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Sickle cell disease (SCD) patients display skeletal muscle hypotrophy, altered oxidative capacity, exercise intolerance and poor quality of life. We previously demonstrated that moderate-intensity endurance training is beneficial for improving muscle function and quality of life of patients. The present study evaluated the effects of this moderate-intensity endurance training program on skeletal muscle structural and metabolic properties. Of the 40 randomized SCD patients, complete data sets were obtained from 33. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the non-training (n = 18) group maintained a normal lifestyle. Biopsies of the vastus lateralis muscle and submaximal incremental cycling tests were performed before and after the training program. Endurance training increased type I muscle fiber surface area (P = .038), oxidative enzyme activity [citrate synthase, P

The liver is frequently affected in patients with sickle cell disease (SCD), but few reports have described liver transplantation (LT) in patients with SCD. We present a thorough analysis of the largest single-center series of LT in patients with SCD and the first systematic review. There were 21 patients with a median age of 37.6 years. LT was performed for acute liver failure related to the sickling process (57%) or electively for end-stage liver disease (43%). Prior to LT, 13 patients (62%) were in the intensive care unit and required mechanical ventilation (33%), vasopressor therapy (24%), renal replacement therapy (10%), or molecular adsorbent recirculating system therapy (19%). Post-LT morbidity and mortality were 95% and 33%, respectively. Patient survival at 1 and 5 years were 58.3% and 41.7%, respectively, in the urgent group and 88.9% and 77.8%, respectively, in the elective group. A total of 22 transplant patients with SCD are described in 20 articles in the literature. The 1- and 5-year patient survival rates for the 18 evaluable patients were 75% and 65%, respectively. LT improves survival in patients with SCD and acute liver failure or end-stage liver disease but is associated with high morbidity during the early postoperative course.

International audience

BACKGROUND AND OBJECTIVES: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m(2) from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH

It remains unclear whether sickle cell trait (SCT) should be considered a risk factor during intense physical activity. By triggering the polymerization-sickling-vaso-occlusion cascade, lactate accumulation-associated acidosis in response to high-intensity exercise is believed to be one of the causes of complications. However, our understanding of lactate metabolism in response to high-intensity exercise in SCT carriers is incomplete. Thirty male SCT carriers (n = 15) and healthy subjects (n = 15) with and without α-thalassemia performed a 2-min high-intensity exercise. Blood and muscle lactate concentrations were measured at exercise completion. Time courses of blood lactate and glucose concentrations were followed during the subsequent recovery. Additional biochemical analyses were performed on biopsies of the vastus lateralis muscle. SCT was associated with lower blood and muscle lactate concentrations in response to the short high-intensity exercise. Compared to controls, the muscle content among SCT carriers of lactate transporter MCT4 and β2-adrenergic receptor were higher and lower, respectively. During recovery, the lactate removal ability was higher in SCT carriers. In the present study, no effect of α-thalassemia was observed. The lower blood and muscle lactate accumulations in SCT carriers may, to some extent, act as protective mechanisms: (i) against exercise-related acidosis and subsequent sickling, that may explain the relatively rare complications observed in exercising SCT carriers; and (ii) against the deleterious effects of intracellular lactate and associated acidosis on muscle function, that might explain the elevated presence of SCT carriers among the best sprinters.

Background Unexplained sudden death remains one of the leading causes of death in sickle cell disease (SCD) adults. Ventricular arrhythmia is a well-known risk factor for sudden death but its prevalence and determinants in the context of SCD remain understudied. Purpose The aim of this study was to identify echocardiographic predictors of ventricular arrhythmia in SCD. Methods From January 2019 to March 2021, consecutive adult patients with SCD referred to ambulatory cardiology department for possible cardiac involvement were prospectively included (Drepacoeur cohort). All patients that had 24-hour ECG monitoring (24h-holter) and thransthoracic echocardiography (TTE) on the same day were analysed in this study. The primary end point was the occurrence of ventricular arrhythmia, defined as sustained or non-sustained ventricular tachycardia (VT), more than 500 premature ventricular contractions (PVC) on 24h-holter, or history of VT ablation. Results Overall, 90 patients were included and 54 (60%) were analysed. Mean age was 47.6±11.6 years (range 21–69), 53% were male. Heart function was mainly preserved with a mean left ventricular ejection fraction (LVEF) of 57.9±4.9% and a mean global longitudinal strain (GLS) of −18±2.8%. Mean tricuspid regurgitation velocity was 2.6±0.4m/s. Ventricular arrhythmia was observed in 13 (24.1%) patients (4 non-sustained VT [range 4–121 consecutive PVC], 9 with more than 500 PVC [range 500–13000 PVC/24h] and 1 history of VT ablation). Regarding echocardiographic parameters, ventricular arrhythmia was associated with lower GLS (−15.8±1.8% vs. −19±2.7%, P Conclusion In SCD adults with preserved LVEF, GLS was the only independent echocardiographic predictor of ventricular arrhythmia. Funding Acknowledgement Type of funding sources: None.

Aims This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. Methods We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Results Three clusters were identified. Cluster 1 (n=123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n=102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to Cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n=154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n=33) included the majority of pre-capillary PH whilst Cluster 2 (n=34) included post-capillary PH. No PH was found in Cluster 3 (n=27). After a follow-up of 11.4±2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate vs. 12% in Cluster 1 and 5% in Cluster 3 (P log-rank=0,003). Conclusion Cluster analysis of echocardiography variables identified 3 hemodynamic and clinical phenotypes amongst SCD patients, each predicting a different prognosis. This article is protected by copyright. All rights reserved.

International audience; No abstract available

Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family-based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family-based studies to better understand modifiers of SCD.

Introduction Les patients drépanocytaires ont très tôt été considérés comme personnes “fragiles” vis-à-vis de la COVID-19 car, indépendamment du risque propre de l’infection, il est bien établi que toute infection peut déclencher une crise vaso-occlusive (CVO). Il y a cependant peu d’études descriptives sur larges cohortes décrivant les caractéristiques des patients drépanocytaires avec COVID-19. Nous avons voulu comparer les caractéristiques des patients drépanocytaires infectés par le SARS-Cov2 suivant qu’ils aient été ou non hospitalisés afin d’établir un profil des patients ayant nécessité une hospitalisation. Matériels et méthodes Étude de cohorte prospective, multicentrique et observationnelle Française. Dès le 13 mars 2020, nous avons établi en France grâce au réseau des centres de référence/compétence et de la filière de santé MCGRE (pédiatrie et médecine adulte), un appel à déclaration de toutes infections à SARS-CoV-2 consécutives confirmées par test RT-PCR sur écouvillon naso-pharyngé. Les caractéristiques cliniques simples concernant la drépanocytose et son traitement et les signes cliniques de l’infection ont été recueillis sur une fiche de recueil standardisée. Un modèle univarié a été utilisé pour comparer les caractéristiques des patients, par génotypes de drépanocytose et selon qu’ils aient été pris en charge en ambulatoire ou hospitalisés (passage au minimum d’une nuit aux urgences). Résultats 536 patients drépanocytaires infectés par le SARS-CoV-2 ont été inclus : 319 patients hospitalisés et 217 non hospitalisés. Il s’agissait de 431 drépanocytaires de génotypes S/S ou S/b0-thalassémie (âge moyen 27 ± 12,7 ans), 82 de génotype SC (âge moyen de 33,6 ± 15 ans) et 23 de génotype S/b ± halassémie (29,7 ± 15,4 ans). Nous détaillons dans ce résumé les données concernant les patients majoritaires, de génotype S/S ou S/b0-thalassémie. Chez ces patients, l’âge moyen, le sexe, l’index de masse corporelle, les antécédents de syndrome thoracique aigu (STA), d’HTA ou de diabète, le traitement par hydroxyurée ou immunosuppresseurs étaient identiques entre patients infectés hospitalisés et infectés ambulatoires. Les patients hospitalisés avaient très nettement plus de crises vaso-occlusives osseuses (67 % vs. 13 %, P

