Chapter 59. Evaluation of the Child with Suspected Immune Deficiency

Primary immune deficiencies represent a class of disorders in which there is an intrinsic defect in the immune system. In contrast, acquired or secondary immune deficiency states occur as a consequence of external agents such as infection or chemotherapy. Over 150 distinct primary immune deficiency syndromes have been recognized. The true prevalence of primary immune deficiencies is not known as routine screening for these defects is not performed at birth or at any time during life. One well-conducted telephone survey of 10,000 households found that the population rate for the diagnosis of primary immune deficiency was 0.0863%, which translates into approximately 250,000 persons (95% confidence interval: 151,769 to 361,408) with primary immune deficiency in the United States.46

The diagnosis of a primary immune deficiency in a child is one of the more challenging diagnoses in medicine. It requires both an understanding of immune function and development and a clinical understanding of age-related infections and relevant genetic risks and environmental exposures. Children with primary immunodeficiency diseases most commonly present with recurrent infections. When evaluating a child with recurrent infections, it is important to remember the normal pattern of infections for different ages and situations. For example, a normal child living at home may have 6 to 12 infections per year if living only at home, and up to 18 infections per year when cared for at a day care center. Children with primary immunodeficiencies commonly have a positive family history. A thorough physical examination may reveal subtle scaring from previous infections, eczema, lymphadenopathy, or prior surgery.

A history suggestive of childhood immunodeficiency usually contains one or more “red flags” (Table 59–1). Situations that warrant consideration of a primary immune deficiency include frequent chronic infections without any other explanation. Always consider immunodeficiency in children with recurrent infections and associated failure to thrive. Likewise, any severe or unusual infection, in particular, infections with opportunistic organisms warrants consideration of an immunodeficiency state.

The components of the immune response are exceedingly complex and require the close cooperation and orchestration of a variety of cellular elements. For clinical utility, however, the functional categories of immunodeficiency can be categorized as follows: (1) Defects in the T-lymphocyte system (including T cells and lymphokines); (2) defects in the B-lymphocyte system (including B cells and immunoglobulins); (3) defects in the phagocyte system (including neutrophils and macrophages), and (4) defects in the complement system. Combined B- and T-cell defects also occur. Among these functional categories of immunodeficiency, about 75% are either B-cell or combined B- and T-cell defects (Table 59–2). Severe combined immunodeficiencies (typically combined B- and T-cell defects), phagocytic and complement deficiencies tend to manifest in the neonatal period. B-lymphocyte system defects tend to manifest after 4 to 6 months of life, when the maternally passed antibodies have decreased.1,3–5

Each of these functional categories of the immune response provides protection against specific classes of microorganisms. Deficiencies in a particular function of the immune response can lead to infections with certain types of infectious pathogens. Gram-negative bacteria, for example, are recognized by neutrophils. Neutrophils are able to recognize outer membrane molecules on the cell wall of gram-negative bacteria. Encapsulated bacteria have a polysaccharide coat, which hides their cell walls. The immune system responds to these pathogens by generating antibodies to the polysaccharide coat. The antibody–pathogen complex then activates the complement system, leading to further opsonization and subsequent killing by phagocytes. Intracellular pathogens such as viruses and mycobacteria require T-lymphocyte responses for their elimination. When evaluating a patient, frequent infections and suspected immunodeficiency the type of infecting organism and the type of infection can suggest which functional category of the immune response is defective (Table 59–3).5–7

Clinical presentation of immune deficiencies varies by category (Table 59–4). Clinical presentations of specific common primary immune deficiencies are discussed further in the Special Considerations section of this chapter.

Acquired immune deficiency states should always be considered in the differential diagnosis of primary immune deficiencies. Specific acquired causes include drug therapies (e.g., corticosteroids, cytotoxic drugs, chemotherapies; the antiepileptic medications carbamazepine and valproate can cause hypogammaglobulinemia), nutritional or vitamin deficiencies (e.g., zinc), alcoholism, diabetes, cachexia, myelophthistic disorders, various hematologic and nonhematologic malignancies, and acquired immunodeficiency syndrome (AIDS).1–5 Nonimmunologic causes such as structural or anatomic defects should always be considered when evaluating a child with recurrent infections. It is important to query the family for possible environmental or drug exposures. Structural defects such as eczema, burns, urinary tract obstruction, and asplenia can predispose a child to an increased number of infections. Recurrent infections in the same location should raise suspicion of an anatomic defect or foreign body (e.g., right middle lobe pneumonia and an inhaled peanut).

Laboratory tests used to screen for and confirm and define suspected immunodeficiency syndromes are listed in Table 59–5 and Table 59–6, respectively.

