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Harmsen HJ, Welling GW, et al Impact of digestive and oropharyngeal decontamination on the intestinal microbiota in ICU patients Intensive Care Med 2010;36:1394-1402 86 Zhang L, Sriprakash KS, McMillan D, Gowardman JR, Patel B, Rickard CM Microbiological pattern of arterial catheters in the intensive care unit BMC Microbiol 2010;10:266 87 Schlager TA, Hidde M, Rodger P, Germanson TP, Donowitz LG Intravascular catheter colonization in critically ill children Infect Control Hosp Epidemiol 1997;18:347-348 88 Heyland D, Mandell LA Gastric colonization by gram-negative bacilli and nosocomial pneumonia in the intensive care unit patient; Evidence for causation Chest 1992;101:187-193 89 Kerver AJH, Rommes JH, Mevissen-Verhage EAE, et al Colonization and infection in surgical intensive care patients -a prospective study Intensive Care Med 1987;13:347-351 90 Rogers MB, Firek B, Shi M, et al Disruption of the microbiota across multiple body sites in critically ill children Microbiome 2016;4:66 91 Freedberg DE, Zhou MJ, Cohen ME, et al Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection Intensive Care Med 2018;44:1203-1211 92 Gorrie CL, Mirceta M, Wick RR, et al Gastrointestinal carriage is a major reservoir of klebsiella pneumoniae infection in intensive care patients Clin Infect Dis 2017;65:208-215 e3 93 Herzig SJ, Howell MD, Ngo LH, Marcantonio ER Acid-suppressive medication use and the risk for hospital-acquired pneumonia JAMA 2009;301:2120-2128 94 Tacconelli E, De Angelis G, Cataldo MA, et al Antibiotic usage and risk of colonization and infection with antibiotic-resistant bacteria: A hospital population-based study Antimicrob Agents Chemother 2009;53:4264-4269 95 Dickson RP, Singer BH, Newstead MW, et al Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome Nat Microbiol 2016;1:16113 96 Bossa L, Kline K, McDougald D, Lee BB, Rice SA Urinary catheter-associated microbiota change in accordance with treatment and infection status PLoS One 2017;12:e0177633 97 Carlisle EM, Morowitz MJ The intestinal microbiome and necrotizing enterocolitis Curr Opin Pediatr 2013;25:382-387 98 Dickson RP The microbiome and critical illness Lancet Respir Med 2016;4:59-72 99 Dickson RP, Erb-Downward JR, Huffnagle GB Towards an ecology of the lung: New conceptual models of pulmonary microbiology and pneumonia pathogenesis Lancet Respir Med 2014;2:238246 100 Mukherji A, Kobiita A, Ye T, Chambon P Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs Cell 2013;153:812-827 101 Gareau MG Microbiota-gut-brain axis and cognitive function Adv Exp Med Biol 2014;817:357-371 102 Chandrasekharan B, Saeedi BJ, Alam A, et al Interactions between commensal bacteria and enteric neurons, via FPR1 induction of ROS, increase gastrointestinal motility in mice Gastroenterology 2019;157:179-192.e2 103 Zhu W, Gregory JC, Org E, et al Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk Cell 2016;165:111-124 104 Chassaing B, Koren O, Goodrich JK, et al Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome Nature 2015;519:92-96 105 Chassaing B, Van De Wiele T, De Bodt J, Marzorati M, Gewirtz AT Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation Gut 2017;66:1414-1427 106 Yeh A, Conners EM, Ramos-Jimenez RG, et al Plant-based enteral nutrition modifies the gut microbiota and improves outcomes in murine models of colitis Cell Mol Gastroenterol Hepatol 2019;7:872-874.e6 107 Haiser HJ, Gootenberg DB, Chatman K, Sirasani G, Balskus EP, Turnbaugh PJ Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta Science 2013;341:295-298 108 Zhang C, Derrien M, Levenez F, et al Ecological robustness of the gut microbiota in response to ingestion of transient food-borne microbes ISME J 2016;10:2235-2245 109 Suez J, Elinav E The path towards microbiome-based metabolite treatment Nat Microbiol 2017;2:17075 110 Oami T, Chihade DB, Coopersmith CM The microbiome and nutrition in critical illness Curr Opin Crit Care 2019;25:145-149 111 Shen NT, Maw A, Tmanova LL, et al Timely use of probiotics in hospitalized adults prevents clostridium difficile infection: A systematic review with meta-regression analysis Gastroenterology 2017;152:1889-1900.e9 112 Bo L, Li J, Tao T, et al Probiotics for preventing ventilator-associated pneumonia Cochrane Database Syst Rev 2014:CD009066 113 Angurana SK, Bansal A, Singhi S, et al Evaluation of effect of probiotics on cytokine levels in critically Ill children with severe sepsis: A double-blind, placebo-controlled trial Crit Care Med 2018;46:1656-1664 114 McClave SA, Patel J, Bhutiani N Should fecal microbial