Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

Down Syndrome

  • Luke A. Wall
  • Regina M. ZambranoEmail author
Living reference work entry

Latest version View entry history

DOI: https://doi.org/10.1007/978-1-4614-9209-2_190-2

Definition

Down syndrome results from a trisomy of the 21st chromosome. The syndrome encompasses a recognizable, yet highly variable, pattern of clinical features including abnormal facies, intellectual disability, and involvement of multiple organ systems.

Introduction

Down syndrome (DS) is the most common chromosome aneuploidy. According to the Centers for Disease Control and Prevention, approximately 1 in every 700 babies in the United States is born with Down syndrome (Parker et al. 2010). This is a recognizable disorder with variable phenotype and clinical features in multiple organ systems. The majority of patients present with intellectual disability and findings in the cardiovascular (CV), gastrointestinal (GI), neurologic, endocrinologic, hematologic, orthopedic, and immunologic systems are typically described.

Patients with DS have increased susceptibility to infections. Otitis media is one of the most frequently encountered health problems. Bacterial sinusitis and lower respiratory tract infections such as pneumonia, bronchiolitis, and croup are also common. The course of illness due to infection may be longer and more severe compared to general population. Patients with DS have higher incidence of acute lung injury secondary to pneumonia. Among children requiring mechanical ventilation, acute respiratory distress syndrome (ARDS) is much higher among children with DS. In addition, DS may be a risk factor for death due to sepsis (Ram and Chinen 2011). Numerous specific factors, both immunologic and nonimmunologic, place patients with DS at increased risk for infections. Such factors may show significant variability among individuals.

Many immunologic derangements occur in patients with DS including tendency for infections with immune deficiency and for immune dysregulation resulting in autoimmunity, lymphoproliferation, and/or malignancy. Specifically, immune dysregulation includes autoimmune conditions such as hypothyroidism, diabetes (Anwar et al. 1998), and celiac disease (Carnicer et al. 2001), as well as hematologic conditions such as leukemia and transient myeloproliferative disorders.

Nonimmunologic Abnormalities

Essentially, all patients with DS have craniofacial anatomical abnormalities, a major contributing factor to chronic and recurrent bacterial otitis media and sinusitis. Some patients also have abnormalities of the lower airway which can lead to difficulty clearing secretions and increased risk for pulmonary infections. While airway abnormalities may be severe enough to warrant tracheostomy, in the majority of patients, such alterations are at the milder end of the spectrum and may be an occult factor contributing to infections. Functional abnormalities such as gastroesophageal reflux and aspiration (compounded by hypotonia, abnormal anatomical relationships and obstructive sleep apnea) increase the risk for sinopulmonary infections. A list of such nonimmunologic factors is summarized in Table 1.
Table 1

Anatomical and functional factors which may contribute to increased frequency, severity, or duration of infections in individuals with Down syndrome

Nonimmunologic factors

Craniofacial abnormalities

 • Tonsil and adenoid hypertrophy

 • Midface hypoplasia

 • Mandibular hypoplasia

 • Small otic canals and eustachian tubes

Lower airway abnormalities

 • Laryngomalacia

 • Tracheomalacia

 • Tracheal stenosis

 • Pulmonary hypoplasia

Functional abnormalities

 • Gastroesophageal reflux and aspiration

 • Hypotonia

 • Eustachian tube dysfunction

 • Obstructive sleep apnea

Other factors allowing portals for infection

 • Chronic dermatitis

 • Periodontal disease

Immunologic Abnormalities

Primary immune defects may contribute to the higher incidence and prolonged course of infections observed in patients with DS (Ram and Chinen 2011). Intrinsic abnormalities of the immune system are numerous, involving the T and B cell compartment, and neutrophils as summarized in Table 2. In addition, Natural Killer (NK) cell abnormalities have been investigated but its clinical relevance is unclear. The reason why trisomy of chromosome 21 leads to immune alterations remains largely a mystery. Theories which attributed weak immunity to the premature aging process known to occur in DS have fallen out of favor. Recent analyses of the circulating proteome in patients with DS demonstrated higher levels of pro-inflammatory cytokines and pronounced complement consumption. In addition, recent transcriptome analyses by the same group of investigators revealed consistent activation of the interferon transcriptional response. These findings all support a new theory that DS may be variant of type I interferonopathy. Increased gene dosage of the four interferon receptors encoded on chromosome 21 is proposed to play a major role (Sullivan et al. 2017). Autoimmune complications may be related to dysfunction of a central T cell tolerance mechanism, dependent on autoimmune regulator (AIRE) (Giménez-Barcons et al. 2014). AIRE is encoded by AIRE, which is located in 21q22.3. Although allele-specific quantification of AIRE showed that three copies are expressed, overall level of expression was lower. This can compromise tissue-specific antigen presentation and negative selection of autoreactive T cells. Furthermore, autoreactive T cells serve as pool for natural regulatory T cell (nTreg) generation. It has been observed that although nTregs expand in DS patients, they have less inhibitory activity and therefore allow autoreactivity to occur.
Table 2

