ERN-EUROBLOODNET EUROPEAN REGISTRY OF PATIENTS AFFECTED BY RED BLOOD CELL DISORDERS AND COVID-19

Background: Patients with red blood cell disorders (RBCD), are likely to be at increased risk of complications from SARS-Co-2 (Coid-19), but eidence in this population is scarce due to its low frequency and heterogeneous distribution. Aims: ERN-EuroBloodNet, the European Reference Network in rare hematological disorders, established a European registry to determine the impact of COVID-19 on RBCD patients and identify risk factors predicting seere outcomes. Methods: The ERN-EuroBloodNet registry was established in March 2020 by VHIR based on Redcap software in accordance with the Regulation (EU) 2016/679 on personal data. The local Research Ethics Committee confirmed that the exceptional case of the pandemic justifies the waier of informed consent. Eligible patients had confirmed RBCD and COVID-19. Data collected included demographics, diagnosis, comorbidities, treatments, and COVID-19 symptoms and management. For analysis of COVID-19 seerity, two groups were established 1) Mild: asymptomatic or mild symptoms without clinical pneumonia and 2) Seere: pneumonia requiring oxygen/respiratory support and/or admission to intensie care unit. Continuous ariables were compared using the Wilcoxon rank-sum test or Kruskall Wallis test, while categorical ariables were analyzed using the Chi-square test or Fisher's Exact test. Releant factors influencing disease or seerity were examined by the logistic regression adjusted for age. Results: As of February 25, 2022, 42 medical centers from 10 EU countries had registered 428 patients: 212 Sickle cell disease (SCD), 186 Thalassemia major and intermedia (THAL). The mean age of SCD was lower (22y) than of THAL (39.4y). Splenectomy and comorbidities were higher in THAL (51.4% and 61,3%) than in SCD (16,3% and 46,8%) (p<0.001, p=0.004). Age and BMI correlated with COVID-19 seerity, as described in the general population (p=0.003, p<0.001). Fig 1 shows age distribution and COVID-19 seerity by disease seerity groups. The mean age for seere COVID-19 was lower in patients with seere SCD (SS/SB0 s SC/SB+: 23y s 67.5y) and THAL (major s intermedia: 43.5 s 51.3y) (p<0.001). Potential risk factors such as eleated ferritin, current chelation or history of splenectomy did not confer additional risk for deeloping seere COVID-19 in any patient group. Only diabetes as a comorbidity correlated with seerity grade in SCD (p=0.01) and hypertension in THAL (p=0.009). While seere COVID-19 infection in SCD was associated with both ACS (p<0.001) and kidney failure requiring treatment (p<0.001), this was not predicted by a history of preious ACS or kidney disease in steady state. Oerall, 14,6% RBC patients needed oxygen/respiratory support, 4% were admitted to ICU with an oerall mortality rate of 1%, much lower than reported in other similar cohorts. Hospital Son Espases, Palma de Mallorca, Spain;54 Clinical Pharmacology Serice, Hospital Uniersitari Vall d'Hebron, Barcelona, Spain;55 Vall d'Hebron Institut de Recerca, Barcelona, Spain;56 Diision of Hematology and Oncology, Department of Internal Medicine, American Uniersity of Beirut Medical Center, Beirut, Lebanon;57 UOC Pediatric Hematology Oncology, Uniersity of Padoa, Padoa, Italy;58 Department of Haematology, Oxford Uniersity Hospitals NHS Foundation Trust, Oxford, United Kingdom;59 Translational Research in Child and Adolescent Cancer, Vall d'Hebron Institut de Recerca, Barcelona, Spain Background: Patients with red blood cell disorders (RBCD), are likely to be at increased risk of complications from SARS-Co-2 (Coid-19), but eidence in this population is scarce due to its low frequency and heterogeneous distribution. Aims: ERN-EuroBloodNet, the European Reference Network in rare hematological disorders, established a European registry to determine the impact of COVID-19 on RBCD patients and identify risk factors predicting seere outcomes. Methods: The ERN-EuroBloodNet registry was established in March 2020 by VHIR based on Redcap software in accordance with the Regulation (EU) 2016/679 on personal data. The local Research Ethics Committee confirm d that the exceptional case of the pandemic justifies the waier of informed consent. Eligible patients had confirmed RBCD and COVID-19. Data collected included demographics, diagnosis, comorbidities, treatments, and COVID-19 symptoms and management. For analysis of COVID-19 seerity, two groups were established 1) Mild: asymptomatic or mild symptoms without clinical pneumonia and 2) Seere: pneumonia requiring oxygen/respiratory support and/or admission to intensie care unit. Continuous ariables were compared using the Wilcoxon rank-sum test or Kruskall Wallis test, while categorical ariables were analyzed using the Chi-square test or Fisher's Exact test. Releant factors influencing disease or seerity were examined by the logistic regression adjusted for age. Results: As of February 25, 2022, 42 medical centers from 10 EU countries had registered 428 patients: 212 Sickle cell disease (SCD), 186 Thalassemia major and intermedia (THAL). The mean age of SCD was lower (22y) than of THAL (39.4y). Splenectomy and comorbidities were higher in THAL (51.4% and 61,3%) than in SCD (16,3% and 46,8%) (p<0.001, p=0.004). Age and BMI correlated with COVID-19 seerity, as described in the general population (p=0.003, p<0.001). Fig 1 shows age distribution and COVID-19 seerity by disease seerity groups. The mean age for seere COVID-19 was lower in patients with seere SCD (SS/SB0 s SC/SB+: 23y s 67.5y) and THAL (major s intermedia: 43.5 s 51.3y) (p<0.001). Potential risk factors such as eleated ferritin, current chelation or history of splenectomy did not confer additional risk for deeloping seere COVID-19 in any patient group. Only diabetes as a comorbidity correlated with seerity grade in SCD (p=0.01) and hypertension in THAL (p=0.009). While seere COVID-19 infection in SCD was associated with both ACS (p<0.001) and kidney failure requiring treatment (p<0.001), this was not predicted by a history of preious ACS or kidney disease in steady state. Oerall, 14,6% RBC patients needed oxygen/respiratory support, 4% were admitted to ICU with an oerall mortality rate of 1%, much lower than reported in other similar cohorts. Summary/Conclusion: Results obtained so far show that seere COVID-19 occurs at younger ages in more aggressie forms of SCD and THAL. Current preentie approaches focus on age oer disease seerity. Our data highlights the risk of seere COVID-19 infection in some young patients, particularly those with SS/SB0 SCD, suggesting that immunization should be considered in this pediatric group as well. Results between similar sized cohorts of RBCD patients ary between each other and those presented here, highlighting the importance of collecting all of these small cohorts together to ensure adequate statistical power so that definitie risk factors can be reliably identified and used to guide management of patients with these rare disorders in the light of the ongoing pandemic. (Figure Presented).

