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MD Consult: Books: Goldman: Cecil Medicine: Chapter 271 – PRIMARY IMMUNODEFICIENCY DISEASES

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 271 – PRIMARY IMMUNODEFICIENCY DISEASES

 

Mark Ballow

 

Definition

 

A diverse group of abnormalities of the immune system leads to increased susceptibility to infection. More than 100 primary immunodeficiency diseases have been described, and in many of these disorders, the genetic defect has been delineated. Immunodeficiency diseases are relatively uncommon; it is important to rule out other underlying conditions, such as secondary immunodeficiencies that could lead to recurrent infections. Immunodeficiencies are generally divided into the following categories: B-cell or antibody immunodeficiencies, T-cell or cellular immunodeficiencies, immunodeficiencies associated with the phagocytic system, and immune abnormalities associated with the complement system. Many immune abnormalities, such as those associated with the T-cell immune system, have associated B-cell immune abnormalities as well. Although many primary immunodeficiencies are first noticed in infants and young children, the most frequent B-cell (humoral) immunodeficiencies become evident later in life, especially in young adults whose characteristic presentations should be recognized by the physician so diagnosis and treatment can be initiated.

It is not the purpose of this chapter to present an encyclopedic list of all the known immunodeficiencies, but rather to identify the most common presenting clinical characteristics, to define the initial laboratory evaluation, and to discuss the approach to treatment briefly. Antibody deficiencies make up approximately 65% of all primary immunodeficiency diseases, combined T-cell and B-cell immunodeficiencies constitute approximately 15%, cellular immunodeficiencies approximately 5%, phagocytic cell abnormalities 10%, and complement deficiencies only 5% ( Fig. 271-1 ).

 

 

FIGURE 271-1  The relative number of subjects who present with primary immunodeficiency diseases are shown. Subjects who have common variable immunodeficiency (CVID), immunoglobulin G (IgG) subclass deficiency, or IgA deficiency (IgA def) represent about half of the total group. Other deficiencies include transient hypogammaglobulinemia of infancy (THI), chronic granulomatous disease (CGD), antibody deficiency (Ab def), DiGeorge syndrome, hyper-IgM syndrome, other T-cell defects, X-linked agammaglobulinemia (XLA), complement deficiencies, combined defects (def), hereditary angioedema (HANE), phagocytic abnormality (ab), severe combined immunodeficiency (SCID), and the neutropenias.

Pathobiology

 

Genetics

 

The defective gene has been identified in more than 100 primary immunodeficiency disorders ( Table 271-1 ). The mode of inheritance has often been identified in many of the immunodeficiencies as X-linked recessive, autosomal recessive, or autosomal dominant. Many of the immunodeficiencies are caused by mutations of genes required for the development of T cells or B cells or genes needed for the development of precursor cell lineages that differentiate into different types of immune cells. Other genetic abnormalities are widely expressed in many tissues that result in complex multisystem disorders along with the immunodeficiency. Some gene mutations that occur in the same immunologic pathway result in similar clinical manifestations and laboratory findings, such as common γ-chain defect of the interleukin-2 (IL-2) receptor and Janus kinase 3 (JAK3). Conversely, other genetic defects, depending on the nature and the location of the mutation, may result in different clinical phenotypes. An example of the latter is mutations in recombination activating gene (RAG)-1 and RAG-2, which result in severe combined immunodeficiency disease and Omenn’s syndrome. The Wiskott-Aldrich syndrome is another example in which variations in the location of the mutation along the gene sequence, such as a missense mutation that allows expression of a mutated protein, result in different clinical phenotypes and a spectrum of the disease.
TABLE 271-1   — IMMUNODEFICIENCIES AND AFFECTED GENES

Disease Gene/Proteins Chromosome Locus
ANTIBODY DEFICIENCIES
X-linked agammaglobulinemia BTK Xq21.3-q22
Autosomal recessive agammaglobulinemia Constant region of μ heavy chain 14q32.33
Autosomal recessive agammaglobulinemia IGLL1/λ5 or 14.1(CD179b) 22q11.21
Autosomal recessive agammaglobulinemia Igα/B29 (CD79A) 1q13.2
Autosomal recessive agammaglobulinemia BLNK 10q23.22
Immunoglobulin A deficiency IGAD1 6p21.3
Selective Immunoglobulin G subclass deficiencies IGHG1 14q32.33
IGHG2 14q32.33
IGHG3 14q32.33
IGHG4 14q32.33
κ-Chain deficiency IGKC 2P12
Autosomal recessive HIGM type3 TNFRSF5/CD40 20q12-q13.2
Autosomal recessive HIGM type 2 AICDA 12p13
Autosomal recessive HIGM UNG
COMBINED IMMUNODEFICIENCIES
T-B- SCID
RAG-1 RAG1 11p13
RAG-2 RAG2 11p13
Adenosine deaminase deficiency ADA 20q13.11
Athabaskan SCID Artemis 10p13
T-B+ SCID
X-linked SCID IL2Rγ/common γ chain receptor Xq13
JAK3 deficiency JAK3 19p13.1
IL-7 receptor α-chain deficiency IL-7RA/α chain 5p13
OTHER COMBINED IMMUNODEFICIENCIES
Purine nucleoside phosphorylase deficiency PNP 14q13.1
ZAP-70 deficiency ZAP70 2q12
CD3γ deficiency CD3G 11q23
CD3ε deficiency CD3E 11q23
CD25 deficiency Il-2Rα
CD45 deficiency CD45 1q31-32
TAP2 peptide transported deficiency TAP2 6p21.3
MHCII deficiency (defect in CIITA) MHC2TA 16p13
MHCII deficiency (defect in RFX5) RFX5 1q21.1-q21.3
MHCII deficiency (defect in RFXAP) RFXAP 13q14
MHCII deficiency (defect in RFXANK) RFXANK 19p12
X-linked immunodeficiency with increased immunoglobulin M TNFSF5/CD40Ligand Xq26.3q27.1
OTHER WELL-DEFINED IMMUNODEFICIENCIES
Wiskott-Aldrich syndrome WASP Xp11.23-p11.22
DiGeorge syndrome DGCR 22q11.2
Ataxia-telangiectasia ATM 11q22.3
X-linked lymphoproliferative syndrome SH2DIA/SAP Xq25
Familial hemophagocytic lymphohistiocytosis PRF1 10q21-22
ICF syndrome DNMT3B 20q11.2
X-linked immune dysregulation with polyendocrinopathy syndrome FOXP3 Xp11.23-q13.3
Hyper-immunoglobulin M with hypohidrotic ectodermal dysplasia NEMO/IKK γ chain Xq28
APECED AIRE 21q22.3
WHIM CXCR4 2q21
Nijmegan breakage syndrome NBS1/nibrin 8q21
Cartilage-hair hypoplasia RMRP 9p21-p12
Griscelli’s syndrome MYO5A/RAB27A 15q21
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS)
Fas defect TNFRSF6/CD95 10q24.1
Fas ligand defect TNFSF6/FasL/CD95L
Caspase 10 defect CASP10
Caspase 8 defect CASP8
PHAGOCYTIC IMMUNODEFICIENCIES
LAD type I ITGB2 (CD18) 21q22.3
LAD type II GDP-fucose transporter 11
LAD Rac2 deficiency Rac2 22q12.3
Chédiak-Higashi syndrome CHS1 1q42.1-q42.2
CD16 deficiency CD16 (FcγRIII) 1q23
Cyclic neutropenia Neutrophil elastase/ELA2 19p13.3
Neutrophil-specific granule deficiency C/EBPε 14q11.2
Mannose-binding protein deficiency MBP 10q11.2-q21
X-linked CGD gp91 phox CYBB/CD18 Xp21.1
Autosomal recessive CGD p22phox CYBA 16q24
Autosomal recessive CGD p47 phox NCF1 7q11.23
Autosomal recessive CGD p67 phox NCF2 1q25
Myeloperoxidase deficiency MPO 17q23.1
IFN-γ RECEPTOR/IL-12 PATHWAY DEFICIENCY
IFN-γ 1 receptor deficiency IFNGR1 6q23-q24
IFN-γ 2 receptor deficiency IFNGR2 21q22.1-q22.2
IL-12p40 deficiency IL12RB1 19p13.1-33.1
IL-12 receptor β1 deficiency IL12B 5q31.1-q33.1
STAT 1 deficiency STAT1 2q32.2-q32.3
APECED = autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy; CGD = chronic granulomatous disease; HIGM = hyper-immunoglobulin M; ICF = immunodeficiency, centromeric region instability, and facial anomalies; IFN = interferon; IL = interleukin; JAK = Janus kinase; LAD = leukocyte adhesion deficiency; MHC = major histocompatibility complex; RAG = recombinase activating gene; SCID = severe combined immunodeficiency; STAT = signal transducers and activators of transcription 1; WHIM = warts, hypogammaglobulinemia, infections, myelokathexis syndrome.

