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), $54 (South Africa).
- Budget impact in 2030 as share of NTP budget: 62% (Brazil), 10% (Georgia), 67% (Kenya), 44% (South Africa).
Methodological Strengths
- Country-specific, calibrated transmission models with uncertainty ranges and discounted outcomes.
- Comprehensive economic evaluation including health-system and patient costs, plus scenario analyses with and without TPT.
Limitations
- Model-based projections depend on assumptions about program performance and adherence.
- No direct randomized clinical data; real-world implementation constraints may alter effectiveness and costs.
Future Directions: Prospective implementation studies and adaptive program designs should validate model projections, optimize targeting, and assess equity, adherence, and resistance impacts.
BACKGROUND: Closing the tuberculosis diagnostic gap and scaling up tuberculosis preventive treatment (TPT) are two global priorities to end tuberculosis. We aimed to estimate the cost-effectiveness, budget impact, and societal return on investment of a comprehensive intervention to improve tuberculosis screening and prevention in Brazil, Georgia, Kenya, and South Africa-four distinct epidemiological settings. METHODS: In this modelling study, in partnership with national tuberculosis programmes we defined a set of interventions (the intervention package) related to tuberculosis screening and TPT in three priority populations: people with HIV, household contacts, and a country-defined high-risk population (people deprived of liberty [Brazil], people accessing care for injection drug use [Georgia], people in informal settlements in nine districts with a high prevalence of tuberculosis [Kenya], and people in the 22 subdistricts with the highest prevalence of tuberculosis [South Africa]). We developed transmission models calibrated to country-specific epidemiology and collated cost data for tuberculosis-related activities and patient costs in 2023 US dollars (US$). We compared the intervention package scaled up to reach all priority populations by 2030 to a status quo scenario based on projected tuberculosis epidemiology over a 27-year time horizon (Jan 1, 2024, to Dec 31, 2050); to delineate the impact of intervention components, we also evaluated the intervention package without TPT. Outcomes were health system and societal costs, number of tuberculosis episodes, tuberculosis deaths, and disability-adjusted life years (DALYs). We calculated the budget impact, health system cost per DALY averted, and societal return on the health system investment for each country. Outcomes were discounted at 3% per annum. FINDINGS: With the status quo scenario, by 2050, tuberculosis incidence is projected to be 41 per 100 000 population (95% uncertainty range 32-53) in Brazil, 45 per 100 000 population (36-60) in Georgia, 214 per 100 000 population (146-266) in Kenya, and 261 per 100 000 population (133-406) in South Africa. The percentage of all tuberculosis episodes prevented by implementing the intervention package in all priority populations is projected to be 15·0% (12·8-17·5) in Brazil, 14·3% (13·1-15·8) in Georgia, 21·3% (15·2-27·6) in Kenya, and 26·4% (21·1-31·8) in South Africa by 2050. If implemented without TPT (ie, tuberculosis disease screening alone), corresponding reductions were lower at 10·4% (8·6-12·2) in Brazil, 10·2% (9·5-11·2) in Georgia, 12·6% (9·5-15·9) in Kenya, and 16·8% (13·0-20·4) in South Africa. In 2030, the percentage of the national tuberculosis programme budget required for the intervention package was 62% in Brazil, 10% in Georgia, 67% in Kenya, and 44% South Africa. The incremental cost per DALY averted of the intervention package compared with the status quo in all priority populations is $386 in Brazil, $491 in Georgia, $53 in Kenya, and $160 in South Africa. The corresponding societal return per health system dollar invested is projected to be $51 in Brazil, $8 in Georgia, $27 in Kenya, and $54 in South Africa. INTERPRETATION: Scaling up tuberculosis screening and TPT requires substantial investment but is projected to be cost-effective compared with the status quo, to greatly reduce tuberculosis incidence, and to provide large returns on investment. FUNDING: World Health Organization.
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.
BACKGROUND: Elexacaftor-tezacaftor-ivacaftor (ETI) is mostly approved in people with cystic fibrosis (pwCF) with a p.Phe508del CFTR variant. The US Food and Drug Administration (FDA) approved ETI for an additional 177 rare CFTR variants and studies identified 7 non-FDA approved variants also responsive to ETI. The global impact of expanding the ETI label to rare responsive CFTR variants on the number of eligible pwCF is unknown. METHODS: Data were obtained from CF registries and individual CF clinics in countries without registries. Individuals were classified according to five mutually-exclusive categories (1) at least one p.Phe508del variant (2) at least one of the 177 FDA-approved variants (3) at least one non-FDA-approved variant responsive to ETI (4) two variants resulting in no CFTR protein (5) all other variants. The first 3 groups were considered responsive to ETI, group 4 was nonresponsive and group 5 of undetermined responsiveness. RESULTS: Data were obtained from 95,838 pwCF living in 69 countries: 78,566 (82.0 %) had at least one p.Phe508del, 6175 (6.4 %) at least one FDA-approved variants, and 2981 (3.1 %) at least one non-FDA-approved responsive variants. Two variants resulting in no CFTR protein were found in 3574 (3.7 %) and other variant combinations in 4490 (4.7 %). The prevalence of p.Phe508del ranged from 7 % to 98 % in individual countries and expanding the eligibility to responsive non-p.Phe508del variants resulted in greatest eligibility increase in countries with low p.Phe508del prevalence. CONCLUSION: Expanding the label of ETI to rare responsive CFTR variants will make at least 91.5 % of pwCF eligible to this disease-modifying therapy.
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.
Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) has been identified as a key enzyme regulating glycolysis. However, the molecular mechanisms underlying PFKFB3 regulation and glycolysis reprogramming in PAH remain unclear. Here, primary cultured pulmonary arterial smooth muscle cells (PASMCs) and monocrotaline-induced PAH rats were used to investigate these unknown mechanisms. We found that PFKFB3 expression and PASMC glycolysis were significantly increased in high mobility group box 1 (HMGB1)-treated cells, accompanied by the dephosphorylation and nuclear translocation of Yes-associated protein (YAP) via Rho-associated protein kinase signaling. Activation of YAP then acted as a transcriptional coactivator in conjunction with transcriptional enhancer activator domain 1, bolstering the transcription of the crucial glycolytic enzyme PFKFB3, consequently amplifying PASMC glycolysis. Rho-associated protein kinase inhibition, YAP or PFKFB3 knockdown, or glycolysis blockage diminished HMGB1-induced PASMC proliferation. In rats with monocrotaline-induced PAH, interventions such as inhibiting HMGB1 with glycyrrhizin, suppressing YAP activation with verteporfin, and targeting PFKFB3 with 3-PO effectively halted PAH progression. Our findings suggest that targeting the HMGB1-YAP-PFKFB3-glycolytic pathway is a promising strategy for preventing and treating PAH.