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OBJECTIVE: Arterial aneurysms are characteristic of medium-size vessel vasculitis but are a very unusual feature of Wegener's granulomatosis (WG). We describe a typical WG case, complicated by arterial aneurysms and review previously reported cases. METHODS: Medline database search of cases published between January 1978 and July 2006, in English, reporting arterial aneurysms complicating WG. RESULTS: Five years after diagnosis, a 29-year-old man with typical WG developed macro- and microaneurysms located on branches of the hepatic and renal arteries during a disease relapse. The main symptoms were abdominal pain, vomiting, and altered general status. He was successfully treated by coil embolization in combination with prednisone, intravenous mycophenolate mofetil, and high-dose immunoglobulins. Twelve additional cases of WG complicated by arterial aneurysms are reported in the English literature. This represents a life-threatening complication since rupture occurred in half of the patients. CONCLUSIONS: Although small-vessel injury predominates in WG, inflammation of medium-size arteries may occur and lead to aneurysm formation. Abdominal angiography should be recommended when unexplained abdominal pain occurs during a WG flare. Copyright © 2008 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Abstract: The prognosis of sickle cell disease (SCD) in adults is determined primarily by damage to targeted organs such as the brain. Cognitive dysfunction in SCD is a common chronic neurological manifestation, but studies remain mostly descriptive in adults. The objective of this study was to better characterize the cognitive profile and the association between cognitive dysfunction and brain lesions. We included adult patients with SCD referred for a neurological assessment. An adapted battery of neuropsychological tests was used to assess cognitive deficits. Brain or arterial abnormalities were assessed using brain magnetic resonance imaging/magnetic resonance angiography and a cervical and transcranial Doppler ultrasound. The cognitive profile of 96 patients was characterized by deficits in processing speed (58%), short-term memory (34%), and working memory (24%). Brain infarcts were found in 56% of patients and intracranial vasculopathy in 49%. Twenty percent of patients had no brain abnormalities. Processing speed dysfunction was associated with territorial infarcts (odds ratio [OR], 3.1; P = .03) and education outside of France (OR, 4.7; P = .02). Short-term memory dysfunction was associated with territorial infarcts (OR, 3.4; P = .01) and a low educational level (OR, 8.2; P = .01). Working memory dysfunction was associated with a low educational level (OR, 4.3; P = .05) and vasculopathy (OR, 3.7; P = .03). Cognitive dysfunction appears to be a hallmark sign of SCD, particularly for adults with sickle cell-related stroke or suspected neurological morbidity. Assessment of such dysfunction could be used in longitudinal follow-up and clinical trials., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

While the coronavirus disease-2019 (COVID-19) might have increased acute episodes in people living with sickle cell disease (SCD), it may also have changed their reliance on emergency department (ED) services. We assessed the impact of the COVID-19 pandemic and lockdowns on ED visits in adult SCD people followed in five French reference centres, with a special focus on 'high users' (≥10 visits in 2019). We analysed the rate of ED visits from 1 January 2015 to 31 December 2021, using a self-controlled case series. Among 1530 people (17 829 ED visits), we observed a significant reduction in ED visits during and after lockdowns, but the effect vanished over time. Compared to pre-pandemic, incidence rate ratios for ED visits were 0.59 [95% CI 0.52-0.67] for the first lockdown, 0.66 [95% CI 0.58-0.75] for the second and 0.85 [95% CI 0.73-0.99] for the third. High users (4% of people but 33.7% of visits) mainly drove the reductions after the first lockdown. COVID-19 lockdowns were associated with reduced ED visits. While most people returned to their baseline utilization by April 2021, high users had a lasting decrease in ED visits. Understanding the factors driving the drop in ED utilization among high users might inform clinical practice and health policy., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The Ghent Altarpiece, a jewel of Gothic art painted by the van Eyck brothers in the fifteenth century, is particularly noteworthy for its use of an innovative dilution of oil, giving it a realistic scope that is particularly conducive to iconodiagnostic hypotheses. For the first time in the literature, we are taking a medical look at this masterpiece, and more specifically at the representation of its patron, whose identity is well known: Joos Vijd, a powerful notable from the town of Ghent, in modern-day Belgium. A vascular turgidity of the temporal artery, which can be suggestive of temporal arteritis, Hertoghe's sign and a slight ear crease were observed. These signs might be vascular lesions accentuated by Vijd's age and attest to van Eyck's virtuosity and anatomic accuracy., (© 2024. Fondazione Società Italiana di Neurologia.)

Few studies have used validated scales to assess the intensity and determinants of fatigue, a major symptom of sickle cell disease (SCD). We aimed to assess the level of basal fatigue in adult patients with SCD, using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire. We prospectively included 102 stable adult outpatients with SCD over 2 months, who answered the FACIT-Fatigue (ranging from 0 (worst imaginable fatigue) to 52 (no fatigue)) and reported on the intensity of fatigue and its impact on quality of life. The cut-off for significant fatigue was <34. The median [IQR] FACIT-Fatigue score was 29 [22-37], indicating moderate-to-severe fatigue. In a multivariate analysis, the FACIT-Fatigue score was significantly associated with female sex, high body mass index, high level of stress, poor sleep quality, and number of previous episodes of acute chest syndrome, but not with the genotype or the haemoglobin level. Most adult patients with SCD experience significant and sometimes intense fatigue; this is probably due to several factors, including disease activity. Fatigue should be evaluated systematically during consultations and in patient education programmes and as an end-point in therapeutic trials., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8 + T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity., Results: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8 + T cells, and (ii) decreased early precursors CD8 + T stem cell-like memory cells (TSCM) and CD27 + CD28 + . The cytokines mentioned above were found at higher concentrations in the COVID-19 + older cohort compared to a younger cohort in which they were not associated with disease severity., Conclusions: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care., (© 2024. The Author(s).)

