Timothy R. La Pine MD
Harry R. Hill MD
A critical and delicate balance in both cellular and humoral function is essential for complete immunologic responsiveness to invasive microbial pathogens. Any alteration in immune regulation or responsiveness may render a host susceptible to recurrent or life-threatening infections. Understanding the specific functional mechanisms involved in leukocyte production, activation, migration, and immune regulation leading to cytoxic killing is of extreme clinical significance when evaluating patients with suspected immunodeficiency.
Leukocyte abnormalities should be suspected in the following patients: (1) those who have an increased frequency of infections compared to patients of similar age and exposure risks; (2) those whose infections with common, often nonpathogenic or usually inconsequential pathogens are more severe than would normally be expected; (3) those whose infections are of prolonged duration and require prolonged antimicrobial therapy often with incomplete clearing between episodes or requiring surgical intervention; (4) those with multiple complicated infections, involving different organ systems; and (5) those who have infections with unusual or opportunistic organisms.
The specific components of immune responsiveness are exceedingly complex and require the close cooperation of a variety of cellular elements (T lymphocytes, B lymphocytes, phagocytes, and natural killer cells) as well as humoral factors (immunoglobulins, lymphokines, monokines, interferons, acute-phase reactants, and the complement system). For clinical utility, defects in leukocyte immunoresponsiveness can be categorized into four functional systems: (1) defects in the T-lymphocyte system (including T cells and lymphokines); (2) defects in the B-lymphocyte system (including B cells and secretory immunoglobulins); (3) defects in the phagocyte system (including neutrophils, monocytes, and macrophages); (4) defects in the complement system. Box 26-1 summarizes the syndromes commonly found with each type of defect. The tests used to screen patients with suspected immunodeficiency are listed in Table 26-1, and further confirmatory tests are listed in Table 26-2.
Essentials of Diagnosis
The T-lymphocyte system is composed of several subtypes of effector cells that include regulatory T cells, helper and suppressor T cells, cytotoxic T cells, and T cells involved in delayed hypersensitivity reactions. The major function of the T-lymphocyte system is in host defense against intracellular pathogens (viruses, fungi, protozoa, and intracellular bacteria such as mycobacteria and Listeria spp.). The T lymphocyte system also functions in tumor surveillance, delayed hypersensitivity reactions, and graft-versus-host disease.
Thymus-dependent T cells are derived from pluripotent hematopoietic stem cells residing in developing bone marrow stores. As early as the eighth gestational week, immature T cells infiltrate the thymus where they differentiate and mature before migrating to specific lymphoid tissues. During their intrathymic maturation, T cells develop specific outer membrane glycoproteins. Mature T cells express T-cell antigen receptors as well as the CD3 membrane glycoproteins. Nearly 70% of the T cells also express the CD4 membrane glycoproteins, the helper-inducer T-cell marker. The remaining 30% express the CD8 membrane glycoprotein, the cytotoxic-suppressor T-cell marker. The CD4 and CD8 membrane glycoproteins are typically not presented on the same mature T cell and serve as functional markers of helper and cytotoxic-suppressor T-cell populations in the peripheral blood or tissues.
BOX 26-1 Defects in Immune Responsiveness
The T-lymphocyte system orchestrates pathogen annihilation through antigen-dependent cellular interactions. Antigen-presenting cells, mainly the monocytes and macrophages (but also the Langerhans cells of the skin, the Kupffer cells of the liver, and specific endothelial cells) process soluble antigen and present it in combination with HLA class II antigens on their cellular surface. Thymus-dependent CD4 helper-inducer T cells recognize and bind to this altered antigen-HLA class II complex through helper T-cell receptors. During this process, interleukin-1 (IL-1) is released from the antigen-presenting cells. The binding of the free IL-1 to its receptor on the helper T-cell surface initiates T-cell activation. Once activated, the CD4 helper T cells produce IL-2, which functions as a T-cell promoter, causing the T cells to proliferate and release a number of factors, thus initiating a cascade of events that serves to amplify and regulate the immune response with the cooperation and recruitment of many other cell types. IL-2 also interacts directly with CD8 cytotoxic T-cells that bind viral antigens
present on the surfaces of infected cells, resulting in cellular destruction.
