Despite marked improvements in survival following preterm birth, the incidence of bronchopulmonary dysplasia (BPD) remains the most prevalent complication of prematurity and carries the risk of long-term morbidity. Characterising the cellular and molecular mechanisms driving disease progression is critical for informing clinical management and improving outcomes. To this end, we conducted a meta-analysis of genome-scale studies to identify molecular pathways implicated in BPD progression in both human cohorts and animal models. Gene lists associated with BPD in humans, and in rodent models, were extracted from systematically identified genome-scale studies. These gene lists were subsequently analysed using the meta-analysis by information content (MAIC) algorithm, which integrates multiple datasets to generate a single aggregated, ranked gene list based on the cumulative strength of evidence for each gene. Comparative analyses were then performed between the human and rodent BPD datasets, as well as between the human BPD dataset and our previously generated Acute Respiratory Distress Syndrome MAIC dataset. Across all analyses, a consistent enrichment of genes involved in leukocyte-mediated antigen presentation and lymphocyte development and activation was observed, suggesting a shift from acute innate immune injury toward a more sustained lymphoid-driven inflammatory process during BPD progression. Comparative analyses revealed limited overlap between BPD and ARDS gene sets, suggesting divergent disease mechanisms, while still highlighting shared immune activation pathways. Human–rodent comparisons showed divergence in tissue remodelling signatures, likely reflecting differences in sample sources, yet converged on key conserved signals such as CD3E and IL1R2, implicating common inflammatory regulatory mechanisms. MAIC effectively identifies conserved molecular signatures in BPD highlighting lymphoid lineage signatures that are not readily apparent in the primary data. These signatures offer insights relevant to immune-modulatory therapeutic strategies, highlighting key processes involved in antigen presentation and modulation of T-cell activation and development during the progression of Bronchopulmonary Dysplasia.

BACKGROUND:Staphylococcus aureus infections are frequently complicated by metastatic foci, recurrence, and death. Antimicrobial resistance and intracellular bacterial persistence limit the effectiveness of conventional antimicrobials. Host-directed therapies could improve outcomes, but the interpretive complexity of pathogen-host interactions impedes identification of critical responses suitable for therapeutic targeting. To address this, we performed a meta-analysis of genome-scale studies aiming to prioritize host responses to S aureus. METHODS:Lists of genes associated with host responses to S aureus were retrieved from systematically identified genome-scale studies, then integrated using the meta-analysis by information content (MAIC) algorithm. This generated a single aggregated gene list, ranked based on the cumulative evidence supporting each gene. RESULTS:MAIC prioritized 3867 host genes. Myeloid cell immune responses were enriched with specific hubs including TLR2, IL-17, IFN-γ, and IL-1β. Noncanonical effector pathways were also enriched: autophagy (specific factors including mTOR and LAMP2), apoptosis (including BAD and BID), ferroptosis and iron metabolism (TFRC ranked 8/3876), and proteasomal antimicrobial responses (including PSME3 and the novel antimicrobial peptide PPP1CB). Prioritized genes were associated with genome-wide association study traits related to platelet count. In a cohort of patients with S aureus bacteremia, platelet count was differentially associated with clinical outcomes. Targets with immediate therapeutic relevance included S aureus/fibrin/platelet microthrombus formation (VWF, GP11b), S aureus-induced platelet loss (ASGR2), autophagy (mTOR), BID-mediated apoptosis, and intracellular bacterial killing (IFN-γ). CONCLUSIONS:This in silico analysis identifies cytokine hubs associated with the response to S aureus infection and prioritizes additional host responses including apoptosis, autophagy, iron metabolism, and thrombosis as therapeutic targets.

