Weekly Respiratory Research Analysis
This week highlighted mechanism-to-practice advances across respiratory medicine. A high-resolution single-cell atlas revealed endothelial thromboinflammation and suppressed FOXO3 signalling as candidate drivers of irreversible post‑tuberculosis lung damage, providing actionable mechanistic targets. A large multicenter RCT found no significant 28‑day mortality benefit from adjunctive corticosteroids in HIV‑negative severe Pneumocystis jirovecii pneumonia, challenging routine steroid use. A Cochr
Summary
This week highlighted mechanism-to-practice advances across respiratory medicine. A high-resolution single-cell atlas revealed endothelial thromboinflammation and suppressed FOXO3 signalling as candidate drivers of irreversible post‑tuberculosis lung damage, providing actionable mechanistic targets. A large multicenter RCT found no significant 28‑day mortality benefit from adjunctive corticosteroids in HIV‑negative severe Pneumocystis jirovecii pneumonia, challenging routine steroid use. A Cochrane meta‑analysis concluded sustained inflations at neonatal resuscitation confer little to no survival or major respiratory benefit, advising against routine adoption.
Selected Articles
1. A single-cell transcriptomic atlas reveals senescence and inflammation in the post-tuberculosis human lung.
Single‑cell RNA sequencing of post‑tuberculosis human lungs identified pervasive senescence, fibrosis, and inflammatory signatures across cell types, with vascular endothelial thromboinflammation and decreased FOXO3 signalling as central features; in vitro FOXO3 silencing and thrombin exposure validated mechanistic links to endothelial senescence and inflammation.
Impact: Provides human‑tissue mechanistic evidence pinpointing endothelial thromboinflammation and FOXO3 suppression as therapeutic targets to prevent or limit progressive post‑TB lung impairment; a resource for translational drug development.
Clinical Implications: Prioritize development and testing of interventions that restore FOXO3 signalling or attenuate NF‑κB–driven thromboinflammation in pulmonary endothelium; consider biomarker-driven trials in post‑TB populations to reduce long‑term respiratory morbidity.
Key Findings
- Single‑cell RNA‑seq of 19 post‑TB and 13 control lungs revealed signatures of senescence, inflammation, fibrosis, and apoptosis across cell types.
- Vascular inflammation with decreased FOXO3 signalling and increased NF‑κB–dependent thromboinflammation was a defining post‑TB feature.
- FOXO3 siRNA and thrombin exposure in pulmonary endothelial cells exacerbated senescence and inflammatory activation, validating mechanistic links.
2. Adjunctive corticosteroids in non-AIDS patients with severe Pneumocystis jirovecii pneumonia (PIC): a multicentre, double-blind, randomised controlled trial.
A multicenter double‑blind RCT (226 randomized; ITT n≈218) in immunocompromised HIV‑negative patients with severe P. jirovecii pneumonia found no statistically significant reduction in 28‑day all‑cause mortality with a 21‑day methylprednisolone taper versus placebo (32.4% vs 21.5%; p=0.069), and no major safety signal differences.
Impact: High‑quality randomized evidence questions extrapolation of steroid benefit from HIV‑positive to HIV‑negative PJP, likely prompting guideline reevaluation and more selective steroid use.
Clinical Implications: Do not routinely use adjunctive corticosteroids for HIV‑negative severe PJP to reduce mortality; instead optimize anti‑Pneumocystis therapy and individualize steroids based on clinical phenotype and biomarkers while awaiting subgroup analyses.
Key Findings
- No statistically significant 28‑day mortality reduction with adjunctive methylprednisolone (32.4% placebo vs 21.5% steroid; p=0.069).
- No significant differences in secondary infections or insulin requirements between groups.
- Multicenter, double‑blind design with stratified randomization across 27 hospitals.
3. Sustained versus standard inflations during neonatal resuscitation to prevent mortality and improve respiratory outcomes.
Cochrane review (14 RCTs, n=1,766) found sustained inflation (SLI) during neonatal PPV likely results in little to no difference in delivery‑room or in‑hospital mortality and major respiratory outcomes, with low certainty overall; a borderline reduction in mechanical ventilation was observed but evidence was downgraded for bias and imprecision.
Impact: As a high‑quality systematic review, it counters adoption of SLI as routine neonatal practice and clarifies research gaps (physiologic monitoring, high‑risk infants, neurodevelopmental outcomes).
Clinical Implications: Avoid routine use of sustained inflation in neonatal resuscitation; continue intermittent PPV and prioritize targeted RCTs in high‑risk infants with robust physiologic and long‑term outcome measures.
Key Findings
- No clear reduction in delivery‑room mortality (RR 1.72; low‑certainty) or death before discharge (RR 0.99; low‑certainty) with SLI.
- Little to no difference for chronic lung disease, pneumothorax, or severe IVH; possible borderline reduction in mechanical ventilation (RR 0.90; low‑certainty).
- Overall evidence downgraded for risk of bias and imprecision across included trials.