Chapter 33: Immunodeficiency

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 other deficiencies of the innate immunity, which include 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 and immune dysregulation, which can lead to associated autoimmunity and chronic inflammation.

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.

Key clinical patterns can indicate the presence of a PID and the category of immune impairment. PID should be considered in patients with frequent, severe, or unusual infections. When the infection history suggests PID, the type of infections can help guide the initial workup. 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. Location of infection can provide important clues. Additional features such as the presence of autoimmunity, poor wound healing, lymphoproliferative disease, age of disease onset, and failure to thrive can help further categorize the PID. 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.

Initial laboratory investigation should be directed by the clinical presentation and the suspected category of host immunity impairment. If antibody deficiency is suspected, a complete blood cell (CBC) count with cell differential and measurement of quantitative immunoglobulins (Igs) will identify most patients. If T-cell deficiency is suspected, lymphocyte phenotyping to quantify blood T cells, B cells, and natural killer (NK) cells should be sent. For phagocyte defects, testing of oxidative burst in stimulated granulocytes should be performed. For complement deficiency, testing of the function of the classical and alternative pathway should be performed. Table 33–2 summarizes the approach to laboratory evaluation of PID.

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). By default, naïve B cells produce IgM, and production of the other isotypes requires further B-cell differentiation. When IgM but not other isotypes are present, a problem in B-cell differentiation is likely. When all Ig isotypes are decreased, an earlier defect in B-cell development should be suspected. Normal IgG, IgM, and IgA, and increased IgE levels usually indicate atopy. Elevated immunoglobulin levels are often seen in autoimmunity.

Some patients may have normal Ig levels but fail to make protective antibodies. Assessing the immunologic response to vaccination is therefore recommended. Specific IgG antibodies to protein antigens (tetanus, diphtheria, rubella, mumps) and protein-conjugated polysaccharide antigens (Streptococcus pneumoniae, Haemophilus influenzae) can be measured after routine immunization. To test the response to pure polysaccharide vaccine, Pneumovax®23 or Typhim Vi® can be administered. The response to polysaccharide antigens develops during the second year of life, but protein-conjugated vaccines elicit an earlier response in immunocompetent children. The gold standard is comparison of pre- and postimmunization titers.

If an initial screen reveals very low concentrations of Ig isotypes, further studies are aimed at identifying the cause of immunoglobulin deficiency. Certain types of hypogammaglobulinemia are characterized by low levels of or absent B lymphocytes, such as X-linked Bruton agammaglobulinemia. 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 and malignancies 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 NK cells (see Table 33–2). T-cell function can be analyzed by in vitro lymphocyte proliferation. 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

Phagocyte defects typically involve reduction in phagocyte numbers or defects in phagocyte function. 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 flow cytometric analysis of stimulated neutrophils pre-loaded with dihydrorhodamine (DHR). 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

Testing for total hemolytic complement activity with the CH50 assay screens for most diseases of the complement system that increase susceptibility to infection (Figure 33–2). 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, or C2. If the AH50 is low but the CH50 is normal, a deficiency in factor D or B or properdin should be suspected. Most quantitative deficiencies of complement components result from pathway activation and resultant consumption. It is therefore essential that complement activation be ruled out prior to diagnosing an inherited complement deficiency.

General Considerations

Severe combined immunodeficiency disease (SCID) is a group of rare immunologic disorders with the defining characteristic of severe deficiency of T-cell function and/or number. Due to the centrality of T cells in the immune system, the severity of T-cell deficit results in widespread immunologic dysfunction and broad susceptibility to infection. Left untreated, SCID uniformly results in death before the first year of life. The treatment approach varies depending on the underlying molecular defect, but for the majority of patients with SCID, the optimal treatment is hematopoietic stem cell transplantation (HSCT). Transplant outcomes are favorable if performed within the first 3 months of life, or if performed prior to the onset of SCID-associated chronic infections. Newborn screening of dried blood spots for evidence of T-cell deficiency occurs universally in the United States and internationally to identify and treat these patients soon after birth. Suspected SCID is a medical emergency, and both the necessary steps to confirm diagnosis and the initiation of treatment must be performed rapidly.