AnaesthesiaEarly View Editorial It ain't what you do (it's the way that you do it): modulating the host response in sepsis Jonathan E. Millar, Jonathan E. Millar orcid.org/0000-0002-4853-9377 jemillarni Baillie-Gifford Pandemic Science Hub, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK Intensive Care Unit, Queen Elizabeth University Hospital, Glasgow, UKSearch for more papers by this authorAnnemarie B. Docherty, Corresponding Author Annemarie B. Docherty [email protected] abdocherty79 Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK Correspondence to: Annemarie B. Docherty Email: [email protected]Search for more papers by this author Jonathan E. Millar, Jonathan E. Millar orcid.org/0000-0002-4853-9377 jemillarni Baillie-Gifford Pandemic Science Hub, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK Intensive Care Unit, Queen Elizabeth University Hospital, Glasgow, UKSearch for more papers by this authorAnnemarie B. Docherty, Corresponding Author Annemarie B. Docherty [email protected] abdocherty79 Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK Correspondence to: Annemarie B. Docherty Email: [email protected]Search for more papers by this author First published: 15 May 2024 https://doi.org/10.1111/anae.16314 1 Baillie-Gifford Pandemic Science Hub, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK 2 Intensive Care Unit, Queen Elizabeth University Hospital, Glasgow, UK 3 Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK 4 Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK This editorial accompanies an article by Robey et al., Anaesthesia 2024; https://doi.org/10.1111/anae.16263. 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Acute respiratory distress syndrome (ARDS) is caused by a complex interplay among hyperinflammation, endothelial dysfunction, and alveolar epithelial injury. Targeted treatments toward the underlying pathways have been unsuccessful in unselected patient populations. The first reliable biological subphenotypes reflective of these biological disease states have been identified in the past decade. Subphenotype targeted intervention studies are needed to advance the pharmacologic treatment of ARDS.

Acute respiratory distress syndrome (ARDS) is characterized by a dysregulated immune response to infection or injury. This framework has driven long-standing interest in immunomodulatory therapies as treatments for ARDS. In this narrative review, we first define what constitutes a dysregulated immune response in ARDS. In this context, we describe the rationale and available evidence for immunomodulatory therapies studied in randomized controlled trials of ARDS patients to date. Finally, we address factors that have contributed to the failure to develop therapies in the past and highlight current and future developments designed to address them.

Acute respiratory distress syndrome (ARDS) is a clinically defined syndrome of acute hypoxaemic respiratory failure secondary to non-cardiogenic pulmonary oedema. It arises from a diverse set of triggers and encompasses marked biological heterogeneity, complicating efforts to develop effective therapies. An extensive body of recent work (including transcriptomics, proteomics, and genome-wide association studies) has sought to identify proteins/genes implicated in ARDS pathogenesis. These diverse studies have not been systematically collated and interpreted. To solve this, we performed a systematic review and computational integration of existing omics data implicating host response pathways in ARDS pathogenesis. We identified 40 unbiased studies reporting associations, correlations, and other links with genes and single nucleotide polymorphisms (SNPs), from 6,856 ARDS patients. We used meta-analysis by information content (MAIC) to integrate and evaluate these data, ranking over 7,000 genes and SNPs and weighting cumulative evidence for association. Functional enrichment of strongly-supported genes revealed cholesterol metabolism, endothelial dysfunction, innate immune activation and neutrophil degranulation as key processes. We identify 51 hub genes, most of which are potential therapeutic targets. To explore biological heterogeneity, we conducted a separate analysis of ARDS severity/outcomes, revealing distinct gene associations and tissue specificity. Our large-scale integration of existing omics data in ARDS enhances understanding of the genomic landscape by synthesising decades of data from diverse sources. The findings will help researchers refine hypotheses, select candidate genes for functional validation, and identify potential therapeutic targets and repurposing opportunities. Our study and the publicly available computational framework represent an open, evolving platform for interpretation of ARDS genomic data.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study did not receive any funding.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Source data was openly available at the time of this study and can be found associated with the original publications detailing studies included in the systematic review.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced are available online at https://github.com/JonathanEMillar/ards\_maic\_manuscript/tree/main/data[https://github.com/JonathanEMillar/ards\_maic\_manuscript/tree/main/data][1] [1]: https://github.com/JonathanEMillar/ards_maic_manuscript/tree/main/data