Competing Interests: The authors declare no conflicts of interest.

Background: Historically, sickle cell disease (SCD) patients experiencing frequent hospitalized vaso-occlusive crises (HVOC) have been associated with increased mortality, yet recent data reflecting the widespread use of hydroxyurea and advancements in disease management remain limited. Our study aims to assess the association between HVOC and mortality or severe complications in patients with SCD in this new treatment landscape., Methods: This was a retrospective observational cohort study using the French national health data system. Between 01-01-2012 and 12-31-2018, all SCD patients ≥16 years old (ICD-10 codes D57.0-2) were included and followed until 12-31-2018. HVOC was defined as a hospitalization of ≥1 night with primary diagnosis of SCD with crisis, following an emergency room visit. The association between HVOC and severe complications was assessed with a Cox proportional hazards model., Findings: In total, 8018 patients (56.6% females; 4538/8018) were included. The 2018 SCD standardized one-year period prevalence was 17.9 cases/100,000 person-years [17.4; 18.3]. The mean rate was 0.84 (1.88) HVOC/person-year. In 2018, 70% (5323/7605), 22% (1671/7605), and 8% (611/7605) of patients experienced 0, 1-2, or 3+ HVOCs, respectively. The median survival time between HVOCs was 415 days [386; 439]. Overall, 312 patients died (3.9%) with a mean age of 49.8 (19.4). Compared to patients without HVOC, the hazard ratios of death in patients with 1-2 or 3+ HVOCs the year prior to death were 1.67 [1.21; 2.30] and 3.70 [2.30; 5.93], respectively. Incidence of acute chest syndrome, pulmonary embolism, osteonecrosis, and sepsis increased with the HVOCs category, but not stroke. In 2018, 29.5% (180/611) of patients with 3+ HVOCs did not take hydroxyurea., Interpretation: Patients must be closely monitored during their hospitalizations to intensify treatment and check treatment compliance. Innovative therapies are also required., Funding: The study was funded by Novartis., Competing Interests: Jean-Benoît Arlet declares that he has received research funding from Theravia, GBT-Pfizer, Novartis, and Vertex, and has been supported at scientific conferences by Novartis France and GBT. Eléonore Herquelot, Fanny Raguideau and Ludovic Lamarsalle work for Heva, the CRO which conducted the study on behalf of Novartis. Pablo Bartolucci declares that he has received research funding and personal fees from Theravia, GBT-Pfizer, Novartis, Vertex and Agios, and he is co-founder of Innovhem., (© 2024 The Authors.)

Purpose: To describe the experience of performing ovarian tissue cryopreservation (OTC) before hematopoietic stem cell transplantation (HSCT), among girls/women with severe sickle cell disease (SCD)(SS or S/β 0 -thalassemia) who are, besides the usual surgical risk, at risk of SCD-related complications during the fertility preservation procedure for improving their counseling and management., Methods: This retrospective study included 75 patients (girls/women) with SCD who have had OTC before myeloablative conditioning regimen (MAC) for HSCT. Characteristics of patients and data on OTC, ovarian status follow-up, and results of ovarian tissue transplantation (OTT) were collected in medical records., Results: At OTC, the median (IQR 25-75; range) age of the patients was 9.6 (6.9-14.1; 3.6-28.3) years, 56/75 were prepubertal, and no SCD or surgery-related complications occurred. The median follow-up post-HSCT was > 9 years. At the last follow-up, among prepubertal patients at HSCT, 26/56 were ≥ 15 years old and presented with a premature ovarian insufficiency (POI), except 2, including the patient who had received an OTT to induce puberty. Eight were 13-15 years old and presented for POI. The remaining 22 patients were under 13. Among the 19 patients who were menarche at HSCT, 2 died 6 months post-HSCT and we do not have ovarian function follow-up for the other 2 patients. All the remaining patients (n = 15) had POI. Five patients had OTT. All had a return of ovarian function. One patient gave birth to a healthy baby., Conclusion: OTC is a safe fertility preservation technique and could be offered before MAC independent of the patient's age., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The primary aim was to describe the patterns of paramacular involvement, not yet reported but that optical coherence tomography angiography can now detect in patients with sickle cell disease. The secondary aim was to search arguments concerning the physiopathogeny of paramacular involvement., Methods: This institutional cohort retrospective study was conducted in a Referral Center for Ophthalmological Rare Diseases. Follow-up included an ophthalmologic examination with optical coherent tomography and optical coherent tomography angiography., Results: One hundred and thirty-two patients with SCD were included. Typical sickle cell maculopathy was observed in temporal area in 84 eyes (40.0%) of SS patients and eight eyes (14.8%) of SC patients ( P < 0.001). Enlargement of the foveal avascular zone was observed in 10 eyes of eight SS patients. Two atypical parafoveal abnormalities were found in SS patients only. The first one consisted of macular thinning with normal vascularization in 15 eyes of 11 patients. The second atypical maculopathy was large areas of loss of vascularization without retinal thinning 10 eyes of six patients. Multivariate analysis did not show a statistically significant relation between the peripheral sickle retinopathy stage and the different type of sickle cell maculopathy ( P = 0.21)., Conclusion: Those atypical sickle cell maculopathy may correspond to early forms preceding a typical sickle cell disease maculopathy (SCDM). This would point toward several physiopathogenic mechanisms. The first one included the existence of ischemia that can be related to anemia. Presence of retinal thinning without vascular involvement point out to a neurogenic mechanism.