Table 26-1. Laboratory tests used to screen for immunodeficiency.1
Table 26-2. Laboratory tests to confirm and define immunodeficiency.1
T-cell immunodeficiency can result from defects in the (1) maturation, differentiation, and activation of hematopoietic stem cells; (2) specific thymic defects, including the thymic microenvironment and associated humoral factors; (3) specific T-cell defects; (4) defective production of cytokines; (5) defective expression of cytokine receptors; (6) defective production of regulatory proteins needed for T-cell activation; and (7) destruction of T cells. Any defect in T-cell immunity is also associated with variable degrees of B-cell deficiency because most of the maturation, differentiation, and activation processes of B cells requires T cell help. Box 26-2 summarizes treatment options for patients who have lekocyte deficiencies.
BOX 26-2 Treatment and Management Options for Patients with Leukocyte Deficiencies
SEVERE COMBINED IMMUNODEFICIENCY
The most severe forms of leukocyte immunodeficiency are the syndromes of severe combined immunodeficiency (SCID). This immunodeficiency category includes a spectrum of X-linked, autosomal recessive, and sporadic genetic defects characterized by the inability to mount normal T-lymphocyte (cell-mediated) and B-lymphocyte (humoral) immunity. These syndromes include X-linked SCID, adenosine deaminase deficiency, and ZAP-70 deficiency, which are characterized by the onset of viral, bacterial, fungal, or protozoal infections before 6 months of age.
Infants lacking both T- and B-cell immunity whose T lymphocytes are phenotypically normal but unable to respond appropriately should be evaluated for the following:
Patients with SCID usually suffer from failure to thrive, persistent oral candidiasis, recurrent diarrhea, and pneumonia (usually interstitial, often caused by Pneumocystis carinii) in the first months of life. Several immunologic defects are associated with a similar clinical pattern. Seventy-five percent of the patients with SCID are male.
Prenatal diagnosis of SCID may be made by fetal blood sampling of T-lymphocyte subsets and T-cell functional studies as early as 20 weeks gestation.
The only curative therapy for SCID is allogeneic bone marrow transplantation, although the use of cytokines, particularly recombinant human IL-2, may be of value for SCID patients who fail to produce IL-2.
In X-linked SCID, the failure to express normal IL-2Rγ may result in impaired early intrathymic T-cell maturation and function, leading to this severe immunodeficiency syndrome. Maternal carriers can be identified by the pattern of T-cell X chromosome inactivation and by the localization of the gene defect to Xq-13 by linkage analysis.
Prenatal diagnosis can be made as early as the 10th gestational week by analysis of unbalanced patterns of X chromosome inactivation in maternal and fetal T cells with the use of somatic cell hybridization or methylation differences between the active and inactive X chromosome. The analysis of X chromosome inactivation has been useful in detecting carriers in the X-linked primary immunodeficiency diseases (X-linked SCID, X-linked agammaglobulinemia, and the Wiskott-Aldrich syndrome). Polymerase chain reaction can also be used to amplify specific DNA sequences used to detect X chromosome inactivation in patients with X-linked SCID and other primary immunodeficiencies.
About 50% of the patients with autosomal recessive SCID have an associated adenosine deaminase (ADA) deficiency. The gene for ADA deficiency has been mapped to chromosome 20q-13. Absence of this enzyme in purine metabolism leads to the accumulation of toxic metabolites including deoxyadenosine triphosphate, which is capable of killing both dividing and resting T cells.
In addition to the classic symptoms of SCID, this disease is characterized by the presence of skeletal abnormalities including concavity and flaring of the anterior ribs, an abnormal contour and articulation of the posterior ribs and transverse processes, platyspondylisis and an abnormal bony pelvis.
The diagnosis is made by measuring ADA levels in hemolyzed red blood cells. Heterozygotes are symptom-free but have half the normal enzyme concentration. Prenatal diagnosis is possible by measuring ADA levels in cultured amniotic cells during the second trimester.
Bone marrow transplantation or enzyme replacement with bovine ADA has been used with some success in the management of this disease. Promising recent attempts to treat patients with ADA deficiency have used autologous lymphocytes or cord blood stem cells corrected in vitro with retroviral vector-inserted normal human ADA DNA.
Another autosomal recessive form of SCID includes the abnormality of the protein kinase ZAP-70.
Two families of protein kinases are involved with T-cell receptor signal transduction leading to T-cell maturation and differentiation: (1) the Src family of protein kinases, Fyn and LCK and (2) the ZAP-70 and Syk protein kinases. Patients with ZAP-70 deficiency have compromised T-cell receptor signal transduction, leading to impaired T-cell differentiation.