Choosing optimal outcome measures maximizes statistical power, accelerates discovery and improves reliability in early-phase trials. We devised and evaluated a modification to a pragmatic measure of oxygenation function, the S/F ratio. Because of the ceiling effect in oxyhaemoglobin saturation, S/F ratio ceases to reflect pulmonary oxygenation function at high S_pO_2 values. We found that the correlation of S/F with the reference standard ( P_aO_2 / F_IO_2 ratio) improves substantially when excluding S_pO_2 > 0.94 and refer to this measure as S/F_94 . Using observational data from 39,765 hospitalised COVID-19 patients, we demonstrate that S/F_94 is predictive of mortality, and compare the sample sizes required for trials using four different outcome measures. We show that a significant difference in outcome could be detected with the smallest sample size using S/F_94 . We demonstrate that S/F_94 is an effective intermediate outcome measure in COVID-19. It is a non-invasive measurement, representative of disease severity and provides greater statistical power.

BACKGROUND:Extracorporeal life support (ECLS) has extensive applications in managing patients with acute cardiac and pulmonary failure. Two primary modalities of ECLS, cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO), include several similarities in their composition, complications, and patient outcomes. Both CPB and ECMO pose a high risk of thrombus formation and platelet activation due to the large surface area of the devices and bleeding due to system anticoagulation. Therefore, novel methods of anticoagulation are needed to reduce the morbidity and mortality associated with extracorporeal support. Nitric oxide (NO) has potent antiplatelet properties and presents a promising alternative or addition to anticoagulation with heparin during extracorporeal support. METHODS:We developed two ex vivo models of CPB and ECMO to investigate NO effects on anticoagulation and inflammation in these systems. RESULTS:Sole addition of NO as an anticoagulant was not successful in preventing thrombus formation in the ex vivo setups, therefore a combination of low-level heparin with NO was used. Antiplatelet effects were observed in the ex vivo ECMO model when NO was delivered at 80 ppm. Platelet count was preserved after 480 min when NO was delivered at 30 ppm. CONCLUSION:Combined delivery of NO and heparin did not improve haemocompatibility in either ex vivo model of CPB and ECMO. Anti-inflammatory effects of NO in ECMO systems have to be evaluated further.

Millar, Jonathan E. MBBS, PhD, FFICM; McAuley, Daniel F. MD; Marini, John J. MD Author Information

"Mesenchymal Stromal Cells in ARDS: More Questions than Answers." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.

BACKGROUND: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preserva-tion by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD. METHODS: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplan-tation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP. RESULTS: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid sta-tus and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups. CONCLUSIONS: Overall, compared to current clinical SCS, recipient outcomes following transplanta-tion are not adversely impacted by extending HMP to 8 hours. These results have important implica-tions for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation. J Heart Lung Transplant 2023;42:1015-1029 & COPY; 2023 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY-NC-ND license

Purpose:To assess the safety and efficacy of extracorporeal carbon dioxide removal (ECCO2R)versusstandard care in patients with acute hypoxaemic respiratory failure (AHRF).Methods:MEDLINE, Embase and clinical trial registries were searched from 1994 to 31 December 2021. We included randomised controlled trials (RCTs) and observational studies. Pairs of reviewers independently extracted data and assessed the risk of bias. The primary outcome was mortality. Secondary outcomes included ventilator-free days, length of stay, safety and adverse events and physiological changes. As a primary analysis, we performed a meta-analysis of mortality until day 30 using a Bayesian random effects model. We then performed a trial sequential analysis of RCTs.Results:21 studies met inclusion criteria: three RCTs, enrolling 531 patients, and 18 observational studies. In a pooled analysis of RCTs, the posterior probability of increased mortality with the use of ECCO2R was 73% (relative risk 1.19, 95% credible interval 0.70–2.29). There was substantial heterogeneity in the reporting of safety and adverse events. However, the incidence of extra and intracranial haemorrhage was higher (relative risk 3.00, 95% credible interval 0.41–20.51) among those randomised to ECCO2R. Current trials have accumulated 80.8% of the diversity-adjusted required information size and the lack of effect reaches futility for a 10% absolute risk reduction in mortality.Conclusions:The use of ECCO2R in patients with AHRF is not associated with improvements in clinical outcomes. Furthermore, it is likely that further trials of ECCO2R aiming to achieve an absolute risk reduction in mortality of ≥10% are futile.

ABSTRACTBackgroundContinuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered ‘aerosol-generating procedures’ (AGPs) in the treatment of COVID-19. We aimed to measure air and surface environmental contamination of SARS-CoV-2 virus when CPAP and HFNO were used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients.Methods30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen ≥0.4 to maintain oxygen saturations ≥94%, were prospectively enrolled into an observational environmental sampling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface samples were collected from each participant and the clinical environment. RT qPCR analyses were performed for viral and human RNA, and positive/suspected-positive samples were cultured for the presence of biologically viable virus.ResultsOverall 21/30 (70%) of participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface samples tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive samples in both air and surfaces samples (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination. Only one nasopharyngeal sample was culture positive.ConclusionsThe use of CPAP and HFNO to treat moderate/severe COVID-19 was not associated with significantly higher levels of air or surface viral contamination in the immediate care environment.

Introduction and Objectives Hyperinflammatory and hypoinflammatory subphenotypes have been identified in patients with the acute respiratory distress syndrome (ARDS) which consistently have different clinical characteristics, biomarker profiles and outcomes. These subphenotypes may not be specific to ARDS. Patients on veno-venous extracorporeal membrane oxygenation (VV ECMO) represent a distinct population in which subphenotypes have not been previously identified. The aim of this research was to identify if subphenotypes are present in a mixed cohort of patients with severe acute respiratory failure requiring VV ECMO. Methods Adult patients requiring VV ECMO from a single centre in Regensburg, Germany were included. Clinical and ventilation data were recorded immediately prior to initiation of ECMO and on the first day thereafter. The inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor alpha (TNF-a) were measured by ELISA from plasma samples taken immediately prior to initiation of ECMO. Latent class analysis (LCA) was used to identify subphenotypes and included both clinical and biomarker variables. Subphenotype association with hospital mortality was assessed. Results 437 patients initiated on VV ECMO were included. The most common indications for ECMO were viral infection (15%), bacterial infection (41%), and post-operative (16%). Using LCA, a two-class model was a better fit for the cohort than a one-class model (p < 0.001). There were 322 (74%) patients in Class 1 and 115 patients in Class 2 (26%). Class 2 was characterised higher cytokine concentrations, more metabolic acidosis, and more non-pulmonary organ failure, consistent with the ARDS hyperinflammatory subphenotype. Patients with the hyperinflammatory subphenotype (Class 2) had worse hospital mortality (49% vs. 31%, p = 0.001) than those with the hypoinflammatory subphenotype (Class 1). Discriminant variables in the LCA model are detailed in figure 1. Conclusions Two subphenotypes were identified in patients with severe acute respiratory failure requiring ECMO, with characteristics similar to those previously identified in data from non-ECMO ARDS patients, including worse outcomes in the hyperinflammatory subphenotype. These subphenotypes could be targeted with precision medicine treatments in future trials of patients on VV ECMO.

COVID-19 is clinically characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied clustering techniques to a large prospective cohort of hospitalised patients with COVID-19 to identify clinically meaningful sub-phenotypes. We obtained structured clinical data on 59,011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25,477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33,534 cases recruited to ISARIC-4C, and in 4,445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-phenotypes. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were also identified, alongside a sub-phenotype of patients reporting few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom sub-phenotypes were highly consistent in replication analysis within the ISARIC-4C study. Similar patterns were externally verified in patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four sub-phenotypes are usefully distinct from the core symptom group: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms.

A plethora of leukocyte modulations have been reported in critically ill patients. Critical illnesses such as acute respiratory distress syndrome and cardiogenic shock, which potentially require extracorporeal membrane oxygenation (ECMO) support, are associated with changes in leukocyte numbers, phenotype, and functions. The changes observed in these illnesses could be compounded by exposure of blood to the non-endothelialized surfaces and non-physiological conditions of ECMO. This can result in further leukocyte activation, increased platelet-leukocyte interplay, pro-inflammatory and pro-coagulant state, alongside features of immunosuppression. However, the effects of ECMO on leukocytes, in particular their phenotypic and functional signatures, remain largely overlooked, including whether these changes have attributable mortality and morbidity. The aim of our narrative review is to highlight the importance of studying leukocyte signatures to better understand the development of complications associated with ECMO. Increased knowledge and appreciation of their probable role in ECMO-related adverse events may assist in guiding the design and establishment of targeted preventative actions.

