CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

33. Immunodeficiency

Pia J. Hauk, MD

Richard B. Johnston, Jr, MD

Andrew H. Liu, MD

Immune deficiencies that present in childhood comprise rare disorders that have been characterized by a combination of clinical patterns, immunologic laboratory tests, and often molecular identification of the mutant gene. Children with primary immunodeficiency (PID) commonly present with recurrent and/or severe bacterial infections, failure to thrive, and/or developmental delay as a result of infection. Immunodeficiency should be considered when infections are recurrent, severe, persistent, resistant to standard treatment, or caused by opportunistic organisms. Because delayed diagnosis of PIDs is common, heightened diagnostic suspicion is warranted.

The human immune system consists of the phylogenetically more primitive innate immune system and the adaptive immune system. For the purpose of clinical categorization, PIDs are commonly divided into four main groups: antibody deficiencies, combined T- and B-cell immunodeficiencies, phagocyte disorders, and complement deficiencies. Understanding the role each part of the immune system plays in host defense allows critical evaluation for possible immunodeficiency as the cause of recurrent infections.

IMMUNODEFICIENCY EVALUATION: PRIMARY CONSIDERATIONS

When evaluating for a possible PID, other conditions that increase susceptibility to infections have to be considered, such as allergic rhinitis, asthma, cystic fibrosis, foreign body aspiration, and conditions that interfere with skin barrier function. Common causes of secondary or acquired immunodeficiency need to be excluded. These include malnutrition, aging, certain drugs (chemotherapy, immunosuppressive medications, glucocorticoids, disease-modifying antirheumatic drugs, rituximab), protein loss via gastroenteropathy or kidney disease, and other diseases associated with impaired immunity (bone marrow and blood cell malignancies, and certain chronic infections, including AIDS). If a single site is involved, anatomic defects and foreign bodies may be present. Figure 33–1 outlines when PIDs should be considered.

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image Figure 33–1. General approach to primary immunodeficiencies.

Key clinical patterns can indicate the presence of a PID and the category of immune impairment. Frequency, severity, and age of onset of infections are important clues. The Modell Foundation warning signs for PID are shown in Figure 33–2. Children who meet two or more of these signs should be screened for PID. The type of infections should guide initial investigation, as antibody, complement, and phagocyte defects predispose mainly to bacterial infections, but diarrhea, superficial candidiasis, opportunistic infections, and severe herpesvirus infections are more characteristic of T-lymphocyte immunodeficiency. Combined immunodeficiency syndromes will present with a combination of infections typical for B- and T-lymphocyte deficiencies. Table 33–1 classifies PID into four main host immunity categories based on age of onset, infections with specific pathogens, affected organs, and other special features. Finally, male gender increases the likelihood of an X-linked (XL) PID, while consanguinity increases the likelihood of an autosomal recessive (AR) form of PID.

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image Figure 33–2. Warning signs of primary immunodeficiency. (Data from the Jeffrey Modell Foundation.)

Table 33–1. Clinical features of primary immunodeficiencies.

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Research on deficiencies of the innate immune response is an evolving field. Pattern-recognition receptors (PRRs) are important for the recognition of pathogen-associated molecular patterns specific for different microbes, initiation of the innate immune response, and cross talk with adaptive immunity. They are expressed on the surface or in the cytoplasm of cells of the innate immune system, dependent on where specific microbes are encountered. Four classes of PRRs have been identified. Toll-like receptors (TLRs) recognize a spectrum of bacteria, viruses, selected fungi, and protozoa. C-type lectin receptors (CLRs) that include dectin-1 and mannose-binding lectin are involved in recognition of bacteria and fungi. Cytoplasmic PRRs include nucleotide-binding oligomerization domain (NOD) leucine-rich-repeat containing receptors (NLRs) that recognize peptidoglycan structures on bacteria, and retinoic acid-inducible gene I protein (RIG-1) helicase receptors that recognize viral nucleic acids. Dependent on the defect in PRR signaling, patients may present with an increased susceptibility of bacterial, viral, or fungal infections.

Laboratory investigation should be directed by the clinical presentation and the suspected category of host immunity impairment. A complete blood cell count (CBC) with cell differential and measurement of quantitative immunoglobulins (Igs) will identify the majority of patients with PID, as antibody deficiencies account for at least 50% of PIDs (Figure 33–3). Table 33–2 summarizes the approach to laboratory evaluation of PID.

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image Figure 33–3. Relative frequencies of primary immunodeficiencies. (Adapted, with permission, from Stiehm ER et al (eds): Immunologic Disorders in Infants and Children, 5th ed. Elsevier; 2004.)

Table 33–2. Laboratory evaluation for primary immunodeficiency.

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Antibodies & Immunoglobulins

The initial laboratory screening for antibody deficiency includes the measurement of serum Igs: IgG, IgM, IgA, and IgE, which have age-dependent normal ranges (Table 33–3). Normal IgG, IgM, and IgA and increased IgE levels are indicative of atopy. Some patients may have normal Ig levels but fail to make protective antibodies to certain microbes; other patients have subnormal Ig levels but make protective antibodies. Specific antibodies include isohemagglutinins, naturally occurring IgM antibodies that are detectable by age 6 months except in children with blood group AB. Specific IgG antibodies to protein antigens (tetanus, diphtheria, rubella, mumps) and polysaccharide antigens (Haemophilus influenzaeStreptococcus pneumoniae) can be measured after immunization. The response to polysaccharide antigens develops during the second year of life, but protein-conjugated vaccines elicit an earlier response in immunocompetent children. Assessing the antibody response to pneumococcal polysaccharide antigens can be helpful in the face of repeated pneumococcal infections. The gold standard is comparison of pre- and postimmunization titers.

Table 33–3. Normal values for immunoglobulins by age.

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Obtaining a CBC with differential and T- and B-lymphocyte counts are recommended if an initial screen reveals very low concentrations of all Ig classes. Certain types of hypogammaglobulinemia are characterized by low levels of or absent B lymphocytes, such as XL Bruton agammaglobulinemia. Protein electrophoresis can help identify monoclonal gammopathy as seen in XL lymphoproliferative syndrome, which can be complicated by fatal Epstein-Barr virus (EBV) infection, and in heavy-chain diseases. Serum albumin should be measured in patients with hypogammaglobulinemia to exclude secondary deficiencies due to protein loss through bowel or kidneys. IgG or IgA subclass measurements may be abnormal in patients with varied immunodeficiency syndromes, but they are rarely helpful in an initial evaluation.

T Lymphocytes

The initial laboratory screening for a T-lymphocyte deficiency includes a CBC with cell differential to evaluate for a decreased absolute lymphocyte count (< 1000/μL) and enumeration of absolute numbers of T cells and their subsets, B cells, and natural killer (NK) cells (see Table 33–2). T-cell function can be analyzed by in vitro lymphocyte proliferation assays to mitogens that stimulate all T cells and by specific antigens that stimulate only antigen-specific T cells. Borderline function must be interpreted based on clinical correlation. T-lymphocyte function is often also studied in vivo by delayed hypersensitivity skin tests to specific antigens, including Candida albicans, tetanus, or mumps, but a negative result is not helpful, as it may be due to young age, chronic illness, vitamin D deficiency, or poor test technique. T-lymphocyte deficiencies will often not manifest as skin-test anergy until the impairment is severe, for example as in AIDS. It is important to evaluate a patient’s specific antibody production because proper B-lymphocyte function and antibody production are dependent on adequate T-lymphocyte function. Therefore, most T-lymphocyte deficiencies manifest as combined T- and B-lymphocyte deficiencies.

Phagocyte Immunity

The initial laboratory screening for phagocyte disorders, mainly impaired neutrophil function, should include a CBC and cell differential to look for neutropenia. A blood smear can detect Howell-Jolly bodies in erythrocytes, indicative of asplenia, and abnormalities in lysosomal granules in neutrophils. An abnormality of the neutrophil respiratory burst, which would lead to impaired neutrophil bactericidal activity, can be tested by nitroblue tetrazolium (NBT) reduction. The dihydrorhodamine (DHR) flow cytometry assay assesses the same function more quantitatively. Leukocyte adhesion molecules can be studied by flow cytometry. Assays to study neutrophil phagocytosis of bacteria and phagocytic microbicidal activity are available in specialized laboratories. The clinical symptom pattern that suggests a possible defect of phagocytic cell function should dictate which tests are used.