International audience; No abstract available

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PHRC Backgroung Echocardiography is the cornerstone in the diagnosis of cardiopulmonary involvement in sickle cell disease (SCD). However, given the unique pathophysiology of SCD associating high cardiac output, and various degrees of peripheral vasculopathy, differentiate the pathological from the physiological using echocardiography can be particularly challenging. Purpose This study sought to link cardiac phenotypes in homozygous SCD patients with clinical profiles and outcomes using cluster analysis. Methods We analyzed data of 379 patients with a sufficient echographic dataset included in the French Etendard Cohort, a prospective cohort initially designed to assess the prevalence of pulmonary hypertension. A cluster analysis was performed on echocardiographic variables, and the association between clusters and clinical profiles and outcomes was assessed. Results Three clusters were identified. Cluster 1 (N = 122) patients had the lowest cardiac output, only mild left cavities remodeling, diastolic dysfunction, and high tricuspid regurgitation velocity (TRV). They were predominantly female, as old as cluster 2, and displayed the most severe functional limitation. Cluster 2 (N = 103) patients had the highest cardiac output, left ventricular mass and a severely dilated left atrium. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (N = 154) patients had mild left cavities remodeling, the best diastolic function and the lowest TRV. They were younger patients with the highest hemoglobin and lowest hemolytic markers. Right heart catheterization was performed in 94 patients. Cluster 1 gathered the majority of precapillary PH while cluster 2 gathered postcapillary PH and no PH was found in cluster 3. After a follow-up of 9.9 years (IQR: 9.3 to 10.5 years) death occurred in 38 patients (10%). Clusters 2 had the worst prognosis with 18% mortality rate vs. 12% in cluster 2 and 5% in cluster 1 (P log-rank = 0,02). Results are summarized in the central illustration. Conclusions Cluster analysis of echocardiographic variables identified 3 phenotypes among SCD patients, each associated with different clinical features and outcome. These findings underlines the necessity to rethink echocardiographic evaluation of SCD patients, with an integrative approach based on simultaneous evaluation of TRV along with left cavities remodeling and diastolic parameters. Abstract Figure.

Several controlled studies have evidenced good efficacy and short- and mid-term safety profiles for hydroxyurea (HU), which has become the cornerstone for prevention of sickle-cell disease (SCD)-related vaso-occlusive crises. However, there are few large-scale reports on its long-term use and certain caregivers and patients have concerns about its safety. Following the licensing of HU in Europe for children and adults with severe forms of SCD, ESCORT-HU was designed as a Phase IV observational cohort study. It included 1,906 participants, of whom 55% were adults. The most common hemoglobin (Hb) genotypes were HbSS (84.7%) and HbSβ+ (7.0%). The median duration of follow-up was 45 months, for a total of 7,309 patient-years of observation. The dose of HU after one year was 20.6 mg/kg/d for children and 16.3 mg/kg/d for adults. There was a statistically significant decrease in the number of vaso-occlusive episodes lasting > 48 hours, acute chest syndrome episodes, hospitalizations, and the percentage of patients requiring blood transfusions within the first 12 months relative to the year before enrolment. Neutropenia and thrombocytopenia were the most commonly reported adverse effects. No new HU toxicity was identified. Overall, 125 pregnancies were reported in 101 women and no malformations were observed in the neonates. There were 12 pregnancies for partners of male patients treated with HU. One case of fatal myelodysplastic syndrome was reported, for which a causal association with HU could not be excluded. This cohort study of patients with SCD highlights the positive benefit-to-risk ratio of HU in children and adults. This article is protected by copyright. All rights reserved.

It is essential to limit hemolytic transfusion reactions in polytransfused individuals, and the prevention of alloimmunization is a key solution. CD4+ T lymphocyte (TL) markers, particularly follicular T helper (Tfh) cells, may differentiate between responder and nonresponder alloimmunization statuses. We tested this hypothesis by studying the phenotype of CXCR5+PD1+ TLs in whole blood. Our results suggest that high levels of CXCR5+PD1+CD4+ TLs in whole blood may be a characteristic of nonalloimmunized patients. However, these cells did not display the phenotypic characteristics of active Tfh cells. Instead, a decrease in blood quiescent Tfh-cell levels was observed in nonalloimmunized polytransfused patients. High levels of CXCR5+PD1+CD4+ TLs may be associated with inhibitory signaling functions of T cells, as reflected by the low levels of PD1+ICOS+ cells in the nonalloimmunized polytransfused group. The description of these particular phenotypes, and their comparison among groups of patients, responders, and nonresponders, suggests that new immunological components should be considered when trying to understand posttransfusion alloimmunization.

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34

International audience; Delayed hemolytic transfusion reaction (DHTR) is an unpredictable severe complication of transfusion in patients with sickle cell disease (SCD). It presents clinically as a vaso-occlusive crisis (VOC), often associated with the failure of one or more organs, after the transfusion of packed red blood cells (pRBC).1,2 Hyperhemolysis is encountered in the most severe forms. Both transfused and autologous red blood cells (RBC) are lysed.The mechanisms underlying DHTR remain unclear. Alloantibodies against RBC antigens were initially thought to underlie the pathophysiology, but no such antibodies are detected in about a third of the cases.3RBC degradation products, such as hemoglobin and heme, are released into the bloodstream during intravascular hemolysis. These elements and heme-loaded membrane microvesicles have recently been implicated in inflammation and organ injury in DHTR.4 Complement is activated via the classical pathway, by alloantibodies, and/or via the alternative pathway, by free heme.5 Hemedependent complement deposits on the endothelium contribute to organ damage.6 Due to these vascular lesions, hyperhemolysis often progresses to multiple organ failure and, in some cases, death.

