1294 SECTION XI Pediatric Critical Care Immunity and Infection mortality, and healthcare costs Nevertheless, there is an ongoing need for quality epidemiologic studies of sepsis in children Qual ity e[.]
1294 S E C T I O N X I Pediatric Critical Care: Immunity and Infection incidence of 42,371 cases of severe sepsis in individuals younger than 20 years of age (0.6 cases/1000 population) The highest incidence was in neonates (5.2 cases/1000 population), compared with children ages to 14 years, who had an incidence of 0.2 cases/1000 population The overall mortality rate in this population was 10.3% (4364 deaths/year nationally) In addition, patients younger than year of age and patients with comorbidities had higher mortality rates than patients between and 14 years old and patients without comorbidities, respectively Their study also estimated an annual national healthcare cost of $1.7 billion associated with severe sepsis In a follow-up study, these investigators used a similar approach to investigate severe sepsis trends in the United States from 1995 to 2005.3 They reported an overall decrease in the case-fatality rate over this period, from 10.3% to 8.9%, but an overall increase in the prevalence of severe sepsis Most of this increase was accounted for by an increase in the prevalence of severe sepsis in newborns Czaja and colleagues used the discharge diagnosis of severe sepsis for Washington State to investigate the readmission rates and late mortality for children (1 month to 18 years old) following severe sepsis.4 From 1990 through 2004, 7183 children were diagnosed with severe sepsis and 6.8% of these patients died during the sentinel admission or within 28 days of discharge Importantly, death certificates confirmed that an additional 434 (6.5%) of the initial survivors died during the follow-up period, with the highest late death rate occurring within years of the initial hospitalization Although most of the early and the late deaths occurred in children with comorbidities (8% early death, 10.4% late death), 8% of children with no comorbidities died during their initial hospitalization, with 2% of the 28-day survivors being classified as late deaths Schlapbach and colleagues recently reported on the epidemiology of invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand.5 The age-standardized incidence increased every year, from 2002 to 2013, for all three study categories Critically ill children with invasive infections, sepsis, or septic shock accounted for 26% of all pediatric deaths among all of the critically ill children in this cohort Comparing 2008 to 2013 to 2002 to 2007, risk-adjusted mortality significantly decreased for invasive infections and sepsis but not for septic shock In 2015, Weiss and colleagues published the first international prospective epidemiologic study of pediatric severe sepsis.6 Almost 7000 patients younger than 18 years were screened on days from 2013 to 2014 at 128 sites from 26 countries using a point prevalence study method Severe sepsis was defined using the 2005 International Pediatric Sepsis Consensus Conference criteria.7 This large, comprehensive study demonstrated an 8.2% prevalence of pediatric severe sepsis in international pediatric ICUs (95% confidence interval [CI], 7.6%–8.9%), consistent with adult epidemiologic data Hospital mortality was 25% regardless of age or country Multiorgan dysfunction was demonstrated in 67% of patients at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction The higher mortality rate for severe sepsis reported in this study, relative to previous studies, might reflect the point prevalence methodology, given that the retrospective use of ICD9 codes is susceptible to underestimating disease severity Thus, this most recent study suggests that mortality from pediatric sepsis can approach that of adults Collectively, these data illustrate that sepsis continues to pre sent a major pediatric public health problem in terms of incidence, mortality, and healthcare costs Nevertheless, there is an ongoing need for quality epidemiologic studies of sepsis in children Quality epidemiologic studies are necessary for our understanding not only of incidence but also of the impact of new knowledge and therapies One major issue that must be addressed is the development of more meaningful and consistent case definitions Consistent case definitions will also facilitate and improve the design of more effective interventional trials specific to the pediatric population Equally important is objectively measuring long-term outcomes in these patients (i.e., quality of life) beyond the dichotomy of “alive” or “dead.” Progress in this important area is steadily coming to fruition.8–12 Definitions Intuitively, experienced pediatric intensivists usually know when they encounter a patient with sepsis Thus, strict definitions of sepsis and septic shock could be viewed as having relatively limited value in daily practice Despite this common perception, there is a clear need for standard definitions of sepsis and septic shock for four primary reasons First, with the development of standard definitions, we will be able to more accurately characterize the epidemiologic features of septic shock in the pediatric population Second, as novel, expensive, and potentially higherrisk therapies are developed, it will be important to accurately