transplantation be used in the ICU? Curr Opin Crit Care 2018;24: 105-111 115 Wei Y, Yang J, Wang J, et al Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis Crit Care 2016;20:332 116 Li Q, Wang C, Tang C, et al Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: A case report Crit Care 2015;19:37 117 Weiss SL, Balamuth F, Hensley J, et al The epidemiology of hospital death following pediatric severe sepsis: when, why, and how children with sepsis die* Pediatr Crit Care Med 2017;18:823-830 118 Petros A, Silvestri L, Booth R, Taylor N, Van Saene H Selective decontamination of the digestive tract in critically ill children: Systematic review and meta-analysis Pediatr Crit Care Med 2013;14:89-97 119 Daneman N, Sarwar S, Fowler RA, Cuthbertson BH Effect of selective decontamination on antimicrobial resistance in intensive care units: A systematic review and meta-analysis Lancet Infect Dis 2013;13:328-341 120 Murthy S, Pathan N, Cuthbertson BH Selective digestive decontamination in critically ill children: A survey of Canadian providers J Crit Care 2017;39:169-171 121 Martinez KB, Leone V, Chang EB Microbial metabolites in health and disease: Navigating the unknown in search of function J Biol Chem 2017;292:8553-8559 122 Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites Cell 2016;165:1332-1345 123 Zhu W, Winter MG, Byndloss MX, et al Precision editing of the gut microbiota ameliorates colitis Nature 2018;553:208-211 124 Takahashi MK, Tan X, Dy AJ, et al A low-cost paper-based synthetic biology platform for analyzing gut microbiota and host biomarkers Nat Commun 2018;9(1):3347 125 Browne HP, Forster SC, Anonye BO, et al Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation Nature 2016;533:543-546 126 Chen GY The role of the gut microbiome in colorectal cancer Clin Colon Rectal Surg 2018;31:192-198 127 Sivan A, Corrales L, Hubert N, et al Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy Science 2015;350:1084-1089 128 Alderton GK Tumour immunology: Intestinal bacteria are in command Nat Rev Cancer 2016;16:4 e4 Abstract: Adult humans are home to multiple microbial ecosystems and approximately 40 trillion microorganisms These microbes colonize newborn infants and reach an ecological steady state in the skin, mouth, gut, lungs, and genitourinary tract later during childhood They adapt to geographical location, nutritional habits, state of health, and even changes in mood The physiologic changes, pharmacologic interventions, and surgical interventions associated with critical illness have been shown to profoundly affect the microbiome This chapter provides an introduction to microbiome science, describes the microbiome’s role in pediatric critical illness, and details its potential to be monitored and provide a therapeutic target in critical illness Key Words: Microbiome, pediatrics, critical illness, intensive care unit, dysbiosis 103 Congenital Immunodeficiency HANNAH LAURE ELFASSY, TROY TORGERSON, AND CHRISTINE Mc CUSKER • • • • The immune system plays a vital, integral role in human health and, because of the interactions with every other organ system in the body, immunopathology is an important factor in many different disease states In one way or another, it plays particularly important roles in diseases that often affect patients admitted to pediatric ICUs (PICUs), including those patients with severe • • • • • • • Greater than 300 single-gene defects have now been associated with specific immunodeficiencies, with new disorders continually being recognized Chronic granulomatous disease is the most frequently diagnosed phagocytic cell immune defect The most common form is X-linked, caused by mutations in the CYBB gene and accounting for approximately two-thirds of all affected patients All mutations affect the formation or function of the nicotinamide adenine dinucleotide phosphate oxidase complex on neutrophil phagolysosomes X-linked agammaglobulinemia is the prototypic B-cell disorder It is caused by mutations in the Bruton tyrosine kinase gene (BTK), required for the maturation of B-cell precursors in the bone marrow Mutations in BTK cause an arrest of B-cell development at the pre2B-cell stage, leading to virtual absence of circulating B cells in the peripheral blood Common variable immunodeficiency is a heterogeneous disorder that is likely caused by a variety of molecular mechanisms Characterized by poor antibody formation, these diseases often have similar clinical phenotypes With immunoglobulin G (IgG) supplementation, there are reductions in recurrent infections in this group of patients and improved long-term survival, although