Key Words Immunodeficiency, infections, autoimmunity, CVID, humoral, cellular, lymphocytes, complement Abstract Primary immunodeficiency is a rare but underdiagnosed disease Patients mainly present wi[.]
e4 Abstract: Primary immunodeficiency is a rare but underdiagnosed disease Patients mainly present with four main features: recurrent/severe/opportunistic infections, atypical autoimmunity, major atopy, and blood cancers Each year, new disorders are identified with the improvements in genetic research and targeted therapies Key Words: Immunodeficiency, infections, autoimmunity, CVID, humoral, cellular, lymphocytes, complement 104 Acquired Immune Dysfunction BRENT J PFEIFFER • • • Most patients admitted to the pediatric intensive care unit are immunosuppressed to varying degrees Secondary immune dysfunction happens because of dysregulation between proinflammatory and antiinflammatory responses that fail to restore immune system homeostasis Worldwide protein-energy malnutrition is the most common cause of acquired immunodeficiency Children with chronic immunosuppression or human immunodeficiency virus/acquired immunodeficiency syndrome The immune system is a collection of responses that protects an individual from disease states Immunity provides protection to an individual balancing proinflammatory and antiinflammatory responses, returning the affected individual to homeostasis after infection or injury Innate and adaptive immunity broadly categorize host immunity defenses These complementary systems are detailed in Chapters 100 and 101 Acquired immune dysfunction can occur when one or more of the innate and/or adaptive immunity defenses becomes impaired, leading to disturbed immunity homeostasis, and may be a secondary phenomenon following another disease process Common disease processes in the pediatric intensive care unit (PICU) contributing to acquired immunity include sepsis (viremia/bacteremia), severe trauma/burns, cardiopulmonary bypass, autoimmunity, malignancy, pancreatitis, prematurity/newborn, malnutrition, or intended/unintended effects of therapies (e.g., antirejection or chemotherapy medications).3–9 Acquired immune dysfunction may occur before a pediatric patient presents to a hospital, as is the case with malnutrition, recent chemotherapy treatment, or antirejection therapies In addition, acquired immune dysfunction may occur later in the hospital course of a pediatric patient, as is the case with pediatric multiple-organ dysfunction syndrome (MODS).10 Ultimately, the host’s immune system fails to return to homeostasis because of hyperinflammation, immunosuppression, and derangement of cellular metabolic processes.11 The Centers for Disease Control and Prevention (CDC) WebBased Injury Statistics Query and Reporting System (CDC WISQAR) fatal injury data from the United States in 2017 ranks the 10 leading causes of death by age groups Between and 14 years of age, unintentional (accidental) injury (No 1) is the most likely cause • • • PEARLS (HIV/AIDS) are at risk for reactivation of latent viruses, such as cytomegalovirus and Epstein-Barr virus, as well as tuberculosis Pneumocystis is still the most common AIDS-defining illness in children and can present with variable pulmonary infiltrates; however, hypoxemia is often out of proportion to clinical and radiographic examination Exposure to immunomodulatory medications increasingly accounts for cases of secondary immunodeficiency of fatality followed by malignant neoplasms (No 3), influenza and pneumonia (No 6), and sepsis (No 8).12 Taking into account the CDC WISQAR child fatalities—along with the use of therapies to treat malignancies, autoimmune diseases, or transplant rejection—it becomes apparent that many children admitted to PICUs have acquired immune dysfunction to varying degrees Sepsis is the most PICU-relevant disease process characterizing acquired immune dysfunction.13 Severe acute malnutrition, formerly called protein-calorie malnutrition, is an enormous global health burden and accounts for the greatest number of immunodeficient patients worldwide.6,14 Human immunodeficiency virus (HIV) is the most widely recognized cause of acquired immune dysfunction.15 Critical illness often involves the activation of innate and adaptive immune responses that must be regulated for the patient to survive Whether from an invading pathogen, severe burns/ trauma, or cardiopulmonary bypass (CPB), the elicited immune response can become unbalanced, prolonging its activation and causing progressive organ dysfunction if homeostasis cannot be restored Patients with acquired immune dysfunction are at risk for secondary and/or opportunistic infections, which sustain the inflammatory response In this clinical setting, the presentation of common infections can be unusual If