Purpose: To assess risk factors for arterial and venous thromboses (AVT) in patients hospitalized in general wards for COVID-19 pneumonia and requiring oxygen therapy., Methods: Our study was based on three randomized studies conducted as part of the CORIMUNO-19 platform in France between 27 March and 26 April 2020. Adult inpatients with COVID-19 pneumonia requiring at least 3 l/min of oxygen but not ventilation were randomized to receive standard care alone or standard care plus biologics. Patients were followed up for 3 months, and adverse events were documented. Risk factor for AVT and bleeding was identified by analyzing clinical, laboratory, and treatment data at baseline among the 315 patients with complete datasets. A Fine and Gray model was used to take account of competing events., Results: During the 3-month follow-up period, 39 AVT occurred in 38 (10%) of the 388 patients: 26 deep vein thromboses and/or pulmonary embolisms in 25 (6%) patients, and 14 arterial thrombotic events in 13 (3%) patients. A history of diabetes at inclusion [sHR (95% CI) = 2.65 (1.19-5.91), P = .017] and the C-reactive protein (CRP) level (sHR = 1 [1-1.01], P = .049) were significantly associated with an elevated risk of thrombosis. Obesity was not associated with a higher risk of thrombosis (sHR = 1.01 [0.4-2.57], P = .98). The CRP level and diabetes were not risk factors for hemorrhage., Conclusion: Among patients hospitalized in general wards for COVID-19 pneumonia during the first wave of the epidemic, diabetes (but not obesity) and a high CRP level were risk factors for AVT. The use of higher doses of anticoagulant in these high-risk patients could be considered., (© The Author(s) 2023. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To identify risk factors for sickle cell maculopathy due to hematological parameters (especially anemia and hemolysis) or cerebral vasculopathy., Methods: This retrospective study was conducted at a Referral Center. The follow-up included optical coherent tomography / optical coherent tomography angiography, neuro-radiological imaging, and a hematological assessment ( hemoglobin, hemoglobin S level, reticulocytes, mean corpuscular volume, bilirubin, and lactate dehydrogenase)., Results: Hundred and thirty-two sickle cell patients were included. Maculopathy was observed in 127 eyes of SS patients and 10 eyes of SC patients ( p < 0.001), unrelated to peripheral retinopathy. Cerebral vasculopathy was more frequent in SS patients ( p < 0.001) and was also associated with the presence of maculopathy ( p = 0.049), and it was related to peripheral retinopathy ( p < 0.001). All biological parameters significantly differed according to the genotype ( p < 0.001) but not according to the presence of cerebral vasculopathy or maculopathy. In the multivariate analysis, reticulocytes and bilirubin were associated with the presence of cerebral vasculopathy and maculopathy., Conclusion: The data obtained were consistent with the role of anemia or hemolysis markers in cerebral vasculopathy and macular involvement. As a trend of hemolysis appears to be a risk factor for these complications, this validates the use of preventive plasmapheresis in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Orssaud, Flamarion, Michon, Ranque and Arlet.)

The spleen filters blood cells and contributes to the immune defense. The red pulp clears the blood from altered red blood cells via its unique microcirculatory network ; while the white pulp is a secondary lymphoid organ, directly connected to the bloodstream, whose specificity is the defense against encapsulated bacteria through the production of "natural" IgM in the marginal zone. Various health conditions can cause acquired impairment of the splenic function (or hyposplenism) directly and/or through therapeutic splenectomy. Hypo/asplenia is complicated by an increased susceptibility to encapsulated germ infections, but an increased risk of thrombosis and pulmonary hypertension has also been reported after surgical splenectomy. Homozygous sickle cell disease is the most common disease associated with functional asplenia. The latter appears early in childhood likely through repeated ischemic alterations caused by the sickling of red blood cells. In addition, specific complications such as hypersplenism and acute splenic sequestration can occur and may be life-threatening. We provide here an update on the role and physiology of the spleen, which will allow a better understanding of the pathophysiology of spleen damage and its consequences in sickle cell disease., (Copyright © 2023. Published by Elsevier Masson SAS.)

