Association Between Availability of ECMO and Mortality in COVID-19 Patients Eligible for ECMO: A Natural Experiment

RATIONALE: The outcomes of patients with COVID-19 who are medically eligible to receive ECMO, but do not because of limited health system capacity, have not been reported. METHODS: We analyzed prospectively collected clinical data from consecutive patients with SARS-CoV-2 referred for ECMO to a single center between January 1, 2021 and August 31, 2021. Each patient underwent a systematic assessment of medical eligibility to receive ECMO followed by a separate assessment of the health system's resources to provide ECMO. When health system resources were available, the patient was transferred to an ECMO center. When health system resources were not available, the patient was not transferred to an ECMO center and did not receive ECMO. Patients were followed until the time of death or hospital discharge. Among medically eligible patients, we compared those for whom health system capacity permitted transfer to receive ECMO to those for whom health system capacity did not permit transfer to receive ECMO with regard to the primary outcome of all-cause in-hospital mortality using Cox proportional hazards regression analysis adjusting for age, acute kidney injury, and receipt of vasopressors. RESULTS: Among the 240 patients with COVID-19 referred for ECMO, 90 patients (37.5%) were determined to be medically eligible to receive ECMO and were included in this study. Median age was 40 years (IQR, 34-48). The health system capacity to provide ECMO was available for 35 patients (38.9%), of whom 32 received ECMO and 3 died or developed a contraindication to ECMO after transfer but prior to cannulation. Death before hospital discharge occurred in 15 of the 35 patients (42.9%) for whom health system capacity permitted transfer to receive ECMO compared with 49 of the 55 patients (89.1%) for whom health system capacity did not permit transfer to receive ECMO (adjusted hazard ratio 0.23;95% confidence interval, 0.12 to 0.43;P < 0.001) (Figure 1). CONCLUSIONS: In this cohort of adults with COVID-19, nearly 90% of patients who were eligible for ECMO but did not receive it due to limited health system resources died before hospital discharge, despite young age and limited comorbidities. Periods of resource limitation during which provision of ECMO is determined by resource availability and not patient characteristics may act as a natural experiment, and these results suggest that ECMO provides a significant mortality benefit in the treatment of COVID- 19.

L'augmentation du pourcentage de lymphocytes Th17 est associée à un risque d'évolution vers une forme grave d'infection à SARS-CoV-2

Depuis décembre 2019, plus de 20 millions de français ont été infectés par le SARS-CoV-2 et plus de 130 000 en sont décédés. La physiopathologie de cette infection n'est pas totalement élucidée. Il a été démontré qu'elle provoquait une importante sécrétion de cytokines pro-inflammatoires, en particulier d'interleukine-6 (IL-6) [1]. Lorsque les patients infectés sont hospitalisés, ils reçoivent généralement de la dexaméthasone et parfois un traitement anti-infectieux. Si la maladie s'aggrave, le tocilizumab peut être ajouté [2]. Actuellement, seule l'évolution clinique incite à débuter le tocilizumab, mais parfois trop tardivement. Il manque aux cliniciens un marqueur précoce leur permettant de prédire le risque d'aggravation de la maladie. Cette étude, menée chez des patients hospitalisés pour infection à SARS-CoV-2 pendant la 2e vague, avait pour objectif de rechercher un marqueur d'aggravation de la maladie en comparant la réponse lymphocytaire entre les patients évoluant vers une forme grave et les autres. Les patients hospitalisés pour infection à SARS-CoV-2 prouvée par RT-PCR datant de moins d'une semaine ont