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JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] EClinicalMedicine 000 (2021) 100769 Contents lists available at ScienceDirect EClinicalMedicine journal homepage: https://www.journals.elsevier.com/eclinicalmedicine Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy 21 Research Society and the UK ISARIC4C survey Anke Hu€ lsa, Alberto C.S. Costa#,b, Mara Dierssen#,c,d,e, R. Asaad Bakshf,g, Stefania Bargagnah, Nicole T. Baumeri, Ana Claudia Branda ~oj, Angelo Carfik, Maria Carmona-Iraguil,m, Brian Allen Chicoine , Sujay Ghosh , Monica Lakhanpaulp,q, Coral Mansor, n o Miguel-Angel Mayers, Maria del Carmen Ortegat, Diego Real de Asuau, Anne-Sophie Rebillatv, Lauren Ashley Russellw, Giuseppina Sgandurrax,y, Diletta Valentiniz, Stephanie L. Sherman#,a, Andre Strydom#,b,c,d,*, on behalf of the T21RS COVID-19 Initiative a Department of Epidemiology and Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA b Departments of Pediatrics and of Psychiatry, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA c Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain d Universitat Pompeu Fabra (UPF), Barcelona, Spain e Centro de Investigacio n Biomedica en Red de Enfermedades Raras (CIBERER), Spain f Institute of Psychiatry, Psychology, and Neuroscience, Department of Forensic and Neurodevelopmental Sciences, King’s College London, London, United Kingdom g The London Down Syndrome (LonDownS) Consortium, London, United Kingdom h Fondazione Stella Maris IRCCS, Pisa, Italy i Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA j Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil k Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy l Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Auto noma de Barcelona, Barcelona, Spain m Barcelona Down Medical Center, Fundacio  Catalana de Síndrome de Down, Barcelona, Spain n Advocate Medical Group Adult Down Syndrome Center, Park Ridge, IL, USA o Cytogenetics and Genomics Reserach Unit. Department of Zoology, University of Calcutta.Kolkata. West Bengal, India p UCL- Great Ormond Street Institute of Child Health, London, United Kingdom q Whttington NHS Trust, London, United Kingdom; Down Syndrome Medical Interest Group, London, United Kingdom r CM: DOWN ESPANA, e Madrid, Spain s Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute and DCEXS Universitat Pompeu Fabra, Barcelona, Spain t Department of Psychiatry, Research Institute i+12. Hospital Universitario 12 de Octubre. Madrid, Spain u Department of Internal Medicine and Instituto de Investigacio n Biomedica-La Princesa, Hospital Universitario de La Princesa, Madrid, Spain v Institut Jero ^me Lejeune, Paris, France w Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA x Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy y Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy z Pediatric Unit, Bambino Gesu  Children's Hospital, IRCCS, Rome, Italy aa Department of Human Genetics, School of Medicine, Emory University, Atlanta, Georgia, USA bb Institute of Psychiatry, Psychology, and Neuroscience, Department of Forensic and Neurodevelopmental Sciences, King’s College London, London, United Kingdom cc The London Down Syndrome (LonDownS) Consortium, London, United Kingdom dd South London and the Maudsley NHS Foundation Trust A R T I C L E I N F O A B S T R A C T Article History: Background: Health conditions, immune dysfunction, and premature aging associated with trisomy 21 (Down Received 14 December 2020 syndrome, DS) may impact the clinical course of COVID-19. Revised 5 February 2021 Accepted 5 February 2021 Available online xxx See page (11) for detail of “on behalf of the T21RS COVID-19 Initiative”. * Corresponding author. E-mail address: andre.strydom@kcl.ac.uk (A. Strydom). # equal contribution. https://doi.org/10.1016/j.eclinm.2021.100769 2589-5370/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] 2 € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu Methods: The T21RS COVID-19 Initiative launched an international survey for clinicians or caregivers on patients with COVID-19 and DS. Data collected between April and October 2020 (N=1046) were analysed and compared with the UK ISARIC4C survey of hospitalized COVID-19 patients with and without DS. Findings: The mean age of COVID-19 patients with DS in the T21RS survey was 29 years (SD = 18). Similar to the general population, the most frequent signs and symptoms of COVID-19 were fever, cough, and shortness of breath. Joint/muscle pain and vomiting or nausea were less frequent (p < 0.01), whereas altered con- sciousness/confusion were more frequent (p < 0.01). Risk factors for hospitalization and mortality were simi- lar to the general population with the addition of congenital heart defects as a risk factor for hospitalization. Mortality rates showed a rapid increase from age 40 and were higher in patients with DS (T21RS DS versus non-DS patients: risk ratio (RR) = 3.5 (95%-CI=2.6;4.4), ISARIC4C DS versus non-DS patients: RR = 2.9 (95%- CI=2.1;3.8)) even after adjusting for known risk factors for COVID-19 mortality. Interpretation: Leading signs/symptoms of COVID-19 and risk factors for severe disease course are similar to the general population. However, individuals with DS present significantly higher rates of medical complica- tions and mortality, especially from age 40. Funding: Down Syndrome Affiliates in Action, DSMIG-USA, GiGi’s Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, The Matthew Foundation, NDSS, National Task Group on Intellectual Disabilities and Dementia Practices. © 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) life-threatening disease due to infection by the novel severe acute Research in context respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. Immune-response dysfunction associated with trisomy 21 Evidence before this study includes alterations in the number of different types of immune cells Up to now, most reports of COVID-19 in individuals with Down (T- and B-cells, monocytes and neutrophils) [2] and adverse antibody syndrome (DS) have been based on less than 10 individuals. responses [3]. The unusual inflammatory profile of individuals with One recent report used primary care data from the UK which DS is associated with more severe illness following viral infections, includes 8 million adults with and without Down syndrome. such as the viral infection during the H1N1 influenza pandemic [4], However, while only 37 of the 4053 individuals with Down respiratory syncytial virus (RSV) [5], and may also lead to worse out- syndrome had COVID-19 (positive test result reported), 27 comes due to coronavirus disease 2019 (COVID-19). The cytokine COVID-19 related deaths were reported among the individuals storm reported to be associated with COVID-19 [6], refers to an with Down syndrome. As many individuals with Down syn- excessive immune response to external stimuli and is thought to be a drome might not have had access to their primary care physi- predictor of increased severity of SARS-CoV-2 infection and of poor cians during the first peak of the pandemic, this study may be COVID-19 prognosis [7]. Admission to intensive care units (ICU) fol- unrepresentative of mild cases. lowing COVID-19 diagnoses was found to be associated with higher plasma levels of many cytokines [7]. Individuals with DS frequently Added value of this study display elevated levels of cytokines in blood, even in the absence of viral infection, and a proinflammatory profile that includes increased Our results, which are based on >1,000 COVID-19 patients with numbers of natural killer (NK) cells and CD8+ T-cells, decreased CD19 DS, show that individuals with DS may present with more + B-cell counts, and an increased spontaneous production of inter- severe symptoms at hospitalisation (e.g. confusion), and experi- feron gamma, TNFa, and IL-10 [8,9]. Recent findings in this fast- ence high rates of lung complications associated with increased evolving field, however, suggest COVID-19 may not be characterized mortality. In terms of sheltering/shielding individuals to pre- by a cytokine storm after all [10]. Moreover, it is also reasonable to vent infection, more caution should be taken with individuals speculate that increased levels of cytokines, particularly interferon over age 40, which is about 20 years younger than the typical gamma, may actually help patients fight off the SARS-CoV-2 infec- at-risk group in the general population. Individuals with DS tion. aged 40 and older have a three-fold increased risk for mortality DS is associated with several co-occurring health conditions compared to the general population, which is not explained by including obesity, diabetes, hypotonia, obstructive sleep apnea, cra- additional comorbidities. niofacial dysmorphogenesis, and congenital heart defects, as well as gastroesophageal reflux that may contribute to the increased risk of Implications of all the available evidence respiratory tract infection [1,11 13]. Moreover, adults with DS have Individuals with DS (especially those older than 40 years) are many age-related health conditions including Alzheimer’s disease vulnerable to medical complications and increased risk for [14], that often occur 20 25 years earlier than in individuals without death related to COVID-19. Therefore individuals with DS DS which is a profile that suggests premature aging [1,11,14]. Yet, should be considered a priority group for COVID-19 there is also evidence that persons with DS are protected from car- vaccination. diovascular disease, including hypertension [15]. Additionally, the incidence and severity of various comorbid conditions are quite vari- able among people with DS. Therefore, it is difficult to predict whether individuals with DS are particularly susceptible to COVID-19 and its complications. 