Critical care management of chimeric antigen receptor T-cell therapy recipients.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.

Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement From the American Heart Association and Neurocritical Care Society.

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

Biological Phenotyping in Sepsis and Acute Respiratory Distress Syndrome.

Heterogeneity in sepsis and acute respiratory distress syndrome (ARDS) is increasingly being recognized as one of the principal barriers to finding efficacious targeted therapies. The advent of multiple high-throughput biological data ("omics"), coupled with the widespread access to increased computational power, has led to the emergence of phenotyping in critical care. Phenotyping aims to use a multitude of data to identify homogenous subgroups within an otherwise heterogenous population. Increasingly, phenotyping schemas are being applied to sepsis and ARDS to increase understanding of these clinical conditions and identify potential therapies. Here we present a selective review of the biological phenotyping schemas applied to sepsis and ARDS. Further, we outline some of the challenges involved in translating these conceptual findings to bedside clinical decision-making tools.

The Rise of Adaptive Platform Trials in Critical Care.

As durable learning research systems, adaptive platform trials represent a transformative new approach to accelerating clinical evaluation and discovery in critical care. This Perspective provides a brief introduction to the concept of adaptive platform trials, describes several established and emerging platforms in critical care, and surveys some opportunities and challenges for their implementation and impact.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

Use of the Win Ratio Analysis in Critical Care Trials.

Composite outcomes are commonly used in critical care trials to estimate the treatment effect of an intervention. A significant limitation of classical analytic approaches is that they assign equal statistical importance to each component in a composite, even if these do not have the same clinical importance (i.e., in a composite of death and organ failure, death is clearly more important). The win ratio (WR) method has been proposed as an alternative for trial outcomes evaluation, as it effectively assesses events based on their clinical relevance (i.e., hierarchical order) by comparing each patient in the intervention group with their counterparts in the control group. This statistical approach is increasingly used in cardiovascular outcome trials. However, WR may be useful to unveil treatment effects also in the critical care setting, because these trials are typically moderately sized, thus limiting the statistical power to detect small differences between groups, and often rely on composite outcomes that include several components of different clinical importance. Notably, the advantages of this approach may be offset by several drawbacks (such as ignoring ties and difficulties in selecting and ranking endpoints) and challenges in appropriate clinical interpretation (i.e., establishing clinical meaningfulness of the observed effect size). In this perspective article, we present some key elements to implementing WR statistics in critical care trials, providing an overview of strengths, drawbacks, and potential applications of this method. To illustrate, we conduct a reevaluation of the HYPO-ECMO (Hypothermia during Venoarterial Extracorporeal Membrane Oxygenation) trial using the WR framework as a case example.

Clinical Phenotypes and Molecular Characteristics of Respiratory Syncytial Virus in Adults: A Monocentric Prospective Study Between 2019 and 2022.

Respiratory syncytial virus (RSV) infection is a major cause of pneumonia in adults. Little is known on the viral genetic diversity and the associated clinical phenotypes in this population. This single-center prospective cohort study included RSV-infected patients hospitalized between January 2019 and December 2022. Of 100 patients, including 41 with severe infection, 72 were infected with RSV-B. RSV genome sequencing showed no clustering according to severity. Patients infected with RSV-B with risk factors for severe pneumonia had significantly higher fusion protein diversity scores. No amino acid substitutions conferring resistance to nirsevimab were detected.

Technology in the management of diabetes in hospitalised adults.

Suboptimal glycaemic management in hospitals has been associated with adverse clinical outcomes and increased financial costs to healthcare systems. Despite the availability of guidelines for inpatient glycaemic management, implementation remains challenging because of the increasing workload of clinical staff and rising prevalence of diabetes. The development of novel and innovative technologies that support the clinical workflow and address the unmet need for effective and safe inpatient diabetes care delivery is still needed. There is robust evidence that the use of diabetes technology such as continuous glucose monitoring and closed-loop insulin delivery can improve glycaemic management in outpatient settings; however, relatively little is known of its potential benefits and application in inpatient diabetes management. Emerging data from clinical studies show that diabetes technologies such as integrated clinical decision support systems can potentially mediate safer and more efficient inpatient diabetes care, while continuous glucose sensors and closed-loop systems show early promise in improving inpatient glycaemic management. This review aims to provide an overview of current evidence related to diabetes technology use in non-critical care adult inpatient settings. We highlight existing barriers that may hinder or delay implementation, as well as strategies and opportunities to facilitate the clinical readiness of inpatient diabetes technology in the future.

