Down Syndrome and COVID-19: A Perfect Storm?
Authors: Joaquin M. Espinosa
Journal: Cell Reports Medicine (2020)

People with Down syndrome show signs of chronic immune dysregulation, including a higher prevalence of autoimmune disorders, increased rates of hospitalization during respiratory viral infections, and higher mortality rates from pneumonia and sepsis. At the molecular and cellular levels, they show markers of chronic autoinflammation, including interferon hyperactivity, elevated levels of many inflammatory cytokines and chemokines, and changes in diverse immune cell types reminiscent of inflammatory conditions observed in the general population. However, the impact of this immune dysregulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and CoV disease of 2019 (COVID-19) remains unknown. This Perspective outlines why individuals with Down syndrome should be considered an at-risk population for severe COVID-19. Specifically, the immune dysregulation caused by trisomy 21 may result in an exacerbated cytokine release syndrome relative to that observed in the euploid population, thus justifying additional monitoring and specialized care for this vulnerable population. People with Down syndrome show signs of chronic immune dysregulation, including a higher prevalence of autoimmune disorders, increased rates of hospitalization during respiratory viral infections, and higher mortality rates from pneumonia and sepsis. At the molecular and cellular levels, they show markers of chronic autoinflammation, including interferon hyperactivity, elevated levels of many inflammatory cytokines and chemokines, and changes in diverse immune cell types reminiscent of inflammatory conditions observed in the general population. However, the impact of this immune dysregulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and CoV disease of 2019 (COVID-19) remains unknown. This Perspective outlines why individuals with Down syndrome should be considered an at-risk population for severe COVID-19. Specifically, the immune dysregulation caused by trisomy 21 may result in an exacerbated cytokine release syndrome relative to that observed in the euploid population, thus justifying additional monitoring and specialized care for this vulnerable population. Individuals with Down syndrome (DS) show widespread and chronic immune dysregulation. This population shows increased rates of diverse autoimmune conditions, including autoimmune thyroid disease,1Iughetti L. Predieri B. Bruzzi P. Predieri F. Vellani G. Madeo S.F. Garavelli L. Biagioni O. Bedogni G. Bozzola M. Ten-year longitudinal study of thyroid function in children with Down's syndrome.Horm. Res. Paediatr. 2014; 82: 113-121Crossref PubMed Scopus (41) Google Scholar, 2Aversa T. Valenzise M. Salerno M. Corrias A. Iughetti L. Radetti G. De Luca F. Wasniewska M. 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Despite the clear limitations imposed by the lack of available data, I provide evidence that individuals with trisomy 21 should be considered at high risk of developing more severe symptoms and increased rates of hospitalization, intensive care, secondary bacterial infections, and mortality from SARS-CoV-2 infections relative to the general population, thus justifying increased monitoring and specialized care for those with COVID-19 and DS. Mounting evidence supports the notion that morbidity and mortality during SARS-CoV-2 infections are driven by the exacerbated immune response to the virus, leading to a cascade of events involving a cytokine storm, acute respiratory distress syndrome (ARDS), and eventual myocardial damage and multi-organ failure.34Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. 