This disorder is characterized by the presence of normal numbers of peripheral T cells with a deficiency of the CD8, cytotoxic-suppressor, T cells and a T-cell receptor signal transduction defect present in the helper CD4 T cells. These patients have normal immunoglobulin concentrations and natural killer cell function. Some intrathymic CD4 maturation occurs in these patients, but their peripheral blood is deficient in CD8 cells.
The diagnosis of this disease is suggested by family history, symptoms of SCID, and the characteristic peripheral T-cell phenotype and function.
At present, bone marrow transplantation is the only curative therapy.
Purine-nucleoside phosphorylase (PNP) deficiency is an extremely rare autosomal recessive disorder characterized by a deficiency in the enzyme PNP, which is associated with marked T-cell immunodeficiency with a relatively intact humoral immunity. The gene coding PNP is located on chromosome 14q. The accumulation of deoxyguanosine triphosphate destroys dividing T cells.
Patients usually have recurrent viral, bacterial, and fungal infections. Two-thirds of these patients have neurologic disorders ranging from mild developmental delay or muscle spasticity to severe mental retardation.
The diagnosis can be made by measuring PNP in hemolyzed erythrocytes. Heterozygotes have half the normal level of this enzyme and associated serum uric acid levels are low in these patients. Prenatal diagnosis is possible by assaying PNP levels cultured in amniotic cells during the second trimester.
Bone marrow or stem cell transplant is the only successful therapy. Enzyme replacement therapy, as well as viral gene transfer, are currently being investigated as promising future therapies.
DiGeorge syndrome is a polytropic developmental defect consisting of congenital aplasia or dysplasia of the thymus and parathyroid glands, leading to lymphopenia with decreased T-cell populations as a result of monosomy of chromosome 22q-11. DiGeorge syndrome mainly affects the structures derived from the 3rd, 4th, and 5th pharyngeal pouches, but the 1st, 2nd, 5th, and 6th pouches and all branchial arches may also be involved. This is due to the failure of a population of neural crest cells to migrate and interact with endodermally derived cells of the branchial pouches and arches.
Prenatal diagnosis of DiGeorge syndrome can be performed by fluorescence in situ hybridization of fetal tissue to look for the chromosomal monosomy at 22q-11.
Treatment of patients with DiGeorge syndrome has included the implantation of fetal thymic tissue, fetal thymic epithelium, or fetal thymus in a diffusion chamber, all of which have demonstrated limited success. Bone marrow transplantation, which provides donor postthymic T cells to reconstitute the patient's immunity, has been successfully used to treat patients with DiGeorge syndrome.
The Wiskott-Aldrich syndrome gene has been mapped to the short arm of the X chromosome. Recently a novel gene has been isolated that is absent in Wiskott-Aldrich syndrome patients. This gene encodes a protein that appears to be an important immunoregulator of both T-lymphocytes and platelets.
Prenatal diagnosis is facilitated by fetal blood sampling and the analysis of thrombocyte numbers and size, as well as an analysis of the pattern of X chromosome inactivation to detect carriers.
Bone marrow transplantation, or more recently stem cell transplantation, may correct the immunologic defects and platelet disorder observed in these patients.
Ataxia telangiectasia, an autosomal recessive disorder, is thought to be a specific gene defect affecting mitogenic signal transduction, miotic recombination, and cell cycle control. The defect can result in recombination errors that interfere with the rearrangement of T- and B-cell genes and the inability to repair damaged DNA. The defects observed in DNA repair in these patients after x-ray irradiation results in a high incidence of chromosomal translocation, specifically in chromosomes 7 and 14.
Serum α-fetoprotein levels are persistently elevated in these patients, which may be a useful but nonspecific aid in the diagnosis.
Therapy consists of intravenous immunoglobulin therapy using IgA-depleted preparations. Gene therapy for ataxia telangiectasia is currently under investigation.
Essentials of Diagnosis
The B-lymphocyte system is derived from stem cells residing in bone marrow stores. These stem cells produce cytoplasmic IgM heavy chains, which become pre-B cells. These pre-B cells continue to differentiate to become mature surface IgM- or IgM- and IgD-bearing B cells, which seed peripheral lymphoid tissue via the circulation. Upon stimulation, IgM-bearing B cells undergo class switching to IgG, IgA, or IgE-bearing B cells. These B cells can then differentiate to immunoglobulin-secreting plasma cells with the help of T cells and T-cell-derived lymphokines. Some of the B cells further differentiate into small memory B cells, which are involved in secondary immune responses.
