1216 e1 eTABLE 103 2 Cellular Phenotype and Molecular Defects in Severe Combined Immune Deficiency Disorder Gene Inheritance Features T2B2NK2 Adenosine deaminase deficiency ADA1 AR Costochondral abnor[.]
1216.e1 eTABLE 103.2 Cellular Phenotype and Molecular Defects in Severe Combined Immune Deficiency T B NK 2 T B NK 2 T2B1NK2 T B NK 1 T1/2B1NK1 Disorder Gene Inheritance Features Adenosine deaminase deficiency ADA1 AR Costochondral abnormalities, neonatal hepatitis Purine nucleotide phosphorylase deficiency PNP AR Progressive neurologic decline Reticular dysgenesis AK2 AR SCID phenotype Neutropenia RAG1 deficiency RAG1 AR RAG2 deficiency RAG2 AR Artemis deficiency DCLRE1C AR Radiosensitivity DNA-PKcs deficiency PRKDC AR Radiosensitivity DNA ligase IV deficiency LIG4 AR Radiosensitivity, microcephaly, growth retardation Cernunnos/XLF deficiency NHEJ1 AR Radiosensitivity, microcephaly, growth retardation Common g-chain deficiency IL2RG XL JAK3 deficiency JAK3 AR CD45 PTPRC AR IL-7 receptor-a (CD127) deficiency IL7RA AR DiGeorge syndrome 22q11.2 del AD Hypoparathyroidism, cardiac defects, dysmorphic facies CHARGE syndrome CHD7 AD Multiple congenital anomalies—clinical complex of CHARGE syndrome CD3d deficiency CD3D AR CD3e deficiency CD3E AR CD3g deficiency CD3G AR CD3z deficiency CD3Z AR P56Lck deficiency LCK AR Coronin-1A deficiency CORO1A AR Lymphadenopathy MHC class I deficiency TAP1 AR CD81 T cells are typically decreased but not absent, recurrent respiratory infections TAP2 AR TAPBP AR CIITA AR RFXANK AR RFX5 AR RFXAP AR ORAI1 deficiency ORAI1 AR Myopathy, calcium flux defect in B and T cells, poor T-cell proliferation STIM1 deficiency STIM1 AR Myopathy, calcium flux defect in B and T cells, poor T-cell proliferation MHC class II deficiency AD, Autosomal dominant; AR, autosomal recessive; MHC, major histocompatibility complex; XL, X-linked recessive Modified from Cossu F Genetics of SCID Ital J Pediatr 2010;36:76 Some natural killer cells may be present CD41 T cells are typically decreased but not absent, chronic diarrhea CHAPTER 103 Congenital Immunodeficiency Classical pathway (immune complexes) C1-INH C1q C1r C2 Lectin pathway (pathogen oligosaccharides) C1s C4 MBL Alternative pathway (pathogen surfaces) MASP C2 C4 1217 C3b Factor B Factor D C3 Factor I C5 Factor H C6 MCP C7 Membrane attack complex C8 CD59 C9 • Fig 103.1 The complement cascade is activated via three major mechanisms: the (1) classical pathway, which is initiated by antigen/antibody complexes; (2) alternative pathway, which is initiated directly by bacterial cell wall components; and (3) lectin pathway, which is initiated by carbohydrate moieties present on bacteria binding lectin (MBL) deficiency is relatively common in the general population (up to 14%), and the clinical importance of this deficiency is debatable as there are overlapping responses that may compensate for a lack of MBL Other complement deficiencies, such as C2, confer significant increased risks for infection and autoimmunity.4 Clinical Presentations Patients with defects in early complement components in the classical pathway typically present with recurrent invasive infections caused by encapsulated organisms (particularly Streptococcus pneumoniae) or with symptoms of autoimmunity (systemic lupus erythematosus [SLE] or glomerulonephritis) Patients with defects in the late complement components (C5–C9) that are involved in formation of the MAC typically present with recurrent or severe Neisseria infections.4 Patients who lack functional C1 esterase inhibitor have hereditary angioedema in which several stimuli can trigger massive, localized, severe attacks of edema that can be life threatening, especially if they involve the airway Patients with defects in complement regulatory proteins of the alternative pathway (factor I, factor H, and MCP) are at risk of developing familial hemolytic uremic syndrome (HUS) and age-related macular degeneration.5–7 Compartment 2: Phagocytes One of the major roles of phagocytic cells (neutrophils and macrophages) is to continuously survey the body for signs of infection Upon sensing an infection, they migrate from the circulation into the tissues toward the site of the infection, where they ingest both opsonized and nonopsonized pathogens and debris The ingested material is processed, and fragments of digested proteins are loaded into class II major