DS is the most common genetic disorder associated with intellectual disability, affecting over 200,000 individuals in the United States alone [3]. The syndrome presents a unique set of health challenges, particularly regarding immune system function and infection susceptibility. Research consistently shows that individuals with DS experience significant immune dysregulation, affecting both the innate and adaptive immune systems [11].
Children with DS are notably vulnerable to respiratory infections, which are a leading cause of morbidity and mortality. A study by Dieudonné et al. found that recurrent respiratory infections are prevalent in this population, and are significantly more likely to be hospitalized due to respiratory syncytial virus (RSV) infections [1]. A systematic review by Chan et al. quantified the hospitalization rate for children with DS at 117.6 per 1000 child-years, compared to 15.2 per 1000 child-years in unaffected children, indicating a 6.8-fold increased risk [12]. Similarly, our study population showed a significant prevalence of respiratory infections in this cohort of DS patients but also revealed the range of recurrent classifications of infections in DS (Fig. 2). This study was however limited in that we did not analyze the severity of the infections, just the quantitative infections themselves.
As individuals with DS age, their immune challenges persist. Adults with DS may exhibit an aberrant lymphocyte phenotype, with decreased naïve/memory T cell ratios and reduced numbers of switched memory B cells [1]. Interestingly, while infection rates tend to decrease slightly in mid-life, infection-related mortality rises in older age [13]. Our population did not include phenotyping of naïve/memory T cell subsets but there was a high incidence of lymphopenia overall and also for B cell abnormalities, particularly in phenotyping. One limitation of our study is that the DS patient population is quite young with an average age at evaluation of 7.4 years and did not follow patients over time as it was a limited cross-sectional study. Children with DS may exhibit premature aging of the immune system, which can lead to progressive multi-system deterioration, and increased sensitivity to DNA-damaging agents [14, 15]. Studies have shown that in patients with DS, cell aging measured by telomerase activity and cell death measured by DNA fragmentation are increased compared to controls [16]. This is hypothesized to add to the immune dysfunction in DS that mimics natural aging but is accelerated in DS. Our study demonstrates that this immune dysfunction in DS can be present at a very young age, likely due to this premature aging of the immune system.
Anatomical features in individuals with DS such as midfacial hypoplasia, flattened nasal bridges, high-arched palates, and macroglossia significantly contribute to recurrent lower respiratory and ear infections by obstructing airflow and hindering drainage [2, 17, 18]. These anatomical abnormalities compound the infectious risk in DS but cannot fully explain the increased frequency of illnesses observed in these patients. In fact, we suspect that this common misconception that the increased infectious risk in DS is only due to anatomic variant is misleading and leads many Pediatricians to not readily refer patients with DS to immunologists. Emerging research underscores the critical role of immune system dysfunction and dysregulation in DS, suggesting that underlying immune abnormalities are pivotal in their heightened susceptibility to infections. This study demonstrates that immunologists can make recommendations for treatment in DS to prevent infections. This is most aptly demonstrated by the fact that 9/12 (75%) of patients were recommended to receive additional Pneumococcal vaccination (Table 2). While this study is limited in that it did not look at the efficacy of the additional Pneumococcal vaccination in preventing infections, it did show that 3/8 (38%) achieved protective titers, while 4/8 (50%) did not achieve protective titers, and 1/8 (12%) did not have post-vaccination titers assessed. Furthermore, 7/14 (50%) had some degree of hypogammaglobulinemia and 1/17 (6%) of patients were recommended to start immunoglobulin replacement. While the sample size is quite small, this data demonstrates that there are some patients with DS whom an immunologist can make tangible recommendations to increase immune protection for these patients and patients with DS and increased infections should referred to immunology for evaluation and management.
Our study revealed lymphopenia in 53% of DS patients (Table 2). This finding resonates with prior research documenting lymphopenia in individuals with DS [1, 19–22]. However, reported lymphopenia rates vary significantly across studies, ranging from 23.5% [20] to 80% [1] and our cohort cannot be directly compared to other cohorts due to small sample size and referral bias as these were patients already with recurrent infections. The underlying mechanisms of lymphopenia in DS are not fully understood but are believed to be multifaceted, involving a lack of lymphocyte expansion and severe thymic dysfunction [20, 21]. Accelerated thymic involution and altered thymocyte maturation patterns are noted contributors [23–25]. Reduced T cell levels in DS are also thought to be due to diminished emigration of T lymphocytes from the thymus [3, 26]. Additionally, studies have reported increased apoptosis in both B cells and T cells [27, 28]. This lymphopenia is likely also contributing to the high rate of hypogammaglobulinemia (7/14, 50%) seen in our cohort and is likely also an independent risk factor for infections.
Our study observed that T cell lymphopenia may also result from cardiac surgery, but that cardiac surgery cannot explain all the cases of lymphopenia (Table 2). Preoperatively, 40% of patients had normal absolute lymphocyte counts, and 20% had lymphopenia, but postoperatively, 80% developed lymphopenia. This aligns with known evidence of lymphopenia occurring as a consequence of apoptosis post-surgery, peaking within two hours to two days post-surgery [29, 30].