Complement Pathways (Figure 33–4)

Testing for total hemolytic complement activity with the CH50 assay screens for most of the diseases of the complement system. A normal CH50 titer depends on the ability of all 11 components of the classic pathway and membrane attack complex to interact and then lyse antibody-coated sheep erythrocytes. Alternative complement pathway deficiencies are identified by subnormal lysis of rabbit erythrocytes in the AH50 assay. For both assays the patient’s serum must be separated and frozen at –70°C within 30–60 minutes after collection to prevent loss of activity. Measuring levels of individual components is not necessary when both CH50 and AH50 are normal. If both the CH50 and AH50 are low, a deficiency in their shared terminal pathway (C3, C5, C6, C7, C8, or C9) would be the most common explanation. If the CH50 is low but the AH50 is normal, the deficiency must affect C1, C4, C2, or components of the lectin pathway. If the AH50 is low but the CH50 is normal, a deficiency in factors D or B or properdin should be suspected.

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image Figure 33–4. Pathways of complement activation and the central functional role of C3. MASP, MBL-associated serine protease; MBL, mannose-binding lectin.

Pattern-Recognition Receptors

Selected laboratories offer tests to assess TLR function upon stimulation with ligands for different TLRs that have been identified. Mannose-binding lectin levels can be measured in clinical laboratories. However, expression or function of pattern recognition receptors (PRRs) and associated gene mutations are studied mostly in a research setting at the current time.

ANTIBODY DEFICIENCY SYNDROMES

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Recurrent bacterial infections, typically due to encapsulated pyogenic bacteria.

image Low immunoglobulin levels.

image Inability to make specific antibodies to vaccine antigens or infections.

image General Considerations

Antibody deficiency syndromes include both congenital and acquired forms of hypogammaglobulinemia with low levels of one or more of the immunoglobulins IgM, IgG, and IgA. Deficiencies result in recurrent bacterial infections, typically with encapsulated bacteria, including pneumonia, otitis, sinusitis, meningitis, cellulitis, and sepsis. As a group, antibody deficiencies represent nearly half of all PIDs. They can be divided into (1) early defects of B-cell development, with absent B cells and severe hypogammaglobulinemia; (2) hyper-IgM syndromes with defects in Ig class switching; (3) common variable immunodeficiency (CVID), with insufficient antibody production; and (4) specific antibody deficiencies. Table 33–4 outlines primary antibody deficiency syndromes, laboratory findings, and genetic inheritance in these disorders.

Table 33–4. Antibody deficiency disorders.

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1. X-Linked Agammaglobulinemia

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Infections early in life, usually after age 4 months.

image Typical bacterial infections include infections with encapsulated bacteria, for example, H influenzae, S pneumoniae , Staphylococcus aureus, and Pseudo-monas aeruginosa, but also Mycoplasma species.

image Risk for severe enteroviral infections and, rarely, polio due to live polio vaccine.

image Failure to thrive and absent lymphoid tissue on examination.

image Very low levels of Igs and B lymphocytes.

image General Considerations

X-linked agammaglobulinemia (XLA) accounts for 85% of congenital hypogammaglobulinemia and occurs in about 1:200,000 male births. Children with XLA typically present with infections after 4 months of age, when maternally derived IgG levels have declined. XLA is caused by a gene mutation on the X chromosome (Xq21.33–q22) that affects the expression of a B-cell–specific tyrosine kinase (BTK), halting the maturation of B cells and resulting in low or absent B-cell numbers and serum Igs. Early detection and diagnosis of XLA allow Ig-replacement therapy to start before a potentially life-threatening infection can occur.

image Clinical Findings

A. Symptoms and Signs

Sinopulmonary infections due to H influenzae and S pneumoniae are common, but deep tissue infections and arthritis due to Mycoplasma or Ureaplasma species can occur. Recurrent pulmonary infections may lead to bronchiectasis. Antibody-deficient patients are also at risk for polio due to oral polio vaccine strains, resulting in paralysis, and echoviruses causing chronic encephalitis. At presentation, male infants have scant or absent lymphoid tissue, including tonsils, adenoids, and lymph nodes. A small proportion also has a history of poor growth.

B. Laboratory Findings

Most patients have low levels of or absent Igs M, G, A, and E, and, despite a normal leukocyte count, few or no B lymphocytes. T-lymphocyte numbers and function are normal. Genetic testing for a BTK gene mutation confirms the diagnosis in affected males. Female carriers can be detected by genetic testing or screening for BTK protein expression in platelets followed by mutation analysis if needed.

image Differential Diagnosis

The differential diagnosis includes other causes of antibody deficiency and combined immunodeficiencies (see Table 33–4Table 33–5). Additional causes of recurrent infections and low Ig levels include protein loss through renal or gastrointestinal disease, but patients with these disorders present with normal numbers of B lymphocytes and, typically, an isolated IgG deficiency.

Table 33–5. Severe combined immunodeficiency variants.

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image Treatment

Current therapy consists of lifelong Ig-replacement therapy. In addition to preventing infections, Ig replacement usually results in resolution of inflammatory arthritis and improves growth. Because the severity of infections varies and antibiotics are widely used, the diagnosis is often delayed for years, but XLA should be considered in males with recurrent infections regardless of severity. Early diagnosis can prevent permanent disability and premature death.

2. Autosomal Recessive Congenital Agammaglobulinemia

image General Considerations

Autosomal recessive congenital agammaglobulinemia is rare, accounting for less than 15% of all congenital hypogammaglobulinemia, and occurs in both male and female children. In the most common form, it is caused by mutations of the IgM heavy-chain gene on chromosome 14q32. These mutations result in abnormal or absent IgM expression and abnormal development of B cells with decreased or absent antibody production.

image Clinical Findings

A. Symptoms and Signs

Similarly to patients with XLA, children present with recurrent and severe bacterial infections, typically before age 6 months. Infections include pneumonia, otitis, sinusitis, meningitis, cellulitis, and sepsis. Chronic central nervous system (CNS) infections by enteroviruses have been observed.

B. Laboratory Findings

Patients usually have low numbers of circulating B lymphocytes and low levels of or absent immunoglobulins. Specific antibody function is poor. When the diagnosis is suspected, the detection of a mutation in the μ heavy chain can confirm the most common type. Additional mutations include mutations of the genes encoding the Igα and Igβ molecules, the λ5 surrogate light chain, BLNK or LRRC8 genes.

image Differential Diagnosis

The differential diagnosis is similar to that of XLA and includes XLA for male patients.

image Treatment

Treatment and prognosis are similar to those outlined for XLA.

3. Hyper-IgM Syndromes

Hyper-IgM (HIGM) syndromes are a heterogeneous group of genetic disorders (see Table 33–4) with impaired Ig class switching from IgM to production of IgG, IgA, or IgE associated with normal or elevated serum IgM. If signaling through CD40 is affected, patients present also with opportunistic bacterial infections. Deficiencies of AID or UNG differ from CD40L and CD40 deficiencies in that the patients have large lymph nodes with germinal centers and are not susceptible to opportunistic infections. Patients with HIGM syndrome are at increased risk of autoimmune diseases. Treatment with Ig replacement decreases infections and often normalizes IgM levels. XL CD40L deficiency and NFκB signaling defects will be addressed further in section Other Combined Immunodeficiency Disorders.

4. Common Variable Immunodeficiency

image General Considerations

Common variable immunodeficiency (CVID) is a diagnosis of exclusion after other causes of hypogammaglobulinemia have been eliminated. The onset may be at any age, and the incidence approaches 1:30,000. Many cases are sporadic, but a small percentage of patients have autosomal dominant or recessive inheritance, and some cases are associated with specific HLA-DR/DQ alleles (see Table 33–4).

image Clinical Findings

A. Symptoms and Signs

Patients have recurrent infections, most often of the sinopulmonary tract, but chronic gastrointestinal infections may manifest with recurrent diarrhea. Patients with CVID are at risk for developing bronchiectasis, autoimmune diseases (idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, rheumatoid arthritis, and inflammatory bowel disease), and malignancies (especially gastric carcinoma and lymphoma).

B. Laboratory Findings

Laboratory findings are variable, but typically reveal low levels of IgG and IgA, normal numbers of B lymphocytes, low numbers of memory B lymphocytes (evaluated by flow cytometry), and abnormal specific antibody levels and responses. Some patients have evidence of T-lymphocyte abnormalities as well. Chronic gastrointestinal tract infections are often due to G lamblia or C jejuni.

