1196 SECTION XI Pediatric Critical Care Immunity and Infection as HMGB 1, into the circulation and activates an innate immune response 34 In the ICU, this is often seen postsurgery, especially after c[.]
1196 S E C T I O N X I Pediatric Critical Care: Immunity and Infection as HMGB-1, into the circulation and activates an innate immune response.34 In the ICU, this is often seen postsurgery, especially after cardiopulmonary bypass during cardiac surgery TLR2 and TLR4 both increase their expression on mononuclear cells post–cardiac surgery, which typically occurs over a 48-hour period before returning to baseline There is a concomitant rise in the proinflammatory cytokine IL-6 The response is stronger if there is cerebral ischemia, as occurs during deep hypothermic circulatory arrest.35 Acute kidney injury: The renal tubules are exposed to large numbers of signaling molecules and cytokines; therefore, they are prime candidates for danger recognition For example, kidney epithelial cells express CD40 receptors on their cell surface—activation of CD40 leads to an increase in ROS production and prevents apoptosis of the tubular cells The pathway activates a proinflammatory response, with production and release of inflammatory cytokines This is a common pathway of organ crosstalk in the ICU: injury to one organ may result in a multiorgan effect An overwhelming or dysregulated immune response locally within one organ, such as the lung in ARDS, can lead to multiorgan failure as large concentrations of inflammatory cytokines are sensed by distant organs Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH): These diseases represent a broad spectrum, ranging from familial varieties with recognized genetic mutations to those associated with rheumatologic inflammatory conditions This is an example of a dysregulated immune response Ineffective cytotoxic activity of NK cells means an inability to effectively neutralize a threat such as a viral infection This is a deficiency of the major “immune off-switch” of induced apoptosis of virally infected cells and results in a persistence of immune activation The result is proliferation of phagocytes and a flood of proinflammatory cytokines, leading to a destructive systemic inflammatory state Therapeutic Targets of the Innate Immune System Given the ubiquity of innate immune system activity, often to the detriment of the intensive care patient, it should offer several effective therapeutic targets Sadly, although many magic bullet solutions have been sought, such as APC and BPI, none have been found to be effective The reasons for this are complex, but two possible reasons are immediately apparent: (1) evolution has furnished the innate immune system with a high degree of redundancy in order to be fail-safe Therefore, targeting one component of the signal or response may be mitigated by a separate arm of the pathway (2) The immune response is a juxtaposition of two opposing forces: a proinflammatory response to a threat followed by a regulatory antiinflammatory restitution to baseline Both are necessary, but both can become maladaptive Therefore, any therapeutic measures need to target the maladaptive process specifically Attaining this level of specificity against the proinflammatory or antiinflammatory arm without disrupting the other is difficult Instead, the treatment may have to be adjusted according to the inflammatory profile at the time Attention has now been diverted to accurate profiling of the inflammatory response using genomic, transcriptomic, proteomic, and metabolomic biomarkers Therapeutic Questions Arising from the Innate Immune System The innate immune system is relevant to many interventions in the ICU Many molecules central in (superficially) nonimmune physiologic processes play a role in the immune response Can oxygen be harmful? Matching oxygen delivery to consumption is the foremost physiologic aim in the ICU Measuring oxygen consumption with any degree of accuracy is difficult clinically Oxygen delivery is estimated and guided by surrogate markers such as lactate and central venous saturations Hypoxia is harmful and can initiate an immune response through HIF activation In an attempt to avoid hypoxia, there is a tendency to err toward hyperoxia However, it is emerging that hyperoxia can similarly cause harm by increases in ROS production, tipping the balance to damage Indeed, it is increasingly recognized that the oxygen cascade has evolved to closely regulate the levels of oxygen to which mitochondria are exposed—both hypoxia and hyperoxia can cause harm through ROS generation In the mouse lung model, hyperoxia leads to ROS-mediated DNA damage, inflammation, and loss of barrier integrity Hyperoxia also affects the function of pulmonary macrophages, impairing their ability to kill pathogens.36 This effect, likely mediated by HMGB-1 pathways, is important given the risk of ventilator-associated pneumonia in the ICU Hyperoxia also seems to have longerterm effects; experienced in the neonatal period, it can alter the ability to fight influenza A in adult mice, thought to be mediated by both changes in epithelial cell PRRs and programming of hematopoietic cells.37 Clinically, hyperoxia has been associated with poor outcomes Liberal oxygen therapy is associated with adverse outcomes in acutely unwell patients.38 It is hypothesized that liberal administration of oxygen to cells that are already adapted to a period of hypoxia may accelerate cellular damage Therefore, careful attention needs to be paid to oxygen use in the ICU Randomized controlled trials are currently awaited to identify the optimal oxygen level in different phenotypes (e.g., as in preterm neonates).39 Is nutrition always beneficial? Critical illness is a catabolic state with an increase in energy utilization This has traditionally been believed to be due to the increase in metabolic activity to mount an immune and inflammatory response This may be an oversimplification, however Recent thinking suggests that there is an active switch from aerobic respiration to aerobic glycolysis This is known as the Warburg effect, first