histocompatibility complex (MHC) molecules that are transported to the cell surface, where they can be recognized by cells of the adaptive immune system Phagocytes with ingested pathogens can either remain at the site of infection or migrate back to local draining lymph nodes to present the antigen components of the pathogen to the adaptive immune arm, in this case the T cells Phagocytic disorders can occur as a result of one of four types of defects: (1) a defect in the amount of phagocytes (congenital neutropenia); (2) abnormal phagocyte migration (leukocyte adhesion deficiency and WHIM [warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis] syndrome); (3) inability of phagocytes to process or degrade material or organisms that have been ingested (chronic granulomatous disease [CGD]); or (4) a defect in the response to pathogen signaling and upregulation of the inflammatory response (such as occurs with mutations in STAT1 and STAT3) Clinical Presentations Because of the role that phagocytes play in controlling bacterial and fungal pathogens, patients with phagocytic defects often present with infections and abscesses of skin, deep tissues, and organs caused by bacteria or fungi Symptoms can include boils or cellulitis with or without pus, lymphadenitis, pneumonia, osteomyelitis, delayed shedding of the umbilical cord, omphalitis hepatic abscesses, gastrointestinal disorders, gingivitis, and refractory warts The onset of symptoms of phagocyte disorders is typically in infancy or early childhood Noninfectious complications include colitis, obstructive granulomas in the gastrointestinal/ genitourinary tract, and autoimmune diseases such as SLE Importantly, patients may not show signs of significant inflammation— including fever, swelling, and pain—until late in the infectious process due to a failure to increase inflammation by the innate system In children with these innate defects, fever and sickness behaviors may be a late sign of infection Compartment 3: B Cells and Antibodies The predominant role of B cells in the immune system is to make antibodies (immunoglobulins) in response to antigen challenge (e.g., pathogens, vaccines) The absence of functional antibodies causes susceptibility to bacterial and viral infections Antibody deficiency can occur in one of three different ways: (1) significant hypogammaglobulinemia or low levels of one or more immunoglobulin (Ig) 1218 S E C T I O N X I Pediatric Critical Care: Immunity and Infection classes (IgG, IgA, IgM) occurring as a result of decreased antibody production, which may be associated with specific genetic defects; (2) hypogammaglobulinemia as a result of excessive antibody loss, typically through the kidneys as proteinuria or through the gut as protein-losing enteropathy; (3) functional antibody deficiency, in which immunoglobulin levels are normal but the immunoglobulin lacks the quality required to bind and opsonize pathogens Clinical Presentations Patients who lack sufficient levels of functional antibody often present with recurrent and/or unexpectedly severe bacterial otosino-pulmonary infections (sinusitis, otitis media, bronchitis, and pneumonia) In addition, patients may develop opportunistic bowel infections caused by microorganisms such as Giardia or Cryptosporidium that are usually only modestly pathogenic to normal individuals In addition to these symptoms, patients with certain antibody-deficiency disorders have characteristic clinical features that can provide clues to the specific diagnosis These are discussed in more detail later in the chapter Compartment 4: T Cells A handful of disorders are characterized by the absence of T cells only It is much more common, however, for T-cell deficiency or dysfunction to be part of a more extensive combined immunodeficiency accompanied by defects in B cells and/or natural killer (NK) cells Identification of a number of new genetic defects over the past decade has dramatically expanded the spectrum of this group of disorders Some are typified by significant generalized T-cell lymphopenia while others are characterized by the absence or dysfunction of one or more specialized subsets of T cells Clinical Presentations Patients who have a generalized absence of functional T cells are susceptible to unusual or severe viral infections caused by viruses including cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus Patients