1247CHAPTER 105 Immune Balance in Critical Illness of cecal ligation and puncture followed by airway infection 60 A recent dose finding trial in septic adults with lymphopenia showed that the administ[.]
CHAPTER 105 Immune Balance in Critical Illness 1247 TABLE 105.2 Summary of In Vivo Immunostimulation Studies in Critically Ill Adults and Children Author Study type N Population Drug Results Livingston et al (1994) RCT 98 Adult trauma IFN-g h Monocyte HLA-DR expression Reference 53 Spagnoli et al (1995) RCT 10 Adult trauma GM-CSF h Monocyte HLA-DR expression 54 Döcke et al (1997) Case series Adult sepsis with immunoparalysis IFN-g h Monocyte HLA-DR expression and ex vivo LPS-induced TNF-a production capacity 49 Nakos et al (2002) RCT 21 Adult trauma with immunoparalysis IFN-g (inhaled) h Alveolar macrophage HLA-DR expression, reduced VAP risk 50 Nierhaus et al (2003) Case series Adult sepsis GM-CSF h Monocyte HLA-DR expression and ex vivo LPS-induced TNF-a production capacity 51 Rosenbloom et al (2005) RCT 40 Adult sepsis GM-CSF h Innate immune function 55 Orozco et al (2006) RCT 58 Adult sepsis GM-CSF Improved infection outcomes 56 Meisel et al (2009) RCT 38 Adult sepsis with immunoparalysis GM-CSF h Monocyte HLA-DR expression and ex vivo LPS-induced TNF-a production capacity, improved organ function 52 Hall et al (2011) RCT 14 Pediatric MODS with immunoparalysis GM-CSF h Ex vivo LPS-induced TNF-a production capacity, reduced nosocomial infection risk 23 Paine et al (2012) RCT 130 Adult ARDS GM-CSF No change in ventilator-free days (no immune parameters measured) 58 Hotchkiss et al (2019) Dose finding 20 Adult sepsis Anti-PD-L1 h Monocyte HLA-DR expression 61 ARDS, Acute respiratory distress syndrome; GM-CSF, granulocyte macrophage–colony stimulating factor; HLA-DR, human leukocyte antigen DR isotype; IFN-g, interferon-g; LPS, lipopolysaccharide; MODS, multiple-organ dysfunction syndrome; RCT, randomized controlled trial; TNF-a, tumor necrosis factor a; VAP, ventilator-associated pneumonia of cecal ligation and puncture followed by airway infection.60 A recent dose-finding trial in septic adults with lymphopenia showed that the administration of anti-PD-L1 antibodies was associated with normalization of monocyte HLA-DR expression.61 IL-7 is an endogenous cytokine that promotes lymphocyte development and survival Recombinant IL-7 has been shown, also in mice, to similarly improve survival in two-hit cecal ligation and puncture models.62 Interestingly, it appears that combinatorial therapy with both anti-PD-1 and IL-7 in these models may have greater benefit than either agent alone.63 Unintended Immunomodulation In addition to the forms of intentional immunomodulation described earlier, it is important to understand that many therapies applied to critically ill patients have unintended effects on immune function (Table 105.3) From sedatives and analgesics to inotropes and diuretics, much of the ICU pharmacopeia is immunodulatory, with most of these drugs having direct or indirect immunosuppressive effects In addition, the transfusion of blood products—particularly, stored red blood cells (RBCs)—is thought to modulate immune function (see also Chapter 91) While transfusion-related immunomodulation was once viewed as a proinflammatory syndrome, the broad implementation of prestorage leukoreduction of RBC units has reduced acute proinflammatory transfusion reactions.64 Instead, increasing evidence points to an immunosuppressive effect of RBC transfusion, especially in the setting of prolonged pretransfusion storage.65,66 Last, the use of extracorporeal life support devices causes leukocyte activation due to exposure to artificial tubing and membranes It is unclear as to whether these devices promote the immunoparalyzed phenotype in the subacute phase Intriguingly, the use of adsorptive membranes designed to specifically deplete proinflammatory mediators such as complement, IL-6, and LPS may have the potential to improve innate immune function during sepsis, with improvements in monocyte HLA-DR expression seen in small clinical trials.67 Immune Monitoring in the Intensive Care Unit Routine clinical practice in the United States for immune function monitoring in critically ill patients is currently limited to the measurement of complete blood counts and nonspecific markers of inflammation, such as C-reactive protein levels While the clinical use of measures of immune function, such as monocyte HLA-DR expression and ex vivo LPS-induced TNFa production capacity is possible in Europe, these assays are currently limited to research