ERN-EuroBloodNet European Registry of Patients Affected by Red Blood Cell Disorders and COVID-19

[Formula presented] PV, NR and MMP contributed equally Introduction Patients with red blood cell disorders (RBCD), chronic life threating multisystemic disorders in their severe forms, are likely to be at increased risk of complications from SARS-Cov-2 (Covid-19), but evidence in this population is scarce due to its low frequency and heterogeneous distribution. ERN-EuroBloodNet, the European Reference Network in rare hematological disorders, established a European registry to determine the impact of COVID-19 on RBCD patients and identify risk factors predicting severe outcomes. Methods The ERN-EuroBloodNet registry was established in March 2020 by Vall d'Hebron Research Institute based on REDcap software in accordance with the Regulation (EU) 2016/679 on personal data. The local Research Ethics Committee confirmed that the exceptional case of the pandemic justifies the waiver of informed consent. The ERN-EuroBloodNet registry on RBCD and COVID-19 is endorsed by the European Hematology Association (EHA). Eligible patients had confirmed RBCD and COVID-19. Data collected included demographics, diagnosis, comorbidities, treatments, and COVID-19 (severity grade, clinical manifestations, acute events, treatments, hospitalization, intensive care unit, death). For analysis of COVID-19 severity, two groups were established 1) Mild: asymptomatic or mild symptoms without clinical pneumonia and 2) Severe: pneumonia requiring oxygen/respiratory support and/or admission to intensive care unit. Continuous variables were compared using the Wilcoxon rank-sum test or Kruskall Wallis test, while categorical variables were analyzed using the Chi-square test or Fisher's Exact test. Relevant factors influencing disease or severity were examined by the logistic regression adjusted for age. Results As of June 2021, 42 medical centers from 10 EU countries had registered 373 patients: 191 Sickle cell disease (SCD), 156 Thalassemia major and intermedia (THAL) and 26 other RBCD. 84% of the SCD patients were reported by Spain, Belgium, Italy and The Netherlands and 92% of the THAL patients by Italy and Greece. The mean age of SCD was lower (22.5y) than of THAL (39.6y) with pediatric population accounting for 50.5% in SCD and 9% in THAL (p <0.001). Splenectomy and comorbidities were higher in THAL (51.3% and 65.8%) than in SCD (16% and 48.1%) (p<0.001, p=0.002). Age and BMI correlated with COVID-19 severity, as described in the general population (p=0.002, p<0.001). Fig 1 shows age distribution and COVID-19 severity by disease severity groups. The mean age for severe COVID-19 was lower in patients with severe SCD (SS/SB0 vs SC/SB+: 23.3y vs 67.5y) and THAL (major vs intermedia: 43.5 vs 51.3y) (p<0.001). Potential risk factors such as elevated ferritin, current chelation or history of splenectomy did not confer additional risk for developing severe COVID-19 in any patient group. Only diabetes as a comorbidity correlated with severity grade in SCD (p=0.011) and hypertension in THAL (p=0.014). While severe COVID-19 infection in SCD was associated with both ACS (p<0.001) and kidney failure requiring treatment (p=0.001), this was not predicted by a history of previous ACS or kidney disease in steady state. Overall, 14.8% RBC patients needed oxygen/respiratory support, 4.4% were admitted to ICU with an overall mortality rate of 0.8% (no deaths were registered in pediatric age), much lower than reported in other similar