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1.
Journal of Experimental Medicine ; 220(1):02, 2023.
Article in English | MEDLINE | ID: covidwho-2107236

ABSTRACT

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.

2.
HemaSphere ; 6:2865-2866, 2022.
Article in English | EMBASE | ID: covidwho-2032101

ABSTRACT

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.

3.
HemaSphere ; 6:2679-2681, 2022.
Article in English | EMBASE | ID: covidwho-2032097

ABSTRACT

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.

4.
Phys Ther ; 102(10)2022 10 06.
Article in English | MEDLINE | ID: covidwho-1961141

ABSTRACT

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.


Subject(s)
COVID-19 , Humans , Female , Adult , Male , COVID-19/complications , Dyspnea/etiology , Exercise Test , Exercise Tolerance/physiology , Gases
5.
Int J Gynaecol Obstet ; 2022 Jul 28.
Article in English | MEDLINE | ID: covidwho-1958757

ABSTRACT

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.

6.
Vox Sanguinis ; 117(SUPPL 1):79-80, 2022.
Article in English | EMBASE | ID: covidwho-1916326

ABSTRACT

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.

7.
La Revue de medecine interne ; 43(6):A101-A102, 2022.
Article in French | EuropePMC | ID: covidwho-1898245

ABSTRACT

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.

8.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-334734

ABSTRACT

Remdesivir and Molnupiravir have gained considerable interest due to their activity against SARS-CoV-2. Cellular hydrolysis of their active triphosphate forms, Remdesivir-TP and Molnupiravir-TP, would decrease drug efficiency. We therefore tested Remdesivir-TP as a substrate against a panel of human hydrolases and found that NUDT18 catalyzes the hydrolysis of Remdesivir-TP. The kcat value of NUDT18 for Remdesivir-TP was determined to 2.6 s-1 and the Km value was 156 µM, suggesting that NUDT18 catalyzed hydrolysis of Remdesivir-TP occurs in cells. We demonstrate that the triphosphates of the antivirals Ribavirin and Molnupiravir are hydrolyzed by NUDT18, albeit with a lower efficiency compared to Remdesivir-TP. NUDT18 also hydrolyses the triphosphates of Sofosbuvir and Aciclovir although with significantly lower activity. These results suggest that NUDT18 can act as a cellular sanitizer of modified nucleotides and may influence the antiviral efficacy of Remdesivir, Molnupiravir and Ribavirin. NUDT18 is expressed in respiratory epithelial cells and may limit the antiviral efficacy of Remdesivir and Molnupiravir against SARS-CoV2 replication by decreasing the intracellular concentration of their active metabolites at their intended site of action.

9.
The Neurohospitalist ; 2022.
Article in English | EuropePMC | ID: covidwho-1728052

ABSTRACT

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.

10.
14.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-326936

ABSTRACT

Memory B cells (MBCs) represent a second layer of immune protection against SARS-CoV-2. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant is of major concern. We used bio-layer interferometry to assess the affinity against the receptor-binding-domain (RBD) of Omicron spike of 313 naturally expressed monoclonal IgG that were previously tested for affinity and neutralization against VOC prior to Omicron. We report here that Omicron evades recognition from a larger fraction of these antibodies than any of the previous VOCs. Additionally, whereas 30% of these antibodies retained high affinity against Omicron-RBD, our analysis suggest that Omicron specifically evades antibodies displaying potent neutralizing activity against the D614G and Beta variant viruses. Further studies are warranted to understand the consequences of a lower memory B cell potency on the overall protection associated with current vaccines.

16.
Blood ; 138:974, 2021.
Article in English | EMBASE | ID: covidwho-1582308

ABSTRACT

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.

17.
British Journal of Surgery ; 108:1, 2021.
Article in English | Web of Science | ID: covidwho-1537513
18.
British Journal of Surgery ; 108:1, 2021.
Article in English | Web of Science | ID: covidwho-1537512
20.
La Revue de Médecine Interne ; 42:A340, 2021.
Article in French | ScienceDirect | ID: covidwho-1531777

