Hospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age: A Systematic Review and Meta-Analysis

doi:10.1016/j.jpeds.2018.08.006

The Journal of Pediatrics

Volume 203, December 2018, Pages 92-100.e3

https://doi.org/10.1016/j.jpeds.2018.08.006 Get rights and content

Objectives

To compare the respiratory syncytial virus (RSV)-related hospitalization rate, hospital length of stay (LOS), and need for assisted ventilation in children aged <2 years with Down syndrome and those without Down syndrome.

Study design

MEDLINE, Embase, and CINAHL databases were searched from inception up to December 2017. Studies that provided data on RSV-related hospitalization in children aged <2 years with Down syndrome and those without Down syndrome were included. Data were independently extracted in pairs by 2 reviewers and synthesized with random-effects meta-analysis.

Results

In 10 studies including a total of 1 748 209 children, 12.6% of the children with Down syndrome (491 of 3882) were hospitalized with RSV infection. The presence of Down syndrome was associated with a significantly higher risk of RSV-related hospitalization (relative risk [RR], 6.06; 95% CI, 4.93-7.45; I² = 65%; Grading of Recommendations, Assessment, Development and Evaluation [GRADE], moderate). RSV-related LOS (mean difference, 2.11 days; 95% CI, 1.47-2.75 days; I² = 0%; GRADE, low), and the need for assisted ventilation (RR, 5.82; 95% CI, 1.81-18.69; I² = 84%; GRADE, low). Children with Down syndrome without congenital heart disease (RR, 6.31; 95% CI, 4.83-8.23; GRADE, moderate) also had a significantly higher risk of RSV-related hospitalization. The risk of RSV-related hospitalization remained significant in the subgroup of children aged <1 year (RR, 6.25; 95% CI, 4.71-8.28; GRADE, high).

Conclusion

RSV-related hospitalization, hospital LOS, and the need for assisted ventilation are significantly higher in children with Down syndrome aged <2 years compared with those without Down syndrome. The results should prompt reconsideration of the need for routine RSV prophylaxis in children with Down syndrome up to 2 years of age.

Section snippets

Methods

The study protocol was registered with the PROSPERO database (CRD42017083527) (Supplement; available at www.jpeds.com).

Results

A total of 426 potentially relevant articles were identified, 22 of which were excluded after full text screening (Table II; available at www.jpeds.com). Eleven studies including a total of 1 748 277 children met the study criteria and were included in our quantitative analysis.^19-29 The PRISMA study selection flow diagram is shown in Figure 1.

Discussion

In this systematic review involving 1 748 277 children, children with Down syndrome were found to have a significantly higher risk of RSV-related hospitalization (GRADE, moderate) and a significantly longer LOS (GRADE, low) and need for assisted ventilation (GRADE, low) compared with children without Down syndrome. On sensitivity analysis, the results for RSV-related hospitalization remained significant even after excluding studies with probable use of RSV immunoprophylaxis (GRADE, moderate)

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Cited by (19)

Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome
2022, Immunity
Citation Excerpt :
Despite this initial protection, there is extensive evidence that, once infected, patients with DS are more likely to progress to severe disease, including pneumonia (OR: 4.13–6.60), in particular viral pneumonia, acute respiratory distress syndrome, and sepsis (Bruijn et al., 2007; Uppal et al., 2015; Santoro et al., 2021; Fitzpatrick et al., 2022). Increased rates of hospitalization have been documented for IAV, respiratory syncytial virus (RSV), and severe acute respiratory syndrome (SARS) due to coronavirus 2 (SARS-CoV-2) infections (Pérez-Padilla et al., 2010; Mitra et al., 2018; Malle et al., 2020, 2021). Infection-related mortality accounts for 20%–40% of deaths in people with DS, compared to ∼4.5% in the general population before the COVID-19 pandemic (Bcheraoui et al., 2018; O’Leary et al., 2018).
Down syndrome (DS) is typically caused by triplication of chromosome 21. Phenotypically, DS presents with developmental, neurocognitive, and immune features. Epidemiologically, individuals with DS have less frequent viral infection, but when present, these infections lead to more severe disease. The potent antiviral cytokine type I Interferon (IFN-I) receptor subunits IFNAR1 and IFNAR2 are located on chromosome 21. While increased IFNAR1/2 expression initially caused hypersensitivity to IFN-I, it triggered excessive negative feedback. This led to a hypo-response to subsequent IFN-I stimuli and an ensuing viral susceptibility in DS compared to control cells. Upregulation of IFNAR2 expression phenocopied the DS IFN-I dynamics independent of trisomy 21. CD14⁺ monocytes from individuals with DS exhibited markers of prior IFN-I exposure and had muted responsiveness to ex vivo IFN-I stimulation. Our findings unveil oscillations of hyper- and hypo-response to IFN-I in DS, predisposing individuals to both lower incidence of viral disease and increased infection-related morbidity and mortality.
The impact of obstructive sleep apnea on bronchiolitis severity in children with Down syndrome
2021, Sleep Medicine
Citation Excerpt :
It is speculated that the increased risk of hospitalization, and length of stay (LOS) among children with DS and acute bronchiolitis is mediated by its neuromuscular or cardiopulmonary comorbidities [13–15]. However, little is known about the impact of OSA on the outcomes of hospitalized children with DS and acute bronchiolitis [16–18], and whether this impact is independent of DS-associated comorbidities. We, therefore, analyzed the Kids’ Inpatient Database to investigate the independent effects of OSA on outcomes of children with and without DS hospitalized for acute bronchiolitis.
Acute bronchiolitis commonly causes respiratory failure in children ≤2 years, and is particularly severe in those with Down syndrome (DS). Obstructive sleep apnea (OSA), common in DS, is also associated with respiratory complications. However, it is unknown whether OSA is associated with worse outcomes in children with and without DS, hospitalized with bronchiolitis. We hypothesized that in children with bronchiolitis, OSA is associated with worse outcomes in those with DS, independent of DS-related comorbidities.
Hospital discharge records of children with bronchiolitis aged ≤2 years were obtained for 1997–2012 from the Kid's Inpatient Database. The primary outcome was invasive mechanical ventilation (IMV), and secondary outcomes were non-invasive mechanical ventilation (NIMV), length of hospital stay, and inflation-adjusted cost of hospitalization (IACH). Multivariable regression was conducted to ascertain the associations between OSA and primary and secondary outcomes accounting for DS-associated comorbidities.
There were 928,961 hospitalizations for bronchiolitis. The DS group with bronchiolitis (n = 8697) was more likely to have OSA [241 (2.77%) vs 1293 (0.14%), p < 0.001] compared to the non-DS group (n = 920,264). Multivariable logistic regression showed that OSA was associated with IMV (adjusted odds ratio [OR], 3.32 [95% CI 2.54–4.35], p < 0.0001) in all children with bronchiolitis; and in those with DS, it was associated with IMV (adjusted OR, 2.34 [95% CI 1.38–3.97], p = 0.002), NIMV (adjusted OR, 8.21 [95% CI 4.48–15.04], p < 0.0001) and IACH (adjusted β, 0.18 [95% CI 0.02–0.34], p = 0.031).
OSA is independently associated with assisted ventilation in all children hospitalized with bronchiolitis, regardless of DS-associated comorbidities in those with DS. The severity of bronchiolitis in children with DS may be driven by the high prevalence of OSA.
Children less than 2 with Down syndrome and suffering from respiratory syncytial virus have a longer and more costly hospitalization
2019, Journal of Pediatrics
A Multimodal Imaging-Supported Down Syndrome Mouse Model of RSV Infection
2023, Viruses
Clinical characteristics and comorbidities of COVID-19 in unvaccinated patients with Down syndrome: first year report in Brazil
2022, Human Genetics
Reappraisal of the Subtropical Guidelines on Palivizumab Prophylaxis in Congenital Heart Disease
2022, Frontiers in Pediatrics

View all citing articles on Scopus

: B.P. has served as an advisor and lecturer and has received research funding and compensation from AbbVie Corporation. The other authors declare no conflicts of interest.

: Portions of this study were presented at the Pediatric Academic Societies annual meeting, Toronto, May 5-8, 2018, and at the Canadian Paediatric Society meeting, Quebec City, May 30-June 2, 2018.

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Original ArticlesHospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age: A Systematic Review and Meta-Analysis

Objectives

Study design

Results

Conclusion

Section snippets

Methods

Results

Discussion

Lancet

J Infect Chemother

J Clin Epidemiol

Control Clin Trials

J Clin Epidemiol

An Pediatr (Barc)

J Pediatr

J Pediatr

Paediatr Respir Rev

Microbes Infect

Early Hum Dev

Defining the epidemiology and burden of severe respiratory syncytial virus infection among infants and children in Western countries

Infect Dis Ther

Defining the risk and associated morbidity and mortality of severe respiratory syncytial virus infection among preterm infants without chronic lung disease or congenital heart disease

Infect Dis Ther

Defining the risk and associated morbidity and mortality of severe respiratory syncytial virus infection among infants with chronic lung disease

Infect Dis Ther

Defining the risk and associated morbidity and mortality of severe respiratory syncytial virus infection among infants with congenital heart disease

Infect Dis Ther

Preventing hospitalizations for respiratory syncytial virus infection

Paediatr Child Health

Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection

Pediatrics

Defining the incidence and associated morbidity and mortality of severe respiratory syncytial virus infection among children with chronic diseases

Infect Dis Ther

The burden of respiratory syncytial virus (RSV) associated acute lower respiratory infections in children with Down syndrome: a systematic review and meta–analysis

J Glob Health

Quantifying heterogeneity in a meta-analysis

Stat Med

Measuring inconsistency in meta-analyses

BMJ

Cochrane handbook for systematic reviews of interventions version 5.1.0

Original Articles
Hospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age: A Systematic Review and Meta-Analysis