1. Introduction In the US and many European countries, individuals with DS older than 40 years of age tend to live in group homes and other assisted- Down syndrome (DS), the result of the trisomy of chromosome 21, living situations [16]. Furthermore, it is not uncommon for those is the commonest genetic cause for intellectual disability. It is associ- with DS in their 50 and 60’s to dwell in nursing homes for prolonged ated with specific co-occurring health conditions and immune periods. These living spaces, which many times are occupied by sev- dysfunction that may impact the clinical course and risk for eral individuals and frequently visited by multiple support staff, have € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu 3 been the sites of several well-documented COVID-19 outbreaks in were anonymized according to good clinical practice guidelines and older individuals in the general population [17]. Therefore, one issue data protection regulations. of particular importance is ascertaining whether individuals with DS are at increased risk for hospitalization and mortality following 2.3. Statistical analysis COVID-19 diagnosis at a younger age than their counterparts without DS. However, up to now, most reports of COVID-19 in individuals For this analysis, we included data from all cases that were with DS have been based on less than 10 individuals [18,19]. One entered between April 9, 2020 and October 22, 2020. Only individuals recent report used primary care data from the UK, but included a with information on age and gender were included in the analyses. small sample of individuals with DS who have died (n = 27), and may We used descriptive statistics to show the demographic information, be unrepresentative of mild cases, due to patients not having access COVID-19 signs, symptoms, outcomes, and comorbidities of the par- to their primary care physicians during the first peak of the pandemic ticipants included in our analyses. To prevent study participants from [20]. being included twice in the analyses (reported by both caregiver and In order to obtain large scale information on specific vulnerabil- clinician), we excluded duplicated participants based on age, gender ities, clinical presentation, and outcomes of COVID-19 in individuals and country and other specific demographics. with DS, the Trisomy 21 Research Society (T21RS) launched an online To contrast the COVID-19 related signs, symptoms, and medical survey, with input from stakeholders including leading clinicians and complications with those observed in the general population, we DS organisations (details provided in the acknowledgements). The compared the T21RS DS cases to data from the UK ISARIC4C survey. survey was designed to address three primary questions: 1) What are The ISARIC4C survey is a prospective observational cohort study the presenting signs and symptoms of COVID-19 in individuals with engaging 208 acute-care hospitals in England, Wales, and Scotland DS and are these different than in individuals without DS? 2) Are [23]. In this study, we included 59,025 hospitalized patients with those with DS at an increased risk for complications associated with COVID-19 from the ISARIC4C survey, which were entered between SARS-CoV-2 infection? 3) Is the profile of risk factors associated with February 2020 and July 9, 2020 (downloaded on July 24, 2020). poor outcomes for COVID-19 in persons with DS the same as in the Among the 59,025 hospitalized patients, 109 individuals had DS general population? Here we report on the data collected from (58,916 did not). Of these, 100 had complete data on age, gender and Europe, United States (US), Latin America, India, as well as hospital ethnicity. These 100 individuals, referred to as “ISARIC4C DS cases”, data from other sources. were matched to 400 COVID-19 patients without DS (referred to as “controls”) from the same survey (matching 1:4). To account for dif- 2. Methods ferences in study design and country-specific differences between the UK ISARIC4C survey and the international T21RS survey, we used 2.1. T21RS DS survey the hospitalized patients with DS from the ISARIC4C survey as start- ing point and matched those to hospitalized patients in the T21RS An online survey was developed in March 2020, to identify dataset based on age, gender and ethnicity. Only a 1:1 match was patients with COVID-19 among individuals with DS (a copy of the possible because of matching criteria (see supplementary tables S2 survey is provided in the supplementary material). Two equivalent and S3 for characteristics of the matched samples). While this match- surveys were developed, one to be completed by caregivers/family ing procedure reduced our sample size from 586 to 100 T21RS cases, members of COVID-19 affected individuals with DS and one to be it added an additional level of confidence because we were able to completed by clinicians. Most often, either the caregiver or the clini- conduct two comparisons - ISARIC4C patients without DS (i.e., con- cian completed the survey per person. When both forms were com- trols) versus ISARIC4C patients with DS (i.e., ISARIC4C DS cases) and pleted for the same individual (i.e., linked surveys), information was ISARIC4C controls versus T21RS patients with DS. Fisher’s exact test combined to maximize the amount of available data per person. The was used to probe for differences in the prevalence of signs, symp- survey collected information on: 1) basic demographics, 2) living sit- toms, and medical complications between matched hospitalized uation during the pandemic, 3) pre-existing health conditions, vacci- cases with DS (from the ISARIC4C and T21RS surveys) and without nations and medications, 4) SARS-CoV-2 testing, 5) presenting signs DS (controls from the ISARIC4C survey). and symptoms, 6) hospital and ICU admission, 7) complications asso- To compare the mortality rates of hospitalized COVID-19 patients ciated with SARS-CoV-2 infection (clinician only), 8) medications and with and without DS in different age groups, we combined data from treatments used during COVID-19 illness (clinician only), and 9) sta- different sources. Case counts and mortality rates among hospitalized tus at last evaluation. The survey was implemented through REDCap patients from the general population were estimated from individu- [21,22], a survey and database management system, and was hosted als without DS included in the UK ISARIC4C survey combined with at Emory University. As we include data from the early phase of the published hospital reports from Spain [24] and New York City [25]. COVID-19 pandemic and the testing capacities differ between coun- Mortality rates among hospitalized patients with DS were based on tries, we use the term “case” to refer to individuals with DS of all combined data from the UK ISARIC4C survey and hospitalized indi- ages, who tested positive for SARS-CoV-2 or reported signs or symp- viduals from the T21RS survey. In addition, we used the matched toms of COVID-19. The survey was disseminated through clinical samples described above to perform a comparison of mortality rates routes (e.g. Down syndrome medical interest group listservs and corrected for age, gender and ethnicity using logistic regression. To health service providers), Down syndrome associations in the US, test whether differences in mortality rates of individuals with and India, Spain, UK, France, Italy, Germany, Brazil, and Spanish-speaking without DS can be explained by differences in the prevalence of Latin America, and DS registries (e.g., NIH DS-ConnectÒ ) as well as via known risk factors for COVID-19-related mortality, we adjusted the the T21RS website. association analyses for chronic cardiac disease, chronic pulmonary disease, chronic kidney disease, liver disease, obesity, chronic neuro- 2.2. Ethics statement logical disorder, dementia, malignant neoplasm [23]. In a sensitivity analysis, we analysed the association between DS and COVID-19- Each institution that planned to disseminate the survey within related mortality in the whole ISARIC4C sample (52,142 individuals health services obtained IRB/ethics approval (Table S1). The study without DS and no missing data for age, gender and ethnicity, 100 was performed according to the Declaration of Helsinki and national individuals with DS) adjusted for i) age, gender and ethnicity and ii) guidelines and regulations for data privacy and all participants who additionally for chronic cardiac disease, chronic pulmonary disease, completed the questionnaires provided informed consent. All data chronic kidney disease, liver disease, obesity, chronic neurological € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] 4 € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu disorder, dementia, malignant neoplasm. In addition, we conducted Table 1 age-stratified association analyses for individuals younger than T21RS study characteristics grouped by data source (reported by clinician versus family/caregiver). 