are also susceptible to fungal infections caused by organisms such as Pneumocystis jirovecii, which are not pathogenic in normal individuals but commonly cause pneumonias in this group of patients In parts of the world where the attenuated mycobacterium bacilli Calmette-Guérin (BCG) is used as a vaccine, patients with T-cell deficiency often develop invasive and disseminated mycobacterial infection that is often fatal A lack of functional T cells also makes it impossible to provide adequate T-cell help to allow B cells to undergo normal immunoglobulin class-switching; thus, patients usually have functional antibody deficiency as well, hence the “combined” name In addition, patients with T-cell deficiencies frequently have symptoms of autoimmunity, including diarrhea (secondary to autoimmune enteropathy), cytopenias (autoimmune hemolytic anemia [AIHA]), and idiopathic thrombocytopenic purpura (ITP), and hepatitis Specific Disorders Likely to Be Encountered in the Pediatric Intensive Care Unit Specific Disorders: Complement C1 Inhibitor Deficiency Deficiency or dysfunction of C1 esterase inhibitor is the cause of hereditary angioedema (HAE) HAE is an autosomal dominant disorder that affects in 10,000 to in 50,000 Unlike many of the other early-complement component deficiencies, absence of C1 esterase inhibitor (C1-INH) does not lead to increased risk for infection Instead, this protein regulates the activity of kallikrein, which causes bradykinin release as a result of cleavage of highmolecular-weight kininogen (HMWK) In the absence of C1-INH, minor irritants such as the menstrual cycle, dental procedures, or surgery can cause unabated production of bradykinin and other mediators of vascular permeability, leading to rapid swelling of the soft tissues (angioedema), severe abdominal pain, and, at times, acute obstruction of the airway Diagnosis of C1-INH deficiency can be made by measuring the level and function of the C1 inhibitor in blood Patients with C1-INH deficiency also have low complement C4 levels as well, which can provide an additional clue to the diagnosis Effective treatments are now available for HAE, including purified C1 esterase inhibitor, a kallikrein inhibitor, and a bradykinin B2 receptor antagonist.8–10 These therapies can be life-saving during an acute attack These products may be administered at the beginning of an attack to abort symptoms or prophylactically to prevent the onset of an attack Unlike angioedema associated with anaphylaxis, which responds well to epinephrine injections, patients with C1-INH deficiency typically exhibit no responses to epinephrine as the pathophysiology is not mediated through mastocyte degranulation Early Pathway Defects (C1, C2, C3, C4) Patients with defects in early complement pathway proteins C1 to C4 are susceptible to invasive infections with encapsulated organisms Streptococcus pneumoniae and Haemophilus influenzae are particularly fulminant pathogens in these patients The infectious susceptibility is compounded by functional antibody deficiency in some patients Among these disorders, C2 deficiency is the most common complement component deficiency associated with susceptibility to infections, occurring in approximately of 20,000 people In addition to the dramatic infectious susceptibility, patients with defects in early classical pathway proteins are at high risk of developing autoimmunity (SLE and/or glomerulonephritis) As an example, in patients with homozygous C2 deficiency, approximately 50% of patients develop SLE or glomerulonephritis.11 The autoimmunity caused by complement deficiency is difficult to treat because no amount of immunosuppression will control the underlying pathophysiologic mechanism of disease There are a growing number of anecdotal reports and small case series in which severe SLE caused by complement deficiency was effectively treated with intermittent infusions of fresh frozen plasma, which contains active complement proteins Late Pathway Components: Membrane Attack Complex Defects (C5, C6, C7, C8, C9) Patients with defects in the late complement pathway proteins that form the MAC (C5–C9) are susceptible to invasive infections with Neisseria species These patients have a 7000- to 10,000-fold higher risk of developing meningococcal disease than the normal population.12 On the basis of this, some have suggested that every patient who develops