Utilization of Virtual Consultations in Facial Plastic Surgery during the COVID-19 Pandemic.

BACKGROUND: The coronavirus disease 2019 pandemic affected many aspects of medical practice, particularly surgical fields. The American College of Surgery initially recommended the cancellation of all elective procedures. As a result, virtual consultations (VCs; a form of telemedicine), became widely used in the field of facial plastic and reconstructive surgery. With more facial plastic and reconstructive surgeons (FPRS) conducting both in-person and virtual visits, it is imperative to understand how VCs are utilized in practice. METHODS: An electronic, anonymous survey was distributed to 1,282 electronic mail addresses in the 2018 American Academy of Facial Plastic and Reconstructive Surgery directory. The survey collected responses on various topics including demographic information and past, current, and future use of VCs. RESULTS: The survey yielded 84 responses. Most surgeons (66.7%) were 11+ years out of fellowship. There was a significant increase in the percentage of VCs scheduled after the pandemic than before (p = 0.03). FPRS most frequently responded that VCs should always be followed by an in-person visit (48.6%). A majority of FPRS (66.2%) believe that VCs have improved the delivery of health care in at least some cases. Almost all FPRS (86.5%) plan on using VCs after the pandemic. CONCLUSION: Since the pandemic, VCs are more frequently used by surgeons and are mostly utilized as an initial patient visit. A majority of FPRS believe that VCs have improved health care in at least some cases, and plan on using VCs after the pandemic.

CO3.4 - Association entre précarité et consultations non-urgentes aux urgences pédiatriques en Ile-de-France

Introduction Le nombre de consultations aux urgences augmente d'année en année, y compris aux urgences pédiatriques. Les enfants et adultes qui y ont recours pour des pathologies non-urgentes sont une des illustrations du mésusage des urgences qui risque de surcharger les services. Afin d'aider à la mise en place de politiques publiques adaptées, l'objectif de cette étude était de déterminer s'il existe une association entre le niveau de précarité et le recours aux urgences pédiatriques pour des consultations non-urgentes. Méthodes Toutes les consultations d'enfants de moins de 18 ans entre 2017 et 2021 dans huit centres franciliens de l'AP-HP ont été incluses dans cette étude de cohorte rétrospective. La précarité a été approximée par le FDep, un index de déprivation sociale basé sur le code postal, qui prend en compte le revenu médian, le pourcentage de bacheliers dans la population de plus de 15 ans, le pourcentage d'ouvriers dans la population active et le taux de chômage. Les consultations non-urgentes étaient définies par les consultations ayant un score de triage dans les deux niveaux les moins urgents, sur une échelle de cinq points. D'autres variables socio-économiques basées sur le code postal ont été analysées, comme l'accessibilité potentielle localisée aux médecins généralistes ou aux pédiatres libéraux, la part de migrants dans la population, le taux de ménages monoparentaux, ou encore la proximité du lieu de domicile avec l'hôpital consulté. L'analyse de l'association entre la précarité et les consultations non-urgentes a été réalisée à l'aide de modèles logistiques mixtes avec intercept aléatoire sur le centre, afin de prendre en compte la non-indépendance des données entre les centres. Les variables quantitatives ont été modélisées par des splines cubiques naturelles afin de prendre en compte des associations non linéaires. La population parisienne représentant une part importante de notre échantillon, et au vu de la nature particulière de la ville de Paris en termes d'hétérogénéité économique, d'offre de soins, et de densité de réseau de transport, une analyse de sensibilité excluant les enfants résidant à Paris a été réalisée. La pandémie de COVID-19 ayant impacté le fonctionnement des urgences pédiatriques, une autre analyse de sensibilité a exclu les consultations ayant eu lieu en 2020 et 2021. Résultats L'analyse principale a porté sur 1 499 108 consultations. Dans le groupe le plus précaire, 56 % des consultations étaient non urgentes, contre 47 % dans le groupe le moins précaire. Une précarité plus grande, une plus grande proximité géographique avec l'hôpital et un âge entre 1 et 12 ans étaient associés à un plus grand risque de consulter pour des consultations non-urgentes (p<0,01 pour chacun des facteurs). L'analyse de sensibilité excluant les enfants habitant à Paris a retrouvé une association plus marquée entre les consultations non-urgentes et la précarité. L'analyse de sensibilité avant la pandémie de COVID-19 a retrouvé des résultats similaires à l'analyse principale. Conclusion Les populations les moins favorisées semblent plus à risque de consulter pour une consultation non-urgente dans notre région, mais cette association semble faible, ce qui laisse suggérer que d'autres déterminants sont davantage impliqués. Ces résultats pourraient permettre d'orienter les prochaines politiques de santé publique afin de diminuer le mésusage des urgences pédiatriques et ainsi optimiser leur fonctionnement. Mots clés Précarité , Urgences pédiatriques , Recours aux soins Déclaration de liens d'intérêts Les auteurs n'ont pas précisé leurs éventuels liens d'intérêts.