Background Echocardiography is the main non-invasive screening tool for pulmonary hypertension (PH) in Sickle Cell Disease (SCD), but relies mostly on the tricuspid regurgitation velocity (TRV) assessment, without distinction between pre and postcapillary patterns. Purpose Using Etendard Cohort data, the aim of this study was to refine echocardiographic assessment of PH in SCD patients. Methods The French Etendard Study is a prospective cohort initially designed to assess the prevalence of PH among 398 SCD participants. We analyzed echocardiography data of the 96 Etendard patients who underwent Right Heart Catheterization (RCH), because of a TRV≥2.5m/s, and compared them to invasive haemodynamic measurements. Based on RHC results, patients were classified as follows: Absence of pulmonary hypertension if mean pulmonary arterial pressure (mPAP) was 15mmHg. Results PH was found in 24/96 patients with 11 precapillary and 13 postcapillary. In addition to TRV, multivariate analysis identified indexed left atrial volume (LAVind) and lateral E' wave velocity (E'lat) as independent echocardiographic predictors of PH (OR=1.06 and 0.6 respectively, p48ml/m2 and E'lat Moreover, comparing echocardiography data of pre and post-capillary PH patients, we observed that Pulmonary acceleration time (PAcT) was different in the two groups (104±22ms vs. 160±21ms, p115ms ruled out pre-capillary PH with a NPV of 97%. Conclusion Echocardiography can accurately estimates the probability of PH in SCD patients with an integrated approach using TRV, LAVind and E'lat. In addition, among patients with suspected PH, measuring PAcT as a PVR surrogate allows a good differentiation between pre and post-capillary phenotypes. We propose a new echocardiographic algorithm for the diagnosis of PH in SCD that could be a true assistance in referring patients for RHC. TTE Algorithm for PH in SCD Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Funded by the French Ministry of Health and Assistance Publique–Hôpitaux de Paris

International audience; No abstract available

Aims This prospective study aimed to develop a population pharmacokinetics (PK) model of hydroxyurea (HU) in patients with sickle cell disease. This model can be used to determine the impact of glomerular filtration rate (GFR) on HU kinetics. Methods We included 30 patients. They underwent HU pharmacokinetics analyses of plasma and urine. Six underwent PK analyses in 2 periods with and without angiotensin-converting enzyme inhibitor. HU was assayed with a validated high-performance liquid chromatography-UV method. Noncompartmental PK analysis was conducted and a population PK model built with Monolix. This model was validated externally on another 56 patients. HU PK was simulated as a function of GFR. Results The HU PK model was constructed as a 2-compartment model with first-order absorption and elimination. The quality criteria were good, including for external validation. We found that estimated GFR (eGFR) and body weight affected HU PK, with lower eGFR or body weight associated with a higher HU area under the curve. We recommend the monitoring of HU through eGFR and body weight, which together account for 47% of its variability. Urinary HU fractions and renal clearance were higher in the glomerular hyperfiltration group and lower in the moderate chronic kidney disease group, respectively. No differences in nonrenal HU clearance were observed. Conclusion Estimated GFR has an impact on the kinetics of hydroxyurea, and HU dose should be adapted accordingly. Angiotensin-converting enzyme inhibitor seems to have minor effect on HU PK in adults with sickle cell disease.

Leg ulcers are a major complication of sickle cell disease (SCD) that can cause severe complications. They are particularly challenging to treat and therapeutic innovation is needed. We previously showed that SCD ulcers display a delayed wound healing due to decreased angiogenesis. During pregnancy, fetal microchimeric cells (FMC) transferred to the mothers are recruited to maternal wounds and improve angiogenesis. After delivery, FMC persist in maternal bone marrow for decades. Here, we questioned whether fetal cells could also improve SCD ulcers in the post-partum setting. We found that skin healing was similarly improved in post-partum mice and in pregnant mice, through increased proliferation and angiogenesis. In a SCD mouse model that recapitulates SCD refractory ulcers, we showed that post-partum SCD mice healed more quickly as compared to virgin ones. This was associated with the recruitment of fetal cells in maternal wounds where they harbored markers of leukocytes and endothelial cells. In a retrospective cohort of SCD patients, we demonstrated using several parameters that ever parous SCD women had a decreased burden related to leg ulcers compared to nulliparous women. Taken together, these results indicate that healing capacities of FMC are maintained long after delivery and may be targeted to promote wound healing in post-partum SCD patients.

Significance The root cause of pathology in sickle cell disease is the polymerization of the mutant hemoglobin S upon deoxygenation in the tissues to form fibers. Both the amount of fiber at equilibrium and the kinetics of fiber formation depend on the partial pressure of oxygen. We show that control of polymerization by oxygen at equilibrium can be better explained by a recent extension of the famous two-state allosteric model of Monod, Wyman, and Changeux. Because of the unusual kinetics, polymerization is far out of equilibrium, which explains why patients with the disease manage to survive, while those with high levels of fetal hemoglobin and those with sickle trait (the heterozygous condition) have relatively benign conditions., The pathology of sickle cell disease is caused by polymerization of the abnormal hemoglobin S upon deoxygenation in the tissues to form fibers in red cells, causing them to deform and occlude the circulation. Drugs that allosterically shift the quaternary equilibrium from the polymerizing T quaternary structure to the nonpolymerizing R quaternary structure are now being developed. Here we update our understanding on the allosteric control of fiber formation at equilibrium by showing how the simplest extension of the classic quaternary two-state allosteric model of Monod, Wyman, and Changeux to include tertiary conformational changes provides a better quantitative description. We also show that if fiber formation is at equilibrium in vivo, the vast majority of cells in most tissues would contain fibers, indicating that it is unlikely that the disease would be survivable once the nonpolymerizing fetal hemoglobin has been replaced by adult hemoglobin S at about 1 y after birth. Calculations of sickling times, based on a recently discovered universal relation between the delay time prior to fiber formation and supersaturation, show that in vivo fiber formation is very far from equilibrium. Our analysis indicates that patients survive because the delay period allows the majority of cells to escape the small vessels of the tissues before fibers form. The enormous sensitivity of the duration of the delay period to intracellular hemoglobin composition also explains why sickle trait, the heterozygous condition, and the compound heterozygous condition of hemoglobin S with pancellular hereditary persistence of fetal hemoglobin are both relatively benign conditions.

International audience; The complement system is an innate immune defense cascade that can cause tissue damage when inappropriately activated. Evidence for complement over activation has been reported in small cohorts of patients with sickle cell disease (SCD). However, the mechanism governing complement activation in SCD has not been elucidated. Here, we observe that the plasma concentration of sC5b-9, a reliable marker for terminal complement activation, is increased at steady state in 61% of untreated SCD patients. We show that greater complement activation in vitro is promoted by SCD erythrocytes compared to normal ones, although no significant differences were observed in the regulatory proteins CD35, CD55, and CD59 in whole blood. Complement activation is positively correlated with the percentage of dense sickle cells (DRBCs). The expression levels of CD35, CD55, and CD59 are reduced in DRBCs, suggesting inefficient regulation when cell density increases. Moreover, the surface expression of the complement regulator CD46 on granulocytes was inversely correlated with the plasma sC5b-9. We also show increased complement deposition in cultured human endothelial cells incubated with SCD serum, which is diminished by the addition of the heme scavenger hemopexin. Treatment of SCD patients with hydroxyurea produces substantial reductions in complement activation, measured by sC5b-9 concentration and upregulation of CD46, as well as decreased complement activation on RBCs in vitro. In conclusion, complement over activation is a common pathogenic event in SCD that is associated with formation of DRBCs and hemolysis. And, it affects red cells, leukocytes and endothelial cells. This complement over activation is partly alleviated by hydroxyurea therapy.