Uromodulin in sepsis and severe pneumonia: a two-sample Mendelian randomization study.

The outcome for patients with sepsis-associated acute kidney injury in the intensive care unit (ICU) remains poor. Low serum uromodulin (sUMOD) protein levels have been proposed as a causal mediator of this effect. We investigated the effect of different levels of sUMOD on the risk of sepsis and severe pneumonia and outcomes in these conditions. A two-sample Mendelian randomization (MR) study was performed. Single-nucleotide polymorphisms (SNPs) associated with increased levels of sUMOD were identified and used as instrumental variables for association with outcomes. Data from different cohorts were combined based on disease severity and meta-analyzed. Five SNPs associated with increased sUMOD levels were identified and tested in six datasets from two biobanks. There was no protective effect of increased levels of sUMOD on the risk of sepsis [two cohorts, odds ratio (OR) 0.99 (95% confidence interval 0.95-1.03), P = 0.698, and OR 0.95 (0.91-1.00), P = 0.060, respectively], risk of sepsis requiring ICU admission [OR 1.04 (0.93-1.16), P = 0.467], ICU mortality in sepsis [OR 1.00 (0.74-1.37), P = 0.987], risk of pneumonia requiring ICU admission [OR 1.05 (0.98-1.14), P = 0.181], or ICU mortality in pneumonia [OR 1.17 (0.98-1.39), P = 0.079]. Meta-analysis of hospital-admitted and ICU-admitted patients separately yielded similar results [OR 0.98 (0.95-1.01), P = 0.23, and OR 1.05 (0.99-1.12), P = 0.86, respectively]. Among patients with sepsis and severe pneumonia, there was no protective effect of different levels of sUMOD. Results were consistent regardless of geographic origins and not modified by disease severity. NEW & NOTEWORTHY The presence of acute kidney injury in severe infections increases the likelihood of poor outcome severalfold. A decrease in serum uromodulin (sUMOD), synthetized in the kidney, has been proposed as a mediator of this effect. Using the Mendelian randomization technique, we tested the hypothesis that increased sUMOD is protective in severe infections. Analyses, however, showed no evidence of a protective effect of higher levels of sUMOD in sepsis or severe pneumonia.

Pathophysiological Responses to Bloodstream Infection in Critically Ill Transplant Recipients Compared With Non-Transplant Recipients.

BACKGROUND: Identification of bloodstream infection (BSI) in transplant recipients may be difficult due to immunosuppression. Accordingly, we aimed to compare responses to BSI in critically ill transplant and non-transplant recipients and to modify systemic inflammatory response syndrome (SIRS) criteria for transplant recipients. METHODS: We analyzed univariate risks and developed multivariable models of BSI with 27 clinical variables from adult intensive care unit (ICU) patients at the University of Virginia (UVA) and at the University of Pittsburgh (Pitt). We used Bayesian inference to adjust SIRS criteria for transplant recipients. RESULTS: We analyzed 38.7 million hourly measurements from 41 725 patients at UVA, including 1897 transplant recipients with 193 episodes of BSI and 53 608 patients at Pitt, including 1614 transplant recipients with 768 episodes of BSI. The univariate responses to BSI were comparable in transplant and non-transplant recipients. The area under the receiver operating characteristic curve (AUC) was 0.82 (95% confidence interval [CI], .80-.83) for the model using all UVA patient data and 0.80 (95% CI, .76-.83) when using only transplant recipient data. The UVA all-patient model had an AUC of 0.77 (95% CI, .76-.79) in non-transplant recipients and 0.75 (95% CI, .71-.79) in transplant recipients at Pitt. The relative importance of the 27 predictors was similar in transplant and non-transplant models. An upper temperature of 37.5°C in SIRS criteria improved reclassification performance in transplant recipients. CONCLUSIONS: Critically ill transplant and non-transplant recipients had similar responses to BSI. An upper temperature of 37.5°C in SIRS criteria improved BSI screening in transplant recipients.

