Infants with Down syndrome and congenital heart disease have altered peri-operative immune responses

Abstract

Background Infants with Down syndrome (DS) have an altered immune response. We aimed to characterise the inflammatory response in infants with DS and congenital heart disease (CHD) peri-operatively in comparison to infants with CHD and a normal chromosomal complement, and to healthy infants pre-operatively. Methods Infants with DS/CHD, infants without DS but with CHD (CHD only) and healthy infants were prospectively recruited and serial serum cytokines evaluated peri-operatively using multiplex ELISA: tumour necrosis factor (TNF)-α and TNF-β; interferon (IFN)-γ, interleukin (IL)-1α, IL-2, IL-6, IL-8, IL-18, IL-1β, IL-10, and IL-1ra; vascular endothelial growth factor (VEGF); granulocyte macrophage colony-stimulating factor (GM-CSF); and erythropoietin (EPO). Results Ninety-four infants were recruited including age-matched controls (n = 10), DS/CHD (n = 55), and CHD only (n = 29). Children with DS/CHD had significantly lower concentrations of several cytokines (IL-10, IL-6, IL-8, IL-1β, VEGF) in the pre- and post-operatively vs CHD only and controls. EPO and GM-CSF were significantly higher in DS/CHD (p value <0.05). Conclusions Children with DS/CHD had significantly lower concentrations of several cytokines compared to controls or children with CHD only. EPO and GM-CSF were significantly higher in children with DS/CHD. The assessment of the immune response may be suitable for the predictable clinical outcomes in these children. Impact This study demonstrated that children with Down syndrome (DS) and congenital heart disease (CHD) have significant alterations in pro-inflammatory and anti-inflammatory immune responses peri-operatively. These changes may contribute to adverse clinical outcomes, including sepsis, chylothorax, and autoimmunity. They may impact the pathogenesis and outcome post-operatively and long term in this population. Children with DS and CHD have significantly lower cytokine concentrations, increased EPO and GM-CSF, and decreased VEGF pre- and post-operatively. Assessing their inflammatory state peri-operatively may facilitate the development of a predictive model that can inform tailored management of these infants using novel therapies including immunomodulation.

Epigenomic signature of major congenital heart defects in newborns with Down syndrome

“…Increased nRBC counts are thought to follow fetal hypoxemia through elevated erythropoietin (EPO), a hormone that stimulates production of erythrocytes (red blood cells) in an effort to increase oxygen delivery to tissues [ 59 , 60 ]. Interestingly, EPO is higher in children with DS-CHD compared to non-syndromic CHD [ 61 ]. Because CHDs reduce cerebral oxygen [ 62 ] and may induce fetal hypoxemia [ 63 ], high nRBC proportions may be more common in individuals with CHDs and, in particular, in DS newborns with CHDs given the placental abnormalities seen in fetuses with trisomy 21 (PMID: 31683073).…”

In reply: Additional Insights into the REPLICA-PH study

“…Finally, we wish to humbly register our counterpoint in reference to Dr Karamsi’s concerns about excluding the multisystem syndromic cohort from our analysis [ 1 ] . Adequately supporting our choice of a homogeneous non-syndromic surgical subset, Zakharchenko et al’s [ 5 ] prospective observational study quite recently outlines considerable alterations in the perioperative pro-inflammatory and anti-inflammatory immune responses mounted by CHD infants with Down syndrome as opposed to those with a normal chromosomal complement [ 2 ] .…”

Biomarker response to infant cardiac surgery: A curious tale of inflammation!

“…4 The authors simultaneously ought to have clarified if the syndromic subset was formally excluded from their analysis or not, more so when altered perioperative immune responses happen to be outlined for the infants with Down syndrome undergoing congenital cardiac surgery. 1,5 Of further note, Thorlacius et al declare that they did not consider the study drugs while sub-analyzing the patient population, the infants had received either milrinone or levosimendan in the MiLe-1 trial. 1 However, we wish to humbly opine that the corresponding agents should have also been accounted for the vasoactive drug computation in the study, given their concomitant inotropic and vasodilator effects.…”