COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study of 8 Million AdultsFREE
Background: At the start of the coronavirus disease 2019 (COVID-19) pandemic, many national health organizations emphasized nonpharmacologic interventions, such as quarantining or physical distancing. In the United Kingdom, strict self-isolation (“shielding”) was advised for those deemed to be clinically extremely vulnerable on the basis of the presence of selected medical conditions or at the discretion of their general practitioners.
Down syndrome features on neither the U.K. shielding list nor the U.S. Centers for Disease Control and Prevention list of groups at “increased risk.” However, it is associated with immune dysfunction, congenital heart disease, and pulmonary pathology and, given its prevalence, may be a relevant albeit unconfirmed risk factor for severe COVID-19 (1).
Objective: To evaluate Down syndrome as a risk factor for death from COVID-19 through a comprehensive analysis of individual-level data in a cohort study of 8.26 million adults (aged >19 years), as part of a wider COVID-19 risk prediction project commissioned by the U.K. government (2).
Methods and Findings: We used QResearch, a population-level primary care database that has collected data for more than 35 million persons in England since 1998 and is linked at the individual patient level to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing results from Public Health England, hospital episode statistics, and the Office of National Statistics death registry. Data extracted included age, sex, ethnicity, alcohol intake, smoking status, body mass index (BMI), a range of preexisting comorbid conditions, and concurrent medications. The primary outcome of interest was COVID-19 mortality in or out of the hospital, defined as confirmed or suspected COVID-19 on the death certificate or death within 28 days of a confirmed SARS-CoV-2 infection in the study period. The secondary outcome of interest was hospital admission related to COVID-19. The study period was 24 January 2020 (first confirmed SARS-CoV-2 infection in the United Kingdom) to 30 June 2020. We used Cox proportional hazards models to estimate adjusted hazard ratios (HRs) with 95% CIs, accounting for death from non–COVID-19 causes as a competing event by censoring all persons who did not have the outcome of interest at the study end date. We tested for interactions between Down syndrome and age, BMI, and sex.
The Table shows selected demographic and clinical characteristics for the cohort. Of 8.26 million adults in the study cohort, 4053 had Down syndrome. Sixty-eight persons with Down syndrome died, 27 (39.7%) of COVID-19, 17 (25.0%) of pneumonia or pneumonitis, and 24 (35.3%) of other causes. Of the 8 252 105 persons without Down syndrome, 41 685 died, 8457 (20.3%) of COVID-19, 5999 (14.4%) of pneumonia or pneumonitis, and 27 229 (65.3%) of other causes.
Adjusted for age and sex, the HR for COVID-19–related death in adults with versus without Down syndrome was 24.94 (95% CI, 17.08 to 36.44). After adjustment for age, sex, ethnicity, BMI, dementia diagnosis, care home residency, congenital heart disease, and a range of other comorbid conditions and treatments (Table), the HR for COVID-19–related death was 10.39 (CI, 7.08 to 15.23); for hospitalization, it was 4.94 (CI, 3.63 to 6.73) (Figure). There was no evidence of interactions between Down syndrome and age, sex, or BMI. The HR for death was not affected by further adjustment for smoking status and alcohol intake (HR, 10.12 [CI, 6.90 to 14.84]). For those with learning disabilities other than Down syndrome, the adjusted HR for COVID-19–related death was 1.27 (CI, 1.16 to 1.40).
Discussion: We estimated a 4-fold increased risk for COVID-19–related hospitalization and a 10-fold increased risk for COVID-19–related death in persons with Down syndrome, a group that is currently not strategically protected. This was after adjustment for cardiovascular and pulmonary diseases and care home residence, which our results suggest explained some but not all of the increased risk. These estimated adjusted associations do not have a direct causal interpretation because some adjusted variables may lie on causal pathways, but they can inform policy and motivate further investigation. Participation in day care programs or immunologic deficits could be implicated, for example. Down syndrome is the most common genetic cause of intellectual disability, with multiorgan manifestations (3). Predisposition to pneumonias and acute respiratory distress syndrome in children, airway anomalies, pulmonary hypoplasia, and inhibited pulmonary angiogenesis have been reported (4, 5).
We are unaware of the effects of Down syndrome on COVID-19 outcomes being reported elsewhere yet during this pandemic. Novel evidence that specific conditions may confer elevated risk should be used by public health organizations, policymakers, and health care workers to strategically protect vulnerable individuals.
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Author, Article, and Disclosure Information
University of Oxford, Oxford, United Kingdom
University of Nottingham, Nottingham, United Kingdom
London School of Hygiene & Tropical Medicine, London, United Kingdom
University College London, Health Data Research UK, and National Institute for Health Research Biomedical Research Centre, London, United Kingdom
Acknowledgment: The authors thank the EMIS (Egton Medical Information Systems) practices that contribute to the QResearch database and EMIS, as well as the universities of Nottingham and 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 (NIHR). The data on COVID-19 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. The authors thank Professors Ewen Harrison, Calum Semple, and Aziz Sheikh for their feedback on this work.
Financial Support: By the NIHR (United Kingdom). Dr. Hemingway is an NIHR Senior Investigator and is funded by grant LOND1 from the NIHR University College London Hospitals Biomedical Research Centre and Health Data Research UK. Dr. Keogh is supported by a UKRI Future Leaders Fellowship (MR/S017968/1).
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-4986.
Reproducible Research Statement: Study protocol and statistical code: Available from Prof. Hippisley-Cox (e-mail, julia.
Corresponding Author: Julia Hippisley-Cox, MD, Nuffield Department of Primary Care Health Sciences, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 4GG, United Kingdom; e-mail, julia.
This article was published at Annals.org on 21 October 2020.