eficiencies are the second largest group, making up about 30%. Phagocytic defects and complement disorders make up about 18% and 2% of immunodeficiencies. Only the more common primary immune deficiency syndromes will be emphasized in this chapter. HIV infection is covered in a separate chapter.

1. Transient hypogammaglobulinemia in infancy (THI). THI is due to a normal variability of the developing immune system in infants with prolonged periods of physiologic hypogammaglobulinemia. All infants develops physiologic hypogammaglobulinemia at approximately 5-6 months of age. In these age groups, the serum Ig level reaches its lowest point (approximately 350mg/dl), and many normal infants begin to experience recurrent respiratory tract infections. The diagnosis of THI is based on low levels of IgG and normal levels of IgA with variable levels of IgM. The normal levels of IgA exclude other congenital hypogammaglobulinemia. Most children with THI are typically able to synthesize specific antibodies in response to immunizations. However, inadequate specific antibody responses do not exclude the diagnosis of THI, but should prompt further investigation for other forms of immunodeficiency. Most cases of THI will spontaneously resolve by 4 years of age.

2. X-linked agammaglobulinemia (XLA) is characterized by four findings: 1) Onset of recurrent bacterial infections in the first 5 years of life; 2) Serum IgG, IgM and IgA values that are at least 2SD below the normal for age; 3) Absent isohemagglutinins or poor response to vaccines; and 4) Less than 2% CD19+ B cells in the peripheral circulation. It should be noted that the variability of clinical and laboratory findings for XLA is exist. Some XLA cases have been undiagnosed and untreated for more than five decades. 10-20% of XLA have serum IgG values greater than 200mg/dl at the time of diagnosis. The most consistent findings in XLA are the marked reduction in the number of B cells in the peripheral circulation.

The primary defect in XLA is the failure of pre-B cells to differentiate into mature B lymphocytes due to a gene mutation of Bruton's tyrosine kinase (Btk) which plays a multifaceted role in signal transduction for normal B cell development. However, approximately 10% of boys with presumed XLA do not have the mutation in Btk and 10% of patients with the early onset of recurrent infections, profound hypogammaglobulinemia and absent B cells, are girls. These observations suggest that there are autosomal recessive disorders clinically indistinguishable from XLA.

Intravenous immunoglobulin (IVIG) has been used as a mainstay therapy for XLA and other antibody deficiency disorders or combined immunodeficiency including autosomal recessive agammaglobulinemia, CVID, Hyper-IgM syndrome, SCID, WAS and AT. IVIG therapy may be beneficial for a selective antibody deficiency with IgG1 or IgG2 deficiency and significant recurrent infections. The usual dose of IVIG is 400 mg/kg every 4 weeks and then the dose should be adjusted based on the IgG level after 3-4 infusions (to keep IgG levels above 500mg/dl). Headache, fever, myalgia, chills, rigors, nausea and vomiting are common adverse reactions of IVIG infusion; however, aseptic meningitis has been reported.

3. Common variable immunodeficiency (CVID) is a heterogeneous syndrome, presenting with low IgG levels and no association with drugs or diseases known to cause secondary antibody deficiency. More than 95% of CVID clinically presents with recurrent sinopulmonary infections just like XLA or other hypogammaglobulinemia syndromes. The cause of CVID has not been identified yet. However the intrinsic defects of B cells, diminished T helper cells and dysregulation of cytokines have been described. Most of the patients usually do not become symptomatic until 15-35 years of age. CVID patients have an increased risk of developing autoimmune diseases, lymphatic and gastrointestinal malignancies, malabsorption and granulomatous inflammation.

The diagnosis of CVID is based on low IgG levels and poor specific antibody responses to immunizations without an identified cause of the hypogammaglobulinemia. IgM and IgA levels may present in significant amounts or absent. A patient with borderline immunoglobulin levels needs an evaluation of specific antibody responses with immunizations. T cell and B cell enumeration are usually normal; however, decreasing numbers of the cells have been occasionally seen. Some patients may have abnormal T cell function studies such as absent delayed hypersensitivity or depressed responses of mitogen stimulation. Treatment of CVID is identical to XLA. Frequent use of broad-spectrum antibiotics is required. The delayed diagnosis and treatment leads to chronic lung diseases such as bronchiectasis so periodic screening with chest x-rays, high resolution chest CT and pulmonary function tests are needed.