cohorts. Discussion Results obtained so far show that severe COVID-19 occurs at younger ages in more aggressive forms of SCD and THAL. Current preventive approaches (shielding, vaccinations) focus on age over disease severity. Our data highlights the risk of severe COVID-19 infection in some young patients, particularly those with SS/SB0 SCD, suggesting that immunization should be considered in this pediatric group as well. Results between similar sized cohorts of RBCD patients vary between each other and those presented here, highlighting the importance of collecting all of these small cohorts together to ensure adequate statistical p wer so that definitive risk factors (eg. age, genotype, comorbidities) can be reliably identified and used to guide management of patients with these rare disorders in the light of the ongoing pandemic. [Formula presented] Disclosures: Longo: Bristol Myers Squibb: Honoraria;BlueBird Bio: Honoraria. Bardón-Cancho: Novartis Oncology Spain: Research Funding. Flevari: PROTAGONIST COMPANY: Research Funding;ADDMEDICA: Consultancy, Research Funding;BMS: Research Funding;IMARA COMPANY: Research Funding;NOVARTIS COMPANY: Research Funding. Voskaridou: BMS: Consultancy, Research Funding;IMARA: Research Funding;NOVARTIS: Research Funding;ADDMEDICA: Consultancy, Research Funding;GENESIS: Consultancy, Research Funding;PROTAGONIST: Research Funding. Biemond: GBT: Honoraria, Research Funding, Speakers Bureau;Novartis: Honoraria, Research Funding, Speakers Bureau;Novo Nordisk: Honoraria;Celgene: Honoraria;Sanquin: Research Funding. Nur: Celgene: Speakers Bureau;Roche: Speakers Bureau;Novartis: Research Funding, Speakers Bureau. Beneitez-Pastor: Agios: Honoraria;Alexion: Honoraria;Novartis: Honoraria;Forma Therapeutics: Honoraria. Pepe: Chiesi Farmaceutici S.p.A: Other: no profit support;Bayer S.p.A.: Other: no profit support. de Montalembert: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Addmedica: Membership on an entity's Board of Directors or advisory committees;BlueBirdBio: Membership on an entity's Board of Directors or advisory committees;Vertex: Membership on an entity's Board of Directors or advisory committees. Glenthøj: Agios: Consultancy;Novo Nordisk: Honoraria;Novartis: Consultancy;Alexion: Research Funding;Bluebird Bio: Consultancy;Bristol Myers Squibb: Consultancy;Saniona: Research Funding;Sanofi: Research Funding. Benghiat: Novartis: Consultancy;BMS: Consultancy. Labarque: Novartis: Consultancy;Bayer: Consultancy;Sobi: Consultancy;NovoNordisk: Consultancy;Octapharma: Consultancy. Diamantidis: Genesis Pharma: Honoraria;Uni-Pharma: Honoraria;Bristol Myers Squibb: Consultancy;IONIS Pharmaceuticals: Research Funding;NOVARTIS, Genesis Pharma SA: Research Funding. Kerkhoffs: Sanofi: Research Funding;Terumo BCT: Research Funding. Iolascon: Celgene: Other: Advisory Board;Bluebird Bio: Other: Advisory Board. Taher: Vifor Pharma: Consultancy, Research Funding;Agios Pharmaceuticals: Consultancy;Ionis Pharmaceuticals: Consultancy, Research Funding;Bristol Myers Squibb: Consultancy, Research Funding;Novartis: Consultancy, Research Funding. Colombatti: Novartis: 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, Research Funding;Novonordisk: Membership on an entity's Board of Directors or advisory committees;Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees;Addmedica: Membership on an entity's Board of Directors or advisory committees;BlueBirdBio: Research Funding. Mañú Pereira: Novartis: Research Funding;Agios Pharmaceuticals: Research Funding.