Although CVID is typically a diagnosis of exclusion, recent research has revealed multiple specific genetic mutations in patients with CVID. One example is a mutation in a member of the tumor necrosis factor receptor family, identified as transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), which mediates isotype switching in B lymphocytes. TACI mutations were recently found in 10%–15% of patients with CVID, as well as in some relatives of CVID patients with IgA deficiency. The mutations appear to be autosomal dominant, with variable penetrance of clinical immunodeficiency and autoimmune disease, and impairment of T-regulatory cell function.

image Differential Diagnosis

When a patient presents with recurrent infections, low immunoglobulin levels, and potentially autoimmune symptoms, many different diagnoses must be considered, including other causes of low immunoglobulin levels (loss and abnormal production) and autoimmune diseases. CVID patients have normal numbers of B lymphocytes despite their poor specific antibody responses, which differentiates them from patients with XLA and AR agammaglobulinemia. Patients with CVID also lack the specific mutations responsible for those other disorders. However, CVID patients often have decreased numbers of memory B cells (IgM/IgD/CD27+/CD20+ B cells).

image Treatment

Treatment includes lifelong Ig-replacement therapy and routine assessment for bronchiectasis, autoimmune disorders, and malignancies. The prognosis can be good and depends on the time to diagnosis and implementation of Ig-replacement therapy. Other complications include B-cell hyperplasia in the gut that may be severe enough to resemble Crohn disease, and gastric atrophy with achlorhydria, sometimes followed by pernicious anemia. Lymphoreticular proliferation can occur after EBV infection and is not always malignant.

5. Acquired Hypogammaglobulinemia

Acquired forms of hypogammaglobulinemia are common and may develop at any age. Causes of secondary hypogammaglobulinemia (nephrotic syndrome and protein-losing enteropathy) should be excluded by measuring serum albumin. The loss of albumin (MW 69323 Da) is usually paralleled by a loss of IgG (MW 150000 Da). Generally, acquired forms are not treated with Ig-replacement therapy because, although immunoglobulin levels are low, antibody function is adequately protective. Morphologic disorders or associated syndromes may point to a specific diagnosis.

6. Transient Hypogammaglobulinemia

Serum IgG levels normally decrease during an infant’s first 4–6 months of life as maternal IgG transmitted in utero is metabolized. Transient hypogammaglobulinemia represents a delay in the onset of immunoglobulin synthesis that results in a prolonged nadir. Symptomatic patients present with recurrent infections, including upper respiratory tract infections, otitis, and sinusitis. The diagnosis is suspected in infants and young children with low levels of IgG and IgA (usually two standard deviations below normal for age), but normal levels of IgM and normal numbers of circulating B lymphocytes. Most affected children have normal specific antibody responses and T-lymphocyte function. Apart from appropriate antibiotics, no treatment is required. Infants with severe infections and hypogammaglobulinemia could be given Ig replacement, but benefits and risk must be considered and this is rarely necessary. Recovery occurs between 18 and 30 months of age, and the prognosis for affected children is excellent provided infections are treated promptly and appropriately.

7. Selective Immunoglobulin Deficiencies

Selective IgA deficiency is the most common immune abnormality, found in approximately 1:700 persons. It is defined by a serum IgA level less than 7 mg/dL. Serum IgM, IgG, specific antibodies, and B- and T-lymphocyte numbers and function are normal. IgA is primarily effective in its secreted form on mucosal surfaces. Therefore, symptomatic patients with low serum IgA develop upper respiratory tract infections, diarrhea, or both, but most people are asymptomatic.

Associations also exist with inflammatory bowel disease, allergic disease, asthma, and autoimmune disorders (thyroiditis, arthritis, vitiligo, thrombocytopenia, and diabetes). IgA replacement is currently not feasible. For the majority of symptomatic IgA-deficient patients, antibiotics and appropriate autoimmune therapies are sufficient. Caution must be exercised, as IgA-deficient patients are at risk for developing anti-IgA antibodies with blood product exposure, and the administration of blood products can result in anaphylaxis. Therefore, when blood products are needed, washed packed red blood cells and volume expanders without blood products are recommended.

The possibility that deficiency of an IgG subclass (eg, abnormally low serum IgG2, IgG3, or IgG4) might predispose to recurrent upper respiratory tract infections in patients with normal total serum immunoglobulin levels is not well established. Normally, IgG1 comprises over 60% of total IgG, IgG2 over 10%, IgG3 about 5%, and IgG4 may be undetectable in up to 20% of healthy persons. Additionally, serum levels are age related. It has been difficult to establish a link between IgG subclass deficiencies and any consistent pattern of infections. IgG replacement should be reserved for patients with defects in specific antibody production and recurrent infections, which is rarely seen in patients with selective IgA or IgG subclass deficiencies.

Treatment of Hypogammaglobulinemia

The mainstay of therapy for hypogammaglobulinemia is replacement with IgG, but appropriate management of infections is also important. Curative therapy with bone marrow transplantation (BMT) has been successful in patients with XL HIGM syndrome. Replacement IgG is usually given by intravenous infusions at a dose of 400–600 mg/kg every 3–4 weeks to maintain trough serum IgG levels above 500–800 mg/dL (a higher trough level is targeted for patients with established pulmonary disease). Subcutaneous replacement is available, but it requires more frequent injections and may limit maximum dosing. The aim of treatment is to prevent future infections and minimize any progression of chronic lung disease (bronchitis or bronchiectasis). Despite the passive immunity provided by replacement IgG, infections remain a persistent risk for affected patients. The prognosis also depends on timely and appropriate antibiotic therapy. Typical infecting organisms include encapsulated bacteria, but Ureaplasma and Mycoplasma species must also be considered. Infusions are generally well tolerated, with most reactions being mild, including headache, back and limb pain, anxiety, and chest tightness. Rare systemic reactions can occur, including tachycardia, shivering, fever, and, in severe cases, anaphylactoid shock. These adverse symptoms can be prevented by pretreatment with corticosteroids, antihistamines, and nonsteroidal anti-inflammatory drugs. For patients with congenital hypogammaglobulinemia, replacement therapy is currently lifelong. As a precautionary measure, patients with agammaglobulinemia or hypogammaglobulinemia should not receive live vaccines, but nonlive vaccines may be beneficial, particularly in patients with CVID.

SEVERE COMBINED IMMUNODEFICIENCY DISEASES

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Onset in first year of life.

image Recurrent infections caused by bacteria, viruses, fungi, and opportunistic pathogens.

image Chronic diarrhea and failure to thrive.

image Absent lymphoid tissue.

image General Considerations

Severe combined immunodeficiency diseases (SCIDs) encompass congenital diseases caused by different genetic mutations that result in severe deficiency of T and B lymphocytes. Despite differences in underlying mutations, affected patients present similarly, with recurrent infections caused by bacteria, viruses, fungi, and opportunistic pathogens. Patients often suffer from chronic diarrhea and failure to thrive, and typically die within the first year of life without treatment. Children with atypical SCID usually survive longer due to mutations in SCID-associated genes with residual protein function. SCID must be considered in the differential diagnosis in any infant with diarrhea and hypogammaglobulinemia.

image Clinical Findings

A. Symptoms and Signs

Common presentations include persistent cough, tachypnea, or hypoxia secondary to underlying Pneumocystis carinii infection, or persistent oral or diaper candidiasis. Physical examination is notable for a lack of lymphoid tissue including tonsils and lymph nodes. A chest radiograph usually demonstrates an absent thymic shadow.

B. Laboratory Findings

Laboratory evaluation often reveals lymphopenia and some degree of hypogammaglobulinemia. Occasionally, an infant with SCID will present with normal numbers of lymphocytes resulting from transfusion-related engraftment or maternal T-lymphocyte engraftment via peripartum transfusion. NK cells and B-lymphocyte numbers may be decreased, normal, or elevated. Numbers of CD31+/CD45RA+/CD4+ recent thymic emigrant T cells reflect thymic T-cell output and are usually decreased in SCID patients. Additionally, in vitro lymphocyte assays show poor response to mitogens, and specific antibodies are absent. Antenatal diagnosis is possible. Once the diagnosis of SCID is suspected, genetic testing should be pursued to confirm the diagnosis and the mutation present for both prognostic and genetic counseling purposes. Clinical presentation and treatment are generally similar. The variants of SCID can be organized by the presence or absence of specific lymphocytes, including T, B, and NK cells (see Table 33–5).

image Differential Diagnosis

The differential diagnosis of SCID includes other causes of recurrent and severe infections and abnormal immune responses, most notably HIV disease. Other causes of hypogammaglobulinemia or agammaglobulinemia may be considered but can usually be ruled out in the presence of abnormal T-lymphocyte numbers and function. The infection spectrum and severity of presentation in children with SCID is more severe and of earlier onset than that seen with agammaglobulinemia. Symptoms of congenital abnormalities with combined immunodeficiency features are discussed later in this chapter (see section on Genetic Syndromes Associated With Immunodeficiency).