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients., Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707)., Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034)., Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens., Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole., Competing Interests: Dr. Zuily reports grants from French Ministry of Health, grants from The Grand Est Regional Council, grants from The Grand Nancy Métropole, grants from The Comité ad hoc de pilotage national des essais thérapeutiques et autres recherches sur le COVID-19 (CAPNET, label Priorité Nationale de Recherche–National Research Priority), during the conduct of the study; personal fees from Leo Pharma, personal fees from Bristol Myers Squibb, personal fees from Pfizer, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Viatris, personal fees from Sanofi, grants from Boehringer Ingelheim, grants from Bayer, outside the submitted work; Dr. Lefevre reports grants from Gilead, grants from ViiV, outside the submitted work; Dr. Sanchez reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from Boehringer Ingelheim, personal fees from Inari, personal fees from Boston Scientific, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Chiesi, grants from Oxyvie, outside the submitted work; Dr. Empis De Vendin has nothing to disclose; Dr. De Ciancio has nothing to disclose; Dr. Arlet reports grants from Addmedical, grants and other from Novartis, outside the submitted work; Dr. Khider has nothing to disclose; Dr. Terriat has nothing to disclose; Dr. Greigert has nothing to disclose; Dr. Robert has nothing to disclose; Dr. Louis has nothing to disclose; Dr. Trinh-Duc has nothing to disclose; Dr. Rispal has nothing to disclose; Dr. Accassat reports other from Leo Pharma, other from Janssen, other from MSD, outside the submitted work; Dr. Thiery has nothing to disclose; Dr. Montani reports grants and personal fees from Acceleron, grants and personal fees from Janssen, grants and personal fees from Merck, personal fees from Bayer, outside the submitted work; Dr. Azarian has nothing to disclose; Dr. Meneveau reports grants, personal fees and other from Bayer, grants, personal fees and other from Bristol Myers Squibb, grants, personal fees and other from Pfizer, grants from Medtronic, grants and personal fees from Boston Scientific, grants, personal fees and other from Abbott, personal fees from Inari, personal fees from Terumo, outside the submitted work; Dr. Soudet reports grants and personal fees from Leo Pharma, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, outside the submitted work; Dr. Le Mao has nothing to disclose; Dr. Maurier has nothing to disclose; Dr. Le Moing has nothing to disclose; Dr. Quéré reports other from Leo Pharma, outside the submitted work; Dr. Yelnik has nothing to disclose; Dr. Lefebvre reports personal fees and other from Pfizer, other from Eumedica, outside the submitted work; Dr. Martinot reports other from Menarini, other from Overcome, outside the submitted work; Dr. Delrue has nothing to disclose; Dr. Benhamou has nothing to disclose; Dr. Parent reports grants from Oxyvie, personal fees from MSD, outside the submitted work; Dr. Roy reports personal fees and other from Bayer, personal fees and other from Boehringer Ingelheim, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, personal fees and other from Aspen, personal fees and other from Sanofi, outside the submitted work; Ms. Presles has nothing to disclose; Dr. Goehringer has nothing to disclose; Dr. Mismetti reports personal fees from Bayer Healthcare, personal fees from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Aspen, personal fees from Pfizer, outside the submitted work; Dr. Bertoletti reports grants from Bayer, grants and personal fees from MSD, personal fees and other from Leo Pharma, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, outside the submitted work; Dr. Rossignol reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Boehringer-Ingelheim, personal fees from Cincor, personal fees from KBP, personal fees from Novartis, personal fees from NovoNordisk, personal fees from Roche, personal fees from Vifor/Relypsa, personal fees from Fresenius, personal fees and other from CardioRenal, personal fees from Idorsia, personal fees from Sequana, personal fees from Vifor, non-financial support from G3P, outside the submitted work; Dr. Couturaud reports grants and personal fees (board memberships, symposia or travel) from Bayer, grants and personal fees (board memberships, symposia or travel) from Bristol-Myers Squibb/Pfizer, personal fees (board memberships, symposia or travel) from Merck Sharp and Dohme, personal fees (board memberships, symposia or travel) from Astra Zeneca, personal fees (board memberships or symposia) from Sanofi, personal fees (board memberships or symposia) from Janssen, personal fees (board memberships, symposia or travel) from Leo Pharma, outside the submitted work; Dr. Wahl has nothing to disclose; Dr. Thilly has nothing to disclose; Dr. Laporte reports personal fees from Lilly/Boehringer Ingelheim, personal fees from Bristol Myers Squibb/Pfizer, personal fees from Merck, personal fees from Leo-Pharma, outside the submitted work., (© 2023 The Authors.)

Data on acute chest syndrome (ACS) in adult sickle cell disease patients are scarce. In this study, we describe 105 consecutive ACS episodes in 81 adult patients during a 32-month period and compare the characteristics as a function of the time to onset after hospital admission for a vaso-occlusive crisis (VOC), that is early-onset episodes (time to onset ≤24 h, 42%) versus secondary episodes (>24 h, 58%; median [interquartile range] time to onset: 2 [2-3] days). The median age was 27 [22-34] years, 89% of the patients had an S/S or S/β 0 -thalassaemia genotype; 81% of the patients had a history of ACS (median: 3 [2-5] per patient), only 61% were taking a disease-modifying treatment at the time of the ACS. Fever and chest pain were noted in respectively 54% and 73% of the episodes. Crackles (64%) and bronchial breathing (32%) were the main abnormal auscultatory findings. A positive microbiological test was found for 20% of episodes. Fifty percent of the episodes required a blood transfusion; ICU transfer and mortality rates were respectively 29% and 1%. Secondary and early-onset forms of ACS did not differ significantly. Disease-modifying treatments should be revaluated after each ACS episode because the recurrence rate is high., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

