The burden of infection and immune dysregulation in infants with CHD

Over 1 million infants worldwide are born each year with CHD and receive cardiopulmonary bypass for surgical correction. ^{Reference Zimmerman, Smith and Sable1} The burden of infection is high in these children, including before surgery. In the developed world, a substantial portion of children with CHD is hospitalised with lower respiratory tract infections and bacteraemia preoperatively, with a significantly elevated risk of mortality. ^{Reference MacDonald, Hall, Suffin, Alexson, Harris and Manning2} Children with CHD are also susceptible to acquisition of and death from infections postoperatively. ^{Reference Wheeler and Wong3} Infection risk is concentrated in infants, with 8–9% of infants under 6 months experiencing a serious postoperative infection. ^{Reference Kansy, Jacobs and Pastuszko4} The increased risk of infection in children with CHD is multifactorial and incompletely understood. Many children with CHD have genetic syndromes that affect immune function. ^{Reference Pierpont, Brueckner and Chung5} In children without known syndromes, neutrophil functional capacity is altered ^{Reference Parikh, Bharucha, Kandar and Kshirsagar6} and T-cell maturation is delayed, with greater delays in maturation associated with increased hospitalisation for infection. ^{Reference Davey, Elder and Cloutier7}

Immune paralysis is depletion and decreased function of immune cells in both the innate and adaptive immune systems. ^{Reference Mithal, Arshad, Swigart, Khanolkar, Ahmed and Coates8,Reference Hall, Greathouse, Thakkar, Sribnick and Muszynski9} Cardiopulmonary bypass and cardiac surgery are significant inflammatory insults with significant immune activation ^{Reference Bronicki and Hall10,Reference Tárnok and Schneider11} and subsequent immune paralysis. ^{Reference Tárnok and Schneider11} Children with immune paralysis after cardiac surgery have an increased risk of postoperative infection and death. ^{Reference Cornell, Sun and Hall12}

Infant development of the intestinal microbiome and its role in immune function

The intestinal microbiome plays a central role in development and maintenance of immune function. ^{Reference Thaiss, Zmora, Levy and Elinav13} In healthy infants, the gut microbiome is established at birth. Over the first two years of life, the composition of the intestinal microbiome is dynamic, ^{Reference Bäckhed, Roswall and Peng14} and stabilises in early childhood. ^{Reference Ronan, Yeasin and Claud15} The microorganisms that eventually colonise the intestine have diverse immunologic effects. These effects are mediated by production of small molecule metabolites with distant effects and direct stimulation of immune effector cells by microorganisms. ^{Reference Kim16,Reference Zhang, Zhang, Liao, Zhang and Tang17} While the composition of the microbiome is variable between individuals, there is a core set of immunologic functions that are typically maintained by diverse bacteria in different individuals. ^{Reference Bäckhed, Roswall and Peng14}

The intestinal microbiome and the immune system develop concurrently in infants, with the microbiome promoting maturation of the immune system and the immune system altering the microbiome. ^{Reference Zhang, Zhang, Liao, Zhang and Tang17} Short-chain fatty acids produced by bacteria in the large intestine, particularly butyrate, maintain epithelial barrier function ^{Reference Kelly, Zheng and Campbell18} and directly stimulate immune effector cells. ^{Reference Nastasi, Candela and Bonefeld19} Butyrate-producing anaerobes also protect against intestinal overgrowth of pathogenic microorganisms by altering the microenvironment. ^{Reference Byndloss, Olsan and Rivera-Chávez20} Intestinal microorganisms exist in a symbiotic balance with the immune system. In neonates, local differentiation and adaptation of T cells are dependent on microbial by-products and microbial ligand-T cell interaction. ^{Reference Constantinides, Link and Tamoutounour21–Reference Ansaldo, Farley and Belkaid23} In infants, normal immune development is characterised by an initial monocyte expansion, followed by a gradual increase in memory regulatory T cells (Tregs) and subsequent T cell expansion. ^{Reference Henrick, Rodriguez and Lakshmikanth24} This cycle of immune activation and tolerance is partially modulated by bacteria in the Bifidobacterium genera, commensal anaerobes that dominate the microbiome in most breastfed infants. ^{Reference Henrick, Rodriguez and Lakshmikanth24} Infants without Bifidobacterium have increased pro-inflammatory cytokines and immune cell populations and immune dysregulation. ^{Reference Henrick, Rodriguez and Lakshmikanth24} Other microbes promote the normal maturation of both innate and adaptive immunity through interactions with immature T cells, including bacteria from the Bacteroides, Enterobacterales, Proteus, and Klebsiella orders. ^{Reference Ansaldo, Farley and Belkaid25} Many other interactions between the developing immune system and the microbiota are similarly important.

