Daily Respiratory Research Analysis
A multicenter randomized trial found a high probability that awake prone positioning reduces intubation and/or death in nonintubated patients with COVID-19 hypoxemic respiratory failure. A phase 2 study showed the selective MET inhibitor vebreltinib achieved a 48.8% objective response in MET amplification-driven advanced NSCLC. Metabolomic profiling of bronchoalveolar lavage identified methionine oxidation and ornithine as early predictors of structural lung disease in children with cystic fibro
Summary
A multicenter randomized trial found a high probability that awake prone positioning reduces intubation and/or death in nonintubated patients with COVID-19 hypoxemic respiratory failure. A phase 2 study showed the selective MET inhibitor vebreltinib achieved a 48.8% objective response in MET amplification-driven advanced NSCLC. Metabolomic profiling of bronchoalveolar lavage identified methionine oxidation and ornithine as early predictors of structural lung disease in children with cystic fibrosis.
Research Themes
- Noninvasive respiratory strategies in hypoxemic failure
- Precision oncology for MET-amplified lung cancer
- Early biomarkers and neutrophil-driven pathology in cystic fibrosis
Selected Articles
1. Awake Prone Positioning in Patients With COVID-19 Respiratory Failure: A Randomized Clinical Trial.
In 445 nonintubated adults with COVID-19 hypoxemic respiratory failure, offering ≥6 hours/day of awake prone positioning resulted in a 93.8% posterior probability of reducing intubation and/or death (mean OR 0.74). Secondary outcomes showed small, probabilistic improvements in days alive outside ICU and hospital.
Impact: This pragmatic multicenter RCT provides high-level evidence supporting a low-cost, scalable intervention that can reduce escalation to intubation in hypoxemic COVID-19 pneumonia.
Clinical Implications: Offer daily awake prone positioning for at least 6 hours to nonintubated adults with hypoxemic COVID-19 pneumonia, with monitoring for tolerance and adherence; incorporate into respiratory support bundles.
Key Findings
- Primary composite (intubation/death by day 28): posterior probability of benefit with APP 93.8% (mean OR 0.74; 95% CrI 0.48–1.09).
- Secondary outcomes favored APP with probabilistic gains in days alive outside ICU (+1.28 days, 95% CrI −0.78 to 3.34) and outside hospital (+1.55 days, 95% CrI −0.22 to 3.32).
- Intervention target was ≥6 hours/day awake prone positioning; analysis was intention-to-treat with Bayesian modeling.
Methodological Strengths
- Multicenter randomized design with Bayesian analysis and intention-to-treat approach
- Clinically relevant composite endpoint (intubation/death) with prespecified secondary outcomes
Limitations
- Credible interval crossed 1.0; not blinded and standard care allowed spontaneous APP
- Adherence and actual prone duration variability may dilute effect estimates
Future Directions: Define optimal duration, timing, and patient selection for APP; evaluate synergistic protocols with HFNC/NIV and implementation strategies across healthcare systems.
2. Vebreltinib in MET amplification-driven advanced non-small-cell lung cancer (KUNPENG): a single-arm, multi-cohort, multicentre, phase 2 study.
In 86 evaluable Chinese patients with MET amplification-driven advanced NSCLC (gene copy number ≥6), vebreltinib achieved a 48.8% objective response by independent review, with grade ≥3 treatment-related adverse events in 31% (mainly hepatic). Median follow-up was 18.6 months.
Impact: Provides targeted therapy evidence for a genomically defined NSCLC subgroup (MET amplification) with historically poor outcomes on existing inhibitors, informing precision treatment pathways.
Clinical Implications: Consider MET copy number testing (threshold ≥6) in advanced NSCLC; vebreltinib represents a potential option for MET amplification-driven disease, with hepatic monitoring due to enzyme elevations.
Key Findings
- Objective response rate 48.8% (42/86; 95% CI 38.3–59.4) by masked independent review in MET amplification NSCLC.
- Grade ≥3 treatment-related adverse events occurred in 31% (notably liver function abnormalities 9%).
- Median follow-up 18.6 months; population included chemo-pretreated and chemo-naïve patients; eligibility required MET copy number ≥6.
Methodological Strengths
- Multicentre prospective phase 2 with masked independent response review
- Genomically selected cohort using a prespecified MET copy number threshold
Limitations
- Single-arm design without comparator limits causal inference and estimates of survival benefit
- All participants were Chinese; generalizability to broader populations requires validation
Future Directions: Randomized comparisons against standard regimens; exploration of resistance mechanisms and sequencing with other MET inhibitors; broader multiethnic validation.
3. Early life elevations of methionine oxidation and ornithine track and predict cystic fibrosis structural lung disease.
Untargeted BAL metabolomics in 67 young children with CF identified metabolites linked to structural lung disease and neutrophil enzyme activity. Methionine sulfoxide, percent oxidized methionine, N-acetyl methionine, and ornithine predicted bronchiectasis development in an independent longitudinal cohort, outperforming established biomarkers.
Impact: Introduces mechanistically anchored, early-life biomarkers that track neutrophil-driven oxidative/proteolytic injury and predict future structural damage in CF, enabling earlier intervention strategies.
Clinical Implications: BAL-based metabolite profiling (e.g., MetO, %OxMet, NAcMet, ornithine) may help risk-stratify young children with CF for intensified surveillance and anti-inflammatory/anti-protease interventions targeting neutrophil activity.
Key Findings
- Identified BAL metabolites (including methionine sulfoxide and ornithine) associated with structural lung disease and with MPO/NE activities in 1–5-year-old children with CF.
- MetO, %OxMet, NAcMet, and ornithine predicted development of bronchiectasis by age 9 in an independent cohort, outperforming established biomarkers.
- Findings implicate neutrophil-driven oxidizing and proteolytic processes as early drivers of CF structural lung injury.
Methodological Strengths
- Untargeted metabolomics with linear mixed-effects modeling linking metabolites to SLD and neutrophil enzymes
- Independent longitudinal validation cohort predicting future bronchiectasis
Limitations
- BAL sampling is invasive and may limit routine applicability; sample size modest
- Observational design; external replication across centers and platforms needed
Future Directions: Translate markers to less invasive matrices (e.g., sputum/exhaled breath condensate), test targeted interventions modulating neutrophil oxidative/proteolytic pathways, and embed in prospective risk-guided trials.