T-Lymphocyte Defects

Defects in the T-lymphocyte system generally present shortly after birth as severe infections and failure to thrive. They may also present as recurrent viral infections, systemic illness, or both after vaccination with live viruses. A complete blood count and differential, quantitation of T-cell and T-cell subsets (CD4 and CD8), skin testing, and mitogen/antigen proliferation assays are useful aides in the diagnosis of T-lymphocyte defects.

B-Lymphocyte Defects

Defects in the B-lymphocyte system are generally characterized by recurrent sinopulmonary and gastrointestinal infections presenting after the first 4 to 6 months of life. A complete blood count with differential, quantitation of B cells, quantitation of serum immunoglobulins (Table 59–7) with specific IgG subclasses, and IgG challenge testing, which determines the ability of the patient to mount an IgG response, are useful aids in the diagnosis of B-lymphocyte defects. IgG challenge testing includes vaccination with the following substances, followed by serum titer measurements (diphtheria and tetanus vaccination predominantly for IgG1; pneumococcal vaccination with the adult 23-valent polysaccharide vaccine to evaluate the response IgG2; and influenza vaccination to evaluate IgG3 production can be utilized). Do not, however, give live virus vaccines to patients suspected of having immunodeficiency as serious illness may ensue.

Phagocytic System Defects

Defects in the phagocytic system are characterized by perianal or periodontal abscesses; recurrent soft tissue abscesses, with or without a history of delayed separation of the umbilical cord (greater than one month). A complete blood count with differential, dihydrorhodamine oxidation assays, quantitation of the beta-2 integrins CD11/18 by flow cytometry and myeloperoxidase assays are useful aids in the diagnosis of phagocytic defects.

Complement System Defects

Complement system defects are characterized by recurrent infections with encapsulated bacteria (deficiencies of C3 and C5) and Neisseria species (deficiencies of C5–8 and properdin). Collagen vascular diseases are associated with deficiencies of C1, C2, and C4. Total hemolytic complement activity and specific complement component assays are useful diagnostic aids. It is important to note that complement levels in neonates are half that of adults and complement levels may be reduced in patients with rheumatoid arthritis, nephritis, and immune complex diseases.3,5,8–15

T-Lymphocyte System

Thymus-dependent T cells are derived from pluripotent hematopoietic stem cells in developing bone marrow stores. By the eighth gestational week, immature T cells infiltrate the thymus where they differentiate and mature and present specific outer membrane glycoproteins before migrating to their target lymphoid tissues. The main function of the T-lymphocytic systems is in host defense against intracellular pathogens (viruses, fungi, protozoa, and intracellular bacteria such as mycobacterial and Listeria species).16

The T-lymphocyte system is also involved in delayed hypersensitivity reactions, tumor surveillance, and graft-versus-host disease. The T-lymphocyte system orchestrates pathogen annihilation through antigen-dependent cellular interactions. Deficiency of T-cell-mediated immunity can result from defects in (1) the maturation, differentiation, and activation T-cell precursors, (2) the thymus and the thymic microenvironment, (3) the T cell itself, and (4) the production of regulatory cytokines or their receptors. Defects in T-cell immunity are usually associated with variable degrees of B-cell deficiency because most of the maturation, differentiation, and activation processes of B-cells require T-cell help. The patient with abnormal cell-mediated immunity usually has an increased incidence of infections with intracellular pathogens and a predisposition for malignancy.10,16,17

Selected T-Lymphocyte System Disorders

The most severe forms of immunodeficiency are the syndromes of severe combined immunodeficiency (SCID). Diseases in this category include a spectrum of at least five X-linked and autosomal recessive genetic defects characterized by the inability to mount normal cell-mediated and humoral immunity. SCID diseases lead to severe and often fatal infections with failure to thrive that usually present shortly after birth. Infections include persistent oral candidiasis, diarrhea, and pneumonia (usually interstitial, often caused by Pneumocystis jiroveci). Seventy-five percent of the patients with SCID are male. A prenatal diagnosis of SCID may be made in some cases by fetal blood sampling at 20 weeks’ gestation through enumeration of lymphocyte subsets and functional studies.18,19 SCID variants include the following:

X-Linked SCID

X-linked SCID is the most common SCID variant and the diagnosis can be confirmed by the identification of the mutation for the IL-2 receptor gamma chain on the X chromosome. This defect will produce T-cell maturational arrest, as this receptor is the mediator of T-cell growth by several cytokines. B-cell development is affected as well. Maternal carriers can be identified by the pattern of X-chromosome inactivation in T cells. Bone marrow transplantation and more recently retroviral mediated gene therapy have been used successfully in treating these patients.10,16,17,19

