Weekly Ards Research Analysis
This week’s ARDS literature highlights three high-impact directions: a mechanistic preclinical discovery (GGPPS–AXL) that identifies a druggable isoprenoid pathway to restore macrophage efferocytosis and accelerate lung‑injury resolution; a multicentre RCT showing multimodal prehabilitation (including high‑intensity respiratory muscle training) halves postoperative pulmonary complications after lung resection and shortens length of stay; and an ML–driven multicenter target‑trial emulation demons
Summary
This week’s ARDS literature highlights three high-impact directions: a mechanistic preclinical discovery (GGPPS–AXL) that identifies a druggable isoprenoid pathway to restore macrophage efferocytosis and accelerate lung‑injury resolution; a multicentre RCT showing multimodal prehabilitation (including high‑intensity respiratory muscle training) halves postoperative pulmonary complications after lung resection and shortens length of stay; and an ML–driven multicenter target‑trial emulation demonstrating that corticosteroid benefit in sepsis/pneumonia/ARDS is heterogeneous and depends on predicted organ‑dysfunction trajectories, arguing for trajectory‑guided immunomodulation. Together these studies push translational targets, perioperative prevention, and precision immunotherapy toward clinical testing.
Selected Articles
1. Geranylgeranyl diphosphate synthase deficiency impairs efferocytosis and resolution of acute lung injury.
Myeloid‑specific GGPPS knockout mice show impaired AXL‑dependent efferocytosis in recruited macrophages, prolonged lung inflammation, and delayed resolution of acute lung injury; geranylgeraniol rescues efferocytosis and accelerates resolution, identifying the isoprenoid/GGPPS–AXL axis as a druggable target to promote ARDS recovery.
Impact: Uncovers a specific, druggable metabolic–receptor pathway (GGPPS→AXL) that controls macrophage efferocytosis and resolution of lung inflammation — a clear translational target to accelerate recovery in ARDS.
Clinical Implications: Supports development of isoprenoid pathway modulators or AXL‑directed strategies to enhance efferocytosis and hasten ARDS resolution; necessitates validation in human ARDS macrophages and translational models prior to trials.
Key Findings
- Myeloid‑specific GGPPS knockout prolongs lung inflammation, increases apoptotic neutrophil accumulation, and reduces resident macrophages.
- GGPPS deficiency disrupts AXL signaling in recruited macrophages and suppresses efferocytosis; geranylgeraniol (GGOH) rescues efferocytosis and accelerates injury resolution.
2. Multimodal prehabilitation before lung resection surgery: a multicentre randomised controlled trial.
In a prospective multicentre RCT (N=122, high‑risk lung resection patients), multimodal prehabilitation including high‑intensity respiratory muscle training reduced postoperative pulmonary complications from 55% to 34% and shortened hospital stay from a median 9 to 7 days, demonstrating a scalable perioperative intervention to reduce pulmonary morbidity.
Impact: A high‑quality RCT that delivers immediately actionable perioperative practice change — preventing PPCs and reducing LOS — with potential system‑level benefits.
Clinical Implications: Support incorporation of structured, multimodal prehabilitation programs (including targeted respiratory muscle training) into preoperative pathways for high‑risk thoracic surgical patients to lower PPCs and resource use.
Key Findings
- Postoperative pulmonary complications reduced from 55% to 34% with prehabilitation (OR 2.29; P=0.029).
- Hospital length of stay shortened from median 9 days to 7 days (P=0.038); intervention included high‑intensity respiratory muscle training.
3. Multicenter target trial emulation to evaluate corticosteroids for sepsis stratified by predicted organ dysfunction trajectory.
Employing a two‑stage machine‑learning approach to define and predict organ‑dysfunction trajectories, then emulating a target trial, this multicentre analysis found that associations between corticosteroid use and 28‑day mortality vary by predicted trajectory across sepsis, pneumonia, and ARDS cohorts — supporting trajectory‑guided precision immunomodulation rather than one‑size‑fits‑all steroid strategies.
Impact: Introduces a practical, data‑driven framework (trajectory stratification + target‑trial emulation) to resolve heterogeneity in steroid effects across critical infectious syndromes and to inform future stratified RCTs.
Clinical Implications: Encourage cautious, individualized steroid use guided by predicted organ‑dysfunction trajectories; prospective trajectory‑stratified RCTs and integration of real‑time prediction tools into decision support are warranted before broad adoption.
Key Findings
- Two‑stage ML subphenotyping and trajectory prediction performed across sepsis/pneumonia/ARDS cohorts.
- Target‑trial emulation showed steroid–mortality associations varied by predicted trajectory, arguing for pathobiology‑matched therapy.