40 years versus 40 years or older. To identify risk factors associated with adverse outcomes of Overall Clinician survey Family survey COVID-19 in individuals with DS, we conducted adjusted logistic n 1046 591 455 regression analyses in symptomatic COVID-19 cases from the T21RS Additional information 52 (5.0) 27 (4.6) 25 (5.5) survey data. Associations between potential risk factors and admis- through linked surveys sion to hospital or all-cause mortality were analysed. Associations (%)1 Country (%) with age and gender were adjusted for the data source (caregiver ver- India 405 (39.7) 218 (37.8) 187 (42.3) sus clinician survey) and associations with living situation, level of United States 163 (16.0) 90 (15.6) 73 (16.5) intellectual disability, and comorbidities were adjusted for age, gen- Spain 155 (15.2) 113 (19.6) 42 (9.5) der, data source and country of residence. We only included comor- Brazil 75 (7.4) 32 (5.5) 43 (9.7) bidities that were present in at least 15% of our study samples to United Kingdom 72 (7.1) 27 (4.7) 45 (10.2) France 67 (6.6) 61 (10.6) 6 (1.4) reduce the burden of multiple testing and the chance of false posi- Italy 35 (3.4) 20 (3.5) 15 (3.4) tives due to small numbers of cases. other2 47 (4.6) 16 (2.8) 31 (7.0) We did all data analyses using R (version 4.0.0). Age in years (mean (SD)) 29.35 (17.92) 35.58 (18.12) 21.26 (14.01) Male (%) 564 (54.0) 336 (56.9) 228 (50.3) 2.4. Role of the funding sources Ethnicity (%) White 440 (42.1) 247 (41.8) 193 (42.4) South Asian 414 (39.6) 225 (38.1) 189 (41.5) Funding sources provided help with dissemination of the online Latin American 49 (4.7) 19 (3.2) 30 (6.6) surveys and partial support of the biostatisician’s efforts. They were Black 17 (1.6) 13 (2.2) 4 (0.9) not involved in: the study design; collection, analysis, or interpreta- Arab 2 (0.2) 1 (0.2) 1 (0.2) East Asian 1 (0.1) 1 (0.2) 0 (0.0) tion of data; writing of the manuscript; or in the decision to submit West Asian 1 (0.1) 1 (0.2) 0 (0.0) the paper for publication. Admixed3 23 (2.2) 13 (2.2) 10 (2.2) Unknown 99 (9.5) 71 (12.0) 28 (6.2) 3. Results Living situation (%) Living at home with 712 (73.3) 307 (59.0) 405 (89.6) family 3.1. Description of study population Living alone with support 7 (0.7) 4 (0.8) 3 (0.7) Small group home with 89 (9.2) 71 (13.7) 18 (4.0) Of the 1906 records in the T21RS database entered between April support 9, 2020 and October 22, 2020, 1103 individuals had signs and symp- Residential care facility 157 (16.2) 134 (25.8) 23 (5.1) Other 7 (0.7) 4 (0.8) 3 (0.7) toms of COVID-19 or a positive test result and provided information Type of trisomy 21 (%) on age and gender. After removing potential duplicates, the final Full/standard 784 (92.5) 401 (93.0) 383 (91.8) sample size was 1046 COVID-19 patients with DS (Figure S1). The Mosaic 51 (6.0) 24 (5.6) 27 (6.5) majority of these cases were symptomatic (981 (94.5%)) and 861 Partial trisomy 4 (0.5) 2 (0.5) 2 (0.5) (83%) were tested for COVID-19 (750 (91%) with a positive test result) Translocation 9 (1.1) 4 (0.9) 5 (1.2) Level of intellectual disabil- (Table S4). Of the 1046 COVID-19 patients with DS, 591 (57%) were ity (%) reported by a clinician and 455 (43%) by a family member or care- Borderline/normal/mild 169 (18.1) 77 (14.8) 92 (22.3) giver (Table 1). The largest number of cases were from India (405 Moderate 580 (62.2) 314 (60.3) 266 (64.6) (40%)), followed by the United States (163 (16%)), Spain (155 (15%)) Severe/Profound 184 (19.7) 130 (25.0) 54 (13.1) Admitted to hospital (%) 581 (56.0) 388 (65.9) 193 (43.1) and Brazil (75 (7%)). The mean age was 29 years (SD=18); cases Days in hospital (mean 12.90 (9.29) 13.05 (8.50) 12.62 (10.68) reported by a clinician were on average 15 years older than cases (SD))4 reported by a family member or caregiver. The majority of cases lived Admitted to ICU (%)4 279 (49.6) 185 (49.7) 94 (49.5) at home with their family (712 (73%)). The proportion of cases living Days in ICU (mean (SD)) 4 8.46 (4.91) 8.57 (4.85) 8.25 (5.04) in a residential care facility was higher in the clinician than family/ Mechanical ventilation 207 (28.5) 131 (24.9) 76 (37.8) (%)4 caregiver reports (134 (26%) versus 23 (5%)). The majority of cases Clinical situation at last eval- (784 (93%)) had full trisomy 21 and moderate level of intellectual dis- uation (%) ability (580 (62%)), similar to that observed in the population of indi- Currently in hospital with 136 (13.7) 85 (14.9) 51 (12.0) viduals with DS at large [11]. About half of the cases were admitted symptoms Died 131 (13.2) 114 (20.0) 17 (4.0) to hospital (581 (56%)), of which 279 (50%) were admitted to an ICU Not currently in hospital 130 (13.1) 46 (8.1) 84 (19.8) and 207 (29%) were connected to a mechanical ventilator. More than but with symptoms half of the cases (547 (55%)) had recovered from COVID-19 at the last Other 27 (2.7) 5 (0.9) 22 (5.2) evaluation. Recovered from COVID-19 547 (55.0) 303 (53.1) 244 (57.5) Tested positive but still no 24 (2.4) 18 (3.2) 6 (1.4) symptoms 3.2. Signs and symptoms presenting in COVID-19 patients with DS and 1 without DS When both the clinician and caregiver/family member surveys were completed for a participant with DS (linked survey), information from each source were com- bined (clinician linked to the family survey and family linked to the clinician survey, The leading signs and symptoms related to COVID-19 in individu- see methods for more details als with DS were fever, cough and shortness of breath (Fig. 1, Table 2), 2 countries with fewer than 10 individuals were summarized as “other”. These which is in line with those reported in the general population include Argentina (4 cases), Germany (4 cases), Mexico (4 cases) and other countries with <4 cases reported. 3The category “admixed” refers to individuals who selected (Table 2, ISARIC4C controls). Nasal signs (excess nasal drainage or more than one ethnic groups. 4Only answered if admitted to hospital; % were calcu- ‘runny nose’) and pharyngitis (‘sore throat’) were also common lated after excluding missing information among COVID-19 patients from the T21RS survey, particularly in chil- dren and adolescents (younger than 20 years), where nasal signs were present in 229 (61%) and sore throat in 165 children and adoles- cents (44%) independent of the data source (family or clinician € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu 5 survey, Figure S2). Chills (33%), abdominal pain (32%), nausea or vom- and ethnicity) showed that joint pain or muscle aches was less fre- iting (26%) and muscle or joint pain (18%) were particularly common quently reported in individuals with DS (controls: 29%, ISARIC4C DS: in the age group 20 30 years. Signs and symptoms that were more 5%, (p < 0.001), T21RS DS: 11% (p < 0.001), Table 2). Altered con- prevalent in individuals with DS 40 years and older include extreme sciousness or confusion was more frequently reported in individuals fatigue or confusion (30%) and not eating or drinking (21%). with DS (controls: 18%, ISARIC4C DS: 33% (p = 0.004), T21RS DS: 32% Family members and caregivers tended to report more signs and (p = 0.003)) and vomiting/nausea was less often reported in individu- symptoms, and more often reported extreme fatigue and confusion als with DS (controls: 27%, ISARIC4C DS: 11% (p = 0.003), T21RS DS: than clinicians, particularly in individuals 40 years and older (clini- 14% (p = 0.008)). Nasal signs were more often reported in individuals cian reports: 73/284 (26%), family reports: 25/51 (49%); Figure S2). with DS only from the T21RS survey, which might be due to differen- The signs and symptoms reported for cases with a positive test result ces in study design (ISARIC4C: hospital reports by clinicians; T21RS: did not differ from those reported for the whole study sample (e.g. voluntary online survey by family or clinicians). fever, cough and shortness of breath were reported in 77%, 50% and 48%, respectively, of all cases and 80%, 47% and 54% of the cases with 3.3. Medical complications among COVID-19 patients with and without a positive test result; Figure S3). Furthermore, reported signs and DS symptoms were similar between individuals with mild-to-moderate and severe intellectual disability (e.g. fever, cough and shortness of Overall, 360 (60%) of the T21RS DS cases reported by clinicians breath were reported in 79%, 51% and 48%, respectively, of