Primary Immunodeficiency Diseases

Shradha Agarwal

Charlotte Cunningham-Rundles

Normal immune function is necessary for maintenance of health, though the first line of defense to infections are the natural physical barriers, skin and the epithelial surfaces of the respiratory, intestinal, and genital tracts, all of which serve to exclude such microbial invaders. Because the mucosal epithelium is a more permeable mechanical barrier than skin, other mechanisms in this location augment resistance, including ciliary clearance, mucus, low stomach pH, lysozyme, and lactoferrin. When infectious agents penetrate these tissues, other host factors, such as cytokines, complement, and phagocytic cells (neutrophils and macrophages) provide a second line of defense. At both the mucosal and systemic levels, a third line of immune defense includes the adaptive immune system: B lymphocytes, which produce antibodies, and T-cell-mediated immunity. Defects in components of these two systems lead to a spectrum of clinical manifestations, depending on the system(s) affected, the extent of impairment, and the compensatory mechanisms that can be recruited.

Deficiencies of the immune system can be congenital or acquired and are diagnosed in infants, children, or adults. Because primary immune (PI) defects have heterogeneous clinical manifestations, it can be difficult to determine which patients might benefit from an evaluation of the immune system and what tests are appropriate in each case. While patients with PI defects have infections with the same pathogens and may need repeated courses of antibiotics, the majority of patients seen in the office with recurrent infections are immunocompetent. This is especially the case in children since allergic rhinitis and asthma are among the most common diseases leading to repeated upper and lower respiratory tract infections. Other diseases, such as cystic fibrosis or the immotile cilia syndrome, may need to be considered to provide an accurate diagnosis and determine the correct therapy. Determining if an immune defect is likely to be present can be problematic, but some guidelines can aid the practicing clinician.

I. CLASSIFICATION OF PRIMARY IMMUNODEFICIENCY

The overall incidence of PI diseases is estimated at about 1 in 10,000, excluding selective IgA deficiency, which is much more common (see Section I.C); for unknown reasons, more than half of the reported immune defects (also excluding IgA deficiency) involve defects in antibody production. Despite the major advance in the molecular characterization of these diseases, many patients remain undiagnosed or are diagnosed after severe complications have already occurred, making early recognition important. To evaluate a patient for immunodeficiency, a basic understanding of the immune system is useful. The International Union of Immunologic Sciences (IUIS) has compiled a catalog of the known defects of the immune system that is periodically updated.

An overview of major immunodeficiency syndromes, divided by type, is given in Table 18-1. Within these major headings, recognized clinical syndromes can be grouped, according to the predominant mechanism(s) that is defective.

A. Combined cellular and antibody (T- and B-cell) deficiencies. The most severe and characteristic form of combined immune defects are the severe combined immunodeficiencies (SCID), a group of defects characterized by significant T-cell defects and B-cell dysfunction (Table 18-2). Since combined immune deficiencies also impair the production of antibodies, multiple severe infections are likely to occur in the first few months of life. Most infants have decreased numbers of T lymphocytes, hypogammaglobulinemia, and loss of antibody production. Another well-known combined defect is Wiskott-Aldrich syndrome, found in males, commonly associated with thrombocytopenia and eczema.

B. Cellular deficiency (T-cell) disorders. DiGeorge’s syndrome is the best characterized T-cell defect, and most DiGeorge patients have cardiac abnormalities and hypocalcemia, though the syndrome can be quite heterogeneous with only subtle defects such as cleft palate in some. Although it is operationally useful to classify DiGeorge’s syndrome as an isolated T-cell disorder, when thymic development and T-cell function is markedly impaired, antibody formation is also deficient.

C. Antibody deficiency (B-cell) disorders are the most common PI defects. Selective IgA deficiency is the most common, of these, and has an incidence of approximately 1 in 500 to 1,000 in patients of European origin. While most of these individuals do not have medical problems, allergies, asthma, and various autoimmune diseases (e.g., celiac disease, thyroiditis) are more common in patients with selective IgA deficiency. More medically important are the defects in which serum immunoglobulin (Ig) levels (IgG, IgA, and/or IgM) may be markedly decreased or completely absent. The best known of these defects is Bruton’s X-linked agammaglobulinemia (XLA), which is almost always diagnosed in males in early childhood. Aside from this B-cell defect, the majority of patients with significant antibody defects such as common variable immune deficiency (CVID) are adults when the defect is recognized. Of uncertain incidence, antibody deficiency with normal serum immunoglobulin concentrations may also occur. Antibody deficiency in these cases can be broad (both antibody to protein and polysaccharide antigens are absent) or more restricted (e.g., to carbohydrate bacterial capsular antigens).

