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 pre−B-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, 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 CD4 + and CD8 + 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 early-onset, 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.
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 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.
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. 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). 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.
|B Cells/Antibodies||T Cells|
|T − B − NK −||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|
|T − B − NK +||RAG1 deficiency||RAG1||AR|
|DNA ligase IV deficiency||LIG4||AR||Radiosensitivity, microcephaly, growth retardation|
|Cernunnos/XLF deficiency||NHEJ1||AR||Radiosensitivity, microcephaly, growth retardation|
|T − B + NK −||Common γ-chain deficiency||IL2RG||XL|
|CD45||PTPRC||AR||Some natural killer cells may be present|
|T − B + NK +||IL-7 receptor-α (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|
|T + / − B + NK +||MHC class I deficiency||TAP1||AR||CD8 + T cells are typically decreased but not absent, recurrent respiratory infections|
|MHC class II deficiency||CIITA||AR||CD4 + T cells are typically decreased but not absent, chronic diarrhea|
|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|
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. Defective activation of the entire complement cascade can be caused by the absence or dysfunction of only 1 of more than 20 complement proteins. Mannose 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.
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. 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.
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 ).
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) 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.
Patients who lack sufficient levels of functional antibody often present with recurrent and/or unexpectedly severe bacterial oto-sino-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.
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 1 in 10,000 to 1 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 high-molecular-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. 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 1 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. 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. 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 ( 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 soft-tissue 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.
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 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 3 (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 .
LAD-I, the most common form of LAD, is caused by mutations in the ITGB2 gene encoding the β2-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 (sLe X ), a fucose-containing ligand on neutrophils. sLe X 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 β1-, β2-, and β3-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.
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.
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. 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. 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. , 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.
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 all CGD patients. The remaining forms, caused by mutations in the CYBA , NCF1 , NCF2 , or NCF4 genes, are all autosomal recessive. All mutations affect the formation or function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex on neutrophil phagolysosomes. The NADPH oxidase is required to generate a burst of reactive oxygen species in response to phagocytosis of pathogens. Reactive oxygen species activate proteases in the phagolysosomes that destroy ingested bacteria. In CGD, the oxidative burst cannot be generated, leading to defective processing of ingested organisms and an inability to appropriately eliminate bacterial and fungal pathogens. Catalase-positive organisms—including Staphylococcus species, Aspergillus species, Burkholderia cepacia , Serratia marcescens , and others—are the most common pathogens. The most common types of infection at presentation are pneumonia, lymphadenitis, osteomyelitis, cellulitis, and hepatic abscesses (particularly with Aspergillus ). The most common cause of premature death is Aspergillus infection. In addition to the infectious susceptibilities of CGD, a substantial percentage of patients struggle with inflammatory complications that are common to this disorder, including an inflammatory colitis that occurs in approximately 40%, hepatic dysfunction, gingivitis, and others.
Treatment of CGD revolves around aggressive management of acute infections followed by prophylaxis against future infections using a combination of daily antibiotic (typically, trimethoprim-sulfamethoxazole), daily antifungal (typically, itraconazole), and thrice-weekly interferon-γ injections. This combination has dramatically improved outcomes in CGD. However, despite appropriate use of this regimen, some patients ultimately have increasing symptoms that lead to a decline in survival beginning in the late-teens or early 20s. The prospects for long-term survival appear to be correlated with the amount of residual oxidative burst activity that can be generated by a particular patient’s phagocytes. Many now recommend that for patients who have mutations that severely impact oxidative burst activity, bone marrow transplantation should be considered preemptively, early in life before patients develop comorbidities.
Specific disorders: B cells and antibodies
X-linked agammaglobulinemia (XLA) is the prototypic B-cell disorder. It is caused by mutations in the Bruton tyrosine kinase (BTK) gene. BTK is a cytoplasmic tyrosine kinase that is required for the maturation of B-cell precursors in the bone marrow. Mutations in BTK therefore cause an arrest of B-cell development at the pre−B-cell stage, leading to virtual absence of circulating B cells in the peripheral blood. Mutations that only partially interfere with the enzymatic function of BTK have also been described and are associated with milder forms of the disease that have defects only in generation of specific antibody responses.
