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1. Joint modeling of monocyte HLA‐DR expression trajectories predicts 28‐day mortality in severe SARS‐CoV‐2 patients

Author

Gaelle Baudemont, Coralie Tardivon, Guillaume Monneret, Martin Cour, Thomas Rimmelé, Lorna Garnier, Hodane Yonis, Jean‐Christophe Richard, Remy Coudereau, Morgane Gossez, Florent Wallet, Marie‐Charlotte Delignette, Frederic Dailler, Marielle Buisson, Anne‐Claire Lukaszewicz, Laurent Argaud, Cédric Laouenan, Julie Bertrand, Fabienne Venet, and for the RICO study group

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Abstract The recent SarsCov2 pandemic has disrupted healthcare system notably impacting intensive care units (ICU). In severe cases, the immune system is dysregulated, associating signs of hyperinflammation and immunosuppression. In the present work, we investigated, using a joint modeling approach, whether the trajectories of cellular immunological parameters were associated with survival of COVID‐19 ICU patients. This study is based on the REA‐IMMUNO‐COVID cohort including 538 COVID‐19 patients admitted to ICU between March 2020 and May 2022. Measurements of monocyte HLA‐DR expression (mHLA‐DR), counts of neutrophils, of total lymphocytes, and of CD4+ and CD8+ subsets were performed five times during the first month after ICU admission. Univariate joint models combining survival at day 28 (D28), hospital discharge and longitudinal analysis of those biomarkers’ kinetics with mixed‐effects models were performed prior to the building of a multivariate joint model. We showed that a higher mHLA‐DR value was associated with a lower risk of death. Predicted mHLA‐DR nadir cutoff value that maximized the Youden index was 5414 Ab/C and led to an AUC = 0.70 confidence interval (95%CI) = [0.65; 0.75] regarding association with D28 mortality while dynamic predictions using mHLA‐DR kinetics until D7, D12 and D20 showed AUCs of 0.82 [0.77; 0.87], 0.81 [0.75; 0.87] and 0.84 [0.75; 0.93]. Therefore, the final joint model provided adequate discrimination performances at D28 after collection of biomarker samples until D7, which improved as more samples were collected. After severe COVID‐19, decreased mHLA‐DR expression is associated with a greater risk of death at D28 independently of usual clinical confounders.

Published
2024
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2. Cefiderocol in Difficult-to-Treat Nf-GNB in ICU Settings

Author

Charles-Hervé Vacheron, Anne Kaas, Jean-Philippe Rasigade, Frederic Aubrun, Laurent Argaud, Baptiste Balanca, Jean-Luc Fellahi, Jean Christophe Richard, Anne-Claire Lukaszewicz, Florent Wallet, Olivier Dauwalder, and Arnaud Friggeri

Subjects
Cefiderocol, ICU, Relapse, Clinical cure, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background The efficacy and safety of cefiderocol in ICU patients with difficult-to-treat resistance (DTR) non-fermenting Gram-negative bacteria (Nf-GNB) are not as well-established. Consequently, we conducted a cohort study to compare Cefiderocol with the Best Available Therapy (BAT) in ICU patients. Methods We included adult patients from 9 different ICUs, including a burn ICU unit, from 2019 to 2023 treated with Cefiderocol for DTR Nf-GNB isolated from the blood or lungs. We matched each patient at a 1:2 ratio based on the same DTR Nf-GBN isolated pathogen, and when possible, within the same type of ICU (burn unit or not). The primary endpoint of the study was the clinical cure at 15 days, with secondary endpoints including clinical cure at 30 days, relapse, and in-ICU mortality. For each outcome, adjusted odds ratios were estimated using bidirectional stepwise regression in a final model, which included 13 preselected confounders. Results We included 27 patients with cefiderocol, matched with 54 patients receiving the BAT. Four patients were not exactly matched on the type of ICU unit. Characteristics were comparable between groups, mostly male with a Charlson Comorbidity Index of 3 [1–5], and 28% had immunosuppression. Cefiderocol patients were most likely to have higher number of antibiotic lines. The main DTR Nf-GNB identified was Pseudomonas aeruginosa (81.5%), followed by Acinetobater baumanii (14.8%) and Stenotrophomonas maltophilia (3.7%). Pneumonia was the identified infection in 21 (78.8%) patients in the Cefiderocol group and in 51 (94.4%) patients in the BAT group (p = 0.054). Clinical cure at 15 and 30-day and the in-ICU mortality was comparable between groups, however relapse was higher in the cefiderocol group (8-29.6% vs. 4-7.4%;aOR 10.06[1.96;51.53]) Conclusion Cefiderocol did not show an improvement in clinical cure or mortality rates compared to BAT in the treatment of DTR Nf-GNB, but it was associated with a higher relapse rate.

Published
2024
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3. Monitoring monocyte HLA-DR expression and CD4 + T lymphocyte count in dexamethasone-treated severe COVID-19 patients

Author

Guillaume Monneret, Nicolas Voirin, Jean-Christophe Richard, Martin Cour, Thomas Rimmelé, Lorna Garnier, Hodane Yonis, Remy Coudereau, Morgane Gossez, Christophe Malcus, Florent Wallet, Marie-Charlotte Delignette, Frederic Dailler, Marielle Buisson, Laurent Argaud, Anne-Claire Lukaszewicz, Fabienne Venet, and for the RICO study group

Subjects
Immunomonitoring, Monocyte, HLA-DR, CD4, COVID-19, Dexamethasone, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background A 10-day dexamethasone regimen has emerged as the internationally adopted standard-of-care for severe COVID-19 patients. However, the immune response triggered by SARS-CoV-2 infection remains a complex and dynamic phenomenon, leading to various immune profiles and trajectories. The immune status of severe COVID-19 patients following complete dexamethasone treatment has yet to be thoroughly documented. Results To analyze monocyte HLA-DR expression (mHLA-DR) and CD4 + T lymphocyte count (CD4) in critically ill COVID-19 patients after a dexamethasone course and evaluate their association with 28-day ICU mortality, adult COVID-19 patients (n = 176) with an ICU length of stay of at least 10 days and under dexamethasone treatment were included. Associations between each biomarker value (or in combination) measured at day 10 after ICU admission and 28-day mortality in ICU were evaluated. At day 10, the majority of patients presented decreased values of both parameters. A significant association between low mHLA-DR and 28-day mortality was observed. This association remained significant in a multivariate analysis including age, comorbidities or pre-existing immunosuppression (adjusted Hazard ratio (aHR) = 2.86 [1.30–6.32], p = 0.009). Similar results were obtained with decreased CD4 + T cell count (aHR = 2.10 [1.09–4.04], p = 0.027). When combining these biomarkers, patients with both decreased mHLA-DR and low CD4 presented with an independent and significant elevated risk of 28-day mortality (i.e., 60%, aHR = 4.83 (1.72–13.57), p = 0.001). Conclusions By using standardized immunomonitoring tools available in clinical practice, it is possible to identify a subgroup of patients at high risk of mortality at the end of a 10-day dexamethasone treatment. This emphasizes the significance of integrating immune monitoring into the surveillance of intensive care patients in order to guide further immumodulation approaches.

Published
2024
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4. Clinical description and outcome of overall varicella-zoster virus-related organ dysfunctions admitted in intensive care units: the VAZOREA cohort study

Author

Jolan Malherbe, Pierre Godard, Jean-Claude Lacherade, Valentin Coirier, Laurent Argaud, Hervé Hyvernat, Francis Schneider, Julien Charpentier, Florent Wallet, Juliette Pocquet, Gaëtan Plantefeve, Jean-Pierre Quenot, Pierre Bay, Agathe Delbove, Hugues Georges, Tomas Urbina, David Schnell, Charlène Le Moal, Matthieu Stanowski, Corentin Muris, Maud Jonas, Bertrand Sauneuf, Olivier Lesieur, Amaury Lhermitte, Laure Calvet, Ines Gueguen, and Damien du Cheyron

Subjects
Varicella-Zoster virus, Intensive care units, Encephalitis, Pneumonia, Immunocompromised host, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Due to aging population and increasing part of immunocompromised patients, a raise in life-threatening organ damage related to VZV can be expected. Two retrospective studies were already conducted on VZV in ICU but focused on specific organ injury. Patients with high-risk of VZV disease still must be identified. The objective of this study was to report the clinical features and outcome of all life-threatening VZV manifestations requiring intensive care unit (ICU) admission. This retrospective cohort study was conducted in 26 French ICUs and included all adult patients with any life-threatening VZV-related event requiring ICU admission or occurring in ICU between 2010 and 2019. Results One-hundred nineteen patients were included with a median SOFA score of 6. One hundred eight patients (90.8%) were admitted in ICU for VZV disease, leaving 11 (9.2%) with VZV disease occurring in ICU. Sixty-one patients (51.3%) were immunocompromised. Encephalitis was the most prominent organ involvement (55.5%), followed by pneumonia (44.5%) and hepatitis (9.2%). Fifty-four patients (45.4%) received norepinephrine, 72 (60.5% of the total cohort) needed invasive mechanical ventilation, and 31 (26.3%) received renal-replacement therapy. In-hospital mortality was 36.1% and was significantly associated with three independent risk factors by multivariable logistic regression: immunosuppression, VZV disease occurring in ICU and alcohol abuse. Hierarchical clustering on principal components revealed five phenotypically distinct clusters of patients: VZV-related pneumonia, mild encephalitis, severe encephalitis in solid organ transplant recipients, encephalitis in other immunocompromised hosts and VZV disease occurring in ICU. In-hospital mortality was highly different across phenotypes, ranging from zero to 75% (p

Published
2024
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5. Comparison of mortality and outcomes of four respiratory viruses in the intensive care unit: a multicenter retrospective study

Author

Baptiste Grangier, Charles-Hervé Vacheron, Donatien De Marignan, Jean-Sebastien Casalegno, Sandrine Couray-Targe, Audrey Bestion, Florence Ader, Jean-Christophe Richard, Emilie Frobert, Laurent Argaud, Thomas Rimmele, Anne-Claire Lukaszewicz, Frédéric Aubrun, Frédéric Dailler, Jean-Luc Fellahi, Julien Bohe, Vincent Piriou, Bernard Allaouchiche, Arnaud Friggeri, Florent Wallet, and The Lyon Sud COVID-19 ICU

Subjects
CARV, SARS COV 2, Influenza, RSV, ARDS, Medicine, Science
Abstract

Abstract This retrospective study aimed to compare the mortality and burden of respiratory syncytial virus (RSV group), SARS-CoV-2 (COVID-19 group), non-H1N1 (Seasonal influenza group) and H1N1 influenza (H1N1 group) in adult patients admitted to intensive care unit (ICU) with respiratory failure. A total of 807 patients were included. Mortality was compared between the four following groups: RSV, COVID-19, seasonal influenza, and H1N1 groups. Patients in the RSV group had significantly more comorbidities than the other patients. At admission, patients in the COVID-19 group were significantly less severe than the others according to the simplified acute physiology score-2 (SAPS-II) and sepsis-related organ failure assessment (SOFA) scores. Using competing risk regression, COVID-19 (sHR = 1.61; 95% CI 1.10; 2.36) and H1N1 (sHR = 1.87; 95% CI 1.20; 2.93) were associated with a statistically significant higher mortality while seasonal influenza was not (sHR = 0.93; 95% CI 0.65; 1.31), when compared to RSV. Despite occurring in more severe patients, RSV and seasonal influenza group appear to be associated with a more favorable outcome than COVID-19 and H1N1 groups.

Published
2024
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6. Multicenter Retrospective Study of Invasive Fusariosis in Intensive Care Units, France

Author

Jordane Demonchy, Lucie Biard, Raphaël Clere-Jehl, Florent Wallet, Djamel Mokart, Anne-Sophie Moreau, Laurent Argaud, Camille Verlhac, Frédéric Pène, Alexandre Lautrette, Naïke Bige, Audrey de Jong, Emmanuel Canet, Jean-Pierre Quenot, Nahéma Issa, Yoann Zerbib, Inès Bouard, Muriel Picard, and Lara Zafrani

Subjects
Fusarium, fungi, antimicrobial resistance, invasive fusariosis, intensive care unit, hematologic malignancy, Medicine, Infectious and parasitic diseases, RC109-216
Abstract

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002­–­­2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

Published
2024
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7. Association between SARS‐CoV‐2 viral kinetics and clinical score evolution in hospitalized patients

Author

Nadège Néant, Guillaume Lingas, Alexandre Gaymard, Drifa Belhadi, Maya Hites, Thérèse Staub, Richard Greil, Jose‐Artur Paiva, Julien Poissy, Nathan Peiffer‐Smadja, Dominique Costagliola, Yazdan Yazdanpanah, Maude Bouscambert‐Duchamp, Amandine Gagneux‐Brunon, Florence Ader, France Mentré, Florent Wallet, Charles Burdet, Jérémie Guedj, and the DisCoVeRy study group

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Abstract The role of antiviral treatment in coronavirus disease 2019 hospitalized patients is controversial. To address this question, we analyzed simultaneously nasopharyngeal viral load and the National Early Warning Score 2 (NEWS‐2) using an effect compartment model to relate viral dynamics and the evolution of clinical severity. The model is applied to 664 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020‐000936‐23) randomly assigned to either standard of care (SoC) or SoC + remdesivir. Then we use the model to simulate the impact of antiviral treatments on the time to clinical improvement, defined by a NEWS‐2 score lower than 3 (in patients with NEWS‐2

Published
2023
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8. Severe infections requiring intensive care unit admission in patients receiving ibrutinib for hematological malignancies: a groupe de recherche respiratoire en réanimation onco-hématologique (GRRR-OH) study

Author

Louise Baucher, Virginie Lemiale, Adrien Joseph, Florent Wallet, Marc Pineton de Chambrun, Alexis Ferré, Romain Lombardi, Laura Platon, Adrien Contejean, Charline Fuseau, Laure Calvet, Frédéric Pène, Achille Kouatchet, Djamel Mokart, Elie Azoulay, and Antoine Lafarge

