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There are many potential sites where developmental aberrations in the immune system can lead to abnormalities in immunocompetence (Figure 3–4; Tables 3–4 and 3–5). When these defects are genetic in origin, they are referred to as primary immunodeficiency disorders. This is in contrast to compromised immunity secondary to pharmacologic therapy, HIV, malnutrition, or systemic illnesses such as systemic lupus erythematosus or diabetes mellitus.
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Clinical investigations of various congenital defects have helped characterize many aspects of normal immune physiology. The very nature of a defect in host immune responses places the susceptible individual at high risk for a variety of infectious, malignant, and autoimmune diseases and disorders. The nature of the specific functional defect will significantly influence the type of infection that affects the host. Table 3–5 lists some of the typical organisms causing infection in patients with various immunodeficiency disorders. Any immunopathogenic mechanism that impairs T-lymphocyte function, or cell-mediated immunity, predisposes the host to the development of serious chronic and potentially life-threatening opportunistic infections with viruses, mycobacteria, fungi, and protozoa involving any or all organ systems. Similarly, immunopathogenic dysfunction of B lymphocytes resulting in antibody deficiency will predispose the host to pyogenic sinopulmonary and mucosal infections. As the molecular bases of many primary immunodeficiency disorders are being discovered, it has become apparent that different molecular defects can result in common clinical phenotypes.
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The T lymphocyte plays a central role in inducing and coordinating immune responses, and dysfunction can be associated with an increased incidence of autoimmune phenomena. These include diseases clinically similar to rheumatoid arthritis, systemic lupus erythematosus, and immune hematologic cytopenias. Patients with impaired immune responses are also at greater risk for certain malignancies than the general population. The occurrence of cancer may be related to an underlying impairment of tumor surveillance, dysregulation of cellular proliferation and differentiation, chromosomal translocations during defective antigen receptor gene rearrangement, or the presence of infectious agents predisposing to or causing cellular transformation. Non-Hodgkin lymphoma or B-cell lymphoproliferative disease, skin carcinomas, and gastric carcinomas are the most frequently occurring tumors in patients with immunodeficiency.
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Traditionally, the primary immunodeficiencies are classified according to which component of the immune response is principally compromised: the humoral response, cell-mediated immunity, complement, or phagocytic cell function (Table 3–4). Distinct developmental stages characterize the maturation and differentiation of the cellular components of the immune system. The underlying pathophysiologic abnormalities leading to primary immunodeficiency are diverse and include the following: (1) early developmental defects in cellular maturation, (2) specific enzyme defects, (3) abnormalities in cellular proliferation and functional differentiation, (4) abnormalities in cellular regulation, and (5) abnormal responses to cytokines.
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Combined Immunodeficiency
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Severe Combined Immunodeficiency Disease
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Clinical Presentation
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Clinically, many primary immunodeficiency disorders present early in the neonatal period. In patients with SCID, there is an absence of normal thymic tissue, and the lymph nodes, spleen, and other peripheral lymphoid tissues are devoid of lymphocytes. In these patients, the complete or near-complete failure of development of both the cellular and the humoral component of the immune system results in severe infections. The spectrum of infections is broad because these patients may also suffer from overwhelming infection by opportunistic pathogens, disseminated viruses, and intracellular organisms. Failure to thrive may be the initial presenting symptom, but mucocutaneous candidiasis, chronic diarrhea, and pneumonitis are common. Vaccination with live viral vaccines or bacillus Calmette-Guérin (BCG) may lead to disseminated disease. Without immune reconstitution by bone marrow transplantation, SCID is inevitably fatal within 1–2 years.
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Pathology and Pathogenesis
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SCID is a heterogeneous group of disorders characterized by a failure in the cellular maturation of lymphoid stem cells, resulting in reduced numbers and function of both B and T lymphocytes and hypogammaglobulinemia. The molecular basis for many types of SCID have been discovered (Table 3–4). The genetic and cellular defects can occur at many different levels, starting with surface membrane receptors but also including deficiencies in signal transduction or metabolic biochemical pathways. Although the different molecular defects may cause clinically indistinguishable phenotypes, identification of specific mutations allows for improved genetic counseling, prenatal diagnosis, and carrier detection. Moreover, specific gene transfer offers hope as a future therapy.
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Defective Cytokine Signaling—
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X-linked SCID (XSCID) is the most prevalent form, resulting from a genetic mutation in the common γ chain of the trimeric (αβγ) IL-2 receptor. This defective chain is shared by the receptors for IL-4, IL-7, IL-9, and IL-15, leading to dysfunction of all of these cytokine receptors. Defective signaling through the IL-7 receptor appears to block normal maturation of T lymphocytes. Circulating B-cell numbers may be preserved, but defective IL-2 responses inhibit proliferation of T, B, and NK cells, explaining the combined immune defects seen in XSCID patients. A defect in the α chain of the IL-7 receptor can also lead to an autosomal recessive form of SCID through mechanisms similar to XSCID but with intact NK cells.
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Defective T-Cell Receptor—
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The genetic defects for several other forms of the autosomal recessive SCID have also been identified. A deficiency of ZAP-70, a protein tyrosine kinase important in signal transduction through the TCR, leads to a total absence of CD8 T lymphocytes. ZAP-70 plays an essential role in thymic selection during T-cell development. Consequently, these patients possess functionally defective CD4 T lymphocytes and no circulating CD8 T lymphocytes but normal B-lymphocyte and NK-cell activity. Mutations of CD3δ, CD3γ, and CD3ε subunits may lead to partially arrested development of TCR expression and severe T-cell deficiency.