Facteurs de risque de COVID-19 sévère chez des patients drépanocytaires hospitalisés : étude nationale Française chez 319 patients

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<0,001). Aucun patient de moins de 20 ans n’a été intubé. Lorsque l’on stratifie en fonction de la présence ou non d’une CVO (67 % des patients) ou d’un syndrome thoracique aigu (STA 30,5 %), la survenue d’une intubation ou d’un décès était plus faible chez les patients pour lesquels une CVO ou un STA était présents (aOR : 0,24 [0,06–0,92] ;p=0,037 pour la CVO ;aOR : 0,71 [0,08–6,16] ;p=0,760 pour le STA). En analyse multivariée, le génotype SC (n=33 patients) était indépendamment associé à un risque plus élevé de nécessiter une ventilation mécanique ou de mourir (24,2 % contre 3,6 % pour les patients SS/Sβ0, P<0,001 ;aOR : 6,99 [IC 95 % 1,42–34,5]). L’âge était l’autre facteur significatif. Par rapport aux patients SS/Sβ0, les patients SC présentaient également un risque plus élevé de survenue de thromboses (28,1 % vs 6,3 % pour les SS/Sβ0, P<0,001 ;aOR : 5,86 [IC 95 % 1,59–21,59]). Dans le sous-groupe SS/Sβ0 (n=276), les facteurs associés à la ventilation mécanique ou au décès étaient l’âge, l’indice de masse corporelle, l’hypertension artérielle, le diabète et l’utilisation de médicaments immunosuppresseurs. L’âge plus élevé était le principal facteur de risque de ventilation mécanique ou de décès chez les patients SC. Conclusion Nos résultats montrent que les patients drépanocytaires SC hospitalisés avec la COVID-19 ont un risque beaucoup plus élevé d’évolution sévère, associé à davantage de complications thrombo-emboliques. Ces résultats sont surprenant tant ce génotype (20 % des drépanocytaires en France) est considéré comme le moins sévère, associé à une espérance de vie meilleure que les homozygotes. Ces patients SC devraient, avec l’ensemble des drépanocytaires de plus de 40 ans, constituer un groupe de patients ultraprioritaires pour la vaccination, notamment dans des pays où la vaccination est peu accessible. L’utilisation d’une anticoagulation curative chez un patient SC hospitalisé avec la COVID est une question ouverte par ce travail.

Caractéristiques des patients drépanocytaires infectés par le SARS-CoV-2 en fonction de leur prise en charge ambulatoire ou en hospitalisation : étude nationale chez 536 patients

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<0,001) et étaient moins transfusés dans les 60jours avant la PCR (10,1 % vs. 24,5 %, P=0,01). Ils étaient plus anémiques que les patients ambulatoires (-0,8g/dl d’hémoglobine en médiane, P=0,003). Parmi les symptômes de l’infection, les patients hospitalisés avaient plus souvent de la fièvre (55 % vs. 35 %, P<0,001) et de la dyspnée (19,2 % vs 6,4 %, p<0,001), mais beaucoup moins de symptômes ORL (incluant rhinorrhée et/ou agueusie et/ou anosmie) (11,8 vs. 36,9 %, p<0,001). Chez les patients SC les mêmes tendances étaient observées même si elles n’étaient pas toujours significatives du fait d’un effectif plus faible (33 hospitalisés vs. 49 non hospitalisés). C’est le cas des CVO osseuses présentes chez 57,6 % des SC hospitalisés vs 12,8 % des non hospitalisés (P<0,001) et de la dyspnée (24,2 % vs 6,8 %, p<0,045). Conclusion Les CVO osseuses expliquent l’hospitalisation d’un grand nombre d’infections COVID-19 chez le patient drépanocytaire. La transfusion dans les 2 mois pourrait prévenir ces CVO « viro-induites » et ces hospitalisations alors que l’ hydroxyurée ne semble pas être un facteur protecteur. La présence de signes ORL est associée à moins d’hospitalisations, comme l’ont montré d’autres études en population générale avec COVID-19. Cela pourrait être un élément de « tri » des malades en cas de forte affluence épidémique, en plus des éléments de gravité classiques de la COVID-19 ou de la CVO.