cases with had developed medical complications due to COVID-19 (medical mild-to-moderate and 79%, 52% and 52% of the cases with severe complications were not included in the caregiver survey, Table S5). intellectual disability; Figure S4). Individuals admitted to hospital Experiencing medical complications was correlated with higher mor- had more signs and symptoms in general compared with those who tality rates. The most prevalent complications were viral pneumonia were not hospitalized, with shortness of breath being particularly (36%) and acute respiratory distress syndrome (34%), followed by sec- more common among individuals admitted to hospital (66% versus ondary bacterial pneumonia (17%) and septic shock (11%). Of the 26%, Fig. S5). individuals who died, 69% had viral pneumonia and 85% an acute Comparing the signs and symptoms of hospitalized individuals respiratory distress syndrome. The prevalence of medical complica- with DS to matched individuals without DS (based on age, gender, tions increased by age. While 64 (41%) of the 0 19 year-olds Fig. 1. Signs and symptoms reported among the COVID-19 cases with Down syndrome grouped by age (T21RS survey). The signs and symptoms “not eating or drinking”, “conjunc- tivitis” and “skin lesions” were added in the second wave of the survey (smaller sample size for these symptoms). € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] 6 € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu Table 2 Signs and symptoms related to COVID-19 in individuals with and without Down syndrome. Hospitalized individuals with Down syndrome from the UK ISARIC4C and the T21RS surveys are compared to matched hospitalized individuals without Down syndrome (controls) from the ISARIC4C survey. The 100 individuals with Down syndrome reported through the UK ISARIC4C survey were matched to 400 individuals without Down syndrome (controls) from the same survey (matching 1:4) as well as to 100 individuals with Down syndrome from the T21RS survey (matching 1:1). The matching was based on age, gender and ethnicity (see supplementary tables S2 and S3 for characteristics of the matched samples). ISARIC4C controls ISARIC4C individuals with Down syndrome T21RS matched individuals with Down syndrome n (%) N n (%) N p value (comparison n (%) N p value (comparison with controls) with controls) Cough1 270 (71.8) 376 65 (67.7) 96 0.451 54 (54.0) 100 0.001 Fever 294 (76.4) 385 64 (68.1) 94 0.112 80 (80.0) 100 0.505 Sore throat 39 (13.0) 301 8 (12.1) 66 1.000 17 (17.0) 100 0.320 Runny nose2 13 (4.4) 293 2 (3.3) 61 1.000 16 (16.0) 100 <0.001 Joint pain or muscle aches 90 (28.8) 313 3 (4.8) 63 <0.001 11 (11.0) 100 <0.001 Fatigue/Malaise3 149 (46.4) 321 33 (45.8) 72 1.000 32 (32.0) 100 0.011 Shortness of breath 248 (68.9) 360 66 (74.2) 89 0.368 76 (76.0) 100 0.176 Disturbance or loss of taste/smell4 15 (9.3) 162 0 (0.0) 27 0.206 3 (3.0) 100 0.076 Headache 55 (18.3) 301 2 (3.1) 64 0.001 14 (14.0) 100 0.362 Altered consciousness or confusion3 61 (17.6) 346 25 (32.9) 76 0.004 32 (32.0) 100 0.003 Abdominal pain 60 (18.2) 330 10 (14.3) 70 0.493 11 (11.0) 100 0.094 Vomiting/nausea 92 (27.0) 341 8 (10.7) 75 0.003 14 (14.0) 100 0.008 Diarrhoea 77 (23.1) 334 10 (12.3) 81 0.034 17 (17.0) 100 0.216 Skin rash or skin ulcers5 13 (4.0) 321 4 (5.1) 78 0.754 2 (x) 44 0.700 1 ISARIC4C: combination of the signs “cough”, “cough with sputum production” and “cough bloody sputum / haemoptysis”; 2 The T21RS survey asked for the presence of “nasal signs”; 3 In the T21RS survey, this is referred to as “extreme fatigue, confusion, difficulty staying alert”; 4 ISARIC4C: combined ageusia and anosmia; 5 ISARIC4C: combined skin rash and skin ulcers; n/a: these questions were not included in the T21RS survey; % were calculated after excluding missing information. developed medical complications due to COVID-19, the numbers Among individuals with DS who were hospitalized with COVID- increased to 103 (65%) in 20 39 year-olds and 193 (69%) in individu- 19, we observed an increased mortality rate from age 40, while in the als with DS 40 years or older (Table S6). general population mortality rate increased at age 60 (Fig. 2A, Tables Comparing the medical complications observed in hospitalized S9 and S10). Mortality rates under the age of 40 were low, but still patients with DS to matched patients without DS (based on age, gen- higher in patients with DS than in the general population (7% of hos- der and ethnicity) showed that pulmonary complications (pneumo- pitalized COVID-19 patients with DS died, compared to 3% in the gen- nia and acute respiratory syndrome) were more common in eral population; Fig. 2A). individuals with DS (Table 3). These differences were significant for Comparing mortality rates among the matched ISARIC4C and all three pulmonary complications (viral pneumonia, bacterial pneu- T21RS samples, individuals with DS hospitalized with COVID-19 monia and acute respiratory syndrome) comparing the T21RS data to were around three times more likely to die than individuals without the ISARIC4C controls (p < 0.01) and suggestive for the comparison DS, assuming the same age, gender and ethnicity (Fig. 2B, individuals of viral pneumonia within the ISARIC4C data (p = 0.059). There was with and without DS from ISARIC4C: risk ratio (RR) = 2.9 (95%- no difference in the frequency of cardiac complications, anaemia, or CI = 2.1; 3.8), individuals with DS from T21RS vs. individuals without acute renal injury. Among those with COVID-19-related viral pneu- DS from ISARIC4C: RR = 3.5 (95%-CI = 2.6; 4.4)). Adjusting for known monia, individuals with DS were more likely to die than individuals COVID-19 related risk factors for mortality (chronic cardiac disease, without DS (controls: 23%, ISARIC4C DS: 53% (p < 0.001); T21RS DS: chronic pulmonary disease, chronic kidney disease, liver disease, obe- 57% (p < 0.001)). Mortality rates were also higher among patients sity, chronic neurological disorder, dementia, malignant neoplasm), with DS and acute respiratory syndrome and cardiac complications, reduced the RR to 2.5 (95%-CI = 1.5; 3.7) (ISARIC4C DS versus controls, but the differences were only significant for the comparison between Table S11A). That means that even after accounting for known risk the T21RS DS cases to the ISARIC4C controls (acute respiratory syn- factors, individuals with DS were still 2.5 times more likely to die drome: controls: 36%, ISARIC4C DS: 47% (p = 0.563); T21RS DS: 75% after being hospitalized with COVID-19. However, mortality rates of (p < 0.001); cardiac complications: controls: 31%, ISARIC4C DS: 33% individuals younger than 40 years of age were substantially lower (p = 1.000); T21RS DS: 100% (p = 0.007)). Overall, medical complica- (3% in controls, 12% in matched individuals with DS from the ISAR- tions were more common in the T21RS data than in individuals with IC4C survey and 13% in matched individuals from the T21RS survey), DS from the ISARIC4C survey and the frequencies differed between which is in line with mortality rates in individuals under the age of countries, with India, Spain and United States reporting the highest 40 with and without DS from the whole study sample (Fig. 2A, Tables numbers of medical complications (Table S7). Thus, observed differ- S5 and S6). The differences in mortality rates between these younger ences might be due to differences in study design or due to small individuals with and without DS were not significant after adjusting numbers (e.g., cardiac complications). for known risk factors for COVID-19 mortality (chronic cardiac dis- ease, chronic pulmonary disease, chronic kidney disease, liver dis- 3.4. Mortality rates among COVID-19 patients with and without DS ease, obesity, chronic neurological disorder) (RR = 2.4, 95%-CI = 0.1; 12.9, Table S11B), suggesting that excess mortality in younger indi- Overall, 13% of the 1046 COVID-19 patients with DS from the viduals with DS was potentially due to differences in comorbid condi- T21RS DS data died (Table 1). Eighty-seven percent of the fatal out- tions or to small sample sizes of those who died. However, comparing comes were reported by clinicians; 13% were reported by family individuals with DS younger than 40 and those over 40 admitted to members or caregivers. The mean age of cases who died was 51 years hospital while adjusting for comorbidities known to be associated (SD = 12), whereas the mean age of cases who did not die was with COVID-19 and those common in DS, suggest that the reduction 27 years (SD = 17) (Table S8). in risk for mortality is between 68% (95%-CI 18 93%; ISARIC4C € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu 7 Table 3 Medical complications related to COVID-19. Prevalence of cardiac complications and other medical complications that occurred in at least 10% of the matched control group and the associated mortality rate. Hospitalized individuals with Down syndrome from the UK ISARIC4C and the T21RS surveys are compared to matched individuals without Down syn- drome (controls) from the ISARIC4C survey. The 100 individuals