Capacity building in operational research on obstetric fistula: Experience in the Democratic Republic of Congo, 2017-2021.

OBJECTIVE: To implement a Flexible Operational Research Training (FORT) course within the Fistula Care Plus Project, Democratic Republic of Congo, from 2017 to 2021. METHODS: A descriptive study using design and implementation (process and outcome) data. Two to four members of medical teams from three supported sites were selected for the training based on their research interests and level of involvement in the program. RESULTS: Two courses (13-14 months each) involving nine facilitators and 17 participants overall were conducted between 2017 and 2021. Most participants in both courses were medical doctors (67% and 71%, respectively) from the supported hospitals (83% and 77%, respectively). About half were women. In addition to classic face-to-face didactic modules, the courses integrated online platforms to cope with the changing contexts (Ebola virus and COVID-19). Most participants reported having gained new skills in developing research protocols, collecting, managing, and analyzing data, and developing research manuscripts. The two courses resulted in six scientific manuscripts and three presentations at international conferences. Participants subsequently published five papers from their research after the first course. The total direct costs for both courses were representing a cost of $3669 per participant trained. CONCLUSION: The FORT model proved feasible, efficient, and successful. However, scaling up will require more adaptation efforts from programs and participating sites.

Utilisation des immunoglobulines polyvalentes intraveineuses au cours des anémies hémolytiques auto-immunes de l'adulte : série rétrospective multicentrique de 34 cas