Subjects
Ibrutinib, Opportunistic infections, Intensive care, Lymphoproliferative disease, Targeted drugs, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background In the last decade, Ibrutinib has become the standard of care in the treatment of several lymphoproliferative diseases such as chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphoma. Beyond Bruton tyrosine kinase inhibition, Ibrutinib shows broad immunomodulatory effects that may promote the occurrence of infectious complications, including opportunistic infections. The infectious burden has been shown to vary by disease status, neutropenia, and prior therapy but data focusing on severe infections requiring intensive care unit (ICU) admission remain scarce. We sought to investigate features and outcomes of severe infections in a multicenter cohort of 69 patients receiving ibrutinib admitted to 10 French intensive care units (ICU) from 1 January 2015 to 31 December 2020. Results Median time from ibrutinib initiation was 6.6 [3–18] months. Invasive fungal infections (IFI) accounted for 19% (n = 13/69) of severe infections, including 9 (69%; n = 9/13) invasive aspergillosis, 3 (23%; n = 3/13) Pneumocystis pneumonia, and 1 (8%; n = 1/13) cryptococcosis. Most common organ injury was acute respiratory failure (ARF) (71%; n = 49/69) and 41% (n = 28/69) of patients required mechanical ventilation. Twenty (29%; n = 20/69) patients died in the ICU while day-90 mortality reached 55% (n = 35/64). In comparison with survivors, decedents displayed more severe organ dysfunctions (SOFA 7 [5–11] vs. 4 [3–7], p = 0.004) and were more likely to undergo mechanical ventilation (68% vs. 31%, p = 0.010). Sixty-three ibrutinib-treated patients were matched based on age and underlying malignancy with 63 controls receiving conventional chemotherapy from an historic cohort. Despite a higher median number of prior chemotherapy lines (2 [1–2] vs. 0 [0–2]; p

Published
2023
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9. Prognosis of critically ill immunocompromised patients with virus-detected acute respiratory failure

Author

Guillaume Dumas, Maxime Bertrand, Virginie Lemiale, Emmanuel Canet, François Barbier, Achille Kouatchet, Alexandre Demoule, Kada Klouche, Anne-Sophie Moreau, Laurent Argaud, Florent Wallet, Jean-Herlé Raphalen, Djamel Mokart, Fabrice Bruneel, Frédéric Pène, and Elie Azoulay

Subjects
Immunocompromised, Respiratory virus, Influenza, Pneumonia, Mechanical ventilation, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Acute respiratory failure (ARF) is the leading cause of ICU admission. Viruses are increasingly recognized as a cause of pneumonia in immunocompromised patients, but epidemiologic data are scarce. We used the Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologie’s database (2003–2017, 72 intensive care units) to describe the spectrum of critically ill immunocompromised patients with virus-detected ARF and to report their outcomes. Then, patients with virus-detected ARF were matched based on clinical characteristics and severity (1:3 ratio) with patients with ARF from other origins. Results Of the 4038 immunocompromised patients in the whole cohort, 370 (9.2%) had a diagnosis of virus-detected ARF and were included in the study. Influenza was the most common virus (59%), followed by respiratory syncytial virus (14%), with significant seasonal variation. An associated bacterial infection was identified in 79 patients (21%) and an invasive pulmonary aspergillosis in 23 patients (6%). The crude in-hospital mortality rate was 37.8%. Factors associated with mortality were: neutropenia (OR = 1.74, 95% confidence interval, CI [1.05–2.89]), poor performance status (OR = 1.84, CI [1.12–3.03]), and the need for invasive mechanical ventilation on the day of admission (OR = 1.97, CI [1.14–3.40]). The type of virus was not associated with mortality. After matching, patients with virus-detected ARF had lower mortality (OR = 0.77, CI [0.60–0.98]) than patients with ARF from other causes. This result was mostly driven by influenza-like viruses, namely, respiratory syncytial virus, parainfluenza virus, and human metapneumovirus (OR = 0.54, CI [0.33–0.88]). Conclusions In immunocompromised patients with virus-detected ARF, mortality is high, whatever the species, mainly influenced by clinical severity and poor general status. However, compared to non-viral ARF, in-hospital mortality was lower, especially for patients with detected viruses other than influenza.

Published
2023
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10. Clinical spectrum and prognostic impact of cancer in critically ill patients with HIV: a multicentre cohort study

Author

Piotr Szychowiak, Thierry Boulain, Jean-François Timsit, Alexandre Elabbadi, Laurent Argaud, Stephan Ehrmann, Nahema Issa, Emmanuel Canet, Frédéric Martino, Fabrice Bruneel, Jean-Pierre Quenot, Florent Wallet, Élie Azoulay, and François Barbier

Subjects
Human immunodeficiency virus, Cancer, Intensive care unit, Treatment limitation decision, Outcome, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Both AIDS-defining and non-AIDS-defining cancers (ADC/NADC) predispose people living with HIV (PLHIV) to critical illnesses. The objective of this multicentre study was to investigate the prognostic impact of ADC and NADC in PLHIV admitted to the intensive care unit (ICU). Methods All PLHIV admitted over the 2015–2020 period in 12 university-affiliated ICUs in France were included in the study cohort. The effect of ADC and NADC on in-hospital mortality (primary study endpoint) was measured through logistic regression with augmented backward elimination of potential independent variables. The association between ADC/NADC and treatment limitation decision (TLD) during the ICU stay (secondary study endpoint) was analysed. One-year mortality in patients discharged alive from the index hospital admission (exploratory study endpoint) was compared between those with ADC, NADC or no cancer. Results Amongst the 939 included PLHIV (median age, 52 [43–59] years; combination antiretroviral therapy, 74.4%), 97 (10.3%) and 106 (11.3%) presented with an active NADC (mostly lung and intestinal neoplasms) and an active ADC (predominantly AIDS-defining non-Hodgkin lymphoma), respectively. Inaugural admissions were common. Bacterial sepsis and non-infectious neoplasm-related complications accounted for most of admissions in these subgroups. Hospital mortality was 12.4% in patients without cancer, 30.2% in ADC patients and 45.4% in NADC patients (P

Published
2023
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11. Correction: Cefiderocol in Difficult-to-Treat Nf-GNB in ICU Settings

Author

Charles-Hervé Vacheron, Anne Kaas, Jean-Philippe Rasigade, Frederic Aubrun, Laurent Argaud, Baptiste Balanca, Jean-Luc Fellahi, Jean Christophe Richard, Anne-Claire Lukaszewicz, Florent Wallet, Olivier Dauwalder, and Arnaud Friggeri

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Published
2024
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12. Correction: Clinical spectrum and prognostic impact of cancer in critically ill patients with HIV: a multicentre cohort study

Author

Piotr Szychowiak, Thierry Boulain, Jean-François Timsit, Alexandre Elabbadi, Laurent Argaud, Stephan Ehrmann, Nahema Issa, Emmanuel Canet, Frédéric Martino, Fabrice Bruneel, Jean-Pierre Quenot, Florent Wallet, Élie Azoulay, and François Barbier

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Published
2024
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13. Necrotizing soft tissue infections in critically ill neutropenic patients: a French multicentre retrospective cohort study

Author

Romain Arrestier, Anis Chaba, Asma Mabrouki, Clément Saccheri, Emmanuel Canet, Marc Pineton de Chambrun, Annabelle Stoclin, Muriel Picard, Florent Wallet, François Perier, Matthieu Turpin, Laurent Argaud, Maxens Decavèle, Nahéma Issa, Cyril Cadoz, Kada Klouche, Johana Cohen, Djamel Mokart, Julien Grouille, Tomas Urbina, Camille Hua, Olivier Chosidow, Armand Mekontso-Dessap, Elie Azoulay, and Nicolas de Prost

Subjects
Necrotizing soft tissue infection, Neutropenic, Sepsis, Immunocompromised, Intensive care, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Necrotizing soft tissue infections (NSTIs) are rare life-threatening bacterial infections. Few data are available regarding neutropenic patients with NSTIs. Our objectives were to describe the characteristics and management of neutropenic patients with NSTIs in intensive care units (ICUs). We conducted a retrospective multicentre cohort study in 18 ICUs between 2011 and 2021. Patients admitted with NSTIs and concomitant neutropenia at diagnosis were included and compared to non-neutropenic patients with NSTIs. The relationship between therapeutic interventions and outcomes was assessed using Cox regression and propensity score matching. Results 76 neutropenic patients were included and compared to 165 non-neutropenic patients. Neutropenic patients were younger (54 ± 14 vs 60 ± 13 years, p = 0.002) and had less lower limb (44.7% vs 70.9%, p

Published
2023
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14. ICU admission for solid cancer patients treated with immune checkpoint inhibitors

Author

Anne-Claire Toffart, Anne-Pascale Meert, Florent Wallet, Aude Gibelin, Olivier Guisset, Frédéric Gonzalez, Amélie Seguin, Achille Kouatchet, Myriam Delaunay, Didier Debieuvre, Boris Duchemann, Gaëlle Rousseau-Bussac, Martine Nyunga, David Grimaldi, Albrice Levrat, Elie Azoulay, and Virginie Lemiale

Subjects
Solid tumor, Immune checkpoint inhibitor, Intensive care, Immune-related adverse event, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Immune checkpoint inhibitors (ICI) have revolutionized the management of cancer. They can induce immune-related adverse events (irAE) leading to intensive care unit (ICU) admission. We aimed to describe irAEs for ICU admissions in solid cancer patients treated with ICIs. Methods This prospective multicenter study was conducted in France and Belgium. Adult patients with solid tumor and treated with systemic ICIs within the last 6 months, requiring non-programmed ICU admission were included. Patients admitted for microbiologically documented sepsis were excluded. Imputability of irAEs in ICU admissions was described according to the WHO-UMC classification system at ICU admission and at ICU discharge. The use of immunosuppressant treatment was reported. Results 115 patients were eligible. Solid tumor was mainly lung cancer (n = 76, 66%) and melanoma (n = 18, 16%). They were mainly treated with an anti-PD-(L)1 alone (n = 110, 96%). Main ICU admission reasons were acute respiratory failure (n = 66, 57%), colitis (n = 14, 13%), and cardiovascular disease (n = 13, 11%). ICU admission was considered “likely” associated with irAE for 48% (n = 55) of patients. Factors independently associated with irAE were a good ECOG performance status (PS) (ECOG-PS of 0 or 1 vs. ECOG-PS of 2–3, odds ratio [OR] = 6.34, 95% confidence interval [95% CI] 2.13–18.90, and OR = 3.66, 95% CI 1.33–10.03, respectively), and a history of irAE (OR = 3.28, 95% CI 1.19–9.01). Steroids were prescribed for 41/55 (75%) patients with ICU admission “likely” related to irAE. Three patients were subsequently treated with immunosuppressants. Conclusion IrAEs accounted for half of ICU admissions in cancer patients receiving ICIs. They could be treated with steroids. Identifying the imputability of irAEs in ICU admissions remains a challenge.

Published
2023
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17. Undernourished patients do not have increased risk of severe COVID-19 outcomes

Author

Ahmad Fneich, Pierre Poinsot, Christelle Elias, Lioara Restier, Philippe Vanhems, Florent Wallet, Cyrielle Caussy, Antoine Duclos, and Noël Peretti

Subjects
Undernutrition, Covid-19, Intensive care, Invasive mechanical ventilation, Death, Nutrition. Foods and food supply, TX341-641
Abstract

Background: Undernutrition has been previously identified as a deleterious factor in acute infections. In covid-19 infection, obesity is a risk-factor of severe evolution, but initial undernutrition has not been evaluated yet. Methods: We retrospectively analyzed correlation between nutritional status at admission and severe outcomes (intensive care unit admission, invasive mechanical ventilation requirement and death) of patients hospitalized for confirmed covid-19 infection. Results: Risk of intensive care unit admission and invasive mechanical ventilation requirement was not significantly different between undernutrition and normoweight sub-groups, but increased in excessive weight sub-group (ODDR (IC 95%) 1.048 (1.011-1.086), p = 0.011). Risk of death was the same in all sub-groups. Conclusion: Undernutrition didn't appear as a factor of severe outcomes in covid-19 infection.

Published
2022
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18. Impact of prolonged requirement for insulin on 90-day mortality in critically ill patients without previous diabetic treatments: a post hoc analysis of the CONTROLING randomized control trial

Author

François Thouy, Julien Bohé, Bertrand Souweine, Hassane Abidi, Jean-Pierre Quenot, Fabrice Thiollière, Jean Dellamonica, Jean-Charles Preiser, Jean-François Timsit, Vincent Brunot, Amna Klich, Nicholas Sedillot, Xavier Tchenio, Jean-Baptiste Roudaut, Nicolas Mottard, Hervé Hyvernat, Florent Wallet, Pierre-Eric Danin, Julio Badie, Richard Jospe, Jérôme Morel, Ali Mofredj, Abdelhamid Fatah, Jocelyne Drai, Anne Mialon, Ali Ait Hssain, Alexandre Lautrette, Eric Fontaine, Charles-Hervé Vacheron, Delphine Maucort-Boulch, Kada Klouche, and Claire Dupuis

Subjects
Prolonged requirement for insulin, Critical care, Mortality, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Stress hyperglycemia can persist during an intensive care unit (ICU) stay and result in prolonged requirement for insulin (PRI). The impact of PRI on ICU patient outcomes is not known. We evaluated the relationship between PRI and Day 90 mortality in ICU patients without previous diabetic treatments. Methods This is a post hoc analysis of the CONTROLING trial, involving 12 French ICUs. Patients in the personalized glucose control arm with an ICU length of stay ≥ 5 days and who had never previously received diabetic treatments (oral drugs or insulin) were included. Personalized blood glucose targets were estimated on their preadmission usual glycemia as estimated by their glycated A1c hemoglobin (HbA1C). PRI was defined by insulin requirement. The relationship between PRI on Day 5 and 90-day mortality was assessed by Cox survival models with inverse probability of treatment weighting (IPTW). Glycemic control was defined as at least one blood glucose value below the blood glucose target value on Day 5. Results A total of 476 patients were included, of whom 62.4% were male, with a median age of 66 (54–76) years. Median values for SAPS II and HbA1C were 50 (37.5–64) and 5.7 (5.4–6.1)%, respectively. PRI was observed in 364/476 (72.5%) patients on Day 5. 90-day mortality was 23.1% in the whole cohort, 25.3% in the PRI group and 16.1% in the non-PRI group (p

Published
2022
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19. A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients

Author

Claire Tardiveau, Guillaume Monneret, Anne-Claire Lukaszewicz, Valérie Cheynet, Elisabeth Cerrato, Katia Imhoff, Estelle Peronnet, Maxime Bodinier, Louis Kreitmann, Sophie Blein, Jean-François Llitjos, Filippo Conti, Morgane Gossez, Marielle Buisson, Hodane Yonis, Martin Cour, Laurent Argaud, Marie-Charlotte Delignette, Florent Wallet, Frederic Dailler, Céline Monard, Karen Brengel-Pesce, Fabienne Venet, and the RICO study group

Subjects
transcriptomic multiplex tool, SARS-CoV-2 infection, immune response, 28-day mortality prediction, personalized medicine, Immunologic diseases. Allergy, RC581-607
Abstract

Immune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients’ age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care.