described in cancer cells The driver for such a switch in cancer cells is initial hypoxia, activating HIFs, which inhibit pyruvate dehydrogenase The effect of such a metabolic switch is to prevent cellular apoptosis (due to loss of mitochondrial membrane potential and mitophagy) and increase cell proliferation In sepsis, the Warburg effect is seen in monocytes and macrophages in order to proliferate and mount an effective response The use of glycolysis for energy production requires a large amount of glucose; therefore, glucose uptake and protein and lipid breakdown are upregulated Traditionally, intensive care physicians have attempted to provide nutrition to match this energy-hungry catabolic state Studies of early parenteral nutrition to meet estimated nutritional versus withholding parenteral nutrition in the first week have suggested that the overall mortality in both groups was the same, although those with no supplementation had fewer CHAPTER 100 Innate Immunity infections in the ICU.40 The mechanism for this effect is contested: one hypothesis is that the increase in nutrition leads to impaired autophagy and therefore inefficient cellular metabolism and DAMP production Neutrophils exposed to parenteral lipids show impaired ability to eliminate pneumococci.41 In contrast, enteral nutrition may have a beneficial effect on the innate immune response through the effect of enteral nutrition on intestinal integrity and the gut microbiome The microbiome has a protective effect on gut integrity However, specific nutritive interventions have not necessarily had the magnitude of effect expected: probiotics have been shown to be effective in the treatment of Clostridium difficile infections but have not had a significant effect in overall critical illness outcomes.42 In neonates, the gut microbiome is least poorly established Metaanalysis evidence points to a survival benefit with probiotic treatment in preterm necrotizing enterocolitis.43 Compared with the nutritional addition of probiotics, manipulation of the microbiome using selective digestive tract decontamination (SDD) shows reasonable promise: goodquality evidence points to the effects of SDD in reducing hospital-acquired infections in the ICU.44 The microbiome has only recently been recognized as a major influence on how our immune system functions Crosstalk between the mucosal microbiome (not only limited to the gut but also skin and lung) and epithelial and immune cells maintains a symbiotic relationship between the carefully controlled microbiome and mucosal barrier This not only prevents pathogen invasion but has far reaching effects in health and disease, including responses to sepsis, obesity, carcinogenesis, and aging (Fig 100.5).45 Should catecholamine use be limited? Catecholamines, as described, have effects on the immune system while also promoting pathogen proliferation and virulence Catecholamines are Crosstalk between epithelial cells and microbiome through TLR-dependent recognition • Maintains epithelial barrier • Influences the composition of the microbiome • Prevents pathogen invasion • Suppresses proinflammatory responses • Coordinates endocrine function (of the gut) Maturation of the recently discovered ILCs depends on signalling from the microbiome ILCs are key to IL-22 production which maintains barrier integrity ILCs are also involved in enteral tolerance, barrier inflammation, and antigen presentation systemically 1197 necessary in the intensive care armory, now more so given the recent doubts cast over the association between fluid resuscitation and mortality in sepsis The risks and benefits of using catecholamines have not been directly demonstrated, but there is enough supportive evidence for their use However, whether catecholamine use needs to be better tailored to the individual immune profile is yet to be determined Catecholamines have wide-ranging effects: hemodynamic, metabolic, and endocrine in addition to the immune effects Teasing out the beneficial and detrimental effects of each property will be challenging For now, catecholamine use must be supported, but use should be titrated to effect closely, being mindful of the immunosuppressive and pathogen-promoting effects of catecholamines.29 Should fever be treated? Despite the conservation of fever as an immune response across a wide range of species evolution, we are yet to be convinced that it has a beneficial role in overcoming danger Preventing fever in most animal classes seems to increase mortality In humans, fever reduces time to recovery in varicella infections, reduces rhinovirus shedding, and increases malaria parasite clearance Concern exists in critically ill patients regarding the energy expenditure needed to produce a fever and the hemodynamic effects, such as tachycardia and hemodynamic changes Observational studies in the intensive care environment have challenged this concern A retrospective review of more than 600,000 patients admitted to the ICU demonstrated that a peak temperature above 39°C in patients admitted with infective illness has a reduced risk of mortality.13 This points to a beneficial effect of fever in critical illness, particularly in those with infection This is likely to be mediated by neutrophils: the neutropenic subpopulation in the first study did not show the beneficial effect of fever Fever increases both ROS and nitric oxide species production by neutrophils; this may be a potential mechanistic explanation.46 Microbiome metabolites such as short chain fatty acid PRR activation and signalling also drives myelopoieisis myeloid cell differentiation Microbiome delivered TLR signalling promotes the maturation and aging of neutrophils Microbiome metabolites (e.g., shortchain fatty acids) also affect the migration and activation of tissue-specific immune cells, • Fig 100.5 Interactions between the microbiome and cells of the innate immune system The microbi- ome is recognized by pattern recognition receptors (PRRs) mostly on the epithelial surface, which leads to a cascade of intracellular reactions Microbiome particles and metabolites also interact directly and indirectly