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- Open Access
Infection risk among adults with down syndrome: a two group series of 101 patients in a tertiary center
Orphanet Journal of Rare Diseases volume 14, Article number: 15 (2019)
Down syndrome (DS) is the most common form of viable chromosomal abnormality. DS is associated with recurrent infections, auto-immunity and malignancies in children. Little is known about immunity and infections in DS at adulthood.
We studied two separate group of adults (> 18 years old) with DS in a single referral tertiary center (Strasbourg University Hospital). The first group included 37 ambulatory DS patients between November 2014 and May 2017. We analyzed exhaustive serological and immunobiological parameters, at one point, together with the prevalence of infections, autoimmune manifestations and malignancies. The second group included 64 hospitalized patients (138 stays) in the same center, between January 2005 and December 2016.
One hundred and one adult patients with DS were included. Unlike children and despite a global lymphopenia, adults with DS underwent few infections in our ambulatory group. They did not experience any malignancy and, apart from hypothyroidism, they presented only occasional autoimmune manifestations. Hospitalized DS patients were older than ambulatory ones (median age 47 years (18–73) vs. 27 (18–52), p < 0.0001) and admitted mostly for infections (76.8%). Infections were associated with epilepsy and dementia (OR 6.5 (2.2–19), p = 0.001; p = 0.0006 in multivariate analysis) and higher mortality (OR 7.4 (1.4–37), p = 0.01).
Despite persistent immunobiological abnormalities at adulthood, young ambulatory adults with DS remain healthy with a low rate of infections. Infections are associated with neurological degeneration and increase the mortality arguing for a dedicated support of older DS patients.
ClinicalTrials.gov: NCT01663675 (August 13, 2012). Hospital Clinical Research Program (PHRC): number 2012-A00466–37 (Dr Y. Alembik).
Down syndrome (DS) caused by trisomy 21 is the most common form of viable chromosome abnormality in children and the prevalence of DS continues to increase with life expectancy . Survival of patients with DS improved drastically in the past few decades, with the detection and the early surgical care of congenital heart malformations (atrioventricular septal, ventricular septal, and atrial septal defects or persistent patent ductus arteriosus) . The median age at death is now mid-50’s compared to 10 years of age in the 1970’s [3, 4]. Children with DS have a high incidence of infections of the respiratory tracts . Over the last 3 decades, these infections have been linked to both innate and adaptive immunological abnormalities. Studies describing the immune system of infants with DS report the reduction and an altered distribution of T and B cell populations [6, 7] coupled to a poor response to vaccines [8,9,10,11]. Thus, it has been suggested that children with DS share similarities with patients affected with primary immunodeficiency (PID) and some PIDs classifications include DS [12, 13]. In contrast with pediatric literature, there is a lack of information about infections and immune parameters in adults with DS. Herein we report the features of 101 adults with DS.
Following approvement of our Institutional Boards, we studied two separate groups of adults (> 18 years old) with DS in Strasbourg University Hospital (Fig. 1). The first group included ambulatory DS patients (Department of Medical Genetic) between 2014 and 2017. We analyzed at one point serological and immunobiological parameters, together with the retrospective prevalence of infections, autoimmune manifestations and malignancies. The second group included hospitalized patients between 2005 and 2016 with associated DS ICD codes or key words “Down syndrome” or “Trisomy 21” in medical letters with the mean of systematic research by the medical information department of the hospital. We excluded patients hospitalized for scheduled exams.
We used Fisher’s exact test to compare qualitative variables and Student test for quantitative variables in univariate analysis. Mann-Whitney test was used to compare non-normally distributed variables. Multivariate analyzes were done for a p-value < 0.10 in univariate analysis using ridge logistic regression. Statistical significance was defined by p < 0.05 in 2-tailed tests.
Thirty-seven patients came to the medical genetic consultation for DS (Table 1). Median age was 27 years (18–52). None was in institutional care. Frequent infections were reported during childhood for 20 DS patients (54%), the leading manifestations involving respiratory tract (49%) and ENT (16%). Only one patient was identified with recurrent infectious events after the age of 18. Total lymphocyte counts of DS patients were low when compared to standards (1480 cells/μL vs. 2170 cells/μL, p = 0.004) concerning especially naïve and memory B cell subsets as described in DS children. 15 patients presented with hypergammaglobulinemia (IgG > 15 g/L) and increased IgG1 and IgG3 levels. Serological status following vaccination for DPT (Diphteria, Polio and Tetanus), Streptococcus pneumoniae and Haemophilus influenzae showed protective titers in most cases.