image Treatment

When SCID is suspected, Pneumocystis prophylaxis with trimethoprim–sulfamethoxazole and replacement Ig therapy should be initiated. Patients with suspected SCID should only be transfused with irradiated blood products and should not receive any live vaccines. Confirmation of the diagnosis should include screening for SCID subtypes listed in Table 31–5. BMT offers the best possibility of cure, with use of a human leukocyte antigen (HLA)–matched sibling offering the highest chance of success. In affected patients without HLA-identical donors, HLA haploidentical bone marrow cells from family members or HLA-matched unrelated donors are used. For most patients, myeloablation is not necessary as the patient is without T lymphocytes. Additionally, most patients do not require prophylaxis for graft-versus-host disease (GVHD) unless the donor is unrelated. T-lymphocyte reconstitution takes approximately 4 months, but only about 50% of patients regain full B-lymphocyte function, with the majority requiring long-term Ig replacement. For months post transplantation, patients are susceptible to many serious infections, and prophylaxis is usually continued. Additionally, any signs or symptoms of infection must be promptly investigated and aggressively treated. The highest rate of success is in the youngest patients prior to developing infections (> 95% survival), but overall rates of survival range from 50% to 100% depending on the underlying mutation. XL SCID and ADA deficiency have been treated with gene therapy. Normal gene function was transduced in XL SCID patients, but owing to insertion of the retroviral vector near an oncogene, some patients developed lymphoproliferative disorders. At this time, safer vectors are being sought.

1. X-Linked Severe Combined Immunodeficiency

XL SCID, the most common form (40%) of SCID, results from mutations in IL2RG (IL-2 receptor gene) that encodes the common γ chain. The γ-chain protein is shared by multiple cell surface receptors for cytokines that are essential for T-lymphocyte maturation, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Within the first 3 months of life, male infants present with diarrhea, cough, and rash. Laboratory evaluation reveals low T-lymphocyte numbers, normal numbers of B lymphocytes (which do not produce functional antibody), and absent NK cells.

2. Adenosine Deaminase Deficiency

Adenosine deaminase deficiency (ADA) is an AR form of SCID caused by absence of adenosine deaminase, which is important for removal of toxic metabolites formed in lymphocytes, including adenosine, 2′-deoxyadenosine, and 2′O-methyladenosine. Increased levels of these metabolites result in lymphocyte death. Subsequently, affected patients develop complete absence of T-lymphocyte function and progressive decrease in immunoglobulin production. ADA SCID is distinguished from other variants of SCID by the following findings: the most profound lymphopenia (< 500/mm3); skeletal abnormalities, including chondro-osseous dysplasia (flared costochondral junctions and bone-in-bone anomalies in vertebrae); and deficiency of all types of lymphocytes. Diagnosis is suspected in patients with profound lymphopenia and recurrent infections. The diagnosis is confirmed with a red blood cell assay for ADA activity. The genetic mutation is on chromosome 20q13.2–13.11. In addition to BMT, restoration of immune competence can occur in some patients with weekly infusions of polyethylene glycol–stabilized ADA enzyme conjugate. Gene therapy of stem cells with an ADA-incorporating retroviral vector has been successful, but the vector caused oncogenic adverse effects.

3. Janus Kinase 3 Deficiency

Another form of AR SCID is due to mutations in the gene encoding janus kinase 3, which is important for intracellular signaling through the common γ chain. The clinical presentation and lymphocyte phenotype most closely resemble XL SCID, with low T and NK lymphocytes, and normal or elevated, nonfunctional B lymphocytes.

4. Interleukin-7-Receptor-α-Chain Deficiency

IL-7-receptor-α-chain (IL-7R α) deficiency SCID is transmitted by AR inheritance. The IL-7 receptor is important for T-lymphocyte maturation and mutations result in low T-lymphocyte numbers, but normal numbers of dysfunctional B lymphocytes and NK cells.

5. Recombinase-Activating Gene Deficiencies

Another form of AR SCID is due to mutations in recombinase-activating genes (RAG1 and RAG2), which encode proteins critical for assembling antigen receptor genes for both T and B lymphocytes. Several mutations in these genes have been described. The clinical presentation is similar to that of other forms of SCID, but the lymphocyte phenotype differs, as patients with SCID due to RAG1 or RAG2 mutations lack both T and B lymphocytes but maintain normal or elevated numbers of NK cells.

Omenn syndrome is an autosomal AR syndrome characterized by SCID, eczematoid rash, hepatosplenomegaly, lymphadenopathy, and alopecia. The disease is caused by mutations in RAG1RAG2, or Artemis mutations (see as follows). Laboratory evaluation reveals absent B lymphocytes, normal to elevated T-lymphocyte numbers with restricted function, and normal functional NK cells. Additionally, affected patients often have eosinophilia and elevated levels of IgE. The syndrome is typically fatal, although BMT has been used successfully.

6. CD3-δ-Chain Deficiency

CD3-δ-chain (CD3δ) deficiency is a rare form of AR SCID. Homozygous defects in the CD3δ chain halt T-lymphocyte maturation. Clinical presentation and lymphocyte phenotype are similar to IL-7Rα deficiency, but CD3δ-chain deficiency differs from other forms of SCID in that these patients have a normal-appearing thymic silhouette on chest radiograph.

7. CD45 Deficiency

Another rare form of AR SCID is due to mutations in the gene for CD45. CD45 is a tyrosine phosphatase important for regulating signal transduction. Affected patients have a similar presentation to other forms of SCID and a lymphocyte phenotype with low to absent T and NK cells, but normal B lymphocytes.

8. Artemis Deficiency

Artemis is a DNA repair factor important for repairing cuts in the double-stranded DNA essential for the assembly of antigen receptors for T and B lymphocytes. Inheritance is AR, and clinical presentation and lymphocyte phenotype are similar to those seen in RAG1 and RAG2 deficiencies.

9. ZAP-70 Deficiency

Deficiency of ζ-chain–associated protein (ZAP)-70 results in a rare form of AR SCID. ZAP-70 is a tyrosine kinase critical for T-lymphocyte signaling and activation. Clinical presentation is similar to that of other forms of SCID, but most affected patients have palpable lymph nodes and visible thymic silhouette. Lymphocyte evaluation reveals absence of CD8+ T lymphocytes, normal but nonfunctional CD4+ T lymphocytes, normal numbers of poorly functioning B lymphocytes, and normal numbers and function of NK cells.

OTHER COMBINED IMMUNODEFICIENCY DISORDERS

Combined immunodeficiencies include defects that directly impair both T and B lymphocytes, as well as T-lymphocyte–specific defects, because proper B-lymphocyte function and antibody production are dependent on T-lymphocyte help. Therefore, most T-lymphocyte deficiencies manifest as combined impairments.

1. Wiskott-Aldrich Syndrome

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Immunodeficiency with recurrent infections.

image Microplatelet thrombocytopenia.

image Eczema.

image Occurs only in males.

image General Considerations

Wiskott-Aldrich syndrome (WAS) is an XL recessive disease characterized by immunodeficiency, microplatelet thrombocytopenia, and eczema. The syndrome results from mutations of the gene encoding WAS protein (WASP) at X11p. WASP is a protein involved in the rearrangement of actin and is important in interactions between T lymphocytes and antigen-presenting cells.

image Clinical Findings

A. Symptoms and Signs

Common presenting symptoms include mucosal bleeding, bloody diarrhea, cerebral hemorrhage, and severe infections with polysaccharide-encapsulated bacteria, but the clinical presentation can vary from classic severe WAS to mild thrombocytopenia without immunodeficiency, or X-linked thrombocytopenia (XLT), depending on the mutation. Early deaths are due to bleeding and infections, but malignancies and autoimmune syndromes can develop over time. Survival beyond adolescence is rare in patients not receiving treatment, although XLT is sometimes diagnosed in adults.

