Antibody Deficiencies

The quantitative measurement of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) is the single best test to screen for primary antibody deficiencies. An abnormality in the level of one or more of these classes of immunoglobulins is present in the majority of patients with primary antibody deficiencies. The pattern of the levels of IgG, IgA, and IgM gives important insight into the likely etiology of the antibody deficiency. For example, clinical immunologists are frequently consulted about whether a patient on corticosteroids has a primary antibody deficiency. In steroid-induced hypogammaglobulinemia, IgG levels are usually only moderately depressed (usually > 400 mg/dL) and the magnitude of reduction reflects the dosage and duration of corticosteroid usage. IgA and IgM levels tend to be preserved. In CVID, IgG levels are usually more profoundly depressed (<400 mg/dL), IgA levels are reduced (<10 mg/dL) in 70% of patients, and IgM levels are reduced (<25 mg/dL) in more than 80% of patients. Finally, in comparison with patients with steroid-induced hypogammaglobulinemia, patients with CVID have a more profound defect in their ability to make antigen-specific antibodies following immunization.

The enumeration of B cells, typically measured by flow cytometry using monoclonal antibodies directed against the CD19 or CD20 surface antigens, may also provide clues to the type of B-cell immunodeficiency present. In XLA and autosomal recessive (AR) forms of agammaglobulinemia, the numbers of B cells are usually severely reduced. In contrast, the number of B cells in CVID is frequently, but not always, normal. It is important to obtain a careful medication history because novel agents such as rituximab, a chimeric monoclonal antibody directed against CD20, can lead to profound decreases in B-cell numbers for months after treatment.

In assessing response to immunization, it is important to immunize with both a protein and polysaccharide (PS) antigen and to assess the response 4 to 6 weeks post immunization. The immunologic requirements to make antibodies (e.g., T-cell help, cytokine requirements) in response to immunization with a protein or PS antigen differ. Some patients with normal quantitative immunoglobulins or selective IgA deficiency exhibit a selective inability to make antibody to PS, but not to protein antigens. This immunologic defect (specific antibody deficiency) results in recurrent sinopulmonary infections and, in selected instances, may require replacement immunoglobulin therapy.

Protein antigens commonly used to assess specific antibody responses include tetanus and diphtheria toxoids. The Haemophilus influenzae type B (Hib) vaccine in present use conjugates the capsular polyribose phosphate to a protein carrier. Therefore, quantitation of antibodies to H. influenzae following immunization with the Hib vaccine measures competence of the immune system to make specific antibodies to a protein, not to PS antigens. Many adults have not been immunized to Hib, making the Hib vaccine particularly useful in the evaluation of this group of patients.

PS antigens used to test antibody responses are available in two unconjugated vaccines: the pneumococcal PS and Neisseria meningitidis vaccines. (Some pneumococcal vaccines are conjugated to a protein carrier and do not measure a response to the PS antigen [e.g., Prevnar]). When using the pneumococcal vaccine, the measurement of antibody responses to several (12 or more) capsular antigens is indicated. There is considerable controversy about what constitutes a normal response to the pneumococcal vaccine, and a clinical immunologist should make the interpretation of specific antibody responses. Finally, children younger than 2 years of age frequently do not make antibody responses to PS antigens. Thus, the use of PS vaccines to diagnose antibody-deficient states in this age group is not indicated.

Cellular Immunodeficiency

Many patients with impaired cellular immunity will have either reduced T-cell numbers, abnormal T-cell function, or both (see Table 92-3 ). T-cell numbers are easily screened by flow cytometry. The CD3 antigen measures the total number of T cells, whereas CD4 and CD8 antigens are present on the T-helper and T-cytotoxic subsets, respectively. T-cell function is easily assessed by testing cutaneous delayed-type hypersensitivity (DTH). In the DTH test, a small amount of an antigen is injected into the dermis and a positive reaction is indicated by induration (>2 mm) 48 to 72 hours later at the site of the injection. Antigens such as tetanus toxoid, Candida, and Trichophyton are frequently used because most individuals will have had a prior immune response to these antigens. However, DTH responses are frequently absent in normal infants, and in vitro assays of T-cell function are indicated in this group of patients. The measurement of natural killer (NK) cell numbers (CD16 ⁺ /CD56 ⁺ ) and function is indicated in the evaluation of infants for possible SCID or of patients with recurrent, severe herpesvirus infection. The pattern of abnormalities in the numbers of specific lymphocyte subpopulations (T cells, NK cells, B cells) is helpful in identifying the molecular abnormality in infants with SCID ( Table 92-4 ).