été inclus prospectivement dans cette étude monocentrique. Une infection grave était définie par un transfert en soins intensifs, en réanimation ou le décès. Des prélèvements sanguins ont été obtenus à l'admission à l'hôpital et avant de débuter la corticothérapie afin d'étudier les sous-populations lymphocytaires par cytométrie en flux et doser l'IL-6 plasmatique par immunofluorimétrie. Les données sont exprimées en nombre (%) ou médiane (espace inter-quartile). De septembre à décembre 2020, 37 patients (18 hommes, 19 femmes) hospitalisés pour infection à SARS-Cov2 ont été inclus : âge = 81,7 (70,3–87,5) ans, IMC = 25,7 (23,7–29) kg/m2, hypertension artérielle (54 %), diabète (24 %), dyslipidémie (35 %), tabagisme (24 %), cardiopathie ischémique (8 %), maladie cérébrovasculaire (11 %). La durée de suivi était de 10 (8–15) jours. Parmi les 37 patients inclus, 11 (30 %) ont présenté une infection à SARS-CoV-2 grave dont 4 transferts en réanimation et 8 décès. À l'admission, les patients ayant une infection évoluant vers une forme grave étaient plus âgés (p = 0,021), avaient une créatininémie plus élevée (p = 0,003) et une diminution du pourcentage de lymphocytes B (p = 0,04), de lymphocytes T (p = 0,009) et de lymphocytes T CD4+ (p = 0,004) circulants parmi les lymphocytes totaux comparativement aux patients dont l'évolution était favorable. Parmi les sous-populations lymphocytaires T étudiées (mémoires, naïfs, Th1, Th2, Th17, Treg, Tc1, Tc17, T CD8 cytotoxiques), il n'y avait pas de différence significative entre les deux groupes en dehors du pourcentage de lymphocytes Th17 à l'admission qui était deux fois plus élevé chez les patients dont l'infection évoluait vers une forme grave (0,44 vs 0,23 % des LT CD4 totaux ;p = 0,028). Chez les patients ayant une infection évoluant vers une forme grave, l'IL-6 plasmatique à l'admission était plus élevée (39 vs 13,1 pg/mL ;p = 0,018) et la CRP à l'admission avait tendance à être plus élevée sans atteindre le seuil de significativité (58 vs 18,5 mg/L ;p = 0,17). En analyse multivariée (régression logistique binaire comprenant les variables : âge, créatininémie, CRP, hémoglobine, lymphocytes T CD4, Th17, Treg activés (CD4 + CD45RA-FoxP3high), lymphocytes B, IL-6 sérique), la seule variable associée au risque d'évolution vers une forme grave de l'infection était le pourcentage de lymphocytes Th17 circulants (p = 0,034). L'aire sous la courbe de la courbe ROC évaluant la sensibilité et la spécificité du pourcentage de lymphocytes Th17 pour prédire une forme grave d'infection à SARS-CoV-2 chez un patient hospitalisé était de 0,75 (intervalle de confiance à 95 % : 0,56–0,95). Enfin, le fait d'avoir un pourcentage de lymphocytes Th17 > 0,435 % des lymphocytes T CD4 totaux au moment de l'admission en hospitalisation était associ © à une moins bonne survie (p = 0,024). Cette étude suggère qu'une élévation du pourcentage de lymphocytes Th17 chez des patients hospitalisés pour infection à SARS-CoV-2 augmente significativement le risque d'évolution vers une forme grave de la maladie. Ce résultat est cohérent avec le fait qu'il a été démontré que le tocilizumab, qui est efficace dans le traitement des formes graves de COVID-19 [2] , inhibe la réponse lymphocytaire Th17 [3]. Ces données méritent d'être confirmées chez un plus grand nombre de patients afin de confirmer ce résultat car cette mesure pourrait permettre de mieux cibler la population de patients à qui proposer précocement un traitement par tocilizumab pour diminuer le risque d'évolution vers une forme grave d'infection à SARS-CoV-2. (French) [ FROM AUTHOR] Copyright of Revue de Médecine Interne is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. 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Antibody Response to 2-Dose Sars-Cov-2 mRNA Vaccine in Allogeneic Hematopoietic Cell Transplant Recipients