XLA is typically suspected in male patients with recurrent bacterial sinopulmonary infections and B-cell lymphopenia. Other infections that occur relatively frequently in patients with XLA before the initiation of IgG replacement therapy include skin infections (furunculosis, pyoderma, and cellulitis) and sepsis. The diagnosis can be confirmed either by identifying a mutation in the BTK gene or demonstrating absence of the BTK protein in monocytes or platelets. A positive family history suggestive of an X-linked recessive mode of inheritance increases the suspicion for XLA. It is uncommon for patients with XLA to develop symptoms in the first months of life because newborns are protected from most infections by transplacentally acquired maternal IgG. There are few distinguishing physical features of XLA that can provide clues to the diagnosis, but absence of visible tonsils or adenoids (by physical examination, radiograph, or computed tomography [CT] scan) is a useful clue.
In addition to the common sinopulmonary pathogens, patients with XLA are also susceptible to infections by particular opportunistic organisms that can cause unusual clinical syndromes. For example, Helicobacter cinaedi can cause a syndrome of dermatomyositis and cellulitis that presents with cutaneous ulcerations, particularly on the lower legs. , The organism can sometimes be recovered from the blood but is fastidious and difficult to culture using the usual methods. A combination of antibiotics is often necessary to effectively clear the infection. Similarly, Mycoplasma species, including M. hominis , can cause lung, abdominal, or bone infections that are remarkably hard to eradicate and Ureaplasma urealyticum infections are a rare cause of arthritis, urethritis, and pneumonia.
Before the widespread use of IgG supplementation in these patients, opportunistic viral infections, particularly with viruses that require an extracellular phase, were especially problematic. For example, echovirus encephalitis was estimated to be the cause of death in ∼10% of boys with XLA in the 1970s, but that number has fallen dramatically with aggressive use of IgG supplementation. There continue to be rare cases of echovirus encephalitis in patients with XLA, even in those on adequate IgG replacement therapy. However, these are thought to be caused by viral strains for which there may not be high antibody titers in the particular IgG preparation being used. , Similarly, a mink astrovirus strain was identified by deep sequencing from the brain of an XLA patient who developed a neurodegenerative disorder as a teen. Interestingly, he had lived next to a mink farm as a child but was started on immunosuppression early in his teens for inflammatory bowel disease (IBD), which may have allowed the virus to escape control. Lastly, infections with vaccine-strain poliovirus were pathogenic in undiagnosed patients with XLA who were immunized with the live-viral vaccine after transplacentally acquired maternal antibody had waned. The shift from live attenuated to killed poliovirus for immunization has essentially eliminated new cases.
Inflammatory conditions are associated with XLA. Even though autoantibodies are not produced, up to 25% of patients had complaints consistent with autoinflammation, such as arthritis, hypothyroidism, or IBD.
Hyperimmunoglobulin M syndromes
Under normal circumstances, binding of antigen to cell surface IgM on naïve B cells induces activation of the B cell.
The antigen that is bound to surface IgM on the B cell is ingested and proteolytically digested. Antigenic peptide fragments are displayed on the B-cell surface in MHC class II molecules. Antigen-specific T cells then engage the B cell via MHC II/T-cell receptor (TCR) interactions. Once engaged, the activated helper T cell (Th) provides additional costimulatory signals to the B cell that are critical to promote immunoglobulin class-switching from IgM to IgG, IgA, and IgE. The most important of these costimulatory signals comes via the interaction of CD40 ligand on activated T cells with CD40 on B cells. Activation of the B cell through CD40 and cytokines that are secreted by the Th cause it to undergo class-switch recombination (CSR), during which the µ-heavy chain gene segment within the immunoglobulin gene is replaced by either a γ, α, or e gene segment. This is accomplished by nicking and double-strand breakage of the deoxyribonucleic acid (DNA) in the immunoglobulin heavy-chain locus, which requires a series of enzymatic steps that involve activation-induced cytidine deaminase (AID), uracil DNA glycosylase (UNG), and others. Therefore, genetic defects that affect CD40 ligand (CD40L), CD40, AID, or UNG can prevent class-switch recombination, thus thwarting the B cells’ ability to make significant amounts of any antibody isotype besides IgM.