High Burden of COVID-19-Associated Pulmonary Aspergillosis in Severely Immunocompromised Patients Requiring Mechanical Ventilation.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a frequent superinfection in critically ill patients with COVID-19 and is associated with increased mortality rates. The increasing proportion of severely immunocompromised patients with COVID-19 who require mechanical ventilation warrants research into the incidence and impact of CAPA during the vaccination era. METHODS: We performed a retrospective, monocentric, observational study. We collected data from adult patients with severe COVID-19 requiring mechanical ventilation who were admitted to the intensive care unit (ICU) of University Hospitals Leuven, a tertiary referral center, between 1 March 2020 and 14 November 2022. Probable or proven CAPA was diagnosed according to the 2020 European Confederation for Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) criteria. RESULTS: We included 335 patients. Bronchoalveolar lavage sampling was performed in 300 (90%), and CAPA was diagnosed in 112 (33%). The incidence of CAPA was 62% (50 of 81 patients) in European Organisation for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC) host factor-positive patients, compared with 24% (62 of 254) in host factor-negative patients. The incidence of CAPA was significantly higher in the vaccination era, increasing from 24% (57 of 241) in patients admitted to the ICU before October 2021 to 59% (55 of 94) in those admitted since then. Both EORTC/MSGERC host factors and ICU admission in the vaccination era were independently associated with CAPA development. CAPA remained an independent risk factor associated with mortality risk during the vaccination era. CONCLUSIONS: The presence of EORTC/MSGERC host factors for invasive mold disease is associated with increased CAPA incidence and worse outcome parameters, and it is the main driver for the significantly higher incidence of CAPA in the vaccination era. Our findings warrant investigation of antifungal prophylaxis in critically ill patients with COVID-19.

Risk factors and outcome associated with fungal infections in patients with severe burn injury: 10-year retrospective IFI-BURN study.

BACKGROUND: In burn patients, skin barrier disruption and immune dysfunctions increase susceptibility to invasive fungal diseases (IFDs) like invasive candidiasis (IC) and invasive mold infections (IMI). We provide an in-depth analysis of IFD-related factors and outcomes in a 10-year cohort of severe burn patients. METHOD: Retrospective cohort study including adult patients admitted to the Burn Intensive Care Unit (BICU) between April 2014 and May 2023 with Total Burn Surface Area (TBSA) ≥15%. Patients were classified as proven IFD according to EORTC/MSGERC criteria applicable for IC. Putative IMIs were defined with: ≥2 positive cultures from a skin biopsy/bronchoalveolar lavage OR ≥2 positive blood specific-qPCRs OR a combination of both. RESULTS: Among 1381 patients admitted, 276 consecutive patients with TBSA ≥15% were included. Eighty-seven (31.5%; IC n=30; IMI n=43; both n=14) patients fulfilled the criteria for probable/putative IFD. At Day 30 after the burn injury, the estimated cumulative incidence pr/pu IFD was 26.4% (95%CI 21.4-31.8%). Factors independently associated with IFDs were TBSA, severity scores and indoor burn injury (i.e., from confined space fire). Overall mortality was 15.3% and 36.8% in the no IFD, pr/pu IFD groups respectively (p<0.0001). IFD was independently associated with a risk of death (HR: 1.94 for pr/pu IFD; 95%CI, 1.12-3.36; p=0.019). DISCUSSION: This study describes 21st-century characteristics of IFDs in sever burn patients confirming known risk factors with thresholds and identifying the indoor injury as an independent factor associated to IFDs. This suggests a link to contamination caused by fire damage, which is highly susceptible to aerosolizing spores.

Pre-existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

Nosocomial Infections in Adults Receiving Extracorporeal Membrane Oxygenation: A Review for Infectious Diseases Clinicians.