The major function of B cells and the plasma cells is to produce antibodies to protein and carbohydrate antigens present on microorganisms, toxins, or other antigenic substances potentially harmful to the host. These antibodies are classified into nine different immunoglobulin isotypes, including IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, and IgE. IgM antibodies are made first and are the most efficient in activating the classical complement system, which facilitates the opsonization and subsequent ingestion of microorganisms.
IgG antibodies are the only maternal antibodies that are transplacentally passed to developing infants. These antibodies are responsible for much of the infant's defense against invading microorganisms and their toxic substances through their opsonization and neutralization effects. IgA antibodies are selectively transported across mucous membranes by a secretory moiety. These IgA antibodies prevent the attachment of microorganisms or absorption of harmful antigens through mucous membranes. IgE antibodies are mainly responsible for allergic reactions and protection against parasites. Any defect in the maturation and differentiation of B cells (from the hematopoietic stem cells to plasma cells and their secretory immunoglobulins) or T cells and their receptors or lymphokines may produce B-cell immunodeficiency syndromes.
Patients with B-cell deficiencies, usually have recurrent pyogenic infections, particularly of the sinopulmonary tract, and to a lesser extent the gastrointestinal tract. Enterovirus infections may also be problematic.
Bruton's agammaglobulinemia is an X-linked recessive disease that affects only males. The underlying defect is an arrest in the differentiation of pre-B cells caused by the absence of a Bruton's tyrosine kinase, which functions in B-cell differentiation.
Female carriers do not exhibit antibody deficiency and can be detected by analyzing the unbalanced pattern of X chromosome inactivation in peripheral blood mononuclear cells. Prenatal diagnosis of suspected patients is facilitated by sex determination of the fetus and direct sampling of fetal blood for mature B cells or by DNA markers.
Therapy (Box 26-2) consists of the administration of intravenous immunoglobulin and clinical surveillance for infections and the development of lymphoreticular and other malignancies.
X-LINKED HYPOGAMMAGLOBULINEMIA WITH NORMAL TO INCREASED IgM CONCENTRATIONS
Patients with this immune deficiency have an increased IgM concentration, recurrent pyogenic infections, autoimmune disease, and lymphoproliferative disease, especially IgM surface-bearing B-cell lymphomas of the intestinal tract. The hyper-IgM syndrome can be inherited in an X-linked or an autosomal recessive fashion. The underlying cause of the X-linked hyper-IgM syndrome is a deficiency in the expression of the T-cell CD40 ligand, which specifically binds B cells and drives the immunoglobulin isotype switch. The gene for the CD40 ligand has been cloned and mapped to Xq-26.
Prenatal diagnosis can be performed by DNA analysis and from cytometry for the CD40 ligand on T cells.
Bone marrow transplantation has recently been tried in the treatment of hyper-IgM syndrome. Stem cell transplantation has also been attempted. Replacement therapy with a recombinant, soluble form of the CD40 ligand or gene therapy may be developed for these patients in the future.
SELECTIVE IgA DEFICIENCY
The incidence of selective IgA deficiency is ~1/400–1/1000. Studies of the IgA heavy-chain constant-region genes, situated on chromosome 14, have revealed that there are no structural deletions in individuals with selective IgA deficiency. A gene located in the major histocompatibility complex class III region on chromosome 6 recently has been implicated for both selective IgA deficiency and common variable immunodeficiency, suggesting a relationship in these two disorders. The cause of selective IgA deficiency appears to be a terminal block in B-cell differentiation to plasma cells capable of secreting the IgA isotype.
Symptomatic patients usually have recurrent infections of the respiratory and gastrointestinal tracts, autoimmune disease, allergy, and malignancy. Approximately two-thirds of the patients do not have an increased susceptibility to infection, presumably because of the protective effects of IgG and IgM.
Selective IgA deficiency has been defined as a serum IgA concentration of < 5 mg/dL in severe deficiency and less than two standard deviations below the mean of age-matched control in partial deficiency. In some IgA deficient patients, secretory IgA is low but present; the serum concentration of IgA may return to normal within 4 years of diagnosis. These patients have normal T-cell immunity.