Highlights • Less than 20% of febrile acute chest syndromes are microbiologically documented in adults presenting with sickle cell disease. • Molecular testing for respiratory pathogens slightly improves the microbiological diagnosis for viral detection but allows for reducing the antibiotic therapy duration. • Beyond the technical limits of microbiological molecular testing in standard clinical settings, our findings suggest the limited role of infections in the pathophysiology of acute chest syndrome., Background Differentiating acute chest syndrome (ACS) from community-acquired pneumonia (CAP) is challenging in adults presenting with major sickle cell disease (SCD) (semiological similarity, rare microbiological documentation). We aimed to assess the usefulness of nucleic acid amplification test (NAAT) for respiratory pathogens, in combination with standard bacteriological investigations, in febrile ACS adult patients presenting with major SCD. Methods We performed a prospective, monocentric, observational study of 61 SCD adults presenting with febrile ACS from February 2015 to April 2016. Systematic blood, urine, and respiratory specimens were collected, before antibiotic initiation, for culture, urinary antigen tests, serology, and NAAT for respiratory pathogens. Results A pathogen was detected in 12 febrile ACS (19.7%): four viruses (6.6%) (Rhinovirus; Influenza A/B), seven bacteria (11.4%) (S. aureus, S. pneumoniae, K. pneumoniae, L. pneumophila, M. pneumoniae), one mixed infection (1.6%) (S. aureus and Influenza B). NAAT only detected L. pneumophila in one case (serogroup 2). Apart from a significantly shorter antibiotic therapy duration (6.1 vs. 7.8 days, P = 0.045), no difference was observed between undocumented and microbiologically-documented febrile ACS. Conclusion Using NAAT for the detection of respiratory pathogens in adults presenting with SCD slightly improved the microbiological diagnostic of febrile ACS, although respiratory infections are not the main etiological factor.

Background Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis. Results A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients. Conclusion The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients’ healthcare and probably has to be democratized notably for complex cases.

Primary hyperparathyroidism (pHPT) is the third most common endocrine disorder and usually affects patients between 60 and 70 years of age. To our knowledge, this condition has never been studied in young patients with sickle cell disease (SCD). Our objective was to describe the clinical and biological characteristics of pHPT in adult patients with SCD and its management. We conducted a retrospective study that included SCD patients who were diagnosed with pHPT in four SCD referral centers. pHPT was defined by the presence of elevated serum calcium levels with inappropriate normal or increased parathyroid hormone (PTH) serum levels or histopathological evidence of parathyroid adenoma or hyperplasia. Patients with severe renal impairment (GFR &lt, 30 mL/min) were excluded. Twenty-eight patients (18 women, 64%, 22 homozygous genotype, 79%) were included. The median age at pHPT diagnosis was 41 years (interquartile range &ndash, IQR- 31.5&ndash, 49.5). The median serum calcium and PTH concentration were, respectively, 2.62 mmol/L (IQR 2.60&ndash, 2.78) and 105 pg/mL (IQR 69&ndash, 137). Bone mineral density (BMD) revealed very low BMD (&minus, 2.5 SD) in 44% of patients explored (vs. 12.5% among 32 SCD patients matched for SCD genotype, sex, age, and BMI, p = 0.03). Fourteen patients (50%) received surgical treatment, which was successful in all cases, but four of these patients (29%) presented with pHPT recurrence after a median time of 6.5 years. Three of these patients underwent a second cervical surgery that confirmed the presence of a new parathyroid adenoma. These results suggest that SCD is a condition associated with pHPT in young subjects. SCD patients with pHPT have a high risk of very low BMD. A diagnosis of pHPT should be suspected in the presence of mild hypercalcemia or low BMD in SCD patients.

Sickle cell disease (SCD) is among the most common genetic diseases, with a recent increase in life expectancy. Patients may therefore need similar surgical procedures as does the general population, including cardiac surgery. Cardiopulmonary bypass is a homeostasis challenge for SCD patients, with high risk of vasoocclusive crisis. In the most severe cases of cardiogenic shock, venoarterial extracorporeal membrane oxygenation (VA-ECMO) may be required, with prolonged exposure to extreme nonphysiological conditions. We report a case of postcardiotomy shock in an SCD patient successfully managed with VA-ECMO. This highlights that SCD should not be a counterindication to VA-ECMO, pending multidisciplinary management.

Sickle cell disease (SCD) induces a chronic prothrombotic state. Central venous access devices (CVADs) are commonly used for chronic transfusions and iron chelation in this population. CVADs are an additional venous thromboembolism (VTE) risk factor. The role of thromboprophylaxis in this setting is uncertain. The objectives are: (1) to determine whether thromboprophylaxis reduces VTE risk in SCD patients with CVAD and (2) to explore characteristics associated with VTE risk. We identified adults with SCD and CVAD intended for chronic use (≥3 months) at two comprehensive SCD centers. Thromboprophylaxis presence; type; intensity; and patient-, catheter-, and treatment-related VTE risk factors were recorded. Among 949 patients, 49 had a CVAD (25 without and 24 with VTE prophylaxis). Thromboprophylaxis type and intensity varied widely. Patients without thromboprophylaxis had higher VTE rates (rate ratio (RR) = 4.0 (95% confidence interval: 1.2–12.6), p = 0.02). Hydroxyurea was associated with lower VTE rates (RR = 20.5 (6.4–65.3), p < 0.001). PICC lines and Vortex and Xcela Power implantable devices were associated with higher rates compared with Port-a-Cath (RR = 5.8 (1.3–25.9), p = 0.02, and RR = 58.2 (15.0–225.0), p < 0.001, respectively). Thromboprophylaxis, hydroxyurea, and CVAD subtype were independently associated with VTE. The potentially protective role of thromboprophylaxis and hydroxyurea for VTE prevention in patients with SCD and CVAD merits further exploration.

In a recent clinical trial, the metabolite L-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To confirm this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a causal relationship between L-glutamine levels and painful crises (N=1,278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52 – 0.89], P=0.0048). In two smaller SCD cohorts (N=299 and 406), the protective effect of L-glutamine was observed (OR=0.82 [0.50-1.34]), although the MR result was not significant (P=0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid was associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

Introduction Les patients drépanocytaires sont à risque de surinfection bactérienne du fait de l’asplénie fonctionnelle induite par la maladie. Leur fragilité vis-à-vis d’une infection virale n’a jamais bien été établie si ce n’est que celle-ci augmente le risque de crise vaso-occlusive (CVO) et donc d’hospitalisation. Les patients drépanocytaires ont très tôt été considérés comme personnes “fragiles” vis-à-vis de la COVID-19 mais cela reste controversé et les facteurs de gravité dans cette population sont mal connus. Nous avons voulu identifier les facteurs de risque associés à des formes sévères de COVID-19 dans une cohorte de patients drépanocytaires infectés par le SARS-Cov2 et hospitalisés. Matériels et méthodes Cohorte prospective, multicentrique et observationnelle Française incluant des patients drépanocytaires hospitalisés avec une infection SARS-CoV-2 confirmée (par test RT-PCR sur écouvillon naso-pharyngé) entre mars 2020 et mai 2021. Les données cliniques et le devenir durant l’hospitalisation ont été recueillis. Un modèle de régression logistique multivarié a été utilisé pour identifier les facteurs associés aux formes sévères de COVID-19 définies par le recours à une ventilation mécanique ou un décès intra-hospitalier. Nous avons effectué des comparaisons en fonction des génotypes de drépanocytose. Résultats 319 patients drépanocytaires, d’âge moyen 27,4 ans (de 2 mois à 85,5 ans), ont été hospitalisés concomitamment à la découverte d’une infection par le SARS-CoV-2. Sept (2,2 %) sont décédés, uniquement des adultes. Chez les adultes, les patients âgés de plus de 40 ans (n = 59) présentaient un risque 8,3 fois plus élevé [IC 95 % 2,6–31,2] de décès ou d’intubation par rapport aux patients âgés de 20 à 40 ans (n = 153) (P