THERAPEUTIC APPROACHES IN SICKLE CELL DISEASE. Sickle cell disease, the most common genetic disease in France, is still burdened with morbidity and early mortality before the age of 50. When the first-line treatment, hydroxyurea, is insufficient or in the case of organic damage(s) (in particular cerebral vasculopathy), a therapeutic intensification must be considered. New molecules are now available, such as voxelotor and crizanlizumab, but only hematopoietic stem cell (HSC) transplantation can cure the disease. Allogeneic HSC transplantation during childhood with a sibling donor is the reference but it is now possible to perform this procedure in adults with a reduced pre-transplant conditioning. Gene therapy, which consists of an autograft of genetically modified HSCs, has obtained promising results but has not yet demonstrated a complete cure of the disease (protocols underway). The toxicity of myeloablative conditioning (used in pediatrics or for gene therapy), particularly the sterility induced, and the risk of graft-versushost disease (for allogeneic transplantation) are limiting factors of these treatments., Competing Interests: L. Joseph déclare des interventions ponctuelles pour Novartis, des avis d’experts ponctuels pour GBT et Vertex et avoir été prise en charge à l’occasion de congrès scientifiques par Novartis France et GBT. J.-B. Arlet déclare des interventions ponctuelles pour Novartis, des avis d’experts ponctuels pour GBT et Vertex, et avoir été pris en charge à l’occasion de congrès scientifiques par Novartis France et GBT. F. Bernaudin déclare avoir touché des honoraires de la part d’Addmedica, une participation financière pour participer au congrès de l’ASH en 2021, et être consultante pour bluebird bio, Vertex et GBT. N. Dhedin déclare avoir touché des honoraires de Vertex dans le cadre d’un board scientifique.

Competing Interests: J.-B. Arlet déclare des interventions ponctuelles pour Novartis, des avis d’experts ponctuels pour GBT et Vertex, et avoir été pris en charge à l’occasion de congrès scientifiques par Novartis France et GBT.

Competing Interests: D. A. Diallo déclare être membre des comités scientifiques de la Fondation Pierre Fabre et de l’Organisation non gouvernementale Drep.Afrique, cocoordinateur et enseignant du diplôme interuniversitaire international francophone sur la drépanocytose.A. Habibi déclare des interventions pour Novartis, GBT, Addmedica, être consultant pour bluebird bio, GBT, Vertex et Novartis et avoir été pris en charge à l’occasion de congrès scientifiques par GBT et Addmedica. Il est responsable du diplôme et du certificat universitaires syndromes drépanocytaires majeurs à l’UPEC. J.-B. Arlet déclare des interventions ponctuelles pour Novartis, des avis d’experts ponctuels pour GBT et Vertex, et avoir été pris en charge à l’occasion de congrès scientifiques par Novartis France et GBT. Il est membre fondateur bénévole de l’ONG Drep.Afrique, coordinateur de son conseil scientifique et coresponsable du DIU international francophone.

EPIDEMIOLOGY OF SICKLE CELL DISEASE IN FRANCE AND IN THE WORLD. In a few decades, sickle cell disease has become the leading rare disease in France, with nearly 30,000 patients. It is the country in Europe where the most patients live. For historical reasons of immigration, half of these French patients live in the Paris area. The number of births of affected children increases every year, which explains the recurrent and increasing hospitalizations for vaso-occlusive crises, impacting the care system. Sub-Saharan African countries, along with India, are the countries most affected by the disease with an incidence of up to 1% of births. While infant mortality has become rare in industrialized countries, it is major in Africa where more than half of the children will not reach the age of 10., Competing Interests: J.-B. Arlet déclare des interventions ponctuelles pour Novartis, des avis d’experts ponctuels pour GBT et Vertex, et avoir été pris en charge à l’occasion de congrès scientifiques par Novartis France et GBT.

Competing Interests: J.-B. Arlet déclare des interventions ponctuelles pour Novartis, des avis d’experts ponctuels pour GBT et Vertex, et avoir été pris en charge à l’occasion de congrès scientifiques par Novartis France et GBT.

Given the lack of information about safety of the COVID-19 vaccines for sickle cell disease (SCD) patients, we sought to determine whether COVID-19 vaccine was associated with subsequent hospital admission for vaso-occlusive events (VOEs). We included 402 patients with SCD, including 88 regularly transfused. As of July 31, 2021, 213 (53.0%) of them had received a least one dose of COVID vaccine (Pfizer 93.0%). We showed similar risk of hospital admission for a VOE among vaccinated patients (whether transfused or not) and among a control group of non-vaccinated patients matched for age, sex and genotype., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

We present a case report of transbronchial cryobiopsy proven diffuse amyloid cystic lung disease complicating a homozygous Val122Ile (V122I) transthyretin mutated amyloidosis (ATTRm). To the best of our knowledge, this is the first case in the literature reporting such pulmonary lesions in ATTRm amyloidosis, and notably diagnosed through cryobiopsy. A 51-year-old man from Mali with a past medical history of bilateral carpal tunnel syndrome presented erectile dysfunction, asthenia and worsening dyspnoea over the past year. He presented signs of cardiac failure; histological and radiological investigations diagnosed cardiac amyloidosis. He was found homozygote for the V122I mutation in transthyretin. A diffuse cystic lung disease (DCLD) was noted on computed tomography (CT) scan. We performed a transbronchial pulmonary cryobiopsy that revealed histological transthyretin amyloid deposits. This case report illustrates the safety and usefulness of cryobiopsy in the setting of DCLD and extends ATTRm amyloidosis as a possible cause of DCLD.