Complement Deficiencies

The screening tests for complement deficiency states associated with increased infections are the CH ₅₀ and AH ₅₀ , which measure the integrity of the classical and alternative pathways of complement activation, respectively (see Table 92-3 ). The CH ₅₀ measures the volume (or dilution) of serum required to lyse 50% of the sample erythrocytes; AH ₅₀ is a similar measure testing the alternative pathway. Abnormalities in CH ₅₀ or AH ₅₀ could be due to inappropriate activation and consumption of complement or to deficiencies in individual components of complement. Many times these possibilities can be distinguished by the measurement of two or more individual components of the classical or alternative complement pathway and the measurement of complement split products. Complement consumption is indicated by low levels of more than one component of complement, which may vary over time, and by the elevation of complement split products. In contrast, complement deficiency states show fixed, depressed levels of individual members of the complement pathway with normal levels of complement split products.

Phagocyte Deficiencies

The initial screening test for phagocytic defects includes a complete blood count, with quantitation of leukocyte number and morphology (see Table 92-3 ). The dihydrorhodamine (DHR) test has replaced the nitroblue tetrazolium (NBT) test in most centers to diagnose defects in the generation of superoxide, such as is seen in chronic granulomatous disease (CGD). Advantages to the DHR test include its ease, rapidity, and reproducibility, along with the capacity to detect CGD carrier states. Both the NBT and DHR tests measure the ability of phagocytes to generate superoxide free radicals. In the DHR test, phagocytes are loaded with a fluorescent dye (DHR) and activated with phorbol myristate acetate. Activated phagocytes then produce superoxide free radicals that reduce DHR, leading to a change in fluorescence that is quantitated by flow cytometry. Other functional assays for phagocytes include enzyme assays for myeloperoxidase and glucose 6-phosphate dehydrogenase, chemotaxis assays, phagocytic tests, and bactericidal assays. Abnormalities in the adhesion molecules CD18 and CD15 that result in leukocyte adhesion deficiency 1 and leukocyte adhesion deficiency 2, respectively, are detected by flow cytometry.

Severe Combined Immunodeficiency

SCID is a syndrome that encompasses a variety of molecular defects that result in absent or severely impaired T-cell and B-cell number and function. One commonly used method to classify SCID is based on whether the molecular defects decrease the numbers of T, B, and/or NK cells (see Table 92-4 ).

The molecular defects that lead to SCID include mutations that lead to abnormalities in cytokine signaling (e.g., the common γ chain [γc] of the interleukin [IL]-2 receptor; Janus activating kinase 3 [JAK3], or IL-7 receptor) and T-cell receptor signaling (e.g., CD45, ZAP-70, CD3y, CD3e, CD3C); defective T-cell and B-cell receptor gene recombination (e.g., RAG1, RAG2 ); defective nucleotide salvage pathway ( adenosine deaminase [ADA] deficiency); and defects in the expression of major histocompatibility complex class I or class II molecules. X-linked SCID caused by the mutation in the common γc of the IL-2 receptor is the most common form of SCID, accounting for approximately 50% of all cases. The γc of the IL-2 receptor is utilized by several other cytokine receptors, including the receptors for IL-4, IL-7, IL-11, IL-15, and IL-21. Consequently, the immunodeficiency due to mutation of the γc is due to the combined effects of loss of function in all of these cytokine receptors. Atypical forms of SCID may also result from mutations of genes associated with classical SCID that are hypomorphic, meaning that the mutation leads to a protein with reduced function. One such example is the Omenn syndrome, whose clinical manifestations include severe skin disease (erythroderma, granuloma, and desquamation), hepatosplenomegaly, lymphadenopathy, and high IgE levels. Additionally, there are other single gene defects that can lead to combined immunodeficiencies such as Wiskott-Aldrich syndrome, DiGeorge syndrome, Ataxia-telangiectasia, X-linked lymphoproliferative disorder, and some forms of hyper-IgM syndrome. For purposes of this chapter, these latter diseases are discussed separately from SCID.