Introduction Les plus frequentes complications aigues de la drepanocytose sont les crises vaso-occlusives (CVO) douloureuses osseuses et les syndromes thoraciques aigus. Une premiere etude avait suggere une relation entre la frequence des CVO et une mortalite accrue [1] . Alors que la prise en charge de la drepanocytose s’est amelioree, il parait important d’etudier a nouveau cette association. Ainsi, l’objectif de cette etude etait d’evaluer l’association entre CVO hospitalisees et mortalite chez les patients drepanocytaires en France. Patients et methodes Etude de cohorte observationnelle retrospective realisee a partir des bases de donnees du Systeme National des Donnees de Sante (SNDS). Celle-ci inclut les donnees hospitalieres, les donnees de remboursement de soins en ville et la date de deces de la quasi-totalite des francais. Entre le 01/01/2012 et le 31/12/2018, tous les patients âges de plus de 16 ans identifies comme atteints de drepanocytose (hospitalises et/ou presentant une ALD avec un code CIM-10 D57,0-2) ont ete inclus. La date index a ete definie comme la premiere interaction avec le systeme de soins (en lien ou non avec la drepanocytose). Les patients ont ete suivis pendant un minimum de 1 an et jusqu’a la fin de l’etude (31/12/2018). Une CVO hospitalisee etait definie par un sejour hospitalier avec un diagnostic principal ou relie de drepanocytose avec crises (D57,0), contenant au moins une nuit d’hospitalisation et precede par un passage par le service des urgences (afin d’eviter d’inclure des sejours pour drepanocytose pour d’autres motifs qu’une CVO). Le taux annuel de CVO hospitalisees a ete defini par le nombre total de CVO hospitalisees pendant le suivi divise par le nombre d’annees de suivi. Les patients ont ete categorises en 3 groupes en fonction du taux annuel de CVO : L’effet du taux cumulatif de CVO hospitalisees sur le deces a ete estime par des modeles de Cox prenant l’âge comme echelle de temps et ajustes sur le genre. Resultats 17 726 patients drepanocytaires ont ete inclus, dont 65,3 % de femmes–une grande proportion du fait d’hospitalisations chez des femmes enceintes. L’âge variait de 16 a 99 ans et l’âge moyen etait de 35,0 ans (±17,8, mediane 32,0). Chaque annee, 86 a 89 %, 9 a 10 % et 2 a 4 % des patients ont presente respectivement Conclusion Notre etude confirme, dans une cohorte nationale francaise en vie reelle, que les patients presentant frequemment des CVO hospitalisees ont un risque de deces plus eleve que les patients presentant rarement des CVO. Le risque le plus eleve de recidive de CVO survient dans les 100 jours suivant une precedente CVO hospitalisee. Ces resultats rappellent que les patients presentant des CVO recurrentes doivent etre la cible d’intensifications therapeutiques permettant de reduire ou prevenir ces evenements, pour esperer ameliorer la survie.

Introduction Les ulceres de jambe (UDJ) sont une complication chronique et severe des syndromes drepanocytaires majeurs dont le traitement est mal codifie. Il n’existe pas d’etude evaluant l’interet de la greffe de peau autologue dans cette indication. Le principal objectif etait d’evaluer l’efficacite de la greffe de peau autologue dans la cicatrisation et la prevention de la recidive des ulceres de jambe drepanocytaires. Materiel et methodes Cette etude de cohorte observationnelle a ete menee sur deux sites du centre de reference de la drepanocytose entre 2006 et 2019 et a inclus 103 patients drepanocytaires ayant presente au total 111 UDJ evoluant depuis au moins 2 semaines. Le critere de jugement principal de l’etude etait la cicatrisation complete a 12 et 24 semaines de l’UDJ drepanocytaire traite soit avec un traitement conventionnel sans greffe de peau, soit avec une greffe de peau precoce ( 6 semaines). Resultats Les 103 patients de la cohorte etaient majoritairement des hommes 62,1 % versus 37,9 % de femmes. L’âge median etait de 37,9 ans. 20,4 % des patients presentaient un antecedent de maladie thromboembolique veineuse et 38,7 % une insuffisance veineuse superficielle. Parmi les 111 UDJ inclus, 26 (23,4 %) etaient cicatrises a 12 semaines et 50 (45 %) a 24 semaines. Le delai median de realisation de la greffe apres prise en charge etait de 62,5 jours, [interquartile range IQR 19,8-139]. En analyse univariee, les facteurs predictifs de cicatrisation complete de l’ulcere a 12 et 24 semaines respectivement, etaient la surface de l’ulcere Discussion La greffe de peau autologue semble efficace pour la cicatrisation et la prevention de la recidive des UDJ associes a drepanocytose si elle est realisee precocement dans la prise en charge (

INTRODUCTION Vaso-occlusive crisis (VOC), hallmark of sickle-cell disease (SCD), is the first cause of patients' emergency room (ER) admissions and hospitalizations. Acute chest syndrome (ACS) is a life-threatening complication that can occur during VOC and prolong hospitalization and is one of the main causes of death in SCD patients. The PRESEV score, established by team members and colleagues, assesses the risk of developing ACS (Bartolucci et al., 2016). In addition, the score has been validated by an international multicenter study, involving 13 centers, distributed in five different countries (PRESEV 2 - ASH 2020). Throughout the first wave of the Covid-19 pandemic, VOC management for SCD patients was a major concern. Our sickle cell referral center set up a hotline to monitor patients suffering from VOC daily, and organized the deployment of home-care services when required. The success of this system during the first wave of the pandemic led to the establishment of DREPADOM, a home-care and hospitalization protocol for VOC management in patients who are at a low risk of developing ACS, as standard care. DESCRIPTION OF SETTING Patients eligible for DREPADOM are patients that arrive at the ER for a VOC with a low PRESEV score, meaning low risk of developing ACS; or patients that are discharged early following hospitalization for VOC. After physical examination and calculation of the PRESEV score, DREPADOM home hospitalization is systematically offered to patients arriving to the ER with a PRESEV score ≤ 5. If the patient agrees, the DREPADOM nurse coordinator then acts as a link between the pharmacist, the oxygen supplier, the homecare provider, and the DREPADOM medical platform to activate the home hospitalization protocol. This entails the delivery of oxygen supply at the patient's house, dispatch of a medical prescription of opioids and parenteral treatments, twice/thrice-daily visits from homecare nurses, and an on-call SCD expert. DREPADOM relies on a system of daily telephone calls with three levels of expertise and warning and a decision-making algorithm. This is supervised by SCD experts, who arbitrate according to the evolution of the situation (stopping the follow-up, continuing the follow-up as an outpatient, hospitalization) (Fig.1). Furthermore, nurses enter patient vitals in real-time during their daily visits on a dedicated online platform (Link4Life) that contains an integrated automatic alert system. Additionally, a daily phone update between the DREPADOM coordination and the homecare provider's coordination concerning status and evolution of the patient's global condition takes place. RESULTS Over a 6-month period, 39 patients were included in the DREPADOM home hospitalization protocol, 3 of which were included multiple times for a total of 42 inclusions. Mean age was 40 years old [±9], sex ratio was 14/25 (male/female), ER vs early discharge ratio was 21/22, and mean homecare follow-up was 3 days (±1) for both, patients arriving from the ER and early discharge patients. Throughout the third wave of the pandemic, when hospital saturation was a major concern, patients with PRESEV scores 5 ≤ 11 were also offered DREPADOM. Three patients were hospitalized (7%): one for an ACS, who was included during the 3 rd wave of the pandemic with a PRESEV score of 8; one for pyelonephritis unrelated to the VOC; and one for difficulties with venous access. No death was reported. PERSPECTIVES Preliminary satisfaction surveys show a great enthusiasm for DREPADOM, partly due to the high standard of care received, but also due to the shorter length of hospitalization. In fact, median hospital stay for VOC is 4 [3-7] days (Bartolucci, 2016) whereas median homecare follow-up was 3 [1-6] days. Figure 1 Figure 1. Disclosures Bartolucci: Hemanext: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Emmaus: Consultancy; GBT: Consultancy; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, 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; Fabre Foundation: Research Funding.

