Background: Patients with severe COVID-19 have clearly emerged as a population with a high risk of invasive fungal infections (IFI). However, the prevalence of IFI has not yet been assessed in large populations of mechanically ventilated COVID-19 patients. We aimed to determine the prevalence, risk factors, and mortality associated with IFI in mechanically ventilated COVID-19 patients in the ICU.Methods: We performed a national multicenter observational cohort study among 18 French ICUs and enrolled 576 mechanically ventilated COVID-19 patients. Patients were systematically screened for fungi once/twice a week during the period of mechanical ventilation up to ICU discharge. The trial is registered at ClinicalTrials.gov, NCT04368221. Findings: In total, 509 patients with > 3 screening samples were analyzed (mean age of 59·4 years, 78·6% male). The prevalence, as declared by the local investigators, was 11·2% (57/509) for putative invasive pulmonary aspergillosis (IPA), and 14·9% (76/509) and 4·7% (24/509) for probable and possible COVID-19-associated pulmonary aspergillosis (CAPA), respectively, using the recently published CAPA definitions. Patients with CAPA were significantly older and more frequently received the combination of dexamethasone and anti-IL6 treatment. Thirty-eight (7·5%) patients experienced one or more other IFIs: 32 candidemia (6·3%), six mucormycosis (1·2%), and one fusariosis. Multivariate analysis of factors associated with death for the 509 patients showed three significant factors: age >62 (HR: 1·70 [95% CI 1·25-2·30]), solid organ transplantation (2·44 [1·52-3·92]), and probable CAPA (1·48 [1·05-2·08]). Severity scores were significantly higher for CAPA and mortality was significantly higher in cases of probable and possible CAPA than no CAPA: 61·8%, 45·8%, and 31·3%, respectively ( p<0·0001 ).Interpretation: This study shows the high prevalence of invasive aspergillosis and candidemia associated with a high mortality rate in mechanically ventilated COVID-19 patients. These findings highlight the need for active surveillance for fungal pathogens in severe COVID-19 patients.Clinical Trial Registration Details: The trial is registered at ClinicalTrials.gov, NCT04368221.Funding Information: Pfizer Inc., NY, USA.Declaration of Interests: submitted work. ED reports grants and non-financial support from MSD, grants and non- financial support from Gilead, non-financial support from Pfizer, non-financial support from Astellas, outside the submitted work. AF reports personal fees and non-financial support from MSD, grants from Janssen, personal fees and non-financial support from Gilead, non-financial support from Pfizer, outside the submitted work. C-EL reports personal fees from Carmat, personal fees from Merck, personal fees from Biomérieux, personal fees from Thermofischer Brahms, personal fees from Bayer Healthcare, personal fees from Faron, outside the submitted work. FB reports grants from Astellas, personal fees from MSD, non-financial support from Pfizer, non-financial support from MSD, non-financial support from Astellas, outside the submitted work. J-FT reports personal fees from Pfizer, personal fees from Merck, personal fees from Astellas, personal fees from Gilead, outside the submitted work. FP reports non-financial support from Gilead, non-financial support from Pfizer, outside the submitted work. EC reports personal fees from Gilead, personal fees from Baxter, personal fees from Sanofi-Genzyme from null, outside the submitted work. AA reports personal fees from Pfizer, personal fees from Gilead, outside the submitted work. MC reports grants from Pfizer, outside the submitted work. JM reports non-financial support from Gilead, outside the submitted work. SE reports grants, personal fees and non-financial support from Aerogen Ltd, grants, personal fees and non-financial support from Fisher & Paykel, outside the submitted work. GV reports grants and personal fees from BioMérieux, grants from SOS Oxygène, grants from Janssen, outside the submitted work. JM reports other from Pfizer, other from Gilead, outside the submitted work. J-RZ reports grants, personal fees and other from MSD, personal fees from Novartis, personal fees from Pfizer, outside the submitted work. M-EB reports grants from Pfizer during the conduct of the study; grants and non-financial support from GILEAD and from Pfizer, non-financial support from MSD outside the submitted work. Other authors report no disclosures.Ethics Approval Statement: The MYCOVID study was conducted in full concordance with the principles of the Declaration of Helsinki and the laws, and regulations of France. This study was approved by the French authorities (Comité Consultatif sur le Traitement de l'information en matière de Recherche dans le domaine de la Santé, and Commission Nationale de L'Informatique et des Libertés). According to French policy, a non-opposition statement was obtained for all included patients signifying that all received written detailed information about the objectives of the study and were free to request withdrawal of their data at any time. The study protocol was reviewed and approved by the ethics committee of Rennes University Hospital, Rennes, France (Approval no. 20.56).