4. Hyper-IgM syndrome (HIM) is characterized by high levels of IgM with deficiency of IgG, IgA and poor specific antibody responses to immunizations. X-linked hyper-IgM syndrome is the commonest type which has a defect of the CD40 ligand (CD40L or CD154) gene of T cells. The interaction between CD40 on the B cells and CD40L on T cells is essential for the immunoglobulin class switching from IgM to IgG production, which explains why a deficiency in CD40L leads to hyper-IgM production with deficiency of IgG and IgA. HIM presents with recurrent sinopulmonary infections and Pneumocystis carinii pneumonia (PCP). There are associated abnormalities including neutropenia, hemolytic anemia and aplastic anemia. The unique susceptibility to opportunistic infections and neutropenia with high IgM levels distinguishes HIM from XLA or other hypogammaglobulinemias. Treatment of HIM is based on regular administration of IVIG and use of trimethoprim-sulfamethoxazole to prevent PCP. IVIG not only reduces the severity and frequency of infections, but also diminishes IgM levels and neutropenia. G-CSF (granulocyte colony stimulating factor) may be given for severe neutropenia. Recently stem cell transplantation has been performed successfully. The long term prognosis of HIM appears to be worse than in other forms of congenital hypogammaglobulinemia. Pneumocystis carinii infection has an important impact on morbidity and mortality during the first years of life, whereas liver disease mainly contributes to late mortality.

5. Selective IgA deficiency is the most common primary immunodeficiency disorder with the prevalence between 1 in 400 to 1 in 800. Although many patients are asymptomatic, IgA deficiency predisposes to respiratory, GI and urogenital tract infections, autoimmune diseases, sprue-like syndrome, malignancy, allergy and anaphylaxis reactions to blood products. Moreover, the progression of selective IgA deficiency to CVID or IgG2 subclass deficiency has been reported. The cause of the disease has not been known. Some infectious agents and drugs such as congenital rubella, EBV infection or phenytoin, may cause low IgA levels. The physiologic lag in serum IgA may delay the diagnosis until after the age of 2. The diagnosis can be made if a patient presents with IgA levels less than 7 mg/dL with no other evidence of any immune defects. Unlike XLA, HIM or CVID, selective IgA deficiency has a normal IgM and IgG response to pathogens and vaccines, therefore the routine schedule of immunization is suggested. IVIG replacement is not indicated. Aggressive treatment with broad spectrum antibiotics is recommended for recurrent sinopulmonary infections to avoid permanent pulmonary complications. Some selective IgA deficiency patients may develop antibody to IgA, in which case, there is a risk of anaphylaxis with blood product transfusions.

6. Selective IgG subclass deficiencies are generally defined as a serum IgG subclass concentration that is at least 2 standard deviations below the normal for age. There are four subclasses of human IgG, designated IgG1, IgG2, IgG3 and IgG4. Approximately 67% of serum IgG is IgG1, 20-25% is IgG2, 5-10% is IgG3 and 5% is IgG4. The concentrations of IgG subclasses are physiologically varied with age; IgG1 reaches adult levels by 1 to 4 years of age, whereas IgG2 level normally begins to rise later in childhood compared to other subclasses. The subclass deficiency has been reported in patients with recurrent infections, despite normal total IgG serum or with an associated deficiency of IgA and IgM deficiency.

The diagnosis and its implication have long been problematic since there are insufficient normative data for very young children and major technical problems of measurement of IgG subclass. Additionally, normal healthy children with low IgG2 subclass levels and normal responses to polysaccharide antigens as well as completely asymptomatic individuals with lacking IgG1, IgG2, IgG4 have been reported. A low value of IgG2 in a child may be a temporary finding which normalizes in adulthood. Approximately 10% of males and 1% of females have IgG4 deficiency without significant infections. IgG3 levels may be low with an active infection because it has the shortest half life and the greatest susceptibility to proteolytic degradation. Therefore, IgG subclass measurements are not routinely recommended and treatment with IVIG should be reserved for the patients who have been clearly demonstrated to have impaired responses to both protein and polysaccharide antigens to which they have been immunized.