Allogeneic bone marrow transplantation (BMT) is the only curative treatment available for sickle cell disease (SCD). The effectiveness of the treatment is primarily assessed by the chimerism rate, which is the fraction of cells derived from the donor's hematopoietic stem cells (HSCs) relative to the recipient's cells. New less toxic conditioning agents, described as reduced, nonmyeloablative (as opposed to myeloablative conditioning agents) are now used for BMT with sibling donors. Moreover, most sibling donors are sickle cell trait carriers (heterozygous A/S genotype). In the absence of a test performed on erythroid cells, the rate of chimerism is currently assessed either on different subpopulations of myeloid cells by molecular biology techniques or on hemoglobin measurement by chromatography (HPLC). However, the percentage of myeloid chimerism is rarely representative of the percentage of erythroid chimerism in these patients and HPLC cannot allow analysis at the single cell level. An easy-to-implement method for accurate measurement of fetal hemoglobin (HbF) content in individualized red blood cells (RBCs) has recently been developed (Hebert, et. al, AJH 2020). This method relies on flow cytometry for cell individualization and intracellular labeling of HbF with a fluorescent monoclonal antibody for quantification. Based on the same approach, we propose the use of monoclonal antibodies directed against adult hemoglobins (HbA0 and HbA2) or hemoglobin S (HbS). This strategy allows to discriminate, from a blood sample, the different RBC subpopulations coming from either the recipient or the donor, or from the transfusion associated with this procedure, thus allowing us to precisely determine the rates of erythroid chimerism in patients. As a proof of concept, we show here the evaluation of the percentage of erythroid chimerism during a longitudinal follow-up performed on 3 patients with SCD (P1 - 18 months, P2 - 4 months, and P3 - 4 months). The 3 patients received allogeneic BMT from a sibling A/S donor following nonmyeloablative conditioning consisting of the administration of an anti-CD52 antibody associated with radiotherapy (300 cGy TBI - total-body irradiation). We observed for P1 and P2 donor erythroid chimerism >90% and >95%, 1 and 2 months after BMT, respectively (measured after exclusion of transfused RBCs). These results are in accordance with the presence of most RBCs HbA- and HbS-positive, as determined by flow cytometry. In addition, the analysis of the reticulocyte (retic) subpopulations (CD71-positive cells) of these patients provides precise information on the RBC production of the bone marrow following transplantation. Retic donor chimerism levels were >99% for both P1 and P2, 1 month after BMT procedure. P1 and P2 showed stable donor reticulocyte and donor erythroid chimerism levels during the follow-up. On the contrary, P3 presented a different response with 43%, 41% and 5% donor erythroid chimerism 1, 2 and 3 months after BMT, respectively. Retrospectively, this bad response in P3 would have been predicted by low donor reticulocyte chimerism levels (5%, 6% and 0.5% at 1, 2 and 3 months after BMT, respectively). Our erythroid specific chimerism results were also compared to the assessment of chimerism performed on either total white blood cells (WBCs) or lineage specific subpopulations after sorting. Over 18 months after BMT in P1, the correlation between retic chimerism and total WBCs or T lymphocytes (CD3-positive cells) chimerism were not statistically significant (P = 1 and P = 0.833, respectively - Spearman test) (Figure 1). This new tool to monitor BMT outcome to treat SCD shows great precision and potentially a stronger predictive capability than total WBCs or lineage specific chimerism assessed by molecular biology. Our results highlight the importance of analyzing reticulocyte population to better assess BMT efficacy and predict the outcome a few days after the transplant. Its use could also be considered in the context of the various gene therapy strategies currently under development using modified β-globin gene addition or direct mutation correction through CRISPR/Cas9 and homologous recombination system. Figure 1 Figure 1. Disclosures Bencheikh: Innovhem: Current Employment. Bartolucci: Innovhem: Current holder of individual stocks in a privately-held company.

Background SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β- globin gene, with either homozygous inheritance, or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. This point mutation results in the production of hemoglobin S, which polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. In addition to VOEs, patients with SCD may experience severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. The current treatment strategy for patients with SCD includes hydroxyurea, along with newer treatments such as L-glutamine, crizanlizumab, and voxelotor. However, despite the availability of these treatments, considerable morbidity and mortality among patients with SCD represents a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crisis, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. Crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety in a Phase I/II study (Röth et al. Blood 2020), in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder. Study Design and Methods CROSSWALK-c (NCT number pending) is a placebo-controlled, randomized, double-blind, Phase IIa study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0), and presenting with ≥ 2 to ≤ 10 VOEs are eligible for this study. Patients on concurrent SCD-directed therapies are also eligible. Vaccination against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumonia are required for enrollment. Patients with a history of hematopoietic stem cell transplant are excluded from the study. Eligible patients will be randomized 1:1 to the crovalimab or placebo treatment arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be administered on Day 1 Week 1, followed by four weekly SC doses on Day 2 Week 1, and then on Weeks 2-4. Maintenance dosing will be administered from Week 5, followed by once every 4 weeks thereafter, for 48 weeks. All patients will receive study treatment according to a weight-based tiered dosing schedule. The primary objective is to evaluate the efficacy of crovalimab compared with placebo, based on the annualized rate of medical facility VOEs. Secondary efficacy objectives include the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin-creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetics, immunogenicity, and exploratory biomarker objectives will also be evaluated. Figure 1 Figure 1. Disclosures Callaghan: Agios Pharmaceuticals: Current Employment; Roche/Genentech: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy, Speakers Bureau; Forma: Consultancy; Hema Biologics: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; BioMarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Chiesi: Consultancy; Kedrion: Consultancy; Pfizer: Consultancy. Ataga: Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: CSL Behring: Other: Endpoint adjudicator ; Forma: Consultancy; Novo Nordisk: Consultancy; Chiesi: Consultancy; Bluebird Bio: Other: Endpoint adjudicator ; Novartis: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy. Balachandran: F. Hoffmann-La Roche Ltd: Current Employment. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Perretti: F. Hoffmann-La Roche Ltd: Current Employment. Ramos: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Bartolucci: Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; INNOVHEM: Other: Co-founder; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Hemanext: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy.