Clinical Manifestations

 

This chapter concentrates on presenting to the practicing physician the common clinical signs and the important details of the history and physical examination for the evaluation of a patient with recurrent infections. The association of particular bacterial and viral pathogens with certain immunodeficiencies is also helpful in directing the physician toward a differential diagnosis and an appropriate choice of screening laboratory tests.

History

 

Clues from the Infecting Pathogen and the Organ System Involved

 

The organ systems affected by the infection and identification of the isolated pathogens can give clues to the nature of the possible defect. A patient presenting with lymphadenitis or recurrent abscesses caused by low-virulence gram-negative organisms such as Escherichia coli, Serratia, or Klebsiella, may have an abnormality in phagocyte function. Infec-tions with unusual pathogens such as Staphylococcus epidermidis or Pseudomonas, especially Burkholderia cepacia, can suggest a leukocyte phagocytic disorder. Another characteristic presentation of patients with a phagocyte defect is a history of recurrent skin infections with catalase-positive Staphylococcus aureus, a finding underscoring the importance of effective phagocytosis and intracellular superoxide-mediated killing in controlling these infections. A history of delayed separation of the umbilical cord of more than 6 to 8 weeks or poor wound healing suggests the diagnosis of a leukocyte adhesion defect. Suppurative adenitis is common in patients with chronic granulomatous disease, and it can be an important clue in the diagnosis when gram-negative bacteria are recovered from the tissues. The mucous membranes can also be involved in patients with an immunodeficiency of a phagocytic cell. Gingivostomatitis and dental erosions are characteristic of patients with a phagocytic cell defect such as in leukocyte adhesion deficiency. Recurrent oral ulcers are characteristic of patients with cyclic neutropenia. Defects in the late complement components, C5 to C9, are classically associated with infections with neisserial species such as meningitis caused by Neisseria meningitidis or septic arthritis caused by Neisseria gonorrhoeae. Patients with C3 deficiency can present with overwhelming septicemia, especially with gram-negative organisms, a finding consistent with the important role of complement, particularly C3b, in opsonization and the facilitation of phagocytosis.

B-cell abnormalities most commonly lead to recurrent sinopulmonary infections that are frequently caused by encapsulated bacteria, such as Streptococcus pneumoniae or Haemophilus influenzae. Examination of the pharynx and nasal cavities for signs of sinusitis including posterior pharyngeal cobblestoning, postnasal drainage, or purulent nasal discharge is important. Tympanic membranes can appear scarred and disfigured as a sign of recurrent and chronic infection of the middle ear. Rales on auscultation of the chest may suggest bronchiectasis occurring as a complication of recurrent lung infections. Digital clubbing points to significant lung disease. Pulmonary hypertension can occur in patients with chronic lung disease. These types of infection underscore the importance of immunoglobulins in opsonization for effective phagocytosis and killing of the microorganism. A characteristic feature of patients with X-linked agammaglobulinemia (XLA) is an unusual susceptibility to a viral meningoencephalitis caused by enteroviruses (e.g., coxsackievirus, echovirus). Chronic gastrointestinal symptoms caused by Giardia lamblia are likely related to impaired mucosal immunity and lack of secretory IgA, and they commonly occur in patients with common variable immunodeficiency (CVID) and IgA deficiency. Small bowel bacterial overgrowth and infections with Yersinia and Campylobacter can lead to chronic gastrointestinal symptoms; diarrhea and occasionally malabsorption are frequent presenting symptoms in patients with CVID.

T cells are essential not only in controlling viral, fungal, mycobacterial, and protozoal infections but also in providing crucial signals to help B cells produce immunoglobulins. Extensive mucous membrane candidiasis would suggest a T-cell defect. Patients with cellular immune defects often present with opportunistic infections such as Mycobacterium avium intracellulare and Pneumocystis jirovecii.

Lymphatic System in Patients with Immunodeficiency

 

The examination of the lymphatic system for hepatosplenomegaly and for the presence or absence of lymphoid tissue is an important aspect of the physical examination in a patient suspected of immunodeficiency. Patients with severe combined immunodeficiency disease or infantile XLA do not have palpable lymphoid tissue or visible tonsils. However, the presence of lymphoid tissue can be misleading: adult patients with common variable hypogammaglobulinemia may actually have enlarged lymphoid tissue and even hepatosplenomegaly. This occurs because the reticuloendothelial system undergoes hyperplasia in the absence of opsonic antibody. Draining abscesses of the lymph nodes suggest a phagocyte defect.

Immunodeficiency and Autoimmunity

 

Deficiencies of the early complement components, such as C4 and C2, are associated with autoimmune disease often first manifesting with arthritis, frequently in conjunction with dermal vasculitis. A lupus-like rash with negative or low-titer antinuclear antibodies may occur in deficiencies of the early components of the classical complement pathway. Patients with some primary immunodeficiencies can present with features of autoimmunity involving hematopoietic or other organ systems. For example, the diagnosis of CVID can be preceded by autoimmune hemolytic anemia.