Published
2022
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20. Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial

Author

Jean-Christophe Richard, Hodane Yonis, Laurent Bitker, Sylvain Roche, Florent Wallet, Claire Dupuis, Hassan Serrier, Laurent Argaud, Guillaume Thiery, Bertrand Delannoy, Christian Pommier, Paul Abraham, Michel Muller, Frederic Aubrun, Florian Sigaud, Guillaume Rigault, Emilie Joffredo, Mehdi Mezidi, Nicolas Terzi, and Muriel Rabilloud

Subjects
COVID-19, SARS-CoV-2, Acute respiratory distress syndrome, Mechanical ventilation, Ultraprotective ventilation, Ultra-low tidal volume ventilation, Medicine (General), R5-920
Abstract

Abstract Background Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34–50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg−1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. Methods The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg−1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg−1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. Discussion The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. Trial registration ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020

Published
2021
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22. Performance of the ROX index to predict intubation in immunocompromised patients receiving high-flow nasal cannula for acute respiratory failure

Author

Virginie Lemiale, Guillaume Dumas, Alexandre Demoule, Frederic Pène, Achille Kouatchet, Magali Bisbal, Saad Nseir, Laurent Argaud, Loay Kontar, Kada Klouche, Francois Barbier, Amelie Seguin, Guillaume Louis, Jean-Michel Constantin, Julien Mayaux, Florent Wallet, Vincent Peigne, Christophe Girault, Johanna Oziel, Martine Nyunga, Nicolas Terzi, Lila Bouadma, Alexandre Lautrette, Naike Bige, Jean-Herle Raphalen, Laurent Papazian, Fabrice Bruneel, Christine Lebert, Dominique Benoit, Anne-Pascale Meert, Samir Jaber, Djamel Mokart, Michael Darmon, Elie Azoulay, and The Groupe de Recherche en Reanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH)

Subjects
High-flow nasal oxygen, Immunocompromised, Acute respiratory failure, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Delayed intubation is associated with high mortality. There is a lack of objective criteria to decide the time of intubation. We assessed a recently described combined oxygenation index (ROX index) to predict intubation in immunocompromised patients. The study is a secondary analysis of randomized trials in immunocompromised patients, including all patients who received high-flow nasal cannula (HFNC). The first objective was to evaluate the accuracy of the ROX index to predict intubation for patients with acute respiratory failure. Results In the study, 302 patients received HFNC. Acute respiratory failure was mostly related to pneumonia (n = 150, 49.7%). Within 2 (1–3) days, 115 (38.1%) patients were intubated. The ICU mortality rate was 27.4% (n = 83). At 6 h, the ROX index was lower for patients who needed intubation compared with those who did not [4.79 (3.69–7.01) vs. 6.10 (4.48–8.68), p

Published
2021
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23. Center effect in intubation risk in critically ill immunocompromised patients with acute hypoxemic respiratory failure

Author

Guillaume Dumas, Alexandre Demoule, Djamel Mokart, Virginie Lemiale, Saad Nseir, Laurent Argaud, Frédéric Pène, Loay Kontar, Fabrice Bruneel, Kada Klouche, François Barbier, Jean Reignier, Annabelle Stoclin, Guillaume Louis, Jean-Michel Constantin, Florent Wallet, Achille Kouatchet, Vincent Peigne, Pierre Perez, Christophe Girault, Samir Jaber, Yves Cohen, Martine Nyunga, Nicolas Terzi, Lila Bouadma, Christine Lebert, Alexandre Lautrette, Naike Bigé, Jean-Herlé Raphalen, Laurent Papazian, Dominique Benoit, Michael Darmon, Sylvie Chevret, and Elie Azoulay

Subjects
Center effect, Intubation, Neutropenia, Leukemia, Hypoxemia, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Acute respiratory failure is the leading reason for intensive care unit (ICU) admission in immunocompromised patients, and the need for invasive mechanical ventilation has become a major clinical endpoint in randomized controlled trials (RCTs). However, data are lacking on whether intubation is an objective criteria that is used unbiasedly across centers. This study explores how this outcome varies across ICUs. Methods Hierarchical models and permutation procedures for testing multiple random effects were applied on both data from an observational cohort (the TRIAL-OH study: 703 patients, 17 ICUs) and a randomized controlled trial (the HIGH trial: 776 patients, 31 ICUs) to characterize ICU variation in intubation risk across centers. Results The crude intubation rate varied across ICUs from 29 to 80% in the observational cohort and from 0 to 86% in the RCT. This center effect on the mean ICU intubation rate was statistically significant, even after adjustment on individual patient characteristics (observational cohort: p value = 0.013, median OR 1.48 [1.30–1.72]; RCT: p value 0.004, median OR 1.51 [1.36–1.68]). Two ICU-level characteristics were associated with intubation risk (the annual rate of intubation procedure per center and the time from respiratory symptoms to ICU admission) and could partly explain this center effect. In the RCT that controlled for the use of high-flow oxygen therapy, we did not find significant variation in the effect of oxygenation strategy on intubation risk across centers, despite a significant variation in the need for invasive mechanical ventilation. Conclusion Intubation rates varied considerably among ICUs, even after adjustment on individual characteristics.

Published
2019
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24. Life Support Limitations in Mechanically Ventilated Stroke Patients

Author

Etienne de Montmollin, MD, PhD, Carole Schwebel, MD, PhD, Claire Dupuis, MD, PhD, Maité Garrouste-Orgeas, MD, Daniel da Silva, MD, Elie Azoulay, MD, PhD, Virginie Laurent, MD, Guillaume Thiéry, MD, PhD, Alexandra Grinea, MD, Guillaume Marcotte, MD, Johanna Oziel, MD, Marc Gainnier, MD, Shidasp Siami, MD, PhD, Jean Reignier, MD, PhD, Benjamin Sztrymf, MD, PhD, Christophe Adrie, MD, Stephane Ruckly, MSc, Romain Sonneville, MD, PhD, Jean-François Timsit, MD, PhD, on behalf of the OUTCOMEREA Study Group, Jean-François Timsit, Elie Azoulay, Jean-Ralph Zahar, Bruno Mourvillier, Michael Darmon, Jean-Francois Timsit, Corinne Albert, Stephane Ruckly, Sébastien Bailly, Aurélien Vannieuwenhuyze, Christophe Adrie, Carole Agasse, Bernard Allaouchiche, Olivier Andremont, Pascal Andreu, Laurent Argaud, Claire Ara-Somohano, Francois Barbier, Jean-Pierre Bedos, Thomas Baudry, Jérome Bedel, Julien Bohé, Lila Bouadma, Jeremy Bourenne, Noel Brule, Frank Chemouni, Julien Carvelli, Elisabeth Coupez, Martin Cour, Claire Dupuis, Etienne de Montmollin, Loa Dopeux, Anne-Sylvie Dumenil, Jean-Marc Forel, Marc Gainnier, Charlotte Garret, Dany Goldgran-Tonedano, Steven Grangé, Antoine Gros, Hédia Hammed, Akim Haouache, Tarik Hissem, Vivien Hong Tuan Ha, Sébastien Jochman, Jean-Baptiste Joffredo, Hatem Kallel, Guillaume Lacave, Virgine Laurent, Alexandre Lautrette, Clément Le Bihan, Virgine Lemiale, David Luis, Guillaume Marcotte, Jordane Lebut, Mathild Neuville, Laurent Nicolet, Johanna Oziel, Laurent Papazian, Juliette Patrier, Benjamin Planquette, Aguila Radjou, Marie Simon, Romain Sonneville, Jean Reignier, Bertrand Souweine, Carole Schwebel, Shidasp Siami, Nicolas Terzi, Gilles Troché, Fabrice Thiollieres, Guillaume Thierry, Guillaume Van Der Meersch, Marion Venot, Florent Wallet, Sondes Yaacoubi, Olivier Zambon, Jonathan Zarka, Mireille Adda, Vanessa Vindrieux, Marion Provent, Sylvie de la Salle, Pauline Enguerrand, Vincent Gobert, Stéphane Guessens, Helene Merle, Nadira Kaddour, Boris Berthe, Samir Bekkhouche, Kaouttar Mellouk, Mélaine Lebrazic, Carole Ouisse, Diane Maugars, Christelle Aparicio, Igor Theodose, Manal Nouacer, Veronique Deiler, Fariza Lamara, Myriam Moussa, Atika Mouaci, and Nassima Viguier

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Objectives:. The determinants of decisions to limit life support (withholding or withdrawal) in ventilated stroke patients have been evaluated mainly for patients with intracranial hemorrhages. We aimed to evaluate the frequency of life support limitations in ventilated ischemic and hemorrhagic stroke patients compared with a nonbrain-injured population and to determine factors associated with such decisions. Design:. Multicenter prospective French observational study. Setting:. Fourteen ICUs of the French OutcomeRea network. PATIENTS:. From 2005 to 2016, we included stroke patients and nonbrain-injured patients requiring invasive ventilation within 24 hours of ICU admission. INTERVENTION:. None. MEASUREMENTS AND MAIN RESULTS:. We identified 373 stroke patients (ischemic, n = 167 [45%]; hemorrhagic, n = 206 [55%]) and 5,683 nonbrain-injured patients. Decisions to limit life support were taken in 41% of ischemic stroke cases (vs nonbrain-injured patients, subdistribution hazard ratio, 3.59 [95% CI, 2.78–4.65]) and in 33% of hemorrhagic stroke cases (vs nonbrain-injured patients, subdistribution hazard ratio, 3.9 [95% CI, 2.97–5.11]). Time from ICU admission to the first limitation was longer in ischemic than in hemorrhagic stroke (5 [3–9] vs 2 d [1–6] d; p < 0.01). Limitation of life support preceded ICU death in 70% of ischemic strokes and 45% of hemorrhagic strokes (p < 0.01). Life support limitations in ischemic stroke were increased by a vertebrobasilar location (vs anterior circulation, subdistribution hazard ratio, 1.61 [95% CI, 1.01–2.59]) and a prestroke modified Rankin score greater than 2 (2.38 [1.27–4.55]). In hemorrhagic stroke, an age greater than 70 years (2.29 [1.43–3.69]) and a Glasgow Coma Scale score less than 8 (2.15 [1.08–4.3]) were associated with an increased risk of limitation, whereas a higher nonneurologic admission Sequential Organ Failure Assessment score was associated with a reduced risk (per point, 0.89 [0.82–0.97]). Conclusions:. In ventilated stroke patients, decisions to limit life support are more than three times more frequent than in nonbrain-injured patients, with different timing and associated risk factors between ischemic and hemorrhagic strokes.

Published
2021
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25. Correction to: Performance of the ROX index to predict intubation in immunocompromised patients receiving high-flow nasal cannula for acute respiratory failure

Author

Virginie Lemiale, Guillaume Dumas, Alexandre Demoule, Frederic Pène, Achille Kouatchet, Magali Bisbal, Saad Nseir, Laurent Argaud, Loay Kontar, Kada Klouche, Francois Barbier, Amelie Seguin, Guillaume Louis, Jean-Michel Constantin, Julien Mayaux, Florent Wallet, Vincent Peigne, Christophe Girault, Johanna Oziel, Martine Nyunga, Nicolas Terzi, Lila Bouadma, Alexandre Lautrette, Naike Bige, Jean-Herle Raphalen, Laurent Papazian, Fabrice Bruneel, Christine Lebert, Dominique Benoit, Anne-Pascale Meert, Samir Jaber, Djamel Mokart, Michael Darmon, Elie Azoulay, and The Groupe de Recherche en Reanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH)

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Published
2021
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26. High-flow nasal oxygen vs. standard oxygen therapy in immunocompromised patients with acute respiratory failure: study protocol for a randomized controlled trial

Author

Elie Azoulay, Virginie Lemiale, Djamel Mokart, Saad Nseir, Laurent Argaud, Frédéric Pène, Loay Kontar, Fabrice Bruneel, Kada Klouche, François Barbier, Jean Reignier, Anabelle Stoclin, Guillaume Louis, Jean-Michel Constantin, Julien Mayaux, Florent Wallet, Achille Kouatchet, Vincent Peigne, Pierre Perez, Christophe Girault, Samir Jaber, Johanna Oziel, Martine Nyunga, Nicolas Terzi, Lila Bouadma, Christine Lebert, Alexandre Lautrette, Naike Bigé, Jean-Herlé Raphalen, Laurent Papazian, Antoine Rabbat, Michael Darmon, Sylvie Chevret, and Alexandre Demoule

Subjects
Acute respiratory failure, Immunosuppression, Immunocompromised Hematology, Mortality, High-flow oxygen, Oxygen, Medicine (General), R5-920
Abstract

Abstract Background Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in immunocompromised patients. High-flow nasal oxygen (HFNO) therapy is an alternative to standard oxygen. By providing warmed and humidified gas, HFNO allows the delivery of higher flow rates via nasal cannula devices, with FiO2 values of nearly 100%. Benefits include alleviation of dyspnea and discomfort, decreased respiratory distress and decreased mortality in unselected patients with acute hypoxemic respiratory failure. However, in preliminary reports, HFNO benefits are controversial in immunocompromised patients in whom it has never been properly evaluated. Methods/design This is a multicenter, open-label, randomized controlled superiority trial in 30 intensive care units, part of the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH). Inclusion criteria will be: (1) adults, (2) known immunosuppression, (3) ARF, (4) oxygen therapy ≥ 6 L/min, (5) written informed consent from patient or proxy. Exclusion criteria will be: (1) imminent death (moribund patient), (2) no informed consent, (3) hypercapnia (PaCO2 ≥ 50 mmHg), (4) isolated cardiogenic pulmonary edema, (5) pregnancy or breastfeeding, (6) anatomical factors precluding insertion of a nasal cannula, (7) no coverage by the French statutory healthcare insurance system, and (8) post-surgical setting from day 1 to day 6 (patients with ARF occurring after day 6 of surgery can be included). The primary outcome measure is day-28 mortality. Secondary outcomes are intubation rate, comfort, dyspnea, respiratory rate, oxygenation, ICU length of stay, and ICU-acquired infections. Based on an expected 30% mortality rate in the standard oxygen group, and 20% in the HFNO group, error rate set at 5%, and a statistical power at 90%, 389 patients are required in each treatment group (778 patients overall). Recruitment period is estimated at 30 months, with 28 days of additional follow-up for the last included patient. Discussion The HIGH study will be the largest multicenter, randomized controlled trial seeking to demonstrate that survival benefits from HFNO reported in unselected patients also apply to a large immunocompromised population. Trial registration ClinicalTrials.gov, ID: NCT02739451. Registered on 15 April 2016.