D. Complement deficiencies account for a small percentage of primary immunodeficiencies. The most commonly diagnosed is deficiency of the C1 inhibitor, which results in recurrent attacks of angioedema (this is covered in Chapter 12, Urticaria and Angioedema). As complement activation leads to appropriate opsonization of microbes, this loss can result in inadequate coating of bacteria with antibody, reduced or absent phagocytosis, or ineffective lysis of microorganisms, leading to severe bacterial infections such as meningitis, sepsis, or organ abscesses. Defects in the early components of the classical complement pathway (C1, C2, C4) typically manifest as systemic lupus erythematosus-like autoimmune manifestations, but recurrent sinopulmonary infections also occur with C2 deficiency. C2 deficiency is the most common defect in subjects of European descent and estimated to occur in 1:10,000 subjects. Defects in the late components of complement (C5 to C9), necessary for generation of the membrane attack complex (MAC), result in susceptibility to infections
with Neisseria meningitidis, sepsis, or gonococcal arthritis. Alternative complement pathway defects, such as factors B, D, and properdin, can also lead to Neisseria infections.

Table 18-1 Types of Primary Immunodeficiency Syndromes

	Clinical Findings	Lab Findings	Inheritance	Molecular Defects
Predominately antibody deficiencies
Agammaglobulinemia	Recurrent and severe bacterial infections, enteroviral infections, absent lymphoid tissue, autoimmunity	Absent IgM, IgG, and IgA; B cells <1% of lymphocytes; absent specific antibody response	XL and AR	X-linked (BTK), autosomal recessive (µ heavy chain, λ5, Igα, Igβ, BLNK)
Common variable immunodeficiency (CVID)	Variable phenotype: Recurrent bacterial infections, autoimmune disease, lymphoproliferative and/or granulomatous disease	Low IgG and IgA and/or IgM; absent specific antibody response; normal or decreased B-cell numbers; variably decreased T-cell responses	Variable	Mutations in ICOS, CD19, CD20, CD81, TNFRS-F13B, TNFRSF13C, mostly unknown
Hyper-IgM syndrome	Recurrent bacterial infections, opportunistic infections, neutropenia, autoimmune disease, sclerosing cholangitis	Low IgG and IgA; normal or increased IgM; normal or increased B-cell numbers; decreased T-cell responses in CD40L/CD40 deficiency	XL and AR	Mutations in CD40L, CD40, AICDA, UNG
Selective IgA deficiency	Usually asymptomatic; some with recurrent bacterial infections, atopy, autoimmunity, and gastrointestinal disorders	Low/absent IgA; normal IgG and IgM; impaired specific antibody responses in some patients	Variable	Unknown
Specific antibody deficiency	Recurrent upper respiratory tract infections	Normal IgG, IgM, and IgA levels; impaired specific antibody response (polysaccharides); normal B-cell numbers	Variable	Unknown
IgG subclass deficiency	Usually asymptomatic, some with recurrent bacterial infections, atopy, and autoimmunity	Low levels of one or more IgG subclasses; normal total IgG, IgA, and IgM; normal B-cell numbers; impaired specific antibody responses in some patients	Variable	Unknown
Transient hypogammaglobulinemia of infancy (THI)	Recurrent upper respiratory tract infections	Low IgG levels with variably low IgA and rarely low IgM; normal specific antibody responses in most; normal B-cell numbers	Variable	Unknown
Combined T- and B-Cell immunodeficiencies
T-B+NK-SCID	Failure to thrive, chronic diarrhea, oral thrush, recurrent and severe bacterial, viral, and/or fungal infections early in life	Decreased serum immunoglobulins; normal or increased B-cell numbers; markedly decreased T-cell numbers	XL or AR	Defects in JAK3, γ-chain of receptors for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
T-B-NK-SCID	Failure to thrive; chronic diarrhea; recurrent and severe bacterial, viral, and/or fungal infections early in life; costochondral junction flaring; neurologic features; hearing impairment; lung and liver manifestations	Decreased serum immunoglobulins; absent T- and B-cell numbers	AR	Defects in adenosine deaminase
T-B-NK+SCID	Failure to thrive, chronic diarrhea, oral thrush, recurrent and severe bacterial, viral, and/or fungal infections early in life; those with Omenn’s syndrome have erythroderma, adenopathy, hepatosplenomegaly, eosinophilia; those with Cernunnos have microcephaly, growth retardation, radiation sensitivity	Decreased serum immunoglobulins; markedly decreased T- and B-cell numbers	AR	Defect in RAG 1/2, Artemis, ligase 4, Cernunnos
T-B+NK+ SCID	Failure to thrive, chronic diarrhea, oral thrush, recurrent and severe bacterial, viral, and/or fungal infections early in life	Decreased serum immunoglobulins; normal or increased B-cell numbers, markedly decreased T-cell numbers	AR	IL-7 receptor α-chain