Immunodeficiency and Gastrointestinal Disease

 

Many patients with primary immunodeficiency disease have symptoms and clinical findings referable to the gastrointestinal tract. In a survey of 248 patients with CVID, 21% had significant gastrointestinal disease. Liver disease occurred in an additional 12%. Bacterial overgrowth of the small bowel, including infections with Yersinia and Campylobacter, parasitic infestations with such organisms as G. lamblia, and chronic viral enteritis caused by enteroviruses and cytomegalovirus are relatively common in patients with B- or T-cell immune defects. The incidence of lactose intolerance is higher in patients with immunodeficiency than in the immunologically normal population. Patients with the X-linked syndrome of immune dysregulation, polyendocrinopathy, and enteropathy (IPEX) have protracted diarrhea.

Immunodeficiency and Family History

 

A detailed family history in patients suspected of immunodeficiency can add valuable information. Numerous immunodeficiencies are X-linked; therefore, a family history of maternal male relatives affected with unusually frequent infections or who died in early infancy should alert the physician to the possibility of an X-linked form of immunodeficiency. The mother in these cases would be expected to be a carrier, although the rate of new mutations for X-linked disorders is significant, so a negative family history may not exclude this inheritance pattern. CVID and IgA deficiency are familial disorders and are often seen in a setting of other family members with autoimmune disorders, such as pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, or autoimmune hematologic diseases.

   DEFECTS IN THE INNATE IMMUNE SYSTEM: COMPLEMENT AND PHAGOCYTE DEFICIENCIES

 

   Deficiencies of Complement Proteins

 

Definition

 

The complement (C) system is important in host defense and is composed of a complex system of plasma proteins and cell surface receptors ( Chapter 47 ). Important functions of the complement system include opsonization to enhance phagocytosis, clearance of immune complexes, the induction of the humoral immune response, and the clearance of apoptotic cells. Complement deficiencies present as severe or recurrent invasive infection with encapsulated bacteria (resulting from loss of the opsonic function of C3 fragments), immune complex disease (because complement is important in the clearance and solubilization of immune complexes and in their removal from the circulation), angioedema, or the loss of bactericidal and bacteriolytic functions leading to recurrent or invasive infection with Neisseria species.

Epidemiology

 

The proportion of patients with primary immunodeficiency who have complement deficiencies is approximately 5%. Although rare, C2 deficiency is the most common of the classical early complement component diseases; it occurs in 1:10,000 whites. C6 deficiency is the most common of the late complement component disorders. The frequency of complement deficiency in sporadic cases of systemic meningococcal infection has been estimated to be 15%. In patients with recurrent meningococcal disease, the prevalence is as high as 40%.

Clinical Manifestations

 

These disorders are usually inherited as autosomal codominant traits, in which the parents of the patients have half-normal levels of the involved complement component, whereas the patient has a complete absence of the component in question. The complement deficiencies can be broadly divided into those of the early classical complement pathway (C1, C2, and C4), the components of the alternative complement pathway (factors B, D, and P), the mannose binding proteins and their associated proteases (MASP-1 and MASP-2), the late complement components (C5, C6, C7, C8, and C9), and the complement regulatory proteins (C1 inhibitor and others). Persons deficient in C3 share characteristics of both early and late component complement deficiencies. Patients lacking one of the early complement components often present with a rheumatic disease. Patients often have the typical features of systemic lupus erythematosus, except they often may be seronegative, that is, anti-DNA antibodies are absent, and antinuclear antibodies are present in low titer. Individuals with C2 deficiency may have systemic lupus erythematosus or discoid lupus. Other rheumatic disorders associated with complement deficiencies of the early complement components include dermatomyositis, scleroderma, vasculitis, and membranoproliferative glomerulonephritis. Homozygous factor H deficiency, a complement regulatory protein, may manifest as hemolytic-uremic syndrome. Likewise, deficiencies of late complement components may occasionally be associated with vasculitis or other lupus-like illnesses. Less frequently, patients with late component deficiencies have developed Raynaud’s syndrome, scleroderma, or dermatomyositis.

Patients with deficiencies in the late complement components usually present with recurrent infections caused by Neisseria species, with invasive meningococcal or gonococcal infection, such as recurrent meningococcal meningitis, gonococcal arthritis, or gonococcal septicemia. However, patients with deficiencies of early or alternative pathway complement components, such as properdin deficiency, may also present with recurrent or invasive neisserial infections.

Diagnosis

 

Individuals with recurrent blood-borne infection with encapsulated bacteria (e.g., S. pneumoniae, H. influenzae, invasive meningococcal or gonococcal disease) or immune complex disease should be screened for complement deficiency by determining the total hemolytic complement activity (CH50) in the serum, a test of classical pathway activity. The CH50 should be undetectable. If the CH50 is normal, alternative pathway function should be tested with the AH50. Hemolytic activity is very sensitive to heat degradation, so blood samples must be handled appropriately, and the serum should be separated and frozen at -70° C as soon as possible. Abnormalities in CH50 or AH50 could be pursued by analysis of specific component concentrations in serum.

Treatment

 

 

 

 

 

 

Patients should be immunized with the meningococcal vaccine. Some debate exists on whether to use prophylactic antibiotics because of the emergence of resistant strains.

   C1 Esterase Inhibitor Deficiency

 

Definition

 

C1 esterase inhibitor (C1 INH) deficiency is associated with life-threatening edema and is inherited as an autosomal dominant disorder ( Chapter 273 ). This complement regulatory plasma protein inhibits the enzymatic activity of C1r and C1s and thus regulates the activation of the early complement cascade. Type I C1 INH deficiency in 85% of patients is associated with diminished serum levels of C1 INH protein and therefore with deficient functional activity. In type II C1 INH deficiency (15%), the protein level is normal, but it possesses little or no functional activity. In acquired C1 INH deficiency, the clinical presentation is similar to the hereditary type but patients have developed an antibody to C1 INH. Many of these patients have an underlying lymphoproliferative disease.

   Phagocytic Cell Defects

 

Patients with defects in phagocyte function experience repeated infections at locations where the body surface interfaces with the environment. The evaluation of the patient with suspected phagocyte dysfunction requires an understanding of the steps involved in normal antimicrobial activity of these cells. Normal function of the phagocyte compartment of host defense requires adequate numbers of neutrophils and monocytes, as well as the normal performance of a number of closely integrated functions to result in the effective killing of a pathogen by the leukocyte. Defects in neutrophil number (neutropenia, cyclic neutropenia, Kostmann’s syndrome, Shwachman-Diamond syndrome), adherence, deformability, locomotion, chemotaxis, recognition of foreign particles and attachment, phagocytosis, oxidative respiratory metabolism, and intracellular microbial killing have all been reported. Data from the history and physical examination will help the clinician to focus attention on which phagocyte function is most likely to be defective. Absence of pus at the sites of infection, for example, suggests that the patient either has a decreased number of granulocytes or that these cells have an impaired ability to concentrate at the site of bacterial invasion, that is, defective chemotaxis or adhesion. A critical aspect of host defense is the accumulation of neutrophils at the site of infection. This process requires both the elaboration of chemotactic substances and a normal response by leukocytes to chemoattractants. Chemotactic substances important in vivo include complement activation fragments and the chemotactic peptides and lipids released by a variety of inflammatory cells including mast cells in the allergic response. A history of persistent abscesses with exudates, conversely, suggests that the phagocytes can migrate to the appropriate site but are defective in intracellular bacterial killing. A history of recurrent gingivitis, skin infections with furunculosis, abscesses of the viscera or perirectal tissues, and lymphadenitis should prompt evaluation of the phagocyte host immune defenses. Because of defective phagocyte function, the manifestations of infections may be blunted; erythema, swelling, and pus formation may be limited or absent. Phagocyte defects frequently manifest as infections caused by bacteria of relatively low virulence, such as S. aureus, fungi, and gram-negative enteric bacteria, including Klebsiella, E. coli, B. cepacia, and Serratia species. Infections often fail to respond optimally to the usual courses of antimicrobial agents. Many patients also have a history of poor wound healing, a finding reflecting the critical role of phagocytes in tissue repair. The clinical features of phagocytic cell defects are shown in Table 271-2 . The spectrum of phagocyte defects is discussed in more detail in Chapter 175 .
TABLE 271-2   — CLINICAL CHARACTERISTICS OF DISEASES OF PHAGOCYTIC CELL DYSFUNCTION