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Deficiencies of both p56lck and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction. P56lck is a TCR-associated tyrosine kinase that is essential for T-cell differentiation, activation, and proliferation. Jak3 is a cytokine receptor–associated signaling molecule.
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Defective Receptor Gene Recombination—
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Patients have been identified with defective recombination-activating gene (RAG1 and RAG2) products. RAG1 and RAG2 initiate recombination of antigen-binding proteins, immunoglobulins, and TCRs. The failure to form antigen receptors leads to a quantitative and functional deficiency of T and B lymphocytes. NK cells are not antigen specific and for that reason are unaffected. Artemis and DNA ligase-4 proteins are involved in double-stranded DNA breakage and repair, during VDJ recombination of T-cell receptors and BCRs. Mutations of Artemis may also lead to increased sensitivity to ionizing radiation. Because NK cells are invariant, their numbers are typically preserved, even as T- and B-cell numbers are severely deficient.
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Defective Nucleotide Salvage Pathway—
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Approximately 20% of SCID cases are caused by a deficiency of adenosine deaminase (ADA), which is an enzyme in the purine salvage pathway, responsible for the metabolism of adenosine. Absence of the ADA enzyme results in an accumulation of toxic adenosine metabolites within the cells. These metabolites inhibit normal lymphocyte proliferation and lead to extreme cytopenia of both B and T lymphocytes. The combined immunologic deficiency and clinical presentation of this disorder, known as SCID-ADA, is identical to that of the other forms of SCID. Skeletal abnormalities and neurologic abnormalities may be associated with this disease. In similar fashion, purine nucleoside phosphorylase deficiency leads to an accumulation of toxic deoxyguanosine metabolites. T-cell development is impaired, possibly through induced apoptosis of double-positive thymocytes in the corticomedullary junction of the thymus. B-cell dysfunction is more variable.
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Cell-Mediated Immunodeficiency
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Congenital Thymic Aplasia (DiGeorge Syndrome)
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Clinical Presentation and Pathogenesis
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The clinical manifestations of DiGeorge syndrome reflect the defective embryonic development of organs derived from the third and fourth pharyngeal arches, including the thymus, parathyroids, and cardiac outflow tract. Occasionally, the first and sixth pharyngeal pouches may also be involved. Cytogenetic abnormalities, most commonly chromosome 22q11 deletions, are associated with DiGeorge syndrome, especially in patients manifesting cardiac defects. DiGeorge syndrome is classified as complete or partial depending on the presence or absence of immunologic abnormalities. In this syndrome, the spectrum of immunologic deficiency is wide, ranging from immune competency to conditions in which there are life-threatening infections with organisms typically of low virulence. Patients affected by the complete syndrome have a profound T lymphocytopenia resulting from thymic aplasia with impaired T-lymphocyte maturation, severely depressed cell-mediated immunity, and decreased suppressor T-lymphocyte activity. B lymphocytes and immunoglobulin production are unaffected in most patients, although in rare instances patients may present with mild hypogammaglobulinemia and absent or poor antibody responses to neoantigens. In this subset of patients, inadequate helper T function as a result of dysfunctional T- and B-cell interaction and inadequate cytokine production leads to impaired humoral immunity.
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DiGeorge syndrome is truly a developmental anomaly and can be associated with structural abnormalities in the cardiovascular system such as truncus arteriosus or right-sided aortic arch. Parathyroid abnormalities may lead to hypocalcemia, presenting with neonatal tetany or seizures. In addition, it is common for patients to exhibit facial abnormalities such as micrognathia, hypertelorism, low-set ears with notched pinnae, and a short philtrum.
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Humoral Immunodeficiency
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X-Linked Agammaglobulinemia
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Clinical Presentation
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Formerly called Bruton agammaglobulinemia, X-linked agammaglobulinemia (XLA) is thought to be pathophysiologically and clinically more homogeneous than SCID. It is principally a disease of childhood, presenting clinically within the first 2 years of life with multiple and recurrent sinopulmonary infections caused primarily by pyogenic bacteria and, to a much lesser extent, viruses. Because encapsulated bacteria require antibody binding for efficient opsonization, these humoral immune-deficient patients suffer from sinusitis, pneumonia, pharyngitis, bronchitis, and otitis media secondary to infection with Streptococcus pneumoniae, other streptococci, and Haemophilus influenzae. Although infections from fungal and opportunistic pathogens are rare, patients display a unique susceptibility to a rare but deadly enteroviral meningoencephalitis.
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Pathology and Pathogenesis
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Patients with XLA have pan-hypogammaglobulinemia, with decreased levels of IgG, IgM, and IgA. They exhibit poor to absent responses to antigen challenge even though virtually all demonstrate normal functional T-lymphocyte responses to in vitro as well as in vivo tests (eg, delayed hypersensitivity skin reactions). The basic defect in this disorder appears to be arrested cellular maturation at the pre-B-lymphocyte stage. Indeed, normal numbers of pre-B lymphocytes can be found in the bone marrow, although in the circulation B lymphocytes are virtually absent. Lymphoid tissues lack fully differentiated B lymphocytes (antibody-secreting plasma cells), and lymph nodes lack developed germinal centers. The gene that is defective in XLA has been isolated. The defective gene product, BTK (Bruton tyrosine kinase), is a B-cell–specific signaling protein belonging to the cytoplasmic tyrosine kinase family of intracellular proteins. Gene deletions and point mutations in the catalytic domain of the BTK gene block normal BTK function, necessary for B-cell maturation.