identify and stratify patients early in the course of septic shock if we are to apply those therapies to the most appropriate groups and realize a more favorable benefit-to-risk ratio in a given patient population Third, definitions allow for the development of sepsis recognition algorithms for frontline providers Finally, standard definitions are crucial to the design of much needed pediatricspecific interventional trials The International Consensus Conference on Pediatric Sepsis and Organ Dysfunction was convened in 2002 to develop pediatricspecific definitions for SIRS, sepsis, severe sepsis, septic shock, and organ failure The results of this conference were subsequently published in 2005.7 The standard terms to describe the sepsis spectrum are SIRS, sepsis, severe sepsis, and septic shock Each term is intended to describe a clinical syndrome having increasing illness severity and relatively increasing specificity, which, in turn, drives important clinical decision and therapeutic processes SIRS is not a diagnosis The term is intended to represent a state of relative inflammatory/immune activation in a given patient and is said to be present when a patient meets at least two of the four criteria listed in eBox 110.1, one of which must be abnormal temperature or abnormal leukocyte count Thus, patients with diverse clinical conditions—such as sepsis, pancreatitis, burns, or hypermetabolism following major trauma or surgery— can meet criteria for SIRS Sepsis is defined as SIRS secondary to an infection, either documented by microbiology cultures or in the presence of other clinical evidence of infection Severe sepsis is defined by sepsis criteria plus either cardiovascular dysfunction or acute respiratory distress syndrome (ARDS), or at least two other dysfunctional organ systems Septic shock is defined by sepsis criteria, plus cardiovascular dysfunction Importantly, each criterion takes into account the influence of developmental age on physiologic variables The reader is referred to the original publication by Goldstein et al for further details and definitions of organ dysfunction.7 Of note, in 2016, The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) put forth revised definitions of sepsis and septic shock for adult patients.13 They 1294.e1 • eBOX 110.1 Criteria for Systemic Inflammatory Response Syndrome The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count: Core temperature (rectal, bladder, oral, or central catheter) 38.5°C or ,36°C Tachycardia, defined as a mean heart rate standard deviations above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli; or otherwise unexplained persistent elevation over a 0.5- to 4-hour time period; or for children ,1 year: bradycardia, defined as a mean heart rate ,10th percentile for age in the absence of external vagal stimulus, b-blocker drugs, or congenital heart disease; or otherwise unexplained persistent heart rate depression over a 0.5-hour time period Tachypnea, defined as mean respiratory rate 90th percentile for age; or the need for mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or 10% immature neutrophils CHAPTER 110 Pediatric Sepsis acknowledged that the criteria to meet SIRS is neither sensitive nor specific for sepsis Accordingly, Sepsis-3 defined sepsis as lifethreatening organ dysfunction caused by a dysregulated host response to infection Septic shock is broadened to describe a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality Given that these definitions were developed relatively specific to the adult population, we will continue to use the pediatricspecific definitions described earlier until there is a consensus on the revised definitions for the pediatric population.14 Clinical Presentation As a syndrome potentially affecting the entire body, the clinical presentation of sepsis is highly heterogeneous The most common clinical manifestations of sepsis include fever or hypothermia, tachypnea, tachycardia, leukocytosis or leukopenia, thrombocytopenia, and change in mental status It should be noted, however, that in the absence of meningitis changes in mental status are relatively late manifestations of septic shock and should not be relied on for early recognition of shock One of the earliest signs alerting caregivers to the possibility of infection is fever A number of the cytokines elicited in response to infection are pyrogens, particularly interleukin (IL)-1b and tumor necrosis factor (TNF)a Patients can also have hypothermia, which is generally more common in infants than older children Finally, petechiae and/or purpura can be present and are potentially ominous signs of purpura fulminans.15 Shock states can be grouped into four broad categories: hypovolemic, cardiogenic, obstructive, and distributive shock Septic shock is unique because all four forms of shock may be involved simultaneously The patient may have hypovolemic shock resulting from capillary leak, increased insensible water losses, poor intake, and/or decreased effective blood volume secondary to venodilation and arterial dilation (i.e., increased vascular capacitance) Cardiogenic shock manifests as depressed myocardial contractility and low cardiac output secondary to myocardialdepressant effects of bacterial toxins and inflammatory cytokines Obstructive shock can result indirectly from diffuse microvascular thrombosis, or