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HLH Across Speciality Collaboration, UKCOVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: P1033-P1034Abstract Full Text Full Text PDF PubMed Scopus (6851) Google Scholar There are now multiple clinical trials testing the impact of targeted immunosuppressants, such as inhibitors of IL-6 signaling (e.g., Tocilizumab, Sarilumab), TNF-α signaling (e.g., Humira), IL-1β signaling (e.g., Anakinra), and Janus kinase (JAK) inhibitors (e.g., Ruxolitinib, Baricitinib, Tofacitinib) in the hope that attenuating the cytokine storm will improve prognosis. The exact mechanisms by which trisomy 21 causes the immune dysregulation observed in people with DS remains to be elucidated. However, several genes encoded on chromosome 21 have established roles in immune control, and their overexpression could contribute to the general immune phenotype of DS. Most prominent among the immune regulators encoded on chromosome 21 are four of the six interferon receptors: the two type I IFN receptors IFNAR1 and IFNAR2, the type II IFN receptor IFNGR2, and IL10RB, which serves as a receptor subunit for both type III IFN ligands and the cytokines IL-10, IL-22, and IL-26.45de Weerd N.A. Nguyen T. The interferons and their receptors--distribution and regulation.Immunol. Cell Biol. 2012; 90: 483-491Crossref PubMed Scopus (345) Google Scholar Several lines of evidence demonstrate the hyperactivation of IFN signaling in DS. First, the IFN receptors (IFNRs) encoded on chromosome 21 are overexpressed in multiple cell types of individuals with trisomy 21. This overexpression is obvious not only at the mRNA level in multiple immune and non-immune cell types (Figure 1)46Sullivan K.D. Lewis H.C. Hill A.A. Pandey A. Jackson L.P. Cabral J.M. Smith K.P. Liggett L.A. Gomez E.B. 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Rachubinski A.L. et al.Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome.Cell Rep. 2019; 29: 1893-1908.e4Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar,46Sullivan K.D. Lewis H.C. Hill A.A. Pandey A. Jackson L.P. Cabral J.M. Smith K.P. Liggett L.A. Gomez E.B. Galbraith M.D. et al.Trisomy 21 consistently activates the interferon response.eLife. 2016; 5: e16220Crossref PubMed Scopus (191) Google Scholar as well as brain tissue of diverse mouse models of DS carrying triplication of the IFNR cluster.54Aziz N.M. Guedj F. Pennings J.L.A. Olmos-Serrano J.L. Siegel A. Haydar T.F. Bianchi D.W. Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome.Dis. Model. Mech. 2018; 11: dmm031013Crossref PubMed Scopus (74) Google Scholar In addition, many independent studies have revealed changes indicative of chronic autoinflammation in people with DS, including the elevation of many cytokines and chemokines known to act downstream of IFN signaling.18Zhang Y. Che M. Yuan J. Yu Y. Cao C. Qin X.Y. Cheng Y. Aberrations in circulating inflammatory cytokine levels in patients with Down syndrome: a meta-analysis.Oncotarget. 2017; 8: 84489-84496Crossref PubMed Scopus (52) Google Scholar, 19Sullivan K.D. Evans D. Pandey A. Hraha T.H. Smith K.P. Markham N. Rachubinski A.L. Wolter-Warmerdam K. Hickey F. Espinosa J.M. Blumenthal T. Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation.Sci. Rep. 2017; 7: 14818Crossref PubMed Scopus (127) Google Scholar, 20Araya P. Waugh K.A. Sullivan K.D. Núñez N.G. Roselli E. Smith K.P. Granrath R.E. Rachubinski A.L. Enriquez Estrada B. Butcher E.T. et al.Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity.Proc. Natl. Acad. Sci. USA. 2019; 116: 24231-24241Crossref PubMed Scopus (70) Google Scholar,47Powers R.K. Culp-Hill R. Ludwig M.P. Smith K.P. Waugh K.A. Minter R. Tuttle K.D. Lewis H.C. Rachubinski A.L. Granrath R.E. et al.Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.Nat. Commun. 2019; 10: 4766Crossref PubMed Scopus (60) Google Scholar Of critical importance to the topic of cytokine storms, people with DS show significantly elevated levels of key cytokines such as CRP, IL-6, IL-2, TNF-α, IP-10, IL-10, and MCP-1.19Sullivan K.D. Evans D. Pandey A. Hraha T.H. Smith K.P. Markham N. Rachubinski A.L. Wolter-Warmerdam K. Hickey F. Espinosa J.M. Blumenthal T. Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation.Sci. Rep. 2017; 7: 14818Crossref PubMed Scopus (127) Google Scholar,20Araya P. Waugh K.A. Sullivan K.D. Núñez N.G. Roselli E. Smith K.P. Granrath R.E. Rachubinski A.L. Enriquez Estrada B. Butcher E.T. et al.Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity.Proc. Natl. Acad. Sci. USA. 2019; 116: 24231-24241Crossref PubMed Scopus (70) Google Scholar,47Powers R.K. Culp-Hill R. Ludwig M.P. Smith K.P. Waugh K.A. Minter R. Tuttle K.D. Lewis H.C. Rachubinski A.L. Granrath R.E. et al.Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.Nat. Commun. 2019; 10: 4766Crossref PubMed Scopus (60) Google Scholar To further strengthen this point, I include here data demonstrating that individuals with DS display signs of a mild cytokine storm even in the absence of any obvious infections (Figure 2) (http://explorer.trisome.org/proteome/). Lastly, metabolomics studies of both plasma and cerebrospinal fluid have revealed that individuals with DS display dysregulation of the IFN-inducible kynurenine pathway of tryptophan catabolism, leading to elevated levels of quinolinic acid, a neurotoxic tryptophan catabolite.47Powers R.K. Culp-Hill R. Ludwig M.P. Smith K.P. Waugh K.A. Minter R. Tuttle K.D. Lewis H.C. Rachubinski A.L. Granrath R.E. et al.Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.Nat. Commun. 2019; 10: 4766Crossref PubMed Scopus (60) Google Scholar The reduction of the copy number of IFNRs reversed this metabolic dysregulation in vitro, pointing to IFNR triplication as the driving event.Figure 2Elevated Baseline Cytokine Levels in Individuals with Down SyndromeShow full captionBox and whisker plots showing cytokine levels in typical people versus people with Down syndrome. Plasma cytokine levels were measured using the Meso Scale Discovery V-PLEX 54-PLEX Human Cytokine Kit and a U-PLEX custom array, as described in Powers et al.47Powers R.K. Culp-Hill R. Ludwig M.P. Smith K.P. Waugh K.A. Minter R. Tuttle K.D. Lewis H.C. Rachubinski A.L. Granrath R.E. et al.Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.Nat. Commun. 2019; 10: 4766Crossref PubMed Scopus (60) Google Scholar All p values were calculated using a Kolmogorov-Smirnov (KS) test. All of the boxplots show median, 25th, and 75th percentile values. Error bars are 1.5 times the IQR or the maximum data point if <1.5 IQR. Data are publicly available at http://explorer.trisome.org/proteome/.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Box and whisker plots showing cytokine levels in typical people versus people with Down syndrome. Plasma cytokine levels were measured using the Meso Scale Discovery V-PLEX 54-PLEX Human Cytokine Kit and a U-PLEX custom array, as described in Powers et al.47Powers R.K. Culp-Hill R. Ludwig M.P. Smith K.P. Waugh K.A. Minter R. Tuttle K.D. Lewis H.C. Rachubinski A.L. Granrath R.E. et al.Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.Nat. Commun. 2019; 10: 4766Crossref PubMed Scopus (60) Google Scholar All p values were calculated using a Kolmogorov-Smirnov (KS) test. All of the boxplots show median, 25th, and 75th percentile values. Error bars are 1.5 times the IQR or the maximum data point if <1.5 IQR. Data are publicly available at http://explorer.trisome.org/proteome/. This body of evidence indicates that the IFN response, which is key for both mounting antiviral responses and initiating and amplifying the cytokine storm, is much more active in people with DS. Given this knowledge, several questions then arise: what is the likely impact of SARS-CoV-2 infections on the immune response of individuals with DS? Are individuals with trisomy 21 more or less likely to develop a severe cytokine storm and downstream pathology? At first glance, IFN hyperactivity may be considered beneficial, in the sense that it may enable cells with trisomy 21 to mount a stronger antiviral response during the first contact with SARS-CoV-2. As the first viral particles enter lung epithelial cells of an individual with trisomy 21, the consequent production of type I and type III IFN ligands may e