Porth's Essentials of Pathophysiology, 4e

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Infection and Immunity

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media and sinus and pulmonary infections), but the onset of infections occurs much later, usually between the ages of 15 and 35 years. In contrast to X-linked agammaglobulinemia, the sex distribution in CVID is almost equal. Most persons with CVID have no iden- tified molecular diagnosis. Because the disorder occurs in first-degree relatives of persons with IgA deficiency, and some persons with IgA deficiency develop agam- maglobulinemia, these disorders may have a common genetic basis. Persons with CVID often have autoantibody for- mation and normal-sized or enlarged tonsils and lymph nodes, and approximately 25% have spleno- megaly. 35 They have an increased tendency toward development of interstitial lung disease, autoim- mune disorders, hepatitis, and chronic diarrhea with associated intestinal malabsorption. There is also an increased risk of gastric cancer and non-Hodgkin B-cell lymphoma. Treatment methods for CVID are similar to those used for X-linked agammaglobulinemia, with IVIG being the cornerstone of therapy. Anaphylaxis to IgA in the IVIG can occur in persons with CVID who are IgA deficient. The use of IgA-depleted IVIG has greatly reduced this risk. Selective Immunoglobulin A Deficiency. Selective IgA deficiency is the most common type of immuno- globulin deficiency. 2 The syndrome is characterized by moderate to marked reduction in levels of serum and secretory IgA, probably due to a block in the path- way that promotes terminal differentiation of mature B cells to IgA-secreting plasma cells. The occurrence of IgA deficiency in both men and women and in mem- bers of successive generations within families suggests autosomal inheritance with variable expressivity. The disorder has also been noted in persons treated with certain drugs (e.g., phenytoin, sulfasalazine), sug- gesting that environmental factors may trigger the disorder. 35 Although an IgA deficiency can occur in apparently healthy persons, it is commonly associated with repeated infections in the respiratory, gastrointestinal, and uro- genital systems. Persons with IgA deficiency also can develop antibodies against IgA, which can lead to severe anaphylactic reactions when blood components con- taining IgA are given. 5 Therefore, only specially washed erythrocytes from normal donors or erythrocytes from IgA-deficient donors should be used. There is no specific treatment available for selective IgA deficiency unless there is a concomitant reduction in IgG levels. Administration of IgA immune globulin is of little benefit because IgA has a short half-life and is not secreted across the mucosa. There also is the risk of anaphylactic reactions associated with IgA antibodies in the immune globulin. Immunoglobulin G Subclass Deficiency. An IgG subclass deficiency can affect one or more of the IgG subtypes, despite normal levels or elevated serum con- centrations of IgG. In general, antibodies directed

against protein antigens belong to the IgG 1 and IgG 3 subclasses, and antibodies directed against carbohy- drate and polysaccharide antigens are primarily from the IgG 2 subclass. As a result, persons who are deficient in IgG 2 subclass antibodies can be at greater risk for development of sinusitis, otitis media, and pneumonia caused by polysaccharide-encapsulated microorgan- isms such as S. pneumoniae, H. influenzae type b, and N. meningitidis. Children with mild forms of the deficiency can be treated with prophylactic antibiotics to prevent repeated infections. Intravenous immunoglobulin can be given to children with severe manifestations of this deficiency. The use of polysaccharide vaccines conjugated to pro- tein carriers can provide protection against some of these infections, whereas protein vaccines conjugated to protein carriers would stimulate an IgG 1 response. X-linked Immunodeficiency with Hyperimmuno­ globulinemia M. Hyper-IgM syndrome is character- ized by low IgG and IgA levels with normal or, more frequently, high IgM concentrations. 35 Being predomi- nantly an X-linked recessive disorder, the disease is primarily seen in boys. Formerly classified as a B-cell defect, it now has been traced to a T-cell defect. The disorder results from the inability of T cells to signal B cells to undergo isotype switching to IgG and IgA; thus, they produce only IgM. 35,39 Like those with X-linked agammaglobulinemia, affected individuals become symptomatic during the first and second years of life. They have recurrent pyo- genic infections, including otitis media, sinusitis, tonsil- litis, and pneumonia. Persons with the syndrome are also at increased risk for development of autoimmune diseases of the formed elements of the blood, includ- ing hemolytic anemia, thrombocytopenia, and recurrent severe neutropenia. 35,39 Cellular (T-Cell) Immunodeficiency Disorders Unlike B cells, in which a well-defined series of differ- entiation steps ultimately leads to the production of immunoglobulins, mature T lymphocytes consist of dis- tinct subpopulations with diverse immunologic assign- ments. 39 They protect against fungal, protozoan, viral, and intracellular bacterial infections; control malignant cell proliferation; and are responsible for coordinating the overall immune response. In general, persons with T-cell–mediated immu- nodeficiency disorders have infections or other clini- cal problems that are more severe than those seen with antibody disorders. Children with defects in this branch of the immune response rarely survive beyond infancy or childhood unless immunologic reconstitu- tion is achieved. 35 However, exceptions are being rec- ognized as newer T-cell defects, such as the X-linked hyper-IgM syndrome, are identified. 35 Other recently identified primary T-cell immunodeficiency disorders result from defective expression of the TCR complex, defective cytokine production, and defects in T-cell activation.