Purine Metabolic Pathway Abnormalities

Adenosine deaminase deficiency accounts for about 20% of all SCID cases and 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 leads to the accumulation of toxic metabolites including adenosine and deoxyadenosine triphosphate, which is capable of killing T-cells. This results in reduced numbers of T- and B-cells. In addition to the classic symptoms of SCID, this disease is characterized by the presence of skeletal abnormalities, particularly abnormalities of the ribs and scapula. 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 using bovine ADA have been used with some success in the management of this disease. Promising recent attempts in treatment of patients with ADA deficiency has been the use of autologous lymphocytes corrected in vitro with retroviral-vector-inserted normal human ADA DNA, especially after myeloablative therapy to give an advantage to the corrected cells.10,11,16,17

Purine–Nucleoside Phosphorylase Deficiency

Purine–nucleoside phosphorylase deficiency is an autosomal recessive disorder characterized by a deficiency in the enzyme purine–nucleoside phosphorylase, leading to the accumulation of deoxyguanosine triphosphate, which destroys dividing T cells. B-cell function is often spared and the defect has been localized to chromosome 14q13.12. Patients can have anemia and usually have recurrent viral, bacterial, and fungal infections. Two-thirds of the patients have evidence of neurologic disorders ranging from mild developmental delay or muscle spasticity to severe mental retardation. The diagnosis is made by measuring purine–nucleoside phosphorylase in hemolysed erythrocytes. Heterozygous individuals have half the normal level of this enzyme. Serum uric acid levels are low in these patients because of the absence of this enzyme and a normal uric acid level may help rule out this disease. Prenatal diagnosis is made possible by assaying purine–nucleoside phosphorylase levels cultured in amniotic cells during the second trimester. Bone marrow transplant is the only successful therapy at present. However, enzyme replacement therapy and animal models of vitro viral gene transfer are currently being investigated as promising future therapies.10,11,16,17

Ataxia Telangiectasia

Ataxia telangiectasia is a multisystem disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, chronic sinopulmonary disease, and a high incidence of malignancy. This autosomal recessive disorder has been identified as a single gene disease encoded to chromosome 11q22.23. This gene encodes a protein that is involved signal transduction, recombination, and cell cycle control important in T-cell and B-cell rearrangement and the ability to repair damaged DNA. The defect observed in DNA repair in these patients after X-ray irradiation results in a high incidence of chromosomal translocation, specifically in chromosome 7, 14, and the X chromosome. Progressive ataxia due to Purkinje cell degeneration becomes apparent when the child begins to walk by 2 years of age. Telangiectasia develops between 2 and 8 years of age on the bulbar conjunctiva and exposed flexor surfaces of the arms. Approximately, 70% have a selective IgA deficiency and more than one-half of these patients have an associated IgG-2 subclass deficiency. Approximately 80% of these patients have depressed or absent IgE levels. The most notable T-cell abnormalities are leukopenia and a decrease in helper T-cell/suppressor T-cell ratios. Serum alpha-fetoprotein levels are persistently elevated in these patients, which may aid in the diagnosis. Therapy for these patients consists of intravenous immunoglobulin therapy to reduce the incidence of recurrent infections in patients with IgG-2 subclass deficiency. Gene therapy for ataxia telangiectasia is currently under investigation.10,11,16,20

Wiskott Aldrich Syndrome

Wiskott Aldrich syndrome is an X-linked recessive disease characterized by recurrent pyogenic infections within the first years of life. The decreased production of antipolysaccharide antibody in these patients can lead to overwhelming pneumococcal disease or other encapsulated bacterial infections. These patients also have an associated thrombocytopenia characterized by small-sized and poorly functioning platelets predisposing to bleeding and bruising. Eczema is characteristically found in most patients. The Wiskott Aldrich syndrome gene has been mapped to the short arm of the X chromosome. Patients with Wiskott Aldrich syndrome have low serum levels of IgM. IgA and IgE concentrations are high and the IgG level is normal, elevated, or only slightly depressed. These patients are unable to produce antibody in response to polysaccharide antigens. Both T cell numbers and function progressively decrease in this disorder and a profound leukopenia becomes apparent at approximately 6 years of age. Prenatal diagnosis can be facilitated by fetal blood sampling for the analysis of thrombocyte numbers and size. First trimester diagnosis of Wiskott Aldrich syndrome is possible by DNA markers and analysis of an unbalanced pattern of X chromosome inactivation. Early bone marrow transplantation may correct the immunologic defects and platelet disorders observed in these patients.10,11,16,17,21