B. Laboratory Findings

Laboratory findings that suggest the diagnosis are a low platelet count, small platelets, low or absent isohemagglutinins, and reduced antibody responses to polysaccharide antigens (S pneumoniae and H influenzae). IgM may be low; IgG is usually normal; and IgA and IgE are often high. The diagnosis can be confirmed by genetic testing for a mutation of the WASP gene or by assessing WASP expression. Genetic testing can also be used for carrier screening.

image Differential Diagnosis

In addition to WAS and XLT, the differential diagnosis in a patient with a low platelet count must include other causes of platelet consumption, destruction, and abnormal production, such as idiopathic thrombocytopenic purpura, leukemia or myelodysplasia, drug adverse effect, and infection. WAS can be differentiated from these other conditions by small-sized platelets on smear evaluation, the presence of eczema and other atopic features, and documented immune dysfunction. Additionally, there is a continuous spectrum between WAS and XLT that lacks immunodeficiency. Subsequently, a scoring system has been developed to help clinicians distinguish WAS from XLT.

image Treatment

Treatment includes infection prophylaxis with antibiotics (including trimethoprim-sulfamethoxazole for P carinii pneumonia) and IVIG-replacement therapy for patients with deficient antibody responses. Splenectomy to reduce thrombocytopenia has been helpful in some patients with XLT, but it must be followed by antibiotic prophylaxis because of the increased risk of septicemia and sudden death. Platelet transfusions should be avoided unless severe bleeding has occurred. Finally, BMT using the best-matched donor offers the possibility of a definitive cure, but it is associated with morbidity and mortality.

2. 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Congenital heart defects.

image Hypocalcemia and seizures.

image Distinctive craniofacial features.

image Thymic hypoplasia.

image General Considerations

DiGeorge syndrome or 22q11.2 deletion syndrome is an AD syndrome, resulting in defective development of the third and fourth pharyngeal pouches. There is considerable variability in phenotype based on the location and extent of the deletion, but deletions that include the TBX1 gene appear relevant. Overlapping syndromes include velocardiofacial syndrome and Shprintzen syndrome. The incidence is about 1:4000 births, and the abnormal chromosome is usually inherited from the mother. The associated immunodeficiency is secondary to the aplastic or hypoplastic thymus, where T-lymphocyte maturation occurs. Surprisingly, most patients have no or only mild immune defects. The term partial DiGeorge syndrome is commonly applied to these patients with impaired rather than absent thymic function.

image Clinical Findings

A. Symptoms and Signs

Clinical characteristics include congenital heart defects, hypocalcemia due to hypoparathyroidism, distinctive craniofacial features, renal anomalies, and thymic hypoplasia. Presentation usually results from cardiac failure or from hypocalcemia 24–48 hours postpartum. The diagnosis is sometimes made during the course of cardiac surgery when no thymus is found in the mediastinum. Infections commonly present as recurrent ENT (ear-nose-throat) infections. Additional important clinical issues include delayed speech, cognitive impairment, and behavioral problems. Patients have an increased risk to develop schizophrenia and autoimmune disorders.

B. Laboratory Findings

Laboratory evaluation typically reveals normal to decreased numbers of T lymphocytes with preserved T-lymphocyte function and normal B-lymphocyte function. In the rare patient with absent or dysfunctional T lymphocytes, B-lymphocyte function and antibody production may be abnormal. Over time, T-lymphocyte numbers normalize in the majority of patients who have low numbers of T lymphocytes at initial presentation. The diagnosis is confirmed via fluorescence in situ hybridization (FISH) chromosomal analysis for the microdeletion on chromosome 22, or microarray-based comparative genomic hybridization.

image Treatment

Treatment of the 22q11.2 deletion syndrome may require surgery for cardiac defects, and vitamin D, calcium, or parathyroid hormone replacement to correct hypocalcemia and treat seizures. Transfusion products should be irradiated. Both thymic grafts and BMT have been used successfully in patients with absent T-lymphocyte immunity. Prior to giving live vaccines, T-cell numbers and function should be assessed if not done earlier, to prevent vaccine-related side effects.

3. Ataxia-Telangiectasia

Ataxia-telangiectasia (A-T) is a rare, neurodegenerative, AR-inherited disorder caused by mutations in the ataxia-telangiectasia–mutated (ATM) gene located on chromosome 11q22–23 that encodes the ATM protein, a protein kinase involved in repair of double-stranded DNA and cell cycle regulation. A-T is characterized by progressive cerebellar ataxia, telangiectasia, and variable immunodeficiency. Children usually present as toddlers with slurred speech and balance problems, and also with sinopulmonary infections. Telangiectasias of the conjunctivae and exposed areas (eg, nose, ears, and shoulders) follow later during childhood. Respiratory tract infections promoted by respiratory muscle weakness, swallowing dysfunction and recurrent aspirations, and malignancies, including carcinomas and lymphomas, are the major causes of death between the second and fourth decade of life. Abnormal findings in A-T include elevated serum α-fetoprotein levels that increase over time and are used diagnostically; immunoglobulin deficiencies, including low levels of IgA, IgE, or IgG; and defective ability to repair radiation-induced DNA fragmentation. There is no definitive treatment, although Ig replacement and aggressive antibiotics have been used with limited success. Heterozygotes have an increased risk for breast cancer.

Similarly to A-T, the Nijmegen breakage syndrome is a disorder associated with impaired DNA repair and mutations in the NBS1 gene that shows more severe clinical features, including microcephaly and facial dysmorphisms, small stature, immunodeficiency, and increased risk for lymphoid malignancies.

4. X-Linked Hyper-IgM Syndrome

X-linked hyper-IgM (HIGM) syndrome or CD40L deficiency is the most common and most severe form of HIGM syndrome and involves a mutation in the gene encoding for CD40L (CD154). CD40L is expressed on activated T lymphocytes and necessary for T cells to induce immunoglobulin isotype switching in B cells. Unlike the AR forms of HIGM syndrome, the mutation results in both antibody- and cell-mediated deficiencies, as the interaction between CD40L on T cells and CD40 on B cells and antigen-presenting cells is important for both antibody production and T-cell activation. Affected males have normal numbers of B lymphocytes, low levels of IgG and IgA, but normal or elevated levels of IgM. Typically, male infants present with recurrent bacterial and opportunistic infections such as P carinii pneumonia or Cryptosporidium diarrhea. Additionally, affected males have a high frequency of sclerosing cholangitis, increased liver and biliary tract carcinomas, neutropenia, and autoimmune syndromes, including thrombocytopenia, arthritis, and inflammatory bowel disease. Conservative treatment includes Ig replacement and antibiotic prophylaxis. Because the prognosis is still quite poor, BMT has been used with initial success.

5. NF-κB Signaling defects

Immunodeficiency due to mutations in the gene for nuclear factor-κB (NF-κB)–essential modulator (NEMO; IKBKG gene) is an XL syndrome in which male patients manifest ectodermal dysplasia (abnormal, conical teeth, fine sparse hair, and abnormal or absent sweat glands) and defects of T and B lymphocytes. NF-κB is involved in signaling through CD40 on B cells, and NEMO mutations result in abnormal immunoreceptor signaling. Many mutations are fatal in utero for male infants. Female carriers may have incontinentia pigmenti. Surviving males present with early serious infections, including opportunistic infections with P carinii and atypical mycobacteria. Laboratory evaluation reveals hypogammaglobulinemia that may present as HIGM syndrome and poor specific antibody production, but normal numbers of T and B lymphocytes. Functional evaluation of lymphocytes demonstrates variable response. Because patients with confirmed NEMO mutations are quite rare, the best treatment course is unknown, but aggressive antibiotic therapy in combination with Ig replacement as well as BMT has been used. The prognosis is dependent on the severity of immunodeficiency, with most deaths due to infection. Mutations in the NFBIA gene that encodes IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor alpha) result in an AD-inherited defect with similar clinical presentation.

6. Combined Immunodeficiency With Defective Expression of MHC I & II

Major histocompatibility complex class I (MHC I) deficiency or bare lymphocyte syndrome type I is an AR-combined immunodeficiency. Affected patients have abnormal expression of the transporter associated with antigen processing (TAP). TAP proteins are important for intracellular transport and expression of MHC I on cell surfaces. Patients with bare lymphocyte syndrome type I present with recurrent sinopulmonary and skin infections. The diagnosis is confirmed by demonstrating an absence of MHC I expression.

Major histocompatibility complex class II (MHC II) deficiency or bare lymphocyte syndrome type II is a rare AR-combined immunodeficiency in which cells lack MHC II expression due to mutations in CIITARFX-5RXAP, or RFZANK genes. Clinical presentation includes recurrent viral, bacterial, and fungal infections. Patients with bare lymphocyte syndrome type II have normal numbers of T and B lymphocytes, but low CD4+ lymphocyte numbers, abnormal lymphocyte function, and hypogammaglobulinemia. They also have a high incidence of sclerosing cholangitis. When this diagnosis is suspected, demonstration of absent MHC II molecules confirms the disorder. Severe cases are fatal without BMT, but milder phenotypes may be managed with Ig replacement and aggressive use of antibiotics.