Over the past ten years, there has been a rapid expansion in the use of extracorporeal membrane oxygenation (ECMO) in the care of patients with refractory cardiac or respiratory failure. Infectious diseases clinicians must reconcile conflicting evidence from limited studies as they develop practices at their own institutions, which has resulted in considerably different practices globally. This review describes infection control and prevention as well as antimicrobial prophylaxis strategies in this population. Data on diagnostics and treatment for patients receiving ECMO with a focus on diagnostic and antimicrobial stewardship is then examined. This review summarizes gaps in the current ECMO literature and proposes future needs, including developing clear definitions for infections and encouraging transparent reporting of practices at individual facilities in future clinical trials.

One-year transplant-free survival following hospital discharge after ICU admission for ACLF in the Netherlands.

BACKGROUND & AIMS: Patients with acute decompensation of cirrhosis or acute-on-chronic liver failure (ACLF) often require intensive care unit (ICU) admission for organ support. Existing research, mostly from specialized liver transplant centers, largely addresses short-term outcomes. Our aim was to evaluate in-hospital mortality and 1-year transplant-free survival after hospital discharge in the Netherlands. METHODS: We conducted a nationwide observational cohort study, including patients with a history of cirrhosis or first complications of cirrhotic portal hypertension admitted to ICUs in the Netherlands between 2012 and 2020. The influence of ACLF grade at ICU admission on 1-year transplant-free survival after hospital discharge among hospital survivors was evaluated using unadjusted Kaplan-Meier survival curves and an adjusted Cox proportional hazard model. RESULTS: Out of the 3,035 patients, 1,819 (59.9%) had ACLF-3. 1,420 patients (46.8%) survived hospitalization after ICU admission. The overall probability of 1-year transplant-free survival after hospital discharge was 0.61 (95% CI 0.59-0.64). This rate varied with ACLF grade at ICU admission, being highest in patients without ACLF (0.71; 95% CI 0.66-0.76) and lowest in those with ACLF-3 (0.53 [95% CI 0.49-0.58]) (log-rank p <0.0001). However, after adjusting for age, malignancy status and MELD score, ACLF grade at ICU admission was not associated with an increased risk of liver transplantation or death within 1 year after hospital discharge. CONCLUSION: In this nationwide cohort study, ACLF grade at ICU admission did not independently affect 1-year transplant-free survival after hospital discharge. Instead, age, presence of malignancy and the severity of liver disease played a more prominent role in influencing transplant-free survival after hospital discharge. IMPACT AND IMPLICATIONS: Patients with acute-on-chronic liver failure often require intensive care unit (ICU) admission for organ support. In these patients, short-term mortality is high, but long-term outcomes of survivors remain unknown. Using a large nationwide cohort of ICU patients, we discovered that the severity of acute-on-chronic liver failure at ICU admission does not influence 1-year transplant-free survival after hospital discharge. Instead, age, malignancy status and overall severity of liver disease are more critical factors in determining their long-term survival.

COVID-19 Critical Illness: A Data-Driven Review.

The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges in critical care medicine, including extreme demand for intensive care unit (ICU) resources and rapidly evolving understanding of a novel disease. Up to one-third of hospitalized patients with COVID-19 experience critical illness. The most common form of organ failure in COVID-19 critical illness is acute hypoxemic respiratory failure, which clinically presents as acute respiratory distress syndrome (ARDS) in three-quarters of ICU patients. Noninvasive respiratory support modalities are being used with increasing frequency given their potential to reduce the need for intubation. Determining optimal patient selection for and timing of intubation remains a challenge. Management of mechanically ventilated patients with COVID-19 largely mirrors that of non-COVID-19 ARDS. Organ failure is common and portends a poor prognosis. Mortality rates have improved over the course of the pandemic, likely owing to increasing disease familiarity, data-driven pharmacologics, and improved adherence to evidence-based critical care.

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care.

Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear.

Intensive care unit interventions to promote sleep and circadian biology in reducing incident delirium: a scoping review.