The acute respiratory distress syndrome (ARDS) describes a heterogenous population of patients with acute severe respiratory failure. However, contemporary advances have begun to identify distinct sub-phenotypes that exist within its broader envelope. These sub-phenotypes have varied outcomes and respond differently to several previously studied interventions. A more precise understanding of their pathobiology and an ability to prospectively identify them, may allow for the development of precision therapies in ARDS. Historically, animal models have played a key role in translational research, although few studies have so far assessed either the ability of animal models to replicate these sub-phenotypes or investigated the presence of sub-phenotypes within animal models. Here, in three ovine models of ARDS, using combinations of oleic acid and intravenous, or intratracheal lipopolysaccharide, we investigated the presence of sub-phenotypes which qualitatively resemble those found in clinical cohorts. Principal Component Analysis and partitional clustering identified two clusters, differentiated by markers of shock, inflammation, and lung injury. This study provides a first exploration of ARDS phenotypes in preclinical models and suggests a methodology for investigating this phenomenon in future studies.

Purpose Cold static storage (CSS) is the standard method for heart preservation during transplantation (HTx). However, CSS beyond 4 hours increases the risk of primary graft dysfunction (PGD). Hypothermic ex vivo perfusion (HEVP) of donor hearts allows oxygen delivery during preservation, and may facilitate extended donor preservation without increasing PGD risk. We compared post-HTx survival, systemic inflammation and cardiac function following donor heart preservation by CSS (2 hrs) versus HEVP (2 and 8 hrs). Methods Brain death was induced in donor sheep for 24 hrs. Donor hearts were preserved by a) CSS for 2 hrs (n=7), b) HEVP for 2 hrs (n=4), or c) HEVP for 8 hrs (n=4). Orthotopic HTx was performed in matched recipients. Recipients were weaned from cardiopulmonary bypass and monitored for 6 hrs. Recipient blood was collected and assayed for inflammatory cytokines and cardiac markers. Cardiac function was assessed by echocardiography. Results Six-hour survival was 71% following CSS, and 100% following 2 and 8 hrs HEVP, respectively. Recipients systemic interleukin-6 and 8 levels were reduced using HEVP vs CSS. Post-HTx haemodynamic function was no different between groups, but HEVP reduced the requirement for vasoactive support compared to CSS (2 hrs CSS: 1.57±0.7; 2 hrs HEVP: 0.35±0.09; 8 hrs HEVP: 0.35±0.05 mmHg−1). HEVP was associated with reduced post-HTx lactate (2 hrs CSS: 11.4±1.8; 2 hrs HEVP: 5.2±0.7; 8 hrs HEVP: 6.7±1.3 mmol/L), more stable base excess and physiological pH in blood. Post-HTx cardiac function was no different between groups. Cardiac troponin I levels were comparable between CSS vs. 8 hrs HEVP, but reduced with 2 hrs HEVP. Conclusion Preliminary data on donor heart preservation by HEVP shows promising outcomes in comparison to CSS. Heart preservation by HEVP can be extended up to 8 hours, without compromising post-HTx recipient survival. HEVP may assist in overcoming limitations in preservation time associated with HTx, without increasing PGD risk.

Pulmonary microthrombosis and vasculitis occur in fatal coronavirus disease 2019. To determine whether these processes occur in other life-threatening respiratory virus infections, we identified autopsy studies of fatal influenza (n = 455 patients), severe acute respiratory syndrome ([SARS] n = 37), Middle East respiratory syndrome (n = 2), adenovirus (n = 34), and respiratory syncytial virus (n = 30). Histological evidence of thrombosis was frequently present in adults with fatal influenza and SARS, with vasculitis also reported.