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.
BACKGROUND: Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment. METHODS: Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time. RESULTS: Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L. CONCLUSIONS: In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators.
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.
BACKGROUND: Lung cancer screening (LCS) with low-dose CT (LDCT) reduces lung-cancer-related mortality in high-risk individuals. AI can potentially reduce radiologist workload as first-read-filter by ruling-out negative cases. The feasibility of AI as first reader was evaluated in the European 4-IN-THE-LUNG-RUN (4ITLR) trial, comparing its negative-misclassifications (NMs) to those of radiologists and the impact on referral rates. METHODS: NMs were collected from 3678 baseline LDCTs of the 4ITLR-dataset. LDCTs were read independently by radiologists and dedicated AI software (AVIEW-LCS, v1.1.42.92, Coreline-Soft, Seoul, Korea). A case was designated as NM when nodules > 100 mm RESULTS: Of the 3678 baseline scans, 438 NMs (11.9 %) were identified (age individuals: 68 (IQR: 64-73) years, 241 men); 31 (0.8 %) by AI and 407 (11.1 %) by radiologists. Among the 31 AI-NMs, 3 were classified positive and 28 indeterminate. Among the 407 radiologist-NMs, 4 were classified positive, and 403 were indeterminate, of which 8 were classified positive after receiving a three-month follow-up CT. Radiologists, as first reader, would have led to 12/102 (11.8 %) missed referrals, higher than the 3/102 (2.9 %) of AI. CONCLUSION: This study showed AI outperforms radiologists with significantly less NMs and therefore shows promise as first reader in a LCS program at baseline, by independently ruling-out negative cases without substantially increasing the risk of missed clinical referrals.
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.
OBJECTIVES: Pediatric tuberculosis (TB) diagnosis is complicated by challenges in obtaining invasive respiratory specimens that frequently contain few Mycobacterium tuberculosis (Mtb) bacilli. We report the diagnostic performance of an Mtb antigen-derived peptide (MAP-TB) assay and its ability to monitor TB treatment response. METHODS: Study cohorts enrolled children who presented with presumptive TB at two hospitals in South Africa from 2012 to 2017 (157 children aged <13 years) and at community-based clinics in the Dominican Republic from 2019 to 2023 (101 children aged <18 years). Children were evaluated for TB at enrollment and six months post-enrollment and assigned confirmed, unconfirmed, or unlikely TB diagnoses using the 2015 NIH diagnostic criteria for pediatric TB. MAP-TB assay performance was evaluated using serum collected at baseline and at regular intervals post-enrollment following STARD guidelines. RESULTS: MAP-TB sensitivity for confirmed and unconfirmed TB was comparable to culture and Xpert sensitivity for confirmed TB, but MAP-TB specificity revealed age-dependence, decreasing from 98·1% to 78·4%, when including children aged <1 year. MAP-TB values decreased by six months post-treatment initiation in children with symptom improvement. CONCLUSIONS: Serum MAP-TB results can effectively diagnose pediatric TB, including unconfirmed and extrapulmonary TB missed by current methods, and correspond to effective treatment.