use in the United States As previously noted, it remains unclear as to whether monocyte HLADR expression is best measured using the percent-positive or molecules-per-cell approach As for quantitation of TNF-a production capacity, it has been shown that highly reproducible single- and multicenter results can be obtained using a standardized approach to ex vivo stimulation The lack of an industrystandard approach, however, makes the generalization of specific treatment thresholds difficult since the TNF-a response will vary from protocol to protocol depending on the type of LPS used and other experimental conditions Additional consensus in the field is required in order to move this immune function testing to the clinical laboratory 1248 S E C T I O N X I Pediatric Critical Care: Immunity and Infection TABLE Immunomodulatory Properties of Commonly 105.3 Used ICU Medications Drug Immune Effect Mechanism Catecholamines a Agonists h Direct and indirect potentiation of proinflammatory signaling b Agonists g Direct and indirect potentiation of antiinflammatory signaling b Lactams g Bone marrow suppression, g cytokine production Macrolides g g Cytokine production Insulin g g Proinflammatory signaling Furosemide g g Cytokine production Benzodiazepines g g Cortisol response, direct leukocyte inhibition Barbiturates g g Neutrophil function Opiates g g Proinflammatory cytokine production, h production of TGF-b, h leukocyte apoptosis NSAIDS g g Cytokine production Antibiotics Sedatives Analgesics NSAIDs, Nonsteroidal antiinflammatory drugs; TGF, transforming growth factor The reactivation of latent viruses represents an intriguing indirect measure of immune function that may have utility in the ICU Recent evidence suggests that many patients with critical illness demonstrate PCR positivity for latent viruses in the bloodstream over time and that this viral reactivation is associated with increased mortality.68 Data from septic children suggest that the presence of viral DNAemia is associated with perpetuation of the immunoparalyzed phenotype.69 It is possible that this viral DNAemia represents a sequela of critical illness–associated immune suppression and/or may mediate some of the adverse effects of immunoparalysis Additional research is needed in this area Last, the host genome represents a potential target for immunerelated testing It has been known for many years that there is a familial predisposition to adverse outcomes from critical illness Westendorp et al demonstrated this nicely with an analysis of ex vivo LPS-induced cytokine production capacity in first-degree relatives of patients with meningococcemia.70 Relatives of nonsurvivors could be identified by their production of low amounts of TNF-a and high amounts of the antiinflammatory cytokine IL-10 upon stimulation, suggesting that immunoparalysis may be a heritable trait Unfortunately, no single polymorphism has been consistently associated with clinically relevant derangements of the immune response in critical illness Further complicating this analysis is the fact that epigenetic factors may influence the inflammatory response Cornell et al were able to identify a histone methylation pattern in the IL-10 promoter region, resulting in a “gene on” configuration in children with immunoparalysis following pediatric cardiopulmonary bypass.45 Therefore, the immune phenotype may be influenced by fixed genetic factors as well as potentially modifiable epigenetic factors over the course of critical illness Conclusion The immune response during critical illness, once thought to be limited to a proinflammatory surge, is now known to be highly dynamic, with proinflammatory and antiinflammatory forces at work The balance between these forces determines the patient’s ability to respond to new infectious challenges, to heal injured tissues, and to resolve systemic inflammation It is increasingly apparent that failure to achieve immunologic homeostasis is associated with increased risks for adverse outcomes across the spectrum of adult and pediatric critical illness It is similarly apparent that, while antiinflammatory therapies are appropriate for some patients, immunostimulatory therapies may be indicated for others The development of a personalized approach to the identification and management of an abnormal immune response is needed in pediatric critical illness, involving standardized prospective functional testing In addition, our patients require a more comprehensive understanding of the multilayered interactions between the host, pathogen, and treatment-related factors Key References