Clinical Findings

A. Symptoms and Signs

SCID frequently presents with opportunistic, unusual, and persistent infection. Common organisms include but are not limited to Pneumocystis jirovecii, candidiasis, and cytomegalovirus. In the absence of an identified microorganism, SCID may present with any combination of the following: failure to thrive, chronic diarrhea, or unexplained chronic respiratory illness. 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

The characteristic feature of SCID is the deficiency in production of T cells by the host. Endogenous production of T cells can be verified by quantifying T-cell receptor rearrangement excision circles (TRECs) in blood or by measuring the expression of CD31 on peripheral blood T cells. The presence of normal numbers of lymphocytes in a CBC or even normal numbers of CD3 T cells does not rule out SCID because of the possibility of either maternally derived T-cell populations or abnormally expanded endogenous T-cell populations with severely limited diversity. Associated laboratory findings can include decreases in numbers of NK cells and B cells, poor lymphocyte proliferative response to mitogens, and low immunoglobulin levels. Genetic testing should be pursued to confirm the diagnosis; although, treatment should not be delayed while awaiting results of genetic testing. Known genetic etiologies of SCID are listed in Table 33–4.

Differential Diagnosis

The differential diagnosis of SCID must be carefully considered as misdiagnosis could potentially result in unwarranted HSCT. Disorders that result in either the abnormal loss or the compartmentalization of lymphatic fluid such as chylothorax, lymphangiectasia, gastroschisis, and omphalocele can result in the apparent absence of endogenously generated T cells even though they are actually being normally produced. HIV disease can result in severe deficiency of CD4 T cells and the same infections seen in SCID. Prematurity can be associated with abnormally low TREC levels but these levels ultimately increase with increasing gestational age.

Treatment

A variety of therapies are used in the treatment of SCID. These therapies include HSCT, gene therapy, thymus transplant, and enzyme replacement. Choice of therapy depends upon the specific genetic defect, age at diagnosis, access to a suitable HSCT donor, and comorbidities. To optimize the outcome of any chosen definitive therapy, concerted effort must be made to prevent clinical deterioration in the waiting period. Antimicrobial prophylaxis should be initiated with the aim of preventing pulmonary infection with Pneumocystis, as well as other fungal pathogens. Antiviral prophylaxis can be considered as well. Replacement Ig therapy should be initiated. Patients with suspected SCID should only be transfused with CMV-negative, irradiated blood products, and they should not receive any live vaccines. If the patient has received BCG vaccination, specific therapy should be considered. Isolation precautions should be initiated. Until we understand more about CMV-transmission in CMV-positive mothers, breast-feeding should be discouraged. Additional precautions can be tailored based on the individual risk factor of the patient.

Defective T-Cell Development

T cells develop in a multiple-stage process fostered by supporting cells and directive cytokines. Problems with the production or sensing of these developmental signals can result in a severe deficit of T-cell number.

Deficiency in the formation of a functionally rearranged T-cell receptor and DNA repair mechanisms results in absence of T cells, the latter also being associated with radiation sensitivity. Primary absence of the thymus prevents development of mature T cells in severe presentations of 22q11 deletion syndrome, CHARGE syndrome, and deficiency of FOXN1.

Impaired T-Cell Survival

Impaired T-cell survival is seen in deficiency of both adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), as well as reticular dysgenesis and dyskeratosis congenita. ADA and PNP are components of purine salvage in lymphocytes, and loss of these enzymes results in buildup of toxic purine by-products. Dyskeratosis congenita results from abnormal telomere maintenance and results in survival defects in hematologic cells. Reticular dysgenesis is possibly the most severe form of combined immunodeficiency as a result of increased apoptosis of myeloid and lymphoid precursors. It is associated with sensorineural deafness. Defects in the one-carbon pathway can also result in severe deficiency of hematopoietic cells.

Impaired T-Cell Function

Few syndromes have been identified where T cells mature normally despite a residual impairment in T-cell receptor (TCR) signaling that results in susceptibility to infections typically seen in T-cell deficiency syndromes. In STIM1 and ORAI1 deficiency, defective mobilization of store-operated calcium channels results in inadequate activation of peripheral T cells despite normal numbers. In MHC Class II deficiency, normal T cells are unable to respond to antigen because it is not presented by antigen presenting cells.