Abstract Objectives: To describe clinical characteristics, mechanical ventilation strategies, and outcomes in patients with severe acute respiratory distress syndrome (ARDS) during weaning from venovenous extracorporeal membrane oxygenation (VV ECMO). Design: Retrospective, multicenter cohort study over 7 years. Settings: Two tertiary ICUs, high-volume ECMO centers in France and Italy. Patients: Patients with ARDS on ECMO and successfully weaned from VV ECMO. Measurements and main results: Patients were classified based on their mechanical ventilation modality during the sweep gas-off trial (SGOT) with either controlled mechanical ventilation or spontaneous breathing (i.e. pressure support ventilation). The primary endpoint was the time to successful weaning from mechanical ventilation within 90 days post-ECMO weaning. Among 393 adult patients with severe ARDS successfully weaned from ECMO, 292 were on controlled ventilation, and 101 were on spontaneous breathing during SGOT. The 90-day probability of successful weaning from mechanical ventilation was not significantly different between the two groups (sHR [95%CI], 1.23[0.84-1.82]). However, spontaneous breathing during SGOT was associated with a shorter duration of mechanical ventilation and ICU length of stay after ECMO discontinuation, without an increase of ECMO-related complications, such as severe bleeding or pneumothorax, compared to controlled ventilation. After adjusting for covariates, older age, higher pre-ECMO sequential organ failure assessment score, pneumothorax, ventilator-associated pneumonia, and renal replacement therapy were independently associated with a lower probability of successful weaning from mechanical ventilation after ECMO weaning. Contrarily, mechanical ventilation modalities during SGOT did not demonstrate an independent association with the likelihood of successful weaning. Conclusions: A weaning ECMO strategy incorporating spontaneous breathing during SGOT appears safe and is associated with favorable outcomes. Further research is needed to assess the optimal ventilation strategy during weaning off VV ECMO and its impact on short- and long-term outcomes.
Service de Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France, and Sorbonne Universités, UPMC Université Paris 06, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Paris, France; Service de Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France Dr. Luyt received funding from Bayer Healthcare and Merck Sharp & Dohme. Dr. Dangers disclosed that she does not have any potential conflicts of interest.
Rationale: Whether patients with coronavirus disease (COVID-19) may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. Objectives: To estimate the effect of ECMO on 90-day mortality versus IMV only. Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO versus no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 < 80 or PaCO2 ⩾ 60 mm Hg). We controlled for confounding using a multivariable Cox model on the basis of predefined variables. Measurements and Main Results: A total of 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability on Day 7 from the onset of eligibility criteria (87% vs. 83%; risk difference, 4%; 95% confidence interval, 0–9%), which decreased during follow-up (survival on Day 90: 63% vs. 65%; risk difference, −2%; 95% confidence interval, −10 to 5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand and when initiated within the first 4 days of IMV and in patients who are profoundly hypoxemic. Conclusions: In an emulated trial on the basis of a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and regions with ECMO capacities specifically organized to handle high demand.
Patients with obesity are at increased risk for developing acute respiratory distress syndrome (ARDS). Some centers consider obesity a relative contraindication to receiving extracorporeal membrane oxygenation (ECMO) support, despite growing implementation of ECMO for ARDS in the general population.