7. Severe combined immune deficiency (SCID) is a life-threatening syndrome of recurrent infections, oral candidiasis, persistent diarrhea, dermatitis, graft versus host disease after blood transfusion and failure to thrive caused by a number of molecular defects that lead to severe compromise in T cell function with or without B cell dysfunctions. The defects in SCID block the differentiation and proliferation of T cells and in some types, of B cells and natural killer (NK) cells. Immunoglobulin and antibody production are severely impaired even when mature B cells are present. NK cells, a component of innate immunity, are variably affected. The majority of the patients present by age 3 months with unusually severe and frequent common infections such as bacterial otitis media and pneumonia or opportunistic infections including Pneumocystis carinii, and cryptosporidiosis. Viral infections such as herpes simplex, RSV, rotavirus, adenovirus, enterovirus, EBV, CMV are also commonly seen.

The most common defect of SCID is X-linked SCID (XL-SCID), accounting for 50-60% of cases. Adenosine deaminase (ADA) deficiency, accounting for 15% of SCID, is the second common defect. Other defects are purine nucleoside phosphorylase (PNP) deficiencies, IL-7 receptor alpha chain deficiency, recombination activation gene-1 and gene-2 (RAG1, RAG2) deficiency, CD45 deficiency, CD3 deficiency, MHC class I and II deficiency.

SCID is typically diagnosed by clinical features: absence of lymph nodes and tonsils, lymphopenia, absence of a thymic shadow on chest x-ray, abnormal T, B, NK cell enumeration with flow cytometric analysis, abnormal in vivo T cell function studies with skin tests of delayed skin hypersensitivity to tetanus, candida, diphtheria and in vitro lymphocyte function studies by measuring response to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen, phorbol myristate acetate (PMA) and ionomycin, tetanus and candida.

Skin testing for delayed hypersensitivity (which tests type IV cellular immunity function) is a basic way of testing T cell function. Antigens such as tetanus, candida, trichophyton, and mumps are frequently used because nearly everyone should be positive to all of these; however, occasionally normal young children may have a negative response. A positive response to these intradermal antigens indicates intact T cell function. If no response results from all these antigens, the patient may be "anergic". Thus, this panel of antigens is known as an "anergy panel".

Bone marrow or other stem cell reconstitution is a first-line, specific therapy for almost all forms of SCID. ADA deficiency has specific therapy as an alternative to the transplantation. Polyethylene glycol-treated (PEG) ADA replacement may be administered with improvement but not complete reconstitution of immune function. Currently gene therapy is successful for XL-SCID. Prophylactic antibiotics, IVIG replacement, meticulous skin and mucosal hygienic care, avoidance of exposure to infectious agents, and irradiation of all blood products prior to transfusion are recommended while awaiting stem cell reconstitution. Many patients with SCID are fully reconstituted without complications with bone marrow and other stem cell reconstitution techniques. Patients who are well nourished, uninfected and younger than 6 months prior to transplantation have the best outcomes. Without stem cell reconstitution, it is rare for a patient with SCID to survive.

8. Complement deficiency: Complement proteins are a key component of the innate immune system due to their function of direct lysis of their targets and being an opsonin. Most of the complement deficiency diseases are inherited in an autosomal recessive mode except C1 inhibitor deficiency (autosomal dominant) and properdin deficiency (X-linked). C2 deficiency is the most common defect; however, 50% of individuals with C2 deficiency are asymptomatic. Patients with C1, C4, C2 and C3 deficiencies have a higher incidence of autoimmune diseases such as SLE and encapsulated bacteria infections. Patients with absent factor H and factor I will have excessive consumption of C3; therefore, those patients will have similar infections as those with C3 deficiency states. The most commonly performed test for evaluation of functional complement activity is the CH50 test. APH50 is a useful screening test for the alternative pathway. There is no specific treatment for complement deficiency, except a purified C1 inhibitor preparation for hereditary angioedema due to C1 inhibitor deficiency.