Classic laboratory findings include elevated IgM with very low serum IgG and IgA levels. Specific antibody responses to vaccine antigens are decreased and patients lack switched memory B cells (CD27 + IgM − IgD −) due to failed class-switch recombination.
The overwhelming majority of patients with hyper-IgM syndrome have the X-linked form caused by X-linked recessive mutations in CD40 ligand (CD40L/CD154), which is encoded by the CD40L gene on the X chromosome. CD40L and its receptor CD40 are members of the tumor necrosis factor superfamily of ligands and receptors. In lymphocytes, CD40L is expressed only on activated T cells but is also expressed on platelets, where its role is unknown. Neutropenia may also be found in these patients. Affected boys may present with recurrent bacterial sinopulmonary infections caused by hypogammaglobulinemia. B lymphocytes are present, and T-cell numbers are generally normal. In almost all cases, the diagnosis can be made by using flow cytometry to evaluate the expression and function of the CD40L protein on activated T cells. Expression is evaluated using antibodies specific to the CD40L protein, and the function is evaluated by measuring the binding of a CD40-Ig heavy chain fusion protein to the expressed CD40L. Gene sequencing can then be performed in order to identify a specific mutation.
In addition to the usual bacterial pathogens, patients with CD40L mutations also demonstrate unique susceptibilities to fungal infections, particularly Pneumocystis jirovecii , which causes pneumonia, and to a protozoan, Cryptosporidium parvum , which causes bowel infections, discussed online at ExpertConsult.com .
Pneumocystis jirovecii and cryptosporidium parvum infections among patients with hyperimmunoglobulin M and CD40L mutations
The susceptibility to Pneumocystis and possibly other fungal pathogens has been somewhat of a puzzle because patients do not have other signs of a significant cellular immune defect, such as severe or recurrent viral infections. Interestingly, the susceptibility to Pneumocystis jirovecii (PJ) pneumonia appears to go away in most patients by the age of 5 years. PJ pneumonia is almost always diagnosed by staining bronchoalveolar lavage fluid for the presence of the organism. PJ pneumonia can be readily prevented by prophylactic trimethoprim-sulfamethoxazole administration; active disease is amenable to treatment using higher doses of the same drug. Recent data have suggested that the fungal susceptibility in CD40L deficiency may be a result of defective CD40L signaling into dendritic cells and monocytes that express CD40.
Cryptosporidium parvum (CP) bowel infections are more difficult to diagnose and manage in patients with CD40L deficiency. CP may cause abdominal pain, bloating, diarrhea, malabsorption, and weight loss. It may require multiple stool samples to identify the oocysts; occasionally, the diagnosis can be made only on endoscopically obtained biopsy specimens. Treatment with paromomycin or nitazoxanide can clear the infection, although prolonged courses are typically needed in hyper-IgM patients and treatment failures are not uncommon. CP infections can result in chronic inflammation of the gut and biliary tree, which seems a likely contributor to the high incidence of bile duct cancers seen in these patients. ,
Treatment involves the use of IgG replacement therapy combined with prophylactic antibiotics for prevention of PJ pneumonia at least until the age of 5 years. The role of bone marrow transplantation for CD40L deficiency is still being evaluated. Even though a number of patients have undergone successful bone marrow transplantation, its role remains somewhat controversial in this disease, although in patients with ongoing CP infection, the prognosis for the patients who develop sclerosing cholangitis is so poor that the risks of transplantation are well justified. ,
CD40 deficiency is clinically similar to CD40L deficiency. It is inherited as an autosomal recessive defect that has been described primarily in two cohorts from Italy and the Middle East. It results in a syndrome that is almost identical to CD40L deficiency in which both sexes are affected.
Autosomal recessive mutations in activation-induced cytidine deaminase (AID) and uracil DNA glycosylase (UNG) also cause a hyper-IgM phenotype, but it tends to be milder than either CD40L or CD40 deficiency, likely because the defect is limited to B cells, whereas CD40L/CD40 signaling plays a role in other cell types, including dendritic cells and monocytes. , Patients with AID or UNG typically live into adulthood and do not demonstrate the same susceptibility to PJ pneumonia and CP bowel infections. Patients with mutations in AID do, however, have a significant propensity to develop autoimmunity affecting various organ systems. Patients are typically treated with IgG replacement therapy and antibiotics for acute infections. There are no reports of bone marrow transplantation for AID or UNG deficiency.