The efficacy and long-term effectiveness of hydroxycarbamide/hydroxyurea (HU) in the prevention of painful crises and in the decrease of mortality and morbidity in sickle cell disease (SCD) patients have been established (Charache et al. 1992; Steinberg et al 2010, Voskaridou et al 2010). From January 2009 to March 2019, the non-interventional prospective cohort study ESCORT-HU was conducted to evaluate the use of HU in real-life conditions and to collect information on the long-term safety of HU when used in current practice for the prevention or treatment of symptomatic complications in patients with sickle cell disease (SCD) (Montalembert et al 2021). A total of 1906 patients, 55% of adults, were enrolled in this study in 62 centres (Germany, Greece, Italy and France). The mean exposure to HU in this cohort was 30 months, for a cumulative exposure of 7310 patient-per year. The main objectives of ESCORT-HU have been fulfilled as regards the collection of data on the most common concerns associated with the use of HU in SCD patients: myelosuppression, child growth, concomitant administration of live vaccines, safety in population with renal and hepatic impairment and frequency of SCD events (painful crises, acute chest syndrome, stroke, acute splenic sequestration, infections, blood transfusions and hospitalizations) (Montalembert et al 2021). In order to better identify potential long-term risks and specific concerns of HU therapy, ESCORT-HU extension is being implemented in Europe with the goal of 2500 patients enrolled. Main risks targeted by the study are leg ulcers, one of the most limiting factors to continue a treatment with HU. Patients will be recruited over a 5-year period. In addition to patients already involved in the first ESCORT-HU study, new at-risk patients might be added such as patients with a history of HU exposure of at least 5 years, to allow a follow-up of patients treated with long-term HU to fully estimate the incidence of potential risk of malignancies prepubescent children aged more than 10 years for girls and more than 13 years for boys in order to document impact or not of HU on puberty and realisation of cryopreservation,patients with a history of leg ulcers, to search for discriminating criteria between leg ulcer caused by the disease and HU-induced leg ulcer,pregnant women without interruption of HU 3 months before the beginning of the pregnancy and males treated with HU whose partner is pregnant and without discontinuation of HU 3 months before the beginning of the pregnancy. To date, there is a limited number of pregnancies exposed to HU with documented outcome. Despite no adverse effects on pregnancy or on the health of the foetus/new-born have been registered, an increase of the number of pregnancies with documented outcomes will allow for meaningful assessment of foetal outcome following exposure to HU during pregnancy, 10 months after the beginning of ESCORT-HU extension, 818 patients have been enrolled in 70 investigational sites in 4 countries (Greece, Italy, Germany and France) (see Graph below). A first steering committee was hold in June 2021. Its conclusions were that distribution of patients (genotype, sex, age) was consistent with the first study and the number of events reported until now was coherent with what was expected per year, with no occurrence of major concern. This extension study involves most of competence centres which manage SCD patients. SC patients have become increasingly well cared for in recent decades and have seen their life expectancy increase. HU treatment is now a chronic treatment possibly for life in many patients with SCD, better its knowledge of its efficiency and tolerance, better patient adherence to treatment will be. Figure 1 Figure 1. Disclosures de Montalembert: Addmedica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Voskaridou: ADDMEDICA: Consultancy, Research Funding; BMS: Consultancy, Research Funding; GENESIS: Consultancy, Research Funding; NOVARTIS: Research Funding; PROTAGONIST: Research Funding; IMARA: Research Funding. Oevermann: NOVARTIS: Consultancy; GBT: Consultancy. Joseph: bluebird bio: Consultancy. Colombatti: BlueBirdBio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Bartolucci: INNOVHEM: Other: Co-founder; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Fabre Foundation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy; Emmaus: Consultancy; Hemanext: Consultancy. Brousse: BLUEBIRDBIO: Consultancy; ADDMEDICA: Consultancy. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees.

Background: Sickle cell disease (SCD) is an inherited group of red blood cell disorders with a complex pathophysiology largely driven by vaso-occlusion and hemolytic anemia. Vaso-occlusive crises (VOCs) are the hallmark of SCD. VOCs and continuing silent vaso-occlusion are associated with cycles of inflammation and tissue injury that can lead to acute and chronic organ complications. Sickle cell nephropathy (SCN) is the term used to describe kidney-related complications of SCD; manifestations include hyperfiltration, albuminuria and progressive loss of kidney function. Endothelial dysfunction may play a role in the development of albuminuria in SCD. Increased plasma endothelin-1 (ET-1), a biomarker of endothelial dysfunction, is significantly associated with an increase in the urine albumin-to-creatinine ratio (ACR) (Ataga et al. PLoS One 2016). Patients (pts) with SCN may develop chronic kidney disease (CKD; diagnosed when abnormalities in kidney structure or function persist for >3 mo). Pts with SCD and baseline (BL) albuminuria ≥100 mg/g can develop persistent albuminuria, which is associated with a rapid decline in estimated glomerular filtration rate (eGFR) (Niss et al. Blood Adv 2020). No treatments are approved for CKD due to SCN; current SoC usually consists of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARBs) and/or hydroxyurea/hydroxycarbamide (HU/HC). P-selectin is one of the drivers of multicellular adhesion leading to vaso-occlusion. Preclinical studies have shown that P-selectin expression increases in response to renal ischemia-reperfusion injury (Zizzi et al. J Pediatr Surg 1997). Crizanlizumab, a humanized monoclonal antibody that binds to P-selectin, significantly reduced the median annualized VOC rate vs placebo (Ataga et al. NEJM 2017). The aim of the Phase II STEADFAST study (NCT04053764) is to determine the effect of P-selectin inhibition with crizanlizumab on kidney function in pts with SCD and early-stage CKD. Methods: The STEADFAST trial aims to enroll 148 pts aged ≥16 yrs with CKD due to SCD; pts eligible for inclusion are detailed in the figure. Pts will be randomized 1:1 to receive crizanlizumab 5.0 mg/kg (intravenous infusion over 30 min on Day 1 of Wk 1, Day 1 of Wk 3, then every 4 wks for 1 yr) and their usual SoC or their usual SoC alone. Pts will be stratified based on CKD risk category (moderate risk or high/very high risk, based on eGFR and albuminuria assessed by ACR) and if they are receiving HU/HC. Exclusion criteria include pts with a history of stem cell transplant, evidence of acute kidney injury within 3 mo of study entry, or those receiving renal replacement therapy. The primary endpoint is the proportion of pts with ≥30% decrease from BL in ACR at 12 mo. A logistic regression model including treatment effects and stratification factors will be utilized; the test (based on the log-odds ratio estimated by the model) will be performed at a 1-sided significance level of 0.025. Secondary endpoints include mean change in ACR from BL to 3, 6, 9 and 12 mo, the percentage change in eGFR from BL to 3, 6, 9 and 12 mo, the proportion of pts with a protein-to-creatinine ratio (PCR) improvement (≥20% decrease) or stable PCR (within ±20%) at 12 mo compared with BL and the proportion of pts with progression of CKD (based on pre-defined eGFR decline and ACR increase) from BL to 12 mo. To minimize variability of ACR measurements, 3 urine samples (2/3 samples collected as morning voids) will be collected at all designated timepoints. Exploratory endpoints include assessments of renal and cardiac biomarkers, including ET-1 and soluble P-selectin, at BL, 3, 6, 9 and 12 mo, echocardiography at BL and 12 mo and renal MRI at BL, 6 and 12 mo (at selected sites). Results: As of July 2021, 31 pts have been enrolled, with 36 sites in 10 countries currently open to enrollment. Open sites by country include USA (9 sites), Brazil (5 sites), Spain (4 sites), Italy, Turkey and the UK (3 sites each), France, Greece and Panama (2 sites each), Lebanon, the Netherlands and South Africa (1 site each). Study sites in Bahrain, Egypt, Ghana and Kenya are planned and Ireland, Tanzania and Saudi Arabia have been recently added as new participating countries. Conclusion: The Phase II STEADFAST study has been designed to evaluate whether crizanlizumab, in combination with SoC, can provide a potentially targeted disease-modifying benefit for pts with SCD and CKD. The trial is open for enrollment. Figure 1 Figure 1. Disclosures Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ataga: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Derebail: Travere Therapeutics: Consultancy; Novartis: Consultancy; Bayer: Consultancy; UpToDate: Patents & Royalties. Sharpe: Napp Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy. Lebensburger: Novartis: Consultancy; Bio Products Laboratory: Consultancy. DeBonnett: Novartis Pharmaceuticals Corporation: Current Employment. Zhang: Novartis: Current Employment. Bartolucci: INNOVHEM: Other: Co-founder; Hemanext: Consultancy; AGIOS: Consultancy; Jazz Pharma: Other: Lecture fees; GBT: Consultancy; Emmaus: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding. OffLabel Disclosure: The presentation will discuss use of crizanlizumab as an investigational therapy in patients with sickle cell disease and sickle cell nephropathy