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Common Variable Immunodeficiency Disease
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Clinical Presentation
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Common variable immunodeficiency disease is often referred to as acquired or adult-onset hypogammaglobulinemia. It is the most common serious primary immune deficiency disorder in adults. In North America, for example, it affects an estimated 1:75,000 to 1:50,000 individuals. The clinical spectrum is broad, and patients usually present within the first 2 decades of life. Affected individuals commonly develop recurrent sinopulmonary infections, including sinusitis, otitis, bronchitis, and pneumonia. Common pathogens are encapsulated bacteria such as S pneumoniae, H influenzae, and Moraxella catarrhalis. Bronchiectasis can be the result of recurrent serious respiratory infections, leading to infection with more virulent pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa, which in turn can change the long-term prognosis. A number of important noninfectious disorders are commonly associated with common variable immunodeficiency, including GI malabsorption, autoimmune disorders, and neoplasms. The most frequently occurring malignancies are lymphoreticular, but gastric carcinoma and skin cancer also occur. Autoimmune disorders occur in 20–30% of patients and may precede the recurrent infections. Autoimmune cytopenias occur most frequently, but rheumatic diseases can also be seen. Serologic testing for infectious or autoimmune disease is unreliable in hypogammaglobulinemia. Monthly infusions of intravenous immunoglobulin can reconstitute humoral immunity, decrease infections, and improve quality of life.
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Pathology and Pathogenesis
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Common variable immunodeficiency is heterogeneous disorder in which the primary immunologic abnormality is a marked reduction in antibody production. The vast majority of patients demonstrate an in vitro defect in terminal differentiation of B lymphocytes. Peripheral blood lymphocyte phenotyping demonstrates normal or reduced numbers of circulating B lymphocytes, but antibody-secreting plasma cells are conspicuously sparse in lymphoid tissues. In sharp contrast to XLA, no single gene defect can be held accountable for the multitude of defects known to cause common variable immunodeficiency. In many patients, the defect is intrinsic to the B-lymphocyte population. Approximately 15% of patients with common variable immunodeficiency disease demonstrate defective B-cell surface expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), a member of the TNF receptor family. Lacking a functional TACI, the affected B cells will not respond to B-cell–activating factors, resulting in deficient immunoglobulin production. Another defect that may lead to common variable immunodeficiency disease involves deficient expression of B-cell surface marker CD19. When complexed with CD21 and CD81, CD19 facilitates cellular activation through BCRs. B-cell development is not affected, but humoral function is deficient. A variety of T-cell abnormalities may also lead to immune defects with subsequent impairment of B-cell differentiation. A mutation of inducible T-cell costimulator gene (ICOS), expressed by activated T cells and responsible for B-cell activation/antibody production, may be the molecular defect in some cases of common variable immunodeficiency disease. More than 50% of patients also have some degree of T-lymphocyte dysfunction as determined by absent or diminished cutaneous responses to recall antigens. Immune dysregulation may contribute to the morbidity and the myriad autoimmune manifestations associated with common variable immunodeficiency.
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Hyper-IgM Immunodeficiency
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Clinical Presentation
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In patients with hyper-IgM immunodeficiency, serum levels of IgG and IgA are very low or absent, but serum IgM (and sometimes IgD) levels are normal or elevated. Inheritance of this disorder may be autosomal, although it is most often X-linked. Clinically, this syndrome is manifested by recurrent pyogenic infections and an array of autoimmune phenomena such as Coombs-positive hemolytic anemia and immune thrombocytopenia.
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Pathology and Pathogenesis
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The principal abnormality is the defective expression of CD40-ligand (CD40L), a T-lymphocyte activation surface marker (also known as CD154 or gp39). In the course of normal immune responses, CD40L interacts with CD40 on B-cell surfaces during cellular activation, initiating proliferation and immunoglobulin isotype switching. In hyper-IgM syndrome, defective CD40 coreceptor stimulation during T- and B-cell interactions leads to impairment of B-cell isotype switching and subsequent production of IgM but no production of IgG or IgA. CD40L-CD40 interaction also promotes dendritic cell maturation and IL-12 and IFN-γ secretion, so CD40L deficiency can be associated with impaired cell-mediated immunity and increased risk of opportunistic infection.
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Selective IgA Deficiency
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This is the most common primary immunodeficiency in adults, with a prevalence of 1:700 to 1:500 individuals. Most affected individuals have few or no clinical manifestations, but there is an increased incidence of upper respiratory tract infections, allergy, asthma, and autoimmune disorders. Whereas serum levels of the other immunoglobulin isotypes are typically normal, serum IgA levels in these individuals are markedly depressed, often less than 5 mg/dL.
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As in common variable immunodeficiency, the primary functional defect is an inability of B cells to terminally differentiate to IgA-secreting plasma cells. An associated deficiency of IgG subclasses (mainly IgG2 and IgG4) and low-molecular-weight monomeric IgM is not uncommon and can be clinically significant. Because of the role of secretory IgA in mucosal immunity, patients with this immunodeficiency frequently develop significant infections involving the mucous membranes of the gut, conjunctiva, and respiratory tract. There is no specific therapy, but prompt antibiotic treatment is necessary in patients with recurrent infections. A subset of patients may recognize IgA as a foreign antigen. These patients are at risk for transfusion reactions to unwashed red blood cells or other blood products containing trace amounts of IgA.
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Disorders of Phagocytic Cells & Innate Immunity
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Defective phagocytic cell function presents with infections at sites of interface between the body and the outside world. Recurrent skin infections, abscesses, gingivitis, lymphadenitis, and poor wound healing are seen in patients with macrophage or neutrophil disorders. More difficult to assay, clinical immunodeficiency can occur through defects in phagocytic cell migration, adhesion, opsonization, or killing.
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Chronic Granulomatous Disease
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Clinical Presentation
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Chronic granulomatous disease is typically X-linked and characterized by impaired granulocyte function. This disorder of phagocytic cell function presents with recurrent skin infections, abscesses, and granulomas at sites of chronic inflammation. Abscesses can involve skin or viscera and may be accompanied by lymphadenitis. Catalase-positive organisms predominate; S aureus is thus the most common pathogen, although infections with Nocardia species, gram-negative Serratia marcescens, and Burkholderia cepacia can also occur. Aspergillus species and Candida represent common fungal pathogens in chronic granulomatous disease. Sterile noncaseating granulomas resulting from chronic inflammatory stimuli can lead to GI or genitourinary tract obstruction. Chronic granulomatous disease typically presents in childhood, although cases in adulthood are occasionally reported.
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Pathology and Pathogenesis
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Defects in the gene coding for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibit oxidative metabolism and severely compromise neutrophil killing activity. NADPH oxidase is assembled from two membrane and two cytosolic components after phagocytic cell activation, leading to catalytic conversion of molecular oxygen into superoxide. Oxidative burst and intracellular killing rely on production of superoxide, which is later converted to hydrogen peroxide and sodium hypochlorite (bleach). In patients with chronic granulomatous disease, other neutrophil functions such as chemotaxis, phagocytosis, and degranulation remain intact but microbial killing is deficient. Catalase-negative bacteria are effectively killed because microbes produce small amounts of peroxide, concentrated in phagosomes, leading to microbial death. Catalase-positive organisms scavenge these relatively small amounts of peroxide and are not killed without neutrophil oxidative metabolism. X-linked inheritance is most frequently seen, but autosomal recessive forms and spontaneous mutations can also lead to clinical disease.
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Leukocyte Adhesion Deficiency, Type 1
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Integrins and selectins are specialized molecules that play a role in leukocyte homing to sites of inflammation. These adhesion molecules facilitate cell-cell and cell–extracellular matrix interactions, allowing circulating leukocytes to stick and roll along endothelial cell surfaces prior to diapedesis into extravascular tissues. An autosomal recessive train, leukocyte adhesion deficiency type 1, and defective expression of β2-integrin (CD11/CD18) adhesion molecules result in impaired trafficking of leukocytes, leading to recurrent infections, lack of pus formation, and poor wound healing. Leukocytosis occurs because cells cannot exit the circulation, and recurrent infections of skin, airways, bowels, perirectal area, and gingival and periodontal areas are common.
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Mendelian Susceptibility to Mycobacterial Disease
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In response to mycobacterial infection, macrophages secrete IL-12, stimulating cell-mediated immunity and increased TH1 secretion of IFN-γ. At least a dozen Mendelian, ie, single gene product, mutations lead to impairment of the synthesis of or response to IL-12 or IFN-γ, that underlie Mendelian susceptibility to mycobacterial disease. Associated defects have been described in genes encoding for IFN-γ, IFN-γ receptors-1 and -2, JAK-1 and -2 (Janus kinase, a cytokine receptor signaling protein), STAT-1 and -4 (signal transducer and activator of transcription, a transcription factor activated by JAK), IL-12 and its receptors, and IL-12RB1 and IL-12RB2. Increased susceptibility to less virulent, nontuberculous species of mycobacteria; Mycobacterium intracellulare-avium complex (MAC), Mycobacterium kansasii, Mycobacterium fortuitum, and BCG are characteristic of affected individuals. Infection with non-typhoidal salmonellae may also be associated with Mendelian susceptibility to mycobacterial disease.
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Hyper-IgE Immunodeficiency
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Clinical Presentation
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This disorder is often referred to as “Job syndrome” because affected individuals suffer from recurrent boils like the tormented biblical figure. The initial description of this immunodeficiency disorder was in two fair-skinned girls with recurrent staphylococcal “cold” skin abscesses associated with furunculosis, cellulitis, recurrent otitis, sinusitis, pneumatoceles, and a coarse facial appearance. The predominant organism isolated from sites of infection is S aureus, although other organisms such as H influenzae, pneumococci, gram-negative organisms, Aspergillus sp. and C albicans are often identified also. Characteristically, patients have a chronic pruritic eczematoid dermatitis, defective shedding of primary teeth, growth retardation, coarse facies, scoliosis, osteopenia, vascular abnormalities, and hyperkeratotic fingernails. Extremely high IgE levels (>3000 IU/mL) have also been observed in patients’ serum.
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Pathology and Pathogenesis
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The high IgE levels are thought to be a consequence of dysregulated immunologic responsiveness to cytokines, yet it is unclear whether the hyper-IgE contributes to the observed susceptibility to infection or is simply an immunologic epiphenomenon. Autosomal dominant forms have been associated with mutations in STAT3, a transcriptional factor involved in the activation of cytokine and growth factor receptors. Responses to numerous cytokines do appear impaired, along with decreased TH17 function. A spectrum of immune abnormalities is also observed. Humoral immunodeficiency is suggested by poor antibody responses to neoantigens, deficiency of IgA antibody against S aureus, and low levels of antibodies to carbohydrate antigens. T-lymphocyte functional abnormalities are suggested by decreased absolute numbers of suppressor T lymphocytes, poor in vitro proliferative responses, and defects in cytokine production. Several reports have also documented highly variable abnormalities in neutrophil chemotaxis.
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Toll-Like Receptor 3 Deficiency
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Patients with TLR3 deficiency have shown specific susceptibility to herpes simplex 1 (HSV1) encephalitis. Typically, binding of pathogen-associated molecular patterns to TLR will activate transcription factors, such as nuclear factor kappa beta (NF-κβ), IFN regulatory factors, and activator protein 1, leading to immune responsiveness. Defects in this pathway impair viral immunity. In TLR3 deficiency, defective IFN-α, IFN-β, and IFN-λ synthesis leads to uninhibited HSV1 replication in neurons and oligodendritic cells. A similar phenotype is seen in autosomal recessive UNC-93b deficiency. UNC-93b is required for TLR3 function, as it translocates TLR3 to its endosomal site of action.
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Checkpoint
What are the major clinical manifestations of each of the five categories of primary immune deficiency?
What are the major pathogenetic mechanisms in each category of primary immune deficiency?
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AIDS is the most common immunodeficiency disorder worldwide, and HIV infection is one of the greatest epidemics in human history. AIDS is the consequence of a chronic retroviral infection that produces severe, life-threatening CD4 helper T-lymphocyte dysfunction, opportunistic infections, and malignancy. AIDS is defined by serologic evidence of HIV infection with the presence of a variety of indicator diseases associated with clinical immunodeficiency. Table 3–6 lists criteria for defining and diagnosing AIDS. HIV is transmitted by exposure to infected body fluids or sexual or perinatal contact. Vertical transmission from mother to infant may occur in utero, during childbirth, and also through breastfeeding. Transmissibility of the HIV virus is related to subtype virulence, viral load, and immunologic host factors.
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Acute HIV infection may present as a self-limited, febrile viral syndrome characterized by fatigue, pharyngitis, myalgias, maculopapular rash, lymphadenopathy, and significant viremia, without detectable anti-HIV antibodies. Less commonly, primary HIV infection may also be associated with orogenital or esophageal ulcers, meningoencephalitis, or opportunistic infection. After an initial viremic phase, patients seroconvert and a period of clinical latency is usually seen. Lymph tissues become centers for massive viral replication during a “silent,” or asymptomatic, stage of HIV infection despite an absence of detectable virus in the peripheral blood. Over time, there is a progressive decline in CD4 T lymphocytes, a reversal of the normal CD4:CD8 T-lymphocyte ratio, and numerous other immunologic derangements. The clinical manifestations are directly related to HIV tissue tropism and defective immune function. Development of neurologic complications, opportunistic infections, or malignancy signal marked immune deficiency. The time course for progression is highly variable, but the median time before appearance of clinical disease is about 10 years in untreated individuals. Approximately 10% of those infected manifest rapid progression to AIDS within 5 years after infection. A minority of individuals are “long-term nonprogressors.” Genetic factors, host cytotoxic immune responses, viral load, and virulence appear to have an impact on susceptibility to infection and the rate of disease progression. Although not curative, modern antiretroviral therapies can significantly reduce viral replication, restore immune function, lead to clinical recovery, and markedly extend life expectancy.
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Pathology and Pathogenesis
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HIV is a group of related retroviruses, whose RNA encodes for nine genes (see Table 3–7). Chemokines (chemoattractant cytokines) regulate leukocyte trafficking to sites of inflammation and have been discovered to play a significant role in the pathogenesis of HIV disease. During the initial stages of infection and viral proliferation, virion entry and cellular infection requires binding to two coreceptors on target T lymphocytes and monocyte/macrophages. All HIV strains express the envelope protein gp120 that binds to CD4 surface receptor molecules, but different viral strains display tissue “tropism” or specificity on the basis of the coreceptor they recognize. Changes in viral phenotype during the course of HIV infection may lead to changes in tropism and cytopathology at different stages of disease. Viral strains isolated in early stages of infection and associated with mucosal and intravenous transmission (eg, R5-trophic viruses) bind macrophages expressing chemokine receptor CCR5. X4-trophic strains of HIV are more commonly seen in later stages of disease. X4-trophic viruses bind to chemokine receptor CXCR4, more broadly expressed on T cells, and are associated with syncytium formation. Since chemokine receptors play a role in viral cell entry, specific inherited polymorphisms of chemokine receptors influence susceptibility to infection and disease progression. Presence of certain HLA alleles has also been associated with differences in susceptibility and clinical course.
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Mathematical models estimate that during HIV infection billions of virions are produced and cleared each day. The reverse transcription step of HIV replication is error prone. Mutations occur frequently, and even within an individual patient, HIV heterogeneity develops rapidly. Patients may be infected with more than one strain concomitantly, and through mechanisms of recombination, genes from separate strains may intermingle, contributing to genetic diversity. The development of antigenically and phenotypically distinct strains contributes to progression of disease, clinical drug resistance, and lack of efficacy of early vaccines.
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Cellular activation is critical for viral infectivity and reactivation of integrated proviral DNA. After viral entry and capsid disassembly, HIV reverse transcriptase converts uncoated viral RNA into double-stranded viral DNA. Utilizing several host proteins, the double-stranded viral DNA complex penetrates the host cell nucleus and integrates into the host chromosome. Once integrated, the viral provirus may remain latent or become transcriptionally active, depending on the activation state of the host cell. Cellular activation triggers NF-κβ, a cytoplasmic transcription factor that migrates to the nucleus initiating viral gene expression. HIV protein Nef enhances viral replication and reduces host antiviral immune responses. New infectious virions are assembled. Viral proteins and RNA are packaged at the infected cell’s exterior membrane through a process called “budding.”
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Although only 2% of mononuclear cells are found peripherally, lymph nodes from HIV-infected individuals can contain large amounts of virus sequestered among infected follicular dendritic cells in the germinal centers. For patients infected through vaginal or rectal mucosa, gut-associated lymphoid tissue is a major site of viral replication and persistence. Gut-associated lymphoid tissue harbors the majority of the host’s T cells, and when HIV-infected epidermal Langerhans cells migrate to draining lymph nodes, large numbers of lymphocytes encounter surface-bound virus. The persistence of virus in these secondary lymphoid structures triggers cellular activation and massive, irrevocable depletion of CD4 T-lymphocyte reservoirs, as well as disease latency. The marked decline in CD4 T-lymphocyte counts is due to several mechanisms: (1) direct HIV-mediated infection and destruction of CD4 T lymphocytes during viral replication; (2) depletion by fusion and formation of multinucleated giant cells (syncytium formation); (3) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors; (4) loss of T-lymphocyte costimulatory factors such as CD28; and (5) induction of apoptosis (programmed cell death) of uninfected T cells. CD8 CTL activity is initially brisk and effective at controlling viremia but later induces the generation of viral escape mutations. Ultimately, viral proliferation outstrips host responses, and HIV-induced immunosuppression leads to disease progression. Neutralizing antibodies are generated very late, but mutations in HIV-envelope proteins outfox protective humoral responses. Over time, the infection is characterized by systemic, generalized cytokine dysregulation and immune activation. Hyperactivity of the immune system increases naïve T-cell infection. Ultimately, these events prove deleterious to maintenance of lymphatic organs, bone marrow integrity, and effective immune responses.
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In addition to the cell-mediated immune defects, B- lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. Both anamnestic responses and those to neoantigens can be impaired.
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The development of assays to measure viral burden (plasma HIV-RNA quantification) has led to a better understanding of HIV dynamics and has provided a tool for assessing response to therapy. It is now well recognized that viral replication continues throughout the disease, and immune deterioration occurs despite clinical latency. The risk of progression to AIDS appears correlated with an individual’s viral load after seroconversion. Data from several large clinical cohorts have shown that there is a direct correlation between the CD4 T-lymphocyte count and the risk of AIDS-defining opportunistic infections and malignancy. The viral load and the degree of CD4 T-lymphocyte depletion serve as important clinical indicators of immune status in HIV-infected individuals. CD4 count may be better for disease staging, but viral load may be a better proxy for disease progression or monitoring response to therapy. Prophylaxis for opportunistic infections such as pneumocystis pneumonia (PCP) is started when CD4 T-lymphocyte counts reach the 200–250 cells/μL range. Similarly, patients with HIV infection with fewer than 50 CD4 T lymphocytes/μL are at significantly increased risk for cytomegalovirus (CMV) retinitis and M avium complex (MAC) infection. Unfortunately, some complications of HIV infection, including tuberculosis infection, non-Hodgkin lymphoma, and cardiovascular, hepatic, and neurocognitive diseases, may occur even with robust CD4 counts.
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Monocytes, macrophages, and dendritic cells also express HIV receptors (CD4) and can be infected with HIV. This facilitates transfer of virus to lymphoid tissues and immunoprivileged sites, such as the CNS. HIV-infected monocytes will also release large quantities of the acute-phase reactant cytokines, including IL-1, IL-6, and TNF, contributing to constitutional symptomatology. TNF, in particular, has been implicated in the severe wasting syndrome seen in patients with advanced disease. Concomitant infections may serve as cofactors for HIV infection, facilitate mucosal entry, and increase expression of HIV through enhanced cytokine production, coreceptor surface expression, or increased cellular activation mechanisms. Epidemiologic studies of HSV-2–infected patients demonstrate a 2- to 7-fold increased risk of acquisition of HIV compared with similar cohorts.
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Clinical Manifestations
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The clinical manifestations of AIDS are the direct consequence of the progressive and severe immunologic deficiency induced by HIV. Patients are susceptible to a wide range of atypical or opportunistic infections with bacterial, viral, protozoal, and fungal pathogens. Common nonspecific symptoms include fever, night sweats, and weight loss. Weight loss and cachexia can be due to nausea, vomiting, anorexia, or diarrhea. They often portend a poor prognosis.
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The incidence of infection increases as the CD4 T- lymphocyte number declines. Fungal pathogens may affect immunocompetent hosts but are frequently opportunistic in HIV-infected patients. Infections with Cryptococcus neoformans meningoencephalitis, disseminated Histoplasma capsulatum, and disseminated Coccidioides immitis are typically seen in late stages of disease, when CD4 counts are below 200 cells/mm3. C neoformans meningoencephalitis is manifested by fevers, malaise, headache, photophobia, and nausea. Presentation with altered mental status or elevated intracranial pressure is associated with a higher risk of death or neurologic sequelae. Occasionally, a cerebral cryptococcoma presents as a mass lesion.
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Found endemically in regional soil contaminated with bird and bat droppings, H capsulatum infection is characterized by prominent constitutional symptoms, frequent pulmonary symptoms, and subacute meningoencephalitis. Disseminated disease may represent reactivation of latent disease when cellular immunity fails.
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Previously thought to be a protozoan, now classified as a fungus, Pneumocystis jirovecii is the most common opportunistic infection, affecting 75% of patients. Patients present clinically with fevers, cough, shortness of breath, and hypoxemia, ranging in severity from mild to life threatening. PCP may represent new acquisition or activation of old infections. A diagnosis of PCP can be made by substantiation of the clinical and radiographic findings with Wright-Giemsa or silver methenamine staining of induced sputum samples. A negative sputum stain does not rule out disease in patients in whom there is a strong clinical suspicion of disease, and further diagnostic maneuvers such as bronchoalveolar lavage or fiberoptic transbronchial biopsy may be required to establish the diagnosis. Complications of PCP include pneumothoraces, progressive parenchymal disease with severe respiratory insufficiency, and, most commonly, adverse reactions to the medications used for treatment and prophylaxis.
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As a consequence of chronic immune dysfunction, HIV-infected individuals are also at high risk for other pulmonary infections, including bacterial infections with S pneumoniae, H influenzae, and P aeruginosa; mycobacterial infections with Mycobacterium tuberculosis or MAC; and fungal infections with C neoformans, H capsulatum, Aspergillus sp, or C immitis. Clinical suspicion followed by early diagnosis of these infections should lead to aggressive treatment.
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The risk of M tuberculosis reactivation is estimated to be 5–10% per year in HIV-infected patients compared with a lifetime risk of 10% in those without HIV. The development of active tuberculosis is significantly accelerated in HIV infection as a result of compromised cellular immunity. Furthermore, diagnosis may be delayed because of anergic skin responses. Respiratory symptoms of cough, dyspnea, or pleuritic chest pain may be associated with the insidious onset of fever, malaise, weight loss, and anorexia. Extrapulmonary manifestations occur in up to 70% of HIV-infected patients with tuberculosis, with miliary tuberculosis and meningitis representing more serious complications. The emergence of multidrug resistance may compound the problem. M avium is a less virulent pathogen than M tuberculosis, and disseminated infections usually occur only with severe clinical immunodeficiency. M avium survives intracellularly within macrophages due to defective cytokine (IFN-γ, IL-2, IL-12, TNF) synthesis, leading to impaired killing of phagocytosed organisms. Symptoms of MAC are nonspecific and typically consist of fever, weight loss, anemia, and GI distress with diarrhea.
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The presence on physical examination of oral candidiasis (thrush) and hairy leukoplakia is highly correlated with HIV infection and portends rapid progression to AIDS. Oral candidiasis develops when reduced local and systemic immune function, sometimes combined with metabolic imbalances, contributes to opportunistic outgrowth of Candida, which is normally a common commensal organism. HIV-infected individuals with oral candidiasis are at much greater risk for esophageal candidiasis, which may present as substernal pain and dysphagia. This infection and its characteristic clinical presentation are so common that most practitioners treat with empiric oral antifungal therapy. Should the patient not respond rapidly, other explanations for the esophageal symptoms should be explored, including herpes simplex and CMV infections. Epstein-Barr virus (EBV) is the cause of hairy leukoplakia, another oral complication of HIV, manifested by white thickening of mucosal folds, prominent in the buccal mucosa, the soft palate, and the floor of the mouth.
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Diarrhea has been a hallmark feature of AIDS and leads to significant wasting, morbidity, and mortality. Persistent diarrhea, especially when accompanied by high fevers and abdominal pain, may signal infectious enterocolitis. The degree of CD4-lymphopenia is significantly correlated with the risk of opportunistic GI tract infections. The list of potential pathogens in such cases is long and includes bacteria, MAC, protozoans (cryptosporidium, microsporidia, Isospora belli, Entamoeba histolytica, Giardia lamblia), and even HIV itself. Because of their reduced gastric acid concentrations, patients also have an increased susceptibility to nonopportunistic infectious gastroenteritis with Campylobacter, Salmonella, and Shigella. Co-infection with viral hepatitis (HBV, HCV, CMV) can lead to accelerated cirrhosis and end-stage liver disease, but fortunately, institution of highly active antiretroviral therapy (HAART) can lead to a reduction in clinical disease.
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Skin lesions commonly associated with HIV infection are typically classified as infectious (viral, bacterial, fungal), neoplastic, or nonspecific. Herpes simplex virus (HSV) and herpes zoster virus (HZV) may cause chronic persistent or progressive lesions in patients with compromised cellular immunity. HSV commonly causes oral and perianal lesions but can be an AIDS-defining illness when involving the lung or esophagus. The risk of disseminated HSV or HZV infection and the presence of molluscum contagiosum appear to be correlated with the extent of immunoincompetence. Seborrheic dermatitis caused by Pityrosporum ovale and fungal skin infections (C albicans, dermatophyte species) are also commonly seen in HIV-infected patients. Staphylococcus including methicillin-resistant S aureus can cause the folliculitis, furunculosis, and bullous impetigo commonly observed in HIV-infected patients, which may require aggressive treatment to prevent dissemination and sepsis. Bacillary angiomatosis is a potentially fatal dermatologic disorder of tumor-like proliferating vascular endothelial cell lesions, the result of infection by Bartonella quintana or Bartonella henselae. The lesions may resemble those of Kaposi sarcoma but respond to treatment with erythromycin or tetracycline.
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CNS manifestations in HIV-infected patients include infections and malignancies. Toxoplasmosis frequently presents with space-occupying lesions, causing headache, altered mental status, seizures, or focal neurologic deficits. Cryptococcal meningitis commonly manifests as headache and fever. Up to 90% of patients with cryptococcal meningitis exhibit a positive serum test for C neoformans antigen.
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Patients with HIV-associated neurocognitive disorder typically have difficulty with cognitive tasks, poor short-term memory, slowed motor function, personality or affective changes, and waxing and waning dementia. In the severe form, AIDS dementia may be characterized by severe psychomotor retardation, akinesis, and language impairment, associated with widespread cortical atrophy and ventricular enlargement. Up to 50% of patients with AIDS suffer from this disorder, perhaps caused by glial or macrophage infection by HIV resulting in destructive inflammatory changes within the CNS. R5 viruses are trophic for cells of monocytic lineage in the CNS. The differential diagnosis can be broad, including metabolic disturbances and toxic encephalopathy resulting from drugs. Other causes of altered mental status include neurosyphilis, CMV or herpes simplex encephalitis, mycobacterial or cryptococcal meningitis, lymphoma, and progressive multifocal leukoencephalopathy, a progressive demyelinating disease caused by a JC papovavirus.
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Peripheral nervous system manifestations of HIV infection include sensory, motor, and inflammatory polyneuropathies. Almost 33% of patients with advanced HIV disease develop peripheral tingling, numbness, and pain in their extremities. These symptoms are likely to be due to loss of nerve axons from direct neuronal HIV infection. Alcoholism, thyroid disease, syphilis, vitamin B12 deficiency, drug toxicity (ddI, ddC), CMV-associated ascending polyradiculopathy, and transverse myelitis also cause peripheral neuropathies. Less commonly, HIV-infected patients can develop an inflammatory demyelinating polyneuropathy similar to Guillain-Barré syndrome; however, unlike the sensory neuropathies, this inflammatory demyelinating polyneuropathy typically presents before the onset of clinically apparent immunodeficiency. The origin of this condition is not known, although an autoimmune reaction is suspected. Retinitis resulting from CMV infection is the most common cause of rapidly progressive visual loss in HIV infection. The diagnosis can be difficult to make because Toxoplasma gondii infection, microinfarction, and retinal necrosis can all cause visual loss.
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HIV-related malignancies commonly seen in AIDS include Kaposi sarcoma, non-Hodgkin lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Impairment of immune surveillance and defense and increased exposure to oncogenic viruses appear to contribute to the development of neoplasms.
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Kaposi sarcoma is the most common HIV-associated cancer. In San Francisco, 15–20% of HIV-infected homosexual men develop this tumor during the progression of their disease. Kaposi sarcoma is uncommon in women and children for reasons that are not clear. Unlike classic Kaposi sarcoma, which affects elderly men in the Mediterranean, the disease in HIV-infected patients may present with either localized cutaneous lesions, lymphatic or disseminated visceral involvement. It is often a progressive disease, and pulmonary involvement can be fatal. Histologically, the lesions of Kaposi sarcoma consist of a mixed cell population that includes vascular endothelial cells and spindle cells within a collagen network. Human herpesvirus 8 (HHV-8) in immunocompromised patients appears to promote angiogenesis through growth factor and proinflammatory gene product production. HIV itself appears to induce cytokines and growth factors that stimulate tumor cell proliferation rather than causing malignant cellular transformation. Clinically, cutaneous Kaposi sarcoma typically presents as a purplish nodular skin lesion or painless oral lesion. Sites of visceral involvement include the lung, lymph nodes, liver, and GI tract. In the GI tract, Kaposi sarcoma can produce chronic blood loss or acute hemorrhage. In the lung, it often presents as coarse nodular infiltrates bilaterally, frequently associated with pleural effusions.
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Non-Hodgkin lymphoma is particularly aggressive in HIV-infected patients and usually indicative of significant immune compromise. The majority of these tumors are high-grade B-cell lymphomas with a predilection for dissemination. Chronic B-cell stimulation, immune dysfunction, and loss of immunoregulation of EBV-infected cells are all risk factors for transformation of clonally selected cells and development of non-Hodgkin lymphoma. Large-cell and Burkitt-type lymphoma are often associated with EBV but only account for about half of cases. Many cases are diagnosed at advanced stages of disease, and the CNS is frequently involved either as a primary site or as an extranodal site of widespread disease.
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Anal dysplasia and squamous cell carcinoma are also more commonly found in HIV-infected homosexual men. These tumors appear to be associated with concomitant anal or rectal infection with human papillomavirus (HPV). In HIV-infected women, the incidence of HPV-related cervical dysplasia is as high as 40%, and dysplasia can progress rapidly to invasive cervical carcinoma.
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Adherence to multidrug regimens remains a challenge, but clearly antiretroviral therapy improves immune function. For reasons that are not clear, HIV-infected patients have an unusually high rate of adverse reactions to a wide variety of antibiotics and frequently develop severe debilitating cutaneous reactions. Drug hypersensitivity and toxicity can be severe, potentially life-threatening, and limiting with certain agents. Immune reconstitution syndrome is a described reaction occurring days to weeks after initiation of HAART. Clinical relapse or worsening of mycobacterial, pneumocystis, hepatitis, or neurological infections occurs as a result of a resurgence of immune activity, causing paradoxical worsening of inflammation, possibly as residual antigens or subclinical pathogens are attacked.
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Other complications of HIV infection include arthritides, myopathy, GI syndromes, dysfunction of the adrenal and thyroid glands, hematologic cytopenias, and nephropathy. As patients are living longer due to potent antiretroviral therapy (ART), cardiovascular complications are more prominent. ART has been associated with dyslipidemia and metabolic abnormalities including insulin resistance. HIV infection may be atherogenic as well, through effects on lipids and proinflammatory mechanisms.
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Since the disease was first described in 1981, medical knowledge of the underlying pathogenesis of AIDS has increased at a rate unprecedented in medical history. This knowledge has led to the rapid development of therapies directed at controlling HIV infection as well as the multitude of complicating opportunistic infections and cancers.
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Checkpoint
What are the major clinical manifestations of AIDS?
What are the major steps in development of AIDS after infection with HIV?