During an 11 year period (2005–2016), 64 DS patients were hospitalized at Strasbourg University Hospital, mainly in Internal Medicine, Infectious diseases, Pneumology and Intensive Care Units corresponding to 138 stays (a total of 190,740 stays were recorded in the same departments during this period), (Table 2). Median age was 47 years (18–73), older than ambulatory ones (p < 0.0001). Thirty-seven patients (58%) were in institutional care. The outstanding causes for hospitalization among DS patients were infections (n = 106/138), mostly aspiration pneumonia (n = 91/138). When available, lymphocyte counts and Ig levels were comparable to those of the ambulatory patients. Infections were associated with epilepsy and dementia (OR 6.5 (2.2–19), p = 0.001; p = 0.0006 in multivariate analysis) and higher mortality (OR 7.4 (1.4–37), p = 0.01). We found a median of second infectious event at 6.9 months in the group with neurological diseases vs. more than 120 months in the group without neurological diseases (p = 0.002, Fig. 2). Furthermore, the annual rate of infection dramatically increased with age in hospitalized group with a 5 fold increase of incidental infections after 50 years (Additional file 1: Figure S1).
In DS children, epidemiological [1, 14,15,16,17,18] and pathophysiological [6, 19,20,21,22] evidences argue for a higher risk of infectious events, hematological malignancies and autoimmunity. Our work correlates for the first time detailed immunological findings and infectious events in adult patients with DS. Despite persistent T and B cell alterations, young ambulatory adults with DS have a low risk of infections, suggesting offsetting mechanisms in adulthood. However, infections, mostly bacterial aspiration pneumonia, remain the first cause of hospitalization. The major factor associated with infectious complications and premature death is the occurrence of neurological diseases such as seizures and dementia . Seizures are frequent in adults with Down’s syndrome with about 10 times increased incidence as compared to general population. Seizures are associated with aging and cognitive impairment in DS . Development of dementia in DS syndrome dramatically increases after age of 40 and is one of the main cause of institutionalization and hospitalization [4, 24]. Considering pediatric studies and our work, infections in DS occur early in life up and in the second adulthood period -after 50 years-old- especially when neurological comorbidities are associated. Indeed, neurological impairment marks a turning point in the infectious complications of adults patients with DS and this should be kept in mind by physicians.
Diphtheria, Polio and Tetanus
Ear, Nose and Throat
International Classification of Diseases (version 10)
Primary Immune Deficiency
Irving C, Basu A, Richmond S, Burn J, Wren C. Twenty-year trends in prevalence and survival of Down syndrome. Eur J Hum Genet. 2008;16:1336–40.
Jensen KM, Bulova PD. Managing the care of adults with Down’s syndrome. BMJ. 2014;349:g5596.
Genes and human disease. In: Who World Health Organization. Available from: http://www.who.int/genomics/public/geneticdiseases/en Accessed 18 Dec 2018.
Englund A, Jonsson B, Zander CS, Gustafsson J, Annerén G. Changes in mortality and causes of death in the Swedish Down syndrome population. Am J Med Genet A. 2013;161:642–9.
Ram G, Chinen J. Infections and immunodeficiency in Down syndrome: immunodeficiency in Down syndrome. Clin Exp Immunol. 2011;164:9–16.
Verstegen RHJ, Driessen GJ, Bartol SJW, van Noesel CJM, Boon L, van der Burg M, et al. Defective B-cell memory in patients with Down syndrome. J Allergy Clin Immunol. 2014;134:1346–53.
Schoch J, Rohrer TR, Kaestner M, Abdul-Khaliq H, Gortner L, Sester U, et al. Quantitative, phenotypical, and functional characterization of cellular immunity in children and adolescents with Down syndrome. J Infect Dis. 2017;215:1619–28.
Kusters M a A, Manders NCC, de Jong B a W, van Hout RWNM, Rijkers GT, de Vries E. Functionality of the pneumococcal antibody response in Down syndrome subjects. Vaccine. 2013;31:6261–5.
Kusters MA, Bok VLA, Bolz WEA, Huijskens EGW, Peeters MF, de Vries E. Influenza a/H1N1 vaccination response is inadequate in Down syndrome children when the latest cut-off values are used. Pediatr Infect Dis J. 2012;31:1284–5.
Kusters MA. Jol-Van Der Zijde ECM, Gijsbers RHJM, de Vries E. Decreased response after conjugated meningococcal serogroup C vaccination in children with Down syndrome Pediatr Infect Dis J. 2011;30:818–9.