Range from mild skin infections to severe systemic infections

Skin infections, furunculosis, visceral or perirectal abscess with granuloma formation, lymphadenitis, gingivitis
Poor wound healing, lack of pus
Mainly susceptible to low-grade virulent bacterial infections

Staphylococcus species
Gram-negative organisms

   Interferon-γ/Interleukin-12 Pathway Deficiencies

 

These patients have increased susceptibility to infections with nontuberculous mycobacteria, Salmonella, and certain viruses, as well as disseminated infection following bacille Calmette-Guwérin vaccination. Several genetic defects of the monocyte-macrophage-TH1 T-cell pathway have been identified (see Table 271-1 ). Patients with receptor defects have severe impairment in interferon-γ signaling and fail to form tuberculoid granulomas. Patients with a partial defect have a better prognosis. Other patients with a similar clinical phenotype have an IL-12p40 deficiency or a mutation in the IL-12 receptor.

   DEFICIENCIES OF T-CELL IMMUNITY

 

Profound defects in T-lymphocyte function, or defects arresting development of T cells early in ontogeny, not only affect cell-mediated immunity but also impair the development of B-lymphocyte function (humoral immunity) resulting from the absence of T-cell help and T-cell–derived cytokines. The clinical syndromes resulting from these more profound immune defects are referred to as severe combined immunodeficiency disease. Recurrent infections with organisms of relatively low virulence in an immunologically normal host (opportunistic infections) occur. Patients with T-cell immunodeficiency also have infection with Candida albicans involving the mucous membranes and skin, but this infection is not invasive. Other fungal infections, severe viral diseases, and infection with opportunistic pathogens such as P. carinii or M. avium intracellulare should prompt an evaluation for disorders in T-cell function. Graft-versus-host disease can be a significant problem in patients with severe T-cell immunodeficiency either after transfusion of lymphocyte-containing blood products or as a result of intrapartum or prenatal maternal-fetal transfusion. The clinical characteristics of patients with T-cell deficiency are shown in Table 271-3 .
TABLE 271-3   — CLINICAL CHARACTERISTICS OF T-CELL DEFICIENCIES

Onset of symptoms frequently in early infancy (4–5 mo)
Recurrent infections with fungi (Candida), viruses, and mycobacterial pathogens
Infections with opportunistic organisms: Pneumocystis jirovecii
Failure to thrive, often fatal in childhood
Fatal infections from live virus vaccines or bacille Calmette-Guérin vaccination
Graft-versus-host disease from transfusion of blood products containing viable T lymphocytes

Patients should be evaluated for T-cell deficiency by enumerating peripheral blood T cell subsets and natural killer cells (NK cells) by flow cytometry, as well as functionally by lymphocyte proliferative responses to mitogens and specific antigens in vitro. Delayed hypersensitivity skin testing can serve as an initial screening test for T-cell immunity. Intracutaneous injection of 0.1 mL of recall antigens including Candida at 1:100 dilution wt/vol, tetanus toxoid at 1:100 dilution wt/vol, or Trichophyton at 1:30 dilution to a patient who was previously sensitized to these antigens should produce a reaction of redness and induration greater than 5 mm with a maximum response at 48 to 72 hours. Negative results are seen in patients with impaired T-cell responses, but they can also be seen because of lack of prior antigen exposure. Severe illness or systemic steroid use can also diminish delayed hypersensitivity responses (anergy).

Once the diagnosis of T-cell immunodeficiency has been established in cooperation with a clinical immunologist, the physician needs to be aware of several important issues in providing care to these patients. First, prompt recognition of infections and aggressive treatment is essential to avoid life-threatening complications and to improve prognosis and quality of life. This approach may include initiation of early empirical antibiotic coverage for suspected pathogens, obtaining appropriate cultures, and continued communication with the consulting immunologist. Prophylactic antibiotics are recommended for patients with significant T-cell defects because of the risk of P. jirovecii pneumonia; trimethoprim-sulfamethoxazole is the most commonly used antibiotic for P. carinii pneumonia prophylaxis. Live vaccines such as oral polio, varicella, and bacille Calmette-Guérin should not be given to patients with suspected or diagnosed antibody or T-cell immunodeficiency because vaccine-induced infection is a risk in these patients. Inactivated polio vaccine instead of oral polio vaccine should be given to household members, to prevent transmission of the virus that can occur via shedding of the attenuated virus in the stool. If patients with T-cell defects need blood transfusions, only irradiated, leukocyte-poor, and virus-free (cytomegalovirus) products should be used, to avoid graft-versus-host disease and cytomegalovirus infection. In patients with T-cell deficiency, varicella-zoster immunoglobulin may be indicated following varicella exposure.

With regard to T-cell immunodeficiency disorders, great strides have been made in the delineation of defects in the immune pathways because of advances in molecular biology (see Table 271-1 ). Although these patients usually present with these disorders early in life, advances in immune reconstitution by bone marrow transplantation enable patients to live into adulthood. The impact of the corrected T-cell defect on the occurrence of adult-type disorders, such as cardiovascular disease and others, is currently unknown. These profound T-cell immunodeficiencies manifest in early childhood and are not discussed in this chapter except for ataxia-telangiectasia.

Ataxia-telangiectasia is a form of SCID that manifests in childhood. The disease is due to a mutated gene that encodes for a DNA-dependent protein kinase involved in multiple intracellular functions. The clinical characteristics of this disorder are progressive cerebellar ataxia, ocular and cutaneous telangiectasias, and chronic sinus and lung infections. Patients may also develop a malignancy, either a B-cell lymphoma or T-cell leukemia. Immunoglobulin levels may be variably decreased or absent, and specific antibody levels may be normal or decreased. Patients also exhibit degrees of lymphopenia, decreased cellular immunity, a hypoplastic thymus, and elevated serum levels of α-fetoprotein. Treatment is supportive to include intravenous gamma globulin in those patients with immunoglobulin deficiencies.