Digeorge Syndrome

DiGeorge syndrome mainly affects the structures derived from third, fourth, and fifth pharyngeal pouches. This is due to a failure of a population of neural crest cells to migrate and interact with endodermally derived cells of the branchial pouches and arches. This syndrome can present as neonatal tetany associated with hypocalcemia caused by hypoparathyroidism. Malformation of the cardiac outflow tract is seen in many DiGeorge patients (e.g., interrupted aortic arch, truncus arteriosus, tetralogy of Fallot). Abnormal facial features include low-set ears with or without malformation, hyperpelorism, short philtrum, micrognathia, and a fish-mouth. The thymus of the infants may be absent, hypoplastic, or atopic, and the parathyroid glands may be absent or reduced in number. T-cell immunity in patients with DiGeorge syndrome is variable and ranges from diminished T-cell numbers with low function to complete absence of T-cell immunity. Some patients with DiGeorge syndrome have normal B-cell immunity as measured by normal levels of immunoglobulin and normal antibody response after immunization. DiGeorge syndrome has been isolated to monosomy of chromosome 22q11. Prenatal diagnosis of DiGeorge syndrome can be performed by fluorescence in situ hybridization (FISH) of fetal tissue. Treatment of patients with DiGeorge syndrome has included the implantation of fetal thymic tissue, fetal thymic epithelium, or fetal thymus in a diffusion chamber and has met with limited success. Full restoration of immune function has not been realized in these patients. Bone marrow transplantation, which provides donor postthymic T cells to reconstitute the patient's immunity, has been used successfully to treat patients with DiGeorge syndrome and severe T-cell immunodeficiency.10,11,16,22,23

The B-Lymphocyte System

The humoral or adaptive immune system starts with B stem cells in the bone marrow derived from hematopoietic stem cells. These stem cells produce cytoplasmic IgM heavy chains and become pre-B cells. The pre-B cells continue to differentiate to become mature surface IgM-bearing B cells, which seed peripheral lymphoid tissue. 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 responsible for the secondary immune response. The major function of B cells and plasma cells is to produce antibodies to protein and carbohydrate antigens on microorganisms, toxins, or other antigenetic substances potentially harmful to the host. These antibodies can be classified into nine different immunoglobulin isotypes (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 to facilitate the opsonization and ingestion of microorganisms. IgG antibodies are the only maternal antibodies that are transplacentally passed to the developing fetus. These antibodies are responsible for much of the newborn infant's defense against invading microorganisms and toxic substances. IgA antibodies are selectively transported across mucus membranes by a secretory moiety and the attachment of microorganisms or absorption of harmful antigens through mucus membranes. IgE antibodies are mainly responsible for allergic reactions and parasite defense. 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 lymphokines may produce B-cell immunodeficiency syndromes.10,11,16,24

The clinical presentation of antibody deficiencies results from a decreased defense against the extracellular phases of bacterial and viral infections. Patients with B-cell deficiencies usually have recurrent pyogenic infections without lymphadenopathy or tonsillar enlargement. Sinopulmonary infections are most commonly seen (90–100%) then gastrointestinal infections (usually chronic diarrhea 50–60%). Systemic infections usually involve encapsulated bacteria and blunted or absent responses to certain vaccinations can be seen. Patients with B-cell deficiencies are predisposed to autoimmunity and lymphoreticular malignancies as well (25%).10,11,24–26

Selected B-Lymphocyte System Disorders

B-lymphocyte disorders are characterized by decreased humoral immunity with variable to absent antibody isotype production. Select B-lymphocyte disorders are described below.

Bruton's Agammaglobulinemia

Bruton's agammaglobulinemia is an X-linked recessive disease that affects only males. The underlying defect is the arrested development of B-cell precursors due to the absence of Bruton's tyrosine kinase. This defect is characterized by recurrent pyogenic infections starting in early infancy after transplacental maternal antibody has disappeared. Affected individuals may not be symptomatic before 6 months of age because of maternal transplacentally acquired IgG antibodies. The absence is of immunoglobulins of all classes, panhypogammaglobulinemia, absence of circulating immunoglobulins bearing mature B cells and functional serum antibody, and the absence of plasma cells in lymphoid tissue are hallmarks of Bruton's agammaglobulinemia. T lymphocytes are present in normal numbers and function. Approximately half of the patients have a family history of an affected male sibling or maternal male relative who is affected. Infections are usually caused by encapsulated bacterial organs, including Streptococci, Meningococci, and Hemophilis influenza. Sinopulmonary infections predominant but gastrointestinal infections particularly with Giardia are common. Patients with this syndrome have an unusual susceptibility to persistent echo or Coxsackie virus infection, including lethal meningoencephalitis as well as vaccine-associated polio myelitis. Female carriers do not exhibit antibody deficiency and can be detected by analyzing the unbalanced pattern of X chromosome inactivation in peripheral blood monocytes. Prenatal diagnosis can be made by sex determination of the fetus or direct sampling of fetal blood and finding the absence of mature immunoglobulin-bearing B cells. Therapy consists of monthly intravenous immunoglobulin administration and close surveillance for infection associated with prompt aggressive therapy of infections.10,11,24,26,27