Neisseria meningitides sepsis should be screened for complement deficiency, because of the high incidence of recurrence (40%–50%) in these individuals Complement Regulatory Protein Defects (Factor H, Factor I, MCP) The complement cascade is regulated at multiple levels by a series of regulatory proteins that prevent indiscriminate activation that could lead to inappropriate inflammation and tissue destruction CHAPTER 103 Congenital Immunodeficiency Diseases of immunodysregulation (3%) Phagocytic defects Combined immunodeficiency Complement defects (2%) Others (7%) Antibody defects 9% 7% 54% Cellular defects 18% • Fig 103.2 Distribution of the major primary immunodeficiency disorders (Data from the Jeffrey Modell Foundation Survey, 2009.) (Fig 103.2) Because all complement pathways converge on the activation of C3 before initiation of the MAC, the cell-bound regulatory proteins that deactivate the cleaved C3 are among the most important functionally Mutations in factor H, factor I, or MCP allow the complement cascade to be more readily activated and lead to susceptibility to thrombotic microangiopathy mediated by complement (atypical HUS), which may be triggered even in the absence of bacterial infection Genetic testing and functional assay are available to detect abnormalities in these regulatory proteins In patients with uncontrolled HUS, therapeutic monoclonal antibodies that bind to C5 and prevent formation of the MAC have been used to control disease Specific Disorders: Phagocytes Severe Congenital Neutropenia Patients with severe congenital neutropenia (SCN) typically present early in life with recurrent infections, including invasive softtissue infections and sepsis Staphylococcal infections are particularly problematic Mutations in five different genes have now been associated with SCN: ELANE, which is inherited in an autosomal dominant manner, causes increased myeloid cell apoptosis and can present either with SCN or with a cyclic neutropenia phenotype GFI1, which is also inherited in an autosomal dominant manner, causes defective myeloid cell differentiation HAX1, which is inherited in an autosomal recessive manner, is associated with increased myeloid cell apoptosis and is the cause of the classic Kostmann neutropenia syndrome G6PC3, which is inherited in an autosomal recessive manner, causes excessive myeloid cell apoptosis and is associated with a variety of other congenital defects, including cardiac, urogenital, endocrine, auditory, and facial anomalies WAS, in which specific activating mutations in the CDC42 binding domain of the WASp protein are inherited in an X-linked recessive manner, leads to abnormal and dysregulated actin polymerization that causes defective neutrophil chemotaxis and increased apoptosis.12 Clinical management of SCN involves a heightened suspicion for infections and aggressive treatment if these arise Treatment of acute infections may require antibiotics combined with granulocyte colony-stimulating factor (G-CSF) to increase neutrophil 1219 counts Despite there being little evidence specifically in SCN supporting the use of prophylactic antibiotics, extrapolation from data in leukemic patients with neutropenia suggests a benefit; thus, it is used in most patients Prophylactic long-term therapy with G-CSF is typically used only in those patients who have recurrent severe bacterial infections despite antibiotic prophylaxis or in patients with fungal infections Bone marrow transplantation is effective in SCN, although there is little to no reported experience in those genetic disorders that are rarer, such as glucose-6-phosphatase catalytic subunit (G6PC3) deficiency Leukocyte Adhesion Deficiency Leukocyte adhesion deficiency (LAD) is caused by the absence of functional adhesion receptors that are required for the migration of phagocytes from the circulation into the tissues The characteristic clinical features of LAD include recurrent skin and soft-tissue infections, which often lead to development of cutaneous boils or deep ulcers despite elevated peripheral blood leukocyte counts Interestingly, the inability of leukocytes to migrate to these sites of infection leads to an absence of pus in the lesions, which can be a useful diagnostic clue Wound healing is also compromised, and patients typically have marked gingivostomatitis Three forms of LAD are detailed online at ExpertConsult.com WHIM