Published
2018
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27. Population Pharmacokinetics and Dosing Simulation of Vancomycin Administered by Continuous Injection in Critically Ill Patient

Author

Romain Garreau, Benoît Falquet, Lisa Mioux, Laurent Bourguignon, Tristan Ferry, Michel Tod, Florent Wallet, Arnaud Friggeri, Jean-Christophe Richard, and Sylvain Goutelle

Subjects
vancomycin, pharmacokinetics, continuous infusion, ICU, Therapeutics. Pharmacology, RM1-950
Abstract

Background: Vancomycin is widely used for empirical antimicrobial therapy in critically ill patients with sepsis. Continuous infusion (CI) may provide more stable exposure than intermittent infusion, but optimal dosing remains challenging. The aims of this study were to perform population pharmacokinetic (PK) analysis of vancomycin administered by CI in intensive care unit (ICU) patients to identify optimal dosages. Methods: Patients who received vancomycin by CI with at least one measured concentration in our center over 16 months were included, including those under continuous renal replacement therapy (CRRT). Population PK was conducted and external validation of the final model was performed in a dataset from another center. Simulations were conducted with the final model to identify the optimal loading and maintenance doses for various stages of estimated creatinine clearance (CRCL) and in patients on CRRT. Target exposure was defined as daily AUC of 400–600 mg·h/L on the second day of therapy (AUC24–48 h). Results: A two-compartment model best described the data. Central volume of distribution was allometrically scaled to ideal body weight (IBW), whereas vancomycin clearance was influenced by CRRT and CRCL. Simulations performed with the final model suggested a loading dose of 27.5 mg/kg of IBW. The maintenance dose ranged from 17.5 to 30 mg/kg of IBW, depending on renal function. Overall, simulation showed that 55.8% (95% CI; 47–64%) of patients would achieve the target AUC with suggested dosages. Discussion: A PK model has been validated for vancomycin administered by CI in ICU patients, including patients under CRRT. Our model-informed precision dosing approach may help for early optimization of vancomycin exposure in such patients.

Published
2021
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28. Applicability of Pulse Pressure Variation during Unstable Hemodynamic Events in the Intensive Care Unit: A Five-Day Prospective Multicenter Study

Author

Bertrand Delannoy, Florent Wallet, Delphine Maucort-Boulch, Mathieu Page, Mahmoud Kaaki, Mathieu Schoeffler, Brenton Alexander, and Olivier Desebbe

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Pulse pressure variation can predict fluid responsiveness in strict applicability conditions. The purpose of this study was to describe the clinical applicability of pulse pressure variation during episodes of patient hemodynamic instability in the intensive care unit. We conducted a five-day, seven-center prospective study that included patients presenting with an unstable hemodynamic event. The six predefined inclusion criteria for pulse pressure variation applicability were as follows: mechanical ventilation, tidal volume >7 mL/kg, sinus rhythm, no spontaneous breath, heart rate/respiratory rate ratio >3.6, absence of right ventricular dysfunction, or severe valvulopathy. Seventy-three patients presented at least one unstable hemodynamic event, with a total of 163 unstable hemodynamic events. The six predefined criteria for the applicability of pulse pressure variation were completely present in only 7% of these. This data indicates that PPV should only be used alongside a strong understanding of the relevant physiology and applicability criteria. Although these exclusion criteria appear to be profound, they likely represent an absolute contraindication of use for only a minority of critical care patients.

Published
2016
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29. HLA-DR expression on monocytes and outcome of anti-CD19 CAR T-cell therapy for large B-cell lymphoma

Author

Estelle Bourbon, Pierre Sesques, Morgane Gossez, Jérémie Tordo, Emmanuelle Ferrant, Violaine Safar, Florent Wallet, Guillaume Aussedat, Alizée Maarek, Fadhela Bouafia, Lionel Karlin, Dana Ghergus, Camille Golfier, Hélène Lequeu, Anne Lazareth, Vérane Schwiertz, Sébastien Viel, Maryam Idlhaj, Hervé Ghesquières, Guillaume Monneret, Emmanuel Bachy, Fabienne Venet, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])

Subjects
[SDV]Life Sciences [q-bio], Hematology
Abstract

Despite their unprecedented success in relapsed/refractory (R/R) large B-cell lymphoma (LBCL), anti-CD19 CAR T cells are associated with significant toxicity, and more than half of patients relapse. As monocytes emerged as key players in CAR therapy, we sought to evaluate the evolution of HLA-DR expression on monocytes (mHLA-DR) before and after commercial anti-CD19 CAR T-cell infusion in a large cohort (n = 103) of patients with R/R LBCL and its association with adverse events and treatment response. Cy-Flu-based lymphodepletion (LD) upregulated mHLA-DR in 79% of the cases, whereas in 2l% of cases (15 patients), the mHLA-DR level decreased after LD, and this decrease was associated with poorer outcome. Low mHLA-DR at day minus 7 (D−7) (

Published
2023

30. Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

Author

Bruno Mourvillier, François-Xavier Lescure, Dominique Costagliola, Alain Makinson, Valérie Pourcher, Odile Launay, Clément Dubost, Saad Nseir, Emmanuel Faure, Yazdan Yazdanpanah, Jean-Christophe Richard, Lila Bouadma, Kevin Bouiller, Juliette Saillard, Jean Reignier, Claire Andrejak, Alpha Diallo, Lionel Piroth, Jean-Philippe Lanoix, Violaine Tolsma, Christelle Delmas, Gilles Peytavin, André Cabié, Marion Noret, Karine Lacombe, Elisabeth Botelho-Nevers, Thérèse Staub, Johan Courjon, Florence Ader, Nathan Peiffer-Smadja, Jean-Christophe Navellou, Maya Hites, Jean Reuter, Noemie Mercier, Maude Bouscambert-Duchamp, François Danion, S. Gallien, Julien Poissy, Florent Wallet, Guillaume Martin-Blondel, Raphaël Clere-Jehl, Bruno Lina, Amandine Gagneux-Brunon, Antoine Kimmoun, Rostane Gaci, Olivier Epaulard, Axelle Dupont, François Raffi, Aline Dechanet, François Goehringer, Joy Mootien, Stéphane Jauréguiberry, Sylvie Leroy, Charles Burdet, Toni Alfaiate, Drifa Belhadi, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, Université de Médecine Carol Davila, Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS France Recherche Nord & sud Sida-hiv hépatites, Département d'Epidemiologie, Biostatistique et Recherche Clinique (DEBRC), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Service de Réanimation Médicale [CHRU Nancy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Hospitalized patients, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Lopinavir, Hydroxychloroquine, Odds ratio, law.invention, Randomized controlled trial, law, Internal medicine, medicine, Ritonavir, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking.ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients.DesignOpen-label, randomized, adaptive, controlled trial.SettingMulti-center trial with patients from France.Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory supportInterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-ß-1a (44 μg of subcutaneous IFN-ß-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days).MeasurementsThe primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses.ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavirversuscontrol, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-β-1aversuscontrol, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquineversuscontrol, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE.LimitationsNot a placebo-controlled, no anti-inflammatory agents tested.ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings.RegistrationNCT04315948.FundingPHRC 2020, Dim OneHealth, REACTing

Published
2023

31. Outcome in Multiple Myeloma Patients Treated in the Era of Modern Therapies Who Were Admitted to Intensive Care: A Retrospective Analysis from a Teaching Hospital between 2014 and 2019

Author

Zofia Gross, Maryam Idlhaj, Lionel Karlin, Arnaud Friggeri, Anne Lazareth, Camille Golfier, Helene Lequeu, Fadhela Bouafia Sauvy, Pierre Sesques, Violaine Safar, Emmanuelle Ferrant, Dana Ghergus, Alizee Maarek, Guillaume Aussedat, Gilles Salles, Emmanuel Bachy, Florent Wallet, and Herve Ghesquieres

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

32. Risk factors for therapeutic failure in the management of post-operative peritonitis: a post hoc analysis of the DURAPOP trial

Author

Karim Asehnoune, Sebastien Pease, Philippine Eloy, Alexandre Mignon, Marina Esposito-Farèse, Pascal Raclot, Sami Jaber, Joel Cousson, Soizic Gergaud, Hervé Dupont, Marc Beaussier, Josette Gally, Claude Girard, Melanie Levrard, Claude Meistelman, Gilles Blasco, Jean-Francois Payen, Philippe Gouin, Nathalie Grall, Olivier Collanges, Paer Abback, Thomas Lescot, Sigismond Lasocki, Thomas Gaillard, Sebastien Pily-Floury, Antoine Tesniere, Gaëtan Plantefève, Jean-François Georger, Benoit Veber, Philippe Montravers, Christian Auboyer, Marie-Christine Herault, Florent Wallet, Jean-François Perrier, Regis Bronchard, Yazine Mahjoub, Alain Lepape, Vincent Piriou, Thierry Floch, Emmanuel Samain, Emmanuel Weiss, Thomas Clavier, Mathieu Desmard, Philippe Seguin, Candice Tassin, Yoann Launey, Nouria Belhadj-Tahar, Raphaël Cinotti, Olivier Pajot, Guillaume Besch, Catherine Paugam, Boris Jung, Jean-Marc Delay, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, CHU Rouen, Normandie Université (NU), CHU Pontchaillou [Rennes], Hôpital Beaujon [AP-HP], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Amiens-Picardie, Université de Picardie Jules Verne (UPJV), DURAPOP trial group: Philippe Montravers, Regis Bronchard, Mathieu Desmard, Herve Dupont, Melanie Levrard, Yazine Mahjoub, Sigismond Lasocki, Soizic Gergaud, Thomas Gaillard, Gaetan Plantefeve, Olivier Pajot, Gilles Blasco, Emmanuel Samain, Guillaume Besch, Sebastien Pily-Floury, Catherine Paugam, Sebastien Pease, Paer Abback, Claude Girard, Jean-Francois Payen, Marie-Christine Herault, Sami Jaber, Boris Jung, Jean-Marc Delay, Josette Gally, Claude Meistelman, Jean-François Perrier, Karim Asehnoune, Raphael Cinotti, Antoine Tesniere, Alexandre Mignon, Thomas Lescot, Nouria Belhadj-Tahar, Marc Beaussier, Alain Lepape, Vincent Piriou, Florent Wallet, Candice Tassin, Joel Cousson, Pascal Raclot, Thierry Floch, Philippe Seguin, Yoann Launey, Benoit Veber, Philippe Gouin, Thomas Clavier, Christian Auboyer, Olivier Collanges, Jean-François Georger, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Simplification des soins chez les patients complexes - UR UPJV 7518 (SSPC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and MORNET, Dominique

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Penicillanic Acid, Logistic regression, 0302 clinical medicine, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, Pharmacology (medical), 030212 general & internal medicine, MESH: Penicillanic Acid, Prospective Studies, Original Research, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, AcademicSubjects/MED00290, Piperacillin, Tazobactam Drug Combination, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Piperacillin/tazobactam, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine.drug, Microbiology (medical), MESH: Piperacillin, medicine.medical_specialty, MESH: Peritonitis, Peritonitis, Tazobactam, 03 medical and health sciences, Internal medicine, MESH: Anti-Bacterial Agents, Post-hoc analysis, medicine, AcademicSubjects/MED00740, Humans, Renal replacement therapy, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Pharmacology, Piperacillin, MESH: Humans, business.industry, 030208 emergency & critical care medicine, medicine.disease, Comorbidity, MESH: Prospective Studies, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, AcademicSubjects/MED00230
Abstract

Background Therapeutic failure is a frequent issue in the management of post-operative peritonitis. Objectives A post hoc analysis of the prospective, multicentre DURAPOP trial analysed the risk factors for failures in post-operative peritonitis following adequate source control and empirical antibiotic therapy in critically ill patients. Patients and methods Overall failures assessed post-operatively between Day 8 and Day 45 were defined as a composite of death and/or surgical and/or microbiological failures. Risk factors for failures were assessed using logistic regression analyses. Results Among the 236 analysed patients, overall failures were reported in 141 (59.7%) patients, including 30 (12.7%) deaths, 81 (34.3%) surgical and 95 (40.2%) microbiological failures. In the multivariate analysis, the risk factors associated with overall failures were documented piperacillin/tazobactam therapy [adjusted OR (aOR) 2.10; 95% CI 1.17–3.75] and renal replacement therapy on the day of reoperation (aOR 2.96; 95% CI 1.05–8.34). The risk factors for death were age (aOR 1.08 per year; 95% CI 1.03–1.12), renal replacement therapy on reoperation (aOR 3.95; 95% CI 1.36–11.49) and diabetes (OR 6.95; 95% CI 1.34–36.03). The risk factors associated with surgical failure were documented piperacillin/tazobactam therapy (aOR 1.99; 95% CI 1.13–3.51), peritoneal cultures containing Klebsiella spp. (aOR 2.45; 95% CI 1.02–5.88) and pancreatic source of infection (aOR 2.91; 95% CI 1.21–7.01). No specific risk factors were identified for microbiological failure. Conclusions Our data suggest a predominant role of comorbidities, the severity of post-operative peritonitis and possibly of documented piperacillin/tazobactam treatment on the occurrence of therapeutic failures, regardless of their type.

