, sex, height, weight, smoking status and burden, leukocyte and platelet counts, forced expiratory volume in 1 second (FEV1 as percent predicted), and study site (random effect). RESULTS: Using Visit 2 data and Visit 3 (10-year) follow-up outcomes, we confirmed the reproducibility and prognostic validity of the lung volume-based phenotypes in 1,232 participants with longitudinal data. Over 5.3 ± 1.1 years, spirometric COPD developed in 17% (133/761) of pre-COPD TEPS versus 8% (37/471) of low-risk TEPS (adjOR = 2.51 [1.69-3.75]; P < .001). Among pre-COPD subgroups, [FRC/TLC]high TEPS showed greater progression to GOLD ≥ 2 (adjOR = 2.90 [1.62-5.18]; P < .001) and PRISm (adjOR = 3.29 [1.41-7.69]; P = .005). At baseline (n = 1,959), plasma proteomic analysis identified 165 upregulated and 145 downregulated proteins in [TLC]high TEPS compared with low-COPD-risk TEPS, whereas only 22 proteins were differentially expressed in [FRC/TLC]high TEPS versus low-risk group. Comparison of the two pre-COPD phenotypes 269 differentially expressed proteins (116 proteins upregulated and 153 downregulated in [FRC/TLC]high versus [TLC]high), including previously described COPD-related mediators (e.g., sRAGE, IGFBP2) and novel candidates (e.g., ZG16). Pathway analysis highlighted immune signaling, cellular trafficking, and apoptotic pathways relevant to COPD pathogenesis. CONCLUSIONS: Lung volume-based stratification in TEPS identifies biologically distinct subgroups with differing plasma proteomic signature and COPD risk, underscoring the heterogeneity of early disease and revealing potential circulating biomarkers of pre-COPD states.

Respiratory viral infections, such as influenza and coronavirus, are major threats to humankind. Injectable vaccines for SARS-CoV-2 protect against severe disease but fail to induce immunity in the upper airway mucosa, the virus entry site, thus not preventing infection and transmission. This highlights the urgent need for mucosal-targeted vaccination systems. While intranasal immunization holds promise, achieving local antigen delivery for mucosal immunity remains challenging. To address this, we designed an innovative nanoparticle system to deliver intranasal vaccines, using the receptor-binding domain (RBD) and multiple T-cell epitopes of SARS-CoV-2 antigens. Nonporous silica-based nanoparticles (SiNP) functionalized with a mucoadhesive cyclodextrin polymer (MaP) were selected as a delivery vehicle capable of adhering to and penetrating mucus. In a 3-dose regimen, the nanovaccine induced and sustained high systemic and neutralizing antibody levels for at least 1 year, with robust cellular responses, as well as IgA secretion in the oral and nasal cavities, providing strong protection against SARS-CoV-2 and substantially reducing viral loads in both upper and lower respiratory tracts. Our findings provide evidence that an intranasal vaccination platform combining two distinct nanoscale strategies might be crucial for inducing lasting and broad systemic and upper airway immunity, potentially controlling SARS-CoV-2 infection and transmission.

OBJECTIVES: To evaluate the diagnostic performance of a rapid point-of-care immunoassay measuring pancreatic stone protein (PSP) for early sepsis identification within the first three days of ICU admission. Subgroup analyses (sex, age, febrile status) were conducted, and the combined diagnostic value of PSP and C-reactive protein (CRP) was assessed. DESIGN: Multicenter, prospective, observational study. PATIENT: Four hundred sixty-six adults the ICU. SETTING: Six ICUs in the United States who were expected to required at least 24 hours of ICU care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We calculated the Youden Index to evaluate the clinical performance of the PSP assay, and the resulting threshold was used to identify patients with sepsis. Diagnostic performance metrics included sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-). Receiver operating characteristic analysis were performed for PSP and CRP. At the optimal PSP cutoff point of 117 ng/mL, PSP demonstrated a sensitivity of 74.2%, specificity of 67.8%, accuracy of 71.0%, PPV of 70.3%, NPV of 71.9%, and LR+ and LR- ratios of 2.30 and 0.38, respectively. Combining PSP and CRP improved diagnostic specificity to 95.2%. Subgroup analyses demonstrated consistent performance across sex, and higher specificity was observed in patients 18-60 years old. In febrile patients, PSP achieved high specificity (87.5%) but lower sensitivity (63.6%). In non-febrile patients, sensitivity and specificity were 67.7% and 76.6%, respectively. CONCLUSIONS: PSP can serve as a biomarker for the early identification of sepsis. Diagnostic performance across diverse ages, sex, and clinical presentation supports the assay's broad applicability. The combination of PSP and CRP enhances diagnostic specificity for sepsis detection, offering a complementary approach to improve sepsis detection and lead to earlier appropriate management.