Therapy with IgA is not possible in patients with selective IgA deficiency because (1) the half-life of IgA is short (~7 days), (2) administered IgA is not transported to the mucosal surfaces, and (3) the presence of anti-IgA autoantibodies in IgA-deficient patients may cause anaphylactic reactions when blood components containing IgA are transfused. In ~20% of the IgA-deficient patients who have frequent infections, there is an associated IgG-2 subclass deficiency.
Some of these patients, including those with anti-IgA antibodies, can benefit from treatment with intravenously administered immune globulin containing low levels of IgA.
COMMON VARIABLE IMMUNODEFICIENCY
The underlying clinical defect in common variable immunodeficiency (CVID), or late-onset hypogammaglobulinemia, is that the B cells do not differentiate into plasma cells. This may be caused by a primary B-cell defect (failure to terminally glycosylate and secrete immunoglobulins), a failure of helper T-cell factor production, or an increase in specific suppressor T-cell effects. The immunologic defect seen in this disorder is not limited only to B cells but also includes macrophages and immunoregulatory T cells. The defects in T-cell immunity include abnormalities of activation and lymphokine production, which usually progresses with age.
Many patients (11%) with CVID have a first-degree relative with selective IgA deficiency or CVID. It appears that a susceptibility gene or group of genes for both CVID and selective IgA deficiency are located within the major histocompatibility complex class III region of the chromosome 6. It is likely that in both these disorders there are exogenous factors that act intrinsically or extrinsically on genetically susceptible individuals to determine the degree of expression of the immunoglobulin genes in these patients.
Assessing a male patient with recurrent infections and significant hypogammaglobulinemia, the absence of mature immunoglobulin B cells in the peripheral blood or X chromosome inactivation analysis of the patient's mother can be helpful in distinguishing sporadic cases of X-linked agammaglobulinemia from cases of CVID.
Management of CVID includes immunoglobulin replacement therapy, antimicrobial therapy and pulmonary drainage, and immunomodulatory therapies including recombinant human IL-2 conjugated with polyethylene glycol and cimetidine.
DEFECTS IN THE PHAGOCYTIC SYSTEM & ITS RELATED IMMUNODEFICIENCY SYNDROMES
Essentials of Diagnosis
The phagocytic system includes polymorphonuclear leukocytes (neutrophils and eosinophils) and mononuclear phagocytes (circulating monocytes, tissue macrophages, and fixed macrophages). Major phagocytic functions include adherence to endothelium, aggregation, diapedesis, chemotaxis, attachment, phagocytosis, and degranulation, leading to pathogen destruction. The phagocytic system is responsible for defense against extracellular bacterial or fungal invasion in association with opsonins, antibodies, complement, and some acute-phase proteins. Neutrophils are one of the first lines of defense against bacterial invasion and neutrophil disorders include leukocyte adhesion deficiency, Chediak-Higashi syndrome, chronic granulomatous disease, and Job's syndrome.
LEUKOCYTE ADHESION DEFICIENCY
Neutrophil adherence to and migration through capillary endothelium is a critical early event in the acute inflammatory response. The adhesive interactions between neutrophils and endothelial cell surfaces are regulated by two novel families of glycoproteins: the integrins and the selectins. The β-2 integrins are membrane-bound glycoprotein receptors found on the surface of neutrophils. The β-2 integrins CD11/CD18 are required for neutrophil adherence to endothelial cell surfaces. The selectins also are membrane-bound glycoproteins that mediate neutrophil adhesion to endothelial cells. These include L-selectin, which is found on the surface of neutrophils, and P-selectin and E-selectin, which are expressed on the surface of activated endothelial cells.
The interaction between the β-2 integrins and the selectins serves to regulate neutrophil responses during inflammation. In general, P-selectin and E-selectin on the activated endothelial cell surface and L-selectin on the neutrophil cell surface function to facilitate neutrophil rolling and tethering to activated capillary endothelium. Once this tethering has occurred and the neutrophil itself is activated, the β-2 integrin CD11/CD18 receptors on the neutrophil form a tight adhesion with the endothelial cell surface that facilitates neutrophil polarization, leading to migration.
Two types of leukocyte adhesion deficiency (LAD) have been described. The first is congenital β-2 integrin CD11/CD18 deficiency (LAD-I). A second type, LAD-II, has been described for a deficiency of Sialyl Lewis X, the neutrophil ligand for E-selectin on endothelial cells. Deficiency of the CD11/CD18 complex (LAD-I) is transmitted as an autosomal recessive trait. The gene encoding CD18 has been mapped to chromosome 21. The underlying defect results from heterogeneous mutations affecting the CD18 gene, which impair its synthesis.