Our findings align with those of other studies showing suboptimal B cell immune responses in children with DS [2, 3]. These findings are consistent with the literature reporting B lymphocyte counts below the 10th percentile for age-matched controls in 88% of children with DS [19, 31]. The presence of mostly naive CD21lowCD38- B-cells in DS cohorts may be related to an increased risk of autoimmune disease [32–34]. Transitional B-cells are typically decreased in DS children compared to healthy controls, though findings vary [3, 33, 35]. Low isotype-switched memory B-cell proportions in DS are associated with suboptimal vaccine responses and increased susceptibility to infections [3, 13, 35, 36]. This is consistent with our cohort which found 57% with B cell phenotyping abnormalities and 75% with suboptimal vaccine responses.
Immunoglobulin deficiencies were prevalent in our results, agreeing with previous research noting generally normal IgG and IgA levels but significantly decreased IgM levels [3]. Low IgM levels were seen in 43% of our patients which is quite high in our biased DS cohort of patients already with a high incidence of recurrent infections. However, another report observed mostly normal immunoglobulin levels [1] which is not consistent with our study. Studies have indicated that individuals with DS generally exhibit normal or elevated total IgG levels, though IgG subclass deficiencies, particularly IgG4, are noted in patients with severe infections [37]. One limitation of our study is that it did not analyze IgG subclasses as this was not felt to be clinically relevant to the immunologists ordering the laboratory testing as this was a retrospective chart review. Increased IgG levels and decreased IgM levels have also been reported in children with DS hospitalized for lower respiratory tract infections [38, 39]. These findings suggest that while children with DS can produce sufficient immunoglobulins, their immune dysregulation may involve qualitative defects, leading to recurrent infections and specific antibody deficiencies. This questions the fact that only 1 patient in the study was recommended to receive replacement immunoglobulin although 100% of the patients in the study had recurrent infections and 88% of the cohort had some document immune abnormality. We suspect however that this was largely due to limitations in the United States for insurance approvals for immunoglobulin replacement and that only 1 patient had low IgG and that is the same patient where immunoglobulin was recommended (Table 3). We hypothesize that many if not all of these patients likely would benefit from replacement immunoglobulin, but the price of immunoglobulin and insurance limitations typically require low IgG for approval.
Natural Killer (NK) cell dysregulation in DS is evidenced by significant increases in NK cell percentages coupled with decreased cytotoxic activity [2]. Previous research has shown increased NK cell percentages in DS patients but marked reductions in cytotoxic function, possibly contributing to their higher susceptibility to infections [40, 41]. Defective NK cell responses to interferon-alpha stimulation in DS further contribute to their increased infection risk [42]. Contradictory findings in recent studies suggest variability in NK cell markers used to define these cells, which may overlap with other cell populations [19, 26]. NK cell dysfunction in DS likely also contributes to an atypical inflammatory syndrome that is rare but has been described in DS similar to a viral induced hemophagocytic lymphohistiocytosis [43]. Our sample size was small but did not include any patients with significant immune dysregulation nor a significant number with NK cell abnormalities, though NK cell function was only examined in 2 of 17 cohort patients.
Our study findings align with previous research, which observed lower levels of Streptococcus pneumoniae titers in DS patients compared to those without DS [1, 44, 45]. DS patients experienced an increase in titers following immunization, although the antibody response to pneumococcal antigens is compromised due to reduced interaction between T cells and B cells [1, 44, 46]. This is consistent with our findings that 38% of patients with low titers had a robust response after booster vaccination.
Our study has several limitations, including a small sample size that restricts generalizability and advanced statistical analysis, and being a single-center study. The specific patient population from our immunology clinic may not represent the general DS population, particularly because we had a significantly diverse patient population with 65% Hispanic/Latino and 24% Black or African American. Furthermore, surgical histories and co-morbid conditions could introduce variability that confounds our results. These limitations underscore the need for future research with prospective studies, and larger, more diverse populations across multiple centers.
This study underscores the benefits of routine immunologic evaluation for DS patients. Immunologists can assess vaccine titers and revaccinate as needed as evidenced by our study which found that 75% of patients had non-protective pneumococcal vaccination status. With 50% of the cohort displaying hypogammaglobulinemia, routine screening of immunoglobulin levels is crucial, especially for those with recurrent infections. Although only one patient was recommended immunoglobulin replacement, broader screening can identify more candidates for immunoglobulin replacement therapy, enhancing immune function and reducing infections. Regular immunological assessments, including T-cell and B-cell phenotyping, can facilitate early identification and management of immune deficiencies. Recognizing DS as associated with immunodeficiency could influence clinical guidelines and healthcare policies, and thus influence insurance limitations to allow for improved reimbursements for necessary therapies, thus allowing for a multidisciplinary approach involving primary care physicians and immunologists to address the complex healthcare needs of DS patients.