directly from abdominal compartment syndrome Distributive shock can result directly from abnormally low systemic vascular resistance, leading to maldistribution of blood flow, or can result indirectly from the inability of tissues to adequately use oxygen at the mitochondrial level (i.e., cytopathic hypoxia) The degree to which an individual patient manifests these physiologic perturbations is highly variable In some cases, patients display increased cardiac output with diminished systemic vascular resistance The presenting symptoms in this type of patient are tachycardia, a hyperdynamic precordium, bounding pulses, and warm, flushed skin characteristic of the distributive mode of shock or the so-called “warm” shock state Despite this clinical appearance, the perfusion of major organs during warm shock may remain highly compromised secondary to maldistribution of blood flow Alternatively, a patient with depressed cardiac output and elevated systemic vascular resistance has cool, mottled skin with diminished pulses and poor capillary refill characteristic of the “cold” shock state Limited data and our collective anecdotal experience suggest that this latter presentation, cold shock, is more common in younger children compared with teenagers and adults.16 It has been suggested that patients who develop community-acquired 1295 septic shock more commonly present to the ICU with signs of “cold” shock, whereas patients who develop septic shock secondary to catheter-related infections more commonly present to the ICU with signs of “warm” shock.17 It is important to recognize that a given patient may transition from one shock state to another Recognition and reassessment of these classes of shock are absolutely central to the choice of cardiovascular medications Patients with sepsis often have presenting symptoms of respiratory abnormalities, including tachypnea and hypoxia Tachypnea alone can reflect a compensatory, respiratory alkalosis aimed at counteracting a metabolic acidosis secondary to shock Chest roentgenogram in this setting often reveals a relatively small cardiac silhouette (potentially reflective of relative hypovolemia) with few vascular markings However, in the face of capillary leak and decreased myocardial function, patients with septic shock often develop pulmonary edema and acute respiratory failure as fluid resuscitation proceeds Alternatively, respiratory abnormalities can reflect pneumonia as the primary source of infection and/or the development of ARDS In these situations, chest roentgenography will display patterns of pulmonary infiltrates characteristic of the respective scenarios All organ systems can be adversely affected by poor perfusion and decreased oxygen delivery In addition, all organ systems can be directly or indirectly injured by bacterial toxins, circulating cytokines, and the products of activated white blood cells The end result of these complex and interrelated pathologic mechanisms is MODS, which describes the serial and progressive failure of various organ systems and is associated with increased morbidity and mortality.18–20 Due to the increased mortality associated with MODS, there exist multiple screening tools to identify patients with multiorgan dysfunction who are therefore at increased risk for mortality from sepsis Many of these screening tools have been in place; however, more recent tools, such as quick sequential organ failure assessment (qSOFA) discussed at Sepsis-3, are now being assessed for validity in the pediatric population.13,14,21 Pathogenesis A large number of clinical and basic science studies have focused on the mechanisms underlying the development of sepsis At least three major hypotheses have been proposed to explain the development of sepsis and its sequelae The first hypothesis attributes the development of sepsis to an excessive or uncontrolled host inflammatory response This “proinflammatory” hypothesis is broadly consistent with the concept of SIRS and is generally well supported by experimental and clinical data However, a large number of clinical trials aimed directly at inhibition of various components of this putative excessive inflammatory response have failed, leading to the development of alternative hypotheses One such alternative hypothesis states that sepsis is not directly the result of excessive inflammation but rather a more direct manifestation of failed antiinflammatory responses Thus, in this alternative hypothesis, there is direct failure of the compensatory antiinflammatory response syndrome (CARS), which subsequently permits unchecked proinflammatory responses Related to the CARS concept is the concept of immunoparalysis, which embodies the third overall hypothesis to account for the clinical manifestations of sepsis The hypothesis of immunoparalysis postulates that sepsis is not a manifestation of too much or too little inflammation but rather a form of acquired immunodeficiency (both 1296 S E C T I O N X I Pediatric Critical Care: Immunity and Infection Excessive inflammation overwhelms antiinflammatory mechanisms Proinflammatory Paradigm Excessive inflammation leads to direct injury of host tissues Dysregulation of inflammation adversely affects interactions between the innate and adaptive immune systems Persistence of pathogens enhances and amplifies proinflammatory processes Failure of antiinflammatory