Introduction

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 [1]. 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) [2]. 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 [5]. 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.

Methods

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.

Fig. 1
figure 1

Flow diagram of patients. *Within 190,740 stays - **Patients were excluded for insufficient data when the cause of hospitalization was not mentioned, or when clinical and biological data were unavailable

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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.

Results

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.

Table 1 Ambulatory DS patients
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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).

Table 2 Hospitalized DS patients (n = 64): comparison between DS patients with or without recurrent infections
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Fig. 2
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Time to second infectious event within the DS hospitalised group. The median duration of second infectious event-free survival was 6.9 months within the group with neurological disease, as compared with a median over the last follow up (105 months) in the group with no neurological disease. Hazard ratio 0.05 (p = 0.002)

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Discussion

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 [23]. 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 [24]. 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.