Hypogammaglobulinemia with Normal to Increased IgM Concentrations

Patients with this immune deficiency have 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 defect results from a block in the further differentiation of the B-cell IgM isotypes, and little to no class switching occurs to IgG, IgA, or IgE isotypes. The gene for the T-cell CD40 ligand, which binds B cells and promotes class switching, is absent in 80% of the patients. This gene defect has been cloned and mapped to Xq26.3–27.1. In 20% of the cases, an autosomal recessive CD40 receptor signal transduction defect is present. The patients have normal or increased concentrations of serum IgM and, in some cases, IgD but decreased or absent IgG, IgA, and IgE. T-cell numbers and function usually appear to be normal. The interaction of CD40 with its ligand may also participate in thymic development. It may explain the susceptibility to opportunistic infections such as P. jiroveci pneumonia. Neutropenia is commonly associated with this disease, and about 50% of patients have hepatosplenomegaly. Prenatal diagnosis can be performed by flow cytometry looking for expression of CD40 ligand on T cells. In some patients, IgG replacement therapy results in decreased serum levels of IgM and the regression of lymphoid hyperplasia. Bone marrow transplantation has recently been tried in the treatment of children affected with immunodeficiency with hyper-IgM syndrome and results are promising. Replacement therapy with a recombinant, soluble form of the CD40 ligand or gene therapy may be developed in the future.10,11,24,26

IgA Deficiency

IgA deficiency is the most common immunodeficiency with an incidence of about one in 400 to one in 1000; these estimates are based on screening studies of blood bank donor. In IgA deficiency, there is a terminal block in B-cell differentiation into plasma cells capable of secreting IgA. The susceptibility gene is probably in the class III MCH region on chromosome 6. The T cells, B cells, and other antibody isotypes are usually normal. Many patients (about 30%) are asymptomatic and have no definite increase in infections, presumably because of the protective effects of IgG and IgM. The patients with symptoms usually have recurrent infections of the respiratory and gastrointestinal tracts, autoimmune disease, arthritis, allergy, and malignancy. Patients with IgA deficiency can develop anti-IgA antibodies, which can cause severe anaphylactic reactions when they are transfused with blood containing IgA. IgA deficiency has been defined as a serum IgA concentration of less that 5 mg/dL in severe deficiency, and more than 5 mg/dL (but less than 2 SD below the age-normal mean) in partial deficiency. In partially deficient patients, the low serum concentrations of IgA often return to normal within 2–4 years of diagnosis. Therapy with IgA is not possible in patients with IgA deficiency because (1) the half-life of IgA is short (about 7 days), (2) administered IgA is not transported to the mucosal surfaces, and (3) the presence of anti-IgA autoantibodies in 30–40% of the patients. In approximately 20% of the IgA-deficient patients who have frequent infections, there is an associated IgG2 and/or IgG4 subclass deficiency. Some of these patients, including ones with anti-IgA antibodies, can tolerate treatment with intravenously administered immune globulin, particularly, the preparations containing low levels of IgA.10,11,24,26,28,29

Common Variable Immunodeficiency

Common variable immunodeficiency (CIVD), or late-onset hypogammaglobulinemia, is characterized by markedly decreased serum immunoglobulin levels, normal or nearly normal numbers of circulating immunoglobulin-bearing mature B cells, impaired antibody responses, and recurrent bacterial (usually sinopulmonary) infections. The underlying problem in common variable immunodeficiency is that B cells do not differentiate into plasma cells, resulting in a slow decline of all immunoglobulin classes. IgA levels usually decrease first. Several mechanisms can cause common variable immunodeficiency. It may be caused by a primary B-cell defect (failure to terminally glycosylate and secrete immunoglobulins), decreased IL-2 production, or abnormalities in specific T cell helper/suppressor functions. The immunologic defects are not limited to B cells but also affect macrophages and immunoregulatory T cells. Although some patients appear to have only intrinsic B-cell defects, more than half also have abnormalities of T-cell activation and deficient secretion lymphokines including IL-2, and a B-cell differentiation factor. The defects in T-cell immunity usually progress with age. Clinical manifestations include sinopulmonary infections (90–100%), chronic diarrhea (50–60%), and these patients may also have malabsorption syndromes. Autoimmune disease, hepatitis, gastric carcinoma, and lymphoreticular malignancy may occur in older patients. Nodular lymphoid hyperplasia of the intestine and a sarcoid-like syndrome associated with hepatosplenomegaly are additional features of the disease. Many patients have had first-degree relatives with IgA-deficiency. Similar to IgA deficiency, a susceptibly gene is located in the class III MCH region located on chromosome 6, and affects both males and females. Management of CVID includes immunoglobulin replacement therapy, antimicrobial and pulmonary therapy, and immunomodulatory therapies including recombinant human IL-2 conjugated with polyethylene glycol, IL-20, and cimetidine.10,11,24,26,29