the increased potential for autoimmunity and malignancy exist in some subgroups Selective IgA deficiency is common in the general population Patients with selective IgA deficiency have no apparent symptoms that can be directly linked to their low IgA In patients who have complete IgA deficiency, sensitization to IgA itself can be a problem, leading in rare cases to anaphylactic reactions during infusions of blood products, such as packed red blood cells, containing passenger IgA Deletions within the 22q11.2 region of the long arm of chromosome 22 have been associated with various clinical syndromes, • PEARLS including DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and CATCH22 syndrome The characteristic T-cell lymphopenia of DiGeorge syndrome is thought to arise primarily from the absence of adequate thymic tissue In the complete DiGeorge phenotype, both CD41 and CD81 T cells are low; these patients have a similar clinical phenotype as those with severe combined immunodeficiency Severe combined immunodeficiency (SCID) is among the most severe immunodeficiencies and is made up of a variety of related disorders, all with deficiencies in T-cell numbers and function Variants associated with SCID have been identified in more than 20 different genes although new variants are defined annually Adenosine deaminase deficiency was the first molecularly defined immunodeficiency with discovery of patients with SCID When adenosine deaminase activity is impaired or absent, intracellular levels of deoxy-adenosine triphosphate rise to interfere with ribonucleotide reductase and synthesis Therefore, the repair process is impaired and lymphocyte apoptosis is increased, resulting in panlymphopenia X-linked syndrome is phenotypically defined as immune dysregulation, polyendocrinopathy, and enteropathy IX-linked syndrome is caused by mutations in the FOXP3 gene located on the X chromosome, which encodes a key transcription factor that is required for the generation of functional T regulatory cells Failure to develop these T regulatory cells results in earlyonset, severe, systemic autoimmunity Ataxia telangiectasia is a disorder associated with progressive neurologic decline, immunodeficiency, and propensity to malignancy It is caused by autosomal recessive mutations in the ATM gene, which encodes a serine/threonine kinase that acts together with the NBS1 protein as one of the major sensors of double-stranded deoxyribonucleic acid breaks in the cell In the absence of functional ATM or NBS1, cells have a marked sensitivity to ionizing radiation infections and sepsis; severe autoimmunity; hematologic malignancies; inflammatory disorders, such as hemophagocytic lymphohistiocytosis; asthma; and autoimmunity, such as type I diabetes with diabetic ketoacidosis This chapter focuses particularly on immunologic disorders that are most likely to be encountered in the PICU setting 1215 1216 S E C T I O N X I Pediatric Critical Care: Immunity and Infection The normal and pathogenic roles of each component of the immune system in humans have been significantly clarified by the study of patients with primary immunodeficiency disorders (PIDDs), a group of clinical syndromes originally described in patients with marked susceptibility to particular types of infection This group of disorders has now expanded to include more than 150 clinically defined entities that span the full spectrum of immune dysfunction, ranging from virtually absent immune responses to overwhelming, uncontrolled autoimmunity and susceptibility to malignancy.1 Many of these disorders are inherited, and more than 300 single-gene defects have now been associated with specific immunodeficiencies Through these efforts, it has also become evident that mutations in different genes can lead to a similar clinical phenotype For example, defects in more than 20 different genes have now been associated with a clinical phenotype of severe combined immunodeficiency (SCID).2 Consequently, it has become the practice to refer to disorders by their molecular defect, either in combination with or in lieu of their clinical name or eponym—that is, adenosine deaminase (ADA)– deficiency or ADA-SCID rather than just SCID This chapter follows this practice Basic Framework for Understanding the Immune System To provide structure to facilitate an understanding of the immune system, the diseases associated with immune dysfunction, and how these should be recognized, evaluated, and treated, it is worthwhile to establish a basic framework (see also Chapters 100 and 101) In this framework, the immune system can be divided into