Published
2021

33. B-cell malignancies and COVID-19: a narrative review

Author

David, Luque-Paz, Pierre, Sesques, Florent, Wallet, Emmanuel, Bachy, Florence, Ader, CHU Pontchaillou [Rennes], Université de Rennes (UR), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Microbiology (medical), B-cell malignancies, Infectious Diseases, mRNA vaccine, B-cell depletion, Neutralizing monoclonal antibody, SARS-CoV-2, convalescent plasma therapy, COVID-19, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Direct-active antiviral
Abstract

International audience; Background. COVID-19 has been extensively characterized in immunocompetent hosts and to a lesser extent in immunocompromised populations. Among the latter, patients treated for Bcell malignancies have immunosuppression generated by B-cell lymphodepletion/aplasia resulting in a higher susceptibility to respiratory virus infections and poor response to vaccination. The consequence is that these patients are likely to develop severe or critical COVID-19. Objectives. To examine the overall impact of COVID-19 in patients treated for a B-cell malignancy or receiving chimeric antigen receptor T (CAR-T) immunotherapy administered in case of relapsed or refractory disease. Sources. We searched in the Medline database to identify relevant studies, trials, reviews, or meta-analyses focusing on SARS-CoV-2 vaccination or COVID-19 management in patients treated for a B-cell malignancy or recipients of CART cell therapy up to July 8 th , 2022. Content. The epidemiology and the outcomes of COVID-19 in B-cell malignancy patients and CART cell recipients are summarized. Vaccine efficacy in these subgroups is compiled. Considering the successive surges of variants of concern, we propose a critical appraisal of treatment strategies by discussing the use of neutralizing monoclonal antibodies, convalescent plasma therapy, direct-acting antiviral drugs, corticosteroids and immunomodulators. Implications. For B-cell malignancy patients, preventive vaccination against SARS-CoV-2 remain essential and management of COVID-19 includes the control of viral replication due to protracted SARS-CoV-2 shedding. Passive immunotherapy (monoclonal neutralizing antibody therapy, convalescent plasma therapy) and direct-active antivirals such as remdesivir and nirmatrelvir/ritonavir are the best currently available treatments. Real-world data and subgroup analyses in larger trials are warranted to assess COVID-19 therapeutics in B-cell depleted populations.

Published
2023

35. Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study

Author

Marie-Therese Rubio, Roberta Di Blasi, Gilles Salles, Miguel A Perales, Kada Klouche, Muriel Picard, Pierre Sesques, Eric Mariotte, Michael Darmon, Boris Böll, Philippe R. Bauer, Sanjay Chawla, Kevin Rakszawski, Nahema Issa, Anne Huynh, Guillaume Cartron, Florence Rabian, Peter Borchmann, Michael Joannidis, Sabine Furst, Sophie de Guibert, Lara Zafrani, Patrice Ceballos, Nicolas Boissel, David Beauvais, Catherine Thieblemont, François-Xavier Gros, Alberto Mussetti, Gabriel Moreno-González, Adel Maamar, Florent Wallet, Faezeh Legrand, Julien Leroy, Quentin Quelven, Djamel Mokart, Valentin Ortiz, Christian Recher, Jakob Rudzki, Laura Platon, Pleun Hemelaar, Benoit Tessoulin, Reuben Benjamin, Sandrine Valade, Pedro Castro, Gennadii Galstian, Amélie Seguin, Peter Schellongowski, Anna Sureda, Alice Gallo De Moraes, Philipp Wohlfarth, Bruno Levy, Andry Van de Louw, Jorge Garcia Borrega, Julio Delgado, Ibrahim Yakoub-Agha, Nathalie Fégueux, Laveena Munshi, Yi Lin, Emmanuel Bachy, Stéphanie Harel, Sara Fernández, Bertrand Arnulf, Thomas Gastinne, Elie Azoulay, Didier Blaise, Amandine Le Bourgeois, Louis Voigt, Cécile Borel, Anne-Sophie Moreau, Christian Chabannon, Ulrich Jäger, Virginie Lemiale, Olga Gavrilina, Victoria Metaxa, Thomas Staudingert, Edouard Forcade, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Barcelona, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), King's College Hospital (KCH), Mayo Clinic [Rochester], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Penn State Health Milton S. Hershey Medical Center, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Universitätsklinikum Köln (Uniklinik Köln), Hôpital Saint-André, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Radboud University Medical Center [Nijmegen], Universitat de Barcelona (UB), University of Toronto, Medizinische Universität Wien = Medical University of Vienna, Leopold Franzens Universität Innsbruck - University of Innsbruck, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Soins Intensifs [CHRU Nancy], Radboud University Medical Centre [Nijmegen, The Netherlands], University of Innsbruck, and National Research Center for Hematology [Moscow, Russia]

Subjects
Male, MESH: Neurotoxicity Syndromes, MESH: Registries, [SDV]Life Sciences [q-bio], MESH: Multiple Myeloma, Immunotherapy, Adoptive, Severity of Illness Index, law.invention, MESH: Proportional Hazards Models, Medicina intensiva, Clinical trials, 0302 clinical medicine, law, Clinical endpoint, Medicine, Infection control, Registries, MESH: Treatment Outcome, MESH: Middle Aged, Medical record, Hazard ratio, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, MESH: Follow-Up Studies, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Intensive care unit, 3. Good health, Survival Rate, Cytokine release syndrome, Intensive Care Units, Treatment Outcome, 030220 oncology & carcinogenesis, MESH: Immunotherapy, Adoptive, Female, Neurotoxicity Syndromes, Lymphoma, Large B-Cell, Diffuse, Cytokine Release Syndrome, Multiple Myeloma, Care of the sick, Cohort study, Adult, medicine.medical_specialty, Critical Care, MESH: Survival Rate, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], MESH: Cytokine Realease Syndrome, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, MESH: Critical Care, Internal medicine, Intensive care, MESH: Severity of Illness Index, Humans, Cura dels malalts, Critical care medicine, Proportional Hazards Models, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, MESH: Lymphomz, Large B-Cell, Diffuse, MESH: Adult, MESH: Intensive care Units, medicine.disease, MESH: Male, business, MESH: Female, Assaigs clínics, 030215 immunology, Follow-Up Studies
Abstract

Summary Background Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. Methods This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. Findings 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0–7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1–27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3–4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3–4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37–4·57]), bacterial infection (2·12 [1·11–4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05–3·10]). Interpretation Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. Funding Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique.

Published
2021

36. Protracted viral shedding and viral load are associated with ICU mortality in Covid-19 patients with acute respiratory failure

Author

Louis Chauvelot, François Dhelft, Sophie Trouillet-Assant, Laure Folliet, Laurent Bitker, Jean-Christophe Richard, Bruno Lina, Emilie Frobert, A Belot, Florent Wallet, and Mehdi Mezidi

Subjects
medicine.medical_specialty, SARS-COV-2, Critical Care and Intensive Care Medicine, Acute respiratory failure, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Intensive care, Pulmonary fibrosis, medicine, Viral load, 030212 general & internal medicine, Viral shedding, Bronchiectasis, Lung, Acute respiratory distress syndrome, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, COVID-19, Retrospective cohort study, lcsh:RC86-88.9, medicine.disease, Polymerase chain reaction, Pneumonia, medicine.anatomical_structure, business
Abstract

BackgroundProtracted viral shedding is common in hospitalized patients with COVID-19 pneumonia, and up to 40% display signs of pulmonary fibrosis on computed tomography (CT) after hospital discharge. We hypothesized that COVID-19 patients with acute respiratory failure (ARF) who die in intensive care units (ICU) have a lower viral clearance in the respiratory tract than ICU patients discharged alive, and that protracted viral shedding in respiratory samples is associated with patterns of fibroproliferation on lung CT. We, therefore, conducted a retrospective observational study, in 2 ICU of Lyon university hospital.Results129 patients were included in the study, of whom 44 (34%) died in ICU. 432 RT-PCR for SARS-CoV-2 were performed and 137 CT scans were analyzed. Viral load was significantly higher in patients deceased as compared to patients alive at ICU discharge (p 95 %:15–21] in patients alive at ICU discharge and 26 days [CI95 %:17-infinity] in non-survivors at ICU discharge. Competitive risk regression identified patients who died in ICU and age as independent risk factors for longer time to SARS-CoV-2 negativation on RT-PCR, while antiviral treatment was independently associated with shorter time. None of the CT scores exploring fibroproliferation (i.e., bronchiectasis and reticulation scores) were significantly associated with time to SARS-CoV-2 negativation.ConclusionsViral load in respiratory samples is significantly lower and viral shedding significantly shorter in ICU survivors of COVID-19 associated acute respiratory failure. Protracted viral shedding is unrelated to occurrence of fibrosis on lung CT.

Published
2020

37. An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19 – Final results from the DisCoVeRy trial

Author

Florence Ader, Nathan Peiffer-Smadja, Julien Poissy, Maude Bouscambert-Duchamp, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Noémie Mercier, Axelle Dupont, Toni Alfaiate, François-Xavier Lescure, François Raffi, François Goehringer, Antoine Kimmoun, Stéphane Jaureguiberry, Jean Reignier, Saad Nseir, François Danion, Raphael Clere-Jehl, Kévin Bouiller, Jean-Christophe Navellou, Violaine Tolsma, André Cabie, Clément Dubost, Johan Courjon, Sylvie Leroy, Joy Mootien, Rostane Gaci, Bruno Mourvillier, Emmanuel Faure, Valérie Pourcher, Sébastien Gallien, Odile Launay, Karine Lacombe, Jean-Philippe Lanoix, Alain Makinson, Guillaume Martin-Blondel, Lila Bouadma, Elisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Olivier Epaulard, Lionel Piroth, Florent Wallet, Jean-Christophe Richard, Jean Reuter, Thérèse Staub, Bruno Lina, Marion Noret, Claire Andrejak, Minh Patrick Lê, Gilles Peytavin, Maya Hites, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, and France Mentre

Subjects
immune system diseases, virus diseases
Abstract

ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring.MethodsWe conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely.ResultsThe intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

Published
2022

38. Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study

Author

Gilles Nevez, Brice Autier, Jean-Pierre Gangneux, Yves Cohen, Nadine François, Cécile Aubron, Emmanuel Canet, Sophie Brun, Alexandre Alanio, Philippe Seguin, Nicolas Terzi, Bruno Mégarbane, Jean-François Timsit, Romain Pelletier, Marie Soulié, Dorothée Quinio, Estelle Sabourin, Nicolas de Prost, Juliette Guitard, Frederique Boquel, Valérie Letscher-Bru, Jeff Morcet, Stephan Ehrmann, Guillaume Voiriot, Solène Le Gal, Florent Morio, Bruno Laviolle, Jean-Christophe Richard, Laurent Argaud, Estelle Cateau, Marion Blaize, Matthieu Lesouhaitier, Patrice Le Pape, Carole Schwebel, Florent Wallet, Jordan Leroy, Jean-Ralph Zahar, Ana Novara, Hélène Guegan, Béatrice Riu-Poulenc, Florence Robert-Gangneux, Jean Menotti, Eric Dannaoui, Sorya Belaz, Yves Le Tulzo, Muriel Cornet, Saad Nseir, Ferhat Meziani, Damien Dupont, Boualem Sendid, Antoine Monsel, Florian Reizine, Xavier Iriart, Francoise Botterel, Arnaud Fekkar, Charles-Edouard Luyt, Cécile Garnaud, Melek Manai, Lionel Lamhaut, Jean-Marc Tadié, Julien Mayaux, Sylvie Paulus, Florence Persat, Marie-Elisabeth Bougnoux, Christophe Hennequin, Christine Bonnal, Arnaud W. Thille, Antoine Berry, Sandrine Houze, Guillaume Desoubeaux, Centre Hospitalier Universitaire [Rennes], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Lille, Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Avicenne [AP-HP], Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Necker - Enfants Malades [AP-HP], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Strasbourg, and CarMeN, laboratoire

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Multivariate analysis, Coronavirus disease 2019 (COVID-19), medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, Intensive care, Internal medicine, medicine, Humans, education, Mechanical ventilation, education.field_of_study, Coinfection, SARS-CoV-2, business.industry, Mucormycosis, COVID-19, Articles, Odds ratio, medicine.disease, [SDV] Life Sciences [q-bio], Mycoses, business, Cohort study
Abstract

International audience; BACKGROUND: Patients with severe COVID-19 have emerged as a population at high risk of invasive fungal infections (IFIs). However, to our knowledge, the prevalence of IFIs has not yet been assessed in large populations of mechanically ventilated patients. We aimed to identify the prevalence, risk factors, and mortality associated with IFIs in mechanically ventilated patients with COVID-19 under intensive care. METHODS: We performed a national, multicentre, observational cohort study in 18 French intensive care units (ICUs). We retrospectively and prospectively enrolled adult patients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and requiring mechanical ventilation for acute respiratory distress syndrome, with all demographic and clinical and biological follow-up data anonymised and collected from electronic case report forms. Patients were systematically screened for respiratory fungal microorganisms once or twice a week during the period of mechanical ventilation up to ICU discharge. The primary outcome was the prevalence of IFIs in all eligible participants with a minimum of three microbiological samples screened during ICU admission, with proven or probable (pr/pb) COVID-19-associated pulmonary aspergillosis (CAPA) classified according to the recent ECMM/ISHAM definitions. Secondary outcomes were risk factors of pr/pb CAPA, ICU mortality between the pr/pb CAPA and non-pr/pb CAPA groups, and associations of pr/pb CAPA and related variables with ICU mortality, identified by regression models. The MYCOVID study is registered with ClinicalTrials.gov, NCT04368221. FINDINGS: Between Feb 29 and July 9, 2020, we enrolled 565 mechanically ventilated patients with COVID-19. 509 patients with at least three screening samples were analysed (mean age 59·4 years [SD 12·5], 400 [79%] men). 128 (25%) patients had 138 episodes of pr/pb or possible IFIs. 76 (15%) patients fulfilled the criteria for pr/pb CAPA. According to multivariate analysis, age older than 62 years (odds ratio [OR] 2·34 [95% CI 1·39-3·92], p=0·0013), treatment with dexamethasone and anti-IL-6 (OR 2·71 [1·12-6·56], p=0·027), and long duration of mechanical ventilation (\textgreater14 days; OR 2·16 [1·14-4·09], p=0·019) were independently associated with pr/pb CAPA. 38 (7%) patients had one or more other pr/pb IFIs: 32 (6%) had candidaemia, six (1%) had invasive mucormycosis, and one (\textless1%) had invasive fusariosis. Multivariate analysis of associations with death, adjusted for candidaemia, for the 509 patients identified three significant factors: age older than 62 years (hazard ratio [HR] 1·71 [95% CI 1·26-2·32], p=0·0005), solid organ transplantation (HR 2·46 [1·53-3·95], p=0·0002), and pr/pb CAPA (HR 1·45 [95% CI 1·03-2·03], p=0·033). At time of ICU discharge, survival curves showed that overall ICU mortality was significantly higher in patients with pr/pb CAPA than in those without, at 61·8% (95% CI 50·0-72·8) versus 32·1% (27·7-36·7; p\textless0·0001). INTERPRETATION: This study shows the high prevalence of invasive pulmonary aspergillosis and candidaemia and high mortality associated with pr/pb CAPA in mechanically ventilated patients with COVID-19. These findings highlight the need for active surveillance of fungal pathogens in patients with severe COVID-19. FUNDING: Pfizer.