Common variable immunodeficiency syndromes
Common variable immunodeficiency (CVID) is a heterogeneous disorder that is likely caused by a variety of molecular mechanisms that ultimately lead to a similar clinical phenotype. The International Consensus Document (ICON) for CVID has proposed diagnostic criteria in an effort to standardize the diagnosis of CVID. These include (1) plasma IgG levels that are less than 2 standard deviations below the mean for age combined with a marked decrease in either IgM or IgA, (2) age of onset of immunodeficiency greater than 2 years, (3) absent isohemagglutinins or poor responses to vaccines, and (4) defined causes of hypogammaglobulinemia have been excluded.
The peak age of onset of CVID is in the second or third decade of life and 50% to 60% of patients have a clinical phenotype consisting almost exclusively of increased bacterial sinopulmonary infections. With IgG supplementation, this group of patients has a relatively benign course with long-term survival that is not unlike the normal population. The other half of patients have a complicated disease course with autoimmunity or lymphoproliferative disease that can involve the hematopoietic system, lungs, lymph nodes, liver, and bowel. The long-term outcome of this population is significantly worse, approaching only 40% survival over 40 years.
Among the disorders seen in this population, granulomatous, lymphoproliferative, interstitial lung disease (GLILD) affects approximately 30% to 40% of patients. This often presents with decreasing lung function that is manifested by cough, decreased exercise tolerance, and, sometimes, hypoxemia. Typical findings on chest CT scan include diffuse nodules within the lung, opacities that have a ground-glass appearance, bronchial wall thickening, and, sometimes, bronchiectasis. Lung biopsy generally demonstrates a lymphocytic interstitial pneumonitis with noncaseating granulomas and a follicular bronchiolitis with lymphoid aggregates of both B and T cells. This pattern is sometimes mistaken for sarcoidosis, although there are differences. Over time, this inflammatory process in the lungs will cause destruction of alveoli and contribute to development of bronchiectasis and emphysematous changes. If left unchecked, there is evidence that irreversible damage and fibrosis develop in many patients. High-dose corticosteroids are often used as first-line therapy to treat this process. In many cases, they are effective but do not typically lead to a lasting remission on their own. A recent study using a combination of anti-CD20 monoclonal antibody (rituximab) therapy and azathioprine in a small cohort of CVID patients with GLILD demonstrated dramatic responses, with a prolonged remission of disease in many patients.
In addition to pulmonary symptoms, gastrointestinal complaints are common in CVID, affecting 20% to 30% of patients. Patients who develop disease demonstrate a hypertrophic lymphoproliferation of Peyer patches that causes a nodular lymphoid hyperplasia in the bowel. This is associated with abdominal discomfort, diarrhea, malabsorption, and weight loss and can cause significant morbidity. A variety of approaches have been taken to treat this process, but none have offered particularly dramatic results, although nonabsorbable steroid preparations have shown some benefit with minimal side effects. A more troubling complication observed in 5% to 10% of patients is hepatitis, which can cause severe hepatic dysfunction with development of hepatosplenomegaly and ascites. Infectious causes are almost never identified, and liver biopsy demonstrates a nodular lymphoid hyperplasia in the liver parenchyma, not unlike that observed in the bowel. Liver disease is among the complications associated with a poor outcome.
Some 20% of subjects have additional clinical findings that are suggestive of autoimmunity/immune dysregulation, including immune thrombocytopenia and hemolytic anemia, neuropathy, endocrinopathies, and skin disease. Skin involvement ranges from alopecia and vitiligo to psoriasis and granuloma annulare. ,
In most cases of CVID, the molecular etiology of disease is unknown. However, there has been some progress in identifying genetic defects associated with a CVID phenotype, which is detailed online at ExpertConsult.com .