This disorder is characterized by frequent infections, poor wound healing, leukocytosis, and a history of delayed umbilical cord separation. Patients usually suffer from recurrent bacterial skin abscesses, otitis media, periodontitis, omphalitis, perirectal abscesses, pneumonia, and sepsis.
The striking feature of these infections is the almost total absence of leukocytes in the lesions. The most prevalent invading microorganisms are Staphylococcus aureus, group A streptococci, Proteus mirabilis, Pseudomonas aeruginosa, and Escherichia coli. Based on the severity of the deficiency, two phenotypes (severe and moderate) have been defined.
The severe form is associated with complete absence of CD11/CD18 expression, whereas the moderate form demonstrates ~10–20% of normal expression. The degree of deficiency is closely related to the severity of the patient's clinical manifestations; patients with the severe form of leukocyte adhesion deficiency usually die within the first few years of life. In contrast, the patients with at least some expression of these adhesive glycoproteins usually have a milder disease course and can survive into adulthood.
The diagnosis can be made by assessing the expression of CD11b or CD18 on the patient's neutrophils by flow cytometry. Further confirmation can be made by assessing expression of these glycoproteins after exposure to a degranulating stimuli. The expression of these glycoproteins is increased 5- to 20-fold after stimulation with degranulating agents. This method is also helpful for identification of symptom-free heterozygotes where the expression of these glycoproteins is about half that seen in normal carriers and for prenatal diagnosis.
Therapy consists mainly of early, aggressive antibiotic therapy to reduce bacterial infections (see Box 26-2). During severe infections, granulocyte transfusions in addition to antibiotic therapy have had therapeutic benefit. Bone marrow transplantation has been successfully used to treat some patients. Gene therapy, replacing the defective CD18 gene in the patient's myeloid precursor cells, may become available in the future. In vitro correction of CD18-deficient lymphocytes by retrovirus-mediated gene transfer has been accomplished. A transfection efficiency of 5–10% may be sufficient to change the disease course from severe to moderate.
Job's syndrome of hyperimmunoglobulin E and recurrent infections is transmitted by autosomal dominant inheritance with incomplete penetrance. It is characterized by extremely high serum IgE values (often > 1000–2000 IU/mL), recurrent serious infections, and chronic eczematoid dermatitis usually beginning early in infancy. The infections primarily involve the skin and sinopulmonary tract and usually present as recurrent furunculosis, cutaneous abscess formation, bronchitis, pneumonia, and chronic otitis media and sinusitis. Some of the skin abscesses are cold without classical signs and symptoms of inflammation: redness, heat, and pain.
The most common infecting microorganisms are S aureus, and C albicans, but infections caused by H influenzae group A streptococci, gram-negative pathogens, and fungi are also observed. Pneumatoceles, bronchiectasis, and bronchopleural fistula formation are not uncommon after episodes of acute or chronic pneumonia. Chronic mucocutaneous candidiasis, primarily involving the mouth, nails, skin, and vagina, is also found in about half of the patients.
Associated features include coarse facial features with a broad nasal bridge and broad nasal alae, growth retardation, osteoporosis and bone fractures, keratoconjunctivitis, asymmetric sterile polyarthritis, and eosinophilia.
In addition to markedly elevated serum IgE concentrations, other immunologic abnormalities include elevated specific anti-S aureus and anti-Candida IgE antibodies, an intermittent defect in neutrophil chemotaxis, low antibody response to booster immunizations, and poor antibody and cell-mediated responses to newly encountered antigens. The underlying defect is most likely associated with a T-cell abnormality characterized by inadequate production of γ-interferon, which normally suppresses IgE production. The intermittent neutrophil chemotactic abnormality, which likely has a major role in the pathogenesis of the recurrent abscesses seen in these patients, most likely results from this γ-interferon deficiency.
Differentiation of patients with the Job syndrome from those with atopic dermatitis is sometimes difficult and is dependent on the presence of recurrent deep abscesses along with the classic facial features.