ABSTRACT

Introduction Plusieurs cas de thrombopénie immunologique (PTI) de novo ont été décrits après vaccination anti-SARS-CoV2. Chez les patients avec un PTI, le risque de rechute ou d’aggravation secondaire à une vaccination anti-SARS-CoV2 reste mal connu. Patients et méthodes Nous avons conduit une étude observationnelle multicentrique dans 5 centres français. Les patients adultes ayant un diagnostic de PTI (primaire ou secondaire) selon les critères internationaux et pris en charge dans l’un de ces centres ont été inclus s’ils avaient reçu au moins une injection de vaccin anti- SARS-CoV2 entre janvier et août 2021. Les patients sans chiffre plaquettaire disponible dans les 3 mois précédant le vaccin ou dans les 3 mois suivants le vaccin ont été exclus. Tous les patients étaient inclus dans le registre prospectif CARMEN-France et ne s’étaient pas opposés à une collection des données en vie réelle. Les données cliniques et biologiques étaient recueillies avec un formulaire standardisé, et le suivi était limité à 3 mois après la première injection vaccinale. Résultats Entre janvier et août 2021, 195 patients adultes avec un diagnostic de PTI (61 % femmes), d’âge médian 65 ans (IQR 49-74) ont reçu au moins une dose de vaccin anti-SARS-CoV2. La durée médiane d’évolution du PTI était de 73 mois (IQR 28-134) à la première dose de vaccin, 170 (87 %) patients avaient un PTI primaire, et 89 (46 %) n’avaient aucun traitement au moment de la vaccination. La durée médiane de suivi était de 62jours (IQR 43-90) après la première injection de Tozinameran (Cominarty®;n=167, 86 %), ChadOx1nCoV-19 (Vaxzevria®;n=16, 8 %), mRNA-1273 Moderna (Spikevax®;n=11, 6 %) ou Ad26.COV2-S (Covid-19 vaccine Janssen®;n=1, 1 %). Parmi les 195 patients, 129 (66 %) avaient eu un hémogramme à 7± 3jours après la première injection avec une médiane de plaquettes à 118 G/L (IQR 70-192;plaquettes<30 G/L pour 8 patients), tandis que le dernier chiffre plaquettaire dans les 4 semaines avant le vaccin (donnée disponible pour 160 patients) était en médiane de 117 G/L (IQR 62-186;plaquettes<30 G/L pour 5 patients). Durant le suivi, 154 (79 %) patients recevaient une deuxième dose (même vaccin pour tous), et parmi eux, 96 (62 %) avaient eu un hémogramme à 7±3jours après la deuxième injection, dont 11 avec des plaquettes<30 G/L. Au cours du suivi, 25 patients ont nécessité une intervention thérapeutique (introduction d’un traitement d’urgence ou majoration du traitement du PTI en cours), parmi lesquels 14 patients ayant eu des manifestations hémorragiques et ayant conduit à 9 hospitalisations. Parmi ces 25 patients, 11 (soit 5,6 % de la population) présentaient une rechute du PTI alors que la maladie était stable ou non active dans un délai médian de 4jours (extrêmes 1-10) après la première (n=5) ou la deuxième (n=6) dose de vaccin par Tozinameran (n=10) ou mRNA-1273 Moderna (n=1), avec 9 manifestations hémorragiques dont 4 hospitalisations. L’évolution était rapidement favorable sous traitement chez tous les patients sauf un qui nécessitait une hospitalisation prolongée et plusieurs lignes thérapeutiques. Par ailleurs, 11 autres patients avaient présenté une ou plusieurs rechutes avant la vaccination et l’imputabilité du vaccin semblait faible dans la survenue d’une nouvelle rechute. Enfin, 1 patient présentait une rechute 2 mois après la 2ème injection, et il était difficile de déterminer l’imputabilité du vaccin chez 2 autres patients en cours de sevrage de traitement mais avec aggravation de la thrombopénie post vaccinale. Aucun patient n’était décédé au cours du suivi. Conclusion En conclusion, on note l’absence d’impact significatif de la vaccination sur les plaquettes pour la grande majorité des patients ayant un PTI. Nous avons toutefois observé des rechutes inattendues chez 5,6 % des patients dans les 10jours suivant une vaccination, généralement transitoires mais nécessitant une augmentation du traitement de fond ou un traitement d’urgence. Bien que le lien de causalité reste difficile à établir avec certitude compte tenu du schéma de l’étude, nous proposons sur la base de ces observations qu’un hémogramme systématique soit réalisé 5 à 7jours après chaque injection et que les patients soient informés du risque potentiel de majoration de la thrombopénie dans l’évaluation du rapport bénéfices/risques à l’échelon individuel.

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