with Down syndrome reported through the UK ISARIC4C survey were matched to 400 individuals without Down syndrome (controls) from the same survey (matching 1:4) as well as to 100 individuals with Down syndrome from the T21RS survey (matching 1:1). The matching was based on age, gender and ethnicity (see supplementary tables S2 and S3 for characteristics of the matched samples). A. Prevalence of medical complications among hospitalized patients ISARIC4C controls ISARIC4C individuals with Down syndrome T21RS individuals with Down syndrome n (%) N n (%) N p value (comparison n (%) N p value (comparison with controls) with controls) Viral pneumonia1 151 (42.7) 354 49 (53.8) 91 0.059 60 (83.3) 72 <0.001 Bacterial pneumonia 35 (10.0) 351 14 (15.2) 92 0.189 8 (32.0) 25 0.004 Acute Respiratory Syndrome 47 (13.0) 362 17 (17.9) 95 0.245 41 (60.3) 68 <0.001 Cardiac complications2 32 (8.6) 370 6 (6.3) 95 0.535 5 (8.5) 59 1.000 Anaemia 43 (11.7) 367 11 (12.0) 92 1.000 n/a n/a n/a Acute renal injury/Acute renal failure 51 (13.8) 369 12 (12.8) 94 0.867 11 (17.7) 62 0.434 B. Associated mortality rate Viral pneumonia1 34 (22.5) 151 26 (53.1) 49 <0.001 34 (56.7) 60 <0.001 Bacterial pneumonia 11 (31.4) 35 6 (42.9) 14 0.516 2 (25.0) 8 1.000 Acute Respiratory Syndrome 17 (36.2) 47 8 (47.1) 17 0.563 31 (75.6) 41 <0.001 Cardiac complications2 10 (31.3) 32 2 (33.3) 6 1.000 5 (100.0) 5 0.007 Anaemia 14 (32.6) 43 4 (36.4) 11 1.000 n/a n/a n/a Acute renal injury/Acute renal failure 19 (37.3) 51 5 (41.7) 12 1.000 7 (63.6) 11 0.177 1 T21RS survey: In the 1st wave of our survey, we only asked for pneumonia without differentiating between viral and bacterial pneumonia. As most clinicians answered this question with information on COVID-19-related viral pneumonia, the information provided on “pneumonia” in the 1st wave of the survey was combined with “viral pneumonia” for the analyses. Combination of cryptogenic organizing pneumonia (COP), pneumothorax, pleural effusion, bronchiolitis; 2 ISARIC4C: Combination of congestive heart failure, endocarditis / myocarditis pericarditis, myocarditis / pericarditis, cardiomyopathy, cardiac arrhythmia, cardiac ischemia; % were calculated after excluding missing information. dataset) and 92% (95%-CI 84 96%; T21RS dataset) lower in the youn- complications and mortality than the general population, particularly ger individuals compared with those over 40 (table S12). adults older than 40 years of age. Similar to the general population, fever, cough and shortness of 3.5. Risk Factors for hospitalization and mortality among COVID-19 breath were the leading signs and symptoms related to COVID-19 in patients with DS individuals with DS [23]. From the general population, we know that COVID-19 is usually a mild disease in children and often accompanied Age was the strongest risk factor for hospitalization and mortality with a few upper respiratory symptoms, including nasal congestion in individuals with DS from the T21RS survey (Fig. 3, Table S13). and runny nose [26]. Interestingly, we found that nasal signs were Every additional 10 years of age increased the odds for hospitaliza- much more common in individuals from our T21RS survey than in tion by a factor of 1.75 (95%-CI = 1.47; 2.07) and the odds for mortal- individuals with and without DS from the ISARIC4C survey (hospital ity by a factor of 2.41 (95%-CI = 2.02; 2.89). We further observed reports from the UK), which may relate to earlier signs of COVID-19 increased odds for hospitalization for males (OR (95%-CI) = 1.51 occurring prior to hospitalization or to different reporting by fami- (1.16; 1.97)), individuals with obesity (OR (95%-CI) = 2.03 (1.44; lies/caregivers. This highlights the importance of including data from 2.87)), diabetes (OR (95%-CI) = 1.93 (1.2; 3.1)) and individuals with a community-dwelling individuals with COVID-19 in addition to rou- congenital heart defect (OR (95%-CI) = 1.46 (1.05; 2.03)). We observed tine hospital reports as hospital reports are less likely to capture mild increased odds for mortality for males (1.75, 95% CI = 1.16-2.63) and signs and symptoms that might be important for early detection of individuals with Alzheimer’s disease/dementia (OR (95%-CI) = 2.13 disease. Loss of smell or taste was reported in less than 10% of indi- (1.1; 4.12)). Other potential risk factors (living in residential care viduals with DS, which was similar to the numbers reported in indi- facility, level of intellectual disability, thyroid disorder, seizures/epi- viduals without DS from the ISARIC4C survey, but much lower than lepsy, obstructive sleep apnea, gastroesophageal reflux, behavioral the prevalence reported by other studies (48% loss of smell and 41% and psychiatric condition and chronic lung disease) were not signifi- loss of taste as summarized in reference [27]). The most likely expla- cant (Fig. 3, Table S13). nation for these differences to more recent studies is that most T21RS and ISARIC4C cases were reported during the first wave of the pan- 4. Discussion demic, when we had very little knowledge about the variety of COVID-19 symptoms leading to an underdiagnosis of smell and taste DS is associated with specific co-occurring conditions and an disorders. Future studies are needed to determine if intellectual dis- immune-response dysfunction that may impact the risk of individu- abilities are also linked with an underdiagnosis of these symptoms. als with this disorder for having a more severe course of illness fol- Altered consciousness or confusion were more commonly lowing infection by SARS-CoV-2. To examine this question, we observed in individuals with DS than in the general population. As conducted an international online survey to collect COVID-19 related this sign could be an indicator of disease severity, it suggests that information on signs and symptoms, course of disease, and potential individuals with DS are more likely to become severely ill with risk factors in more than 1,000 patients with COVID-19 and DS, by far COVID-19 than individuals without DS, or that they might be more the largest assessment of individuals with DS who were infected severely ill at the time of hospitalization. Joint pain or muscle aches with SARS-CoV-2 that has been reported to date. Our analyses and vomiting/nausea were less commonly reported in individuals showed that while the leading signs and symptoms related to with vs. without DS. There is little evidence that people with DS COVID-19 are similar to those in the general population, patients experience both acute and chronic pain with a lower frequency than with DS who are hospitalized with COVID-19 were more likely to the rest of the population [28]. However, there is some evidence that experience a severe course of disease with higher rates of medical parental perception of pain is less discriminant for children with DS € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] 8 € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu Fig. 2. Mortality rates among patients hospitalized with COVID-19. A. Age distribution of the proportion of deaths among individuals with DS (combined data from the T21RS and ISARIC4C surveys), who were hospitalized with COVID-19, in comparison to hospitalized cases of COVID-19 from the general population (combined data from the UK ISARIC4C sur- vey (patients without DS), NYC [25] and Spain [24]). B., C. and D. Mortality rates among hospitalized individuals. Hospitalized individuals with Down syndrome from the UK ISAR- IC4C and the T21RS surveys are compared to matched individuals without Down syndrome (controls) from the ISARIC4C survey. The 100 individuals with Down syndrome reported through the UK ISARIC4C survey were matched to 400 individuals without Down syndrome (controls) from the same survey (matching 1:4) as well as to 100 individuals with Down syndrome from the T21RS survey (matching 1:1). As samples were matched based on age, gender and ethnicity, mortality rates are corrected for these characteristics (see supplementary tables S2 and S3 for more information on the matched samples). We had information on the outcome of disease in 91/100 individuals from the matched T21RS dataset. B. All matched individuals. C. Matched individuals younger than 40 years of age. D. Matched individuals 40 years of age or older. than for their siblings without DS [29]. Therefore, it may be difficult identical between clinician (49.7%) and caregiver reports (49.5%) and to detect, discriminate, and report pain in patients with DS. Like pain, is much higher than the one reported in the general population in nausea has to be self-reported by the patient. Hence, it is possible the UK (17%) [23]. This can be another indicator of more severe out- that both pain and nausea were underreported in individuals with comes of disease in individuals with DS. DS and poorly detected and documented by clinicians. This possibility Hospitalized individuals with DS were around three times more highlights the importance of including family members/caregivers in likely to die than individuals without DS, assuming the