Published
2022

39. Effect of Remdesivir on Viral Dynamics in COVID-19 Hospitalized Patients: A Modelling Analysis of the Randomized, Controlled, Open-Label DisCoVeRy Trial

Author

Guillaume Lingas, Nadège Néant, Alexandre Gaymard, Drifa Belhadi, Gilles Peytavin, Maya Hites, Thérèse Staub, Richard Greil, Jose-Artur Paiva, Julien Poissy, Nathan Peiffer-Smadja, Dominique Costagliola, Yazdan Yazdanpanah, Florent Wallet, Amandine Gagneux-Brunon, France Mentré, Florence Ader, Charles Burdet, Jérémie Guedj, Maude Bouscambert-Duchamp, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut des Agents Infectieux [Lyon] (IAI), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR - laboratoire associé), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Centro Hospitalar Universitário São João - Faculty of Medicine - University of Porto - Grupo de Infecção e Sepsis, Porto, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Services de Maladies Infectieuses et Tropicales [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imperial College London, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Emergence de la résistance bactérienne in vivo (EA3964), and Université Paris Diderot - Paris 7 (UPD7)

Subjects
Pharmacology, Microbiology (medical), Alanine, Infectious Diseases, SARS-CoV-2, Humans, Pharmacology (medical), Antiviral Agents, Adenosine Monophosphate, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, COVID-19 Drug Treatment
Abstract

Background The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. Objectives To estimate the effect of remdesivir in blocking viral replication. Methods We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT 04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). Results In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5–3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0–1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8–25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9–4.5 days). Conclusions Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

Published
2022

40. Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19

Author

Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, France Mentré, Charles Burdet, Jérôme Aboab, Hafid Ait-Oufella, Antoine Altdorfer, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, Drifa Belhadi, Leila Belkhir, François Benezit, Marc Berna, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, David Boutoille, Alexandre Boyer, Sandra Braz, Cédric Bruel, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Dominique Costagliola, Sandrine Couffin-Cadièrgues, Johan Courjon, Flora Crockett, François Danion, Aline Dechanet, Agathe Delbove, Jean Dellamonica, Christelle Delmas, Alpha Diallo, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Alexander Egle, Olivier Epaulard, Loïc Epelboin, Hélène Esperou, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Joao-Miguel Ferreira Ribeiro, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Claire Fougerou, Vincent Fraipont, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Alexandre Gaymard, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Richard Greil, Didier Gruson, Jérémie Guedj, Yves Hansmann, Olivier Hinschberger, Stéphane Jaureguiberry, Vanessa Jeanmichel, Michael Joannidis, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Bernd Lamprecht, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Minh-Patrick Lê, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Bruno Lina, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, Noémie Mercier, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Bruno Mourvilliers, Marlène Murris-Espin, Jean-Christophe Navellou, Marion Noret, Saad Nseir, Walid Oulehri, José-Artur Paiva, Thomas Perpoint, Gilles Peytavin, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Julien Poissy, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Jean Reuter, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Roberto Roncon-Albuquerque, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Juliette Saillard, Naomi Sayre, Eric Senneville, Albert Sotto, Thérèse Staub, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Sarah Tubiana, Jean-Marie Turmel, Florent Valour, Fanny Vardon-Bounes, Priyanka Velou, Gil Verschelden, Florent Wallet, Guilhem Wattecamps, Yazdan Yazdanpanah, Yoann Zerbib, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale

Subjects
Hospitalization, Clinical Trials as Topic, Alanine, Infectious Diseases, COVID-19, Humans, Adenosine Monophosphate, COVID-19 Drug Treatment
Published
2022

41. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

Author

Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Minh-Patrick Lê, Gilles Peytavin, Thérèse Staub, Richard Greil, Jérémie Guedj, Jose-Artur Paiva, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Alexander Egle, Michael Joannidis, Bernd Lamprecht, Antoine Altdorfer, Leila Belkhir, Vincent Fraipont, Gil Verschelden, Jérôme Aboab, Hafid Ait-Oufella, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, François Benezit, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, David Boutoille, Alexandre Boyer, Cédric Bruel, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Johan Courjon, Flora Crockett, François Danion, Agathe Delbove, Jean Dellamonica, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Olivier Epaulard, Loïc Epelboin, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Didier Gruson, Yves Hansmann, Olivier Hinschberger, Stéphane Jaureguiberry, Vanessa Jeanmichel, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Marlène Murris-Espin, Jean-Christophe Navellou, Saad Nseir, Walid Oulehri, Thomas Perpoint, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Naomi Sayre, Eric Senneville, Albert Sotto, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Jean-Marie Turmel, Florent Valour, Florent Wallet, Guilhem Wattecamps, Yoann Zerbib, Marc Berna, Jean Reuter, Sandra Braz, Joao-Miguel Ferreira Ribeiro, José-Artur Paiva, Roberto Roncon-Albuquerque, Alexandre Gaymard, Bruno Lina, Sarah Tubiana, Sandrine Couffin-Cadièrgues, Hélène Esperou, Aline Dechanet, Christelle Delmas, Claire Fougerou, Noémie Mercier, Marion Noret, Juliette Saillard, Priyanka Velou, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Internal Medicine, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Imperial College London, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Universidade do Porto = University of Porto, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, 030204 cardiovascular system & hematology, Antiviral Agents, law.invention, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, Randomized controlled trial, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, law, Internal medicine, Humans, Medicine, media_common.cataloged_instance, 030212 general & internal medicine, European union, education, Contraindication, ComputingMilieux_MISCELLANEOUS, Aged, media_common, Mechanical ventilation, education.field_of_study, Alanine, business.industry, COVID-19, Standard of Care, Odds ratio, Articles, Middle Aged, Respiration, Artificial, Adenosine Monophosphate, COVID-19 Drug Treatment, 3. Good health, Europe, Hospitalization, Oxygen, Clinical trial, Infectious Diseases, Clinical research, Female, business
Abstract

Summary Background The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding European Union Commission, French Ministry of Health, Domaine d'interet majeur One Health Ile-de-France, REACTing, Fonds Erasme-COVID-Universite Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation For the French translation of the abstract see Supplementary Materials section.

Published
2021

42. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19

Author

Lionel Piroth, Bruno Mourvillier, Joy Mootien, François-Xavier Lescure, Emmanuel Faure, S. Gallien, Dominique Costagliola, Jean-Christophe Richard, Noemie Mercier, Florent Wallet, Yazdan Yazdanpanah, Marion Noret, Claire Andrejak, Jean-Philippe Lanoix, Julien Poissy, Johan Courjon, Saad Nseir, François Danion, Violaine Tolsma, Alain Makinson, Odile Launay, Raphaël Clere-Jehl, Bruno Lina, Drifa Belhadi, Valérie Pourcher, Antoine Kimmoun, Karine Lacombe, Juliette Saillard, Maude Bouscambert-Duchamp, Stéphane Jauréguiberry, Charles Burdet, Toni Alfaiate, Olivier Epaulard, Minh Patrick Lê, Gilles Peytavin, Elisabeth Botelho-Nevers, Thérèse Staub, Guillaume Martin-Blondel, Alpha Diallo, Lila Bouadma, Aline Dechanet, François Goehringer, Florence Ader, Nathan Peiffer-Smadja, Jean-Christophe Navellou, Christelle Delmas, Rostane Gaci, Kevin Bouiller, Maya Hites, André Cabié, Jean Reuter, Sylvie Leroy, Axelle Dupont, François Raffi, Amandine Gagneux-Brunon, Jean Reignier, Clément Dubost, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, National Institute for Health Research [Cambridge, UK], Imperial College London, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Lille, Centre National de Reference des virus des Infections Respiratoires France Sud [HCL, Lyon], Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS France Recherche Nord & sud Sida-hiv hépatites, Institut de Santé Publique, Université de Médecine Carol Davila, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Service de Réanimation Médicale [CHRU Nancy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre National de Référence du Paludisme [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), Les Hôpitaux Universitaires de Strasbourg (HUS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Nouvel Hôpital Civil de Strasbourg, Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Etablissement français du don du sang [Montpellier], CHU de la Martinique [Fort de France], Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Université Paris-Saclay, Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université de Paris (UP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Reims Champagne-Ardenne (URCA), Université Lille Nord de France (COMUE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP)-Groupe hospitalier Broca-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Physiopathologie et biothérapies des infections muqueuses (GIMAP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Fédération d’Infectiologie Multidisciplinaire de l’Arc Alpin [CHU Grenoble-Alpes], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Institut des Agents Infectieux [Lyon] (IAI), Réseau national de recherche clinique en infectiologie (RENARCI), CHU Amiens-Picardie, Université libre de Bruxelles (ULB), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Université de Lorraine (UL), Hôpital Bicêtre, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Université des Antilles (UA)-Etablissement français du don du sang [Montpellier]-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université de Lille, Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Département d'Epidemiologie, Biostatistique et Recherche Clinique (DEBRC), Centre National de Référence du Paludisme [CHU Pitié-Salpétrière] (CNRpalu), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service des maladies infectieuses et tropicales [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM), CHU Grenoble, Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Laboratoire Chrono-environnement (UMR 6249) (LCE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Lopinavir/ritonavir, law.invention, 0302 clinical medicine, Randomized controlled trial, law, immune system diseases, MESH: Antiviral Agents* / therapeutic use, 030212 general & internal medicine, MESH: Treatment Outcome, education.field_of_study, MESH: Middle Aged, virus diseases, Lopinavir, General Medicine, MESH: Lopinavir / therapeutic use, 3. Good health, Infectious Diseases, MESH: Interferon beta-1a / therapeutic use, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Pharmaceutical Preparations, MESH: Hydroxychloroquine / therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, medicine.drug, Hydroxychloroquine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, Antiviral Agents, 03 medical and health sciences, Interferon β-1a, Internal medicine, medicine, Humans, education, Adverse effect, MESH: COVID-19* / drug therapy, MESH: Drug Combinations, MESH: Humans, business.industry, SARS-CoV-2, Drug Repositioning, Interferon beta-1a, COVID-19, MESH: Adult, MESH: Male, MESH: Ritonavir / therapeutic use, Ritonavir, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Objectives: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.Methods: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely.Results: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.Conclusion: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Published
2021

43. Troponin measurement for risk stratification after cytoreductive surgery

Author

Guillaume Passot, Florent Wallet, C.-H. Vacheron, Vincent Piriou, Naoual Bakrin, A. Lambert, Arnaud Friggeri, Delphine Vaudoyer, M. Fauvernier, V. Kepenekian, Olivier Glehen, and Olivia Vassal

Subjects
medicine.medical_specialty, biology, business.industry, macromolecular substances, Cytoreduction Surgical Procedures, Debulking, Troponin, Risk Assessment, Stratification (mathematics), Internal medicine, Risk stratification, medicine, biology.protein, Cardiology, Troponin measurement, Humans, Surgery, Postoperative Period, Cytoreductive surgery, business, Biomarkers
Abstract

Several studies have raised interest in the use of postoperative troponin levels to stratify risk of postoperative morbidity and mortality. In this study, postoperative troponin concentration after cytoreductive surgery (with or without hyperthermic intraoperative intraperitoneal chemotherapy) was associated with severe postoperative complications, and enhanced the predictive capability of a multivariable model focusing on postoperative complications.