   B-CELL IMMUNODEFICIENCIES

 

Unlike patients with severe combined immunodeficiency disease, in whom the onset of symptoms is at 4 or 5 months of age, patients with severe B-cell deficiencies usually do not have problems with infections until 7 to 9 months of age. The later onset of problems with infections in this group of patients occurs because they are protected initially by the maternal antibodies that passed through the placenta during the third trimester of pregnancy. These patients usually have infections with encapsulated bacterial organisms such as pneumococci and H. influenzae type b. The types of infection, as discussed previously, include otitis media, meningitis, septicemia, sinusitis, pneumonia, abscess, and osteomyelitis. Occasionally, these patients may have problems with fungal or viral pathogens. Male patients with infantile XLA have an unusual susceptibility to enteroviruses and may develop chronic enteroviral encephalomyelitis. Generally, one does not see severe growth failure in patients with B-cell deficiency, as in T-cell–deficient patients. Patients with antibody deficiency can survive into adulthood and can lead normal lives with the use of replacement intravenous immunoglobulin (IVIG) therapy.

Patients with severe B-cell deficiency, such as infantile XLA, typically have a paucity of lymphoid tissue (tonsils, adenoids, and peripheral lymph nodes). In contrast, patients with CVID often have lymphoid hypertrophy or hepatosplenomegaly. The incidence of allergy and autoimmune disease is increased, particularly in patients with IgA deficiency and CVID. The primary antibody deficiency disorders are shown in Table 271-1 , and the clinical characteristics of patients with B-cell deficiency are shown in Table 271-4 .
TABLE 271-4   — CLINICAL CHARACTERISTICS OF B-CELL DEFICIENCIES

Recurrent infections with encapsulated organisms
Sinopulmonary infections, otitis media, meningitis, sepsis, abscess, osteomyelitis, cellulitis
No problems with fungal or viral infections (except enteroviral infection in XLA)
Lymphoid tissues: absent in patients with XLA, hypertrophied in CVID
Increased incidence of atopy and autoimmune disease
Granulomatous lung disease in CVID
Gastrointestinal disease

Celiac disease
Lactose intolerance
Bacterial overgrowth of small bowel
Nodular lymphoid hyperplasia in CVID
Higher incidence of malignancy in CVID
CVID = common variable immunodeficiency; XLA = X-linked agammaglobu-linemia.

   X-Linked Agammaglobulinemia

 

Definition

 

XLA is an X-linked recessive B-cell immunodeficiency with agammaglobulinemia and absent circulating B cells.

Epidemiology

 

Worldwide, the incidence appears to be approximately 1 in 100,000 to 200,000 or 5 to 10 cases per 1 million population. The prevalence is 1 in 10,000.

Pathobiology

 

The gene responsible for XLA is located on the X-chromosome, and it has been identified as a cytoplasmic tyrosine kinase (i.e., Bruton’s tyrosine kinase [Btk]), which is expressed mainly in lymphocytes of the B-cell lineage. Btk is critical in B-lymphocyte signal transduction pathways and B-cell differentiation. Numerous distinct mutations of the BTK gene have been described in patients with XLA, most involving the kinase domain. Mutations in the BTK gene lead to a block in B-cell maturation from pro-B cells to pre-B cells.

Some patients with Btk mutations may not present until later in life. This variation may reflect different types of Btk mutations. In fact, the block in B-cell differentiation may be “leaky,” and the result may be some immunoglobulin synthesis. Study of one family showed marked phenotypic variation among the male members who had the same gene mutation; serum immunoglobulins also showed variability. A subgroup of patients with CVID may also present with profound hypogammaglobulinemia and markedly reduced numbers of B cells. In a study of male patients with recurrent infections and low numbers of B cells (<1%) by flow cytometry using a monoclonal antibody to the Btk protein, 10 patients were older than 15 years of age (∼9%). Investigators have estimated that approximately 10% of adult patients with CVID may be misdiagnosed and may have XLA with deficient Btk.

Clinical Manifestations

 

Infections occur predominantly in the sinopulmonary tract (60% of patients), including otitis media, chronic sinusitis, and pneumonia. Other types of infections include pyoderma (25%), chronic conjunctivitis (8%), gastroenteritis (35%), arthritis (20%), meningitis or encephalitis (16%), and, less commonly, osteomyelitis (3%) and septicemia (10%). The most common pathogens are H. influenzae and S. pneumoniae. Young male patients who are untreated experience repeated pulmonary tract infections, leading eventually to bronchiectasis. Infections may also occur with G. lamblia. Because cellular immunity is intact, most viral infections, fungal infections, and tuberculosis do not seem to be a problem in patients with XLA. Exceptions to this include viral hepatitis, disseminated polio, and chronic enteroviral encephalitis.

Physical findings relate to the occurrence of repeated bacterial infections of susceptible target organs, such as the middle ear, sinuses, and lungs. Patients have a paucity of lymphoid tissues, for example, adenoids, lymph nodes, and spleen, unlike patients with CVID, who often have lymphoid hyperplasia. Unusual complications in XLA include arthritis, a dermatomyositis-like syndrome, and meningoencephalitis, which are usually manifestations of chronic enterovirus infections, including the echoviruses and occasionally coxsackievirus.

Arthritis occurs in fewer than half of the patients with XLA, and it is usually an acute bacterial infection affecting the large joints. Sedimentation rates may be normal, and serologic tests are negative. In some patients, the joint inflammation results from infections with enteroviruses or with Ureaplasma urealyticum. Joint symptoms usually improve or resolve with IVIG therapy. Patients with XLA are highly susceptible to poliovirus infection; vaccine-associated poliomyelitis has been reported in XLA.

Unlike patients with CVID, autoimmune disorders do not seem to be a frequent problem in patients with XLA. Although a predisposition to various cancers seems to be common with many types of immunodeficiencies, it is less clear whether patients with XLA have the same predisposition. The primary immunodeficiency registry reported that only 4.2% of registry patients with malignancy had XLA; lymphoreticular and gastrointestinal malignant diseases were more common.

Patients with XLA have a total absence or marked deficiency in serum immunoglobulins, and they fail to make antibodies to even potent protein antigens. Circulating B cells or surface membrane immunoglobulin-positive lymphocytes are extremely low (<2%) or absent. However, pro-B cells in the bone marrow are normal or even increased in number. T lymphocytes and other lymphoid subpopulations and delayed skin reactivity to recall antigens are normal. The response of peripheral blood mononuclear cells to mitogens and allogeneic cells is normal. Lymphoid tissues show an absence of plasma cells, lymphoid follicles, and germinal centers.

Diagnosis

 

Serum immunoglobulins should be quantified; patients with XLA usually have a profound hypogammaglobulinemia or agammaglobulinemia. Flow cytometry for B-cell numbers shows absent or very low numbers of B cells (e.g., <2%). Molecular analysis for Btk genetic abnormalities, especially those that involve the early stages of B-cell maturation in patients who present with absent B cells, can be very helpful in diagnostic evaluations. T-cell function is normal.