immunosuppression is known or suspected, the physical examination should focus on the mucosal surfaces (trachea/lungs, oral/intestinal/rectal, conjunctival), catheter entry sites, the skin (including wounds), and the central nervous system (CNS) Understanding patterns of disease that are specific to each type of immune dysfunction can lead to both earlier appropriate empiric therapy and diagnostic tests Unlike primary immunodeficiencies, many cases of acquired 1229 1229.e1 Innate immunity comprises three broad categories Barriers are the first category of innate immunity, which include the skin, lung epithelium, gastrointestinal epithelium, and vascular endothelium Circulating factors are the second category, which include complement, clotting factors, antibodies, and antimicrobial peptides Cellular components are the third category, which include macrophages/monocytes, neutrophils, basophils, mast cells, eosinophils, platelets, and antigen-presenting/dendritic cells Innate immunity circulating factors and cellular responses sense pathogens or tissue damage through an assortment of molecular motifs capable of ligating pattern recognition receptors (PRRs) PRRs recognize pathogen-associated molecular patterns (PAMPs; e.g., lipopolysaccharide or endotoxin) and damage-associated molecular patterns (DAMPs; i.e., tissue-derived molecules, such as heat shock proteins, mitochondrial proteins, and deoxyribonucleic acid [DNA]) PRR activation initiates the innate cellular inflammatory process, whether from an infectious agent or tissue injury, recognizing common molecular patterns and triggering the innate immune response Innate immune responses are tied to adaptive immunity, relying on lymphocytes to produce supportive cytokines, chemokines, and growth factors The crosstalk between innate and adaptive cellular components happens through dendritic cell antigen presentation Adaptive immunity comprises various lymphocytes and subpopulations in each group T lymphocytes, such as cytotoxic (CD8) or helper (CD4) lymphocytes, support direct cell destruction or innate cellular defenses/antibody production, respectively B lymphocytes produce antibodies, providing necessary innate circulating factors Natural killer (NK) lymphocytes are analogous to CD8 T lymphocytes destroying infected or malignant/tumor cells but not require priming from antigen-presenting cells Thus, NK lymphocytes function similarly to an innate immune cell Adaptive T- and B-lymphocyte responses tailor an individual’s immune response beyond PRRs, responding to unique and specific antigens, although adaptive T- and B-lymphocyte responses require antigen presentation through specialized cells and antigen presentation and recognition takes time A full discussion of innate and adaptive immunity is beyond the scope of this chapter Both topics are detailed in Chapters 100 and 101 Additional reviews are provided by Bonilla and Oettgen1 and Turvey and Broide.2 1230 S E C T I O N X I Pediatric Critical Care: Immunity and Infection immunodeficiency are reversible with treatment, supportive care, and resolution of the primary cause Immune Dysfunction During Sepsis, Malnutrition, HIV/AIDS, and Other Critical Illness States Sepsis and Immune Dysfunction Sepsis and related subsequent events emphasize the dynamic and disrupted immune responses that cause acquired immune dysfunction Delano and Ward reported the historical sepsis mortality distribution, which is bimodal: early sepsis deaths peak at day and late sepsis deaths peak at day 26.16 The SPROUT international point prevalence sepsis study demonstrated the global public burden of pediatric severe sepsis with a prevalence of 8.2%.The most frequent sites of infection were respiratory (40%) and bloodstream (19%) Hospital mortality was 25%, and nearly one-third of patients developed sepsis-associated new or progressive multiorgan dysfunction.17 The dysregulated immune response of sepsis highlights the hyperinflammatory response, concomitant immunosuppression, and persistent inflammation and catabolism syndrome that threatens organ function and, potentially, patient survival.11,16,18 The hyperinflammatory sepsis response is detailed in Chapter 110 Immunosuppression in Sepsis Immune cell dysfunction during sepsis alters both innate and adaptive immunity by affecting cell metabolism, lifespan, and effector function Previous theories focused on the initial systemic inflammatory response syndrome (SIRS) as the cause of early mortality and the compensatory antiinflammatory syndrome as the cause of late mortality several days to weeks after the initial presentation.16,26 However, it is a failure of the immune response to return to homeostasis from the sustained inflammation and immunosuppression that characterizes an acquired immune dysfunction state