Management consists of controlling the pruritic eczematoid dermatitis with emollient creams, topical steroids, and antihistamines. Prophylactic oral dicloxacillin or trimethoprim-sulfamethoxazole for S aureus infections or oral fluconazole for preventing C albicans infections usually benefit patients. Intravenous immunoglobulin therapy should be reserved for patients with confirmed IgG subclass deficiency, a finding rarely observed in our experience. Plasmapheresis has been attempted for a few patients who do not respond to more conservative therapies. Reported experimental immunomodulatory therapies include the use of levamisole, ascorbic acid, cimetidine, and transfer factor. γ-Interferon therapy has been shown to increase these patient's neutrophil chemotactic response in vitro and decrease eczema and respiratory secretions in vivo.
CHRONIC GRANULOMATOUS DISEASE
Chronic granulomatous disease (CGD) is a group of genetic disorders characterized by recurrent infections with catalase-positive microorganisms of the respiratory tract, skin, and soft tissues. Symptoms usually occur by 2 years of age. CGD has X-linked (65%) or autosomal-recessive (35%) inheritance.
This defect is due to lesions in membrane-associated NADPH-oxidase necessary for the production of oxygen radicals, which are required in intracellular killing (Figure 26-1). This results in the inability of phagocytes to generate superoxide anion, hydrogen peroxide, and other oxygen radicals needed to kill catalase-positive bacteria. The catalase-negative species, including pneumococci, streptococci, and H influenzae, rarely cause serious infections in these patients. CGD should be suspected in any patient with subcutaneous abscesses or furunculosis associated with abscess formation in a lymph node, the liver, or lung, or in patients with infections with organisms normally of low virulence (Staphylococcus epidermidis, Serratia marcescens, and Aspergillus spp.), which are catalase positive.
The underlying defect in X-linked CGD is due to a defect in a gene encoded on the X chromosome that has been identified as the cytochrome b heavy-chain gene.
The diagnosis of CGD is demonstrated by an absent or greatly diminished respiratory burst by stimulated phagocytes. Available assays include nitroblue tetrazolium dye reduction, chemiluminescence, measurement of oxygen consumption, and the products of oxidative metabolism, superoxide anion, and hydrogen peroxide. A documented inability of blood granulocytes to kill ingested catalase-positive bacteria confirms CGD. Symptom-free carriers of the X-linked form of CGD can be identified by determining the respiratory burst activity of their neutrophils, which is approximately half of normal, and by genetic analysis.
Prenatal diagnosis can be made during the second trimester by sampling of fetal blood and nitroblue tetrazolium testing, which serves as a screen for superoxide production. Molecular reagents prepared from cloned DNA may also prove to be clinically useful for prenatal diagnosis in the future.
Figure 26-1. The respiratory burst in phagocytic cells.
Prophylaxis with trimethoprim-sulfamethoxazole may prolong infection-free intervals by preventing infections, especially with staphylococci. Therapy also includes treatment with γ-interferon, which has decreased infections by as much as 70%, and bone marrow transplantation, which to date has shown only limited success and should be reserved for those patients who cannot be optimally treated in other ways. Patients with CGD are excellent candidates for future gene therapy because the genetic lesions have been identified and the genes cloned.
The Chediak-Higashi syndrome is an autosomal recessive disorder, which is characterized by recurrent pyogenic infections, a bleeding tendency caused by a platelet storage pool deficiency, partial oculocutaneous albinism, and giant granules in the cytoplasm of many cells, particularly peripheral leukocytes. The underlying defect results from abnormal cell membrane fluidity, which leads to abnormal granular fusion as well as other defects, including the inability of neutrophils to move normally, concentrate serotonin into platelets, and express normal lytic functions.
Symptoms generally begin in early childhood with recurrent pyoderma, subcutaneous abscesses, otitis, sinusitis, severe periodontal disease, bronchitis, and pneumonia. The most common microorganisms are S aureus and β-hemolytic streptococci. Approximately 85% of patients have an associated organ infiltration by histiocytes and atypical lymphocytes. Hepatosplenomegaly, lymphadenopathy, neurologic abnormalities, pancytopenia, and a bleeding tendency are also commonly seen.
The diagnosis is made by identification of the characteristic giant cytoplasmic granules in the patient's leukocytes or microscopic examination of hair shafts for abnormal giant melanosomes. Prenatal diagnosis is possible by measuring the large acid phosphatase-positive lysosomes in cultured amniotic fluid cells, chorionic villus cells, or fetal blood leukocytes.
In addition to prophylaxis with antibiotics and the prompt treatment of acute infection with antimicrobial agents, high doses of ascorbate may be beneficial. Bone marrow transplantation may be curative.