The clinical presentation of SCID is characterized by severe infections, most commonly of the respiratory and gastrointestinal tract in early infancy. Infections are caused by common and opportunistic pathogens, and disseminated infections are frequent. Other common manifestations of the syndrome include oral thrush, persistent diarrhea, interstitial pneumonitis, impaired growth, and the absence of lymph nodes. Engraftment of maternal T cells in an infant with SCID can lead to graft-versus-host disease. The prompt treatment of infection, administration of IVIG, and prophylaxis against Pneumocystis jirovecii are indicated until HSCT can take place. In the event blood transfusions are necessary, only irradiated, cytomegalovirus (CMV)-negative blood should be used. No live virus vaccinations should be given to infants with known or suspected SCID.

Early diagnosis and treatment by HSCT (<3.5 months of age) of SCID leads to a markedly improved prognosis. Therefore, it is incumbent on the physician to make a prompt diagnosis of SCID. Several U.S. states, starting with Wisconsin in 2008, now screen all newborns for SCID. The disease has been added to the Uniform Panel of newborn screening tests recommended by the U.S. government. In the absence of newborn screening, the lack of a thymic shadow on chest radiograph and severe lymphopenia (<2500/µm) in an infant with recurrent infections should prompt further studies to exclude the diagnosis of SCID. The diagnosis of SCID is confirmed by enumerating lymphocytes and subsets of naïve T cells, B cells, and NK cells by flow cytometry and detecting a deficiency in the capacity of T cells to proliferate to mitogens.

HSCT is the preferred treatment for SCID, except for SCID due to ADA deficiency. For SCID due to ADA deficiency, the administration of polyethylene glycol–ADA is an alternative treatment. In addition, for X-linked SCID and SCID due to ADA deficiency, gene therapy has been successfully used. However, the retroviral vectors used in these earlier studies led to insertional mutagenesis with activation of the proto-oncogene LMO-2 leading to γδ T-cell leukemia in some patients. Trials of gene therapy for SCID using lentiviral vectors, which are safer in preclinical studies, are ongoing.

Immunoglobulin a Deficiency

The prevalence of IgA deficiency varies among different ethnic groups, but the overall prevalence is approximately 1 in 400 live births. The etiology of IgA deficiency remains obscure. Rarely, IgA deficiency may evolve into CVID, and families may develop both IgA deficiency and CVID, suggesting a common genetic basis. Medications, in particular anticonvulsants, infrequently cause IgA deficiency or panhypogammaglobulinemia, and immunoglobulins may normalize with discontinuation of the drug.

There is considerable controversy as to whether IgA deficiency alone predisposes people to infection. Most patients with IgA deficiency do not have increased frequency of infections and are often discovered during an evaluation for problems unrelated to infection. However, some patients with IgA deficiency have recurrent infections, predominantly respiratory tract infections. Whether IgG subclass deficiency and/or deficiencies in mannose-binding lectin identify a subgroup of patients with IgA deficiency who are more prone to infection is not clear. Unlike patients with more severe forms of antibody deficiency such as CVID or X-linked agammaglobulinemia, replacement therapy with IVIG is not warranted with isolated IgA deficiency. In patients with IgA deficiency and concomitant IgG subclass deficiency who have recurrent and persistent respiratory tract infections, determination of the antibody response following vaccination should be used to ascertain if IVIG therapy is warranted.

