Convalescent Plasma for Covid-19-Induced ARDS in Mechanically Ventilated Patients.

BACKGROUND: Passive immunization with plasma collected from convalescent patients has been regularly used to treat coronavirus disease 2019 (Covid-19). Minimal data are available regarding the use of convalescent plasma in patients with Covid-19-induced acute respiratory distress syndrome (ARDS). METHODS: In this open-label trial, we randomly assigned adult patients with Covid-19-induced ARDS who had been receiving invasive mechanical ventilation for less than 5 days in a 1:1 ratio to receive either convalescent plasma with a neutralizing antibody titer of at least 1:320 or standard care alone. Randomization was stratified according to the time from tracheal intubation to inclusion. The primary outcome was death by day 28. RESULTS: A total of 475 patients underwent randomization from September 2020 through March 2022. Overall, 237 patients were assigned to receive convalescent plasma and 238 to receive standard care. Owing to a shortage of convalescent plasma, a neutralizing antibody titer of 1:160 was administered to 17.7% of the patients in the convalescent-plasma group. Glucocorticoids were administered to 466 patients (98.1%). At day 28, mortality was 35.4% in the convalescent-plasma group and 45.0% in the standard-care group (P = 0.03). In a prespecified analysis, this effect was observed mainly in patients who underwent randomization 48 hours or less after the initiation of invasive mechanical ventilation. Serious adverse events did not differ substantially between the two groups. CONCLUSIONS: The administration of plasma collected from convalescent donors with a neutralizing antibody titer of at least 1:160 to patients with Covid-19-induced ARDS within 5 days after the initiation of invasive mechanical ventilation significantly reduced mortality at day 28. This effect was mainly observed in patients who underwent randomization 48 hours or less after ventilation initiation. (Funded by the Belgian Health Care Knowledge Center; ClinicalTrials.gov number, NCT04558476.).

Immunological sub-phenotypes and response to convalescent plasma in COVID-19 induced ARDS: a secondary analysis of the CONFIDENT trial.

BACKGROUND: Convalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP. METHODS: We measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality. RESULTS: Of the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1ß, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97). CONCLUSION: In patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes. TRIAL REGISTRATION: Ethics Committee of the University Hospital of Liège CE 2020/239. CLINICALTRIALS: gov NCT04558476. Registered 2020-09-11, https://www. CLINICALTRIALS: gov/study/NCT04558476 .

A 16-year-old man with leptospirosis and atypical disseminated intravascular coagulation: a case report.

BACKGROUND: Leptospirosis is known for its pulmonary form characterized by intra-alveolar hemorrhage, exhibiting a high mortality rate. Management by venous-venous extracorporeal membrane oxygenation has been reported in a small number of cases. CASE PRESENTATION: We report herein the case of a 16-year-old Caucasian male who was admitted with rapidly deteriorating respiratory and digestive complaints. He developed severe acute respiratory distress syndrome secondary to disseminated intravascular coagulation and intra-alveolar hemorrhage, requiring initiation of venous-venous extracorporeal membrane oxygenation. Initial infectious and immunological assessments were inconclusive, but repeat serology on the tenth day of admission confirmed a diagnosis of leptospirosis. The patient received multiple transfusions, and upon favorable response to treatment with corticosteroids and antibiotics, he was successfully weaned off venous-venous extracorporeal membrane oxygenation, which was discontinued after 12 days. CONCLUSION: Leptospirosis is a rare cause of severe acute respiratory failure following pulmonary hemorrhage. It is typically diagnosed by serology, with detectable IgM antibodies 5-7 days after the onset of symptoms. We report that early support with respiratory extracorporeal membrane oxygenation favors timely clearance of endobronchial clotting, parenchymal recovery, and prevention of ventilator-induced lung injury. Major hypofibrinogenemia, which did not seem to worsen during extracorporeal membrane oxygenation application, was managed by repeated transfusions. Further studies investigating the pathogenesis of this coagulopathy are required to further optimize the management of this rare and severe complication.