La prise en charge des anémies hémolytiques auto-immunes (AHAI) est relativement bien standardisée à la phase aiguë et repose, dans le cadre des AHAI à anticorps chauds, sur la corticothérapie en première intention plus ou moins associée à un recours précoce au rituximab. Les formes sévères d'AHAI conduisant les patients en soins intensifs ne sont pas exceptionnelles et sont associées à une mortalité importante [1,2]. Leur prise en charge immédiate au-delà du support transfusionnel n'est pas codifiée. Les immunoglobulines polyvalentes intraveineuses (IgIV) sont parfois utilisées dans cette situation, mais les données de la littérature qui reposent essentiellement sur une étude rétrospective ancienne montraient un taux d'efficacité faible [3]. Nous avons mené une étude observationnelle rétrospective, multicentrique. Les critères d'inclusion étaient : (1) âge > 18 ans ;(2) diagnostic d'AHAI avec test de Coombs direct positif, quel qu'en soit le profil ;(3) traitement par IgIV administré pour la prise en charge de l'AHAI. Etaient exclues les anémies hémolytiques (AH) non auto-immunes (AI), les AH présumées AI à test de Coombs négatif, et les patients avec AHAI ayant reçu des IgIV pour une indication autre que l'AHAI. Les caractéristiques démographiques et clinicobiologiques des patients, ainsi que les traitements associés étaient recueillis de façon standardisée. Les données clinicobiologiques à j3, j7, j14 et j28 étaient également analysées afin d'évaluer l'efficacité et la tolérance des IgIV. Le critère principal de réponse était évalué à j7 ;la réponse était définie, par une augmentation du taux d'hémoglobine (Hb) ≥ 2 g/dL comparée au taux avant IgIV, en l'absence de transfusion intercurrente. Une bonne réponse était définie par l'obtention d'un taux d'Hb ≥ 10 g/dL avec un gain ≥ 2 g/dL d'Hb. Dans les autres situations, les patients étaient classés comme non répondeurs. Sur 78 dossiers analysés, 33 ne remplissaient pas les critères d'inclusion : 2 AH non AI, 2 AHAI avec tests de Coombs négatif, 26 cas de recours aux IgIV pour une autre indication (Evans/PTI, DICV, Parvovirus B19) et 3 AHAI non traitées par IgIV. Onze patients ont par ailleurs été exclus du fait de données manquantes. Au total, 34 patients issus de 14 centres étaient finalement inclus. Il s'agissait de 18 femmes (53 %) et 16 hommes (47 %), d'âge médian au diagnostic de 59 ans [19 ;91], parmi lesquels 23 (67 %) étaient atteints d'une AHAI à anticorps (Ac) chauds, parmi lesquels 7 patients avec un syndrome d'Evans, 6 (18 %) d'une AHAI à Ac froids et 5 (15 %) d'une AHAI mixte. Dans 22 cas (65 %), l'AHAI était primitive et 12 AHAI (35 %) étaient secondaires (3 déficits immunitaires, 3 hémopathies lymphoïdes, 2 hémopathies myéloïdes, 2 infections, 1 lupus érythémateux systémique, 1 traitement par anti-PD1). La justification mise en avant par les cliniciens pour le recours (hors AMM) aux IgIV était par ordre décroissant : la sévérité de l'AHAI dans 82 % des cas et/ou une dépendance transfusionnelle (41 %), une corticorésistance (38 %) ou encore une suspicion de facteur déclenchant infectieux (32 %). Le nadir d'Hb avant IgIV était de 4,2 g/dL [1,7 ;7,6 g/dL]. Le recours aux IgIV s'est fait au diagnostic initial d'AHAI dans 20 cas (59 %) ou à l'occasion d'une rechute dans 14 cas (41 %). La majorité des patients (94 %) ont reçu des IgIV à la posologie de 2 g/kg. Lors de l'administration des IgIV, la plupart des patients (79 %) étaient sous corticothérapie. Les principaux autres traitements associés étaient l'EPO recombinante (47 %) et le rituximab (32 %). Quatre patients ont eu des échanges plasmatiques et 2 ont eu un traitement par eculizumab. Concernant le critère de jugement principal d'efficacité, 11 patients sur les 32 patients évaluables (34 %) étaient jugés répondeurs à j7, parmi lesquels 2 (6 %) avaient une bonne réponse. La proportion de réponse augmentait à 19/28 (68 %) à j14 (dont 25 % de bonnes réponses) et à 17/ 5 (68 %) à j28 (dont 40 % de bonnes réponses). En termes de tolérance, un seul épisode thrombotique a été observé : 1 thrombose de la veine cave inférieure à j5 de l'initiation du traitement (à noter, infection à SARS-CoV-2 concomitante). Sur la base de cette analyse rétrospective, les IgIV semblent avoir une certaine efficacité à court terme chez 34 % des patients pour le traitement d'une AHAI à la phase aiguë et ce avec une tolérance acceptable. Ce taux de réponse est similaire à celui rapporté précédemment dans la littérature par Flores et al. (30 %) [3] mais, au-delà des seules transfusions, le fait que les patients aient reçus d'autres traitements concomitants ne permet pas d'exclure une surestimation de ce taux de réponse. (French) [ FROM AUTHOR]

PROSPECTIVE OBSERVATIONAL STUDY IN PATIENTS WITH IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) TREATED WITH TPO-R AGONISTS (TPO-RA): ELTROMBOPAG (EPAG) AND ROMIPLOSTIM (ROMI) - THE PEPITE STUDY