Genetic defects associated with a common variable immunodeficiency phenotype
The most common mutations identified are autosomal recessive defects in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which are found in 7% to 10% of patients with CVID. Unfortunately, even in patients who have mutations that abrogate protein expression, the penetrance of disease seems to be highly variable, with individuals from one family harboring the same mutation, having either a CVID phenotype, a selective IgA deficiency phenotype, or no disease at all. This inability to correlate disease phenotype or prognosis with the presence of a TACI mutation has raised the question of whether TACI genotyping offers clinical value. In addition to TACI, autosomal recessive mutations in the genes encoding the Baff receptor ( BAFFR ), the inducible T-cell costimulator ( ICOS ), CD19 , CD20 , CD21 , CD81 , the LPS-responsive vesicle trafficking, beach and anchor containing protein ( LRBA ) and cytotoxic T-lymphocyte-associated protein 4 ( CTLA4 ) have been identified in some patients with features of CVID. These mutations have provided insight into basic immune mechanisms in humans but explain only a handful of all patients with CVID. , Lastly, hypomorphic mutations in BTK (X-linked agammaglobulinemia), CD40L (X-linked hyper-IgM syndrome), SAP/SH2D1A (X-linked lymphoproliferative syndrome), and RAG1/RAG2 can be associated with a CVID-like phenotype and, according to the diagnostic criteria for CVID, need to be excluded before making this diagnosis.
B-cell numbers in peripheral blood are typically normal, but a subset of CVID patients has B-cell lymphopenia. In those patients with normal B-cell numbers, B-cell maturation, memory development, and immunoglobulin class-switching are often abnormal and can be assessed by detailed flow cytometry–based immunophenotyping of B cells. Varying classification schemes have been proposed to subtype patients according to their B-cell phenotype; these subsets have been correlated with differences in risk for autoimmunity and other factors. Thus, B-cell immunophenotyping has become a useful clinical tool in caring for patients with CVID. In addition to the humoral immunodeficiency, many patients with CVID have impaired T-cell function with decreased CD4 or CD8 T-cell numbers as well as abnormal T-cell proliferative responses in vitro to mitogens and antigens. Regulatory T-cell numbers and function have also been found to be decreased in patients with CVID.
Selective immunoglobulin a deficiency
Selective IgA deficiency (SIgAD) is common in the general population, with an incidence as high as 1 in 300 individuals in blood bank studies. The majority (>50%) of patients with selective IgA deficiency have no apparent symptoms that can be directly linked to their immune defect. Severe infections as a consequence of IgA deficiency alone are virtually unheard of. In the patients who do have symptoms, they are typically more suggestive of immune dysregulation and autoimmunity (e.g., allergy, arthritis, diarrhea, celiac disease) than immunodeficiency (sinusitis, otitis media, bronchitis, and pneumonia). In patients who have no peripheral IgA at all, sensitization to IgA itself can be problematic, leading to anaphylactic reactions during infusions of blood products that contain immunoglobulin, red blood cells, and platelets. However, this is quite uncommon and may be managed by pretreatment with antihistamine, acetaminophen, and corticosteroids.
Specific disorders: T cells
22q11 deletion syndrome (digeorge syndrome)
22q11.2 deletion syndrome, or DiGeorge syndrome (DGS), is among the few disorders with isolated T-cell deficiency. Hemizygous deletion within the 22q11.2 region of the long arm of chromosome 22 has been associated with a spectra of clinical syndromes, including DGS, velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTFS), CATCH22 syndrome, and others. DGS is the name most commonly associated with immunodeficiency. The most common disease-causing deletion includes a region containing the TBX1 gene, a transcription factor involved in the development of branchial arch structures. Impaired embryogenesis of the third and fourth pharyngeal arches causes abnormal development of the thymus and parathyroid. While DGS is a complex syndrome that has been associated with a wide array of symptoms, the diagnostic criteria proposed by the European Society of Immune Deficiency (ESID) are relatively straightforward. These propose that a diagnosis of DGS should be strongly considered in patients who have less than 500 CD3 + T cells/μL and any two of the following three characteristics: (1) conotruncal cardiac defect (truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, or aberrant right subclavian); (2) hypocalcemia requiring therapy for more than 3 weeks; and (3) deletion of chromosome 22q11.2. This chromosomal deletion syndrome occurs in approximately 1 in 4000 to 5000 births and causes haploinsufficiency of the genes encompassed in the deletion that can extend to include as much as 3 Mb of the chromosome. ,