Red blood cell production is negatively controlled by the rate of apoptosis at the stage of CFU-E/pro-erythroblast differentiation, depending on the balance between erythropoietin (EPO) levels and activation of the Fas/FasL pathway. At this stage, activation of transient caspases through depolarization via mitochondrial outer membrane permeabilization (MOMP) is also required for terminal erythroid differentiation. Molecular mechanisms regulating the differential levels of MOMP during differentiation and apoptosis, however, remain poorly understood. Here we show a novel and essential role for the caspase-10-P13-tBID axis in erythroid terminal differentiation. Caspase-10 (but not caspase-8, which is activated during apoptosis) is activated at the early stages of erythroid terminal differentiation leading to the cleavage of P22-BID into P18-tBID, and later into P13-tBID. Erythropoietin (EPO) by inducing casein kinase I alpha (CKIα) expression, which in turn phosphorylates P18-tBID, prevents the generation of MYR-P15-tBID (leading to apoptosis) and allows the generation of P13-tBID by caspase-10. Unlike P15-tBID, P13-tBID is not myristoylated and as such, does not irreversibly anchor the mitochondrial membrane resulting in a transient MOMP. Likewise, transduction of a P13-tBID fragment induces rapid and strong erythroid terminal differentiation. Thus, EPO modulates the pattern of BID cleavage to control the level of MOMP and determines the fate of erythroblasts between apoptosis and differentiation. This pathway is impaired in 5q- myelodysplastic syndromes because of CK1α haplo-insufficiency and may contribute to erythroid differentiation arrest and high sensitivity of this disease to lenalidomide (LEN)., (© 2022. The Author(s).)