Splenectomy has been used in the treatment of patients unresponsive to other forms of therapy and has resulted in clinical, hematologic, and immunologic improvement.
THE COMPLEMENT SYSTEM & ITS RELATED DEFECTS
Essentials of Diagnosis
Figure 26-2. The classic and alternative complement pathways. (Modified with permission from PIDJ 1991).
The complement system is composed of an interacting series of glycoproteins, which upon activation, interact in an orderly sequence to produce biologically active substances that enhance leukocyte reactions and that result in the lysis of cells or invading pathogens. The system can be activated through two major pathways: (1) the classical pathway, which is activated by binding of IgG1, IgG2, IgG3, or IgM to antigens; and (2) the alternative pathway, which is initiated by direct attachment of activated C3 to the surface of bacteria, viruses, fungi, and virus-infected cells (Figure 26-2).
Once the alternative pathway is triggered, an amplification loop is activated that induces more C3b formation. Surface-bound C3b in conjunction with C3 convertase, C4b2a (classical pathway), or C3bBb (alternative pathway) serves as a C5 convertase, which initiates the formation of the membrane attack complex (C5b678n). All of the activated components of the complement system are tightly controlled by regulatory proteins including C1 esterase inhibitor, factor I, C4-binding protein, factor H, decay-accelerating factor, S protein, and C8-binding protein.
The major effects of active complement components include anaphylotoxic (C3a and C5a), opsonic (C3b, C3bi, and C4b), chemotactic (C5a), and cytolytic activity (membrane attack complex). Deficiency of early components of the classical pathway result in a high incidence of collagen vascularlike disease (C1q, C1r, C1s, C4, or C3 deficiency). Patients who lack these components often present with some combination of recurrent infections (usually pneumococcal), arthritis, skin rash, and glomerulonephritis. Box 26-2 summarizes treatment options for patients who have these deficiencies. This infection risk is most likely a result of suboptimal removal of circulating immune complexes from the circulation from failure to attach C3b and iC3b to the particles.
DEFICIENCY OF C1 COMPLEX & C4
These deficiencies are also transmitted by autosomal recessive inheritance. Because activation of the alternative pathway may be sufficient for host defense against many pathogens, deficient patients generally have few infectious complications. Lupuslike illness and other autoimmune disorders occur in a majority of the patients.
DEFICIENCY OF C2
C2 deficiency is transmitted as an autosomal recessive trait and is the most commonly reported complement deficiency. The incidence of homozygous C2 deficiency is ~1 in 28,000 to 40,000, whereas the heterozygous carrier rate is estimated at ~1.2% in the general population based on screening of normal blood donors. Patients can have recurrent pneumonia, bacteremia, or meningitis caused by S pneumoniae (present in about two-thirds of reported infections), H influenzae, and N meningitidis. Autoimmune or rheumatic complications are present in about half of the patients. The lupuslike disease in C2-deficient patients is characterized by early onset, marked photosensitivity, low-titered or absent antinuclear antibody, and a low incidence of renal involvement.
DEFICIENCY OF C3
C3 deficiency is transmitted by autosomal recessive inheritance. C3 is positioned at the junction of the classical and alternative complement pathways and is important for opsonization of most encapsulated bacteria; generation of C3a and C5a; and initiation of the membrane attack complex. Patients with total C3 deficiency usually have severe episodes of recurrent pneumonia, sepsis, meningitis, and peritonitis. The most common pathogens isolated are S pneumoniae, H influenzae, N meningitidis, and S aureus. Lupuslike illness and glomerulonephritis occur in 15–21% of patients.
DEFICIENCY OF C5-C9
Individuals with these deficiencies are completely asymptomatic, whereas others have unusual susceptibility to recurrent Neisseria infections (N meningitidis or N gonorrhoeae). Deficiency of the terminal complement components is also transmitted by autosomal recessive inheritance. Recurrent episodes of meningococcemia, meningococcal meningitis, and disseminated gonococcal infection have occurred in ~50% of reported patients. The rate of C5–C9 deficiency in patients with disseminated Neisseria infections may be as high as 10–15%. In contrast to early complement component deficiencies, autoimmune diseases are only occasionally diagnosed in these patients.
This is the only deficiency of complement that is transmitted by X-linked recessive inheritance. Properdin acts to stabilize the alternative pathway C3 convertase (C3bBb). Affected patients have recurrent pyogenic infections and fulminant meningococcemia.
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