with lymphoid (primarily innate lymphoid cells [ILCs]) and myeloid cells such as neutrophils below the epithelial surface, influencing their maturation and function ILCs, in particular, interact with other immune cells to prime immune responses and develop tolerance The overall effect is to maintain microbiome composition and mucosal barrier function while aiding immune maturation and function These have potentially far reaching impacts on health, such as susceptibility to sepsis, carcinogenesis, obesity, inflammation, and degenerative processes (e.g., atherosclerosis) TLR, Toll-like receptor 1198 S E C T I O N X I Pediatric Critical Care: Immunity and Infection Alternatively, the interventions to reduce temperature may be detrimental To further explore this, a large multicenter trial compared paracetamol versus placebo treatment of fever No differences were seen between the two groups, although the temperature profiles for both groups were similar both before and after treatment.47 Does sedation just reduce metabolic demand? So far, we have not mentioned the role that sedation may play on the immune system despite the widespread use of sedation in the ICU However, while sedation may be thought of as beneficial, in order to reduce metabolic demand in critical illness, the innate immune system does not escape its effects Epidemiologically, chronic intravenous opiate abusers have been observed to present with a high number of infections Macrophages and neutrophils have been known to have m-opioid receptors Morphine reduces macrophage recruitment, phagocytosis, and the respiratory burst in vivo In mice, this leads to reduced bacterial clearance, an effect that was abolished in m-opioid receptor knockout mice and by naltrexone In addition, there is a suppression of chemokine production following morphine exposure through suppression of NF-kB Similarly, neutrophil recruitment is also suppressed by opioids, although there may be a differential effect of exogenous (suppressing chemotaxis) and endogenous (promoting chemotaxis) opioids Acute morphine treatment has been shown to delay wound healing in laboratory models However, currently there is no trial evidence in humans to suggest that opioids delay recovery in intensive care patients Benzodiazepines are commonly used as sedative agents in the pediatric ICU Peripheral (non-g-aminobutyric acid) binding sites for benzodiazepines are present on immune cells, including macrophages and neutrophils Neutrophil chemotaxis can be inhibited in vitro by benzodiazepines NF-kB activation is reduced by midazolam in macrophages, with a suppression of proinflammatory cytokines such as TNF-a Furthermore, lipopolysaccharideinduced superoxide production is inhibited by benzodiazepines in neutrophils and macrophages in vitro, affecting successful cytotoxic activity Induced nitric oxide and cyclooxygenase activity is also reduced by benzodiazepines In animal models of pneumonia, benzodiazepine treatment increases mortality Sedative centrally acting a2-agonists, clonidine and dexmedetomidine, not affect human neutrophil chemotaxis, phagocytosis, or superoxide production in vitro In animal models of sepsis, pretreatment (i.e., before the induction of sepsis) with clonidine reduces NF-kB activation and cytokine production (as benzodiazepines) but reduces mortality by dampening the systemic inflammatory response.48,49 Clinical studies suggest that dexmedetomidine can lead to decreased IL-6 and TNF-a release, although it is associated with higher levels of superoxide dismutase activity following surgery Why benzodiazepines and a2-agonists have different effects on animal models of infection even though cytokine production is reduced by both? The differences may be more subtle than cytokine production—both agents have receptors on a variety of cell types and therefore have widespread actions However, the effects of sedatives, as with any modulators of the immune response, may depend on the exact immune profile at any given time (e.g., the balance of proinflammatory and antiinflammatory cytokines that lead to the immune phenotype) In the subgroup analysis of a trial comparing lorazepam-based sedation against dexmedetomidine, those sedated with dexmedetomidine were less likely to die or have brain dysfunction This effect was more pronounced in the context of sepsis Although this adds to the speculation that a2-agonists may have immune-favorable effects in critical illness, further mechanistic work with better phenotypic categorization is needed to prove this Conclusion The innate immune system is the first line of defense against danger, both endogenous and exogenous The pathways are complex, involving a large number of redundant processes and several orders of interactions between pathways and systems Many molecules and cells involved in the innate immune system also have nonimmune functions Therefore, the innate immune system should be thought of as not only a dedicated police force but also a neighborhood watch scheme This has particular relevance in the ICU, as many of our interventions can affect the innate immune function Thus, while we are yet to harness our knowledge of the innate immune system to develop new therapies, there is probably more scope to better use existing therapies so as to not jeopardize the protective benefits of the innate immune response Key References Bianchi ME DAMPs, PAMPs and alarmins: all we need to know about danger J Leukoc Biol 2007;81:1-5 Chu DK, Kim LH, Young PJ, et al Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis Lancet 2018; 391(10131):1693-1705 Eltzschig HK, Carmeliet P Hypoxia and inflammation N Engl J Med 2011;364:656-665 Evans SS, Repasky EA, Fisher DT Fever and the thermal regulation of immunity: the immune system feels the heat Nat Rev Immunol 2015;15:335-349 Fivez T, Kerklaan D, Mesotten D, et al Early versus late parenteral nutrition in critically ill children N Engl J Med 2016;374(12):1111-1122 Hartemink KJ, Groeneveld AB Vasopressors and inotropes in the treatment of human septic shock: effect on innate immunity? 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