Clinical manifestations of IgA deficiency are highly variable. Infectious complications of IgA deficiency include recurrent upper (otitis media, sinusitis) and lower respiratory tract infections. Gastrointestinal tract infections, in particular recurrent giardiasis, may be present. The prevalence of atopic diseases (asthma, allergic rhinitis, eczema) and autoimmune diseases (systemic lupus erythematosus, celiac disease, rheumatoid arthritis) is increased in patients with IgA deficiency.

Serologic studies in IgA deficiency may be subject to false-positive and false-negative results due to the presence of heterophile antibodies. Heterophile antibodies react to the immunoglobulins of other species and may be increased in IgA-deficient patients due to increased exposure of antigens at the gut mucosa to the systemic circulation. The diagnosis of celiac disease in patients with IgA deficiency is problematic because the most specific serologic assay for celiac disease, IgA anti-tissue transglutaminase, is absent in IgA-deficient patients. Therefore, other assays should be performed in the laboratory assessment of celiac disease in IgA-deficient patients.

X-Linked Agammaglobulinemia

XLA (Bruton agammaglobulinemia) is a primary antibody deficiency with an estimated prevalence of 1 in 190,000 male live births. Mutations in the gene for Bruton tyrosine kinase (Btk) are responsible for this immunodeficiency. Btk is required for B-cell receptor signaling, playing a key role in the phosphorylation of phospholipase Cγ2. Btk function is essential for the survival and differentiation of immature B cells. Consequently, nearly all patients with XLA have a marked deficiency in B cells (<2% of lymphocytes) and profound panhypogammaglobulinemia. XLA accounts for approximately 85% of inherited forms of agammaglobulinemia due to defects in early B-cell development, with AR forms of antibody deficiency accounting for the remainder. The clinical manifestations of the AR forms of agammaglobulinemia are similar to XLA.

In addition to B cells, Btk is expressed on myeloid cells and platelets but not on NK cells or T cells. Consequently, T-cell function is normal in XLA, which contrasts with some other antibody deficiency disorders such as CVID or some forms of the hyper-IgM syndrome in which abnormalities in cellular immunity are frequently present. Up to 25% of patients with XLA present with neutropenia, which may contribute to the severity of infection.

Small or absent tonsils and lymph nodes are the only characteristic physical findings in XLA. The vast majority of patients with XLA have recurrent upper (otitis media; sinusitis) and lower respiratory tract infections, with more than 50% of patients having recurrent infections by 1 year of age and nearly all patients symptomatic by age 5. The most common pathogens causing pneumonia are encapsulated bacteria ( S. pneumoniae and H. influenzae ). Respiratory tract infections due to atypical bacteria such as Mycoplasma pneumoniae or Ureaplasma urealyticum are also frequently encountered. Gastrointestinal tract infections develop in nearly one quarter of patients and are most commonly due to Giardia lamblia, although bacteria ( Salmonella spp., Shigella spp., Campylobacter fetus, Helicobacter pylori ) and viruses ( Rotavirus, enteroviruses) are also frequently isolated. Disseminated infections that include encephalitis due to infection with enteroviruses, in particular echovirus, were a major cause of mortality in patients with XLA. However, these infections appear to be declining with use of high-dose immunoglobulin replacement therapy.

The pulmonary complications of XLA continue to be a major cause of morbidity and mortality and include bronchiectasis and cor pulmonale. Complete pulmonary function tests (if possible) and a high-resolution computed tomography (HRCT) scan of the chest are indicated in the initial evaluation of these patients. High-dose IVIG has been shown to decrease pulmonary infections in these patients but may not prevent the progression of bronchiectasis. Bronchiectasis, if detected, should be treated with daily pulmonary hygiene (e.g., inhaled β-agonists, hypertonic saline, chest physiotherapy) and aggressive antimicrobial therapy for intercurrent pulmonary infections. The efficacy of rotating antibiotics or chronic antimicrobial therapy in patients with bronchiectasis and immunodeficiency is unknown.