Introduction : Sickle cell disease (SCD) is an inherited disorder which affects 300,000 newborns per year. Vaso-occlusive episodes (VOEs) cause an important morbi-mortality and a decreased quality of life in patients with SCD. Some risk factors of VOE are well known, like infection, cold exposure, stress, pulmonary diseases and dehydration. Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in few case reports or series. However, no comparative study has been conducted to demonstrate this risk which is still debated, resulting in discrepancies among guidelines on SCD management. This study aimed to assess the risk of hospitalization for VOE associated with out-hospital exposure to systemic corticosteroids in patients with SCD in France. Methods : Data source was the French national health insurance system database, named SNDS (Système National des Données de Santé) between 2010 and 2018. The SNDS links sociodemographic, out- and in-hospital data for the entire French population (>66 million inhabitants). The study population consisted in all patients with SCD with at least one hospitalization for VOE during the study period, identified with a primary discharge diagnosis of VOE (D57.0 code of the international classification of disease, 10 th version; positive predictive value: 98.6%). All genotypes (homozygous SS-SCD and double-heterozygous SCD) were included. Because we assessed out-hospital exposure to corticosteroids, patients hospitalized during the three months before the first VOE were excluded. We performed a case-case-time-control study (Figure 1). This self-controlled design results in self-adjustment for time-independent confounders, including genotype. The outcome was the first hospitalization for VOE. The exposure to oral and injectable corticosteroids, identified using out-hospital reimbursement data, was assessed during a case period (28 days before the outcome) compared to the exposure during a control period (28 days, starting 84 days before the outcome). The same comparison was made among future cases (matched patients hospitalized for VOE the year after the given case), in order to adjust for the trend of exposure to corticosteroids (calendar variations of corticosteroid exposure). Results : Overall, 5,151 cases of VOEs were included in the main analysis. Median age at first VOE was 16.9 years; 317 (6.2%) patients were exposed to corticosteroids during the case period. In the main analysis, corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted Odds Ratio (aOR): 3.81, 95% confidence interval (95% CI): 2.44 to 5.61. In patients exposed to hydroxyurea, the aOR was 2.61, 95% CI: 1.07 to 6.39, compared with an aOR of 4.00, 95% CI: 2.53 to 6.30 in unexposed patients. In the subgroup analysis by age, the aOR was 2.81, 95% CI: 1.49 to 5.30 in children, and 4.45, 95% CI: 2.37 to 8.37 in adults. The results were consistent in all sensitivity analyses. Conclusion : This study showed an association between outpatient exposure to systemic corticosteroids with an increased risk of hospitalization for VOE, in both adults and children. Hydroxyurea may reduce this risk in adults. Figure 1 Figure 1. Disclosures Bartolucci: GBT: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Published literature on cognitive functioning in adults with sickle cell disease (SCD) is sparse when compared to children. A few reports describe deficits in processing speed and executive functioning. Some studies suggest that these deficits are more severe in patients with silent cerebral infarcts (SCI). Even in the absence of radiological evidence of ischemic injury, some cognitive deficits have been depicted in adults . We hypothesize that in SCD adults, the cognitive profile varies with the presence of ischemic injury (SCI or overt stroke). The aims of this study were 1) to describe the neuropsychological profiles of SCD adults, and 2) to characterize clusters of patients with similar cognitive profiles. Methods: We conducted a retrospective analysis of all consecutive SCD adults who underwent comprehensive neuropsychological assessment during routine care at the UMGGR clinic at Henri Mondor Hospital, Créteil (France), between January 2017 and April 2021. The Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) were used for cognitive disorder, anxiety and depression screening, respectively. The cognitive battery combined standardized neuropsychological tests with established clinical utility and validity. Educational attainment was scored based on the number of years of schooling for the highest completed diploma. Principal component analysis was performed. ANOVA was used to compare patients' characteristics between clusters. Results: 80 patients, median age 36.5 [range 19-63] years were included. 40 (50.0%) were male. Genotype distribution was 62 patients (77.5%) with SS/Sbeta 0, 12 (15.0%) with SC and 6 (7.5%) with Sbeta +. On Principal Component Analysis, a 5-factor model presented the best fit (Bartlett's sphericity test (χ²(171)=1174; p Conclusions: Overall, these results suggest at least three different cognitive profiles in adults with SCD: 1) few or no cognitive deficits (cluster 3), 2) some cognitive impairment with a sub-cortical cognitive profile (cluster 2) and 3) more global cognitive impairment with cortical/sub-cortical profile and specific deficits of memory, language and constructional praxis, depending on the location of prior overt neurological events (cluster 1). To reduce the long-term cognitive morbidity of SCD, patients can be identified by their distinct cognitive profiles and neurorehabilitation tailored to their unique profile should be applied. The large proportion of childhood stroke in patients with global cognitive impairment in contrast with majority of those with milder to no cognitive impairment having had their stroke in adulthood emphasize the crucial importance of preventing early childhood stroke and implementing early neurorehabilitation. Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer: Research Funding; Novartis: Honoraria. Kuo: Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Bartolucci: Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Emmaus: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding.