1240 SECTION XI Pediatric Critical Care Immunity and Infection Key References Bourke CD, Berkley JA, Prendergast AJ Immune dysfunction as a cause and consequence of malnutrition Trends Immunol 2016;37[.]
1240 S E C T I O N X I Pediatric Critical Care: Immunity and Infection rejection, and graft versus host disease.262 Broadly, drugs used for immunosuppression can be grouped into corticosteroids, cytotoxic drugs, calcineurin inhibitors, mammalian target of rapamycin (mTOR), and biologicals (monoclonal or polyclonal antibodies targeting cytokines or specific cell surface molecules of immune cells) A detailed description of the categories of immunosuppressive agents is beyond the scope of this chapter The adverse effects of these drugs are the weakening of cellular immune responses, making the patient more susceptible to bacterial, fungal, and viral infections (acute, chronic, and reactivated) Corticosteroids, particularly glucocorticoids, have significant antiinflammatory activity Glucocorticoids bind cytosolic receptors, which then translocate to the nucleus of a cell affecting gene transcription The overall results of glucocorticoid therapy are reduced cytokine production, lymphocyte anergy or apoptosis, impaired phagocytosis of neutrophils, and reduced bactericidal activity of macrophages.262 This wide range of immune defects places the patient at risk for viral, bacterial, and fungal infections Cytotoxic agents interfere with the synthesis of DNA of rapidly dividing cells Common cytotoxic medications are cyclophosphamide, methotrexate, azathioprine, and 6-mercaptopurine These medications inhibit T- and B-lymphocyte proliferation as well as any other rapidly dividing cell The major limitation of cytotoxic agents is their toxicity to other cells, such as hematopoietic cells, gastrointestinal mucosa, and skin cells The inhibition of new adaptive immune responses, possible development of cytopenias, and mucosa/skin barrier deterioration places the patient at risk for bacterial and fungal infections.263 Calcineurin inhibitors and mTOR medications inhibit the activation of IL-2, an essential cytokine and signaling cascade needed for T-lymphocyte activation and proliferation.263 Crippling T-lymphocyte activation and proliferation places the patient at risk for viral infections and lymphoproliferative disorders.263 The biologicals are a relatively new class of immunomodulatory agents; many of their effects are dependent on their target One example is antithymocyte globulin, a medication that targets T lymphocytes via multiple epitopes, causing profound and prolonged periods of lymphopenia, which is associated with reactivation of latent viruses Transfusions Critically ill patients frequently receive red blood cell (RBC) transfusions and modified immune responses have been observed, recently reviewed by Muszynski et al (see also Chapter 91).264 How RBC transfusions modulate the immune system is poorly understood Transfusion-related acute lung injury (TRALI) demonstrates the proinflammatory reaction associated with RBC transfusions.265 Liberally transfused patients demonstrate the immunosuppression effect of RBC transfusions There have been several adult meta-analyses and pediatric prospective observational or randomized controlled trails assessing liberal versus restrictive transfusion practices demonstrating no benefit of liberal transfusion practices in a variety of critical care scenarios Children receiving RBC transfusions have associated outcomes of longer mechanical ventilation days, new-onset multiorgan dysfunction, longer PICU length of stay, and increased mortality.266–268 The connection between adult and pediatric RBC transfusion practices is that the liberal transfusion group are at an increased risk of developing hospital-acquired infections.269,270 In line with immunosuppression, some patients who receive blood transfusions before transplantation have a lower incidence of rejection, although transplant recipients who have received mismatched HLA-DR blood products have accelerated graft rejection.271 The long-term effects of transfusions on the immune system and disease susceptibility are not well understood, but even 19 years after transfusion, blood product recipients have fewer peripheral T lymphocytes, particularly helper T cells, than patients who did not undergo transfusion.272 Transfusions after trauma or CPB are associated with increased infections However, in major surgery or trauma, it is difficult to sort out the effect of transfusion versus the effect of surgery or trauma.269 Uremia Uremia is a condition common in critically ill children with acute or chronic renal disease Many end-stage renal disease patients are dialysis dependent and are at risk for invasive microorganisms independent of their need for dialysis or vascular/peritoneal access devices.273 Uremic patients experience increased incidence and severity of infections compared with the general population Children undergoing