Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality and limited effective pharmacotherapies. Accumulating evidence has established mitochondrial dysfunction as a central pathogenic hub in ARDS. Injured mitochondria exhibit excessive reactive oxygen species production, impaired mitophagy, aberrant dynamics (predominantly Drp1-mediated fission), reduced biogenesis, and release of mitochondrial DNA as a damage-associated molecular pattern. These alterations trigger inflammatory cascades via the cGAS/STING and NLRP3 pathways, while simultaneously driving a metabolic shift from oxidative phosphorylation to aerobic glycolysis, the Warburg effect. Key glycolytic enzymes, including PKM2, PDK4, GAPDH, and PGK1, reinforce mitochondrial damage through lactate production and HIF-1α stabilization, creating a vicious cycle. Notably, PFKFB3 exhibits cell-type-specific duality, exerting protective effects in alveolar epithelial cells while promoting NETosis in neutrophils. Distinct cell types in the lung, alveolar macrophages, neutrophils, alveolar epithelial cells, and pulmonary endothelial cells exhibit unique mitochondrial and metabolic alterations that collectively perpetuate injury and impair repair. Therapeutically, mitochondria-targeted agents (MitoQ, MOTS-c), modulators of mitochondrial dynamics (baicalein, hydrogen), inhibitors of glycolytic enzymes (PFKFB3, PKM2, PDK4), natural compounds (1-octyl itaconate, shikonin, scutellarin), and mesenchymal stromal cell-mediated mitochondrial transfer have shown promise in preclinical models. This review synthesizes current understanding of the regulatory mechanisms linking mitochondrial dysfunction and metabolic reprogramming in ARDS, discusses cell-type-specific contributions, and highlights emerging therapeutic strategies. Targeting mitochondrial homeostasis and the associated glycolytic shift may offer a transformative approach to ARDS treatment, though challenges related to cell specificity, safety, and clinical translation remain.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare inborn error of immunity caused by gain-of-function variants in PIK3CD and characterized by recurrent infections, lymphoproliferation, and impaired viral control. We report a 17-year-old male with a heterozygous PIK3CD c.3061G > A (p.E1021K) variant who presented with progressive edema, extensive hypermetabolic lymphadenopathy, splenomegaly, and Epstein-Barr virus (EBV) DNAemia. A core needle biopsy of the right inguinal lymph node demonstrated an immunodeficiency-associated EBV-positive B-cell lymphoproliferative disorder with extensive monotypic plasmacytoid differentiation. Because the biopsy contained limited mature B-cell tissue, the pathological findings favored a polymorphic B-LPD although EBV-positive diffuse large B-cell lymphoma with plasmacytic differentiation could not be excluded. The patient received anti-B-cell-directed therapy and supportive treatment. He was subsequently readmitted with septic shock and acute respiratory distress syndrome. Blood metagenomic next-generation sequencing detected Escherichia coli and Klebsiella pneumoniae, together with antimicrobial-resistance genes including blaNDM. Despite intensive antimicrobial and organ-supportive treatment, the patient remained critically ill and was discharged at his family's request for transfer to a local hospital; his subsequent outcome was unavailable. This case highlights the diagnostic difficulty of classifying EBV-positive B-cell proliferations using limited biopsy tissue in APDS and the competing risks of lymphoproliferative disease and severe infection. Adequate tissue sampling and pathological characterization, close microbiological surveillance, and individualized multidisciplinary management are essential in this setting.

Efforts to liberate patients from invasive mechanical ventilation (MV) begin when the underlying cause of acute hypoxemic respiratory failure (AHRF) or adult respiratory distress syndrome (ARDS) that led to use of invasive ventilation has resolved or improved and patients can initiate spontaneous breaths. In preparation for liberation, clinicians transition patients to spontaneous modes of ventilation as soon as possible while ensuring that patients' respiratory effort is not insufficient or excessive during weaning attempts. Concurrently, clinicians aim to minimize the effects of sedative and analgesic agents, screen daily to identify patients who are ready to undergo a spontaneous breathing trial (SBT), and conduct SBTs to help assess patients' readiness for extubation. Extubation failure is rarely the consequence of a single physiological abnormality. Rather, it reflects the interaction of multiple mechanisms that often coexist, including an imbalance between respiratory system load and capacity, ineffective cough, and secretion burden among others. For these reasons, single weaning parameters and SBTs may fail to identify some patients who are at risk for extubation failure. Conversely, indices and scores that combine two or more parameters and newer techniques may provide mechanistic insights into the pathways that lead to extubation failure, help to characterize 'at-risk' phenotypes, and identify patients who may benefit from closer monitoring, targeted therapeutic strategies, and/or early application of noninvasive respiratory support strategies such as high-flow nasal cannula (HFNC) and bilevel noninvasive positive pressure ventilation (NIV).