Treatment

 

 

 

 

 

 

Early diagnosis, broad-spectrum antibiotics, and replacement therapy with IVIG have changed the outcome of this disease. Infections, especially chronic enteroviral infections and chronic pulmonary disease, are still the two major complications of XLA. However, with the availability of IVIG in the early 1980s, the management of this disease became much easier. Early IVIG replacement therapy with nadir serum IgG levels higher than 500 mg/dL is important in preventing severe acute bacterial infections and bronchiectasis. Trough serum IgG levels higher than 800 mg/dL may be necessary to prevent chronic sinusitis and enteroviral infections adequately.

   Agammaglobulinemia with Absent B Cells

 

Approximately 10% of patients with agammaglobulinemia and absent B cells are female, and they present clinically similarly to patients with XLA. Any mutation of a gene involved in the early stages of B-cell differentiation could result in an XLA-like phenotype. Mutations that block the early stages of B-cell differentiation are listed in Table 271-1 . Female patients who present with absent B cells and agammaglobulinemia appear to have more severe disease than do boys with Btk mutations. More details can be found in the review by Conley.

   Immunodeficiency with Hyper-Immunoglobulin M

 

Definition

 

Immunodeficiency with hyper-IgM is characterized by severe recurrent bacterial infections with decreased serum levels of IgG, IgA, and IgE but with normal or elevated levels of serum IgM. The X-linked form of this syndrome is more common (type 1), but a similar phenotype with an autosomal recessive inheritance occurs in female patients (type 3).

Pathobiology

 

Mutations in the CD40 ligand (CD154) gene are responsible for the X-linked form of hyper-IgM (type 1), whereas mutations in the CD40 ligand receptor (e.g., CD40) are responsible for hyper-IgM type 3.

Clinical Manifestations

 

Recurrent bacterial infections of the sinopulmonary tract usually begin in the first or second year of life. The clinical history of infection often resembles patients with XLA. Stomatitis and mouth ulcers may occur in association with the neutropenia. P. jirovecii has been reported in patients with this disease. Other opportunistic pathogens include cytomegalovirus, Cryptococcus, and mycobacteria. Patients are susceptible to opportunistic organisms and have a high incidence of autoimmune diseases such as thrombocytopenia, hemolytic anemia, neutropenia, nephritis, and arthritis. Diarrhea is a frequent finding, occurring in more than 50% of patients, often as a result of cryptosporidiosis. Hepatitis B and hepatitis C viral infections produce chronic hepatitis in these patients. Unlike in patients with XLA, these patients have marked hypertrophy of the lymphoid tissues, including the tonsils, lymph nodes, and spleen. However, the lymph nodes are poorly organized, with absence of the germinal centers. Proliferation of IgM-producing plasma cells with extensive invasion of the gastrointestinal tract and liver may occur by the second decade of life. Patients also have an increased risk of malignant diseases, especially lymphomas. An increased incidence of liver and biliary tumors is a unique feature of X-linked hyper-IgM.

Diagnosis

 

Serum levels of IgM are markedly increased and may exceed 1000 mg/dL; however, early in life, the level of serum IgM may be normal. Patients can produce IgM antibody, but the secondary IgG response is usually markedly diminished or absent. Surface immunoglobulin-positive lymphocytes in the peripheral blood are primarily positive for IgM; IgA- and IgG-bearing lymphocytes are decreased or absent. T-lymphocyte numbers and mitogen responses are normal. Patients with X-linked hyper-IgM, such as those with as type 1, lack CD40 ligand on activated T cells as a result of mutations in the gene for CD40 ligand. Patients with hyper-IgM type 3 lack the receptor for CD40 ligand (CD40) on B cells and antigen-presenting cells.

Treatment

 

 

 

 

 

 

Supportive care, use of prophylactic antibiotics for P. carinii, and recognition and treatment of other opportunistic infections are all important. Parenteral nutrition may be necessary for patients with severe gastrointestinal disturbances. Treatment consists of IVIG replacement therapy. The autoimmune neutropenia responds well to treatment with IVIG and granulocyte colony-stimulating factor. Bone marrow transplantation has been used in the treatment of patients with this disease.

   Other Forms of Hyper-Immunoglobulin M Phenotypes

 

Several female patients have been described, a finding suggesting an autosomal form of the disease. These patients normally express CD40L on T cells and CD40 on B cells. Molecular studies have shown that the defects in the autosomal variant of the hyper-IgM syndrome are mutations in the activation-induced cytidine deaminase gene (AICDA) and the uracil DNA glycosylase gene (UNG) (see Table 271-1 ). These patients differ from those with the X-linked form by lymphoid hyperplasia with marked follicular hyperplasia, enlarged germinal centers with highly proliferating B cells, defective immunoglobulin variable region gene somatic mutation generation, and defective immunoglobulin class switch recombination.

Another rare form of X-linked hyper-IgM syndrome is associated with ectodermal dysplasia characterized by the absence or hypoplasia of hair, teeth, and sweat glands and by the presence of immunodeficiency. Patients have increased susceptibility to bacterial infections, including atypical mycobacteria, and herpes viral infections. Most patients have low serum levels of IgG with variable levels of IgM and IgA and poor antibody production; NK cell function is also defective. This disorder is related to mutations in the gene that encodes the nuclear factor-kB (NF-KB) essential modulator (NEMO or IKKγ) that is required for activation of the transcription factor NF-kB. Genetic diagnosis and genetic counseling are important, including carrier testing of the patient’s mother, sisters, and aunts. Treatment consists of IGIV and mycobacterial prophylaxis.

   Common Variable Immunodeficiency

 

Definition

 

CVID comprises a heterogeneous group of disorders involving both B-cell and T-cell immune function whose predominant manifestation is hypogammaglobulinemia. CVID is characterized by recurrent bacterial infections, decreased serum immunoglobulin levels (at least two immunoglobulin isotypes more than 2 SD lower than normal for age), and abnormal antibody responses. These patients may present in early childhood, during adolescence, or as young adults. In most patients, the onset of symptoms is in the second and third decade of life. In a large study, the average age of onset of symptoms was 25 years, and the average age at diagnosis was 28 years.

Pathobiology

 

Several mechanisms have been proposed to explain the immune abnormalities in patients with CVID, including an intrinsic B-cell defect, excessive T-suppressor cell activity, deficient helper T-lymphocyte function, cytokine deficiencies, and suboptimal T-cell–B-cell interactions through deficient expression of the CD40 ligand. T cells in CVID have diminished production of IL-2, IL-4, IL-5, and interferon-γ, and they express lower levels of the IL-2 receptor. A signaling defect may be intrinsic to the B cells, or it may occur between a poorly expressed CD40 ligand on T cells and the CD40 receptor on B cells. Whether these abnormalities are a cause or a consequence of CVID remains to be determined. The number of immune deviations described in patients with CVID underscores the heterogeneous nature of the immune defect or defects in this syndrome. A homozygous deletion in the gene encoding ICOS, a T-cell costimulatory molecule of the CD28 family that enhances the activation of T cells and is important in T-cell–B-cell interactions, was found in a small number of patients with CVID. The clinical phenotype of ICOS deficiency is similar to that of other patients with CVID. Other recent findings are the lack of memory B cells, such as CD27+, and the absence of class-switched B cells in 75% of patients with CVID. These findings have led to the hypothesis that patients with CVID have a defect in the germinal centers of their secondary lymphatics.

