Background: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) require respiratory support with invasive mechanical ventilation and show varying responses to recruitment manoeuvres. In patients with ARDS not related to COVID-19, two pulmonary subphenotypes that differed in recruitability were identified using latent class analysis (LCA) of imaging and clinical respiratory parameters. We aimed to evaluate if similar subphenotypes are present in patients with COVID-19-related ARDS. Methods: This is the retrospective analysis of mechanically ventilated patients with COVID-19-related ARDS who underwent CT scans at positive end-expiratory pressure of 10 cmH₂O and after a recruitment manoeuvre at 20 cmH₂O. LCA was applied to quantitative CT-derived parameters, clinical respiratory parameters, blood gas analysis and routine laboratory values before recruitment to identify subphenotypes. Results: 99 patients were included. Using 12 variables, a two-class LCA model was identified as best fitting. Subphenotype 2 (recruitable) was characterized by a lower PaO₂/FiO₂, lower normally aerated lung volume and lower compliance as opposed to a higher non-aerated lung mass and higher mechanical power when compared to subphenotype 1 (non-recruitable). Patients with subphenotype 2 had more decrease in non-aerated lung mass in response to a standardized recruitment manoeuvre (p = 0.024) and were mechanically ventilated longer until successful extubation (adjusted SHR 0.46, 95% CI 0.23–0.91, p = 0.026), while no difference in survival was found (p = 0.814). Conclusions: A recruitable and non-recruitable subphenotype were identified in patients with COVID-19-related ARDS. These findings are in line with previous studies in non-COVID-19-related ARDS and suggest that a combination of imaging and clinical respiratory parameters could facilitate the identification of recruitable lungs before the manoeuvre.

Neutrophil extracellular traps (NETs) are a vital part of the innate immune response, while excessive NET formation can cause tissue damage. H3.1 nucleosomes, a component of NETs, have emerged as a potential biomarker. This study aimed to evaluate H3.1 nucleosomes in critical illness, assessing their relationship with sepsis, organ failure, inflammatory subphenotypes and outcomes. The MARS cohort was used, comprising of consecutive Intensive Care Unit patients, with plasma samples collected on days 0, 2 and 4. H3.1 nucleosome concentrations were measured using the Nu.Q® NETs Immunoassay. H3.1 nucleosome concentrations were compared across sepsis presence and organ failure, both at baseline and longitudinally. The relationship between H3.1 nucleosome concentrations and clinical outcomes was investigated. 1713 critically ill patients were included, with a total of 3671 plasma samples. Baseline H3.1 nucleosome concentrations differed between sepsis confirmed by clinical adjudication (740 ng/mL), sepsis unconfirmed by clinical adjudication (416 ng/mL) and non-sepsis (463 ng/mL, P < 0.001). H3.1 concentrations were associated with SOFA score (r = 0.40) and were higher in patients with disseminated intravascular coagulation, acute kidney injury and hyperinflammatory sepsis. H3.1 concentration was highly predictive for the need of renal replacement therapy (hazard ratio 2.00 per log10 increase), correcting for mortality. Sepsis and organ failure were closely associated with plasma H3.1 nucleosome concentrations. While individual diagnostic performance for sepsis and organ failure remained low, H3.1 levels predicted the need for renal replacement therapy and disseminated intravascular coagulation, revealing unique insights into the innate immune response. Trial registration: ClinicalTrials.gov identifier NCT01905033; IRB number 10-056C, registered June 16, 2010.