Omenn Syndrome

Omenn syndrome is a presentation of SCID caused by residual autoreactive T cells in the absence of T-cell immune competence. The syndrome can include severe rash, failure to thrive, splenomegaly, diarrhea, eosinophilia, and elevated IgE in association with typical infections seen in conventional SCID. T-cell numbers are elevated, but detailed phenotyping reveals the majority of T cells to have a memory phenotype (CD45RO-positive). Omenn syndrome has been tied to mutations in genes known to cause conventional SCID, arising in part due to mutation-specific factors and partly due to the individual susceptibility of the patient. A similar clinical presentation occurs in SCID patients who have engrafted maternal T cells.

General considerations

Combined immunodeficiencies include all defects that directly impair both T and B lymphocytes, as well as T lymphocyte-specific defects that affect B-lymphocyte function and antibody production. In contrast to SCID, the severity of the immunodeficiency varies, depending on the underlying cause. Several described genetic syndromes have associated combined immunodeficiency that is often identified after the syndrome has been diagnosed. In some cases, the immune defect may not be the major presenting clinical problem. Examples of well-described syndromes with combined immunodeficiencies are described below.

1. 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. 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 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. 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. 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.

2. Ataxia telangiectasia (AT) 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. AT is characterized by progressive cerebellar ataxia, telangiectasia, and variable immunodeficiency. Children usually present as toddlers with slurred speech and balance problems, and also with sinus and pulmonary 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 AT 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 AT, 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.

3. 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 immune-receptor 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 jirovecii 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 HSCT has been used. The prognosis is dependent on the severity of immunodeficiency, with most deaths due to infection. Mutations in the NF-κBIA 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.

4. Major histocompatibility complex class I and II (MHC I, MHC II) deficiency or bare lymphocyte syndrome are AR-combined immunodeficiencies. Patients with MHC I deficiency 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 sinus and pulmonary as well as skin infections. The diagnosis is confirmed by demonstrating an absence of MHC I expression. In MHC II deficiency, cells lack MHC II expression due to mutations in CIITA, RFX-5, RFXAP, or RFXANK 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 HSCT, but milder phenotypes may be managed with Ig replacement and aggressive use of antibiotics.

5. 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.

6. 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. Bloom syndrome is characterized by growth retardation, microcephaly, sun-sensitive rashes, and telangiectasias of the face. The syndrome results from mutations in the Blm gene that encodes a RecQ-helicase involved in DNA repair.

8. 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. Affected patients have severe respiratory, gastrointestinal, and skin infections due to low or absent immunoglobulins and abnormal T-lymphocyte numbers and function.

9. Trisomy 21 or Down syndrome is associated with 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.

10. 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.

11. 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.

12. 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 Staphylococcus 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 jirovecii. 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 STAT3, DOCK8, and TYK2 mutations will help confirm the diagnosis of HIES particularly at a young age. All patients with HIES have impaired T_H17 cell function, and measurement of T_H17+ 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.

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. As a group, antibody deficiencies represent nearly half of all PIDs. They can be divided into (1) defects of B-cell development, (2) defects in Ig class switching, and (3) functional B-cell deficiency. Table 33–5 outlines primary antibody deficiency syndromes, laboratory findings, and genetic inheritance in these disorders.

Clinical Findings

A. Symptoms and Signs

For patients with antibody deficiency, specific infectious susceptibility and other features of immune dysregulation are dependent upon the specific cause of antibody deficiency. In isolated early B-cell development defects, such as X-linked agammaglobulinemia, infections are limited to encapsulated bacteria, mycoplasma species, and enterovirus species. In the class-switching defect caused by defective CD40L, infectious susceptibility can include Pneumocystis and Cryptosporidium, whereas class-switching defects caused by absence of AICDA or UNG can include lymphoproliferation and autoimmunity. Functional defects in B cells or B-cell activation, such as in combined immunodeficiency syndromes or common variable immunodeficiency (CVID) syndromes will include infectious susceptibility dependent on the underlying molecular defect. Antibody deficiency therefore represents a broad and somewhat heterogeneous grouping whose individual features depend on the root cause of immune abnormality.