Family members of patients with CVID have an unusually high incidence of IgA deficiency, autoimmune diseases, autoantibodies, and malignant disease. Some patients with IgA deficiency and CVID have one or both of two extended major histocompatibility complex (MHC) haplotypes: haplotype 1, HLA-DQB1☆0201, HLA-DR3, C4B-Sf, C4A-0, G11-15, Bf-0,4, C2-a, HSP-7.5, TNF-α-a2b3, HLA-B8 and HLA-A1; or the second haplotype, HLA-DQB1☆0201, HLA-DR7, C4B-S, C4A-L, G11-4.5, Bf-0.6, C2-b, HSP-9, TNF-α-a7b4 or a11b4, HLA-B44 and HLA-A29. One or more genes within the MHC region on chromosome 6 (e.g., one near or within the class II region and one in the class III region near the class I locus) may be involved in the pathogenesis of CVID and IgA deficiency. An inheritance pattern of autosomal dominance with variable penetrance has been suggested.

Clinical Manifestations

 

The most frequent presenting infections in adults with CVID involve the respiratory tract, including recurrent otitis media, chronic sinusitis, and recurrent pneumonia, often with resulting bronchiectasis. The bacterial pathogens are similar to those described in XLA. The gastrointestinal tract is affected in approximately half the patients with CVID; patients present with malabsorption or chronic diarrhea. These symptoms can be related to numerous underlying abnormalities, including lactose intolerance, protein-losing enteropathy, and superimposed infection of the small bowel with bacteria such as Campylobacter or Yersinia, with the parasite G. lamblia, or with flora of the large bowel (small bowel bacterial overgrowth syndrome). Atrophic gastritis with achlorhydria may lead to pernicious anemia.

Approximately 5 to 10% of patients with CVID present with noncaseating granulomatous lesions that infiltrate the liver, lymph nodes, lung, and skin. These lesions are often confused with sarcoidosis. Chronic gastrointestinal disease is often associated with nodular lymphoid hyperplasia, characterized by hypertrophy of the Peyer’s patches in the small bowel, and diffuse lymphoid infiltration. Hypertrophy of other lymphoid tissues, including the peripheral lymph nodes, the spleen, and occasionally the liver, are also seen. Rarely, hepatosplenomegaly may be severe enough to result in secondary neutropenia or thrombocytopenia. The pathogenesis of this process is not known, but it may be related to increased production of TNF-α. Patients with granulomatous-lymphocytic interstitial lung disease have a worse prognosis, a restrictive pulmonary pattern with a low-normal diffusing lung capacity for carbon monoxide, and diminished T-cell function. High-resolution computed tomography of the chest is helpful in identifying these patients, who require higher replacement doses of IVIG.

Autoimmune disorders occur frequently in CVID (20 to 25% of patients), and they include rheumatic diseases, autoimmune hematologic disorders, autoimmune neurologic diseases, chronic active hepatitis, and autoimmune endocrinopathies. The incidence of malignant disease is increased (11% to 13%) in CVID during the fifth and sixth decades of life. Most of these malignant diseases involve the gastrointestinal tract and the lymphoid tissues (e.g., non-Hodgkin’s lymphoma).

Diagnosis

 

The serum immunoglobulin levels are markedly diminished in patients with CVID. However, one can see tremendous variability in the degree of hypogammaglobulinemia. Specific antibodies are usually lacking, and isohemagglutinin titers are generally diminished. The proportions of circulating B cells in the peripheral blood are usually normal, but a subset of patients may lack circulating B lymphocytes. T-cell function can be quite variable: it is normal in half of the patients and depressed in the other half, with absent delayed hypersensitivity skin reactivity to recall antigens, low numbers of circulating peripheral blood CD4+ T cells, often with a decrease in the CD4 : CD8 ratio, and depressed in vitro responses to mitogens and specific antigens.

Treatment

 

 

 

 

 

 

Patients with CVID are treated with doses of IVIG of 400 to 600 mg/kg every 4 weeks. Generally, this regimen should achieve a trough serum IgG level higher than 500 mg/dL. Patients who continue to have recurrent infections or who have bronchiectasis should be treated with higher doses of IVIG.

Prognosis

 

The prognosis is generally very good for patients whose illness is diagnosed early and who undergo replacement IVIG therapy. The reported mortality rate over a 25-year period was 24%, mostly because of lymphoma (18%) and chronic pulmonary disease (11%). The mean age at the time of death was 45.5 years in women and 40 years in men. The patients who died were more likely to have lower levels of IgG at the time of diagnosis and poorer T-cell proliferative responses to phytohemagglutinin (PHA). Twenty-year survival after diagnosis of CVID was 64% for men and 67% for women compared with 92 to 94% for the general population.

   Immunodeficiency with Thymoma

 

Immunodeficiency with thymoma was first described in 1954 (Good’s syndrome). It is a disorder of adults, typically between the ages of 40 and 70 years. This immunodeficiency presents with recurrent sinopulmonary infections. Affected individuals have hypogammaglobulinemia, which may affect all major immunoglobulin isotypes. A thymoma may be discovered during the initial investigation of hypogammaglobulinemia by the detection of a mediastinal mass on a routine chest radiograph. Occasionally, the thymoma predates the hypogammaglobulinemia. The thymic tumors are predominantly of the spindle cell type and are usually benign. The clinical symptoms are similar to those found in patients with CVID. In contrast to CVID, however, frequently associated disorders include aregenerative (pure red cell) anemia, agranulocytosis, and myasthenia gravis. These conditions may improve after thymectomy; however, the immunodeficiency persists. Infections commonly associated with T-cell abnormalities can be seen in this disease, including mucocutaneous candidiasis, cytomegalovirus infection, herpes zoster, and P. carinii pneumonia.

   Immunoglobulin A Deficiency

 

Definition

 

Deficiency in serum IgA is one of the most common B-cell immunodeficiencies, with an approximate incidence of 1 in 400 to 2000 individuals in the general population. IgA deficiency is defined as a serum IgA concentration lower than 7 mg/dL, with normal serum levels of IgM and IgG.

Pathobiology

 

The genetic defect responsible for IgA deficiency is not known. IgA deficiency shares with CVID the inheritance of a restricted MHC extended haplotype. Although the pathogenesis of IgA deficiency is still unknown, it may share a common origin with CVID because these two disorders have many immune aspects in common. IgA deficiency may occur in association with the administration of drugs such as phenytoin, sulfasalazine, hydroxychloroquine, and D-penicillamine. IgA deficiency has also been described in association with partial deletion of the long arm of chromosome 18 (18q syndrome) or with a ring chromosome 18.

