Background: Sickle cell disease is a collection of compound heterozygote hemoglobinopathies, including sickle cell anemia (1). The heterozygote hemoglobinopathies are characterized by erythrocyte deformation with hemolysis; immune and coagulation dysfunction; and chronic complications, including pulmonary hypertension and cardiac failure (1, 2). Sickle cell trait is a carrier status for sickle cell disease. Given the established susceptibility to other viral infections and the ethnic “patterning” of sickle cell disorders, affected persons may have increased risks for severe COVID-19. Evidence about COVID-19 risks in sickle cell disorders mostly derives from studies of hospitalized persons or selective registries (3–5). Robust quantification of risks in sickle cell disorders at a population level may be informative for public health strategies.

Objective: To evaluate the risks for COVID-19–related hospitalization and death in children and adults with sickle cell disorders (disease and trait, separately) using a population-level database of linked electronic health care records.

Methods and Findings: A cohort study of 12.28 million persons aged 0 to 100 years was done using QResearch, a primary care database covering approximately 18% of the English population. The cohort comprised 1317 general practices with individual-level linkage to SARS-CoV-2 test results from Public Health England, hospital admissions data, and the Office for National Statistics death register. Follow-up was from 24 January 2020 to 30 September 2020 (hospitalization) and 18 January 2021 (death). Cause-specific Cox regression models stratified by individual general practice were used to estimate hazard ratios (HRs) with 95% CIs for COVID-19–related hospitalization and COVID-19–related death associated with sickle cell disease (genotypes SC, SD, or SE; sickle cell anemia; thalassemia with hemoglobin S; sickle thalassemia; or not otherwise specified) and sickle cell trait. Models were adjusted for age, sex, and ethnicity. Hospitalization related to COVID-19 was defined as confirmed or suspected COVID-19 as reason for admission (International Classification of Diseases, 10th Revision, code U07.1 or U07.2) or admission within 14 days of a positive SARS-CoV-2 test result. Death related to COVID-19 was defined as confirmed or suspected COVID-19 on the death certificate (International Classification of Diseases, 10th Revision, code U07.1 or U07.2) or death of any cause within 28 days of confirmed SARS-CoV-2 infection. Missing ethnicity data were handled using multiple imputation (10 imputed data sets); the imputation model included end points and all variables in the Table. Analyses used Stata, version 16 (StataCorp).