Phagocytic System

The phagocytic system belongs to the nonspecific or innate immune system, which includes polymorphonuclear leukocytes (e.g., neutrophils, eosinophils) and mononuclear phagocytes (e.g., circulating monocyte, tissue macrophage, and fixed macrophages). Phagocytic cell development occurs within the fetal bone marrow by five months gestation. Major phagocytic functions include adherence to endothelial cells, diapedesis, chemotaxis, phagocytosis, and degranulation, leading to pathogen annihilation. Neonatal neutrophils are depressed in their ability to migrate toward and kill bacteria. The phagocytic system is responsible for defense against extracellular bacterial invasion in association with opsonins (e.g., antibodies, complement, and some acute-phase proteins). Neutrophils are one of the first lines of defense against bacterial invasion of the tissues. If there is a defect in number or function of neutrophils, the patients usually have recurrent pyogenic tissue infections (e.g., impetigo, furunculosis, abscesses, deep tissue infections, or pneumonias).9,30–32

Selective Phagocytic System Disorders

Defects in Neutrophil Production

Neutropenia is an absolute neutrophil count less than 1500 cells/μL. Clinically significant neutropenia occurs with absolute neutrophil counts of less than 500 cells/μL. Neutropenia can be either acquired or congenital. Acquired neutropenia can be due to (1) bone marrow stem cell suppression, as in the case of pharmacologic toxicity; (2) increased neutrophil adherence to the microvasculature, as observed with complement activation, and in severe burn patients; and (3) increased neutrophil destruction, as in hypersplenism or in the cases of autoimmune or alloimmune neutropenia. Acquired neutropenia has also been associated with vitamin B12 or folate deficiency. Transient neutropenia is observed in some infants of mothers with pregnancy induced hypertension. Primary or metastatic bone marrow malignancy can present with neutropenia, and transient neutropenia can follow viral infections (Epstein–Barr virus, cytomegalovirus, parvovirus, and human immunodeficiency virus) or immunizations.9,30–33

Congential neutropenia consists of inherited neutrophil production defects. Always think of neutropenia as a sign of sepsis in the newborn. Kostmann syndrome or congenital agranulocytosis is one of a few of the inherited neutropenias. Neutorphil counts are reduced from birth and patients present with sepsis or septic shock. Bone marrow stores in these patients show maturational arrest of the promyelocytes and myelocytes. Kostmann syndrome is associated with an increased risk for acute myeloid leukemia. Defects in the granulocyte colony-stimulating factor (G-CSF) receptors are accountable for some, but not all, cases of Kostmann syndrome and more than 90% of these patients respond to exogenous recombinant G-CSF. In patients refractory to G-CSF, stem cell transplantation from an HLA-matched sibling has shown to be beneficial. Cyclic neutropenia is another form of congenital neutropenia and is characterized by regular fluctuations in circulating neutrophil pools, usually occurring in 21-day cycles. Treatment of cyclic neutropenia with recombinant G-CSF enhances absolute neutrophil counts but does not eliminate the cycling of cell counts. Other congenital disorders associated with a neutropenia include Shwachman–Diamond syndrome, a rare autosomal recessive disorder that usually manifests in infancy characterized by exocrine pancreatic insufficiency, rib abnormalities, short stature, bone marrow dysfunction, and associated neutropenia. These patents respond to treatment with recombinant G-CSF or bone marrow transplantation and are also predisposed to leukemic transformation. Metabolic diseases (glycogen storage disease Ib and Gaucher disease) are also associated with neutropenia in the newborn period.9,17,30–35

Leukocyte Adhesion Deficiency

Three types of leukocyte adhesion deficiency (LAD) exist: LAD I is transmitted as an autosomal recessive trait and features the absence of the neutrophil CD11b/CD18 integrin complex, which prevents tight adhesion of the neutrophil to endothelial cell surfaces. LAD II is also an autosomal recessive trait, which features the absence of the neutrophil sialyl Lewis X ligand that promotes tethering (loose adhesion) to the P and E selectin ligands on endothelial cells. LAD III is a recently described defect in the regulation of integrin complex activation, which prevents tight adhesion. The underlying defect results from heterogenous mutations affecting the CD18 gene, which has been mapped to chromosome 21 at 21q22.3.9,17,30,32,33,36