IVIG and subcutaneous infusion of gamma globulin (SCIG) are the most commonly used forms of antibody replacement for the treatment of profound antibody deficiencies such as XLA and CVID. Compared with IVIG, SCIG has far fewer infusion-related adverse reactions. High doses of gammaglobulin (400 to 600 mg/kg/month) are superior in preventing infections compared with “conventional” doses of IVIG (100 to 150 mg/kg), and the optimal dose should be based on prevention of infection rather than level of IgG. Intercurrent sinopulmonary infections should be aggressively treated with appropriate antimicrobial therapy to include coverage of common encapsulated bacteria, as well as coverage of atypical bacterial pathogens ( Mycoplasma spp., Ureaplasma ) .

A common mistake in managing patients with profound antibody deficiencies (e.g., XLA, CVID) is the inappropriate use of serologic assays in the diagnosis of infectious disorders. With the exception of IgA and IgG subclass deficiency, patients with antibody deficiency do not make specific antibodies in response to exogenous antigens. Therefore, the use of diagnostic studies to detect specific antibodies against pathogens is unreliable and, if positive, usually reflects antibodies present in the IVIG used to treat such patients. Diagnostic studies that detect microbial antigens or nucleic acids (polymerase chain reaction assays) from the pathogen must be used in place of serologic assays.

Common Variable Immunodeficiency

CVID, also known as acquired hypogammaglobulinemia, is a primary immunodeficiency affecting approximately 1:20,000 to 1:50,000 live births. CVID is a clinical syndrome representing a family of disorders that exhibit a common phenotype. Although highly variable, the mean onset of symptoms in patients with CVID is in the third decade of life. There remains a considerable delay, up to 10 years, between the onset of symptoms and the diagnosis of CVID. Unlike in XLA, T-cell abnormalities are common in patients with CVID and contribute to the more protean clinical manifestations of this disease. The diagnosis of CVID should be considered in any person older than age 4 with recurrent respiratory tract infections (i.e., two or more confirmed pneumonias).

The etiology in the vast majority of cases of CVID is unknown. Heterozygous mutations in the gene encoding TACI (a tumor necrosis factor [TNF] receptor family member involved in isotype switching in B cells) are found in approximately 5% to 10% of patients and markedly increase the risk of developing CVID while biallelic mutations always lead to the development of CVID. Mutations in inducible T-cell co-stimulator (ICOS), CD19, CD20, CD21, CD81, and BAFFR are other monogenic causes of CVID in a small percentage of patients. Collectively, mutations or polymorphisms of these genes account for less than 10% to 15% of all cases of CVID.

The laboratory evaluation of patients with CVID demonstrates the complex nature of the disease. The definitive diagnosis of CVID requires the demonstration of a low serum level of IgG (usually < 450 mg/dL), low serum level of IgA and/or IgM, impaired capacity to make specific antibodies in response to immunization or infection, and the exclusion of other primary or secondary antibody deficiencies. B-cell numbers are variable in CVID and, if reduced, may indicate a poor prognosis. B-cell subset analysis by flow cytometry is valuable in predicting risk to develop certain complications of CVID. Low numbers of switched memory B cells (CD27 ⁺ , IgM ⁻ , IgD ⁻ ) in the peripheral blood are frequently found in patients with splenomegaly and systemic granulomatous disease involving the lungs. T-cell abnormalities are found in approximately 40% of patients and include anergy, T-cell lymphopenia, and poor in vitro proliferative responses to mitogens and antigens.

Nearly all patients present with recurrent upper or lower respiratory tract infections, including bronchitis, sinusitis, otitis media, and pneumonia. Common pathogens include encapsulated (H. influenzae, S. pneumoniae) or atypical ( Mycoplasma spp.) bacteria. Pulmonary infections can also be caused by gram-negative rods, in particular in patients with long-standing CVID or impaired cellular immunity. Opportunistic infections develop in less than 10% of patients. Because patients with CVID appear to be particularly susceptible to infections with atypical bacteria such as Mycoplasma spp. and Ureaplasma spp., antimicrobial therapy of respiratory tract infections that is effective against these organisms should be used. Apart from respiratory tract infections, joint and bone infections due to these organisms have also been reported. Gastrointestinal tract infections with pathogens similar to those found in XLA ( Campylobacter jejuni, Salmonella spp., G. lamblia ) are also common. The prevalence of hepatitis is increased in CVID (in ≈ 12% of patients). The prognosis from hepatitis C is poor and may be rapidly progressive in patients with CVID.