In 1986, a group of trauma surgeons recognized an association between late mortality after severe trauma due to secondary infections and suppressed monocyte function, specifically antigen presentation.27 Several subsequent studies demonstrated downregulation of major histocompatibility complex (MHC) class II (human leukocyte antigen [HLA]-DR) molecules on the surface of monocytes after severe trauma, CPB, neurosurgical procedures, acute pancreatitis, and severe sepsis.28–32 Suppressed monocyte/macrophage HLA-DR expression reduces immune complex clearance and impairs antigen-presentation capabilities Thus, monocyte/macrophages HLA-DR-antigen interactions with CD4 T lymphocytes are limited CD4 T lymphocyte–monocyte/macrophage interactions are necessary for monocyte/macrophage activation This interaction maximizes pathogen killing mechanisms, enhances cytokine/ chemokine production, and promotes leukocyte mobility.33 Blood monocytes from septic patients with reduced HLA-DR expression demonstrate an impaired ability to produce inflammatory cytokines upon an ex vivo challenge of lipopolysaccharide (LPS) exposure, termed monocyte anergy.32 This surrogate marker of monocyte anergy may be explained by epigenetic changes Alterations of monocyte proinflammatory gene expression are suppressed because of altered methylation patterns of monocyte genomic DNA.34 Studies have correlated reduced monocyte HLA-DR expression with life-threatening nosocomial infections (including those considered reactivated or opportunistic) and increased mortality.35,36 Myeloid cell dysfunction, adaptive lymphocyte dysfunction, and cytopenia contribute to the immunosuppressive state during sepsis Persistent inflammation alters cellular metabolism throughout the body to a catabolic state and changes cytokine production to balance the proinflammatory process These changes prolong immune system recovery after critical illness and are known as immunoparalysis Catabolism present during hyperinflammation alters the ability of the patient’s bone marrow to produce mature, functional immune cells Bone marrow production of both innate and adaptive immune cells can involve poor production and immaturity resulting in neutropenia and/or lymphopenia Immature neutrophils are impaired in bacterial clearance because of reduced oxidative burst and abnormal migration.37 Granulocytopenia may occur during the acute phase of several specific infections, as detailed in Table 104.3 Dendritic cells and macrophages exhibit reduced phagocytosis, antigen processing, and mobility.11 Thus, adaptive lymphocyte immune responses are unsupported because fewer dendritic cells traffic to secondary lymphoid tissues Impaired dendritic cell trafficking to secondary lymphoid tissues means less CD4 T lymphocyte activation and proliferation and, hence, fewer CD4 T lymphocytes supporting innate cellular functions and fewer B lymphocytes generating antigen-specific antibodies In addition, hyperinflammation associated with sepsis, burns, neurotrauma, CPB, and viremias has been reported to cause an absolute lymphocytopenia in previously healthy patients.38–44 A recent adult study assessed persistent lymphopenia as a biomarker for sepsis-induced immunosuppression, reporting that moderate-to-severe persistent lymphopenia on day following the diagnosis of sepsis predicted early and late mortality.43 In children, prolonged lymphopenia, defined as lymphocyte count less than 1000 cells/µL for more than days, was associated with a greater than sixfold increased risk of death.44 The reasons for persistent lymphopenias are not well understood One hypothesis postulates that elevated endogenous corticosteroids and catecholamines induce apoptosis-mediated lymphopenia.45,46 Exogenous corticosteroids have long been known to induce lymphocyte apoptosis.40 Critical illness elicits a hormonal stress response (see Chapter 80), increasing endogenous corticosteroid release, although there is no direct correlation between cortisol levels and lymphopenia In contrast, prolactin has been shown to affect lymphocyte survival and is required for proliferation and prevention of steroid-induced apoptosis Prolonged prolactin suppression correlated with lymphopenia, nosocomial infection, and death.44 Dopamine inhibits prolactin release, even at very low doses, and reduced prolactin concentrations directly depress lymphocyte function and survival.47 Other drugs commonly used in the ICU are associated with bone marrow suppression (specific antibiotics) and reduced proinflammatory cytokine production (opiates and sedatives).48,49 Proinflammatory cytokines stimulate cytotoxic, cellular, and humoral immunity responses Antiinflammatory cytokines attempt to restore immune homeostasis by limiting proinflammatory states and altering the