Daily Respiratory Research Analysis
Three standout studies advance respiratory medicine across diagnostics, therapeutics, and screening. A pooled analysis links sweat chloride to CFTR function and outcomes under CFTR modulators, supporting sweat chloride as a pharmacodynamic target. Real-world lung cancer screening shows AI as a first reader markedly reduces negative misclassifications and missed referrals, while a blood-based assay enables non-sputum pediatric TB diagnosis and treatment monitoring across two countries.
Summary
Three standout studies advance respiratory medicine across diagnostics, therapeutics, and screening. A pooled analysis links sweat chloride to CFTR function and outcomes under CFTR modulators, supporting sweat chloride as a pharmacodynamic target. Real-world lung cancer screening shows AI as a first reader markedly reduces negative misclassifications and missed referrals, while a blood-based assay enables non-sputum pediatric TB diagnosis and treatment monitoring across two countries.
Research Themes
- Biomarkers and surrogate endpoints in cystic fibrosis therapy
- AI-enabled workflow optimization in lung cancer screening
- Non-sputum diagnostics for pediatric tuberculosis
Selected Articles
1. Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment.
Across pooled phase 3 datasets and translational assays, sweat chloride robustly tracks CFTR function and aligns with clinical benefit under CFTR modulators. Achieving sweat chloride <60 mmol/L—and ideally <30 mmol/L—was associated with superior outcomes, supporting sweat chloride as a pharmacodynamic target and surrogate endpoint.
Impact: Defines actionable biomarker thresholds that link molecular correction to patient-centered outcomes, informing trial endpoints and treat-to-target strategies in cystic fibrosis.
Clinical Implications: Use sweat chloride reduction as a pharmacodynamic goal in CFTR modulator therapy, targeting <60 mmol/L and ideally <30 mmol/L to maximize clinical benefit and guide dose optimization and regulatory endpoints.
Key Findings
- In vivo sweat chloride strongly correlated with CFTR-dependent chloride current in human bronchial epithelial cells.
- Post-modulator sweat chloride values <30 and 30–<60 mmol/L were associated with better lung function, BMI, PROs, fewer pulmonary exacerbations, and favorable longitudinal lung function change versus ≥60 mmol/L.
- Pooled phase 3 analyses support sweat chloride as a surrogate endpoint reflecting restored CFTR function.
Methodological Strengths
- Pooled analyses of multiple phase 3 randomized trials with harmonized outcomes.
- Integrated translational validation linking in vivo sweat chloride to in vitro HBE CFTR current.
Limitations
- Secondary, post hoc analyses; causality cannot be inferred.
- Generalizability may vary by genotype and specific modulator regimens; exact sample sizes not reported in the abstract.
Future Directions: Prospective treat-to-target trials using sweat chloride thresholds to guide dose escalation or combination modulator strategies, and validation across genotypes and age groups.
2. Feasibility of AI as first reader in the 4-IN-THE-LUNG-RUN lung cancer screening trial: impact on negative-misclassifications and clinical referral rate.
In 3,678 baseline LDCTs, AI as a first reader produced far fewer negative misclassifications than radiologists (0.8% vs 11.1%) and reduced missed clinical referrals (2.9% vs 11.8%). These data support AI-first-read filters to safely rule out negatives and decrease radiologist workload in lung cancer screening.
Impact: Demonstrates a practical, safety-relevant AI deployment that could reshape screening workflows by reducing errors and resource burden without compromising referrals.
Clinical Implications: Programs can consider AI first-read filtering at baseline LDCT to rule out negatives, focusing radiologist time on indeterminate/positive studies and potentially standardizing referral decisions.
Key Findings
- Among 3,678 baseline LDCTs, AI had 31 negative misclassifications (0.8%) versus 407 (11.1%) by radiologists.
- Missed clinical referrals would have been lower with AI as first reader (3/102, 2.9%) than with radiologists (12/102, 11.8%).
- AI independently ruled out negative cases without substantially increasing risk of missed referrals, supporting feasibility as a first-reader filter.
Methodological Strengths
- Large, prospectively assembled screening dataset with independent AI and radiologist reads.
- Concrete safety metric (missed referral rate) alongside negative misclassification analysis.
Limitations
- Single AI vendor and baseline-only assessment; external generalizability and longitudinal outcomes not addressed.
- Operational thresholds and definitions (e.g., NM criteria) may vary across programs.
Future Directions: Prospective implementation studies comparing AI-first-read pathways versus standard practice on detection rates, workload, cost-effectiveness, and patient outcomes across diverse settings.
3. Blood-based diagnosis of pediatric tuberculosis: A prospective cohort study in South Africa and Dominican Republic.
In two prospective cohorts (n=258), a serum MAP-TB assay diagnosed pediatric TB—including unconfirmed and extrapulmonary cases—and tracked treatment response. Sensitivity was comparable to culture/Xpert for confirmed TB, though specificity declined when infants <1 year were included.
Impact: Addresses a major diagnostic gap by enabling non-sputum, blood-based testing and treatment monitoring in pediatric TB across diverse settings.
Clinical Implications: Serum MAP-TB could reduce reliance on invasive respiratory sampling in children, support earlier diagnosis—including extrapulmonary disease—and provide a tool for monitoring treatment response.
Key Findings
- MAP-TB sensitivity for confirmed/unconfirmed pediatric TB was comparable to culture/Xpert for confirmed TB.
- Specificity was age-dependent and declined from 98.1% to 78.4% when including children <1 year.
- MAP-TB values decreased by six months after treatment initiation in children with clinical improvement, supporting response monitoring.
Methodological Strengths
- Prospective, multicenter cohorts across two countries adhering to STARD diagnostic standards.
- Serial sampling enabling both diagnostic accuracy and treatment response assessment.
Limitations
- Specificity falls in infants <1 year, which may necessitate age-tailored thresholds.
- Exact operating characteristics by TB phenotype and HIV status are not detailed in the abstract.
Future Directions: Head-to-head implementation studies versus Xpert Ultra and host transcriptomic assays, age-specific threshold optimization, and evaluation in high-HIV-burden settings.