7. Purine Nucleoside Phosphorylase Deficiency

Purine nucleoside phosphorylase (PNP) deficiency is an immunodeficiency due to defects in the gene encoding PNP, which is important in the purine salvage pathway. Deficiency of PNP causes toxic metabolites that result in T-lymphocyte death, but in many patients B lymphocytes are spared. Not only does this AR disease result in recurrent and serious infections, but affected patients also have concomitant neurologic (developmental delay, ataxia, and spasticity) and autoimmune disorders. Infections present at variable ages. Laboratory evaluation reveals low numbers of or absent T lymphocytes and a variable B-lymphocyte deficiency. Without BMT, this disease is fatal due to infection or malignancy.

PHAGOCYTE DISORDERS

Phagocyte defects include abnormalities of both numbers (neutropenia) and function of polymorphonuclear neutrophils. Functional defects consist of impairments in adhesion, chemotaxis, bacterial killing, or, less often, of combinations of these.

1. Neutropenia

The presence of neutropenia should be considered when evaluating recurrent infections. The diagnosis and treatment of neutropenia is discussed in Chapter 30. Additionally, some PID syndromes are associated with neutropenia (eg, XLA).

2. Chronic Granulomatous Disease

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Recurrent infections with catalase-positive bacteria and fungi.

image XL and AR forms.

image Caused by abnormal phagocytosis-associated generation of microbicidal oxygen metabolites (respiratory burst) by neutrophils, monocytes, and macrophages.

image General Considerations

Chronic granulomatous disease (CGD) is caused by a defect in any of several genes encoding proteins in the enzyme complex nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which results in defective superoxide and hydrogen peroxide generation during ingestion of microbes. Most cases (probably 75%) are inherited as an XL recessive trait; the rest are AR in inheritance.

image Clinical Findings

A. Symptoms and Signs

The typical clinical presentation is characterized by recurrent abscess formation in subcutaneous tissue, lymph nodes, lungs, and liver, and by pneumonia and eczematous and purulent skin rashes. Infecting organisms are typically catalase-positive bacteria, which can break down their own hydrogen peroxide and thus avoid death when captured in a CGD phagocytic vacuole. (Streptococci, pneumococci, and H influenzae lack catalase and are not unusually pathogenic in CGD.) Aspergillosis is also common and a frequent cause of death. Lymphadenopathy and hepatosplenomegaly are found on physical examination, and granulomas are seen in histopathologic sections. Granulomatous inflammation can narrow the outlet of the stomach or bladder in these patients, leading to vomiting or urinary obstruction.

B. Laboratory Findings

Patients typically present with serious infection, positive microbial cultures, and neutrophilia. The most common infecting organisms are S aureus, Aspergillus species, Burkholderia cepacia, and Serratia marcescens. (Culture of either of the last two should suggest this diagnosis.) Patients also present with granulomas of lymph nodes, skin, liver, and genitourinary tract. The erythrocyte sedimentation rate may be elevated without obvious infection. The diagnosis is confirmed by demonstrating lack of hydrogen peroxide production using the DHR flow cytometry assay or lack of superoxide production using the NBT test. Both tests can demonstrate carrier status of XL disease.

image Differential Diagnosis

The differential diagnosis includes other phagocyte abnormalities or deficiencies described in this section, as well as the rare neutrophil granule deficiency. Other immunodeficient states leading to severe bacterial or fungal infections should be considered, but none have the striking abscess formation and deficient phagocytosis-associated respiratory burst that characterize CGD.

image Treatment

Daily intake of an antimicrobial agent such as trimethoprim-sulfamethoxazole is indicated in all patients; an oral antifungal agent like itraconazole and regular subcutaneous injections of interferon-γ can greatly reduce the risk of severe infections. BMT has been successful in some cases, but the risk of death is high unless the patient’s condition is stable. Gastric or GU obstruction can be relieved by short-term steroid therapy.

3. Leukocyte Adhesion Defects Types I & II

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Recurrent serious infections.

image “Cold” abscesses without pus formation.

image Poor wound healing.

image Gingival or periodontal disease (or both).

image General Considerations

The ability of phagocytic cells to enter peripheral sites of infection is critical for effective host defense. In leukocyte adhesion defect (LAD), defects in proteins required for leukocyte adherence to and migration through blood vessel walls prevent these cells from arriving at the sites of infection. LAD I is an AR disease caused by mutations in the common chain of the β2 integrin family (CD18) located on chromosome 21q22.3. These mutations result in impaired neutrophil migration, adherence, and antibody-dependent phagocytosis. LAD II is a rare AR disease caused by an inborn error in fucose metabolism that results in abnormal expression of leukocyte Sialyl-Lewis X (CD15s), which binds to selectins on the vessel endothelium. The resulting phenotype is similar to LAD I, with recurrent infections, lack of pus formation, poor wound healing, and periodontal disease. LAD II patients also have developmental delays, short stature, dysmorphic facies, and the Bombay (hh) blood group.

image Clinical Findings

A. Symptoms and Signs

Patients present with variably severe phenotypes, including recurrent serious infections, lack of pus formation, poor wound healing, and gingival and periodontal disease. The hallmark is little inflammation and absent neutrophils on histopathologic evaluation of infected sites (ie, “cold” abscesses), especially when concurrent with neutrophilia, an expression of poor adherence to vessel walls. The most severe phenotype manifests with infections in the neonatal period, including delayed separation of the umbilical cord with associated omphalitis.

B. Laboratory Findings

Laboratory evaluation often demonstrates a striking neutrophilia. Diagnosis of suspected cases is confirmed by flow cytometry analysis for CD18 (LAD I) or CD15s (LAD II).

image Treatment

Treatment includes aggressive antibiotic therapy. Fucose supplementation in LAD II has been reported with some success.

4. Glucose-6-Phosphate Dehydrogenase Deficiency

Rare forms of XL glucose-6-phosphate dehydrogenase deficiency with associated hemolytic anemia affect leukocytes as well as erythrocytes and result in recurrent infections due to an abnormal neutrophil respiratory burst, probably due to NAD/NADPH deficiency.

5. Myeloperoxidase Deficiency

Leukocyte myeloperoxidase (MPO) is important for intracellular destruction of C albicans. Although deficiency is quite common, only a very few patients with concurrent diabetes have had severe candidal infections. Diagnosis can be confirmed with assays measuring MPO levels in leukocytes.

COMPLEMENT DEFICIENCIES

Complement contributes to innate immunity and facilitates antibody-mediated immunity through opsonization, lysis of target cells, and recruitment of phagocytic cells. The complement system includes three interactive pathways of enzymatic reactions: classic, alternative, and lectin (see Figure 33–4). All three pathways generate cleavage of C3 and result in promotion of inflammation, elimination of pathogens, and enhancement of the immune response. Activation of the complement system occurs through microbial products, tissue enzymes, and surface-bound IgG and IgM antibodies or pentraxins, for example C-reactive protein.

1. Complement Component Deficiencies

Deficiencies of individual complement components (C1–C9) are inherited as autosomal codominant traits, each parent contributing one null gene. Serum levels of the deficient component are about half normal in the parents and zero or almost zero in the patients. Deficiencies of C1, C2, or C4 predispose to increased infections but are particularly associated with autoimmune disorders such as systemic lupus erythematosus. Patients with homozygous C2 deficiency can present at any age in childhood with bacteremia or meningitis due to S pneumoniae or H influenzae. Primary C3 deficiency presents with severe pyogenic infections since C3 is critical for opsonization in both the classic and alternative pathways. Deficiency of the control protein factor I, which acts to break up the C3-cleaving complex formed in the classic or alternative pathway, leads to unbridled consumption of C3 and, thereby, severe bacterial infections. Deficiency of a terminal complement component in the membrane attack complex (C5, C6, C7, C8, and C9) or of properdin (an XL alternative pathway control protein) results in recurrent neisserial meningitis or disseminated gonococcal infection. Survivors of either of these serious neisserial infections should be screened for complement deficiency, first with a CH50 assay and later with an AH50 assay if the CH50 is normal.

Mannose-binding lectin and ficolins-1, 2, and 3 serve as the recognition components of the lectin pathway, which recognizes microbial surface carbohydrates. Deficiency of MBL has been linked to increased risk of infections in infancy and in patients who have another defect of host defense. Ficolin-3 deficiency has been associated with severe infections.