The mortality of CVID due to common infectious pathogens has declined with the increased use of high-dose immunoglobulin replacement. Complications such as chronic lung disease, malignancy, liver, and gastrointestinal tract disease are now the most common risk factors for early mortality. Although patients with CVID are unable to make antibodies to foreign antigens, they exhibit an increased propensity to make autoantibodies. Consequently, the prevalence of autoimmune disorders, in particular idiopathic thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AHA) is increased. Oral corticosteroids, the use of immunomodulatory dosages of IVIG (2 g/kg per month), and rituximab have been used to treat ITP and AHA in patients with CVID.

Patients with CVID are at high risk for developing malignancy. In particular, the prevalence of non-Hodgkin lymphomas and gastric carcinoma are increased in CVID and are a major cause of morbidity and mortality in this disorder. Careful periodic examination of the lymph nodes and spleen is important because patients with CVID also frequently have adenopathy and splenomegaly that are nonmalignant in nature. The use of periodic abdominal computed tomography (CT) scans to assess spleen size and/or the presence of intra-abdominal and retroperitoneal adenopathy, along with upper and lower endoscopic evaluation for gastrointestinal symptoms, may also be useful.

The pulmonary disorders associated with CVID are complex and a major cause of mortality. Bronchiectasis is the most common pulmonary disorder, seen in more than 20% of patients. It is not clear whether high-dose gamma globulin replacement therapy can prevent the development of bronchiectasis in patients with CVID. On the basis of studies of patients with bronchiectasis without immunodeficiency, bronchiectasis in patients with CVID is managed with standard approaches including mobilization of pulmonary secretions through the use of medications such as hypertonic saline or β ₂ -agonists combined with chest physiotherapy and the chronic administration of macrolides. Bronchiolitis obliterans organizing pneumonia (now termed cryptogenic organizing pneumonia ) has also been described and appears to respond to corticosteroid therapy.

Diffuse interstitial lung disease, including granulomatous lung disease, lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis, and cryptogenic organizing pneumonia (bronchiolitis obliterans with organizing pneumonia), develops in approximately 10% to 25% of patients with CVID; these diffuse interstitial lung diseases are refractory to IVIG therapy. The presence of granulomatous lung disease led some to believe that this represents a form of sarcoidosis. Common features shared with sarcoidosis include the systemic nature of the disease, frequent presence of mediastinal and hilar adenopathy, and noncaseating granulomas in the lungs and other organs. However, it now appears likely that this lung disorder represents a distinct disease entity. Unlike in sarcoidosis, both granulomatous and lymphoproliferative histopathologic patterns (LIP, follicular bronchiolitis, and lymphoid hyperplasia) often appear together. Thus, the term granulomatous-lymphocytic interstitial lung disease (GLILD) has now been used to characterize the pulmonary disorder in CVID. In comparison with sarcoidosis, GLILD exhibits a lack of spontaneous remission of lung disease; a poor response to corticosteroid therapy; panhypogammaglobulinemia with low numbers of switched memory B cells; a high prevalence of autoimmune disease, in particular ITP; a history of recurrent infections; and large areas of organizing pneumonia on biopsy. Patients with GLILD and CVID more frequently have hepatosplenomegaly, typically have diffuse adenopathy, and are at increased risk for developing non-Hodgkin lymphoma. HRCT of the chest is indicated in the evaluation of patients with GLILD and demonstrates numerous abnormalities, including mediastinal adenopathy; diffuse ground-glass, nodular opacities; and areas of consolidation. The parenchymal abnormalities in GLILD are typically in the lower lung zones, which also contrasts with sarcoidosis.

