LettersApril 2021

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

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    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


    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.

    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.


    • 1. Espinosa JM. Down syndrome and COVID-19: a perfect storm? Cell Rep Med. 2020;1:100019. [PMID: 32501455] doi:10.1016/j.xcrm.2020.100019 Google Scholar
    • 2. Development of a COVID-19 risk prediction model. Nuffield Department of Primary Care Health Sciences. 2020. Accessed at www.phc.ox.ac.uk/research/primary-care-epidemiology/covid-19-risk-tool on 23 June 2020. Google Scholar
    • 3. Antonarakis SE, Skotko BG, Rafii MS, et al. Down syndrome. Nat Rev Dis Primers. 2020;6:9. [PMID: 32029743] doi:10.1038/s41572-019-0143-7 Google Scholar
    • 4. Colvin KL, Yeager ME. What people with Down syndrome can teach us about cardiopulmonary disease. Eur Respir Rev. 2017;26. [PMID: 28223397] doi:10.1183/16000617.0098-2016 Google Scholar
    • 5. Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol. 2011;164:9-16. [PMID: 21352207] doi:10.1111/j.1365-2249.2011.04335.x Google Scholar


    Adam Kortowski5 May 2021
    Down Lifes Matter

    Good move to notice an underprivileged group of "health minority" who have no voting ability.

    Victor G. O. Evangelho 1, Murilo L. Bello 2 , Helena C. Castro 1 , Márcia R. Amorim 18 January 2021

    Dear Editor,

    We read with interest the article entitled "COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study of 8 Million Adults" (1). The authors estimated a 10-fold increased risk for related death in adults with Down syndrome. This study highlights important clinical and epidemiological data however the pathogenesis of severe Sars-Cov-2 infection is poorly understood. Some molecular aspects may explain the severe disease progression in Down Syndrome individuals.

    Initially, it is important to note that TMPRSS2 gene is located on chromosome 21q22.3 and encodes transmembrane protease serine 2. This may indicate a potential overexpression in individuals with Down syndrome.    Expression   of   TMPRSS2   is   developmentally regulated and increases with ageing (2). Thus, it may partially explain the most severe cases of COVID-19 in these individuals. In a recent study, the results indicated that this gene is one of the responsible for viral infection (3).

    Currently we understand that SARS-CoV-2 uses the ACE2 receptor to invade the host cell, as well as SARS-CoV-1. More specifically, the viral spike Receptor Binding Domain (RBD) of SARS-CoV-2 surface glycoprotein interacts with host ACE2 protein. In this context, the process is mediated by the TMPRSS2 receptor-dependent interaction, which is implicated in the activation of  SPIKE protein.  This mechanism enables the entry and initiate the viral replication process (4).

    Evaluating TMPRSS2 gene expression in individuals with Down syndrome may show mechanisms underlying the infectious process in COVID-19, allowing for more targeted treatments and better outcomes for severe cases in general population. In conclusion, clinical data and molecular insights can guide new research focusing on TMPRSS2.


    1. Clift AK, Coupland CAC, Keogh RH, Hemingway H, Hippisley-Cox J. COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study Of 8 Million Adults. Ann Intern Med [Internet]. 2020 Oct 21;(October):M20-4986. Available from: https://www.acpjournals.org/doi/10.7326/M20-4986
    1. Schuler B, Habermann C, Plosa EJ, Taylor CJ, Jetter C, Negretti NM et al, J Clin Invest 2021;131(1):e140766.https://doi.org/10.1172/JCI140766
    1. Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681–7.
    1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8.