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Risk factors for severe COVID‐19 in hospitalized sickle cell disease patients: A study of 319 patients in France

State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, India Cross Cancer Institute, Edmonton, Alberta, Canada Kings College Hospital NHS Foundation Trust, London, UK University Hospitals of Leicester NHS Trust, Leicester, UK City Clinical Hospital #40, Moscow, Russian Federation Baylor University Medical Center, Dallas, Texas, USA University of Nantes, Nantes, France Karyopharm Therapeutics, Newton, Massachusetts, USA Dana-Farber Cancer Institute, Boston, Massachusetts, USA Medical University of Silesia, Katowice, Poland


SUPPORTING INFORMATION
Additional supporting information may be found in the online version of the article at the publisher's website.

Risk factors for severe COVID-19 in hospitalized sickle cell disease patients: A study of 319 patients in France
To the Editor: Whether sickle cell disease (SCD) patients are at higher risk for severe COVID-19 and, among them, who are the most vulnerable is still a controversial issue. Indeed, fever or viral infections may trigger vasoocclusive crisis (VOC) and consequently the need for hospitalization. 1 On the other hand, the tropism of SARS-CoV-2 in lung tissues and the increased risk of pulmonary embolism (PE) caused by this virus also raise questions in regards to SCD patients, in whom acute chest syndrome (ACS) is a leading cause of early mortality. 1,2 In most studies of COVID-19 in SCD, the definition of "serious" or "severe" outcomes was particularly heterogenous. Here, we aimed to identify risk factors associated with mechanical ventilation and mortality in a large cohort of SCD inpatients.  Figure S1).
None of the children or young adults younger than 20 years died or were intubated. In adults, SCD patients older than 40 years (n = 59) had an 8.3-fold increased risk [95% CI 2.6-31.2] of death or intubation compared to 20-to 40-year-old patients (n = 153) (p < .001) ( Figure S2).
In the subset of SS/Sβ 0 inpatients (n = 276), risk factors for mechanical ventilation or death were older age, higher weight, hypertension, diabetes, and the use of steroid and immunosuppressive drugs (Table S1). Hydroxyurea use, chronic transfusion, or a recent RBC transfusion were not associated with a better outcome. In the subset of SC patients (n = 33), age was the only significant risk factor (Table S2).
Considering the unexpected severity in SC inpatients, we compared the characteristics of patients according to SCD genotypes ( In the US, Panepinto et al. found increased mortality (more than a twofold increase) in SC/Sβ + genotypes compared to SS/Sβ 0 outpatients or inpatients with COVID-19. 3 The proportion of inpatients who required critical care was also higher in those with "mild" geno- For the SS/Sbeta 0 subset of patients, more classic factors for severe COVID-19 were found. We emphasize that the cut-off age associated with a dramatic increase in poor outcomes was approximately 40 years, which was younger than that in the general population.
Sub-Saharan African countries have the highest prevalence of SCD worldwide, and some of them, have a very high prevalence of SC patients, up to 50% of SCD patients. 2 Most of these countries have lowest vaccines access. In that case, a priority of vaccination could be a focus on patients with the SC genotype and SS/Sβ 0 patients with comorbidities or older than 40 years.
The limitations of our study include the sparse data about organ complications, past history of VTE, socioeconomic factors, and biological or radiological findings during hospitalization. For example, we cannot rule out that a low glomerular fraction rate may contribute to worse outcomes, as creatinine was not collected. Conclusions regarding the association between SC genotype and more severe complications might also be limited by admission rate bias. Nevertheless, SC patients at the time of admission did not have a higher rate of respiratory symptoms, fever, or VOC than other genotypes.
Finally, in our study, an imaging examination was not systematically performed to screen the thrombotic events in all patients, but driven by clinical practice. It could underestimate the incidence of VTE events. However, this detection bias was normally identical in each group.
The main strengths of our study are the large number of patients identified, and the stringent definition of severe COVID-19.
In conclusion, SCD patients with the SC genotype admitted to the hospital with confirmed SARS-CoV-2 infection have poorer outcomes, with a higher prevalence of thromboembolism complications, than those with the SS/Sβ 0 genotypes. all participants in this study.

CONFLICT OF INTEREST
All authors declare no conflict of interest. Cécile Guillaumat contributed to patient recruitment and the acquisition and interpretation of data. All authors confirm that they had full access to all the data in the study.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author upon reasonable request.

SUPPORTING INFORMATION
Additional supporting information may be found in the online version of the article at the publisher's website.  Here we present our findings in three patients with MPAL, who were treated with VEN combined with FLAG with or without idarubicin. We performed a retrospective review of single-center case series.
After patient informed consent, we extracted clinical, biological data from clinical records and analyzed flow cytometry data, to define patients fulfilling the criteria of MPAL according to WHO classification; 1 and significantly expressing BCL-2 ( Figure 1