Boomer JS, To K, Chang KC, et al Immunosuppression in patients who die of sepsis and multiple organ failure JAMA 2011;306(23):2594-605 Hall MW, Knatz NL, Vetterly C, et al Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome Intensive Care Med 2011;37(3):525-532 Muszynski JA, Nofziger R, Moore-Clingenpeel M, et al Early immune function and duration of organ dysfunction in critically ill children with sepsis Am J Respir Crit Care Med 2018;198(3):361-369 Venet F, Demaret J, Gossez M, Monneret G Myeloid cells in sepsis-acquired immunodeficiency Ann N Y Acad Sci 2020 Epub ahead of print Wong HR, Cvijanovich NZ, Anas N, et al Developing a clinically feasible personalized medicine approach to pediatric septic shock Am J Respir Crit Care Med 2015;191(3):309-315 Wong HR, Weiss SL, Giuliano Jr JS, et al Testing the prognostic accuracy of the updated pediatric sepsis biomarker risk model PLoS One 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discussion 154 57 Meisel C, Schefold JC, Pschowski R, et al Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial Am J Respir Crit Care Med 2009;180(7):640-648 58 Paine R III, Standiford TJ, Dechert RE, et al A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury Crit Care Med 2012; 40(1):90-97 59 Guignant C, Lepape A, Huang X, et al Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients Crit Care 2011;15(2):R99 60 Chang KC, Burnham CA, Compton SM, et al Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis Crit Care 2013;17(3):R85 61 Hotchkiss RS, Colston E, Yende S, et al Immune checkpoint inhibition in sepsis: a phase 1b randomized, placebo-controlled, single ascending dose study of antiprogrammed cell death-ligand antibody (BMS-936559) Crit Care Med 2019;47(5):632-642 62 Unsinger J, Burnham CA, McDonough J, et al Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis J Infect Dis 2012;206(4):606-616 63 Shindo Y, Unsinger J, Burnham CA, Green JM, Hotchkiss RS Interleukin-7 and anti-programmed cell death antibody have differing effects to reverse sepsis-induced immunosuppression Shock 2015;43(4):334-343 64 Blumberg N, Heal JM, Gettings KF, et al An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions Transfusion 2010;50(12):2738-2744 65 Muszynski JA, Frazier E, Nofziger R, et al Red blood cell transfusion and immune function in critically ill children: a prospective observational study Transfusion 2015;55(4):766-774 66 Muszynski JA, Spinella PC, Cholette JM, et al Transfusion-related immunomodulation: review of the literature and implications for pediatric critical illness Transfusion 2017;57(1):195-206 67 Schefold JC, von Haehling S, Corsepius M, et al A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a Shock 2007;28(4):418-425 68 Walton AH, Muenzer JT, Rasche D, et al Reactivation of multiple viruses in patients with sepsis PLoS One 2014;9(2):e98819 69 Davila S, Halstead ES, Hall MW, et al Viral DNAemia and immune suppression in pediatric sepsis Pediatr Crit Care Med 2018;19(1):e14-e22 70 Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, Sturk A Genetic influence on cytokine production in meningococcal disease Lancet 1997;349(9069):1912-1913 e3 Abstract: The immune response to pediatric critical illness is highly dynamic and includes both pro- and antiinflammatory responses, which can occur simultaneously Severe inflammation is strongly linked to adverse outcomes from pediatric critical illness Severe critical illness–induced or injury-induced immunosuppression, termed immunoparalysis, has also been associated with increased risks for prolonged organ dysfunction, nosocomial infection, and death Severe inflammation and immunoparalysis can both be diagnosed in the laboratory with specialized testing The reversal of immunoparalysis with targeted immunostimulatory therapies holds promise to improve pediatric sepsis outcomes through a personalized approach to immune care Key words: inflammation, immune, immunoparalysis, sepsis, pediatric critical illness, immunomodulation ... that this viral DNAemia represents a sequela of critical illness–associated immune suppression and/or may mediate some of the adverse effects of immunoparalysis Additional research is needed in this... critical illness demonstrate PCR positivity for latent viruses in the bloodstream over time and that this viral reactivation is associated with increased mortality.68 Data from septic children suggest... familial predisposition to adverse outcomes from critical illness Westendorp et al demonstrated this nicely with an analysis of ex vivo LPS-induced cytokine production capacity in first-degree