Background: Initially, the marketing authorization (MA) of EPAG and ROMI was to adult patients (p.) with ITP ≥12 months (m.) and refractory to other treatments (t.), splenectomized or contraindicated to splenectomy. The MA was extended for EPAG in 2019 to p. aged ≥1 year with ITP ≥6 m., refractory to other t. (corticoids (CS), IgIV). In 2017, French national guidelines suggested the use of TPO-RA as an option of t. in 2nd line (L). Aims: The PEPITE study, still ongoing, aims to assess the modalities of use, effectiveness and safety of TPO-RAs in reallife. Methods: Prospective, observational, multicenter study including adult p. who initiated TPO-RA with persistent (pITP) or chronic (cITP) ITP. Inclusions occurred between 12/21/2018 and 07/17/2020. Here's the interim analysis, cut-off date: 03/22/2021. Characteristics at baseline were presented in 114 p. (analyzed pop). Efficacy analysis of TPO-RA was assessed in p. with a platelet count (PLAT) <100 G/L at TPO-RA initiation (efficacy pop 113 p.). Responses were defined as: response (R) = PLAT ≥30 G/L, complete response (CR) = PLAT ≥100 G/L and non-response (NR) = PLAT <30 G/L. Results: 123 p. included through 40 centers by 25 hematologists and 15 internists, and 77 p. were still on TPO-RA at 6 m. At baseline, mean age 62.7 ± 20.1 years, 55% men, 29% with at least 1 cardiovascular risk factor. At diagnosis: median PLAT = 26 G/L [0 to 134 G/L], 31% of p. with bleedings. 97% of p. received at least one L of t. before TPO-RA: CS 96%, IVIG 56%, rituximab 47%, dapsone 18%, hydroxychloroquine 11%, danazol 6% and 7% of p. were splenectomized. Median number L of t. = 2 and 8% of p. had more than 4 L. Median time between diagnosis and TPO-RA initiation was 2.6 years [0.3 to 49.3 years], 33% of p. with pITP (n=21 with ITP 3 -<6 months, n=16 with ITP 6 - <12 months) and 67% with cITP. At TPO-RA initiation: 9% of p. were on CS and 48% p. had PLAT <30 G/L (median PLAT = 30 G/L), 95 p. (83%) received EPAG and 19 p. (17%) ROMI. For the 77 p. still on TPO-RA at 6 m., R rate = 97% and CR = 60%. Within 6 m., 10 p. had permanently (perm.) discontinued TPO-RA, main causes were therapeutic effect deemed sufficient (TEDS) for 6 p. and NR for 2 p. For the 27 p. still treated with TPO-RA at 18 m., R rate = 93% and CR = 48%. Within 18 m., 12 p. had perm. stopped TPO-RA, including 7 p. for TEDS and 1 p. NR. P. initiated TPO-RA with ITP 3 -<6 months (N = 21), 9 (43%) p. were still on TPO-RA at 6 months, 5 (56%) in CR. Over the entire follow-up, 24p. (21%) perm. discontinued TPO-RA, main causes were TEDS for 9 p., adverse event (AE) for 5 p. and absence of R for 4 p. Of the 105 p. treated with EPAG at least once, 62 (59%) experienced at least one AE, and 26 SAE occurred in 17 p. The most common AEs were respectively 6% for headache and 3% for SARS-CoV-2 infections, diarrhea, asthenia, insomnia, arthralgia and alopecia. Of the 40 p. treated with ROMI at least once, 19 (48%) experienced at least one AE and 17 SAEs occurred in 10 p. The most common AEs: SARS-CoV-2 infections (5%) and arthralgias (5%). No deaths related to TPO-RA was reported. Summary/Conclusion: Preliminary data from the PEPITE study show that TPO-RA are prescribed in early ITP, including 33% with pITP (18% with ITP 3-<6 m.) and are used in 7% of cases after splenectomy. At 6 m. R on t. was 97% and CR on t. was 60%. Within 6 m., 6 p. had perm. stopped TPO-RA due to TEDS. The real-life effectiveness and safety data for EPAG and ROMI are consistent with data reported in extension studies, with the specificity of occurrence of SARS-CoV-2. The final analysis is scheduled after 24 m.