9. WAS is an X-linked recessive disease, caused by a defective gene encoding Wiskott-Aldrich syndrome protein (WASP), which is expressed only in lymphocytes and megakaryocytes. This protein is involved in the reorganization of the actin cytoskeleton in the cells. WAS has a classic presentation with eczema, microcytic thrombocytopenia and recurrent encapsulated infection in a young boy. The initial manifestations often present at birth and consist of petechiae, bruises, bleeding from circumcision or bloody stools. The diagnosis can be made based on the manifestations and immunologic findings including low IgM, high IgA and IgE, poor antibody responses to polysaccharide antigens, moderately reduced number of T cells and variable depression of in vitro T cell function studies. Treatment includes IVIG infusion, irradiated fresh platelet transfusions and splenectomy for bleeding tendency, prophylactic antibiotics after splenectomy, and bone marrow transplantation.

10. Ataxia-Telangiectasia (AT) is an autosomal recessive disorder characterized by sinopulmonary infections, telangiectasia, progressive ataxia and hypersensitivity to ionizing radiation. Immunologic studies reveal combine immunodeficiency consisting of selective IgA and IgG2 deficiency, cutaneous anergy and depression of in vitro T cell function study. Supportive treatment is recommended. Other treatments which may be considered include IVIG and bone marrow transplantation.

11. Hyper-IgE syndrome is characterized by chronic pruritic dermatitis, recurrent staphylococcal infections (skin and respiratory tract), markedly elevated serum IgE, eosinophilia and coarse facial features. The diagnosis may be difficult since there is no clear definition of high IgE levels and IgE levels may fluctuate from time to time. In addition, a high IgE level with eosinophilia is commonly seen in severe atopic dermatitis. Therefore, recurrent staphylococcal infections involving the skin, lungs and joints with other features including a distinctive facial appearance, dental abnormalities and bone fractures are essential for the diagnosis. Treatment with good skin care and continuous antimicrobial therapy such as trimethoprim-sulfamethoxazole are necessary. No specific immunotherapeutic regimen has been successful. The role of IVIG therapy remains to be determined.

12. Chronic granulomatous disease (CGD) is a defect of phagocytic cells with dysfunction of the NADPH oxidase enzyme complex required for the production of reactive oxygen intermediates to destroy microbes. The defect leads to recurrent and uncontrolled catalase-positive organisms including S. aureus, E. coli, Serratia marcescens, Salmonella, Klebsiella spp, Clostridium difficile, Legionella bosmanii, Pseudomonas cepacia, Mycobacterium fortuitum, Chromobacterium, Aspergillus spp, Nocardia spp and Actinomyces spp. The most common infections are lymphadenitis, abscesses of the skin, and of the viscera such as liver. Granuloma formation occurs in CGD because the defect of the intracellular microcidal mechanism causes persistent antigen presentation and induces a sustained cell-mediated response by CD4 T cells, which recruit other inflammatory cells and set up a chronic local inflammation called a granuloma. The diagnosis of CGD can be ascertained by taking advantage of the metabolic defect in the phagocytic cells. A dye called nitro blue tetrazolium (NBT) is pale yellow and transparent. When it is reduced, it becomes insoluble and turns a deep purple color. In normal blood, the NBT is reduced to a dark purple or blue, easily seen in the phagocytic cells. In CGD blood, no dark purple or blue color is seen. Treatment includes short-term treatment of the infections, prophylactic trimethoprim-sulfa, recombinant human interferon-G (enhancing the production of reactive oxygen intermediates) and bone marrow transplantation. This condition is described in further detail in the chapter on neutrophil disorders.

13. Leukocyte adhesion molecule defect (LAD) syndromes are failures of innate host defenses against bacteria, fungi, and other microorganisms resulting from defective tethering, adhesion, and targeting of myeloid leukocytes (PMN, monocytes) to sites of microbial invasion. Killing of microbes is intact, but since the cells can not be mobilized to the point of inflammation and complement-mediated phagocytosis is impaired, the result is a lack of an inflammatory response. The hallmark of the disease is neutrophilia without PMNs in the infected tissue or pus. Histories of delayed separation of the umbilical cord, recurrent bacterial infections, necrotic skin lesions, severe gingivitis, periodontitis, and alveolar bone loss leading to early loss of deciduous and permanent teeth suggest the diagnosis. A definitive diagnosis with flow cytometric analysis reveals a decreased or absence of CD18 and its associated heterodimers: CD11a,CD11b and CD11c in LAD type I and absence of CD15s in LAD type II. Treatment includes continuous antimicrobial therapy, good oral hygiene, white blood cell transfusions and bone marrow transplantation.