The etiology of GLILD is unknown. The overproduction of TNF-α may contribute to the granulomatous disease in these patients. Case reports have demonstrated that the use of TNF-α antagonists may lead to regression of granulomatous disease in patients with CVID, lending further support to this hypothesis. Limited anecdotal experience suggests that the GLILD may also respond to low-dose cyclosporine therapy. In a retrospective study of seven patients, the use of rituximab and azathioprine improved the radiographic abnormalities and pulmonary function of patients with CVID and GLILD without an increased incidence of infection. This approach, although promising, needs to be validated in a properly controlled prospective study.

The combination of CVID in conjunction with a thymoma is known as Good syndrome. Whether this disorder is distinct from CVID or represents another manifestation of the disease is unclear. The thymoma is often not apparent on routine chest radiograph. Immune evaluation frequently demonstrates low numbers of CD4 T cells and B cells. Autoimmune disorders and opportunistic infections appear to be more common in this group of patients, and diffuse panbronchiolitis has also been described. Resection of the thymoma is recommended, although this will not resolve the immunodeficiency or autoimmunity.

Due to the complexity of the pulmonary disease, patients with CVID should undergo periodic chest radiographs, full pulmonary function tests, and HRCT scans of the chest. In the diagnostic evaluation of patients with GLILD or other forms of interstitial lung disease, it is essential to obtain sufficient tissue to exclude the diagnosis of lymphoma or cryptogenic organizing pneumonia. Therefore, we perform video-assisted thoracoscopic lung biopsies in the evaluation of patients with diffuse interstitial lung disease and CVID.

Specific Antibody Deficiency

Specific antibody deficiency (SAD) is a primary antibody deficiency disorder that is characterized by normal levels of IgG, IgA, and IgM but an inability to make specific antibodies, most commonly in response to PS antigens such as Pneumovax. Patients with specific antibody deficiency present with recurrent sinopulmonary infections, similar to other forms of hypogammaglobulinemia. The diagnosis of SAD is made by measuring an absence of specific antibody responses following immunization with PS vaccines, most commonly the unconjugated pneumococcal vaccine. Cellular immunity is normal in this disorder. The initial treatment of SAD is similar to IgA deficiency; however, IVIG may be indicated in patients with SAD who have recalcitrant sinopulmonary infections and fail more conservative treatment.

Immunoglobulin G Subclass Deficiency

IgG subclass deficiency is defined by normal total serum IgG levels with a low level of one or more IgG subclasses. There are four isotypes of IgG in humans: IgG1, IgG2, IgG3, and IgG4. The predominant subclass is IgG1, accounting for more than 60% of the total IgG. In some patients evaluated for recurrent sinopulmonary infections, low levels of one of the IgG subclasses are found. However, the significance of IgG subclass abnormality is unclear. Some believe that isolated IgG subclass deficiencies predispose patients to recurrent sinopulmonary infections. In contrast, IgG subclass deficiencies, including genetic deletions of IgG subclass loci, are well documented in healthy individuals. Because the clinical significance of isolated IgG subclass deficiencies is unclear, the measurement of IgG subclasses is not warranted in the initial evaluation of patients with recurrent sinopulmonary infections. In patients with an isolated IgG subclass deficiency and recurrent infections, the decision to use IVIG should be based on antibody responses following vaccination.