Introduction: The Radiographic Assessment of Lung Edema (RALE) score provides a semi-quantitative measure of pulmonary edema. In patients with acute respiratory distress syndrome (ARDS), the RALE score is associated with mortality. In mechanically ventilated patients in the intensive care unit (ICU) with respiratory failure not due to ARDS, a variable degree of lung edema is observed as well. We aimed to evaluate the prognostic value of RALE in mechanically ventilated ICU patients. Methods: Secondary analysis of patients enrolled in the ‘Diagnosis of Acute Respiratory Distress Syndrome’ (DARTS) project with an available chest X-ray (CXR) at baseline. Where present, additional CXRs at day 1 were analysed. The primary endpoint was 30-day mortality. Outcomes were also stratified for ARDS subgroups (no ARDS, non-COVID-ARDS and COVID-ARDS). Results: 422 patients were included, of which 84 had an additional CXR the following day. Baseline RALE scores were not associated with 30-day mortality in the entire cohort (OR: 1.01, 95% CI: 0.98–1.03, p = 0.66), nor in subgroups of ARDS patients. Early changes in RALE score (baseline to day 1) were only associated with mortality in a subgroup of ARDS patients (OR: 1.21, 95% CI: 1.02–1.51, p = 0.04), after correcting for other known prognostic factors. Conclusions: The prognostic value of the RALE score cannot be extended to mechanically ventilated ICU patients in general. Only in ARDS patients, early changes in RALE score were associated with mortality.

Patients with acute respiratory distress syndrome (ARDS) have severe respiratory impairment requiring mechanical ventilation resulting in high mortality. Despite extensive research, no effective pharmacological interventions have been identified in unselected ARDS, which has been attributed to the considerable heterogeneity. The identification of more homogeneous subgroups through phenotyping has provided a novel method to improve our pathophysiological understanding, trial design, and, most importantly, patient care through targeted interventions. The objective of this article is to outline a structured, stepwise approach toward identifying and classifying heterogeneity within ARDS and subsequently derive, validate, and integrate targeted treatment options. We present a 6-step roadmap toward the identification of effective phenotype-targeted treatments: development of distinct and reproducible subphenotypes, derivation of a possible parsimonious bedside classification method, identification of possible interventions, prospective validation of subphenotype classification, testing of subphenotype-targeted intervention prospectively in randomized clinical trial (RCT), and finally implementation of subphenotype classification and intervention in guidelines and clinical practice. Based on this framework, the current literature was reviewed. Respiratory physiology, lung morphology, and systemic inflammatory biology subphenotypes were identified. Currently, lung morphology and systemic inflammatory biology subphenotypes are being tested prospectively in RCTs.

Objective To investigate the relationship between sonographic and radiological scores of lung edema with metrics of shunt, dead space, and respiratory mechanics in critically ill patients under invasive ventilation for greater than 24 hours. Methods This is a secondary analysis of a prospective observational study involving invasively ventilated critically ill patients. The radiographic assessment […] ABSTRACT Objective To investigate the relationship between sonographic and radiological scores of lung edema with metrics of shunt, dead space, and respiratory mechanics in critically ill patients under invasive ventilation for greater than 24 hours. Methods This is a secondary analysis of a prospective observational study involving invasively ventilated critically ill patients. The radiographic assessment […]

OBJECTIVES: This study evaluated whether the established efficacy of tocilizumab, an interleukin-6 (IL-6) receptor antagonist, differs between the hypoinflammatory and hyperinflammatory subphenotypes. DESIGN: Retrospective analysis of data from three biobanks. SETTING: ICUs of three university teaching hospitals in the Netherlands. PATIENTS: Mechanically ventilated patients with COVID-19. INTERVENTIONS: Tocilizumab administration vs. no administration. MEASUREMENTS AND MAIN RESULTS: A total of 561 patients were included. Based on a classifier model incorporating IL-6, tumor necrosis factor receptor 1, and bicarbonate, 95% were classified as Hypoinflammatory and 5% as Hyperinflammatory. Tocilizumab was associated with a significant reduction in 30-day mortality in the overall cohort, even after adjustment for confounders ( p = 0.014). However, there was no evidence that treatment effectiveness differed between the two subphenotypes ( p = 0.59). CONCLUSIONS: In this cohort, tocilizumab significantly reduced 30-day mortality overall. Although the number of Hyperinflammatory patients was low, there was no evidence that its efficacy differed between inflammatory subphenotypes. These findings underscore the importance of including both subphenotypes in future trials evaluating the differential effects of tocilizumab.