Sepsis is a life-threatening syndrome characterized by severe immune dysregulation, frequently culminating in acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Current supportive therapies fail to reverse the underlying pathophysiological damage. However, mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic frontier due to their robust immunomodulatory, anti-inflammatory, and tissue-regenerative properties. Despite compelling preclinical evidence, translating these benefits into consistent clinical efficacy remains a major challenge. This review critically examines the biological and anatomical barriers limiting the efficacy of MSCs, particularly the pulmonary first-pass effect, which restricts the systemic delivery of viable cells to distant organs such as the kidneys. To overcome these physical limitations, we highlight the recent paradigm shift toward nanoscale, cell-free therapies, specifically MSC-derived extracellular vesicles (MSC-EVs). EVs effectively bypass pulmonary sequestration and thromboembolic risks, exerting their potent therapeutic effects through the horizontal transfer of bioactive cargo, notably microRNAs, to reprogram cellular fate and restore immune homeostasis. We also discuss the critical need for rigorous clinical trial designs, scalable good manufacturing practice protocols, and the integration of a precision medicine approach. Ultimately, incorporating validated biomarkers for targeted patient stratification will be the decisive step in unlocking the full therapeutic potential of MSCs and their derivatives in critical care.

Pragmatic trials test the effectiveness of an intervention within real-life clinical practice, prioritising applicability and generalisability. By contrast, explanatory trials evaluate the efficacy of an intervention under optimal conditions and in well-defined populations, aiming to minimise bias and confounding and to maximise the treatment effect. The majority of large-scale, multicentre academic ICU studies are overall pragmatic in nature but have repeatedly failed to demonstrate outcome differences against control populations. This relates in part to the marked heterogeneity of ICU populations, often with enrolment based on syndromic categories such as sepsis, acute respiratory distress syndrome, shock and acute kidney injury with significant inter-individual biological variability. Any beneficial treatment effects in specific, often unidentified, subsets are diluted or cancelled out by no effect or even harm in others. A second important factor underlying the lack of intervention effect is suboptimal performance of the trials, particularly poor protocol adherence, which undermines the likelihood of showing benefit, particularly when reliant on intention-to-treat analyses. In this article we discuss these issues and provide some suggestions for improvement.

Circulating histones are critical inflammatory mediators that drive hyperinflammation and organ failure in critical illnesses such as sepsis, acute kidney injury, and acute respiratory distress syndrome. Their plasma levels are significantly correlated with disease severity and mortality in such patients. Although both DNA and sulfonic acid-containing macromolecules bind histones via electrostatic interactions, the primary challenge in integrating these antagonists into a unified anti-histone system lies in their mutual water solubility and similar negative charges. Herein, we fabricate novel chitosan/DNA-poly(sodium-4-styrenesulfonate) porous microspheres (C3D1-PSS) by employing a stepwise strategy involving phase inversion and subsequent in situ crosslinking polymerization. With a high-density, negatively charged histone capture network, the C3D1-PSS microspheres exhibit excellent hemocompatibility and achieve a notable histone adsorption ratio of 86.47% within 2 h and 95.52% within 4 h through synergistic electrostatic interactions mediated by phosphate and sulfonate groups in vitro. Furthermore, the C3D1-PSS microspheres significantly mitigate histone-induced thrombocytopenia, platelet activation, hemolysis, cytokine release, and endothelial cell death. In a histone-induced rabbit sepsis model, the C3D1-PSS microspheres efficiently alleviate histone-induced thrombocytopenia, tissue damage, hyperinflammation, and cell apoptosis. Collectively, this work presents a promising adsorbent for extracorporeal removal of histones and holds potential for managing histone-associated critical illnesses.