MANAGEMENT OF AUTOIMMUNE HAEMOLYTIC ANAEMIA DURING PREGNANCY OR POST-PARTUM: AN INTERNATIONAL MULTI-CENTRE EXPERIENCE

Background: Autoimmune haemolytic anaemia (AIHA) during pregnancy is a rare finding, and few is known about maternal and foetal outcomes. AIHA may either develop or relapse during gestation and postpartum or be an issue in a patient on active therapy who becomes pregnant. AIHA management during pregnancy and lactation is not standardized and drug use is often limited by safety concerns. Aims: We studied AIHA impact on pregnancy focusing on disease severity, treatment need and maternal/foetal outcome. Methods: Through a multicentric retrospective cohort study, we identified 38 pregnancies occurred in 28 women from 1997 to 2021 in 10 European centres in Italy, Denmark, France, the Netherlands, USA, and Spain. All included patients had a previous AIHA history or developed/exacerbated AIHA during gestation or postpartum. AIHA was classified according to the direct antiglobulin test. Results: We registered 18 warm AIHA (10 IgG;8 IgG+C3d), 2 cold agglutinin disease, 3 mixed and 5 atypical forms (Table 1). Evans syndrome (i.e., association of AIHA and immune thrombocytopenia or neutropenia) was present in 4. Mean age at AIHA diagnosis was 27 (3-39) and at pregnancy 32 (21-41) years. AIHA diagnosis predated pregnancy in 15 women and had required at least 1 therapy line in all of them, and >2 lines in 12 (rituximab, N=7;cytotoxic immunosuppressants, N=6;splenectomy, N=5). Among these 15 patients, 6 had a relapse during pregnancy, 3 during postpartum and 9 were on active treatment at the time of pregnancy (steroids, N=8;cyclosporine, N=1;azathioprine, N=1;the latter stopped after positive pregnancy test). A patient with a previous AIHA, relapsed as immune thrombocytopenic purpura during pregnancy. Further 8 patients had an AIHA onset during gestation and 2 postpartum. A patient had AIHA onset during the postpartum of the 1st pregnancy and relapsed during the 2nd one. In the 20 women experiencing AIHA during pregnancy/postpartum, median Hb and LDH levels were 6,4 g/dL (3,1 - 8,7) and 588 UI/L (269-1631), respectively. Management consisted in blood transfusions (N=10) and prompt establishment of steroid therapy+/-IVIG (N=20), all with response (complete N=13, partial N=7). After delivery, rituximab was necessary in 4 patients and cyclosporine was added in one. Anti-thrombotic prophylaxis was given in 7 patients. Overall, we registered 10 obstetric complications (10/38, 26%), including 4 early miscarriages, a premature rupture of membranes, a placental detachment, 2 preeclampsia, a postpartum infection and a biliary colic. Apart from the case of biliary colic and one of the two cases of preeclampsia, 8/10 complications occurred during active haemolysis and treatment for AIHA. Nine foetal adverse events (9/38, 24%) were reported: a transitory respiratory distress of the new-born in a mother with active AIHA, 3 cases of foetal growth restriction, a preterm birth, an infant reporting neurologic sequelae, a case of AIHA of the new-born requiring intravenous immunoglobulins, blood transfusions and plasma exchange, and 2 perinatal deaths. The latter both occurred in women on active AIHA therapy and were secondary to a massive placental detachment and a symptomatic SARS-CoV-2 infection. (Figure Presented ) Summary/Conclusion: AIHA developing/reactivating during pregnancy or postpartum is rare (about 5%) but mainly severe requiring steroid therapy and transfusions. Importantly, severe maternal and foetal complications may occur in up to 26% of cases mostly associated with active disease, pinpointing the importance of maintaining a high level of awareness. Passive maternal autoantibodies transfer to the foetus seems a rare event.

Persistent Exertional Dyspnea and Perceived Exercise Intolerance After Mild COVID-19: A Critical Role for Breathing Dysregulation?

OBJECTIVE: After mild COVID-19, a subgroup of patients reported post-acute-phase sequelae of COVID-19 (PASC) in which exertional dyspnea and perceived exercise intolerance were common. Underlying pathophysiological mechanisms remain incompletely understood. The purpose of this study was to examine outcomes from cardiopulmonary exercise testing (CPET) in these patients. METHODS: In this observational study, participants were patients who were referred for the analysis of PASC after mild COVID-19 and in whom CPET was performed after standard clinical workup turned out unremarkable. Cardiocirculatory, ventilatory, and metabolic responses to and breathing patterns during exercise at physiological limits were analyzed. RESULTS: Twenty-one patients (76% women; mean age = 40 years) who reported severe disability in physical functioning underwent CPET at 32 weeks (interquartile range = 22-52) after COVID-19. Mean peak O2 uptake was 99% of predicted with normal anaerobic thresholds. No cardiovascular or gas exchange abnormalities were detected. Twenty of the 21 patients (95%) demonstrated breathing dysregulation (ventilatory inefficiency [29%], abnormal course of breathing frequency and tidal volume [57%], absent increase of end-tidal Pco2 [57%], and abnormal resting blood gases [67%]). CONCLUSION: Breathing dysregulation may explain exertional dyspnea and perceived exercise intolerance in patients with PASC after mild COVID-19 and can be present in the absence of deconditioning. This finding warrants further study on the levels of neural control of breathing and muscle function, and simultaneously provides a potential treatment opportunity. IMPACT: This study contributes to the understanding of persistent exertional dyspnea and perceived exercise intolerance following mild COVID-19, which is vital for the development of effective rehabilitation strategies.