Abstract Background Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19. Methods All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgium and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score. Results Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay and 491 (23%) during the first 24 h following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO 2 /FiO 2 ratio > 150 mmHg when prone positioning was initiated. Among non-early PP group patients, 1013 (47.4%) patients had finally been placed in PP within a median delay of 3 days after ICU admission. Day-60 mortality in non-early PP group was 34.2% versus 39.3% in the early PP group ( p = 0.038). Day-28 and Day-90 mortality as well as the need for adjunctive therapies was more important in patients with early PP. After propensity score adjustment, no significant difference in survival at Day-60 was found between the two study groups (HR 1.34 [0.96–1.68], p = 0.09 and HR 1.19 [0.998–1.412], p = 0.053 in complete case analysis or in multiple imputation analysis, respectively). Conclusions In a large multicentric international cohort of intubated ICU patients with ARDS due to COVID-19, PP has been used frequently as a main treatment. In this study, our data failed to show a survival benefit associated with early PP started within 24 h after ICU admission compared to PP after day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity.
In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated.Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615.By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60.There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments.F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.
Summary Background Retrospective observational studies suggest that interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, lymphocytes, monocytes, neutrophils, D-dimer, and platelets are associated with disease progression, treatment outcomes, or both, in patients with COVID-19 pneumonia. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti–IL-6 receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 pneumonia. Methods Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomisation) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Findings Modelling in the placebo arm showed all candidate biomarkers except LDH and D-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modelling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction p=0.03), mechanical ventilation (predictive interaction p=0.01), and clinical status (predictive interaction p=0.02) compared with placebo. Interpretation Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28. RESEARCH IN CONTEXT Evidence before this study The efficacy and safety of the anti–interleukin-6 receptor antibody tocilizumab in the treatment of patients hospitalised with COVID-19 pneumonia was investigated in COVACTA, a double-blind, randomised, placebo-controlled trial. The primary endpoint of improved clinical status on a seven-category ordinal scale (1, discharged/ready for discharge; 7, death) at day 28 was not met in this trial. Among the secondary endpoints, no difference in mortality at day 28 was observed, but time to hospital discharge was shorter in the tocilizumab group. Subgroup analysis suggested there might be a treatment benefit in patients grouped according to their ordinal scale category at baseline. We searched PubMed on September 14, 2020, using the terms “tocilizumab AND (COVID-19 OR coronavirus) AND biomarker” with no language or date restrictions. The search retrieved 18 articles, four of which identified laboratory measures as potential biomarkers in patients who received tocilizumab for the treatment of COVID-19 pneumonia. The biomarkers reported in these studies include interleukin-6, C-reactive protein, ferritin, fibrinogen, liver transaminases, lymphocytes, platelets, and D-dimer. However, these previous studies were single-centre, retrospective, observational studies. Larger, prospective, controlled trials are needed to investigate potential prognostic and predictive biomarkers to assess the outcomes and response to treatments for COVID-19. Added value of this study This exploratory analysis of data from COVACTA demonstrated interleukin-6, C-reactive protein, ferritin, neutrophils (percentage and absolute count), neutrophil-to-lymphocyte ratio, lymphocytes (percentage and absolute count), monocytes (percentage), and platelets as strong prognostic biomarkers in patients hospitalised with severe COVID-19 pneumonia. More important, ferritin showed predictive value for tocilizumab treatment effects on day 28 clinical outcomes of mortality, mechanical ventilation (among the subgroup of patients not receiving mechanical ventilation at randomisation), and clinical status compared with placebo. Implications of all the available evidence In patients with elevated levels of ferritin at baseline, tocilizumab decreased the probability of death, mechanical ventilation, and worsening clinical status at day 28 compared with placebo, suggesting that ferritin might be useful as a predictive biomarker of efficacy outcomes for tocilizumab in patients with severe COVID-19 pneumonia.
