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      COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study Of 8 Million Adults

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      , MA, MBBS, , PhD, , DPhil, , PhD, , MD
      Annals of Internal Medicine
      American College of Physicians

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          Abstract

          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. Table. Selected Clinical and Demographic Features of the Study Cohort, by Down Syndrome Status* Table. Selected Clinical and Demographic Features of the Study Cohort, by Down Syndrome Status* 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). Figure. Adjusted HR (95% CI) for the association between Down syndrome and death from COVID-19. Adjusted for the variables shown, deprivation, fractional polynomial terms for body mass index (BMI), and age. The model includes fractional polynomial terms for age, BMI, and interaction terms between age terms and type 2 diabetes. We used the QResearch database, version 44. The study period was 24 January 2020 to 30 June 2020. CF = cystic fibrosis; COVID-19 = coronavirus disease 2019; GP = general practitioner; HR = hazard ratio; LABA = long-acting β2-agonist; MND = motor neurone disease; MS = multiple sclerosis; SLE = systemic lupus erythematosus. * HR for type 2 diabetes reported at mean age. Figure. Adjusted HR (95% CI) for the association between Down syndrome and death from COVID-19. Adjusted for the variables shown, deprivation, fractional polynomial terms for body mass index (BMI), and age. The model includes fractional polynomial terms for age, BMI, and interaction terms between age terms and type 2 diabetes. We used the QResearch database, version 44. The study period was 24 January 2020 to 30 June 2020. CF = cystic fibrosis; COVID-19 = coronavirus disease 2019; GP = general practitioner; HR = hazard ratio; LABA = long-acting β2-agonist; MND = motor neurone disease; MS = multiple sclerosis; SLE = systemic lupus erythematosus. * HR for type 2 diabetes reported at mean age. 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 and article information

          Journal
          Ann Intern Med
          Ann Intern Med
          aim
          Annals of Internal Medicine
          American College of Physicians
          0003-4819
          1539-3704
          21 October 2020
          : M20-4986
          Affiliations
          [1 ]University of Oxford, Oxford, United Kingdom (A.K.C., J.H.)
          [2 ]University of Nottingham, Nottingham, United Kingdom (C.A.C.)
          [3 ]London School of Hygiene & Tropical Medicine, London, United Kingdom (R.H.K.)
          [4 ]University College London, Health Data Research UK, and National Institute for Health Research Biomedical Research Centre, London, United Kingdom (H.H.)
          Author notes
          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).
          Reproducible Research Statement: Study protocol and statistical code: Available from Prof. Hippisley-Cox (e-mail, julia.hippisley-cox@ 123456phc.ox.ac.uk ). Data set: Access to QResearch is via application of bona fide researchers, which is reviewed by the QResearch Access Committee ( www.qresearch.org).
          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.hippisley-cox@ 123456phc.ox.ac.uk .
          Author information
          https://orcid.org/0000-0002-2327-3306
          https://orcid.org/0000-0001-6504-3253
          https://orcid.org/0000-0003-2279-0624
          https://orcid.org/0000-0002-2479-7283
          Article
          aim-olf-M204986
          10.7326/M20-4986
          7592804
          33085509
          46d63a43-2c20-4951-a79f-19cc387bf7a5
          Copyright @ 2020

          This article is made available via the PMC Open Access Subset for unrestricted re-use for research, analyses, and text and data mining through PubMed Central. Acknowledgement of the original source shall include a notice similar to the following: "© 2020 American College of Physicians. Some rights reserved. This work permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited." These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

          History
          Categories
          Letters
          Observations: Brief Research Reports
          early, Currently Online First
          coronavirus, Coronavirus Disease 2019 (COVID-19)
          3122457, COVID-19
          2357, Health care providers
          11279, SARS coronavirus
          9715, Patients
          6354, Upper respiratory tract infections
          1541398, Pulmonary diseases
          3282, Infectious diseases
          8910, Epidemiology
          7245, Lungs

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