Early Prediction of High-Flow Oxygen Therapy Failure in COVID-19 Acute Hypoxemic Respiratory Failure: A Retrospective Study of Scores and Thresholds.

Background High-flow oxygen therapy (HFOT) has been widely used as an effective alternative to invasive mechanical ventilation (IMV) in some critically ill patients with COVID-19 pneumonia. This study aimed to compare different tools, including the respiratory rate and oxygenation (ROX) index, to predict HFOT failure in this setting. Methodology This single-center retrospective observational study was conducted from September to December 2020 and assessed COVID-19 patients who required HFOT as the first treatment at admission; HFOT failure was defined as IMV use. Prognostic scoring tools were as follows: the Sequential Organ Failure Assessment (SOFA), Acute Physiology And Chronic Health Evaluation (APACHE) II, and Simplified Acute Physiology Score (SAPS) III scores; C-reactive protein; lung consolidation percentage on chest CT; mean partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio; and ROX index and modified ROX index, calculated using PaO2 instead of blood oxygen saturation, within the first 24 hours after admission to the intensive care unit (ICU). These scores were analyzed using a multivariate Cox proportional hazard model; optimal cutoffs were computed using the R system for statistical computing. Results The study enrolled 52 patients, 31 (60%) of whom experienced HFOT failure. The best predictors of HFOT failure measured 24 hours after HFOT initiation were as follows: PaO2/FiO2 (threshold 123.6, sensitivity 87%, specificity 81%, hazard ratio [HR] 7.76, and 95% confidence interval [CI] 2.39-17.1); ROX index (threshold 5.63, sensitivity 68%, specificity 95%, HR 6.18, and 95% CI 2.54-13.4); and modified ROX index (threshold 4.94, sensitivity 81%, specificity 90%, HR 8.16, and 95% CI 3.16-21.5) (P < 0.001 for all). Conclusions Early assessment of the ROX index, modified ROX index, and PaO2/FiO2 ratio can adequately predict, with high accuracy, HFOT failure in COVID-19 patients. Because thresholds remain debated and are still not sufficiently validated, we advocate using them with caution for clinical decision-making in this context.

Reduced anticoagulation targets in extracorporeal life support (RATE): study protocol for a randomized controlled trial.

BACKGROUND: Although life-saving in selected patients, ECMO treatment still has high mortality which for a large part is due to treatment-related complications. A feared complication is ischemic stroke for which heparin is routinely administered for which the dosage is usually guided by activated partial thromboplastin time (aPTT). However, there is no relation between aPTT and the rare occurrence of ischemic stroke (1.2%), but there is a relation with the much more frequent occurrence of bleeding complications (55%) and blood transfusion. Both are strongly related to outcome. METHODS: We will conduct a three-arm non-inferiority randomized controlled trial, in adult patients treated with ECMO. Participants will be randomized between heparin administration with a target of 2-2.5 times baseline aPTT, 1.5-2 times baseline aPTT, or low molecular weight heparin guided by weight and renal function. Apart from anticoagulation targets, treatment will be according to standard care. The primary outcome parameter is a combined endpoint consisting of major bleeding including hemorrhagic stroke, severe thromboembolic complications including ischemic stroke, and mortality at 6 months. DISCUSSION: We hypothesize that with lower anticoagulation targets or anticoagulation with LMWH during ECMO therapy, patients will have fewer hemorrhagic complications without an increase in thromboembolic complication or a negative effect on their outcome. If our hypothesis is confirmed, this study could lead to a change in anticoagulation protocols and a better outcome for patients treated with ECMO. TRIAL REGISTRATION: ClinicalTrials.gov NCT04536272 . Registered on 2 September 2020. Netherlands Trial Register NL7969.

Pulmonary lobectomy in two multitrauma patients under extracorporeal circulation placed preoperatively in an intensive care unit: A case report.

The clinical course of our two patients highlights the feasibility of using venovenous extracorporeal membrane oxygenation (ECMO) with heparin for multitraumatic patients needing thoracic surgery. Further research is required to determine if surgery can be performed with totally heparin-free vv-ECMO. All ICU teams should become familiar with this technique.