Sickle Cell Disorders and Severe COVID-19 Outcomes: A Cohort Study
Authors: Ashley Kieran Clift, Defne Saatci, Carol A.C. Coupland, Hajira Dambha-Miller, Julia Hippisley-Cox
Journal: Annals of Internal Medicine (2021)

Letters20 July 2021Sickle Cell Disorders and Severe COVID-19 Outcomes: A Cohort StudyFREEAshley Kieran Clift, MBBS, Defne Saatci, MBChir, Carol A.C. Coupland, PhD, Hajira Dambha-Miller, PhD, and Julia Hippisley-Cox, MD, Ashley Kieran Clift, MBBSUniversity of Oxford, Oxford, United KingdomSearch for more papers by this author, Defne Saatci, MBChirUniversity of Oxford, Oxford, United KingdomSearch for more papers by this author, Carol A.C. Coupland, PhDUniversity of Nottingham, Nottingham, United KingdomSearch for more papers by this author, Hajira Dambha-Miller, PhDUniversity of Southampton, Southampton, United KingdomSearch for more papers by this author, and Julia Hippisley-Cox, MDUniversity of Oxford, Oxford, United KingdomSearch for more papers by this author, on behalf of the International Investigator Group for Ethnicity and COVID-19*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-1375 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail 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).Table Characteristics of the Study CohortThe Table describes the study cohort. There were 5059 (0.04%) persons with sickle cell disease and 25 682 (0.21%) persons with sickle cell trait. During the study, there were 23 699 COVID-19–related hospitalizations, 19 068 COVID-19–related deaths, and 104 499 deaths from any cause.There were fewer than 5 COVID-19–related hospitalizations in children with sickle cell disorders but no COVID-19–related deaths. Adults with sickle cell disease had 40 (0.79%) hospitalizations and 10 (0.20%) deaths. In the cohort, sickle cell disease was associated with increased risks for COVID-19–related hospitalization (HR, 4.11 [95% CI, 2.98 to 5.66]) and death (HR, 2.55 [CI, 1.36 to 4.75]) (Figure). E-values for HRs for COVID-19–related hospitalization and death were 7.69 (lower limit of the CI, 5.41) and 4.54 (lower limit of the CI, 2.06), respectively, suggesting robustness to residual confounding.Figure. Adjusted HRs with 95% CIs for the observed associations between sickle cell disease and sickle cell trait with COVID-19–related hospitalization and COVID-19–related death; the reference group is persons without any sickle cell disorder.Cause-specific Cox regression models were stratified by individual general practice and adjusted for age (restricted cubic spline with 5 knots), sex, and self-reported ethnicity (White, South Asian, Black, and other [including Chinese, multiracial, and Arab]). We did post hoc analyses restricted to those with sickle cell disorders. For COVID-19–related hospitalization, compared with persons with sickle cell trait, those with sickle cell disease had an adjusted HR of 3.00 (95% CI, 1.99 to 4.52). For COVID-19–related death, persons with sickle cell disease had an adjusted HR of 1.37 (CI, 0.62 to 3.02) compared with those with sickle cell trait. HR = hazard ratio. Download figure Download PowerPoint Persons with sickle cell trait had 98 (0.38%) hospitalizations and 50 (0.19%) deaths. In the cohort, sickle cell trait was also associated with higher risks for COVID-19–related hospitalization (HR, 1.38 [CI, 1.12 to 1.70]) and death (HR, 1.51 [CI, 1.13 to 2.00]). E-values for COVID-19–related hospitalization and death were 2.1 (lower limit of the CI, 1.49) and 2.39 (lower limit of the CI, 1.51), respectively.Discussion: Our analysis estimated a 4-fold increased risk for COVID-19–related hospitalization and a 2.6-fold increased risk for COVID-19–related death for sickle cell disease. Sickle cell trait was also associated with increased risks for both outcomes, albeit to a lesser extent. Several aspects of sickle cell phenotypes overlap with the pathophysiology of severe COVID-19 (1, 2), which could be relevant mechanisms worthy of further study, as should the directionality of infection and sickle crisis.Study limitations include the potential underdiagnosis of sickle cell trait in the population, the rarity of outcomes limiting extended adjustments and sickle subtype–specific or age- or sex-specific analyses, the lack of information on symptoms or presentation, and that the HRs do not possess a direct causal interpretation.Given that sickle cell disease affects approximately 15 000 persons in the United Kingdom, 100 000 persons in the United States, and 8 million to 12 million persons globally, we believe our results are relevant to policymakers and decision making about vaccination prioritization for potentially high-risk groups.Appendix: Members of the International Investigator Group for Ethnicity and COVID-19Members of the International Investigator Group for Ethnicity and COVID-19 who contributed to this work but did not author it: Dr. Pui San Tan, Dr. Martina Patone, Dr. Francesco Zaccardi, Dr. Baiju R. Shah, Professor Simon J. Griffin, and Professor Kamlesh K. Khunti.References1. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010. [PMID: 29542687] doi:10.1038/nrdp.2018.10 CrossrefMedlineGoogle Scholar2. Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest. 2017;127:750-760. [PMID: 28248201] doi:10.1172/JCI89741 CrossrefMedlineGoogle Scholar3. McCloskey KA, Meenan J, Hall R, et al. COVID-19 infection and sickle cell disease: a UK centre experience [Letter]. Br J Haematol. 2020;190:e57-e58. [PMID: 32369606] doi:10.1111/bjh.16779 CrossrefMedlineGoogle Scholar4. Panepinto JA, Brandow A, Mucalo L, et al. Coronavirus disease among persons with sickle cell disease, United States, March 20-May 21, 2020. Emerg Infect Dis. 2020;26:2473-2476. [PMID: 32639228] doi:10.3201/eid2610.202792 CrossrefMedlineGoogle Scholar5. Arlet JB, de Luna, Khimoud D, et al. Prognosis of patients with sickle cell disease and COVID-19: a French experience. Lancet Haematol. 2020;7:e632-e634. [PMID: 32563282] doi:10.1016/S2352-3026(20)30204-0 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Ashima Singh (1), Amanda M. Brandow (1,2)1. Medical College of Wisconsin 2. Children’s Wisconsin, Milwaukee, WI16 August 2021 A call for further research to understand the interaction of comorbidities with the underlying genetic condition of sickle cell disease and trait The recently published study by Clift et al shows that persons with sickle cell disease (SCD)/sickle cell trait (SCT) have higher risk of hospitalization and death as compared to persons without sickle cell disorders1. These data, derived from a robust dataset, are an important contribution to the growing body of evidence focused on COVID-19 outcomes in individuals with SCD and SCT. Individuals with SCD are at high risk of having chronic end organ damage impacting the brain, heart, kidney and lungs2. Individuals with SCT are also at high risk of certain comorbidities like kidney disease3. Further, existing evidence from the general population shows that individuals with comorbid conditions such as hypertension, cardiovascular disease, diabetes, acute organ dysfunction, obesity are at risk of worse COVID-19 outcomes4-6. Collectively, in light of these data, it is essential to account for pre-existing comorbidities when attempting to identify the attributable risk of SCD and SCT on worse COVID-19 outcomes. Our prior published study comparing COVID-19 outcomes between individuals with SCD/SCT and Black individuals without SCD/SCT found that individuals with SCD are at increased risk of hospitalization, development of pneumonia and pain due to COVID-19, even after matching for age, sex, and various clinical comorbidities7. However, we observed no significant differences in mortality between the matched group of SCD individuals and Black individuals without SCD/SCT. Also, there were no significant differences in any of the COVID-19 outcomes between individuals with SCT and Black individuals without SCD/SCT, after matching for age, sex and clinical comorbidities. This study was done using electronic health record data from multiple sites, primarily in the United States (US), which contribute data to a research network, TriNetX. The network includes a large number of individuals; however, these data remain restricted to those receiving care at institutions that are part of research network. Thus differences in findings between the two studies could certainly be due to differences in population between the two studies and also due to clinical practice variation between the two countries. The Clift et al study and our prior published study, both provide evidence that concerted efforts are needed to ensure individuals with SCD have access to vaccinations. Future studies are needed to understand the interaction of SCD and SCT with other pre-existing conditions, and the collective impact on COVID-19 outcomes. Importantly, future work using standardized definitions and methodologies is needed to compare clinical practice patterns and outcomes between various countries. References Clift AK, Saatci D, Coupland CAC, Dambha-Miller H, Hippisley-Cox J. Sickle Cell Disorders and Severe COVID-19 Outcomes: A Cohort Study. Annals of Internal Medicine. 2021. Vichinsky EP. Overview of the clinical manifestations of sickle cell disease. UpToDate. Waltham, MA Web site. Published Accessed January 2020. Accessed. Published 2020. Accessed 08.01.2021. Naik RP, Derebail VK, Grams ME, et al. Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. Jama. 2014;312(20):2115-2125. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430-436. Gupta S, Hayek SS, Wang W, et al. Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US. JAMA Internal Medicine. 2020;180(11):1436-1447. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Singh A, Brandow AM, Panepinto JA. COVID-19 in individuals with sickle cell disease/trait compared with other Black individuals. Blood Advances. 2021;5(7):1915-1921. Author, Article, and Disclosure InformationAuthors: Ashley Kieran Clift, MBBS; Defne Saatci, MBChir; Carol A.C. Coupland, PhD; Hajira Dambha-Miller, PhD; Julia Hippisley-Cox, MDAffiliations: University of Oxford, Oxford, United KingdomUniversity of Nottingham, Nottingham, United KingdomUniversity of Southampton, Southampton, United Kingdom* For members of the International Investigator Group for Ethnicity and COVID-19, see the Appendix.Acknowledgment: The authors thank the EMIS (Egton Medical Information Systems) practices that contribute to the database as well as the University of Nottingham and University of Oxford for expertise in establishing, developing, and supporting the QResearch database. QResearch acknowledges funding from the Nottingham Biomedical Research Centre funded by the National Institute for Health Research. The data on SARS-CoV-2 reverse transcriptase polymerase chain reaction tests were used with permission from Public Health England. The Hospital Episode Statistics data and civil registration data used in this analysis are reused by permission from NHS Digital, which retains the copyright. This study was undertaken as part of a larger project, which is detailed at www.qresearch.org/research/approved-research-programs-and-projects/quantifying-the-association-between-covid-19-ethnicity-and-mortality-a-cohort-study-across-three-uk-national-databases.Financial Support: By grant MR/V027778/1 from the UK Medical Research Council. Dr. Clift is supported by a Clinical Research Training Fellowship from Cancer Research UK (DCS-CRUK-CRTF20-AC, C2195/A31310).Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-1375.Reproducible Research Statement: Study protocol: Available at www.qresearch.org/research/approved-research-programs-and-projects/quantifying-the-association-between-covid-19-ethnicity-and-mortality-a-cohort-study-across-three-uk-national-databases. Statistical code: Available on request to Dr. Clift (e-mail, ashley.clift@phc.ox.ac.uk). Code groups used by the researchers are available at www.qresearch.org/qcode-group-library. Data set: Access to the anonymized health care data in the QResearch database is on application to the QResearch Scientific Committee by bona fide researchers employed at U.K. academic institutions according to information on www.qresearch.org.Corresponding Author: Ashley Kieran Clift, MBBS, Nuffield Department of Primary Care Health Sciences, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 4GG, United Kingdom; e-mail, ashley.clift@phc.ox.ac.uk.This article was published at Annals.org on 20 July 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byDeveloping a mortality risk prediction model using data of 3663 hospitalized COVID-19 patients: a retrospective cohort study in an Egyptian University HospitalUptake of COVID-19 vaccination in people with blood cancer: Population-level cohort study of 12 million patients in EnglandPresentations and outcomes among sickle cell disease patients with COVID-19 at a large southern healthcare systemHost and viral proteins involved in SARS‐CoV ‐2 infection differentially bind hemePrevention and treatment of COVID-19 in patients with benign and malignant blood disordersCOVID-19 outcomes in sickle cell disease and sickle cell traitAssociation of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell TraitAn Approach to the Treatment of Children With COVID-19Anti‐SARS‐CoV ‐19 antibodies in children and adults with sickle cell disease: A single‐site analysis in New York CityClinical outcomes of COVID-19 in patients with sickle cell disease and sickle cell trait: A critical appraisal of the literatureFavorable outcomes of patients with sickle cell disease hospitalized due to COVID‑19: A report of three casesCOVID-19 and Sickle Cell Disease–Related Deaths Reported in the United StatesPrognostic factors associated with COVID-19 related severity in sickle cell disease October 2021Volume 174, Issue 10 Page: 1483-1487 Keywords Sickle cell disease ePublished: 20 July 2021 Issue Published: October 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...