mechanisms facilitates a proinflammatory phenotype Antiinflammatory Paradigm Antiinflammatory mechanisms fail and indirectly allow injury to host tissues HETEROGENEITY Pathogen Class Genetic Factors A strong antiinflammatory phenotype can lead to inactivation of monocytes and lymphocytes Surgery Trauma Developmental Factors Immunosuppression Paradigm Adaptive immune mechanisms fail to clear pathogens Variable Therapies Comorbidities • Fig 110.1 Three major paradigms for understanding the pathophysiology of sepsis and septic shock Although the paradigms are mechanistically distinct, they are not mutually exclusive Each paradigm has the potential to influence the others, and all are potentially operative in a heterogeneous patient cohort Heterogeneity is a major component of septic shock, resulting from multiple host and environmental factors innate and adaptive immunity), leading to an inability to effectively clear pathogens and their products, causing direct tissue and organ injury.22,23 A conceptual framework for integrating these hypotheses/ paradigms is provided in Fig 110.1 All three paradigms are biologically plausible and supported by the existing literature.24 While seemingly vastly different in concept, they are not mutually exclusive in the context of a highly heterogeneous syndrome such as human sepsis It is plausible that all three paradigms are valid across a given cohort of heterogeneous patients with sepsis In addition, each paradigm has the potential to influence all of the other paradigms, as indicated in Fig 110.1 The following sections review the existing literature supporting these three paradigms and will serve to frame the important concept of heterogeneity in sepsis A major challenge in the field of sepsis is to more effectively understand how a given patient fits into one of these three paradigms (i.e., stratify or phenotype patients more effectively) Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) is a relatively new concept to describe patients with sepsis who not seem to respond to therapy and require long-term hospital care PICS is characterized by long-term, ongoing inflammation leading to long-term immunosuppression and organ injury and maladaptive metabolic derangements resulting in catabolism As opposed to patients who respond rapidly to resuscitation and antimicrobial treatment, these patients are more likely to have prolonged stays in the ICU and suffer from subsequent sepsis episodes Why some patients fall into this state and others respond rapidly to treatment is likely multifactorial and incompletely understood.25,26 While PICS is best described among adult patients, studies documenting late mortality and frequent readmission among children who survive their initial episode of sepsis suggests that this phenotype might also exist in the pediatric population.4 CHAPTER 110 Pediatric Sepsis Pathogen Recognition and Signal Transduction The fundamental role of the immune system is to detect, contain, and eradicate invading pathogens The first step in this process involves pathogen recognition, which is achieved by the activation of pattern recognition receptors (PRRs) on immune cells by pathogen-associated molecular patterns (PAMPs).27 Examples of PAMPs include lipopolysaccharide from the cell wall of gramnegative bacteria; lipoteichoic acid from the cell wall of grampositive bacteria; mannans from the cell wall of yeast; doublestranded RNA of viruses; and unmethylated, CpG-rich deoxyribonucleic acid (DNA) unique to bacterial genomes The most well-studied PRRs include the family of toll-like receptors (TLRs), which can have relatively specific recognition of PAMPs.27 For example, TLR-4 recognizes lipopolysaccharide, whereas TLR-2 recognizes lipoteichoic acid Other examples of PRRs or PRR components include CD-14, scavenger receptors, nucleotide oligomerization domain (NOD) receptors, pentraxins, and collectins.28 Engagement of PRRs on the cell surface of immune cells by PAMPs leads to activation of the immune system in the form of phagocytosis, proliferation, and production/secretion of cytokines The latter process, cytokine expression, serves to orchestrate, direct, and amplify the innate and adaptive immune response toward pathogen eradication However, if this process becomes dysregulated, this same production of cytokines, though required for pathogen eradication, can inadvertently lead to autoinjury of the host Much of the activation of the immune system upon PRR activation relies on signal transduction mechanisms, which serve to transfer the signal of pathogen recognition at the cell surface to the intracellular compartment in order to induce new gene expression or a change in cellular function One of the major signal transduction mechanisms of the immune system is the nuclear factor-kB (NF-kB) pathway, which serves as a master “switch” for the expression of a wide variety of genes involved in inflammation and immunity Indeed, activation of the NF-kB pathway is a major signaling pathway in the pathophysiology of sepsis and may represent a potential therapeutic target.29,30 Another major signaling pathway for the regulation of genes involved in inflammation and immunity is the mitogen-activated protein kinase (MAPK) signaling pathway The MAPKs consist of three major families: p38 MAP kinase, extracellular-regulated protein kinase (ERK), and