Immunologic factors which may be abnormal in patients with Down syndrome

Immunologic factors

T cell abnormalities

 • Reduced T cell numbers

 • Reduced naïve T cell percentage

 • Impaired T cell proliferation with mitogens

 • Limited T cell repertoire

 • Small thymus size with decreased AIRE expression

 • Abnormal regulatory T cell function

B cell abnormalities

 • Reduced B cell numbers

 • Impaired vaccine response

 • Decreased IgG2

 • Impaired Memory B cells

Neutrophil abnormalities

 • Decreased neutrophil chemotaxis

T Cell Abnormalities

T cell count and in-vitro proliferation with mitogen are often moderately reduced in children with DS. While T cell counts often increase with age, the T cell receptor diversity may remain limited. The thymic size is small and the percentage of naïve T cells is reduced in infants, corresponding with low T cell receptor excision circle (TREC) counts (Ram and Chinen 2011; Joshi et al. 2011). Therefore, DS should be included in differential diagnosis for patients with T cell lymphopenia identified by newborn screening for severe combined immune deficiency (SCID). While patients with DS do not typically contract opportunistic infections, any patient found to have an extremely impaired T cell compartment could be considered at risk. This would be unusual among patients with DS.

B Cell Abnormalities

B cell numbers are typically reduced. In addition, antibody response to polysaccharide vaccines may be sub-optimal (Joshi et al. 2011). While immunoglobulin levels are normal or elevated in most patients, hypogammaglobulinemia may occur. Reduced IgG2 subclass has been documented (Ram and Chinen 2011; Saha et al. 2017). Patients with DS are less able to produce and maintain switched memory B cells, the main player in the antibody recall response (Joshi et al. 2011).

Neutrophil Abnormalities

While respiratory burst capacity is typically normal in DS, neutrophil chemotaxis is impaired (Ram and Chinen 2011). Patients with DS do not typically manifest the type of infections generally thought to be associated with neutrophil defects. However, the impaired chemotaxis could be a contributing factor in the susceptibility to infections, in general.

Diagnostic and Treatment Approach

Regarding the diagnostic approach and treatment interventions, there are no specific guidelines regarding infections in DS. Certainly, any child, especially one with underlying DS, deserves to be evaluated by an immunologist if infections are occurring at increased frequency or severity compared to the general population. Immunologic evaluation in patients with DS should encompass B and T cell enumeration, including naïve T cell and switched memory B cell percentage. Immunoglobulins and vaccine titers to common immunizations are also necessary. If protection to vaccines is low, additional boosters should be administered, and postvaccine titers measured. Reevaluation every 6–12 months, depending on the clinical progress of the patient, should be considered. Daily prophylactic antibiotics may be a viable treatment option in select patients and may reduce the frequency of sinopulmonary, periodontal, and skin infections. The risks and benefits of daily antibiotics should be weighed carefully. Some patients may benefit from immunoglobulin replacement, especially those with low immunoglobulin levels, weak vaccine response, and a pattern of severe infections.

The Complexity of Care

In addition to the factors mentioned above surrounding the approach to patients with DS and an abnormal pattern of infections, the complexity goes much deeper. Some patients have complex congenital abnormalities which may require repeated surgeries and hospital admissions with frequent exposure to nosocomial pathogens. Apart from this, patients with DS are often highly affectionate and may closely encounter other individuals, even strangers, with hugs and handshakes much more than the average person. This contact increases exposure to bacteria and viruses. Hygiene may present a challenge due to factors such as limited cognitive ability and limited coordination to proceed through multiple steps required to effectively perform tasks such as cleansing one’s hands.

Behavioral and psychological aspects of DS impact all angles of the disorder. Repetitive scratching and picking at wounds lead to delayed healing and increased contamination. Anxiety regarding medical interventions and impaired capacity to understand the procedures are factors which should always be considered by the medical team. The care of patients with DS who experience increased frequency or severity of infections requires a multidisciplinary approach involving pulmonology, otolaryngology, immunology, dentistry, dermatology, genetics, and psychology. Good communication with, and involvement of, the patient’s family is an absolute necessity.

References

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Section of Allergy ImmunologyNew OrleansUSA
  2. 2.Section of Clinical GeneticsNew OrleansUSA
  3. 3.Department of PediatricsLouisiana State University Health Sciences Center and Children’s HospitalNew OrleansUSA

Section editors and affiliations

  • Jolan Walter
    • 1
  1. 1.USF HealthTampaUSA