Independent of underlying cause, untreated antibody deficiency results in typical infections. Pulmonary infection can be severe and chronic, resulting in bronchiectasis or other permanent lung damage. Severe pulmonary infections are generally preceded by chronic, recurrent middle ear and sinus infections. Additional infections can include bacteremia, bacterial meningitis, skin infection, and joint infection. Other sites of infection can arise depending on the underlying genetic defect.

B. Laboratory Findings

Numerous blood tests are available for the investigation of antibody production. Serum immunoglobulin levels are routinely tested and reference values are widely accessible. Antibodies to a particular antigen are measured to ensure that antibody production is specific. For instance, the amount of antibody to tetanus toxoid is frequently measured because the tetanus toxoid vaccine is routinely administered in developed countries. Vaccine titers to pneumococcal serotypes are frequently measured following vaccination with the unconjugated polysaccharide S pneumoniae vaccine. The increase in titers represents the ability of B cells to form antibodies in the absence of T-cell costimulation. Production of allo-specific IgM to red-cell antigens is also a measure of T-cell–independent antibody formation. When abnormalities are detected in immunoglobulin levels or antibody production, lymphocyte surface phenotyping may reveal additional aspects of the underlying abnormality, such as B- or T-cell deficiency.

The characteristic feature of antibody deficiency is the absence or severe deficiency of one of the three predominant immunoglobulins found in blood, IgG, IgA, or IgM. All three immunoglobulin isotypes are severely reduced in early B-cell development defects; although, IgG deficiency is rarely seen in children younger than 4 months due to the presence of placentally transferred maternal IgG. In class switching defects, IgM production can be normal or elevated, whereas production of IgG and IgA is deficient. In functional B-cell deficiencies, a combination of antibody production abnormalities may be detected. For instance, CVID is defined by the combination of poor vaccine response and a decrease in blood levels of IgG in conjunction with a severe decrease in levels of either IgM or IgA, or a decrease of both.

Blood cell abnormalities also vary according to the underlying cause of antibody deficiency. Many early B-cell development defects are limited to the B-cell compartment, and as a result, B-cell numbers are severely reduced, but levels of other blood cells are usually within normal limits. In class switching defects, peripheral B-cell numbers will also approach normal levels. On the other hand, functional antibody deficiency can arise in any combination of deficiency of specific lymphocyte subsets and other blood cells. For these deficiencies, the underlying genetic abnormality is most relevant to understand the resulting hematologic abnormality.

Differential Diagnosis

The differential diagnosis of antibody deficiency includes secondary causes of decreased amount of immunoglobulin in the peripheral blood. Several medications are known to specifically decrease immunoglobulin levels in the blood. For some of these medications, the mechanism is idiosyncratic. For others, low immunoglobulin levels result from inhibition of normal B-cell development processes, such as in chronic prednisone use, or they result from direct effects on the B-cell compartment, such as with rituximab therapy. Additional secondary causes of low immunoglobulin include protein-losing states, malnutrition, and autoimmune conditions.

Treatment

Treatment of antibody syndromes is primarily directed at preventing bacterial infection. The primary intervention in achieving this goal is replacing deficient IgG. There are no formulations of isolated IgM or IgA used in clinical practice. Some treatment centers advocate the use of prophylactic antibiotic therapy. In combined immunodeficiency or antibody deficiency syndromes with associated autoimmunity, immunosuppressive therapy or even HSCT may be required.

Antibody Deficiency Classification

Defective B-Cell Development

Aborted B-cell development can occur at multiple developmental stages. Initially, B cells develop from precursors in the bone marrow in a process that is dependent on the generation of a functioning rearranged B-cell receptor. In the absence of the ability to transmit signals through a B-cell receptor, B cells do not continue development. Consistent with this model of B-cell development, congenital defects in several of the proteins essential for the formation and signaling of the B-cell receptor have been identified as causes of severe B-cell deficiency. Additional blocks in B-cell development have been identified prior to the expression of the B-cell receptor and also later in development as cells approach the naïve B-cell stage.

Patients with defects in B-cell development are generally immunologically normal with the exception of a severe reduction of B cells in the blood and infections that result from their absence. Patients with early defects have little detectable lymphoid tissue, and upon physical examination, one may find an absence of tonsils or palpable lymph nodes. Patients with later defects may have palpable lymphoid tissue. In both groups, the spleen is generally normal in size.

