What is the risk of infection in children with Down syndrome and how can it be managed?

Risk of Infection in Children with Down Syndrome

Children with Down syndrome face a 3.5-fold increased risk of respiratory tract infections requiring hospitalization compared to children without Down syndrome, driven by anatomical abnormalities, intrinsic immune dysfunction, and frequent congenital heart disease. 1

Magnitude of Infection Risk

Respiratory Syncytial Virus (RSV)

• RSV hospitalization rates are 42/1000 child-years for children with Down syndrome without cardiopulmonary disease, compared to 12/1000 child-years in controls—a 3.5-fold increase. 1
• When concurrent cardiac or pulmonary disease is present, RSV hospitalization rates escalate to 67/1000 child-years. 1
• Approximately 45% of children with Down syndrome have congenital heart disease (atrioventricular canal, ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot), which compounds infection risk. 1
• Children with Down syndrome hospitalized for RSV have a median length of stay of 4 days versus 3 days for controls, though mortality from RSV is not significantly elevated. 1, 2

General Respiratory Infections

• More than 54% of hospitalizations in children with Down syndrome are due to lung infections. 1
• Children aged 2-7 years with Down syndrome are significantly more likely to be hospitalized for acute lower respiratory tract infections and RSV-associated bronchiolitis than age-matched controls. 1
• Influenza, pneumonia, pneumonitis, and respiratory failure are the most common causes of death in patients with Down syndrome. 1

Underlying Mechanisms of Increased Infection Risk

Anatomical Factors

• Upper airway abnormalities include macroglossia, adenotonsillar hypertrophy, laryngomalacia, smaller and narrower trachea, tracheo- and bronchomalacia, and tracheal-bronchus obstruction. 1
• Lower airway alterations include up to 25% decrease in alveolar number and reduced branch generation number. 1
• Impaired mucociliary clearance and failure to adequately clear bacteria and mucus contribute to recurrent infections. 1
• Muscle dystonia affects airway patency and secretion clearance. 1

Immunological Defects

• Intrinsic immune dysfunction is a primary contributor to infection susceptibility. 1
• Adults with Down syndrome demonstrate aberrant lymphocyte phenotypes with decreased naïve/memory T cell ratios and reduced switched memory B cells. 3
• Children with Down syndrome have changes in both innate and adaptive immunity, including T and B cell anomalies, monocyte dysfunction, and neutrophil chemotaxis defects. 4, 5
• Suboptimal antibody responses to polysaccharide antigens occur, with 50% of patients in one series failing to develop adequate responses. 6
• Some patients develop agammaglobulinemia with presence of B cells, requiring immunoglobulin replacement therapy. 6
• T-cell lymphopenia occurs in a subset of patients, with occasional combined immune compromise. 6

Cardiopulmonary Complications

• Impairment in respiratory blood vessels (immature double capillary network) and lymphatic vessels predisposes to pulmonary hypertension, pulmonary hemosiderosis, pulmonary capillaritis, and lymphangiectasia. 1
• Congenital heart disease further negatively impacts cardiorespiratory failure pathophysiology. 1

Management Strategies

RSV Prophylaxis Considerations

• Palivizumab prophylaxis is NOT routinely recommended for children with Down syndrome without other qualifying conditions (prematurity, chronic lung disease, hemodynamically significant congenital heart disease). 1
• The absolute number of RSV hospitalizations prevented by universal prophylaxis in Down syndrome is small: approximately 2-3 hospitalizations per year would be avoided from prophylaxis administered to 680 children (assuming 55% reduction). 1
• Children with Down syndrome AND qualifying cardiac disease (hemodynamically significant CHD requiring medication) or chronic lung disease requiring medical therapy within 6 months before RSV season SHOULD receive palivizumab. 1, 7
• RSV prophylaxis for the first year of life has limited effect on RSV hospitalization for children with Down syndrome without other risk factors, as the mean age of hospitalization is 9.6 months and extends through 17 years. 1

Antibiotic Prophylaxis

• Antibiotic prescription following respiratory tract infection-related primary care consultations reduces subsequent hospitalization risk ONLY in infants with Down syndrome, not older children. 8
• After adjustment for covariates, antibiotics were effective in infants but showed no benefit in older children with Down syndrome. 8
• Antibiotic chemoprophylaxis should be considered for patients who fail to develop polysaccharide antibody responses. 6

Immunoglobulin Replacement

• Immunoglobulin replacement therapy is indicated for children with Down syndrome who develop agammaglobulinemia or fail to develop adequate polysaccharide responses with recurrent infections. 6
• Regular screening for antibody deficiencies should be performed in children with recurrent infections. 6

Vaccination Strategies

• Additional active immunizations beyond standard schedules should be considered, including pneumococcal and influenza vaccines. 5
• Screening for adequate vaccine responses is warranted given suboptimal antibody production. 4, 5

Multidisciplinary Interventions

• Ear, nose, and throat surgical interventions (adenotonsillectomy) may reduce infection burden but require careful evaluation given anatomical considerations. 4
• Potential immunoprophylactic agents such as pidotimod, azithromycin, and Broncho-Vaxom may help alleviate infectious consequences, though evidence is limited. 5

Clinical Pitfalls to Avoid

• Do not assume all increased infection risk in Down syndrome is due to immune dysfunction alone—anatomical abnormalities and cardiac disease are major contributors. 1
• Do not provide universal palivizumab prophylaxis to all children with Down syndrome—41% of hospitalized children with Down syndrome and RSV had concurrent qualifying risk factors (cardiac or pulmonary disease), suggesting many would qualify for prophylaxis regardless of Down syndrome diagnosis. 1
• Maintain heightened awareness and urgency in the setting of sepsis in children with Down syndrome given their immune compromise. 5
• Screen regularly for signs of chronic inflammation and autoimmune conditions, which are more prevalent in this population. 4, 5
• Consider that infection-related mortality in older patients with Down syndrome may be favored by multiple factors including neurological impairment and nosocomial antigen exposure, not just immune dysfunction. 3