COVID-19 convalescent plasma for hospitalized COVID-19 patients not requiring assisted ventilation. A randomized controlled trial

Background: The efficacy of COVID-19 convalescent plasma (CCP) as passive immunotherapy in hospitalized COVID-19 patients remains uncertain. The transfusion of a large volume of high titre CCP in recently hospitalized patients may be beneficial. Aims: To evaluate the ability CCP transfusion to improve early outcome in patients with moderate to severe COVID-19 pneumonia. Methods: The CORIPLASM study was a multicentric, open-label, Bayesian randomized, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalized with COVID-19 in 14 French centers, requiring at least 3 L/min of oxygen but without mechanic ventilation assistance and a WHO Clinical progression scale [CPS, 1 to 10] of 4 or 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomization list stratified on center, to receive usual care plus 4 units of CCP (2 units/day over 2 days) (CCP group) or usual care alone (usual care group) on day 1 and 2 post-enrollment. Primary outcomes were the proportion of patients withWHO CPS greater than 5 on the 10-point scale on day 4 and survival without ventilation or additional immunomodulatory treatment by day 14. Results: One hundred and twenty patients were recruited from April 16th 2020 and April 21th 2021 and randomly assigned to the CCP group (n = 60) and to the usual care group (n = 60) and followed up for 28 days. Immunosuppressed patients comprised 43% (26/60) and 50% (30/60) of patients in the CCP and usual care groups, respectively. Median time from symptoms onset to randomization (days) was 7.0 [interquartile range (IQR): 5.0-9.0] in the CCP group and 7.0 [IQR: 4.0- 8.5] in the usual care group. Thirteen (22%) patients in the CCP group had a WHO CPS greater than 5 at day 4 versus 8 (13%) in the usual care group (adjusted odds ratio (OR): 1.88 [95% CI: 0.71 to 5.24]. By day 14, 19 (31.6%) patients in the CCP and 20 (33.3%) patients in the usual care group had needed ventilation, additional immunomodulatory treatment or had died (adjusted HR: 1.04 [95% CI: 0.55 to 1.97]). The cumulative incidence of death was 3 (5%) in the CCP group and 8 (13%) in the usual care group at day 14 (adjusted HR: 0.40 [95% CI: 0.10 to 1.53]), and 7 (12%) in the CCP group and 12 (20%) in the usual care group at day 28 (adjusted HR: 0.51 [95% CI: 0.20 to 1.32]). Frequency of severe adverse events did not differ significantly between both treatment arms. Subgroup analysis revealed that mortality at day 28 was mostly observed in the immunosuppressed patients (15/56 vs. 4/64) and that CCP was associated with less mortality in these patients (4/26 in the CCP group vs. 11/30 in the usual care group)(HR: 0.36 [95% CI: 0.14-0.97]). Summary/Conclusions: CCP treatment did not improve early outcome in patients with moderate-to-severe COVID-19 pneumonia. CCP-associated early respiratory worsening as well as CCP-associated reduced D14 and D28 mortality were observed, while not reaching statistical significance. CCP treatment was associated with reduced D28 mortality in immunosuppressed patients.

Le déficit en interféron de type I n’altère pas la réponse lymphocytaire B mémoire contre le SARS-CoV-2 après vaccination par ARNm