Class Switching Defects

Normal immunoglobulin isotype class switching occurs in germinal centers in response to antigenic and T-cell costimulatory signals, and the class switching defects involve severe dysfunction of this process. Defects in either T-cell surface CD40L or B-cell surface CD40 impair the initial step in the class-switching cascade, and as a result, no class switching occurs. Further downstream, defects in either AICDA or UNG impair class switching by preventing the formation of double-stranded breaks that are essential for the genomic rearrangement required to switch isotypes. Additional defects in class switching can be seen with genetic abnormalities in the NF-κB and also PIK3D activating mutations, but in either case, the class switching phenotype can be variable. Consultation of an immunologist will help determine where the class switching defect is located and direct clinical care.

Class switching presents with various associated features depending on the genetic cause. Defects in CD40L and CD40 can have risk of associated opportunistic infection with Pneumocystis and Cryptosporidium, the latter increasing the risk for sclerosing cholangitis, and they have hypoplastic lymphoid tissue. Patients with defective AICDA can have associated autoimmunity, including ITP, hemolytic anemia, autoimmune hepatitis, inflammatory bowel disease, arthritis, and interstitial lung disease. Both AICDA- and UNG-deficient patients suffer from lymphoid hyperplasia.

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.

Functional Antibody Deficiency

The group of functional antibody deficiency disorders includes any disorder in which a persistent deficiency in immunoglobulin production has been identified, and the deficiency is not the result of a secondary cause. This group includes genetic syndromes, combined immunodeficiency syndromes, CVID, and monogenetic syndromes previously classified as CVID. As expected, this group contains highly variable phenotypes, in part due to the variety of associated non-B–cell immune abnormalities, and also due to modifying factors in the individual. If possible, understanding the underlying genetic defect of the individual syndrome dramatically improves the ability to anticipate additional complications and decide on treatment approaches. Even the need for immunoglobulin G replacement therapy will vary from individual to individual.

Monogenetic Causes of Functional Antibody Deficiency

A number of monogenetic causes of functional antibody deficiency have been identified in scattered individuals that had previously been diagnosed with CVID. These syndromes encompass the range of phenotypes conventionally included in the broad category of CVID. Severe defects in the classic B-cell coreceptor complex, including CD19, CD21, CD81, and CD225, have been identified in individuals mainly with poor antibody response and infections that would be expected to follow. These defects presumably arise from an impaired germinal center reaction to foreign antigens in lymph nodes. Similar phenotypes were shown to result both with defects in other B-cell coreceptors such as BAFFR or TACI and also with defects in molecules that signal through these receptors such as ICOS. Additional syndromes that include involvement of T-cell dysfunction as well as functional antibody deficiency have been identified in molecules that function in both cell types. These syndromes include, but are not limited to, CD27 deficiency, PIK3D gain of function, and IL-21 deficiency. Additional syndromes with predominant features outside of functional antibody deficiency are discussed later in the chapter.

CVID

Common variable immunodeficiency is a heterogeneous category of functional antibody deficiencies in which no other more appropriate classification is available. CVID is defined by the combination of poor vaccine response and a decrease in blood levels of IgG in conjunction with a severe decrease in levels of either IgM or IgA, or a decrease of both (see Table 33–5). Associated cellular abnormalities can include reduced numbers of memory B-cell subsets in the blood, as well as T-cell lymphopenia. Patients have recurrent infections, most often of the sinus and pulmonary 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).

