ERN-EuroBloodNet European Registry of Patients Affected by Red Blood Cell Disorders and COVID-19
Authors: Velasco Pablo , Longo Filomena , Piolatto Andrea , Bardón-Cancho Eduardo J. , Ponce-Salas Beatriz , Flevari Pagona , Voskaridou Ersi , Biemond Bart J. , Nur Erfan , Delaporta Polyxeni , Besse-Hammer Tatiana , Ruiz-Llobet Anna , Raso Simona , Spasiano Anna , Guerzoni Maria Elena , Beneitez-Pastor David , Dedeken Laurence , Pepe Alessia , Rosso Rosamaria , Kunz Joachim B. , de Montalembert Mariane , Campisi Saveria , Glenthøj Andreas , Gonzalez Urdiales Paula , Benghiat Fleur Samantha , Azerad Marie-Agnès , Saunders Christopher J. , Ferreira Faria Teresa , Casini Tommaso , Bagnato Sabrina , Van de Velde Ann , Labarque Veerle , Bertoni Elisa , Van Damme An , Diamantidis Michael D. , Russo Roberta , Stiakaki Eftichia , Quota Alessandra , Christou Soteroula , Teles Maria Jose , Lafiatis Ioannis , Kerkhoffs Jean-Louis , Argüello Marina María , Lorite Mikael , Rodriguez Alexis , Iolascon Achille , Taher Ali T. , Colombatti Raffaella , Roy Noemi , Mañú Pereira Maria Del Mar 
Published: November 2021

Abstract

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 &lt;0.001). Splenectomy and comorbidities were higher in THAL (51.3% and 65.8%) than in SCD (16% and 48.1%) (p&lt;0.001, p=0.002).
Age and BMI correlated with COVID-19 severity, as described in the general population (p=0.002, p&lt;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&lt;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&lt;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 power 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.
Figure 1 Figure 1.

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.