This disorder is characterized by defective neutrophil mobilization and frequent infections in patients with poor wound healing, leukocytosis, and a history of delayed umbilical cord separation (more than 2 weeks after birth). Patients usually suffer from recurrent skin abscesses, otitis media, periodontitis, omphalitis, perirectal abscesses, sepsis, and pneumonia. The striking feature of these infections is the almost total absence of leukocytes in the lesions despite high peripheral white cell counts. The most prevalent invading microorganisms are Staphylococcus aureus, group A streptococci, Proteus mirabilis, Pseudomonas aeruginosa, and Escherichia coli. The diagnosis of this disease can be made by assessing the expression of CD11b/CD18 on the patient's neutrophils by flow cytometry. Therapy consists mainly of early, aggressive antibiotic therapy for bacterial infection, long-term trimethoprim-sulfamethoxazole prophylaxis, or both and early bone marrow transplantation. In severe infection, granulocyte transfusions in addition to antibiotic therapy have been reported to have therapeutic benefit. Bone marrow transplantation has been used successfully to treat these patients; it is the definitive therapy at this time. Successful gene therapy, replacing the defective subunit (CD18) gene into 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 course from fatal to moderate.9,17,30,32,33,37,38

Chediak–Higashi Syndrome

This syndrome is an autosomal recessive disorder, which involves abnormal granules and abnormal microtubule formation. Giant lysosomal granules exist in phagocytes, melanocytes, and other cells. The neutrophils of these patients have an inhibited ability to degranulate, which results in poor bacterial killing and a predisposition to infection. Defective melanosomes cause partial albinism. The defective neutrophil microtubule formation leads to decreased chemotaxis, diapedesis, and engulfment of bacteria. Chediak–Higashi syndrome 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 is likely a result of abnormal membrane fusion, leading to defects in chemotaxis, degranulation, and bactericidal activity. 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 hemolytic streptococci. Approximately 85% of patients have an accelerated phase characterized by widespread organ infiltration by histiocytes and atypical lymphocytes. Hepatosplenomegaly, lymphadenopathy, neurologic abnormalities, pancytopenia, and a bleeding tendency are also common. The diagnosis is made by identification of the characteristic large azurophilic cytoplasmic granules in the patient's leukocytes or microscopic examination of hair shafts for abnormal giant melanosomes. Prenatal diagnosis can be made by measuring the largest acid phosphatase-positive lysosomes in cultured amniotic fluid cells, chorionic villus cells, or fetal blood leukocytes. In addition to prophylaxis with antibiotics and prompt treatment of acute infection with antimicrobial agents, high doses of ascorbate (500 mg/day orally) and bone marrow transplantation may have benefit in some patients.9,17,30–33

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is an X-linked or autosomal disorder characterized by an absent neutrophil respiratory burst activity. The lack of O2 uptake by granulocytes and absent superoxide production, as well as and other oxygen radicals, in response to phagocytosis leads to diminished bactericidal activity for catalase-positive microorganisms. 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 a subcutaneous abscess or furunculosis associated with abscess formation in a lymph node, the liver, or the lung. The underlying defect in X-linked CGD is due to a defect in a gene (C4BB) encoded by the X chromosome for the 91 kD heavy chain of cytochromes b558. The diagnosis of CGD is based on the demonstration of an absent or greatly diminished respiratory burst by stimulated phagocytes. Available assays now include dihydrorhodamine fluorescence, nitroblue tetrazolium dye reduction, and measurement of oxygen consumption and the products of oxidative metabolism (superoxide anion and hydrogen peroxide). A documented inability of blood granulocytes to kill ingested catalyze-positive bacteria provides confirmatory evidence of CGD. The symptom-free carrier of the X-linked form of CGD can be identified by determining the respiratory burst activity of their neutrophils, which shows a population of both normal and abnormal cells. Prenatal diagnosis can be made during the second trimester by direct sampling of fetal blood followed by tests, which screen for superoxide production. Prophylaxis with trimethoprim–sulfamethoxazole may prolong infection-free intervals by preventing infections, especially with staphylococci and aspergillous. Interferon-gamma administration showed significant reduction in serious infections (70%) among CGD patients, especially when the patient was younger than 10 years. Alternative therapy includes bone marrow transplantation. Patients with CGD are potential candidates for gene therapy because the specific genetic lesions have been identified and the genes cloned.9,17,30–33,37,39–42

