Decreased thymic output accounts for decreased naive T cell numbers in children with Down syndrome.

Children with Down syndrome (DS) have low numbers of naive T cells and abnormal thymus development and function. Because next to thymic production, peripheral proliferation greatly contributes to naive T cell generation in healthy children, we examined the cause of reduced naive T cell numbers in children with DS. Compared with aged matched controls, the total number of signal joint TCR excision circles (sjTREC) per ml blood was reduced in DS. Reduced frequencies and absolute numbers of protein tyrosine kinase 7-positive recent thymic emigrants, but similar levels of naive T cell apoptosis and Ag-driven activation in DS, suggested that reduced thymic output and not increased peripheral loss of naive T cells caused the reduced sjTREC numbers. We found no support for defective peripheral generation of naive T cells in DS. In DS the naive T cells responded to IL-7 and, based on Ki-67 expression, had similar proliferation rates as in healthy controls. sjTREC content per naive CD8(+) T cells was not increased, but even decreased, pointing to increased survival or peripheral generation of naive T cells in DS. In conclusion, we show in this study that reduced thymic output, but not reduced peripheral generation nor increased loss of naive T cells, results in the low naive T cell numbers found in DS.

Distinct abnormalities in the innate immune system of children with Down syndrome.

OBJECTIVE: To analyze the frequency and phenotype of cells of the innate immune system in the peripheral blood of children with Down syndrome (DS). STUDY DESIGN: Flow cytometric analysis of expression of cell surface markers was performed in children with DS (n = 41) and healthy age-matched controls (n = 41). RESULTS: Compared with controls, children with DS had significantly lower absolute total leukocyte counts, lymphocytes, monocytes, and granulocytes, but 1.5-times higher absolute numbers of CD14(dim)CD16(+) monocytes (147 x 10(6)/L vs 93 x 10(6)/L; P = .02). This difference is fully explained by a higher percentage of CD14(dim)CD16(+) monocytes within the monocyte compartment (28.7% vs 13.4%; P <.001). The absolute numbers of myeloid dendritic cells were lower in DS (13.8 x 10(6)/L vs 22.7 x 10(6)/L; P <.001). The numbers of plasmacytoid dendritic cells and natural killer cells were normal. Absolute numbers of invariant natural killer T cells were very low overall, but significantly lower in children with DS than in controls (1.2 x 10(6)/L vs 3.7 x 10(6)/L; P = .01). CONCLUSIONS: Children with DS exhibited distinct abnormalities in cells of the innate immune system. Most strikingly, they had a high number of proinflammatory CD14(dim)CD16(+) monocytes. This elevated level of CD14(dim)CD16(+) monocytes may play an important role in the onset and maintenance of chronic inflammatory disease in DS.

Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study.

BACKGROUND AND OBJECTIVES: Children with Down syndrome (DS) are at significant risk for respiratory syncytial virus (RSV) infection and related hospitalization. We compared hospitalization rates due to respiratory tract infection in children with DS aged <2 years who prospectively received palivizumab during the RSV season with a previously published, similar untreated DS birth cohort. METHODS: A total of 532 children with DS who prospectively received palivizumab were assembled from the prospective Canadian RSV Evaluation Study of Palivizumab registry between 2005 and 2012. The untreated group included 233 children with DS derived from a nationwide Dutch birth cohort from 2003 to 2005. Events during the RSV seasons were counted. Poisson regression analysis was performed to compare incidence rate ratios (95% confidence intervals [CIs]) between groups while controlling for observation length and known risk factors for severe RSV infection. RESULTS: In total, 31 (23 untreated, 8 treated) RSV-related hospitalizations were documented. The adjusted risk of RSV-related hospitalizations was higher in untreated subjects than in palivizumab recipients (incidence rate ratio 3.63; 95% CI, 1.52-8.67). The adjusted risk of hospitalization for all respiratory tract infection (147 events; 73 untreated, 74 treated) was similar (incidence rate ratio untreated versus palivizumab 1.11; 95% CI, 0.80-1.55). CONCLUSIONS: These results suggest that palivizumab is associated with a 3.6-fold reduction in the incidence rate ratio for RSV-related hospitalization in children with DS during the first 2 years of life. A randomized trial is needed to determine the efficacy of RSV immunoprophylaxis in this specific high-risk patient population.

Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system.

Down syndrome (DS) is the most common chromosomal abnormality among live-born infants. Respiratory tract infections are the most important cause of mortality in individuals with DS at all ages. In recent decades several studies have been performed to elucidate abnormalities of the immune system in DS. However, the influence of the immune system on the occurrence of respiratory tract infections in these children has never been reviewed.