The characteristic T-cell lymphopenia of DGS is thought to arise primarily from the hypoplastic thymic tissue; at times, the diagnosis is suspected when the cardiac surgeon correcting a congenital heart defect finds little or no thymic tissue in the mediastinum. Most affected infants have low but not absent T cells, and absolute counts tend to improve over the first year of life. Both CD4 + and CD8 + T cells are low, yet CD8 + T-cell numbers tend to be more affected in most patients. Despite low T-cell counts, most patients do not have significant problems with recurrent or severe viral or fungal infections. Some patients may have recurrent candidiasis. Bacterial infections of the upper respiratory tract, including otitis media and sinusitis, do occur but may be related more to anatomic issues associated with the facial anomalies than to the immunodeficiency per se. Rare patients (1%) have severe T-cell lymphopenia with essentially no T cells and are termed complete DGS as opposed to partial DGS. These patients may have a clinical phenotype similar to SCID and require hematopoietic stem cell transplantation. ,
Other prominent clinical features include hypocalcemia, which can be severe and persistent due to parathyroid hypoplasia; dysmorphic facial features that include small, low-set ears, hypertelorism, and micrognathia; renal anomalies, including horseshoe kidney and a duplicated collecting system; and developmental delay, including problems with speech acquisition, learning disabilities, and behavioral problems. Patients with DGS have also been found to have an increased incidence of autoimmunity, including cytopenias (particularly affecting red cells and platelets), juvenile idiopathic arthritis, and thyroiditis.
In symptomatic patients, the diagnosis of DGS is typically made by confirming a deletion within the 22q11.2 region by fluorescence in situ hybridization or quantitative polymerase chain reaction for deletion of the TBX1 gene that lies within the deletion. In approximately 10% of patients, deletion of this region cannot be detected despite presence of the classic clinical features.
Treatment of DGS initially involves supportive care that may include cardiac support and calcium supplementation. In patients with severe T-cell lymphopenia or evidence of decreased T-cell function, prophylaxis against PJ pneumonia and IgG supplementation may be used. Blood transfusion for these patients should be irradiated to prevent the risk of graft-versus-host disease (GVHD). For those patients with the severe complete form of the syndrome, grafting of allogeneic thymus slices into the thigh muscle has proven to be successful in recovering the T-cell lymphopenia, improving T-cell responses, and correcting the infectious susceptibility. , Hematopoietic stem cell transplantation (HSCT) has been used in a handful of patients with mixed results. , In general, HSCT restores the T-cell counts and protects patients against further infection. However, in the absence of a thymus, the T-cell graft is thought to consist primarily of long-lived, committed lymphoid progenitor T cells and not of cells derived from donor bone marrow stem cells. As a result, there is concern that the T-cell grafts may senesce over time, once again leaving the patient lymphopenic and susceptible to infection. There are currently no long-term therapies that can successfully correct the parathyroid defect.
Severe combined immunodeficiency
SCID is among the most severe immunodeficiencies. It is now known that this category of diseases is made up of a variety of related disorders caused by mutations in more than 20 different genes. The one thing that is common to all forms of SCID is deficiency of one or more subsets of T cells. In many cases, there are no circulating T cells. Depending on the genetic defect, patients may also lack B cells and/or NK cells. This has led to the useful convention of defining cases of SCID by their cellular phenotype (i.e., T − B + NK + , T − B + NK − , T − B − NK + , T − B − NK − ). The cellular phenotype suggests what the underlying genetic defect may be ( eTable 103.3 ). Because of the absence of functional T cells, patients with SCID typically come to medical attention because of severe or chronic viral infections, fungal infections, or autoimmunity. Physical examination findings in SCID that may provide some clues to the diagnosis include a paucity of palpable lymph nodes and absence of a thymic shadow on chest radiograph. In the overwhelming majority of SCID cases, this leads to death in infancy or early childhood if patients do not undergo curative treatment, such as HSCT or gene therapy. Unfortunately, the presence of infections makes HSCT or gene therapy much more complicated and substantially decreases the chances of survival. Because of this, efforts have been underway in the United States and other countries to perform screening of all newborns using dried blood spot cards obtained at birth to identify those who may have SCID. These efforts have led to the recognition that the incidence of SCID is approximately 1 in 40,000 live births in the United States. ,