same age, the clinical assessment of COVID-19 patients with DS to avoid under- gender and ethnicity, and this association was only slightly attenu- representation of self-reported symptoms. ated when adjusted for known risk factors for COVID-19-related mor- Mortality rates could only be compared among hospitalized tality. However, additional analysis showed that children and young COVID-19 patients with and without DS. We know that mortality adults (younger than age 40) were about 90% less likely to die once rates among all individuals with COVID-19 can be sensitive to report- admitted to hospital with COVID-19 in comparison to older adults ing bias and to the amount of testing that is done in the population. with DS. Nevertheless, pulmonary medical complications (pneumo- For the US, the CDC reported a hospitalization rate of 14% (16% of nia and Acute Respiratory Syndrome) were more prevalent and dead- these were admitted to an ICU) and a mortality rate of 5% [30]. In the lier in individuals with DS, which is in line with the more severe T21RS survey sample, the admission rate to the ICU was 50% among complications during other viral respiratory infections such as influ- all hospitalized individuals with DS; this proportion was almost enza and RSV [5]. € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu 9 Fig. 3. Risk factors associated with adverse outcomes of COVID-19 in individuals with Down syndrome from the T21RS survey. Associations with A. hospitalization and B. mortality in symptomatic COVID-19 patients with Down syndrome from the T21RS survey estimated in adjusted logistic regression models (odds ratios (OR) and 95%-confidence intervals (95%-CI)). Associations with age and gender were adjusted for the data source (caregiver versus clinician survey) and associations with living situation, level of IDD and comorbid- ities were adjusted for age, gender, data source and country of residence. Abbreviations: IDD, intellectual and developmental disabilities; ref, reference category. Age was the strongest risk factor for hospitalization and mortality COVID-19 and individuals from all age groups, which is in contrast to in COVID-19 patients with DS, which is in line with findings from the most previous large-scale studies on COVID-19 that are based on hos- general population as reported in previous results from the ISARIC4C pital reports(23 25). In addition, our survey has been distributed in survey [23]. Importantly, we observed an increased mortality rate many different countries, which increased the sample size and added from age 40, at much earlier age than in the general population. diversity to our study. Nonetheless, as a sample of convenience, our Many markers of accelerated aging have been well documented in study population might not be representative of the population of individuals with DS [31], chief among them being the premature individuals with DS at large. development of Alzheimer’s disease pathology and dementia. This The primary limitation of this study is that not all of the COVID-19 emphasizes the need to protect older individuals with DS from SARS- cases were confirmed by COVID-19-specific laboratory tests. Given CoV-2 infections. While mortality rates among children and young that our survey was launched at the beginning of the pandemic when adults with DS were low, they were still higher than in individuals testing was scarce, we would have lost more than 20% of our cases without DS from the same age groups; however more data are (particularly from Spain, France, and Italy) if we were to include only needed to confirm this pattern. individuals with laboratory-confirmed COVID-19. Nonetheless, the Additional risk factors for hospitalization were male gender, obe- comparison with individuals from the general population was sity, diabetes and congenital heart defect and those for mortality restricted to patients hospitalized with COVID-19, providing an added were male gender and Alzheimer’s disease/dementia. As most of level of confidence for the clinical diagnosis even when laboratory these are known risk factors for severe outcomes of COVID-19 [23], tests were not reported. Another limitation of our study is the inclu- our findings suggest that the risk factors for individuals with DS are sion of cases from different countries and thus different health sys- similar to those observed in the general population. However as obe- tems. Some countries had more COVID-19 cases than others, health sity, dementia and congenital heart defect occur at higher rate in DS care systems differ substantially between countries (e.g. India versus than the general population, their role in increasing risk for severe Western European countries) and some countries experienced a surge outcomes in this population is highly significant. in cases later than others, so that they had more time to prepare and Except for congenital heart defects, we did not identify any other risk develop treatment strategies. To address this potential bias, we con- factors that were specific for individuals with DS. More studies with ducted the comparison to the general population for cases that were larger sample sizes may be needed to investigate whether other com- matched based on age, gender and ethnicity; and adjusted the associa- mon comorbidities of DS (e.g. obstructive sleep apnea, gastroesophageal tion analyses with risk factors for hospitalization and mortality for reflux, or seizures) increase the risk for a severe course of COVID-19. Of country of residence. Lastly, most COVID-19 patients from the T21RS note, we did not find any indication that living in residential care facili- and in the ISARIC4C surveys were reported during the first wave of the ties or the level of intellectual disability increases the risk for COVID-19 pandemic, when there were few treatment strategies available and related hospitalization or mortality. It has been reported that individuals mechanical ventilation was often the only treatment for severe living in residential care facilities are more vulnerable to COVID-19 COVID-19 cases with respiratory distress. It is unknown if anatomical infection [32], but it has also been noted by other authors “that people differences in the upper respiratory tract of individuals with DS are with [intellectual and developmental disabilities] living in congregate linked to a poor survival rate after mechanical ventilation and if this care settings can benefit from a coordinated approach to infection con- contributed to the high mortality rates during the first wave of the trol, case identification and cohorting” [33]. Possibly as evidence of ade- pandemic. quate management or rapid response in many of these facilities, we The comparison with data from the general population also has observed in our study population that infected individuals in congregate some limitations. The inclusion criteria are different between studies care settings were not more vulnerable to adverse outcomes of disease due to limited testing capacity [23 25]. Furthermore, we could only than those living with their families. compare data from hospitalized individuals and it is unknown Including both family and clinician reports has the advantage whether COVID-19 patients with DS are admitted more or less often of capturing information from a broad spectrum of severity of to hospitals and which factors or reasons may affect their rate of € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] 10 € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu hospitalization. Lastly, the samples for the matched comparison were Funding from the UK, whereas the T21RS study samples came from many dif- ferent countries and country-specific differences could have biased This work is supported by grants from: Down Syndrome Affiliates our results. Furthermore, we cannot determine whether the 11 in Action, Down Syndrome Medical Interest Group-USA, GiGi’s Play- matched hospitalised T21RS cases from the UK were also part of the house, Jerome Lejeune Foundation, LuMind IDSC Foundation, The ISARIC4C survey. Matthew Foundation, National Down Syndrome Society, National There are several open questions we could not answer with our Task Group on Intellectual Disabilities and Dementia Practices. study. As our study only included individuals infected with SARS- AH is supported by the HERCULES Center (NIEHS P30ES019776) CoV-2, we could not address whether individuals with DS are more and the LuMind IDSC Foundation. The REDCap survey and database likely to get infected. Furthermore, due to our limited sample size, management system at Emory University was supported by Library we were not able to identify any risk factors for a severe course of Information Technology Services grant support (UL1 TR000424). COVID-19 that might be specific for individuals with DS. Another ACSC is supported by the Alana USA Foundation, Awakening Angels question we could not specifically address is whether COVID-19 Foundation, and the Infectious Diseases Society of America (IDSA). patients with DS are subject to