INTRODUCTION Immunocompromised patients have been excluded from initial trials evaluating SARS-CoV-2 mRNA vaccines and there is a critical need to warrant vaccine efficacy in hematopoietic stem cell transplant (HSCT) recipients. In this study, we evaluated antibody responses to 2 doses mRNA SARS-CoV-2 vaccine in allogeneic HSCT recipients. METHODS We retrospectively enrolled successive hematopoietic cell transplant recipients across France who completed the 2-dose SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273) between January 1 st and July 15 th 2021. All included patients had an available semi-quantitative antispike serologic testing after the second dose (from Roche, DiaSorin, Abbott or Siemens). We excluded patients with a prior COVID-19 confirmed by serology or PCR. For detectable antibody, we calculated the binding antibody units per milliliter (BAU/mL) according to the WHO International Standard by applying conversion factors given by the manufacturers (Kristiansen et al., The Lancet 2021). Antibody response was categorized as “weak” or “good” with a threshold of 264 BAU/mL which has been associated to an estimate of 80% of mRNA vaccine-induced protection against symptomatic COVID-19 in immunocompetent patients (Feng S. et al., medRxiv 2021). We built a multivariate logistic regression model to assess factors independently associated with the absence of antibody response after the second dose of mRNA vaccination. RESULTS Overall, 620 allogeneic HSCT recipients from 12 hospitals across France were included in the analysis (60% male with a median age of 59 years old [IQR 47-66]), most with a myeloid (69%) or lymphoid (26%) malignancies. Donors were matched unrelated for 51%, HLA-identical sibling for 31% and haplo-identical for 18%. Thirty-one percent of HSCT recipients underwent a myeloablative conditioning, while 69% received a reduced intensity conditioning. The two doses of vaccines were given one month apart and the median time between transplantation and the initiation of vaccination was 29 months [IQR 14-58]. At a median of 33 [IQR 27-50] days after dose 2, an antibody response was detectable in 496 patients (80% [95CI: 77 to 83%]). Median [IQR] antibody levels was 243 BAU/mL [29.4-1391]. We classified detectable antibody responses as “weak” in 189 patients (30% [95CI 27 to 34%]) and as “good” in 306 (49% [95CI: 45 to 53%]). In the multivariate analysis including 533 patients (420 with detectable antibodies), factors associated with the absence of humoral responses were a time-interval from HSCT < 12 months (ajusted Odds-Ratio (aOR) 2.8 [95CI 1.6 to 4.8]), absolute lymphocyte count <1G/L (aOR 3.0 [95CI 1.7 to 5.0]), systemic immunosuppressive treatments within 3 months of vaccination (aOR 4.5 [95CI 2.7 to 7.5]), together with the use of rituximab within 6 months (aOR 15.1 [95CI 4.3 to 52.7]). In a subsequent multivariate analysis conducted a subset of 227 patients (170 with detectable antibodies) with available gammaglobulinemia as well as B and T lymphocytes counts, factors remaining associated with the absence of antibody response were only low B-lymphocytes count (aOR 5.5 [95CI 2.4 to 12.3]) and time-interval from HSCT < 12 months (aOR 3.3 [95CI 1.5 to 7.2]). CONCLUSION After 2 dose mRNA vaccination, the majority of allogeneic HSCT recipients developed an antibody response although a significant proportion of these responses may be insufficient. Studies are still needed to investigate the effect of a third vaccine dose in patients with a null or weak humoral response. Disclosures: Loschi: Servier: Ended employment in the past 24 months, Honoraria;Novartis: Ended employment in the past 24 months, Honoraria;Gilead: Ended employment in the past 24 months, Honoraria;AbbVie: Ended employment in the past 24 months, Honoraria;CELGENE/BMS: Honoraria;MSD: Honoraria.