High incidence of recurrent wheeze in children with down syndrome with and without previous respiratory syncytial virus lower respiratory tract infection.

BACKGROUND: Respiratory syncytial virus (RSV)-induced lower respiratory tract infection (LRTI) is associated with the subsequent development of recurrent wheeze. In a recent study, we found a high incidence (9.9%) of hospitalization for RSV-induced LRTI among children with Down syndrome (DS), indicating DS as a new risk factor for RSV-induced LRTI. In the current study we aimed to investigate the development of long-term airway morbidity in children with DS after hospitalization for RSV-induced LRTI. METHODS: A combined retrospective cohort and prospective birth cohort of children with DS with a history of hospitalization for RSV-induced LRTI was studied (n = 53). Three control populations were included: children with DS without hospitalization for RSV-induced LRTI (n = 110), children without DS but with hospitalization for RSV-induced LRTI (n = 48), and healthy siblings of the previous 3 groups mentioned (n = 49). The primary outcome was physician-diagnosed wheeze up to 2 years of age. RESULTS: The incidence of physician-diagnosed recurrent wheeze in children with DS with a history of hospitalization for RSV-induced LRTI was 36%. Unexpectedly, up to 30% of children with DS without a history of RSV-induced LRTI had physician-diagnosed recurrent wheeze (no significant difference). In children without DS physician-diagnosed wheeze was found more frequently in children hospitalized for RSV-induced LRTI than healthy controls (31% vs. 8%, P = 0.004). CONCLUSIONS: In this combined retrospective/prospective cohort study RSV-induced LRTI did not significantly contribute to the risk of recurrent wheeze in children with DS. An unexpected finding was that recurrent wheeze was very common among children with DS.

Down syndrome: a novel risk factor for respiratory syncytial virus bronchiolitis--a prospective birth-cohort study.

OBJECTIVES: Respiratory syncytial virus is the single-most important cause of lower respiratory tract infections in children. Preterm birth and congenital heart disease are known risk factors for severe respiratory syncytial virus infections. Although Down syndrome is associated with a high risk of respiratory tract infections, little is known about the incidence of respiratory syncytial virus infections in this group. The aim of our study was to determine the incidence of respiratory syncytial virus lower respiratory tract infection-associated hospitalization among children with Down syndrome. PATIENTS AND METHODS: We performed a retrospective observational study and a prospective nationwide birth-cohort study of children with Down syndrome. The retrospective cohort comprised 176 children with Down syndrome. A birth cohort of 219 children with Down syndrome was prospectively followed until 2 years of age. All 276 siblings of the birth cohort were used as controls. RESULTS: Of the 395 patients with Down syndrome, 180 (45.6%) had a known risk factor for severe respiratory syncytial virus infections; 39 (9.9%) of these were hospitalized for respiratory syncytial virus lower respiratory tract infections. Two control children (0.7%) versus 9 term children with Down syndrome without congenital heart disease (7.6%) were hospitalized for respiratory syncytial virus lower respiratory tract infections. The median duration of hospitalization was 10 days; mechanical ventilation was required for 5 children (12.8%). CONCLUSIONS: This is the first study, to our knowledge, to demonstrate that Down syndrome is a novel independent risk factor for severe respiratory syncytial virus lower respiratory tract infections. These findings should prompt studies to investigate possible mechanisms that underlie severe respiratory syncytial virus lower respiratory tract infections in children with Down syndrome. The effect of respiratory syncytial virus prophylaxis in this specific population needs to be established.

Implantable loop recorders in pediatric practice.

Symptoms of syncope and palpitations are not uncommon in children with and without heart disease. They present a diagnostic dilemma when conventional cardiovascular testing is inconclusive. The implantable loop recorder (ILR) has been shown to play an important role in diagnosing recurrent syncope in adult patients. In pediatric practice its role still has to be defined. The aim of this review is to assess the diagnostic yield of the ILR in children and young adults. Seven patients, 4 male and 3 female, were included in the study. Mean age at implantation was 12.8, range 0.8 to 25.9. Indications for ILR were syncope (N=6), near-syncope (N=1), palpitations (N=2) and acute life threatening event (N=2). Previous testing included 12-lead ECG (N=7), echo (N=7), 24 hour Holter (N=7), 4 week ambulatory Holter (N=3), exercise test (N=4) and invasive electrophysiologic study (N=3). Over a mean follow-up period of 7.5 months (range 3 to 16 months), 4 (57%) patients continued to have symptoms. The ILR enabled the correct diagnosis to be established in all, allowing for appropriate therapy.