chronic dialysis have mortality rates 30 times greater than the general population even when disparities in age, sex, race, and diabetes are taken into account.273 Essentially, uremia and dialysis cause a state of chronic immune activation, thus leading to a proinflammatory state and immune hyporesponsiveness characterized by reduced lymphocyte numbers, impaired NK cell function, reduced dendritic cell antigen presentation, and failure to generate antibody responses to administered vaccines.274–276 Neonatal Period The impaired immunity of the neonate is related to the immaturity of lymphoid tissues, innate cells, and T/B lymphocytes This immune system immaturity increases the neonate’s susceptibility to infectious organisms and is inversely associated with prematurity Neonates have an absence of memory T lymphocytes because of the protective in utero environment The lymphoid tissues are undeveloped, lacking marginal zones that support B-lymphocyte maturation.277 This includes the lymphoid tissue of the respiratory and gastrointestinal tracts Neutrophils and NK lymphocytes have reduced activity, especially phagocytosis, cytokine production, and toll-like receptor signaling.278–280 Key References Bourke CD, Berkley JA, Prendergast AJ Immune dysfunction as a cause and consequence of malnutrition Trends Immunol 2016;37:386398 Chinen J, Shearer WT Secondary immunodeficiencies, including HIV infection J Allergy Clin Immunol 2010;125:S195-S203 Commins SP, Borish L, Steinke JW Immunologic messenger molecules: cytokines, interferons, and chemokines J Allergy Clin Immunol 2010;125:S53-S72 Delano MJ, Ward PA Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 2016;126:23-31 Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS Persistent lymphopenia after diagnosis of sepsis predicts mortality Shock Shock 2014;42:383-391 Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure J Immunol 2005;174:3765-3772 Ibrahim MK, Zambruni M, Melby CL, Melby PC Impact of childhood malnutrition on host defense and infection Clin Microbiol Rev 2017;30:919-971 CHAPTER 104 Acquired Immune Dysfunction Luzuriaga K, Mofenson LM Challenges in the elimination of pediatric HIV-1 infection N Engl J Med 2016;374:761-770 Muszynski JA, Spinella PC, Cholette JM, et al Transfusion-related immunomodulation: review of the literature and implications for pediatric critical illness Transfusion 2017;57:195-206 Schulte W, Bernhagen J, Bucala R Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view Mediators Inflamm 2013;2013:165974 1241 van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG The immunopathology of sepsis and potential therapeutic targets Nat Rev Immunol 2017;17:407-420 Wiseman AC Immunosuppressive Medications Clin J Am Soc Nephrol 2016;11:332-343 The full reference list for this chapter is available at ExpertConsult.com e1 References Bonilla FA, Oettgen HC Adaptive immunity J Allergy Clin Immunol 2010;125:S33-S40 Turvey SE, Broide DH Innate immunity J Allergy Clin Immunol 2010;125:S24-S32 Hall MW, Knatz NL, Vetterly C, et al Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome Intensive Care Med 2011;37:525-532 Etzioni A Immune deficiency and autoimmunity Autoimmun Rev 2003;2:364-369 Proulx F, Joyal JS, Mariscalco MM, Leteurtre S, Leclerc F, Lacroix J The pediatric multiple organ dysfunction syndrome Pediatr Crit Care Med 2009;10:12-22 Bourke CD, Berkley JA, Prendergast AJ Immune dysfunction as a cause and consequence of malnutrition Trends Immunol 2016; 37:386-398 Herndon DN, Voigt CD, Capek KD, et al Reversal of growth arrest with the combined administration of oxandrolone and propranolol in severely burned children Ann Surg 2016;264:421-428 Ibrahim MK, Zambruni M, Melby CL, Melby PC Impact of childhood malnutrition on host defense and infection Clin Microbiol Rev 2017;30:919-971 Kawasaki T Update on pediatric sepsis: a review J Intensive Care 2017;5:47 10 Carcillo JA, Podd B, Aneja R, et al Pathophysiology of pediatric multiple organ dysfunction syndrome Pediatr Crit Care Med 2017;18:S32-S45 11 van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG The immunopathology of sepsis and potential therapeutic targets Nat Rev Immunol 2017;17:407-420 12 CDC WISQAR Fatality Data: 10 Leading causes of death by age group, US 2017 2017 Available at: https://www.cdc.gov/injury/ images/lcchartsleading_causes_of_death_by_age_group_ 2017_1100w850h.jpg 13 Angus DC, Opal S Immunosuppression and secondary infection in sepsis: Part, Not All, of the Story JAMA 2016;315:1457-1459 14 Bhutta ZA, Berkley JA, Bandsma RHJ, Kerac M, Trehan I, Briend A Severe childhood malnutrition Nat Rev Dis Primers 2017; 3:17067 15 Hemelaar J, Elangovan R, Yun J, et al Global and regional molecular epidemiology of HIV-1, 1990–2015: a systematic review, global survey, and trend analysis Lancet Infect Dis 2019;19:143-155 16 Delano MJ, Ward PA Sepsis-induced immune dysfunction: can immune therapies reduce mortality? 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