Mesenchymal Stromal Cell (MSC) Compassionate Use in France in Treatment of Steroid-Refractory Graft-Versus-Host-Disease (GVHD) after Approval By the Expert Committee of Société Française De Greffe De Moelle Et Thérapie Cellulaire (SFGM-TC)

Hematopoietic stem cell transplantation is a well-established efficient therapy for hematological diseases, but Graft-Versus-Host Disease (GVHD) is a major and frequent complication encumbering its outcome despite the administration of calcineurin inhibitor based GvHD-prophylaxis. Corticosteroids represent the worldwide first line treatment, however in case of steroid refractory acute GVHD there is no consensus about a subsequent treatment although Ruxolitinib is subject to a phase III trial. Multiple molecules have been tried, most of them immunosuppressive, increasing the risk of deadly infections and transplantation-related mortality (TRM). Recent studies reported that mesenchymal stromal cells (MSC) infusion which have immune modulatory abilities might be effective and harmless in steroid or treatment-refractory GVHD (R-GVHD). In France, MSCs are considered as an Advanced Therapy Medicinal Product. For 4 years, its administration as a compassionate use is subject to approval by an expert committee from SFGM-TC before its validation by the French regulatory agency (ANSM). We retrospectively analyzed the demands for MSC use in France since 2011 for patients suffering from R-GVHD. We evaluated the response at day 28 (range 23-28) and at the last follow-up and its safety. Eleven demands were validated by both expert committee and ANSM, 8 patients (pts) received ex-vivo expanded MSCs, 1 pt refused the therapy, 1 infusion was postponed due to COVID-19 related sanitary crisis and the last 1 didn't receive MSCs due to relapse. Among pts who received MSCs, median age was 6 years (2-69), sex ratio was 0,6. All pts underwent their first HSCT for either malignant disease (62,5%) or non-malignant disease (37,5%). Four pts were transplanted from sibling donor, 2 pts from mismatched unrelated donors and 2 pts from haplo-identical donors. Stem cells source was bone marrow for 4 pts, peripheral blood stem cells for 3 and cord blood for 1. Donors median age was 28,8 years (0-49,5), 1 male had a female donor. Six pts got a myeloablative conditioning regimen (TBI-based for 2). All pts received a ciclosporin-based (CSA) GVHD prophylaxis (CSA alone, n=1;CSA + Mycophenolate Mofetil (MMF) or Methotrexate, n=7). Five pts had ATG. Six pts were suffering from acute GVHD, while 2 from extensive chronic GVHD (cGVHD). All 6 pts with acute GVHD presented a grade III or IV, refractory to corticosteroids and at least 2 other lines of GVHD therapy. All but one had a multipolar GVHD with at least 2 affected organs. Five pts were still taking corticosteroids, and six were taking additional immunosuppressive molecules (Tacrolimus, Ruxolitinib, Etanercetp, Inolimomab, MMF) at time of MSC infusion. Five pts received German commercialized MSCs (Obnitixâ, MEDAC, Germany;see Bader et al, 2018), 2 get mother's derived MSCs (not the initial donor), and 1 from a third-party donor. A median of 4 infusions were administered (1-4), once a week for 4 weeks. Mean single dose of MSCs was 1.23.10e6/kg (range: 0,86 - 3). No toxicity was reported except for 1 pt who experienced anaphylactic reaction within minutes, leading to the interruption of infusion (mother's derived MSCs prepared with fetal bovine serum where all other preparations were performed with platelet lysate). The median time from GVHD onset to first MSC infusion was 135 days (63-457). Overall response rate was 86% (6/7) at the first and at the last evaluation with 1 complete response (CR) and 5 partial responses (reduction of at least one grade of at least one affected organ). One pt did not respond and the last 1 was not evaluable due to anaphylactic reaction. Both were suffering from cGVHD. Among the seven pts who received complete MSC infusions, median follow-up was 1,5 months (1,1-18,5) due to premature TRM, overall survival (OS) at six months was 33,3%. Five pts died, all of them from a transplantation-related cause: GVHD n=2, severe infections n=3. Literature reported better outcomes lately, Bader and al, 2019 reported a 64% OS at 6 months and 51% of CR at last follow up. Those disparities might be explained by a delayed treatment after GVHD onset (135 days versus 28 days) and a median of 3 (2-10) therapies after receiving corticosteroids before MSC infusion due to difficulty to obtain MSCs in France. Besides, we included patient suffering from R-cGVHD. Regarding those results, MSC efficacy and safety should be confirmed in a proper clinical trial. [Formula presented] Disclosures: Rubio: Neovii: Research Funding;Novartis: Honoraria;MSD: Honoraria;Gilead: Honoraria;Medac: Consultancy. Dalle: Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria;AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bellicum: Consultancy, Honoraria;Medac: Consultancy, Honoraria;Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.