Introduction Les vaccins à ARN messagers ont joué un rôle majeur dans la lutte contre la pandémie de SARS-CoV-2 grâce à une excellente efficacité et sécurité clinique. Ces vaccins ont été développés suite à des années de recherche fondamentale, dont l’une des étapes cruciales a été de remplacer l’uridine de l’ARNm par de la 1-méthyl-pseudo-uridine afin d’éviter la reconnaissance par les récepteurs de l’immunité innée, notamment le toll-like-receptor (TLR) 7. Une hypothèse, très fréquemment défendue mais jamais étayée expérimentalement, est que cet ARN modifié garde une activité immunostimulatrice à bas bruit permettant la production d’interféron de type I, agissant comme un adjuvant du vaccin. Les interférons de type I sont des cytokines antivirales essentielles et les patients ayant un déficit dans les voies de l’interféron de type I sont à haut risque de COVID-19 sévère. Dans ce travail, nous avons analysé la réponse lymphocytaire B au vaccin à ARNm de patients présentant l’absence de signalisation par les interférons de type I. Ceci nous a permis de savoir si les vaccins par ARNm permettaient d’établir une réponse lymphocytaire B robuste en l’absence d’interféron de type I. Patients et méthodes Nous avons constitué trois cohortes de patients (i) des patients avec des déficits génétiques sur les voies de l’interféron de type I : 2 patients avec une mutation homozygote d’IRF7 (facteur de transcription responsable de la production d’interférons de Type I, notamment en aval de TLR7) et un patient avec une déficit hémizygote de TLR7 (ii) des patients ayant des auto-anticorps neutralisant les interférons alpha et oméga, dans le cadre d’une polyendocrinopathie auto-immune de type I (APS-1, n = 14) (iii) des patients ayant des auto-anticorps neutralisant les interféron, associés à l’âge, une entité récemment décrite et particulièrement fréquente chez les sujets âgés (n = 8). Ces sujets ont été comparés à 29 contrôles sains. Tous étaient naïfs du COVID-19 et ont reçu 2 doses de vaccin à ARNm (BNT162n2 ou mRNA1273). Les patients ont été prélevés à différents point de temps, dans les 3 premiers mois et entre 3 et 7 mois après la seconde dose. La réponse sérologique a été évaluée par ELISA anti-IgG et IgA RBD (receptor binding domain de la Spike) et la neutralisation sérique a été testée in vitro contre le D614G-SARS-CoV-2. Les lymphocytes B (LB) mémoires CD19 + IgD-CD27± spécifiques du RBD ont été analysés en cytométrie en flux et triés en cellule unique pour séquençage des régions variables de la chaîne lourde de l’immunoglobuline. Résultats La réponse sérologique anti-RBD IgG et IgA était comparable aux temps précoces et tardifs de la réponse vaccinale, évoluant de façon similaire chez les patients déficients en interféron de type I et les sujets sains. La capacité de neutralisation des sérums contre le SARS-CoV-2 était également identique dans tous les groupes, et corrélait fortement avec le taux d’IgG anti-RBD, suggérant que le RBD était également la cible de la réponse neutralisante chez les patients déficients en interféron de type I. Des LB mémoires circulants spécifiques du RBD étaient retrouvés dans toutes les cohortes de patients déficients en interféron de type I au cours des 3 mois suivant la vaccination. Ceux-ci se maintenaient dans le temps et étaient encore présents entre 3 et 7 mois après la vaccination (0,18 % des LB IgD-CD27+ chez les sujets sains, 0,24 % chez les sujets avec déficit génétiques, 0,16 % chez les APS-1 et 0,26 % chez les AAB, pas de différence statistiquement significative). Le séquençage de la chaîne lourde des régions variables de l’immunoglobuline des LB mémoires spécifiques du RBD révélait l’accumulation progressive des mutations jusqu’à 7 mois chez les sujets sains, témoignant d’une réaction des centres germinatifs permettant la maturation d’affinité et la génération de lymphocytes B mémoires à longue durée de vie. Chez les patients IRF7 déficients, les LB mémoires spécifiques du RBD acquerraient progressivement des mutations de M1 à M6, et les LB mémoires spécifiques du RBD de patients TLR7 et APS-1 arboraient un nombre élevé de mutation dès M4, témoignant que même en l’absence de réponse à l’interféron de type I, le vaccin permettait la génération des LB mémoire issus des centres germinatifs, comme chez les sujets sains. Enfin, des clones partagés étaient retrouvés entre les sujets sains et les patients déficient en interféron de type I témoignant d’une réponse qualitativement normale. Conclusion Notre travail apporte des données rassurantes sur la vaccination de ces patients à haut risque de forme de grave de COVID-19 et suggère que l’ARNm contenu dans les vaccins n’a pas de rôle adjuvant intrinsèque.

Acute Hemorrhagic Leukoencephalopathy Triggered by COVID-19 Infection

Background: This study represents an additional case of a rare entity and complication of COVID-19. Purpose: To further describe COVID’s association with acute hemorrhagic leukoencephalopathy (AHL), a variant of acute disseminated encephalomyelitis. Besides, subsequent neuropsychological evaluation is described. Methods: The present case report describes clinical, laboratory, radiological, and electroencephalographic characteristics of AHL triggered by COVID-19, in addition to outcomes in the neuropsychological findings. Results: Radiologic findings of demyelinating lesions in supratentorial white matter permeated by multiple hemorrhagic foci supported the diagnostic of AHL, reinforced by clinical improvement after corticosteroid therapy. Conclusions: There are few similar cases previously reported, and this case highlights the early diagnosis and prompt treatment looking forward to better outcomes in AHL. Further studies are needed to elucidate the involved pathophysiological mechanisms.