Selective Immunoglobulin Deficiencies

Deficiency of an IgA or an IgG subclass can be seen in the presence of both recurrent infections and other immune abnormalities; however, these deficiencies are often seen in the absence of any other identifiable immune abnormality. With an incidence of 1:700, isolated IgA deficiency is a common laboratory finding. The majority of patients with isolated IgA deficiency are asymptomatic, but associations also exist with inflammatory bowel disease, allergic disease, asthma, and autoimmune disorders (thyroiditis, arthritis, vitiligo, thrombocytopenia, and diabetes). Deficiency of IgG subclasses 2–4 can be identified in the absence of other laboratory immune abnormalities; whereas, severe deficiency of IgG1 universally presents with an overall decrease in total IgG levels because it makes up the majority of IgG detectable in the blood. Deficiency of IgG2 can be seen in association with decreased IgA, and in that context, it is suggestive of an underlying functional antibody deficiency with a possibly identifiable genetic cause. IgG3 and IgG4 make up the smallest fraction of the total IgG pool, and in the absence of any other immune abnormality, deficiency of either of these IgG subclasses is generally not considered to cause increased susceptibility to infection. IgG replacement is not indicated in either IgA deficiency or IgG subclass deficiency when no other quantitative or functional immune abnormality has been identified. When other immune abnormalities are seen, antibody deficiency syndromes listed elsewhere in this chapter should be considered.

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

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 in the United States and Europe (probably 75%) are inherited as an XL recessive trait; however, in regions with widespread consanguineous mating, AR inheritance is seen with equal frequency.

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. Aspergillosis is also common and a frequent cause of death. 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 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 an XL mutation.

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.

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

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.

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, and 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).

Treatment

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

General considerations

Deficiencies in the innate immune response comprise defects that are not the result of an impaired adaptive T- and B-cell response. Besides impaired neutrophil function, they include deficiencies in complement function and other components of the innate immunity.

1. 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 33–2). 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.

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 meningitidis or disseminated gonococcal infection. Survivors of either of these serious neisserial infections should be screened for complement deficiency, first with a CH50.

2. 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 meningitidis, but also viral and fungal infections can occur in context of mannose-binding lectin deficiency.

3. Mendelian Susceptibility to Mycobacterial Disease

IFN-γ is critical for macrophage activation and resistance to mycobacterial infections. Mutations that cause deficiency or reduced function of proteins that participate in IFN-γ signaling result in Mendelian susceptibility to mycobacterial disease (MSMD). Thus far, 11 genes are known to harbor such mutations in affected individuals: IL12B, IL12RB1, ISG15, TYK2, IRF8, SPPL2A, CYBB, IFNGR1, IFNGR2, STAT1, and NEMO. The infection susceptibility seen in patients with these mutations includes infection with typically nonpathogenic mycobacteria such as Mycobacterium avium complex or bacille Calmette-Guérin (BCG), with some also demonstrating susceptibility to salmonellosis and candida infection. 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.

4. 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.

General considerations

Aberrant development of the immune system predisposes not only to a defective host immune response. Autoimmunity, chronic inflammation, and features of atopy may occur concurrently. Mechanisms contributing to autoimmunity include impaired development and function of regulatory T and B cells, production of autoantibodies often seen with B-cell defects affecting immunoglobulin class switching, and clearance of apoptotic cells. States of immune dysregulation can be associated with lymphoproliferation and enhanced inflammation.

1. 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. HSCT has been attempted with variable success. 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, signal transducer and activator of transcription (STAT) 1, STAT3, STAT5 b, and ITCH. 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 or other suspected mutations will be helpful to identify affected patients and carriers of the gene mutation. In addition to IPEX syndrome, early onset pediatric inflammatory bowel disease has been described as a consequence of loss-of-function mutations in IL-10 and IL-10 receptor (encoded by IL10RA and IL10RB).

2. Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dysplasia Syndrome

Autoimmune polyendocrinopathy, candidiasis, ectodermal dysplasia (APECED) syndrome is characterized by autoimmune endocrinopathies, ectodermal dystrophies, and recurrent Candida infections as a result of an abnormal T-lymphocyte response to Candida. Generalized lympho-proliferation is absent. APECED is caused by AR 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 T_H17 response and contribute to chronic mucocutaneous candidiasis (CMC). Several other gene defects have been associated with chronic 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 as in APECED syndrome. Mutations in the signal transducer and activator of transcription 3 (STAT3) gene and gain-of-function mutations in STAT1 can lead to defective T_H17 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. Treatment of CMC includes antifungal therapy in combination with therapy for associated endocrinopathies.

3. 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⁺CD4⁻CD8⁻ (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.

4. Other Lymphoproliferative Syndromes

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.