Clinical Manifestations

 

Many individuals with selective IgA deficiency do not have symptoms. The variability in clinical expression may be related to two factors. First, the IgA-deficient patients who tend to be relatively asymptomatic appear to have a compensatory increase in secretory monomeric IgM in their saliva, upper respiratory tract secretions, and gastrointestinal fluids. Second, the association of IgG2/IgG4 or IgG4 subclass deficiencies with IgA deficiency may predispose IgA-deficient patients to more severe and recurrent sinopulmonary infection than is seen in those patients with isolated selective IgA deficiency.

Symptoms of IgA deficiency include sinopulmonary infections and involvement of the gastrointestinal tract with giardiasis, nodular lymphoid hyperplasia, ulcerative colitis, Crohn’s disease, or a spruelike disease. An increased frequency of autoimmune disorders has also been associated with IgA deficiency, including arthritis, a lupus-like illness, autoimmune endocrinopathies, chronic active hepatitis, and autoimmune hematologic disorders. IgA-deficient patients are at risk for the development of anti-IgA antibodies on receipt of blood products. Caution must be exercised in the administration of IVIG for replacement of IgG subclass deficiency in IgA-deficient patients because most of these preparations contain small amounts of IgA. However, this risk does not appear to be a problem in those patients with partial IgA deficiency.

Diagnosis

 

IgA deficiency is defined as serum IgA levels lower than 7 mg/dL. The peripheral blood B cells of IgA-deficient patients coexpress IgA, IgM, and IgD, an immature phenotype. However, the lymphoid tissues are deficient in IgA-producing plasma cells. Studies of T-cell function have been normal in most patients with selective IgA deficiency.

Treatment

 

 

 

 

 

 

No specific treatment for IgA deficiency exists. Prophylactic antibiotics may be helpful in patients with recurrent sinopulmonary tract infections. Patients with chronic lung disease should receive conventional therapy, to prevent the development of bronchiectasis. IVIG is not indicated in patients with isolated IgA deficiency. Other supportive treatments are aimed at associated diseases. Patients should be transfused only with washed red cells, to avoid sensitization to the IgA in plasma products.

Prognosis

 

The prognosis is good in most cases. Respiratory infections and autoimmune disease are more common in IgA-deficient patients. A few patients with IgA deficiency presenting in childhood may recover spontaneously; other patients may develop CVID.

   Immunoglobulin G Subclass Deficiencies and Selective Antibody Deficiency

 

Definition

 

Considerable controversy exists over the biologic significance of IgG subclasses and the clinical significance of an isolated IgG subclass outside the normal range. Because healthy individuals without recurrent infections may have an abnormally low serum IgG subclass concentration, investigators question whether IgG subclass deficiency represents a true immunodeficiency disease. Deficiency in an IgG subclass is defined as a serum IgG subclass concentration that is more than 2 SD lower than the normal mean for age. The age at which each of the IgG subclasses reaches adult levels varies. Gm allotype also influences serum concentrations of certain IgG subclasses, particularly IgG2 and IgG3. In adults, deficiencies in IgG3 subclass are most common, whereas in children, IgG2 is the most prevalent IgG subclass deficiency. IgG subclass deficiency may be seen in conjunction with other primary immunodeficiency disorders, such as ataxia-telangiectasia and IgA deficiency. IgG subclass deficiency occurs in approximately 18% of IgA-deficient patients. An IgG subclass deficiency may occur as an isolated immune defect, or two or more IgG subclass deficiencies may coexist (e.g., IgG2 and IgG4 deficiency).

Patients with selective antibody deficiency have abnormal responses to immunization with polysaccharides such as H. influenzae type b (Hib) capsular antigen or to the pneumococcal polysaccharide antigens, but they have normal serum immunoglobulin and lgG subclass concentrations. However, patients immunized to Hib-conjugate vaccine responded normally in that the antibody response to the conjugate vaccine falls principally within the IgG1 subclass instead of the IgG2 subclass. Similar observations have been made for selective antibody deficiency after immunization with a pneumococcal polysaccharide vaccine in patients presenting with recurrent sinusitis or chronic sinusitis.

Clinical Manifestations

 

The most frequent clinical problems associated with IgG subclass deficiency are recurrent infections of the upper and lower respiratory tracts. Pathogens are generally limited to bacteria and respiratory viruses. Because IgG2 is important in the response to polysaccharide antigens, patients with IgG2 deficiency typically have infections with H. influenzae or S. pneumoniae. Patients may be unable to produce specific antibodies after immunization with purified polysaccharide antigens (e.g., Pneumovax). Some patients with IgG2 subclass deficiency may be asymptomatic. In part, this may result from a shifting of the antibody response to another IgG subclass or immunoglobulin isotype, which compensates for the selective IgG2 subclass deficiency. IgG3 deficiency has been associated with recurrent upper and lower respiratory tract infections and may occur in combination with IgG1 deficiency. Several studies have suggested that IgG3 is especially important in the primary response to viral respiratory agents. IgG3 is also the predominant antibody response in Moraxella catarrhalis, an organism frequently isolated from patients with chronic sinusitis. IgG4 deficiency occurs in the general population at a rate of approximately 10 to 15%. The clinical significance of IgG4 deficiency is not known.

Diagnosis

 

Serum immunoglobulin concentrations should be measured by quantitative techniques (nephelometry). Values in children must be compared with laboratory normals for age. Immunoelectrophoresis is semiquantitative and should not be used to evaluate the patient with suspected antibody deficiency. Immunoelectrophoresis should be used only to examine serum for paraproteins such as those found in Waldenström’s macroglobulinemia or multiple myeloma. IgG subclass quantitation may be helpful, although debate continues over the utility of these measurements. A careful history and physical examination are important in determining the clinical significance of an IgG subclass deficiency. In addition, the measurement of functional or specific antibodies is important in indicating the clinical relevance of an IgG subclass deficiency.

Patients may have normal levels of total serum immunoglobulins and normal IgG subclasses yet may fail to make specific antibodies to bacterial or common viral pathogens. Therefore, the assessment of specific antibody formation following vaccine administration is an important part of the laboratory evaluation in patients with suspected B-cell deficiency. Usually, repeat titers are obtained 4 weeks after immunization, to assess the specific antibody response. Isohemagglutinins are naturally occurring IgM antibodies to the ABO blood group substances. Responses to protein antigens generally fall in the IgG1 subclass, whereas the immune response to the polysaccharide antigens resides within the IgG2 subclass. With the conjugated vaccines for Hib and pneumococcal polysaccharides, antibody responses occur primarily in the IgG1 rather than IgG2 subclass. Therefore, these conjugate vaccines may not be helpful in the functional evaluation of an IgG2 subclass deficiency or a selective polysaccharide antibody deficiency. Because a common complaint of many of these patients is recurrent upper respiratory tract infections, one can test the serum for the presence of antibodies to common respiratory viral agents such as influenza A and B, mycoplasma, respiratory syncytial virus, adenovirus, and the parainfluenza viruses.

Treatment

 

 

 

 

 

 

Replacement IVIG should be considered only if patients demonstrate poor antibody responses to vaccine immunization such as Pneumovax. Often, prophylactic antibiotics are useful in this group of patients, at least for the winter months.

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