Causes and Circumstances of Death: Analysis in 266 Sickle Cell Adult Patients

Introduction Sickle cell disease is a genetic disease with acute and chronic complications. Pediatric mortality has decreased in recent decades with the introduction of systematic antibiotic therapy, preventive management of cerebral vasculopathy and therapeutic education of families. However, in the absence of cohort follow-up at birth, life expectancy, which is a different concept from age at death, cannot be assessed. In this retrospective, monocentric study, we describe causes and circumstances of death, acute chronic complications, long-term treatments and baseline biology of these patients. It seems important to analyze the risks of morbidity and mortality in order to decide on the necessary preventive measures. Material and method: Records of patients deceased between 2000 and 2020, from the national referral center (Henri Mondor Hospital), were retrospectively reviewed. The referral center follows 3500 patients. All deaths reported to the hospital, by families, other hospitals and health professionals were retrieved from computerized records. Deaths published by the INSEE (National Institute of Statistical and Economical study) from 2000 to December 2020 were accessible and compared with our databases to identify all our deceased patients. All patients with a medical record in our center were included for the study. Patients who had never visited our center were excluded. Results: During this period 226 patients including 128 women and 138 men are recorded. Genotypes for these patients were 204(76%) SS, 41 (15%) SC, 14(5%) Sβ°thalassemia and 7 (2%) Sβ+thalassemia. The median age at death was 41 years with an IQR [32-51]. 186 (70%) patients were hospitalized, 129 (70%) of whom were admitted to intensive care. 36 (13%) patients died at home, including 15 with opioid addiction and 5 patients with psychiatric pathology, and 4 patients on dialysis. This information was not available for 44 (16%) patients. The causes of death were vaso-occlusive complications with multivisceral failure in 44 cases, 42 sepsis, among which there were 11 renal failures, 9 of which were dialyzed. 5 patients died of COVID 19. Cerebral hemorrhage and neurological accident occurred in 22 cases, 4 of which were known to have macrovasculopathy. 25 patients died of a direct complication of renal failure, of which 17 were dialysed, 8 pre-dialysed and 3 transplanted. Acute liver failure in 16 cases, 10 precapillary pulmonary hypertension, 14 DHTR, 10 end-stage heart failure were noted. Two road accidents, 2 suicides, 1 dementia are repoted. For 51 cases, there was no information on the cause or circumstance of death. The causes of death according to genotype is on Table 1. Concerning the chronic complications, 94/266 (35%) patients had significant chronic organ damage. Sixteen patients had required renal or liver transplantation in their history. End-stage organ damage was frequent, 42 had end-stage renal failure, 21 had major liver failure, of which five were transplanted and 16 were awaiting transplantation. Twenty-one patients had known heart failure, 10 of which were associated with end-stage renal disease. Ten patients were followed for significant precapillary pulmonary hypertension. Transfusion difficulties due to a history of DHTR were found for 33 patients. Fourteen patients had an opioid addiction. Nine patients were pregnant and nine had received corticosteroids. Discussion: Causes of death have changed and chronic organ failure is the leading cause of death, especially in patients with kidney, liver and heart disease. This study does not calculate life expectancy, but there was an increase in age at death of about 1/4 of the patients who were between 51 and 81 years old.The management of sickle cell disease has progressed in recent years and new therapies are being proposed. Prevention of the development of these complications is one of the new challenges, especially for renal disease, which is associated with premature mortality. DHTR and cerebral hemorrhage, Covid-19 are new entities and DHTR was probably underdiagnosed in p evious publications. Pregnancy remains a period at risk, for which surveillance should be reinforced. The analysis is ongoing and correlations are currently being investigated between different parameters to find risk factors for mortality. [Formula presented] Disclosures: Habibi: Novartis: Consultancy, Honoraria;bluebird bio: Consultancy, Honoraria, Research Funding. Audard: Addmedica: Consultancy. Michel: Novartis: Consultancy;Amgen: Consultancy;Rigel: Honoraria;Alexion: Honoraria;UCB: Honoraria;Argenx: Honoraria. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci: INNOVHEM: Other: Co-founder;Bluebird: Consultancy, Research Funding;F. Hoffmann-La Roche Ltd: Consultancy;GBT: Consultancy;Jazz Pharma: Other: Lecture fees;AGIOS: Consultancy;Hemanext: Consultancy;Emmaus: Consultancy;Fabre Foundation: Research Funding;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding;Addmedica: Consultancy, Other: Lecture fees, Research Funding.