Job's Syndrome

The syndrome of hyperimmunoglobulin E (HIE) and recurrent infections is transmitted by autosomal dominant inheritance. It is characterized by extremely high serum IgE values (often greater than 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 with recurrent furunculosis, cutaneous abscess formation, bronchitis, pneumonia, chronic otitis media, and sinusitis. Some of the skin abscesses are cold without classical signs and symptoms of inflammation (e.g., redness, heat and pain). The most common infecting microorganisms are S. aureus, and Candida 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 seen after episodes of acute or chronic pneumonia. Chronic mucocutaneous candidiasis, primarily involving the mouth, nails, skin and vagina, is found in about half of the patients. Associated features include coarse facial features with a broad nasal base, growth retardation, osteoporosis, keratoconjunctivitis, asymmetric sterile polyarthritis, and eosinophilia. In addition to markedly elevated serum IgE concentrations, other immunologic abnormalities include elevated specific anti-S. aureus and Candida IgE antibodies, an intermittent defect in neutrophi chemotaxis in 80%, low anamnestic antibody response to booster immunizations and poor antibody and cell-mediated response to newly encountered antigens. The anti-S. aureus IgE antibodies may appear in early infancy before the development of staphylococcal infections. The underlying defect in the hyperimmunoglobulin E syndrome may be associated with a T-cell abnormality characterized by inadequate production of gamma-interferon, which normally suppresses IgE production. The genetic defect in HIE has been recently described.43 Differentiation of the HIE syndrome from atopic dermatitis is sometimes difficult and is mainly dependent on the presence of recurrent deep abscesses and pneumonia in the hyperimmunoglobulin E syndrome.

Management of this syndrome consists of the control of the pruritic eczematoid dermatitis with emollient creams, topical steroids, and antihistamines. Prophylactic oral dicloxacillin or trimethoprim-sulfa-methoxazole for S. aureus or oral ketoconazole for preventing C. albicans infections can benefit patients. Plasmapheresis has been used for a few patients who do not respond to other more conservative therapies. Other reported experimental immunomodulatory therapies include the use of levamisole, ascorbic acid, cimetidine, and transfer factor. Gamma-interferon therapy may increase these patient's neutrophil chemotactic response and reduce symptoms.9,17,30,44,45

The Complement System

The complement system is composed of an interacting series of glycoproteins that, upon activation, interact in an orderly sequence to produce biologically active substances, which enhance the inflammatory reaction and may cause lysis of cells or microorganisms (Figure 59–1). The system can be activated through two major pathways: the classical pathway, which is activated by binding of IgG1, IgG2, IgG3, or IgM to antigens and the alternative pathway, which is initiated by direct attachment of activated C3 to the surface of bacteria, viruses, fungi, and virus-infected cells. Once the alternative pathway is triggered, an amplification loop is activated, which 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 (MAC: C5b678[9]n). 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, C5a), opsonic (C3b, C3bi, C4b), chemotactic (C5a), and cytolytic activity (MAC). Deficiency of early components of the classical pathway results in a high incidence of collagen vascular-like 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. This is most likely a result of suboptimal removal of circulating immune complexes from the circulation.8,17,46

Selected Complement System Disorders

Deficiency of C2

This deficiency is transmitted as an autosomal recessive trait and is the most commonly reported complement deficiency. The incidence of homozygous C2 deficiency is about one in 28,000 to 40,000 whereas the heterozygous carrier rate is estimated at about 1.2% in the general population based on screening of normal blood donors. Patients usually have recurrent pneumonias, bacteremia, or meningitis caused by S. pneumoniae,H. influenzae, and Neisseria meningitides. Autoimmune or rheumatic complications are present in about half of the patients. The lupus-like disease in C2-deficient patients is characterized by early onset, marked photosensitivity, low titers, or absent antinuclear antibody.8,17,46

Deficiency of C3

This 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, C5a, and initiation of the MAC. Patients with total C3 deficiency have severe episodes of recurrent pneumonia, sepsis, meningitis, and peritonitis. The most common pathogens isolated are S. pneumoniae, H. influenzae, N. meningitides, and S. aureus. Lupus-like illness and glomerulonephritis occur in 15–21% of the patients. Heterozygous carriers have C3 concentrations about 50% of normal but are asymptomatic.8,17,46

Deficiency of C1 Complex and C4

These deficiencies are also transmitted by autosomal recessive inheritance. Activation of the alternative pathway through C3 may be sufficient for host defense against many pathogens, but deficient patients still tend to have pneumococcal infectious. Lupus-like illnesses (e.g. nephritis, arthritis, and facial rashes) and autoimmune disorders characterize a majority of the patients.8,17,46

Deficiency of C5–C9

Some individuals with deficiency of C5–C9 (the MAC) have an unusual susceptibility to recurrent Neisseria infections (N. meningitides or Neisseria gonorrhoeae). Deficiency of these terminal components is also transmitted by autosomal recessive inheritance. Recurrent episodes of meningococcemia, meningococcal meningitis, and disseminated gonococcal infection have occurred in about 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. The management of complement deficiencies is symptomatic with antibiotic therapy as clinically indicated.8,17,46