Clinical data demonstrating the relationship between the intestinal microbiome and immune dysregulation in other disease states

Data from patients with cancer and inflammatory bowel disease suggest the therapeutic role of microbiome manipulation in diseases of immune dysregulation. In adults with melanoma, response to immune checkpoint-inhibitor immunotherapy is dependent on composition of the intestinal microbiome, ^{Reference Matson, Fessler and Bao26} and dietary interventions ^{Reference Spencer, McQuade and Gopalakrishnan27} and faecal microbiota transplants ^{Reference Baruch, Youngster and Ben-Betzalel28} change individual responsiveness to immunotherapy. Similarly, faecal microbiota transplants can induce remission in children with ulcerative colitis. ^{Reference Pai, Popov and Hill29} In critically ill adults with sepsis, body temperature trajectory, a marker of immune activation, predicts mortality, and temperature trajectory is determined by the composition of the intestinal microbiome. ^{Reference Bongers, Chanderraj and Woods30} The use of selective decontamination of the digestive tract (enteral administration of antibiotics without anti-anaerobic activity and targeted towards pathogenic and resistant organisms) in mechanically ventilated adults has also been associated with a reduction in mortality, positive blood cultures, and antimicrobial-resistant organisms. ^{Reference Boschert and Broadfield31}

Data suggesting a link between composition of the intestinal microbiome and outcomes in infants after cardiopulmonary bypass

A small placebo-controlled pilot study ^{Reference Umenai, Shime, Asahara, Nomoto and Itoi32} demonstrated safety and feasibility of preoperative administration of probiotics (Bifidobacterium breve) to 21 neonates undergoing planned cardiac surgery. While the study was not powered to detect clinical outcomes, there was a trend towards reduced length of stay and time to goal feeds in the intervention group. A randomised controlled trial ^{Reference Dilli, Aydin, Zenciroglu, Özyazici, Beken and Okumus33} administered a synbiotic (Bifidobacterium lactis plus inulin) to infants with cyanotic CHD preoperatively. In this single-centre trial, patients who received the synbiotic had decreased mortality, feeding intolerance, necrotising enterocolitis, sepsis, and duration of total parenteral nutrition. Infants with CHD have a substantially different microbiome than infants without CHD. ^{Reference Salomon, Ericsson and Price34,Reference Liu, Lu, Shao, Zhang, Tu and Chen35} This is particularly pronounced in those with cyanotic defects ^{Reference Liu, Lu, Shao, Zhang, Tu and Chen35} or critical defects requiring repair in the first month of life due to prolonged hypoxia and variable haemodynamics with altered blood flow to the intestine. ^{Reference Huang, Lu and Zeng36}

Multiple trials have reported association between intestinal epithelial barrier dysfunction ^{Reference Salomon, Ericsson and Price34} , metabolomic derangements ^{Reference Simonato, Fochi and Vedovelli37–Reference Davidson, Pfeifer and Frank39} , and altered microbiome composition in infants after cardiac surgery. Epithelial barrier dysfunction is a frequent complication of cardiopulmonary bypass ^{Reference Salomon, Ericsson and Price34,Reference Pathan, Burmester and Adamovic40} and is associated with endotoxemia, changes in the intestinal microbiome, increased inflammation, and prolonged ICU length of stay. ^{Reference Pathan, Burmester and Adamovic40} Besides dysregulation in short-chain fatty acid production, there are multiple metabolic pathways that are deranged in infants after cardiopulmonary bypass and predict mortality and ICU length of stay. ^{Reference Davidson, Pfeifer and Frank39}

Objectives of the scoping review

There are significant data about the relationship between the microbiome and immune dysregulation in many disease states, including critically ill patients. Additionally, there are known substantial functional changes in the microbiome in children with CHD after cardiopulmonary bypass. Given the frequent immune dysregulation and high risk of secondary infection in these children, we performed a comprehensive scoping review of the existing data on the relationship between microbiome composition and immune function in infants with CHD after cardiopulmonary bypass. We included studies of infants with CHD with any measure of intestinal microbiome composition and immune function. We followed the guidelines set forth in the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews. ^{Reference Tricco, Lillie and Zarin41}