Published
2021

44. BMI and pneumonia outcomes in critically ill COVID‐19 patients: an international multicenter study

Author

Charles Cerf, M. Jourdain, Julie Helms, Morgane Snacken, Benjamine Sarton, Mikael Chetboun, Mitchell M. Levy, Erwan L'Her, Violeta Raverdy, Romaric Larcher, Fabienne Tamion, Massimo Antonelli, Dror Dicker, Alain Duhamel, Emilie Occhiali, Stein Silva, Simone Piva, Loay Kontar, Florent Wallet, Markos Kalligeros, Dimitrios Karamanis, Shaul Lev, Victoria Dubar, François Pattou, Ferhat Meziani, Mathilde Neuville, Julien Labreuche, Luca Busetto, Eleftherios Mylonakis, Leonidas Palaiodimos, Antonio Artigas, Juliette Perche, Cyrielle Caussy, Gemma Gomà, Kada Klouche, Nicola Latronico, Antoine Riviere, Raphael Krouchi, Arthur Simonnet, Jean-Charles Preiser, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Intégré Nord Francilien de l'Obésité (CINFO), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Corporació Sanitària Parc Taulí, CHU Strasbourg, Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Rhode Island Hospital [Providence, RI, États-Unis], Warren Alpert Medical School of Brown University, Università degli Studi di Brescia [Brescia], Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Hôpital Foch [Suresnes], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Rouen, Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université libre de Bruxelles (ULB), CHU Amiens-Picardie, Centre Hospitalier d'Abbeville, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], CH de Dunkerque, Albert Einstein College of Medicine [New York], University of Piraeus, CH de Roubaix, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de Traitement de l'Information Medicale (LaTIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Universita degli Studi di Padova, Rabin Medical Center - Beilinson and Hasharon Hospitals [Petach-Tikva, Israel], Tel Aviv University [Tel Aviv], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università degli Studi di Brescia = University of Brescia (UniBs), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Università degli Studi di Padova = University of Padua (Unipd), and Tel Aviv University (TAU)

Subjects
Male, medicine.medical_specialty, Critical Care, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Critical Illness, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), 030209 endocrinology & metabolism, Logistic regression, COVID-19, Obesity, Prevention, Risk Factors, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, COVID‐19, Internal medicine, Diabetes mellitus, Intensive care, medicine, Humans, 030212 general & internal medicine, Israel, Retrospective Studies, Mechanical ventilation, Nutrition and Dietetics, business.industry, Retrospective cohort study, Pneumonia, Middle Aged, medicine.disease, United States, 3. Good health, Europe, Covid‐19 Call for Papers, Female, business, Body mass index
Abstract

International audience; Objective: Previous studies have unveiled a relationship between the severity of coronavirus disease 2019 (COVID-19) pneumonia and obesity. The aims of this multicenter retrospective cohort study were to disentangle the association of BMI and associated metabolic risk factors (diabetes, hypertension, hyperlipidemia, and current smoking status) in critically ill patients with COVID-19.Methods: Patients admitted to intensive care units for COVID-19 in 21 centers (in Europe, Israel, and the United States) were enrolled in this study between February 19, 2020, and May 19, 2020. Primary and secondary outcomes were the need for invasive mechanical ventilation (IMV) and 28-day mortality, respectively.Results: A total of 1,461 patients were enrolled; the median (interquartile range) age was 64 years (40.9-72.0); 73.2% of patients were male; the median BMI was 28.1 kg/m2 (25.4-32.3); a total of 1,080 patients (73.9%) required IMV; and the 28-day mortality estimate was 36.1% (95% CI: 33.0-39.5). An adjusted mixed logistic regression model showed a significant linear relationship between BMI and IMV: odds ratio = 1.27 (95% CI: 1.12-1.45) per 5 kg/m2 . An adjusted Cox proportional hazards regression model showed a significant association between BMI and mortality, which was increased only in obesity class III (≥40; hazard ratio = 1.68 [95% CI: 1.06-2.64]).Conclusions: In critically ill COVID-19 patients, a linear association between BMI and the need for IMV, independent of other metabolic risk factors, and a nonlinear association between BMI and mortality risk were observed.

Published
2021

45. Description of neurotoxicity in a series of patients treated with CAR T-cell therapy

Author

Lila Sirven-Villaros, Sylvain Lamure, Thomas Gastinne, Florent Wallet, Antoine F. Carpentier, Benoit Tessoulin, David Laplaud, Claire Simard, Catherine Belin, Elie Azoulay, Adrien Paix, Catherine Thieblemont, Perrine Devic, Guillaume Cartron, Renata Ursu, Laura Platon, Xavier Ayrignac, Emmanuel Bachy, Colette Berger, Amélie Dos Santos, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Radiothérapie de Bobigny, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Hopital Saint-Louis [AP-HP] (AP-HP)

Subjects
CAR-T cell therapy, Adult, Male, medicine.medical_specialty, Lymphoma, B-Cell, Lymphoma, medicine.medical_treatment, Receptors, Antigen, T-Cell, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunotherapy, Adoptive, Severity of Illness Index, Article, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Neurotoxicity syndromes, Internal medicine, Severity of illness, Neurotoxicity, medicine, Humans, Prospective Studies, lcsh:Science, Prospective cohort study, Survival analysis, Aged, 030304 developmental biology, 0303 health sciences, Multidisciplinary, business.industry, lcsh:R, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Immunotherapy, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Cytokine release syndrome, C-Reactive Protein, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Female, business
Abstract

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1–2 severity and 34% had grade 3–4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3–4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

Published
2020

46. Respiratory Mechanics and Outcomes in Immunocompromised Patients With ARDS

Author

Alexandre Demoule, Massimo Antonelli, Peter Schellongowski, Peter Pickkers, Marcio Soares, Tine Meyhoff, Jordi Rello, Philippe R. Bauer, Andry van de Louw, Virgine Lemiale, David Grimaldi, Ignacio Martin-Loeches, Martin Balik, Sangeeta Mehta, Achille Kouatchet, Andreas Barratt-Due, Miia Valkonen, Jean Reignier, Victoria Metaxa, Anne-Sophie Moreau, Gaston Burghi, Djamel Mokart, Julien Mayaux, Michael Darmon, Elie Azoulay, Karin Amrein, Thomas Staundinger, Gottfried Heinz, Gürkan Sengölge, Christian Zauner, Peter Jaksch, Fabio S. Taccone, Anne Pascale Meert, Dominique Benoît, Ulysses V.A. Silva, Ana Paula Pierre de Moraes, Thiago Lishoa, Jorge Salluh, William Viana, Guilliana Moralez, Thiago Domingos Correa, Umesh Shah, Thomas Karvunidis, Balik Martin, Katerina Russinova, Anders Perner, Tine Sylvest Meyhoff, Nielsen Jonas, Ramin Brandt Bukan, Ann M. Moeller, Lene B. Nielsen, Amélie Seguin, Akli Chermak, Nicolas Terzi, Isabelle Vinatier, Florent Wallet, Kada Klouche, Laura Platon, Benjamin Gaborit, François Barbier, Frederic Pène, Antoine Rabbat, Virginie Lemiale, Martine N'Yunga, Christophe Girault, Caroline Lemaitre, Elise Artaud-Macari, F. Bruneel, Anne Sophie Moreau, Anne Kuitunen, Brian Marsh, Mater Misericordia, Aisling Mc Mahon, Gilda Cinnella, Antonella Cotoia, Ospedali Riuniti, Lucas Montini, Angélique Spoelstra de Man, Precious Pearl Landburg, Dennis Bergmans, Pleun Hemelaar, Thomas Kaufmann, Andreas Barrat-Due, Pål Klepstad, Belen Encina, Gabriel Moreno, Llorenç Socias Crespi, Emilio Rodriguez-Ruiz, Andry Van De Louw, Philippe Bauer, Yadav Hemang, Service de Pneumologie et Réanimation Médicale [CHU Pitié-Salpêtrière] (Département ' R3S '), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Medizinische Universität Wien = Medical University of Vienna, Radboud University Medical Centre [Nijmegen, The Netherlands], University of Copenhagen = Københavns Universitet (KU), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Mayo Clinic [Rochester], Penn State Health Milton S. Hershey Medical Center, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Trinity College Dublin, Charles Darwin University, University of Toronto, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Oslo University Hospital [Oslo], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Service d'anesthésie et réanimation chirurgicale [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), King's College Hospital (KCH), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pulmonary and Respiratory Medicine, ARDS, medicine.medical_specialty, MESH: Respiratory Distress Syndrome, medicine.medical_treatment, Population, Respiratory physiology, Neutropenia, Critical Care and Intensive Care Medicine, Acute respiratory failure, MESH: Tidal Volume, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Prognosis, 03 medical and health sciences, MESH: Positive-Pressure Respiration, 0302 clinical medicine, Diagnosis, medicine, MESH: Immunocompromised Host, Renal replacement therapy, education, Immunocompromised, Tidal volume, Outcome, MESH: Aged, education.field_of_study, MESH: Humans, MESH: Middle Aged, business.industry, Mortality rate, 030208 emergency & critical care medicine, MESH: Follow-Up Studies, Plateau pressure, medicine.disease, MESH: Male, MESH: Prospective Studies, 3. Good health, 030228 respiratory system, Emergency medicine, Driving pressure, Etiology, MESH: Respiratory Mechanics, Cardiology and Cardiovascular Medicine, business, MESH: Female
Abstract

International audience; Background: In view of the high mortality rate of immunocompromised patients with ARDS, it is important to identify targets for improvement.Research question: This study investigated factors associated with mortality in this specific ARDS population, including factors related to respiratory mechanics (plateau pressure [Pplat,rs], compliance [Crs], and driving pressure [ΔPrs]).Study design and methods: This study consisted of a predefined secondary analysis of the EFRAIM data. Overall, 789 of 1,611 patients met the Berlin criteria for ARDS, and Pplat,rs, ΔPrs, and Crs were available for 494 patients. A hierarchical model was used to assess factors at ARDS onset independently associated with hospital mortality.Results: Hospital mortality was 56.3%. After adjustment, variables independently associated with hospital mortality included ARDS of undetermined etiology (OR, 1.66; 95% CI, 1.01-2.72), need for vasopressors (OR, 1.91; 95% CI, 1.27-2.88), and need for renal replacement therapy (OR, 2.02; 95% CI, 1.37-2.97). ARDS severity according to the Berlin definition, neutropenia on admission, and the type of underlying disease were not significantly associated with mortality. Before adjustment, higher Pplat,rs, higher ΔPrs, and lower Crs were associated with higher mortality. Addition of each of these individual variables to the final hierarchical model revealed a significant association with mortality: ΔPrs (OR, 1.08; 95% CI, 1.05-1.12), Pplat,rs (OR, 1.07; 95% CI, 1.04-1.11), and Crs (OR, 0.97; 95% CI, 0.95-0.98). Tidal volume was not associated with mortality.Interpretation: In immunocompromised patients with ARDS, respiratory mechanics provide additional prognostic information to predictors of hospital mortality. Studies designed to define lung-protective ventilation guided by these physiological variables may be warranted in this specific population.

Published
2020

47. Non-invasive ventilation versus high-flow nasal cannula oxygen therapy with apnoeic oxygenation for preoxygenation before intubation of patients with acute hypoxaemic respiratory failure: a randomised, multicentre, open-label trial

Author

Jean-Pierre Frat, Jean-Damien Ricard, Jean-Pierre Quenot, Nicolas Pichon, Alexandre Demoule, Jean-Marie Forel, Jean-Paul Mira, Rémi Coudroy, Guillaume Berquier, Benoit Voisin, Gwenhaël Colin, Bertrand Pons, Pierre Eric Danin, Jérome Devaquet, Gwenael Prat, Raphaël Clere-Jehl, Franck Petitpas, Emmanuel Vivier, Keyvan Razazi, Mai-Anh Nay, Vincent Souday, Jean Dellamonica, Laurent Argaud, Stephan Ehrmann, Aude Gibelin, Christophe Girault, Pascal Andreu, Philippe Vignon, Laurence Dangers, Stéphanie Ragot, Arnaud W Thille, Delphine Chatellier, Florence Boissier, Anne Veinstein, René Robert, Céline Deletage-Métreau, Morgane Olivry, Claire Dahyot-Fizelier, Auguste Dargent, Audrey Large, Emmanuelle Begot, Claire Mancia, Maxence Decavele, Martin Dres, Samuel Lehingue, Laurent Papazian, Marine Paul, Nathalie Marin, Matthieu Le Meur, Mohammed Laissy, Anaita Rouzé, Saad Nseir, Matthieu Henry-Lagarrigue, Aihem Yehia, Frédéric Martino, Charles Cerf, Pierre Bailly, Julie Helms, Jean Baptiste Putegnat, Armand Mekontso-Dessap, Thierry Boulain, Pierre Asfar, Séverin Cabasson, Florent Wallet, Kada Klouche, Frédéric Bellec, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Service de Réanimation Médicale (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction Générale de l'Organisation des Soins (DGOS)-Université de Bourgogne (UB), Hôpital Dupuytren [CHU Limoges], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Charles Foix [AP-HP], Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Nord [CHU - APHM], Aix Marseille Université (AMU), GHU AP-HP Centre Université de Paris, Hôpital Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Hôpital Foch [Suresnes], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Nouvel Hôpital Civil de Strasbourg, Université de Strasbourg (UNISTRA), Les Hôpitaux Universitaires de Strasbourg (HUS), Centre hospitalier Saint Joseph - Saint Luc [Lyon], CHU Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche sur le Handicap Ventilatoire (GRHV), Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CHU Rouen, Normandie Université (NU), CHU Rouen, Centre d'Investigation Clinique de Limoges (CIC1435), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM), Delphine Chatellier, Florence Boissier, Anne Veinstein, René Robert, Céline Deletage-Métreau, Morgane Olivry, Claire Dahyot-Fizelier, Auguste Dargent, Audrey Large, Emmanuelle Begot, Claire Mancia, Maxence Decavele, Martin Dres, Samuel Lehingue, Laurent Papazian, Marine Paul, Nathalie Marin, Matthieu Le Meur, Mohammed Laissy, Anaita Rouzé, Saad Nseir, Matthieu Henry-Lagarrigue, Aihem Yehia, Frédéric Martino, Charles Cerf, Pierre Bailly, Julie Helms, Jean Baptiste Putegnat, Armand Mekontso-Dessap, Thierry Boulain, Pierre Asfar, Séverin Cabasson, Florent Wallet, Kada Klouche, Frédéric Bellec, Delphine Chatellier, Florence Boissier, Anne Veinstein, René Robert, Céline Deletage-Métreau, Morgane Olivry, Maxence Decavele, Martin Dres, Samuel Lehingue, Laurent Papazian, Matthieu Le Meur, Mohammed Laissy, Anaita Rouzé, Saad Nseir, Matthieu Henry-Lagarrigue, Aihem Yehia, Charles Cerf, Armand Mekontso-Dessap, Thierry Boulain, Pierre Asfar, CCSD, Accord Elsevier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Réanimation, Hôpital Jean Bernard, CHU de Poitiers, Poitiers, France, Equipe LIPNESS (LNC - U1231) (LIPNESS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Coordination des Prélèvements d’Organes et de Tissus (CHPOT), CHU Limoges, Service de Pneumologie et Réanimation Médicale [CHU Pitié-Salpêtrière] (Département ' R3S '), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire pluridisciplinaire de recherche en ingénierie des systèmes, mécanique et énergétique (PRISME), Université d'Orléans (UO)-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Centre d'Etudes Lasers Intenses et Applications (CELIA), Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Service de Réanimation Médicale [Strasbourg], Institut universitaire des systèmes thermiques industriels (IUSTI), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation Médicale [Hôpital de l’Archet], Centre Hospitalier Universitaire de Nice (CHU de Nice)-Hôpital de l'Archet, Service de Réanimation Médicale, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France, parent, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Limoges, Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and CHU Henri Mondor [Créteil]