CD8+CD4-B+NK+ SCID	Failure to thrive, recurrent and severe bacterial, viral, and/or fungal infections early in life	Normal or decreased serum immunoglobulins; normal B-cell numbers; decreased CD4 cells; normal CD8 cells	AR	Mutations in MHC class II proteins
CD8-CD4+B+ NK+ SCID	Failure to thrive, recurrent and severe bacterial, viral, and/or fungal infections early in life	Normal serum immunoglobulins; normal B-cell numbers; decreased CD8, normal CD4 cells	AR	Defects in ZAP70
Other immunodeficiencies
DiGeorge’s syndrome	Conotruncal malformation; hypoparathyroidism; abnormal facies; absent thymus in complete forms	Immunoglobulins usually normal though occasionally IgE elevated and IgA reduced; normal B-cell numbers; low to absent T-cell numbers in complete forms; varying degrees of T-cell function according to thymic deficiency	De novo or AD	Evidence that point mutations in the TBX1 gene is involved
Hyper-IgE syndromes	Distinctive facial features (broad nasal bridge), eczema, osteoporosis, fractures, scoliosis, delayed shedding of primary teeth, bacterial infections (skin and pulmonary abscesses), susceptibility to intracellular bacteria, fungi, and viruses	Elevated IgE >2,000 IU/mL; eosinophilia in some	AD or AR	Mutations in STAT3, TYK2, DOCK8
Chronic mucocutaneous candidiasis	Chronic mucocutaneous candidiasis, autoimmunity	Normal serum immunoglobulins; normal B-cell numbers; normal T-cell numbers (defect of Th17 cells in CARD9 deficiency)	AD, AR, sporadic	Mutations in CARD9 in one family with AR inheritance; AIRE defects in some; unknown in others
Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED)	Autoimmune disease (usually parathyroid and adrenal), candidiasis, dental enamel hypoplasia	Normal T- and B-cell numbers; organ-specific autoantibodies	AR	Defects in AIRE
X-linked lymphoproliferative (XLP)	Clinical and immunologic abnormalities triggered by EBV infection; hepatitis, aplastic anemia, lymphoma	Normal or low immunoglobulins; normal T-cell numbers; normal or reduced B-cell numbers	XL	Defects in SH2D1A, XIAP
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)	Autoimmune diarrhea, early-onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema	Elevated IgA and IgE; normal B-cell numbers; lack of CD4+CD25+ FOXP3+ regulatory T cells; eosinophilia	XL	Defects in FOXP3
Ataxia-telangiectasia	Ataxia, telangiectasia, pulmonary infections, lymphoreticular and other malignancies, increased x-ray sensitivity, chromosomal instability	Often low IgA, IgE, and IgG subclasses; increased IgM monomers; antibodies variably decreased; normal B-cell numbers; progressive decline in T-cell numbers; increased alpha fetoprotein	AR	Mutations in ATM
Autoimmune lymphoproliferative syndrome (ALPS)	Splenomegaly, adenopathy, autoimmune blood cytopenias, defective lymphocyte apoptosis	Increased double-negative T cells; normal B-cell numbers	AD or AR	Defects in TNFRSF6, CASP10, CASP8, NRAS
Wiskott-Aldrich syndrome	Thrombocytopenia, eczema, autoimmune disease, bacterial and viral infections, lymphoreticular malignancy	Decreased IgM; often increased IgA and IgE; antibody response to polysaccharides decreased; normal B-cell numbers; progressive decrease in T-cell numbers with abnormal lymphocyte responses to anti-CD3	XL	Mutations in WAS
Chronic granulomatous disease (CGD)	Diarrhea, colitis, hepatomegaly, splenomegaly, granulomas, abscess, skin infections, recurrent bacterial and fungal infections (Staphylococcus aureus and Aspergillus)	Defective oxidative burst by DHR or NBT equivalent	XL or AR	Mutations in CYBA, CYBB, NCF1, NCF2
Abbreviations: AD, autosomal dominant inheritance; AICDA, activation-induced cytidine deaminase; AIRE, autoimmune regulator; AR, autosomal recessive inheritance; ATM, ataxia-telangiectasia mutated; BLNK, B-cell linker protein; BTK, Bruton’s tyrosine kinase; CARD9; caspase recruitment domain-containing protein 9; CASP, caspase; CYBA, cytochrome b alpha subunit; CYBB, cytochrome b beta subunit; DHR, dihydrorhodamine; DOCK8, dedicator of cytokinesis; FOXP3, forkhead box protein 3; ICOS, inducible costimulator; JAK3, Janus kinase 3; MHC II, major histocompatibility complex class II; NBT; nitroblue tetrazolium; NRAS, neuroblastoma RAS protein; RAG, recombination activating gene; SH2D1A, SH2 domain protein 1A; STAT3, signal transducer and activator of transcription 3; TBX1, T-box 1; TNFRSF, tumor necrosis factor receptor superfamily; TYK2, tyrosine kinase 2; UNG, uracil-DNA glycosylase; WAS, Wiskott-Aldrich syndrome; XL, XIAP, X-linked inhibitor of apoptosis; X-linked inheritance; ZAP70, zeta chain-associated protein kinase, 70kD