significant discrimination that might MD is supported by the Centre for Genomic Regulation Severo Ochoa have affected the offer of invasive interventions. The high rates of ICU excellence grant, the CIBER of Rare Diseases, DURSI 2017SGR595, and admissions within our study sample, however, do not support this acknowledges the Spanish Ministry of Science, Innovation and Uni- hypothesis. Yet, it is possible that patients with DS may have been versities (MSIU) to the EMBL partnership, the Centro de Excelencia admitted to ICU later than patients without DS due to delay in diag- Severo Ochoa and CERCA (GenCat). AS is supported by the MRC (MR/ nosis. S011277/1; MR/S005145/1; MR/R024901/1), Lumind IDSC, The Further research is required to establish whether treatments are LeJeune Foundation and the European Commission (H2020 SC1 Gene equally effective in individuals with DS, and whether specific treat- overdosage and comorbidities during the early lifetime in Down Syn- ments are required to reduce the increased rate of severe outcomes drome GO-DS21- 848077). ML was supported by the National Insti- [1]. There should be a focus on preventing or ameliorating severe out- tute for Health Research (NIHR) Biomedical Research Centre based at comes, which includes prioritisation for immunisation (influenza, UCL Great Ormond Street Institute of Child Health/Great Ormond pneumococcus, and SARS-CoV-2). In addition, our study sample only Street Hospital NHS Foundation Trust). DRdeA was partially sup- includes a small number of asymptomatic cases (6%), likely due to ported by Spanish Fondo de Investigacio n Sanitaria-Instituto Carlos lack of routine testing; thus, it remains unknown whether trisomy 21 III (FIS-ISCIII), grant no. PI19/00634; BAC has research support from or DS-related comorbidities alter the risk of having symptoms after Various Grateful Families of Patients. The Research Programme on infection with SARS-CoV-2. Biomedical Informatics (GRIB) is a member of the Spanish National Our results have implications for preventive and clinical manage- Bioinformatics Institute (INB), funded by ISCIII and EDER (PT17/0009/ ment of individuals with COVID-19 and DS. In terms of sheltering/ 0014). The DCEXS is a ‘Unidad de Excelencia Marí a de Maeztu’, shielding individuals to prevent infection, special caution should be funded by the AEI (CEX2018-000782-M). The GRIB is also supported taken with individuals over age 40, which is about 20 years younger by the Age ncia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR), than the typical at-risk group in the general population. Individuals Generalitat de Catalunya (2017 SGR 00519). with DS aged 40 and older have a three-fold increased risk for severe This study was also supported by the Fondo de Investigaciones outcomes compared to the general population, which is not explained Sanitario (FIS), Instituto de Salud Carlos III (PI18/00335 to MCI, PI14/ by additional comorbidities. Bearing in mind limited data, the present 01126 and PI17/01019 to JF), partly jointly funded by Fondo Europeo study also suggests that younger individuals are unlikely to develop de Desarrollo Regional, Unio  n Europea, Una manera de hacer Europa; severe disease, but more data are needed to confirm this supposition. the Jero^me Lejeune Foundation (No.1319 Cycle 2019B to MCI); the The T21RS survey shows that clinicians and caregivers should primar- National Institutes of Health (NIA grants 1R01AG056850 - 01A1; ily look for the same signs and symptoms seen in the general popula- R21AG056974 and R01AG061566 to JF); Departament de Salut de la tion (e.g. fever, cough, shortness of breath) when monitoring for Generalitat de Catalunya, Pla Estrate gic de Recerca i Innovacio  en COVID-19 in individuals with DS. Milder signs and symptoms such as a Salut (SLT006/17/00119 to JF); and Fundacio  La Marato  de TV3 ‘runny nose’ can also be a sign of COVID-19, particularly in younger (20141210 to JF). patients with DS, which is often underreported. With this information in mind, it is also safe to assume that most of the recommendations Acknowledgments given to the general population, such as limiting exposure by social distancing and access to safe activities with respiratory protection, are Trisomy 21 Research Society (T21RS) COVID-19 Taskforce devel- also important to prevent SARS-CoV-2 infection and spread of COVID- oped the survey, with the financial and dissemination support of 19 among those with DS. Additional strategies include prioritising Down Syndrome Affiliates in Action (DSAIA), Down Syndrome Medi- individuals with DS for COVID-19 immunisations, as well as for flu and cal Interest Group-USA (DSMIG-USA), GiGi’s Playhouse, Jerome pneumococcal vaccination, to reduce the risk for severe outcomes fol- Lejeune Foundation, LuMind IDSC Foundation, The Matthew Founda- lowing infection with SARS-CoV-2. tion, National Down Syndrome Society (NDSS), and the National Task Group on Intellectual Disabilities and Dementia Practices (NTG). Declaration of Competing Interest These and other international Down syndrome organizations are members of the T21RS COVID-19 stakeholders advisory group that Dr. Chicoine reports other from Woodbine House Publishing, provided advice to inform the design of the survey questions and other from Various Grateful Families of Patients, outside the submit- interpretation of results, including the Global Down Syndrome Foun- ted work; dation (USA), DSA (UK), DSMIG (UK), DSMIG (USA), DSRF-UK, DSi, Dr. Strydom reports grants from MRC, grants from EC - Horizon DSE international, Trisomie21-France, Down Espan ~ a, National Down 2020, during the conduct of the study; grants and personal fees from Syndrome Congress (NDSC), Down Madrid, Fundacio  Catalana Sín- AC Immune, other from ProMIS Neurosciences, outside the submitted drome de Down (Spain), EDSA, Royal College of Psychiatrists, Coor- work; Down (Italy), Associazione Italiana Persone Down (AIPD; Italy), AFRT DRdA has been partially supported by the Spanish Fondo de Inves- (France), Fundacio  n Iberoamericana Down 21 (Spain), FIADOWN  n Sanitaria-Instituto Carlos III (FIS-ISCIII), grant no. PI19/ tigacio ~o Brasileira das Associaç o (Latin America), Federaç a ~ es de Síndrome de 00634. All other authors have nothing to declare. Down (Brazil) and the European Down Syndrome Association. We € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu 11 acknowledge the contribution of DS-ConnectÒ (The Down Syndrome translation in French; local ethics submission. LAR: Data management Registry) which is supported by the Eunice Kennedy Shriver National for the T21RS survey; data analyses. GS: Contributed to design of the Institute of Child Health and Human Development (NICHD), NIH for work; acquisition of data. DV: Led the survey in Italy; obtained official the dissemination of the T21RS survey. We also wish to thank the approval for the study in Italy; contribution to the design of some many families and clinicians who contributed to the survey. questions in the survey. SLS: Contributed to the design and develop- This report is independent research which used data provided by ment of the survey; data verification, analyses and interpretation, the MRC funded ISARIC 4C Consortium and which the Consortium major contributions to the writing of the manuscript. AS: Involved in collected under a research contract funded by the National Institute conception and design of the T21RS survey and ISARIC4C analysis; for Health Research. The views expressed in this publication are those major contributions to the writing of the manuscript as well as UK PI. of the author(s) and not necessarily those of the ISARIC 4C consor- All authors critically reviewed early and final versions of the manu- tium. script. Other members of the T21RS COVID-19 Initiative Data sharing TdJ Bermejo, Instituto Hispalense de Psiquiatría, Spain. JM Borrell,  The data code books for the caregiver/family and clinician T21RS DOWN ESPANA, e Huesca, Spain. L Cretu, Institut Je ro^ me Lejeune, Paris, survey are provided in Supplementary Materials. France. R de la Torre, Hospital del Mar Medical Research Institute,  The REDCap data dictionary can be provided on request to the Spain. J Florez, Fundacion Iberoamericana Down 21, Spain. J Fortea, corresponding author. Sant Pau Memory Unit, Department of Neurology, Hospital de la  Written requests for the use of the anonymized data collected Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Univer- through the T21RS survey will be reviewed for approval by the T21RS sitat Auto noma de Barcelona, Barcelona, Spain; Barcelona Down COVID-19 Initiative. Medical Center, Fundacio  Catalana de Síndrome de Down, Barcelona, Spain. P Ghosh, Department of Zoology, Bijoy Krishna Girls’ College, Supplementary materials Howrah, West Bengal, India. D Gonza lez-Lamun ~ o, Hospital Valdecilla, Santander, Cantabria, Spain. A Hiance-Delahaye, Institut Je ro ^ me Supplementary material associated with this article can be found, ro Lejeune, Paris, France. C Laffon, Institut Je ^ me Lejeune, Paris, France. in the