5. Abnormal Responses to Cellular Debris

Large numbers of cells undergo programmed cell death (apoptosis) and need to be cleared daily. Apoptotic cells are being recognized by phagocytes either directly by scavenger receptors or after opsonization by early complement components through binding to complement receptors. Defective clearance of apoptotic cells leads to accumulation of cell debris, which can, similarly to debris from pathogens, trigger inflammation with increased production of type I interferons (IFNs) and a shift to autoimmunity. This has been associated with the high incidence of systemic lupus in patients with C1q deficiency and discoid lupus in female carriers of CGD. Accumulation of nucleic acid debris due to decreased breakdown caused by loss-of-function mutations of endonucleases, for example DNAse I and TREX1, and gain-of-function mutations in intracellular nucleic acid sensors, for example IFIH1 and STING, also contribute to an increased IFN I signature seen in a variety of autoimmune manifestations.

General Considerations

Some have incorrectly assumed that the state of immune deficiency is not compatible with allergy because allergy requires a coordinated allergen-specific immune response. To the contrary, several genetically defined immune deficiencies are known to associate with allergic diseases ranging from allergic rhinitis to food allergy and eczema. Still several more immune deficiencies are highly likely to manifest clinically with symptoms not necessarily the result of a specific allergy, but nonetheless likely to fall under the purview of allergy, such as urticaria and eczema-like rash. Some of these diseases are reviewed later.

Clinical Findings

A. Symptoms and Signs

Immunodeficiencies that associate with allergic disease have varied clinical manifestations. In some cases, such as in DOCK8 deficiency, patients have severe allergic disease and recurrent infection without any accompanying nonimmune features. In other syndromes, patients develop allergy in addition to other immune-related problems. In immunodysregulation polyendocrinopathy X-linked (IPEX), patients develop autoimmune disease in addition to eczema and allergy. In other diseases, patients present with nonimmune features. For example, in Wiskott-Aldrich syndrome, patients present with eczema and bleeding as a result of platelet abnormalities. In PGM3 deficiency, patients have motor and cognitive impairment. Patients with Comel-Netherton syndrome have distinct structural abnormalities of the hair shaft. As can be seen in these examples, the association between allergic disease and immunodeficiency is not uncommon and results from various forms of genetic impairment.

B. Laboratory Findings

It is often difficult to use laboratory testing to distinguish an immunodeficiency that associates with allergy from severe allergy without immunodeficiency. While the finding on CBC of thrombocytopenia and small platelets assists in diagnosing Wiskott-Aldrich syndrome, the majority of immunodeficiency-allergy-overlap diseases lack distinguishing laboratory features. In light of a dearth of specific laboratory findings that indicate a patient’s allergy is related to a more significant immune deficiency, the authors recommend that any severe abnormality discovered in routine hematologic testing be viewed with suspicion in allergic patients. For example, a peripheral eosinophil count persistently above 1500/μL should raise concern for additional immune processes. Likewise, the finding of low levels of serum immunoglobulins could be the first clue to an underlying immune process.

C. Differential Diagnosis

If immune deficiency is suspected in an allergic patient, secondary causes of immune dysfunction should be considered. Hypogammaglobulinemia can result from protein loss through the GI tract or as the result of nutritional deficiency. Additional consideration should be made for the patient’s home environment. Severe allergic sequelae are often the result of chronic exposure to an offending allergen, such as a pet in the house.

D. Treatment

Treatment of allergic symptoms in patients for which there is a suspected immune deficiency parallels treatment for immunocompetent patients with allergy except for the use of systemic immunosuppressants. For patients with cellular immunodeficiency that presents with allergy, the use of corticosteroids and perhaps other systemic immunosuppressants can increase the risk of reactivation of latent viruses either from past infection or even past vaccination. In one report, use of corticosteroids in a patient with DOCK8 deficiency was associated with reactivation of vaccine strain varicella and the development of vasculopathy. Considering this additional risk, the authors recommend diagnostic re-evaluation when considering the use of systemic immunosuppressants for severe or unusual allergic manifestations. When severe immunodeficiency is identified in an allergic patient, treatment is dependent on the underlying diagnosis. Several of the diseases listed in Table 33–6 can be corrected through allogeneic HSCT, whereas others may respond better to replacement immunoglobulin, prophylactic antimicrobials, or immunosuppressive therapy.