ABSTRACT
Introduction: À ce jour, près de 2 milliards de doses vaccinales anti-COVID-19 ont été administrées. Divers effets indésirables dermatologiques ont été décrits (réactions locales au point d'injection, urticaire, éruptions morbilliformes, etc.). Douze cas de nécrolyse épidermique (NE, incluant les syndromes de Stevens–Johnson et de Lyell) ont été publiés. Notre objectif était d'analyser les cas de NE post-vaccin anti-COVID-19 notifiés en pharmacovigilance (PV) et de faire une revue de la littérature. Matériel et méthodes: Nous avons extrait de la base de données mondiale de PV (VigiBase), en requêtant avec le « Prefered terms » NE et les vaccins anti-COVID-19 comme médicaments « suspect », les cas de NE déclarés jusqu'au 03/03/2022. Nous avons analysé les caractéristiques de la NE, le déclarant, le délai d'apparition des symptômes, le type de vaccin et la dose (1re : D1, ou 2e : D2), la présence éventuelle d'un autre médicament suspect. Nous avons décrit plus précisément les cas rapportés dans la base de données de PV française et calculé le score ALDEN pour chaque molécule suspectée. Enfin, nous avons analysé les cas de la littérature en revoyant les photos et les données cliniques publiées. Résultats: Nous avons identifié dans VigiBase 240 cas de NE pour lesquels les vaccins anti-COVID-19 étaient considérés comme « suspects », dans 64 % des cas en provenance des États-Unis, et pour 60,5 % survenus chez des femmes, majoritairement entre 45–64 ans. Il s'agissait de syndrome de Stevens–Johnson (décollement < 10 %) dans 80 % des cas, 7 % sont décédés. Le vaccin le plus souvent suspect était à ARNm (82 %). Ces cas étaient difficiles à interpréter en raison d'un manque de données (biopsies, symptomatologie, nature du déclarant).La base française de PV comporte 8 cas de NE. Un cas survenu chez une patiente asiatique avec HLA favorisant était plutôt lié à la lamotrigine d'après le calcul du score ALDEN (6 pour lamotrigine et 2 pour le vaccin), 4 cas étaient probablement des erreurs diagnostiques ou non médicamenteux (1 érythème polymorphe, 1 NE post-mycoplasme, 1 éruption morbiliforme et 1 surdosage en méthotrexate) et pour 1 cas, les données descriptives étaient manquantes. Nous avons donc retenu 2 cas de NE potentiellement en lien avec le vaccin : un homme de 40 ans dont la NE a débuté dans les 24 heures suivant la D1 du vaccin Pfizer®, et un homme de 81 ans ayant débuté 3 jours après la D2 du vaccin Pfizer® une NE d'issue fatale.Après analyse critique des 12 cas de la littérature, nous n'en avons retenu que 3 correspondant sémiologiquement à une NE possiblement en lien avec le vaccin. Discussion: Notre étude de PV, conjuguée à l'analyse critique de la littérature, ne retient au total que 5 cas de NE possiblement induite par le vaccin anti-COVID-19, sans toutefois pouvoir affirmer le lien de causalité. La majorité des autres cas ne sont pas des NE ou ont d'autres médicaments suspects. Comme avec les autres vaccins, l'éventualité d'une NE post-vaccinale anti-COVID-19 semble donc exceptionnelle et ne remet pas en question le bénéfice attendu de cette vaccination au regard de la morbi-mortalité du SARS-CoV-2.
ABSTRACT
Introduction: In March 2021, a signal for embolic and thrombotic events with Vaxzevria (COVID-19 Vaccine AstraZeneca) was raised in Austria and Germany, and on 7 April 2021, the European Pharmacovigilance Risk Assessment Committee (PRAC) concluded that a causal relationship between Vaxzevria and thrombosis combined to thrombocytopenia (TTS) was at least a reasonable possibility [1]. TTS mechanism is close to heparin-induced thrombocytopenia [2,3]. We report two Luxembourg cases of TTS that occurred one before and one after this confirmed signal. Results: The first case is a 74-year-old woman, with no medical history, who received her first dose of Vaxzevria in March 2021. Fourteen days later, she was hospitalised for sudden loss of consciousness. On admission she had thrombocytopenia (18 G/L), D-Dimers >20 000 ng/mL, antithrombin III 79%, fibrinogen 0.69 g/dL. Brain CT scan showed cerebral and meningeal haemorrhages. She died three days later. Autopsy confirmed multiple intracranial haemorrhages and showed right transverse sinus organised thrombosis. Post-mortem analysis revealed positive heparin-Platelet Factor 4 (PF4) antibodies (HIPA and PIPA). The second case is a 31-year-old man with medical history of splenic infarction in 2017 during mononucleosis. He received his first dose of Vaxzevria in June 2021, and 12 days later was admitted for right lower limb and lumbar pain with severe thrombocytopenia (28 G/L), low fibrinogen and elevated D-Dimers. Angiography showed sub-occlusive cruoric impactions of the left carotid bifurcation, the sub-renal abdominal aorta and the right common femoral artery. PF4 antibody initially negative (Zymutest Hyphen) were positive with IMMUCOR technique. Management included clots removal, intravenous immunoglobulins started for 3 days and anticoagulation with sodium danaparoid. The patient recovered within one month without sequelae. Discussion/Conclusion: The quick communication about TTS signal and the rapid identification of its mechanism both allowed, as reported here for the second patient, adapted management (prohibiting heparin), with full recovery.
ABSTRACT
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.