2. Hereditary Angioedema Due to C1 Inhibitor Deficiency

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Recurrent episodes of angioedema often triggered by trauma.

image No associated urticaria or pruritus.

image Onset at any age but more common after puberty.

image General Considerations

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by mutations in the SERPING1 gene, leading to deficiency of C1 inhibitor (C1-INH), which controls activation of the classic complement pathway, fibrinolytic and coagulation systems, and kallikrein-kinin system. Bradykinin is the most important vasoactive mediator contributing to recurrent swellings, but there is no increased susceptibility to infection. In HAE type I, C1-INH protein levels and function are decreased. In HAE type II, C1-INH protein levels are normal with decreased function. C1-INH protein and function are normal in patients with HAE type III, but they may present with mutations in the gene encoding for factor XII (F12). Acquired forms can occur with B-lymphocyte malignancies, autoantibodies against C1-INH and therefore reduced C1-INH and C1q levels, or use of an angiotensin-converting enzyme inhibitor as medication.

image Clinical Findings

A. Symptoms and Signs

Affected patients can experience edema of skin and bowel and potentially life-threatening edema of the airway. Typical sites of swelling include the face, extremities, and genitals. Trauma, accidental or due to surgery, childbirth, or dental work, may induce edema. Typical problems include episodic intestinal obstruction and dental procedure–induced upper airway obstruction. The edema is usually nonpainful (unless it involves the bowel) and lasts 48–72 hours. There is no associated urticaria, redness, or pruritus. Age of onset is variable, and there is often a positive family history.

B. Laboratory Findings

Initial screening tests for C1-INH deficiency show a decreased CH50 or low levels of C4 and C2. C1q is usually normal. The diagnosis is confirmed by low or absent levels of C1-INH (type I, 85% of cases) or poor or absent C1-INH function (type II).

image Differential Diagnosis

Other causes of acquired angioedema, including that associated with certain medications (most notably angiotensin-converting enzyme modifying drugs), autoimmune diseases, and lymphoproliferative diseases, should be considered. A normal level of C1q in HAE usually distinguishes this form from the acquired forms.

image Treatment

Intravenous C1-INH concentrate is the treatment of choice for the emergency management of acute edema (eg, laryngeal or diffuse facial edema, severe abdominal attacks). Treatment with this concentrate can also be used for long-term prophylaxis when attacks occur monthly or have been life-threatening, or for preparation for surgery or dental work. Fresh frozen plasma may be used as a substitute in the acute situation. Synthetic androgens, for example, oxandrolone prevents attacks by increasing C1-INH levels, and this is approved for cautious use in children. Antihistamines, adrenalin, and steroids have no therapeutic value.

3. Factor H Deficiency & Atypical Hemolytic Uremic Syndrome

The effects of factor H deficiency are like those of factor I deficiency because factor H helps dismantle the alternative pathway C3-cleaving enzyme. Levels of C3, factor B, CH50, and AP50 are all decreased. Some patients have sustained serious infections, and many have had glomerulonephritis or atypical hemolytic uremic syndrome (aHUS). Mutations in genes encoding membrane control protein, factor I, factor B, C3, or the endothelial anti-inflammatory protein thrombomodulin, or autoantibodies to factor H, have also been associated with HUS. In a child with HUS, it seems advisable to screen for a complement deficiency, first with the CH50 assay. With an associated complement disorder the prognosis is less favorable, and recognizing the presence of a complement deficiency should alert the physician to the associated increased risk of infection and/or autoimmune disease.

OTHER WELL-DEFINED IMMUNODEFICIENCY SYNDROMES

1. Hyper-IgE Syndrome

Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare PID characterized by elevated levels of IgE (> 2000 IU/mL), neonatal eczematoid rash, recurrent infections with S aureus, recurrent pneumonia with pneumatocele formation, and typical facies. Mutations in a specific transcription factor, signal transducer and activator of transcription 3 (STAT3), underlie sporadic and AD forms of HIES. Additional clinical findings of HIES include retained primary teeth, scoliosis, hyperextensibility, high palate, and osteoporosis. In addition to staphylococcal infections, affected patients also have increased incidence of infections due to Streptococcus spp, Pseudomonas spp, C albicans, and even opportunistic infections with P carinii. AR HIES is associated with mutations in dedicator of cytokinesis 8 (DOCK8) and tyrosine kinase 2 (TYK2) genes. Patients with AR HIES have an increased susceptibility to viral infections, including recurrent molluscum contagiosum, warts, and herpes simplex infections. Increased susceptibility to mycobacterial infections is found in patients with TYK2 mutations. Laboratory evaluation reveals normal to profoundly elevated levels of IgE and occasionally eosinophilia. However, atopic dermatitis and parasite infection are much more common causes of elevated IgE. Diagnosis is often difficult due to variable presentation, which may become progressively severe with increasing age, but genetic testing for STAT3DOCK8and TYK2 mutations will help confirm the diagnosis of HIES particularly at a young age. All patients with HIES have impaired TH17 cell function, and measurement of TH17+ cells in the peripheral blood can be used as screening test if HIES is suspected. The mainstay of treatment is prophylactic and symptomatic antibiotic use in combination with good skin care. Ig replacement has been used with some success to decrease infections and possibly modify IgE levels. Successful stem cell transplants have been conducted in DOCK8 deficiency.

2. Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disease that usually manifests with severe diarrhea and insulin-dependent diabetes mellitus within the first months of life. Affected males also have severe eczema, food allergy, autoimmune cytopenias, lymphadenopathy, splenomegaly, and recurrent infections. Most die before 2 years of age due to malnutrition or sepsis. IPEX syndrome results from mutations in the FOXP3 gene that encodes a protein essential for developing regulatory T lymphocytes. Leukocyte counts and immunoglobulin levels are generally normal. Immunosuppression and nutritional supplementation produce temporary improvements, but the prognosis is poor and most cases result in early death. BMT has been attempted with variable success. More recently, IPEX-like syndromes have been described as associated with mutations of the gene encoding CD25, the high affinity IL-2 receptor (IL2R) which is constitutively expressed on regulatory T cells. If IPEX or IPEX-like syndromes are suspected, the presence of FOXP3+/CD25+ regulatory T cells should be assessed not only in affected boys but also in girls. Genetic testing for FOXP3 mutations will be helpful to identify affected patients and carriers of the gene mutation.

3. X-Linked Lymphoproliferative Syndrome

X-linked lymphoproliferative syndrome is an immunodeficiency that usually develops following EBV infection. Affected males develop fulminant infectious mononucleosis with hemophagocytic syndrome, multiple organ system failure, and bone marrow aplasia. The mutated gene (SH2D1A/SAP/DSHP) encodes a signaling protein used by T lymphocytes and NK cells called SLAM-adapter protein (SAP). Affected boys are immunologically normal prior to EBV infection and during acute infection they produce antibody to EBV. In most instances, infection with EBV is fatal. Patients who survive the initial episode or who are never infected with EBV in childhood develop lymphomas, vasculitis, hypogammaglobulinemias (with elevated IgM), or CVID in later life. Genetic analysis for a mutation of the SAP (SH2D1A) gene and testing for SAP protein expression are available. Mutations in the genes encoding for the X-linked inhibitor of apoptosis (XIAP), a potent regulator of lymphocyte homeostasis, and for IL-2–inducible T-cell kinase (ITK) have been described to present as an XLP-like syndrome. Testing for mutations of the gene encoding for XIAP (BIRC4) and XIAP protein expression will help establish the diagnosis. A decreased number of naïve, CD45RA+ T cells are indicative of ITK deficiency, and further genetic analysis can establish the diagnosis.

4. Chronic Mucocutaneous Candidiasis

Several gene defects have been associated with chronic mucocutaneous candidiasis (CMC), a disorder characterized by isolated candidal infections of the skin, nails, and mucous membranes. Systemic disease is not characteristic, but case reports of intracranial mycotic aneurysms exist. Primary CMC most commonly occurs as an isolated syndrome, but it can be associated with endocrine or autoimmune disorders. Mutations in the signal transducer and activator of transcription 3 (STAT3) gene and gain-of-function mutations in STAT1 can lead to defective TH17 responses, susceptibility to CMC, and S aureus infections. Mutations in IL17F and IL17R, C-type lectin–associated 7 (CLEC7A or DECTIN1) or caspase recruitment domain-containing protein 9 (CARD9) cells have also been associated with CMC. An AR form of CMC with associated autoimmunity, also known as autoimmune polyendocrinopathy, candidiasis, ectodermal dysplasia (APECED) syndrome, is characterized by recurrent candidal infections, abnormal T-lymphocyte response to Candida, autoimmune endocrinopathies, and ectodermal dystrophies. APECED is caused by mutations in the gene for an important transcription regulator protein called autoimmune regulator (AIRE) that is critical for normal thymocyte development. In APECED, autoantibodies against IL17A and IL17F impair the TH17 response and contribute to CMC. Treatment of CMC includes antifungal therapy in combination with therapy for associated endocrinopathies.