online version, at doi:10.1016/j.eclinm.2021.100769. J Levin, Department of Neurology, German Center of Neurodegenera- tive Diseases; Ludwig-Maximilians-Universit€at (LMU); Munich Clus- References ter for Systems Neurology (SyNergy), Munich, Germany. A Matia, DOWN ESPANA, e Barcelona, Spain. C Mircher, Institut Je ro^me Lejeune, [1] Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, et al. Down Paris, France. F Moldenhauer, Hospital La Princesa, Madrid, Spain. M syndrome. Nat Rev Dis Prim 2020;6(1):1–20 InternetAvailable from:. doi: Mulqueen, Advantage Care Health Centers, Brookville, NY, USA. NJ 10.1038/s41572-019-0143-7. [2] Cetiner S, Demirhan O, Inal TC, Tastemir D, Sertdemir Y. Analysis of peripheral Nowalk, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA. E blood T-cell subsets, natural killer cells and serum levels of cytokines in children ro Prioux, Institut Je ^me Lejeune, Paris, France. F Sanz, Research Pro- with Down syndrome. Int J Immunogenet 2010;37(4):233–7. gramme on Biomedical Informatics, Hospital del Mar; DCEXS Univer- [3] Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol 2011;164(1):9–16. sitat Pompeu Fabra, Barcelona, Spain. J Toulas, Institut Je ro ^me [4] Perez-Padilla R, Fernandez R, García-Sancho C, Franco-Marina F, Aburto O, Lo  pez- Lejeune, Paris, France. Gatell H, et al. Pandemic (H1N1) 2009 virus and down syndrome patients. Emerg Infect Dis 2010 Aug;16(8):1312–4. [5] Bloemers BLP, Van Furth AM, Weijerman ME, Gemke RJBJ, Broers CJM, Van Den Contributions Ende K, et al. Down syndrome: a novel risk factor for respiratory syncytial virus bronchiolitis - a prospective birth-cohort study. Pediatrics 2007;120(4). AH: Planned and conducted the statistical analyses; the major [6] Espinosa JM. Down Syndrome and COVID-19: a perfect storm? Cell Reports Med 2020;1(2):100019. contributor in writing the manuscript. ACSC: Major contributor to [7] Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’’ in design and distribution of the survey; led the efforts in Brazil and COVID-19. J Infect 2020;80(6):607–13. involved in translation; involved in interpretation of findings; major [8] Toma I De, Dierssen M. Network analysis of down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19. Res Sq Prepr 2020:1–23. contributions to the writing of the manuscript. MD: Major contribu- [9] Trotta MBF, Serro Azul JB, Wajngarten M, Fonseca SG, Goldberg AC, Kalil JE. tor to design and distribution of the survey; involved in interpreta- Inflammatory and Immunological parameters in adults with down syndrome. tion of findings; led the Spanish Taskforce. RAB: Contributed to Immun Ageing 2011;8:1–7. statistical analyses, including analysis of ISARIC4C dataset. SB: Con- [10] Kox M, Frenzel T, Schouten J, Van De Veerdonk FL, Koenen HJPM, Pickkers P, et al. COVID-19 patients exhibit less pronounced immune suppression compared with tributed to design of the work, acquisition of data. NTB: Contributed bacterial septic shock patients. Crit Care 2020;24(1):4–7. to design of the work, acquisition of data. ACB: Led the survey in Bra- [11] Startin CM, D’Souza H, Ball G, Hamburg S, Hithersay R, Hughes KMO, et al. Health zil; translated the questionnaire into Portuguese; obtained official comorbidities and cognitive abilities across the lifespan in down syndrome. J Neurodev Disord 2020;12(1):1–13. approval for the study in Brazil; contribution to the design of some [12] Bertapelli F, Pitetti K, Agiovlasitis S, Guerra-Junior G. Overweight and obesity in questions in the survey. AC: Contributed to design of the work, acqui- children and adolescents with Down syndrome—prevalence, determinants, con- sition of data. MCI: Contributed to the design of the work, acquisition sequences, and interventions: a literature review. Res Dev Disabil 2016;57:181– 92. of data. BAC: Participated in study design/modification; data collec- [13] Bergholdt R, Eising S, Nerup J, Pociot F. Increased prevalence of down’s syndrome tion; discussion of data analysis. SG: Led and organized Indian survey in individuals with type 1 diabetes in Denmark: a nationwide population-based on DS; coordinated among the researchers, clinicians and DS families; study. Diabetologia 2006;49(6):1179–82. [14] Hithersay R, Startin CM, Hamburg S, Mok KY, Hardy J, Fisher EMC, et al. Associa- obtained ethical clearance for the survey in India. ML: Contributed to tion of dementia with mortality among adults with down syndrome older than design of survey; interpretation of findings. CM: Helped with Ethics 35 years. JAMA Neurol 2019;76(2):152–60. approval in Spain; survey translation into Spanish; design of proto- [15] Santoro JD, Lee S, Mlynash M, Mayne EW, Rafii MS, Skotko BG. Diminished blood pressure profiles in children with down syndrome. Hypertension 2020 Mar;75 col; distribution of survey; data entry. MAM: Contributed to writing (3):819–25. the report for the Ethical Committee in Spain; involved in the design [16] Stancliffe RJ, Charlie Lakin K, Larson SA, Engler J, Taub S, Fortune J, et al. Demo- of the survey, translating it into Spanish. MCO: Recruitment of cases graphic characteristics, health conditions, and residential service use in adults in Spain and contribution to the design of the psychiatric questions with down syndrome in 25 U.S. states. Intellect Dev Disabil 2012;50(2):92–108. [17] McMichael TM, Currie DW, Clark S, Pogosjans S, Kay M, Schwartz NG, et al. Epide- in the survey. DRdA: Data collection, interpretation of results. ASR: miology of covid-19 in a long-term care facility in King County, Washington. N Design of the survey, data acquisition, collection and interpretation, Engl J Med 2020;382(21):2008–11. € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769 JID: ECLINM ARTICLE IN PRESS [m5G;February 26, 2021;3:55] 12 € ls et al. / EClinicalMedicine 00 (2021) 100769 A. Hu [18] Malle L, Gao C, Bouvier N, Percha B, Bogunovic D. COVID-19 hospitalization is patients hospitalized with COVID-19 in the New York City Area. JAMA 2020;323 more frequent and severe in down syndrome. medRxiv2020.05.26.20112748. (20):2052–9. [19] De Cauwer H, Spaepen A. Are patients with down syndrome vulnerable to life- [26] Dong Y, Dong Y, Mo X, Hu Y, Qi X, Jiang F, et al. Epidemiology of COVID-19 among threatening COVID-19? Acta Neurol Belg 2020:3–5. children in China. Pediatrics 2020;145(6). [20] Clift AK, Coupland CAC, Keogh RH, Hemingway H, Hippisley-Cox J. COVID-19 [27] Ibekwe TS, Fasunla AJ, Orimadegun AE. Systematic review and meta-analysis of mortality risk in down syndrome: results from a cohort study of 8 million adults. smell and taste disorders in COVID-19. OTO Open 2020;4(3) 2473974X2095797. Ann Intern Med 2020 Oct 21. [28] McGuire BE, Defrin R. Pain perception in people with down syndrome: a synthesis [21] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic of clinical and experimental research. Front Behav Neurosci 2015;9:194. data capture (REDCap)-A metadata-driven methodology and workflow process [29] Hennequin M, Faulks D, Allison PJ. Parents’ ability to perceive pain experienced by for providing translational research informatics support. J Biomed Inform their child with Down syndrome. J Orofac Pain 2003;17(4):347–53. 2009;42(2):377–81. [30] Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz KM, El Burai Felix S, et al. [22] Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap Coronavirus disease 2019 case surveillance — United States, January 22 May 30, consortium: building an international community of software platform partners. 2020. MMWR Morb Mortal Wkly Rep 2020;69(24):759–65. J Biomed Inform 2019;95(April):103208. [31] Hartley D, Blumenthal T, Carrillo M, DiPaolo G, Esralew L, Gardiner K, et al. Down [23] Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. Fea- syndrome and Alzheimer’s disease: common pathways, common goals HHS pub- tures of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clini- lic access author manuscript. Alzheimers Dement 2015;11(6):700–9. cal characterisation protocol: prospective observational cohort study. BMJ [32] Turk MA, Landes SD, Formica MK, Goss KD. Intellectual and developmental dis- 2020;369(March):1–12. ability and COVID-19 case-fatality trends: TriNetX analysis. Disabil Health J  [24] Borobia A, Carcas A, Arnalich F, Alvarez-Sala R, Monserrat-Villatoro J, Quintana M, 2020;13(3):100942. et al. A cohort of patients with COVID-19 in a major teaching hospital in Europe. J [33] Mills WR, Sender S, Lichtefeld J, Romano N, Reynolds K, Price M, et al. Supporting Clin Med 2020;9(6):1733. individuals with intellectual and developmental disability during the first [25] Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, 100 days of the COVID-19 outbreak in the USA. J Intellect Disabil Res 2020;64 et al. Presenting characteristics, comorbidities, and outcomes among 5700 (7):489–96. € ls et al., Medical vulnerability of individuals with Down syndrome to severe COVID-19 data from the Trisomy Please cite this article as: A. Hu 21 Research Society and the UK ISARIC4C survey, EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2021.100769