Objective: Immunocompromised patients have an increased risk of a severe form of COVID-19. The clinical efficacy of the tixagevimab/cilgavimab monoclonal antibody combination as pre-exposure prophylaxis against BA.1 and BA.2 SARS-CoV-2 Omicron sublineages is unknown. We aimed to describe the incidence and outcomes of COVID-19 among immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis during the Omicron wave in France., Methods: This was an observational multicentre cohort study of immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis between December 28, 2021 and March 31, 2022. Patients received tixagevimab/cilgavimab 150/150 mg intramuscularly if they had impaired vaccine response and a high risk of severe form of COVID-19., Results: Tixagevimab/cilgavimab was administered to 1112 immunocompromised patients. After a median (range) follow-up of 63 (49-73) days, COVID-19 was confirmed in 49/1112 (4.4%) ≥5 days after treatment. During the study period, mean weekly incidence rate was 1669 in 100 000 inhabitants in Ile-de-France and 530 in 100 000 among patients who received tixagevimab/cilgavimab prophylaxis. Among infected patients, 43/49 (88%) had a mild-to-moderate form and 6/49 (12%) had a moderate-to-severe form of COVID-19. Patients with moderate-to-severe illnesses were less likely to have received early therapies than patients with mild forms (53.5% vs. 16.7% respectively) and 2/49 (4%) patients died from COVID-19., Discussion: Our study reported a low rate of infections and severe illnesses among immunocompromised patients treated with tixagevimab/cilgavimab. A global preventive strategy including vaccines, preexposure prophylaxis with monoclonal antibodies, and early therapies might be effective to prevent severe forms of COVID-19 among severely immunocompromised patients., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: During placements, there is an opportunity to learn clinical skills and to assess their application. However, it represents two different goals. The validity of an end-of-placement assessment is questionable, as the medical competency is contextual. We decided to evaluate the contribution and limits of different assessment modalities as an end-of-placement assessment., Material and Methods: Internal medicine clerks were assessed using the Mini-Cex grid by a structured objective clinical examination (OSCE), a long-case clinical examination (LCE) and a global end-of-placement marking (GEPM). Following these evaluations, students and teachers fulfilled an open questionnaire., Results: In 2021, 41 students and 16 teachers participated in the study. Physical examination was evaluated in 0%, 97% et 76% of cases during OSCE, LCE and GEPM, respectively; teaching skills were assessed for 100, 42 et 49% of students in OSCE, LCE and GEPM, respectively. As compared to OSCE, there was a perceived superiority of LCE regarding its formative value (P=0.07 and P=0.03) and its summative value (P=0.0007 and P=0.02), for students and teachers, respectively. Qualitative analysis highlights the breadth of clinical skills that could be assessed during OSCE stations. Integration into a team was an additional skill that could specifically be assessed during GEPM. GEPM could also take into account the progress made during placement., Conclusion: Despite its subjectivity, LCE seemed to be the preferred modality for an end-of-rotation assessment., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Chronic haemolysis exposes patients with sickle cell disease (SCD) to the development of black pigment gallstones, which can trigger biliary complications. In order to avoid these complications, elective cholecystectomy is recommended in France for all SCD patients with detected gallstones. However, all surgeries, and especially abdominal surgeries, entail an increased risk of vaso-occlusive complications in the peri- and post-operative periods, the most dreadful one being the acute chest syndrome. Preoperative transfusion has been shown in several studies to reduce acute postoperative complications, but exposes the patient to definitive alloimmunization, or even delayed post- transfusion haemolysis, justifying a recent trend towards transfusion sparing. The conditions for avoiding transfusion for a simple and frequent surgery such as cholecystectomy are based on a benefit- risk balance, and must be discussed on a case-by-case basis by the SCD specialist. In particular, it seems fully justified to perform prophylactic preoperative transfusion in patients with a history of recent vaso-occlusive crisis or acute chest syndrome (within 6 months preoperatively), and those operated on in an emergency setting, who are particularly at risk of postoperative events., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Sickle cell disease is a frequent genetic condition, due to a mutation of the β-globin gene, leading to the production of an abnormal S hemoglobin and characterized by multiple vaso-occlusive events. The acute chest syndrome is a severe complication associated with a significant disability and mortality. It is defined by the association of one or more clinical respiratory manifestations and a new infiltrate on lung imaging. Its pathophysiology is complex and implies vaso-occlusive phenomena (pulmonary vascular thrombosis, fat embolism), infection, and alveolar hypoventilation. S/S or S/β 0 -thalassemia genotype, a history of vaso-occlusive crisis or acute chest syndrome, a low F hemoglobin level (<5%), a high steady-state hemoglobin level (> 10 g/dL), or a high steady-state leukocytosis (>10 G/L) are the main risk factors. Febrile chest pain, dyspnea, sometimes cough with expectorations are its main clinical manifestations, and bi-basal crackles are found at auscultation. Inferior alveolar opacities with or without pleural effusions are identified on chest X-ray or CT-scan. Management of the acute chest syndrome should be prompt and implies, besides the recognition of severity signs, a multimodal analgesia, oxygen supplementation, sometimes a parenteral antibiotic treatment and the frequent use of blood transfusions especially in the most severe cases. Prevention is important and includes a regular monitoring of hospitalized patients and the use of incentive spirometry., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Preoperative transfusion (PT) reduces acute postoperative vaso-occlusive events (VOE) in sickle cell disease (SCD), but exposes patients to alloimmunization, encouraging a recent trend towards transfusion sparing. The aim of this study was to investigate the benefit-risk ratio of PT before cholecystectomy on the occurrence of postoperative VOE. Adult SCD patients who underwent cholecystectomy between 2008 and 2019 in our center were included. Patients' characteristics, collected retrospectively, were compared according to PT. A total of 79 patients were included, 66% of whom received PT. Gallbladder histopathology found chronic cholecystitis (97%) and gallstones (66%). Transfused patients underwent more urgent surgeries and had experienced more painful vaso-occlusive crises (VOC) in the month before surgery ( p = 0.05). Four (8.5%) post-transfusion alloimmunizations occurred, and two of them caused a delayed hemolytic transfusion reaction (DHTR) (4.3%). The occurrence of postoperative VOE was similar between the groups (19.2% vs. 29.6%, p = 0.45). Though not statistically significant, a history of hospitalized VOC within 6 months prior to surgery seemed to be associated to postoperative VOE among non-transfused patients (75% vs. 31.6%, p = 0.10). PT before cholecystectomy exposes to risks of alloimmunization and DHTR that could be avoided in some patients. Recent VOCs appear to be associated with a higher risk of postoperative VOE and prompt the preemptive transfusion of these patients.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial., Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979., Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively., Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn., Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche., Competing Interests: The authors have the following interests to declare: Laurent Savale reports personal fees from Janssen and Janssen, andMSD, grants and personal fees from GSK, non-financial support from Acceleron, outside the submitted work. Gilles Pialoux has received consulting fees from Gilead, Abbvie, ViiVHealthcare, MSD and research grants from Gilead. Karine Lacombe Advisory boards in the Covid19 field of MSD, Gilead, GSK, Educational activities in the Covid19 field Chiesi, Sobi, MSD, Gilead, MSD. Xavier Lescure is COVID-19 advisor and has received grant from French ministry of health Jade Ghosn reports grants and personal fees from Gilead, personal fees from MSD, personal fees from ViiV Healthcare, personal fees from Janssen, personal fees from Astra Zeneca, outside the submitted work. Jean Marie Michot reports investigator fees from Amgen, BMS-Celgene, Roche, Sanofi, Xencor, Astex, outside the submitted work. François Raffi personal fees from Gilead Sciences, Janssen, MSD, Pfizer, Roche, ViiV Healthcare, outside the submitted work. Muriel Fartoukh Advisory board (community acquired pneumonia) of Pfizer, educational activities (community acquired pneumonia) of BioMérieux, (ARDS) of Fisher&Paykel. Marc Humbert personal fees from Acceleron, AstraZeneca, Bayer, Merck, Novartis, Roche, Sanofi, GSK, outside the submitted work. Frédéric Pene reports grants from ALEXION, personal fees from GILEAD, outside the submitted work. Gabriel Steg reports grants from Amarin, Bayer, Sanofi, Servier, consulting fees from Amarin, Amgen, AstraZeneca, Bayer, BMS, Idorsia, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Servier, honoraria for lectures from Mylan, support for travels from Astra Zeneca, Co inventor on Patent on alirocumab to reduce cardiovascular risk with all royalties to Sanofi, Participation on a Data Safety Monitoring Board or Advisory Board of Sanofi, New Amsterdam Pharma, Co founder of Bioquantis, all outside the submitted work. Philippe Ravaud has received grant from French ministry of health. All other authors have nothing to declare., (© 2022 The Author(s).)