c-Jun N-terminal kinases (JNK) These major kinase families are also referred to as stress-activated protein kinases (SAPKs) Similar to the NF-kB pathway, the MAPKs are also regarded as potential therapeutic targets in the context of sepsis.29,31,32 Finally, there is now increased attention on the phosphatase family of intracellular signaling molecules in the context of sepsis Whereas kinases direct cellular signaling by adding phosphate groups to intracellular signaling proteins, phosphatases remove phosphate groups from these same intracellular signaling proteins Thus, they can modulate proinflammatory cell signaling.33,34 Cytokines as Principal Mediators of the Sepsis Response Cytokines represent a broad family of proteins that have paracrine, autocrine, and endocrine properties; they have the ability to regulate and modulate virtually all aspects of immunity and inflammation Common features of cytokines are provided in eBox 110.2 This chapter reviews a selected group of cytokines thought to play an important role in the pathophysiology of sepsis 1297 TNF-a is perhaps the most well-studied cytokine causally linked to sepsis Evidence for TNF-a mediation of sepsis includes the observations that TNF is produced by hematopoietic cells, its expression is temporally related to the development of shock, it can by itself induce experimental septic shock in animals, and passive immunization against TNF blunts the endotoxin-induced sepsis response.35 The proinflammatory effects of TNF include leukocyte-endothelial cell adhesion, transformation to a procoagulant phenotype, induction of inducible nitric oxide (NO) synthase, and functioning as a principal “early” cytokine, inducing the subsequent cascade of mediators and cytokines promulgating the septic response Despite a plethora of preclinical studies demonstrating the important proximal role of TNF-a in the pathophysiology of sepsis, multiple clinical trials targeted at neutralization of TNF-a activity have thus far failed to demonstrate efficacy.36 IL-1b has many redundant biological properties to that of TNF-a and is also considered to be a major early cytokine in the sepsis response.37 IL-1b leads to inflammatory and immune cell activation via the NF-kB and MAPK pathways Similar to TNF-a, clinical trials targeted at neutralization of IL-1b activity have thus far failed to demonstrate efficacy despite promising preclinical data IL-6 expression is highly dependent on TNF-a and IL-1b and is consistently found to be elevated during the course of sepsis.38 IL-6 is a pleiotropic cytokine possessing a number of functions, including driving the acute-phase response in hepatocytes, differentiating myeloid cells, stimulating immunoglobulin production, and activating T-cell proliferation.39 Because increased IL-6 admission levels have been correlated with death in the context of sepsis, there has been interest in using IL-6 as a stratification biomarker for interventional clinical trials in sepsis While this stratification approach has been highly effective in animal models of sepsis,40 it has thus far failed when applied in the clinical setting.41 IL-8 is a canonical member of the chemokine subclass of cytokines.42 The term chemokine refers to the ability of certain cytokines to serve as chemoattractants, which direct leukocyte movement to sites of infection and inflammation (chemotaxis) Both TNF-a and IL-1b can induce IL-8 production from a variety of cells, including endothelial cells, macrophages, neutrophils, and epithelial cells IL-8 is the principal human chemoattractant for neutrophils; it appears to play a major role in the recruitment of neutrophils to the lungs in patients with sepsis-induced ARDS.43 Serum IL-8 measurements within 24 hours of presentation to the ICU can robustly predict good outcome in children with septic shock receiving standard care.44 Other chemokines relevant to the pathophysiology of septic shock include monocyte chemoattractant protein (MCP-1) and macrophage inflammatory protein-1 (MIP-1).42 Macrophage migration inhibitory factor (MIF) is another important cytokine in the pathophysiology of sepsis High levels of MIF in patients with septic shock and ARDS correlate with poor outcome.45,46 MIF possesses a number of biological activities generally directed toward a proinflammatory phenotype, including skewing of naïve T cells toward a Th1 phenotype An unusual feature of MIF is that its secretion is enhanced by glucocorticoids, whereas the expression and activity of many cytokines are suppressed by glucocorticoids In turn, MIF has the ability to antagonize the antiinflammatory effects of glucocorticoids IL-18 has also emerged as an important cytokine in the pathophysiology of sepsis.47 Depending on the local cytokine milieu, ... the innate and adaptive immune response toward pathogen eradication However, if this process becomes dysregulated, this same production of cytokines, though required for pathogen eradication, can... increased cardiac output with diminished systemic vascular resistance The presenting symptoms in this type of patient are tachycardia, a hyperdynamic precordium, bounding pulses, and warm, flushed... skin characteristic of the distributive mode of shock or the so-called “warm” shock state Despite this clinical appearance, the perfusion of major organs during warm shock may remain highly compromised