microenvironment Antiinflammatory cytokines in sepsis include interleukin-1 receptor agonist (IL1RA), IL-4, IL-10, and transforming growth factor-b (TGF-b) IL-10 and TGF-b are the most important immunoregulatory cytokines Persistent expression of IL-10 is also believed to have a central role in immunoparalysis IL-10 is an antiinflammatory cytokine expressed by many cell types (T cells, B cells, dendritic cells, macrophages, and neutrophils) and is capable of downregulating cytokine expression, antigen presentation, and costimulatory cell surface molecules, preventing exuberant immune 1230.e1 Sepsis elicits the immune response through an interconnected process involving cytokine/chemokine production, complement activation, and coagulation/platelet activation An immune response starts from PRR activation through PAMPs and DAMPs, complement activation, and coagulation/platelet activation Different cell types respond to PRRs mainly through Toll-like receptors (TLRs), summarized in eTable 104.1.19,20 Innate immune cells, mainly monocytes/macrophages and neutrophils, respond to TLR signaling by translocating nuclear factor-kb (NF-kb) into the nucleus and activating proinflammatory genes.21 Proinflammatory cytokines associated with the SIRS or sepsis include tumor necrosis factor-a (TNF-a), interferon-g (INF-g), interleukins (IL-1b, IL-6, IL-8, IL-12, and IL-17), macrophage migration inhibitory factor (MIF), and chemokines (MCP1, CXCL1, CXCL2, and CXCR3).20,22 eTable 104.2 provides a summary of cytokines involved in sepsis Complement activation through the classical, lectin, or alternative pathways results in the release of proteins or protein fragments that have potent proinflammatory effects.23 In particular, C3a and C5a protein fragments recruit leukocytes, induce opsonization, and activate platelets plus the coagulation cascade.23 The excessive or overwhelming expression of the proinflammatory response is the “cytokine storm” associated with capillary leak, cardiovascular collapse, eTABLE 104.1 Toll-Like Receptors (TLRs) TLR Cellular Localization Pattern-Recognition Receptor Cell surface Triacyl lipoproteins Cell surface Lipoproteins, peptidoglycan, lipoteichoic acid, saturated fatty acids, glycoproteins gB and gH, Zymosan Intracellular (ER, endosomes, or lysosomes) Double-stranded RNA, polyinosinic-polycytidylic acid Cell surface LPS, RSV fusion protein Cell surface Flagellin Cell surface Diacyl lipoproteins, lipoteichoic acid, Zymosan Intracellular (ER, endosomes, or lysosomes) Single-stranded RNA Intracellular (ER, endosomes, or lysosomes) Imidazoquinolines Intracellular (ER, endosomes, or lysosomes) Bacterial DNA, CpG (methylated) deoxyribonucleotide ER, Endoplasmic reticulum; LPS, lipopolysaccharide protein; RSV, respiratory syncytial virus and dysregulation of cellular metabolism during sepsis Associated with the proinflammatory state is the disruption of the endothelial barrier Endothelial cells maintain a tight cell-cell connection During sepsis, the endothelial barrier loses integrity, causing the release of tissue factor and capillary leak This then leads to extracellular fluid accumulation and edema Tissue factor is the main trigger of coagulation activation in sepsis and is released from injured endothelial cells However, inhibition of tissue factor activation and fibrin formation failed to reduce mortality in sepsis patients with international normalized ratio elevations.24 Platelets and the coagulation cascade function to prevent bleeding, adhering to the sites of endothelial injury Formation of a fibrin network is an innate defense mechanism, trapping pathogens, but may also induce proinflammatory signals.25 Strong activation of the coagulation system, which is the case in severe sepsis, may result in disseminated intravascular coagulation, which occurs with clotting factor consumption and thrombocytopenia The innate immune response is designed to provide a rapid and localized response to an infection, resulting in the elimination of a pathogen However, if a pathogen continues to multiply despite the innate immune response or is systemic and persistent, then the inflammatory responses continue and may lead to persistent hyperinflammation ... risk for secondary and/or opportunistic infections, which sustain the inflammatory response In this clinical setting, the presentation of common infections can be unusual If immunosuppression... complement, clotting factors, antibodies, and antimicrobial peptides Cellular components are the third category, which include macrophages/monocytes, neutrophils, basophils, mast cells, eosinophils,... recognition takes time A full discussion of innate and adaptive immunity is beyond the scope of this chapter Both topics are detailed in Chapters 100 and 101 Additional reviews are provided by