X-Linked Lymphoproliferative Syndrome

X-linked lymphoproliferative syndrome (XLP), or Duncan disease, is a rare primary immunodeficiency characterized by an extreme sensitivity to infection with Epstein-Barr virus (EBV). Approximately 80% of XLP (XLP-1) is caused by mutations in the adaptor protein gene SH2D1A (also known as SAP, the gene for slam-associated protein ). The SH2D1A adaptor protein affects multiple intracellular signaling pathways in several different lymphocyte subpopulations, including T cells, B cells, and NK cells, a property that leads to the complex immunologic abnormalities seen in these patients. Mutations in the X-linked inhibitor of apoptosis gene ( XIAP ) account for the remainder of patients with XLP (XLP-2), which results in premature apoptosis of lymphocytes in response to a variety of stimuli. Patients with XLP have a unique predisposition to infection with EBV, an infection that triggers the immunodeficiency in the vast majority of cases. Approximately 60% of patients with XLP present with overwhelming EBV infection leading to hemophagocytic lymphohistiocytosis. Therefore, the diagnosis of XLP should be considered in males with fulminant EBV infections. The clinical phenotypes of XLP-1 and XLP-2 overlap with the exception that lymphoma is seen only in XLP-1 and splenomegaly is frequently the first clinical manifestation in XLP-2. Lymphomas or hypogammaglobulinemia develops following EBV infection in approximately 30% of patients with XLP-1. The only definitive therapy for XLP is HSCT, although IVIG is commonly used in an effort to prevent infections.

Hyper–Immunoglobulin M Syndrome

Hyper-IgM syndrome (HIGM) is a descriptive term that reflects a common laboratory abnormality (high serum IgM level with low serum IgA and IgG levels) found in several otherwise dissimilar types of immunodeficiencies ( Table 92-5 ). Despite the name, high levels of IgM are inconsistently found in all forms of hyper-IgM syndrome. Furthermore, many believe that grouping these distinct immunodeficiencies together, some of which are intrinsic B-cell abnormalities, whereas others are complex combined cellular and humoral immunodeficiencies, leads to diagnostic confusion and is fundamentally flawed. Nevertheless, the classification remains widely used despite the obvious drawbacks. Although we group HIGM under “predominantly antibody deficiencies,” only mutations in activation-induced cytidine deaminase ( AICDA ) or uracil nucleotide glycosylase ( UNG ) result in primary immunodeficiencies that are largely due to antibody deficiency. The other forms of HIGM are complex cellular and humoral immunodeficiencies.

X-Linked Hyper-Igm Syndrome

The classic, X-linked form of HIGM (XHIGM), which accounts for approximately two thirds of cases, is due to a mutation in the CD40 ligand ( CD40LG ) gene. CD40L is inducibly expressed on activated CD4 T cells and interacts with CD40, which is expressed on the surface of B cells. The interaction of CD40 on B cells with CD40L on activated T cells in conjunction with specific cytokines (IL-4) is required for immunoglobulin class switching. Consequently, mutations in CD40LG (or CD40 ) result in a failure to class switch, leading to defective production of the later immunoglobulin isotypes (IgG, IgA, immunoglobulin E [IgE]) and to persistence of IgM. CD40 is also expressed on monocytes and dendritic cells. The lack of CD40L T-cell interaction with CD40 on monocytes and dendritic cells also contributes to defective cellular immunity. Mutations within the CD40 gene are a rare cause of HIGM with a clinical phenotype similar to that of XHIGM. Serum levels of IgG are consistently low, and serum levels of IgA are reduced in the majority of patients. However, serum levels of IgM are inconsistently high in approximately 50% of patients. Antibody responses to immunization show a weak IgM response, without development of IgG- or IgA-specific responses and the absence of immunologic memory. The numbers of switched memory B cells (CD27 ⁺ , IgD ⁻ , IgM ⁻ ) are extremely low. Neutropenia is found in approximately 50% of patients and may respond to treatment with granulocyte colony-stimulating factor (G-CSF).

Patients with XHIGM have recurrent infections beginning early in life. More than half of patients with XHIGM are diagnosed by age 1 and nearly all by age 4. Pneumonia, frequently caused by infection with P. jirovecii, is common, seen in up to 80% of patients. Sinusitis, otitis media, and other respiratory tract infections are frequent. Intractable diarrhea, sometimes due to infection with Cryptosporidium or more frequently idiopathic, develops in nearly one third of patients. Cryptosporidium infection is also a major cause of sclerosing cholangitis in these patients. Infection of the central nervous system (encephalitis, meningitis), frequently due to infection with echovirus, is a major cause of morbidity and mortality. Treatment of XHIGM includes IVIG, prophylaxis against P. jirovecii, G-CSF for neutropenia, and consideration for HSCT.