Kusters MA, Jol-van der Zijde CM, van Tol MJ, Bolz WE, Bok LA, Visser M, et al. Impaired avidity maturation after tetanus toxoid booster in children with Down syndrome. Pediatr Infect Dis J. 2011;30:357–9.
Ming JE, Stiehm ER, Graham JM. Syndromic immunodeficiencies: genetic syndromes associated with immune abnormalities. Crit Rev Clin Lab Sci. 2003;40:587–642.
Cuadrado E, Barrena MJ. Immune dysfunction in Down’s syndrome: primary immune deficiency or early senescence of the immune system? Clin Immunol Immunopathol. 1996;78:209–14.
Bloemers BLP, Broers CJM, Bont L, Weijerman ME, Gemke RJBJ, van Furth AM. Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system. Microbes Infect Inst Pasteur. 2010;12:799–808.
Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet Lond Engl. 2000;355:165–9.
Roizen NJ, Patterson D. Down’s syndrome. Lancet. 2003;361:1281–9.
Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet Lond Engl. 2002;359:1019–25.
Linabery AM, Li W, Roesler MA, Spector LG, Gamis AS, Olshan AF, et al. Immune-related conditions and acute leukemia in children with Down syndrome: a Children’s oncology group report. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2015;24:454–8.
Bloemers BLP, van Bleek GM, Kimpen JLL, Bont L. Distinct abnormalities in the innate immune system of children with Down syndrome. J Pediatr. 2010:804–9.
Bloemers BLP, Bont L, de Weger RA, Otto SA, Borghans JA, Tesselaar K. Decreased Thymic output accounts for decreased naive T cell numbers in children with Down syndrome. J Immunol. 2011;186:4500–7.
Carsetti R, Valentini D, Marcellini V, Scarsella M, Marasco E, Giustini F, et al. Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome: clinical immunology. Eur J Immunol. 2015;45:903–14.
Verstegen RHJ, Kusters MAA, Gemen EFA, DE Vries E. Down syndrome B-lymphocyte subpopulations, intrinsic defect or decreased T-lymphocyte help. Pediatr Res. 2010;67:563–9.
Lott IT, Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurol. 2010;9:623–33.
Menéndez M. Down syndrome, Alzheimer’s disease and seizures. Brain and Development. 2005;27:246–52.
PHRC T21 study group: Emmanuel Andres, MD, PhD, Xavier Argemi, MD, PhD, Frédéric Blanc, MD, PhD, Isabelle Brun, MD, Salima El Chehadeh, MD, Jean-Luc Davideau, MD, Jean-Louis Dietemann, MD, PhD, Hélène Dollfus, MD, PhD, Elise Gazzano, MD, Bernard Goichot, MD, PhD, Julie Helms, MD, Jean-Michel Hiebel, MD, Georges Kaltenbach, MD, PhD, Anne Koenig, MD, PhD, Marie-Cécile Manière, PhD, Yaumara Perdomo, MD, Hélène Petit-Eisenmann, MD, PhD, Alain Pradignac, MD, PhD, Anne-Elisabeth Quoix, MD, PhD, Philippe Sauder MD PhD, Elise Schaefer, MD, Francis Schneider, MD, PhD, Dana Timbolschi, MD, Jean-Christophe Weber, MD (Strasbourg University Hospital) contributed clinical and administrative collaborative efforts. Insightful comments on the manuscript: Laurent Arnaud MD, PhD (Strasbourg University Hospital) and Hans Hartmut Peter MD, PhD (Universitätsklinikum Freiburg). No compensation was received.
We thank the patients, families and staff for their time and dedication.
Dr. Yves Alembik (grant from the French Ministry of Health PHRC 2012-A00466–37),
Pr. Anne-Sophie Korganow (grant from EU-funded (ERDF) project INTERREG V “RARENET”).
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its additional files].
Ethics approval and consent to participate
Ambulatory patients involved in PHRC T21 “Trisomy 21 in Adulthood”: (Dr Alembik Yves): All subjects were recruited under a protocol approved by ethical board CPP-Est IV N°12/47 (research ethical board of Strasbourg University Hospital) including a written informed consent.
Retrospective hospitalized patients: An approval statement from the local ethical committee has been obtained (ethical committee of the Faculties of Medicine and Dentistry of Strasbourg N°2018–8).
Consent for publication
The authors declare that they have no competing interests.
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Guffroy, A., Dieudonné, Y., Uring-Lambert, B. et al. Infection risk among adults with down syndrome: a two group series of 101 patients in a tertiary center. Orphanet J Rare Dis 14, 15 (2019) doi:10.1186/s13023-018-0989-x
- Down syndrome
- Infectious risk
- Neurological impairment