Table 18-2 Lymphocyte Phenotypes Associated with Various Forms of SCID

Phenotype	Form of SCID
T-B-NK-	ADA
T-B+NK-	JAK3, γ-chain of receptors for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
T-B-NK+	RAG 1/2, Artemis, ligase 4, Cernunnos
T-B+NK+	IL-7 receptor α-chain
CD8+CD4-B+NK+	MHC class II
CD8-CD4+B+NK+	ZAP70
Abbreviations: ADA, adenosine deaminase; JAK3, Janus kinase 3; RAG, recombination activating gene; ZAP70, zeta chain-associated protein kinase, 70kD.

E. Phagocytic disorders. Defects of neutrophils can be categorized as due to impaired numbers, loss of chemotaxis, phagocytosis, and/or intracellular killing. The commonest defect is neutropenia, often discovered during the course of an evaluation of bacterial infections or inflammation of the mucus membranes or gingiva. Severe neutropenia, defined as absolute neutrophil count below 500 cells/µL, occurs in Kostmann’s syndrome (congenital neutropenia). This needs to be distinguished from autoimmune neutropenia, which also occurs in infancy but spontaneously resolves by age 5 or 6. Cyclic neutropenia is an autosomal dominant inherited disease characterized by neutropenia that recurs every 14 to 35 days (the majority occur in a 21-day cycle) for 3 to 5 consecutive days per cycle. Most cases are mild and benign but occasionally severe with life-threatening infection. Another well-characterized neutrophil defect is chronic granulomatous disease (CGD) in which there is loss of the genetic mechanisms leading to the oxidative burst, resulting in defective intracellular bacterial killing, abscess formation, and, over time, organ damage. Another genetic defect is leukocyte adhesion deficiency (LAD), in which leukocytes fail to attach to endothelial cell surfaces due to mutations in the CD18 integrin; here, leukocytes are unable to migrate into tissues to eliminate bacteria.

F. Other defects of innate immunity. Mutations in genes encoding the toll-like receptors (TLR) result in a selective susceptibility to pathogens. For example, patients with mutations in the genes encoding IRAK4 and MYD88 are susceptible to severe and invasive pyogenic infections early in life. The infections become less frequent after the first 10 years of life, but mortality is high in the first decade. Heterozygous mutations in TLR3 and biallelic mutations in UNC93B have been also identified in infants with selective susceptibility to herpes simplex encephalitis, with reduced production of type 1 interferon (IFN). Defects of the IL-12/IFN-γ pathway (IL-12 p40 subunit, IL-12 receptor β1 chain, chains of the IFN-γ receptor, and STAT1 gene) are associated with susceptibility to mycobacterial disease. Mutations in the IKBKG gene,
which encodes NF-kB essential modulator (NEMO), a regulatory factor of the nuclear factor κB signaling pathway, lead to an X-linked disorder called NEMO deficiency characterized by ectodermal dysplasia, bacterial infections, and increased susceptibility to mycobacterial disease.

