Daily Respiratory Research Analysis
Three impactful respiratory papers stand out today: a multi-country modeling analysis projects that scaling tuberculosis screening with preventive treatment is cost-effective and yields substantial societal returns; a global registry study shows that expanding ETI eligibility by CFTR variant responsiveness could cover 91.5% of people with cystic fibrosis; and a mechanistic study identifies an HMGB1–YAP–PFKFB3 glycolytic axis driving PAH, with multiple pharmacologic inhibitors halting disease in
Summary
Three impactful respiratory papers stand out today: a multi-country modeling analysis projects that scaling tuberculosis screening with preventive treatment is cost-effective and yields substantial societal returns; a global registry study shows that expanding ETI eligibility by CFTR variant responsiveness could cover 91.5% of people with cystic fibrosis; and a mechanistic study identifies an HMGB1–YAP–PFKFB3 glycolytic axis driving PAH, with multiple pharmacologic inhibitors halting disease in rats.
Research Themes
- TB control: screening, preventive therapy, and economic impact
- Precision medicine in cystic fibrosis (variant-responsive ETI eligibility)
- Metabolic reprogramming and mechanotransduction in pulmonary arterial hypertension
Selected Articles
1. The effectiveness, cost-effectiveness, budget impact, and return on investment of scaling up tuberculosis screening and preventive treatment in Brazil, Georgia, Kenya, and South Africa: a modelling study.
Country-calibrated transmission models show that scaling up TB screening plus TPT across priority populations can avert 14–26% of TB episodes by 2050 versus status quo. The intervention is cost-effective in all four settings, with incremental cost per DALY averted ranging from $53 to $491 and societal returns per health-system dollar invested from $8 to $54.
Impact: This study provides policy-grade, country-specific projections integrating effectiveness, costs, budget impact, and ROI, directly informing national TB program scale-up decisions.
Clinical Implications: National TB programs can prioritize combined screening and TPT scale-up among HIV-positive individuals, household contacts, and locally defined high-risk groups, planning for substantial but justified budget allocations.
Key Findings
- By 2050, the comprehensive package prevents 15.0% (Brazil), 14.3% (Georgia), 21.3% (Kenya), and 26.4% (South Africa) of TB episodes; without TPT, reductions are markedly smaller.
- Incremental cost per DALY averted: $386 (Brazil), $491 (Georgia), $53 (Kenya), $160 (South Africa).
- Societal return per health-system dollar invested: $51 (Brazil), $8 (Georgia), $27 (Kenya), $54 (South Africa).
- Budget impact in 2030 as share of NTP budget: 62% (Brazil), 10% (Georgia), 67% (Kenya), 44% (South Africa).
Methodological Strengths
- Country-specific, calibrated transmission models with uncertainty ranges and discounted outcomes.
- Comprehensive economic evaluation including health-system and patient costs, plus scenario analyses with and without TPT.
Limitations
- Model-based projections depend on assumptions about program performance and adherence.
- No direct randomized clinical data; real-world implementation constraints may alter effectiveness and costs.
Future Directions: Prospective implementation studies and adaptive program designs should validate model projections, optimize targeting, and assess equity, adherence, and resistance impacts.
2. Global prevalence of CFTR variants with respect to their responsiveness to elexacaftor-tezacaftor-ivacaftor.
Across 95,838 individuals with CF in 69 countries, 82.0% carried p.Phe508del, 6.4% had one of 177 FDA-approved rare variants, and 3.1% had other ETI-responsive variants. Expanding ETI eligibility to all responsive variants would make at least 91.5% of people with CF eligible, with the largest gains in countries where p.Phe508del is less prevalent.
Impact: This global registry analysis quantifies the clinical reach of variant-responsive ETI therapy, directly informing regulatory labeling, access policies, and precision treatment strategies.
Clinical Implications: Health systems and regulators can use these data to expand ETI access beyond p.Phe508del, prioritize genotyping, and address geographic inequities in CFTR modulator eligibility.
Key Findings
- Among 95,838 people with CF from 69 countries, 82.0% had at least one p.Phe508del; 6.4% had one of 177 FDA-approved variants; 3.1% had non-FDA-approved but ETI-responsive variants.
- At least 91.5% of people with CF would be eligible for ETI if the label included all responsive variants.
- Countries with low p.Phe508del prevalence gain the most from expanding eligibility to responsive non-p.Phe508del variants.
Methodological Strengths
- Very large, multi-country registry and clinic-based dataset with standardized variant categorization.
- Comparative analysis across five mutually exclusive genotype groups to infer ETI responsiveness and eligibility impact.
Limitations
- Responsiveness inferred from variant-level evidence may not fully predict individual clinical response.
- Incomplete registry coverage in some regions could bias country-level estimates.
Future Directions: Link genotype-responsive eligibility to real-world ETI outcomes, expand variant functional testing, and design equitable access pathways in low p.Phe508del regions.
3. YAP-mediated glycolysis promotes pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension.
In PASMCs, HMGB1 triggers ROCK-dependent YAP activation that transcriptionally upregulates PFKFB3, driving glycolysis and proliferation. In monocrotaline PAH rats, inhibiting HMGB1 (glycyrrhizin), YAP (verteporfin), or PFKFB3 (3-PO) halted disease progression, nominating the HMGB1–YAP–PFKFB3 axis as a therapeutic target.
Impact: This study elucidates a previously unlinked mechanistic pathway integrating inflammation (HMGB1), mechanotransduction (YAP), and glycolysis (PFKFB3) in PAH and demonstrates multiple druggable nodes that reverse disease in vivo.
Clinical Implications: While preclinical, the HMGB1–YAP–PFKFB3 axis suggests translational opportunities to repurpose agents (e.g., verteporfin, glycyrrhizin) or develop PFKFB3 inhibitors for PAH.
Key Findings
- HMGB1 increased PFKFB3 expression and glycolysis in PASMCs via ROCK-dependent dephosphorylation and nuclear translocation of YAP.
- YAP acted with TEAD1 to upregulate PFKFB3, amplifying PASMC glycolysis and proliferation.
- ROCK inhibition, YAP or PFKFB3 knockdown, or glycolysis blockade reduced HMGB1-induced PASMC proliferation.
- In monocrotaline PAH rats, glycyrrhizin, verteporfin, or 3-PO effectively halted PAH progression.
Methodological Strengths
- Integrated in vitro mechanistic studies with in vivo validation in a PAH animal model.
- Multiple orthogonal interventions (HMGB1, YAP, PFKFB3, glycolysis) strengthen causal inference.
Limitations
- Monocrotaline-induced PAH model may not fully recapitulate human disease heterogeneity.
- No human tissue validation or clinical data to confirm translational efficacy.
Future Directions: Validate the HMGB1–YAP–PFKFB3 axis in human PAH tissues, assess pharmacodynamics and safety of repurposed agents, and design early-phase clinical trials.