Syndrome Warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis (retention of neutrophils in the bone marrow; WHIM) syndrome is caused by autosomal dominant mutations in CXCR4, the receptor for the chemokine CXCL12 (SDF-1) Patients with WHIM syndrome typically present in childhood with recurrent bacterial otitis media, sinusitis, bronchitis, pneumonia, and cellulitis The bacterial susceptibility is a result of the combination of hypogammaglobulinemia and neutropenia In addition to bacterial infections, patients with WHIM syndrome have a particular susceptibility to papillomavirus infections, which can be severe and lead to early malignancy The mechanisms that underlie the viral susceptibility are not entirely understood but are thought to possibly be intrinsic to the epithelial cells In the hematopoietic system, CXCL12 causes homing of cells to the bone marrow and controls release of these cells from the marrow Neutrophils and lymphocytes from patients with WHIM syndrome have an increased chemotactic response to CXCL12, suggesting that the neutropenia and lymphopenia observed in WHIM syndrome are the result of inappropriate cell retention in the marrow.17 Treatment with G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) can normalize the neutrophil counts, although these often cause significant bone pain at the doses required.18 Recent studies using the CXCR4 antagonist plerixafor in adults with WHIM syndrome have shown promise for improving neutrophil counts by mobilizing neutrophils from the bone marrow.19,20 Antibiotics and immunoglobulin replacement can significantly reduce the risk of bacterial infections There is little reported experience regarding bone marrow transplantation for WHIM syndrome, although anecdotal evidence suggests that it may correct the neutropenia and hypogammaglobulinemia but may not alter the papillomavirus susceptibility.21 Chronic Granulomatous Disease CGD 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 1219.e1 LAD-I, the most common form of LAD, is caused by mutations in the ITGB2 gene encoding the b2-integrin CD18 Mutations cause an absence of the CD11/CD18 integrin complex on the surface of leukocytes, which can be readily discerned by flow cytometry LAD-II is caused by mutations in the SLC35C1 gene encoding the GDP-fucose transporter These mutations cause defective expression of sialyl Lewis X (sLeX), a fucose-containing ligand on neutrophils sLeX is the ligand for E- and P-selectins, which are expressed on the surface of cytokine-activated endothelial cells and allow neutrophil rolling As a result of the fucose defect, all patients with LAD-II also have the rare Bombay blood group, which is a useful diagnostic test for suspected LAD-II LAD-III is caused by mutations in the FERMT3 gene that encodes kindlin-3, a coactivator that is required for activation and function of b1-, b2-, and b3-integrins Absence of functional kindlin-3 leads to dysfunction of CD18 and causes an LAD phenotype (see LAD-I, discussed earlier) In addition, patients with LAD-III also have a Glanzmann-type bleeding disorder resulting from dysfunctional integrin-mediated aggregation of platelets.13 Patients with LAD-I and LAD-III typically present in childhood and often have a severe course with early mortality, whereas patients with LAD-II are often milder and may live into adulthood Treatment of leukocyte adhesion deficiency can be more complicated than some of the other phagocytic disorders because, in addition to aggressively treating infections with antibiotics, active soft-tissue infections may require recurrent donor white cell infusions of functional neutrophils in order to clear the infection Because the primary defects of LAD are intrinsic to hematopoietic cells, bone marrow transplantation can be curative.14–16 ... deficiency is relatively common in the general population (up to 14%), and the clinical importance of this deficiency is debatable as there are overlapping responses that may compensate for a lack of... draining lymph nodes to present the antigen components of the pathogen to the adaptive immune arm, in this case the T cells Phagocytic disorders can occur as a result of one of four types of defects:... a number of new genetic defects over the past decade has dramatically expanded the spectrum of this group of disorders Some are typified by significant generalized T-cell lymphopenia while others