Subjects
Pulmonary and Respiratory Medicine, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Nose, medicine.disease_cause, Catheterization, 03 medical and health sciences, 0302 clinical medicine, Fraction of inspired oxygen, Intensive care, Oxygen therapy, medicine, Intubation, Intratracheal, Intubation, Humans, Oximetry, Hypoxia, Noninvasive Ventilation, medicine.diagnostic_test, business.industry, Tracheal intubation, Oxygen Inhalation Therapy, 030208 emergency & critical care medicine, Middle Aged, Respiration, Artificial, 3. Good health, [SDV] Life Sciences [q-bio], Pulse oximetry, 030228 respiratory system, Respiratory failure, Anesthesia, Acute Disease, Female, business, Respiratory Insufficiency, Nasal cannula
Abstract

International audience; BACKGROUND: Non-invasive ventilation has never been compared with high-flow oxygen to determine whether it reduces the risk of severe hypoxaemia during intubation. We aimed to determine if preoxygenation with non-invasive ventilation was more efficient than high-flow oxygen in reducing the risk of severe hypoxaemia during intubation. METHODS: The FLORALI-2 multicentre, open-label trial was done in 28 intensive care units in France. Adult patients undergoing tracheal intubation for acute hypoxaemic respiratory failure (a partial pressure of arterial oxygen [PaO2] to fraction of inspired oxygen [FiO2] ratio of \textless/=300 mm Hg) were randomly assigned (1:1; block size, four participants) to non-invasive ventilation or high-flow oxygen during preoxygenation, with stratification by PaO2/FiO2 ratio (\textless/=200 mm Hg vs \textgreater200 mm Hg). Key exclusion criteria were intubation for cardiac arrest, altered consciousness (defined as a Glasgow coma score of less than eight points), other contraindications to non-invasive ventilation (recent laryngeal, oesophageal, or gastric surgery, and substantial facial fractures), pulse oximetry not available, pregnant or breastfeeding women, and refusal to participate. The primary outcome was the occurrence of severe hypoxaemia (pulse oximetry \textless80%) during the procedure, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02668458. FINDINGS: Between April 15, 2016, and Jan 8, 2017, 2079 patients were intubated in the 28 participating units, and 322 were enrolled. We excluded five patients with no recorded data, two who withdrew consent or were under legal protection, one who was not intubated, and one who had a cardiac arrest. Of the 313 patients included in the intention-to-treat analysis, 142 were assigned to non-invasive ventilation and 171 to high-flow oxygen therapy. Severe hypoxaemia occurred in 33 (23%) of 142 patients after preoxygenation with non-invasive ventilation and 47 (27%) of 171 with high-flow oxygen (absolute difference -4.2%, 95% CI -13.7 to 5.5; p=0.39). In the 242 patients with moderate-to-severe hypoxaemia (PaO2/FiO2 \textless/=200 mm Hg), severe hypoxaemia occurred less frequently after preoxygenation with non-invasive ventilation than with high-flow oxygen (28 [24%] of 117 patients vs 44 [35%] of 125; adjusted odds ratio 0.56, 0.32 to 0.99, p=0.0459). Serious adverse events did not differ between treatment groups, with the most common immediate complications being systolic arterial hypotension (70 [49%] patients in the non-invasive ventilation group vs 86 [50%] patients in the high-flow oxygen group) and chest infiltrate on x-ray (28 [20%] vs 33 [19%]), and the most common late complications being death at day 28 (53 [37%] vs 58 [34%]) and ventilator-associated pneumonia during ICU stay (31 [22%] vs 35 [20%]). INTERPRETATION: In patients with acute hypoxaemic respiratory failure, preoxygenation with non-invasive ventilation or high-flow oxygen therapy did not change the risk of severe hypoxaemia. Future research should explore the effect of preoxygenation method in patients with moderate-to-severe hypoxaemia at baseline. FUNDING: French Ministry of Health.

Published
2019

48. Sinusoidal Obstruction Syndrome in Critically Ill Patients in the Era of Defibrotide: A Retrospective Multicenter Study

Author

Pierre-Edouard Debureaux, Michael Darmon, Elie Azoulay, Emmanuel Canet, Julien Mayaux, Claire Lacan, Pierre Perez, Sandrine Valade, Achille Kouatchet, Naïke Bigé, Muriel Picard, Martin Murgier, Florent Wallet, Anne Sophie Moreau, Djamel Mokart, Frédéric Pène, and Guillaume Morel

Subjects
Adult, medicine.medical_specialty, medicine.medical_treatment, Critical Illness, Hepatic Veno-Occlusive Disease, Defibrotide, law.invention, Polydeoxyribonucleotides, law, medicine, Immunology and Allergy, Humans, Renal replacement therapy, Aged, Retrospective Studies, Mechanical ventilation, Transplantation, business.industry, Hazard ratio, Acute kidney injury, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Cell Biology, Hematology, medicine.disease, Intensive care unit, Respiratory failure, Emergency medicine, Molecular Medicine, business, medicine.drug
Abstract

Sinusoidal obstruction syndrome (SOS) is a life-threatening liver complication of high- dose chemotherapy. Defibrotide is the only available therapeutic option approved for SOS. The prognosis of SOS in patients requiring intensive care unit (ICU) admission remains unknown. The primary objective of this study was to assess the outcome of SOS patients in ICU. This retrospective study was conducted between 2007 and 2019 in 13 French ICUs. Seventy-one critically ill adult patients with SOS defined according to European Society for Blood and Marrow Transplantation criteria and treated with defibrotide were included. The main reasons for ICU admission were respiratory failure and acute kidney injury. Mechanical ventilation, vasopressors, and renal replacement therapy were required in 59%, 52%, and 49% of patients, respectively. Twenty-three percent of patients experienced a bleeding event during defibrotide treatment. Hospital mortality was 54%, mainly related to multiorgan failure. Older age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00 to 1.04), mechanical ventilation (HR, 1.99; 95% CI, 1.00 to 3.99), renal replacement therapy (HR, 2.55; 95% CI, 1.32 to 4.91) were independent predictors of hospital mortality. Defibrotide prophylaxis (HR, 0.35; 95% CI, 0.13 to 0.92) was associated with better outcomes. Critically ill patients with SOS have a high mortality rate in the ICU, especially if organ support is required. Additional studies assessing the impact of defibrotide prophylaxis are warranted.

Published
2020

49. Immune monitoring of interleukin-7 compassionate use in a critically ill COVID-19 patient

Author

Sébastien Viel, Guillaume Monneret, Céline Bernet, Florence Ader, Donatien de Marignan, Fabienne Venet, Morgane Gossez, Emilie Frobert, Rémy Coudereau, Florent Wallet, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Compassionate Use Trials, Male, medicine.medical_specialty, Antifungal Agents, Coronavirus disease 2019 (COVID-19), Critical Illness, [SDV]Life Sciences [q-bio], Pneumonia, Viral, Immunology, Immune monitoring, Severe Acute Respiratory Syndrome, Betacoronavirus, Fatal Outcome, Viral genetics, Lymphopenia, Correspondence, medicine, Humans, Immunologic Factors, Immunology and Allergy, Intensive care medicine, Pandemics, Viral immunology, Aged, SARS-CoV-2, Critically ill, business.industry, Interleukin-7, COVID-19, Pneumonia, Ventilator-Associated, Compassionate Use, Interleukin, Diagnostic markers, Acute Kidney Injury, Respiration, Artificial, Anti-Bacterial Agents, Intensive Care Units, Infectious Diseases, Coronavirus Infections, business, Biomarkers
Abstract

International audience; No abstract available

Published
2020

50. Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans

Author

Annika Heuer, Abraham Hulst, NTIRENGANYA Faustin, Giacomo Monti, Stephen Choi, Edward J Caruana, Kresimir Oremus, Kathryn Haigh, Amanda Koh, Denis Protsenko, Ana Maria Minaya Bravo, Abegail Salvana, Mahdad Noursadeghi, Rhiannon Harries, Ayyaz Hussain, Sathish Muthu, Professor T E Madiba, Jie Wu, Maria Wittmann, Donaldo S Arteta-Arteta, Mona Momeni, Mary T. Nabukenya, Birender Balain, Irina Paziuk, Matthew Chan, TRIANTAFYLLIA KOUKOUBANI, Gabrielle Van Ramshorst, Gianluca Pellino, Haya Deeb, Daniele Sances, Salomone Di Saverio, Fernando Cordera, Olufemi Bankole, Patrice Forget, Chu Yik Tang, Daniel Conway, Alejandro Suarez de la Rica, E. Christiaan Boerma, Dion Morton, John Edwards, Markus W. Löffler, ANASTASIA SPARTINOU, Daiana Taddeo, VIKAS KAURA, David Choi, Akbar Vohra, Francesco Della Corte, Alexander Durst, Sebastian Tranca, Samuel Ford, Rajkumar Rajendram, Christina Bali, Bosede Afolabi, Nicola Petrucci, Anne Godier, Dmitri Nepogodiev, Rocco D'andrea, Dana Tomescu, Hans Lederhuber, LAURA GAVRIL, Chetan Khatri, Gabriela Droc, Rupert Pearse, Janet Martin, Ari Ercole, Ibironke Desalu, Dejan Radenkovic, Luis Martin-Villen, Alvaro Rea-Neto, Pablo Monedero, Thomas Pinkney, Stuart White, Antonino Spinelli, Manu Malbrain, Bisola Onajin-Obembe, Tom Lawton, Goran Tulic, R. Arthur Bouwman, Shaktiman Singh, Keith Couper, Benedikt Preckel, Osaid Alser, Isabel Gracia, Daniel Cox, Oumaima Outani, Luís Bento, Stephen Webb, Marzida Mansor, Florent Wallet, Konstantinos Stamatiou, Adesoji Ademuyiwa, Bodil Steen Rasmussen, James Glasbey, Nelson Barros, Adewale Adisa, Olanrewaju Akanmu, Ryckie Wade, Joana Berger-Estilita, Stefano Turi, Sigita Kazune, Ewen Harrison, Mihai Stefan, ANTHONY ADENEKAN, Dhruva Ghosh, Sohini Chakrabortee, Mary Venn, Irène Santos, Michael Sander, Vincent Minville, Francisco Javier Redondo Calvo, Naomi Wright, Ismaïl LAWANI, James Haddow, Axel R. Heller, Anders Oldner, Cesar Aldecoa, Savino Spadaro, Robert Parker, Jibril Bello, Tamas Szakmany, Dhruv Parekh, Alberto ZANGRILLO, LUC HUYGHENS, Beatriz Tena, Tom Abbott, Richard Wilkin, Ulrich Goebel, Anca Irina Ristescu, RODRIGO POVES ALVAREZ, Carlos Silva Faria, Hidde M Kroon, José Azevedo, Herman Lule, Orestis Ioannidis, Sandra Jumbe, Peter Hutchinson, Ayaz Ali, Caroline Holaubek, Luke Hopkins, Kirsten Moller, Morten Bestle, Patricia Alfaro de la Torre, Hyla-Louise Kluyts, Evgeny Grigoryev, Shaman Jhanji, Timothy Cook, Carolina Soledad Romero Garcia, Wolfgang Buhre, Denny Levett, Stefan De Hert, Bianchin Andrea, Monir Jawad, Nicoletta Fossati, Matthias Unterberg, Gianluca Castellani, Oliver Warren, Simon Burg, Jose Trenado Álvarez, Franco Ruberto, Adeline Rankin, Arash Afshari, Gerald Ekwen, Helena Barrasa, Andrew Schache, Carlos Ferrando, Johannes Doerner, Hwei Jene Ng, Ruth Blanco-Colino, Sean Ezekiel Seow, Artigas Antonio, Pablo Lozano Lominchar, Dennis Mazingi, Giovanni LANDONI, Martin Hübner, Weng Ken Chan, Hassan Mashbari, Milagros Niquen-Jimenez, Timothy Short, Mikhail Kirov, Alexander Kulikov, Abdulmueti Alhadi, Frederick Van der Merwe, Mahmoud ElFiky, Kai Henrik Wiborg Lange, Gaetano Gallo, Gustavo Mendonça Ataíde Gomes, Aneel Bhangu, Ioana Grigoras, Carlos Serón, Siobhan McKay, Ruth A Benson, Xavier Borrat, Markus Hollmann, Juan José Segura-Sampedro, Devnandan Chatterjee, and Birgitte Brandsborg

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, General surgery, 030230 surgery, 03 medical and health sciences, 0302 clinical medicine, Case mix index, Surgical recovery, Pandemic, medicine, Elective surgery, Elective Surgical Procedure, business, Elective caesarean, health care economics and organizations, Predictive modelling
Abstract

Background: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. Methods: A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β-regression model was used to estimate 12-week cancellation rates for 190 countries. Elective surgical case-mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country-level surgical volumes. The 12-week cancellation rates were then applied to these figures to calculate the total number of cancelled operations. Results: The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID-19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12-week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID-19 disruption. Conclusion: A very large number of operations will be cancelled or postponed owing to disruption caused by COVID-19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely.

Published
2020

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