5. Autoimmune Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) results from mutations of genes important for regulating programmed lymphocyte death (apoptosis). Most commonly, the defect is in Fas (CD95) or Fas ligand, but other defects in the Fas pathway have also been described (eg, caspase 10). Clinical presentation includes lymphadenopathy, splenomegaly, and autoimmune disorders (autoimmune hemolytic anemia, neutropenia, thrombocytopenia, and sometimes arthritis). Occasionally, patients have frequent infections. The diagnosis is suspected when T-lymphocyte subsets by flow cytometry demonstrate elevated numbers of CD3+CD4CD8 (double negative) T lymphocytes. Several different types of ALPS are distinguished by the response of lymphocytes to Fas-induced apoptosis. Patients are often heterozygous, and inheritance is mostly autosomal dominant. Treatment with prednisone often controls the lymphadenopathy. Infections should be treated appropriately. In some cases, BMT has been curative. Affected patients are also at risk for lymphoma. Mutations affecting another apoptosis-related protein, caspase 8, cause an ALPS variant syndrome in which the susceptibility to infection by herpes simplex virus also increases.

6. WHIM Syndrome

WHIM (warts, hypogammaglobulinemia, infection, myelokathexis) syndrome is a rare AD immunodeficiency caused by gain-of-function mutations in the gene encoding the chemokine receptor CXCR4. Patients have an increased susceptibility to viral infections (including HPV, EBV, and HSV) and recurrent bacterial infections. Laboratory evaluation reveals peripheral blood neutropenia with bone marrow hypercellularity, decreased B-cell numbers and hypogammaglobulinemia, and T-cell lymphopenia with normal CD4+/CD8+ ratio.

7. Diseases Due to Defects in Interferon-f & Interleukin-12 Pathways

IL-12 is a powerful inducer of interferon-γ (IFN-γ) production by T cells and NK cells. IFN-γ, and therefore the IFN-γ –IL-12 axis, is critical for macrophage activation and resistance to mycobacterial infections. Individuals with inherited deficiency in IL-12, macrophage receptors for IFN-γ, lymphocyte receptors for IL-12, or STAT1 signaling suffer a profound and selective susceptibility to infection by nontuberculous mycobacteria such as Mycobacterium avium complex or bacille Calmette-Guérin (BCG). About half of these patients have had disseminated salmonellosis. Treatment with supplemental IFN-γ is effective unless the IFN-γ receptor is not functional. Long-term mycobacterial prophylaxis should be considered in these individuals.

8. MonoMAC Syndrome

Disseminated infection by nontuberculous mycobacteria, viruses (ie, HPV), and fungi were recently described in association with GATA2 mutations or MonoMac (sporadic monocytopenia and mycobacterial infection) syndrome. Patients usually become symptomatic during adulthood, but younger patients may also be affected. Patients have peripheral blood monocytopenia, but presence of macrophages at sites of infections. B lymphocyte and NK cell numbers are reported low with variable T-cell numbers. This is an autosomal dominant inherited disease with an increased risk for malignancies, especially myelodysplasia and leukemia.

9. Pattern-Recognition Receptor Defects

Pattern-recognition receptor (PRR) defects are associated with altered cytokine production and increased susceptibility to specific microbes. The clinical presentation of affected patients is most severe during infancy and early childhood with improvement of infections while patients get older, suggesting that adaptive immune responses compensate for defects in innate immunity. TLRs and members of the interleukin-1 receptor (IL-1R) family signal through IL-1R–associated kinases (IRAK) 1 and 4 while using the adaptor molecule MyD88, leading to activation of NF-κB and inflammatory cytokine production. Patients with AR deficiencies in MyD88 and IRAK-4 are predisposed to severe bacterial infections that are not associated with a high fever or significant increase in C-reactive protein at the beginning of infection. Laboratory results may reveal a decreased antibody response to polysaccharide antigens, increased IgG and IgG4 concentrations, and decreased IL-6 production upon whole blood stimulation through most TLR and IL-1R agonists. TLR3 deficiency increases susceptibility to infections with herpes simplex infections, while polymorphisms of TLR5 predispose to legionella pneumonia infections. Chronic mucocutaneous fungal infections have been linked to defects in the dectin-1/CARD9 pathway. Bacterial infections, specifically with Neisseria meningitis, but also viral and fungal infections can occur in context of mannose-binding lectin deficiency

GENETIC SYNDROMES ASSOCIATED WITH IMMUNODEFICIENCY

Several described genetic syndromes have associated immunodeficiency that is often identified after the syndrome has been diagnosed. Usually, the immune defect is not the major presenting clinical problem.

1. Bloom Syndrome

Characteristics of Bloom syndrome include growth retardation, sunlight sensitivity, and telangiectasias of the face. The syndrome results from mutations in the Blm gene that encodes a RecQ-helicase involved in DNA repair. Affected patients present with growth retardation, microcephaly, and sun-sensitive rashes. They have an increased risk of malignancy and life-threatening infections. B- and T-cell numbers are low. Serum Igs are decreased, and T-lymphocyte function is abnormal.

2. Transcobalamin Deficiency

Transcobalamin deficiency is a rare AR disease due to defective cellular transport of cobalamin associated with mutations in the TCN2 gene. Patients present with megaloblastic anemia, diarrhea, poor growth, neurologic abnormalities, hypogammaglobulinemia, and poor specific antibody production.

3. Immunodeficiency, Centromeric Instability, Facial Anomalies Syndrome

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is a rare AR condition caused by abnormal DNA methyltransferase. In half of the patients, a mutation can be detected in the DNMT3B gene. Unlike other chromosome instability syndromes, ICF syndrome does not have an associated hypersensitivity to sunlight. Affected patients have severe respiratory, gastrointestinal, and skin infections due to low or absent immunoglobulins and abnormal T-lymphocyte numbers and function.

4. Trisomy 21

Patients with trisomy 21 or Down syndrome have increased susceptibility to respiratory infection. Immunodeficiency is variable, and abnormal numbers and function of T and B lymphocytes have been reported. Additionally, patients have an increased incidence of autoimmune diseases.

5. Turner Syndrome

Turner syndrome (partial or complete absence of one X chromosome) is associated with increased risk of otitis media, respiratory infections, and malignancies. Immune defects are variable but may include abnormal T-lymphocyte numbers and function and hypogammaglobulinemia.

6. Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome is a rare AR disease caused by mutations in a lysosomal trafficking regulator (LYST) gene. The neutrophils of affected individuals have giant lysosomes, impaired chemotaxis, neutropenia, and abnormal NK-cell cytotoxicity. Patients present with recurrent infections (particularly periodontitis), partial oculocutaneous albinism, and neuropathy. Most patients progress to generalized lymphohistiocytic infiltration syndrome, which is a common cause of death. Treatment strategies address infections and neuropathy, and the use of immunosuppression attempts to slow lymphoproliferative progression.

7. Griscelli Syndrome

Characterized by partial albinism, neutropenia, thrombocytopenia, and lymphohistiocytosis, Griscelli syndrome is a rare AR syndrome resulting from mutations in the myosin VA gene. Affected patients have recurrent and serious infections caused by fungi, viruses, and bacteria. Immunologic evaluation demonstrates variable immunoglobulin levels and antibody function with impaired T-lymphocyte function. BMT can correct the immunodeficiency. Griscelli syndrome is distinguished from Chédiak-Higashi syndrome by the lack of granules in white blood cells.

8. Netherton Syndrome

Patients with the AR Netherton syndrome present with trichorrhexis (brittle hair), ichthyosiform rash, and allergic diseases. A subset of patients develops recurrent infections. Immune function is variable but may include hypo- or hypergammaglobulinemia, abnormal T-lymphocyte function, or abnormal phagocyte function. The disease results from mutations in a serine protease inhibitor encoded on the SPINK5 gene.

9. Cartilage-Hair Hypoplasia

Cartilage-hair hypoplasia is an AR form of chondrodysplasia manifesting with short-limbed short stature, hypoplastic hair, defective immunity, and poor erythrogenesis. The immune defect is characterized by mild to moderate lymphopenia and abnormal lymphocyte function, but normal antibody function. Affected patients have increased susceptibility to infections and increased risk of lymphoma. The disorder results from mutation in the RMRP gene that encodes the RNA component of an RNase MRP complex. BMT can restore cell-mediated immunity but does not correct the cartilage or hair abnormalities.