G. Disorders of immune dysregulation. A number of the components of the immune system are required for appropriate immune regulation. Because of this, it might not be surprising that some forms of PI are associated with immune dysregulation and autoimmunity. During the early development of the immune system, the first step in the exclusion of autoimmunity occurs in the thymus, with deletion of autoreactive T-cell clones, a process called central immune tolerance. Mutations of the AIRE gene, which is essential for the deletion of T-cell clones that recognize self-antigens, lead to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). In this syndrome, autoimmune manifestations such as hypoparathyroidism and adrenal insufficiency along with chronic mucocutaneous candidiasis occur. Mutations of the FOXP3 gene, which is essential for the development of T-regulatory cells, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The IPEX syndrome in males incorporates severe enteropathy, eczema, and insulin-dependent diabetes. Mutations of Fas (CD95), which is involved in intracellular signaling pathways essential for activation of caspases and cell death, are the predominant cause of autoimmune lymphoproliferative syndrome (ALPS). This constellation is characterized by striking lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenia.

II. CLINICAL FINDINGS IN IMMUNODEFICIENCY DISORDERS

The most frequent clinical indicator of an immune defect is the occurrence of “too many infections.” This is the main manifestation of infants and children with PI and presents a significant challenge to the physician because infections are so common in normal childhood. When frequent and prolonged infections are coupled with failure to thrive, or if unusual infections appear, an evaluation of the immune system is in order. For older children and adults, frequent or unusual infections may also suggest an immune defect, but in these age groups, other medical indications such as autoimmunity, enlarged lymph nodes or spleen, and weight loss, among other signs, may also suggest the presence of an immune defect. For all age groups, a confirmed report of an immunodeficiency disease occurring in a sibling or first-degree relative should also prompt careful clinical assessment and laboratory investigation, even without a history of severe or unusual infections. Some of the more common clinical findings of PI are listed in Table 18-3.

A. History

1. Sinopulmonary infections are a common symptom of most PI diseases. In most cases, sinopulmonary infections, including recurrent otitis media, sinusitis, bronchitis, and pneumonia, are due to common respiratory bacterial pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae (often untypeable), Moraxella catarrhalis, Staphylococcus aureus, and Pseudomonas aeruginosa. Although frequent (6 to 10 per year) upper respiratory infections are common in normal young children, especially if there is exposure to older siblings or to other children (e.g., daycare centers)
or coexisting respiratory allergies, there are some distinguishing characteristics of infections that can suggest abnormal host resistance (such as the presence of fever, more purulent secretions, lack of clear allergy symptoms, lymphadenopathy, positive family history for immunodeficiency, or need for frequent antibiotics). These infections can become chronic and lead to complications, such as perforated tympanic membranes, otitis media with mastoiditis, restrictive lung disease, or bronchiectasis.

Table 18-3 Clinical Features of Immunodeficiency

Usually present	Recurrent upper respiratory infections—sinusitis, bronchitis, pneumonia, otitis media Severe bacterial infections Persistent infections with incomplete or no response to therapy
Often present	Failure to thrive or growth retardation for infants or children Weight loss in adults Intermittent fever Infection with unusual organisms Skin lesions, such as rash, seborrhea, pyoderma, necrotic abscesses, alopecia, eczema, telangiectasia Recalcitrant thrush; cutaneous or mucosal Autoimmune disease such as autoimmune thrombocytopenia, hemolytic anemia, rheumatologic disease, alopecia, thyroiditis, pernicious anemia, vitiligo Diarrhea and malabsorption Hearing loss due to chronic otitis
Occasionally present	Sclerosing cholangitis Lymphadenopathy Hepatomegaly and/or splenomegaly Severe viral disease (e.g., varicella or herpes simplex) Chronic encephalitis Recurrent meningitis Pyoderma gangrenosum Adverse reaction to vaccines Delayed umbilical cord detachment Chronic stomatitis or peritonitis Bronchiectasis Granulomas Lymphoid malignancies Chronic conjunctivitis
(Adapted from Stiehm ER, Ochs HD, Winkelstein JA. Immunodeficiency disorders: general considerations. Immunologic disorders in infants and children, 5th ed. Philadelphia, PA: Elsevier Saunders, 2004:289-355.)

2. Other bacterial infections (e.g., deep infections such as cellulitis, osteomyelitis, meningitis, or sepsis). Although severe infections can occur in healthy individuals, two severe infections of this kind suggest the possibility of PI. A patient presenting with recurrent abscesses caused by
gram-negative organisms such as Escherichia coli, Burkholderia cepacia, Serratia

Only gold members can continue reading. Log In or Register to continue