We aimed to compare the influence of cardiometabolic disorders on the incidence of severe COVID-19 vs. non-COVID pneumonia. We included all consecutive patients admitted with SARS-CoV-2-positive pneumonia between 12 March 2020 and 1 April 2020 and compared them to patients with influenza pneumonia hospitalized between December 2017 and December 2019 at the same tertiary hospital in Paris. Patients with COVID-19 were significantly younger and more frequently male. In the analysis adjusted for age and sex, patients with COVID-19 were more likely to be obese (adjOR: 2.25; 95% CI 1.24-4.09; p = 0.0076) and receive diuretics (adjOR: 2.13; 95% CI 1.12-4.03; p = 0.021) but were less likely to be smokers (adjOR: 0.40; 95% CI 0.24-0.64; p = 0.0002), have COPD (adjOR: 0.25; 95% CI 0.11-0.56; p = 0.0008), or have a previous or active cancer diagnosis (adjOR: 0.54, 95% CI 0.32-0.91; p = 0.020). The rate of ICU admission was significantly higher in patients with COVID-19 (32.4% vs. 5.2% p < 0.0001). Obesity was significantly associated with the risk of direct ICU admission in patients with COVID-19 but not in patients with influenza pneumonia. Likewise, pre-existing hypertension was significantly associated with mortality in patients with COVID-19 but not in patients with influenza pneumonia. Cardiometabolic disorders differentially influenced the risk of presenting with severe COVID-19 or influenza pneumonia.

SARS-CoV-2 infection leads to a highly variable clinical evolution, ranging from asymptomatic to severe disease with acute respiratory distress syndrome, requiring intensive care units (ICU) admission. The optimal management of hospitalized patients has become a worldwide concern and identification of immune biomarkers predictive of the clinical outcome for hospitalized patients remains a major challenge. Immunophenotyping and transcriptomic analysis of hospitalized COVID-19 patients at admission allow identifying the two categories of patients. Inflammation, high neutrophil activation, dysfunctional monocytic response and a strongly impaired adaptive immune response was observed in patients who will experience the more severe form of the disease. This observation was validated in an independent cohort of patients. Using in silico analysis on drug signature database, we identify differential therapeutics that specifically correspond to each group of patients. From this signature, we propose a score-the SARS-Score-composed of easily quantifiable biomarkers, to classify hospitalized patients upon arrival to adapt treatment according to their immune profile., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Russick, Foy, Josseaume, Meylan, Hamouda, Kirilovsky, Sissy, Tartour, Smadja, Karras, Hulot, Livrozet, Fayol, Arlet, Diehl, Dragon-Durey, Pagès and Cremer.)

Context: Sickle cell disease (SCD) is a severe hematological disorder. The most common acute complication of SCD is vaso-occlusive crisis (VOC), but SCD is a systemic disease potentially involving all organs. SCD prevalence estimates rely mostly on extrapolations from incidence-based newborn screening programs, although recent improvements in survival may have led to an increase in prevalence, and immigration could account for a substantial number of prevalent patients in Europe. The primary objective of this study was to estimate SCD prevalence in France., Methods: A cross-sectional observational study was conducted using a representative sample of national health insurance data. SCD patients followed up in France between 2006 and 2011 were captured through hydroxyurea reimbursement and with the International Classification of Diseases (ICD-10) SCD specific code D570.1.2, excluding code D573 (which corresponds to sickle cell trait (SCT)). Nevertheless, we assumed that ICD-10 diagnosis coding for inpatient stays could be imperfect, with the possibility of SCT being miscoded as SCD. Therefore, prevalence was analyzed in two groups of patients [with at least one (G1) or two (G2) inpatient stay] based on the number of SCD-related inpatient stays in the six-year study period, assuming that SCT patients are rarely rehospitalized compared to SCD. The prevalence of SCD in the sample, which was considered to be representative of the French population, was then extrapolated to the general population. The rate of vaso-occlusive crisis (VOC) events was estimated based on hospitalizations, emergencies, opioid reimbursements, transfusions, and sick leave., Results: Based on the number of patients identified for G1 and G2, the 2016 French prevalence was estimated to be between 48.6 per 100,000 (G1) or 32,400 patients and 29.7 per 100,000 (G2) or 19,800 patients. An average of 1.51 VOC events per year were identified, with an increase frequency of 15 to 24 years of age. The average annual number of hospitalizations was between 0.70 (G1) and 1.11 (G2) per patient. Intensive care was observed in 7.6% of VOC-related hospitalizations. Fewer than 34% of SCD patients in our sample received hydroxyurea at any point in their follow-up. The annual average cost of SCD care is €5,528.70 (G1) to €6,643.80 (G2), with most costs arising from hospitalization and lab testing., Conclusion: Our study estimates SCD prevalence in France at between 19,800 and 32,400 patients in 2016, higher than previously published. This study highlights the significant disease burden associated with vaso-occlusive events., Competing Interests: JBA reports honoraria and consultancy/expert testimony for Novartis and Pfizer. MM reports honoraria and consultancy/expert testimony for Novartis and Addmedica, and Board participation for BlueBirdBio; MEJ reports honoraria and consultancy/expert testimony for Novartis and Pfizer; AH reports honoraria and consultancy/expert testimony for Novartis and Addmedica, and Board participation for BlueBirdBio. This does not alter our adherence to PLOS ONE policies on sharing data and materials.