four major compartments: complement, phagocytes, B cells and antibodies, and T cells The complement and phagocyte compartments are part of the innate arm of the immune system, which responds in a similar way each time a particular pathogen is encountered and develops only limited pattern-related immunologic memory (see Chapter 100) In contrast, the B-cell and T-cell compartments compose the adaptive arm of the immune system, which learns each time a pathogen is present and has the capacity to develop a memory response, enabling a more rapid and efficient response should the same pathogen be encountered later (Table 103.1) Immunodeficiency disorders may affect only one compartment of the immune system or may be combined immunodeficiencies with defects in both the B- and T-cell compartments Given the important interplay between the different compartments or “arms” of the immune response, a deficiency in one will often result in problems in the activities of other immune compartments In general, defects in each compartment of the immune system are associated with susceptibility to particular types of infections and/or autoimmunity and malignancy as dictated by the dominant role of that compartment in human immunity In addition, each immunodeficiency typically has unique clinical and laboratory features that differentiate it from other disorders, thus making it possible to predict which disorder a patient may have on the basis of clinical and laboratory findings (eTable 103.2) The overlap between the compartments, however, may make the differential diagnosis more complex Compartment 1: Complement The complement system consists of a series of proteins that are present in the plasma and become activated on encountering pathogens The complement cascade is activated via three major mechanisms (Fig 103.1): (1) the classical pathway, which is initiated by antigen/antibody complexes; (2) the alternative pathway, which is initiated directly by bacterial cell wall components; and (3) the lectin pathway, which is initiated by carbohydrate moieties present on bacteria Activation of early complement components initiates a cascade of protein cleavage and activation events that ultimately lead to formation of the membrane attack complex (MAC) consisting of complement proteins C5, C6, C7, C8, and C9 A number of regulatory proteins—including C1 inhibitor, factor H, factor I, MCP, and CD59—control complement activation at multiple levels, thereby preventing inappropriate complement activation Complement deficiencies make up only a small portion (,2%) of all primary immunodeficiencies, but the consequences can be devastating for affected patients.3 Defective activation of the entire complement cascade can be caused by the absence or dysfunction of only of more than 20 complement proteins Mannose TABLE 103.1 Symptoms Associated With Defects in Each Immune Compartment INNATE ADAPTIVE Complement Phagocytes Invasive infections with encapsulated bacteria (e.g., S pneumoniae, H influenzae) Recurrent, invasive neisserial infections Autoimmunity (systemic lupus erythematosus, glomerulonephritis) Hereditary angioedema Atypical hemolytic uremic syndrome Skin and soft-tissue abscesses, boils, and lymphadenitis Infections with catalase organisms (e.g., S aureus, Serratia, Aspergillus) Poor wound healing Chronic gingivitis and periodontal disease Mucosal ulcerations, colitis Omphalitis/delayed separation of the umbilical cord B Cells/Antibodies T Cells Recurrent bacterial sinopulmonary infections (otitis media, sinusitis, bronchitis, and pneumonia) Unexplained bronchiectasis Chronic or recurrent gastroenteritis (e.g., Giardia, Cryptosporidium, Enterovirus) Echovirus encephalomyelitis Pneumocystis jirovecii pneumonia Recurrent, severe, or unusual viral infections (e.g., cytomegalovirus, Epstein-Barr virus, adenovirus, papillomavirus) Invasive fungal or mycobacterial infections Graft versus host disease (rash, abnormal liver function tests, chronic diarrhea) Failure to thrive ... eponym—that is, adenosine deaminase (ADA)– deficiency or ADA-SCID rather than just SCID This chapter follows this practice Basic Framework for Understanding the Immune System To provide structure... common form is X-linked, caused by mutations in the CYBB gene and accounting for approximately two-thirds of all affected patients All mutations affect the formation or function of the nicotinamide... phenotypes With immunoglobulin G (IgG) supplementation, there are reductions in recurrent infections in this group of patients and improved long-term survival, although the increased potential for autoimmunity