RATIONALE/OBJECTIVES: Despite plausible pathophysiological mechanisms, research is needed to confirm the relationship between sleep, circadian rhythm and delirium in patients admitted to the intensive care unit (ICU). The objective of this review is to summarise existing studies promoting, in whole or in part, the normalisation of sleep and circadian biology and their impact on the incidence, prevalence, duration and/or severity of delirium in ICU. METHODS: A sensitive search of electronic databases and conference proceedings was completed in March 2023. Inclusion criteria were English-language studies of any design that evaluated in-ICU non-pharmacological, pharmacological or mixed intervention strategies for promoting sleep or circadian biology and their association with delirium, as assessed at least daily. Data were extracted and independently verified. RESULTS: Of 7886 citations, we included 50 articles. Commonly evaluated interventions include care bundles (n=20), regulation or administration of light therapy (n=5), eye masks and/or earplugs (n=5), one nursing care-focused intervention and pharmacological intervention (eg, melatonin and ramelteon; n=19). The association between these interventions and incident delirium or severity of delirium was mixed. As multiple interventions were incorporated in included studies of care bundles and given that there was variable reporting of compliance with individual elements, identifying which components might have an impact on delirium is challenging. CONCLUSIONS: This scoping review summarises the existing literature as it relates to ICU sleep and circadian disruption (SCD) and delirium in ICU. Further studies are needed to better understand the role of ICU SCD promotion interventions in delirium mitigation.

Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study.

BACKGROUND: The COVID-19 pandemic resulted in a large number of critical care admissions. While national reports have described the outcomes of patients with COVID-19, there is limited international data of the pandemic impact on non-COVID-19 patients requiring intensive care treatment. METHODS: We conducted an international, retrospective cohort study using 2019 and 2020 data from 11 national clinical quality registries covering 15 countries. Non-COVID-19 admissions in 2020 were compared with all admissions in 2019, prepandemic. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included in-hospital mortality and standardised mortality ratio (SMR). Analyses were stratified by the country income level(s) of each registry. FINDINGS: Among 1 642 632 non-COVID-19 admissions, there was an increase in ICU mortality between 2019 (9.3%) and 2020 (10.4%), OR=1.15 (95% CI 1.14 to 1.17, p<0.001). Increased mortality was observed in middle-income countries (OR 1.25 95% CI 1.23 to 1.26), while mortality decreased in high-income countries (OR=0.96 95% CI 0.94 to 0.98). Hospital mortality and SMR trends for each registry were consistent with the observed ICU mortality findings. The burden of COVID-19 was highly variable, with COVID-19 ICU patient-days per bed ranging from 0.4 to 81.6 between registries. This alone did not explain the observed non-COVID-19 mortality changes. INTERPRETATION: Increased ICU mortality occurred among non-COVID-19 patients during the pandemic, driven by increased mortality in middle-income countries, while mortality decreased in high-income countries. The causes for this inequity are likely multi-factorial, but healthcare spending, policy pandemic responses, and ICU strain may play significant roles.

Identification of molecular subphenotypes in two cohorts of paediatric ARDS.

BACKGROUND: Two subphenotypes of acute respiratory distress syndrome (ARDS), hypoinflammatory and hyperinflammatory, have been reported in adults and in a single paediatric cohort. The relevance of these subphenotypes in paediatrics requires further investigation. We aimed to identify subphenotypes in two large observational cohorts of paediatric ARDS and assess their congruence with prior descriptions. METHODS: We performed latent class analysis (LCA) separately on two cohorts using biomarkers as inputs. Subphenotypes were compared on clinical characteristics and outcomes. Finally, we assessed overlap with adult cohorts using parsimonious classifiers. FINDINGS: In two cohorts from the Children's Hospital of Philadelphia (n=333) and from a multicentre study based at the University of California San Francisco (n=293), LCA identified two subphenotypes defined by differential elevation of biomarkers reflecting inflammation and endotheliopathy. In both cohorts, hyperinflammatory subjects had greater illness severity, more sepsis and higher mortality (41% and 28% in hyperinflammatory vs 11% and 7% in hypoinflammatory). Both cohorts demonstrated overlap with adult subphenotypes when assessed using parsimonious classifiers. INTERPRETATION: We identified hypoinflammatory and hyperinflammatory subphenotypes of paediatric ARDS from two separate cohorts with utility for prognostic and potentially predictive, enrichment. Future paediatric ARDS trials should identify and leverage biomarker-defined subphenotypes in their analysis.