Primary immunodeficiency diseases (PIDDs) can be defined as congenital disorders caused by an intrinsic molecular defect that alters the development or function of the immune system. As a consequence, patients with these conditions display increased susceptibility to infections, neoplasia, and autoimmunity. More than 300 PIDDs have been recognized, and many of the gene defects responsible for the immunologic phenotypes have been identified. Previously considered to be uncommon, PIDDs have been estimated to occur at a minimum incidence of 1 per 10,000 live births. A 2007 US survey of 10,000 households, however, reported a prevalence of 1 in every 1200 people for clinically diagnosed PIDD, suggesting that these conditions occur even more frequently than often suspected. A more recent survey of pediatricians in the United States demonstrated a significant lack of awareness or comfort regarding the recognition and evaluation of patients with PIDDs.
In patients with immune deficiency, PIDDs must be distinguished from secondary immunodeficiency disorders. These latter conditions represent acquired immune defects that occur as either a result of exogenous factors or together with nonimmunologic primary disease processes. They are encountered much more frequently than PIDDs. Causes of secondary immunodeficiency states include infection (e.g., by human immunodeficiency virus [HIV]), medications (e.g., corticosteroids), malnutrition, and neoplastic or metabolic diseases (e.g., Hodgkin disease, diabetes mellitus, cystic fibrosis, and systemic lupus erythematosus [SLE]). These factors may also affect a fetus in utero and present in the neonatal period. Thus they must be considered in infants who exhibit signs or symptoms of immune deficiency.
An immunologic evaluation is indicated when a patient develops unusually frequent or severe infections or when infections are caused by atypical or pathognomonic organisms ( Box 67.1 ). Most of these individuals are immunocompetent and have risk factors for increased frequency of infections, such as allergic disorders, anatomic abnormalities (e.g., eustachian tube dysfunction), or increased exposure to pathogens (e.g., attendance at daycare). They may also have a clinical condition that results in an acquired immunodeficiency state. However a number of children will have an established PIDD and will benefit from prompt referral to a clinical immunologist for early diagnosis and management.
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Frequency of infectious illnesses higher than expected
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Unusual severity or duration of infectious disease
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Poor response to conventional antibiotic therapy
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Unusual organisms or opportunistic infections causing disease
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Failure to thrive secondary to frequent illnesses
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Poor wound healing
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Noninflammatory Staphylococcus spp. skin infection (or absence of pus)
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Recurrent periodontitis
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Low granulocyte or lymphocyte count
This chapter will focus on the elements of the medical history and physical examination that suggest a diagnosis of a PIDD. Relevant laboratory tests are discussed. Representative antibody, combined (primarily T- and often B-cell) immunity, complement, phagocytic, and other innate immunity deficiencies are presented. Finally a summary of PIDDs that are known to be associated with susceptibility to certain infectious pathogens is provided.
Initial Evaluation for Suspected Immunodeficiency
Medical History
A comprehensive medical history remains essential for identifying children with a defective immune response. Children with PIDDs often have a history of frequent or severe infections (e.g., pneumonia, meningitis, septicemia, osteomyelitis, abscesses of soft tissue or an internal organ). Although infections occur routinely throughout childhood, epidemiologic studies have established a range for the average number of infections that a normal child may develop per year. For example, otherwise healthy children younger than 5 years of age average between three and eight episodes of upper respiratory tract infections annually. By 1 year of age, 62% of children have had at least one acute otitis media infection, and 17% have had three or more episodes. By 3 years of age, more than 80% of children have had at least one episode of acute otitis media, and 46% have had three or more episodes. The incidence of gastroenteritis among children in the United States is approximately two to three episodes per child-year, with rates as high as five episodes per child-year among children attending daycare centers. The frequency of these infections in normal children during infancy or early childhood can be modified by several factors, including immunologic immaturity or naïveté (i.e., lack of prior exposure to infectious agents), poor hygiene, mouthing behavior, allergic disease, exposure to tobacco smoke, and frequent exposure to ill contacts in the home, school, or daycare settings.
Other elements of the infection history may raise concern for the presence of a PIDD. Clinicians should suspect immune deficiency when the course of an infection is unusually prolonged or associated with unexpected complications (e.g., lung abscess in a child with pneumonia or osteomyelitis as a complication of sinusitis). In general, infections of multiple body sites over time more highly suggest a defective immune response than infections occurring at only one site (e.g., recurrent otitis media alone). In the latter circumstance, a mechanical or anatomic etiology (e.g., foreign body, occult tracheoesophageal fistula in a child with recurrent pneumonia, allergic inflammation, congenital fistulous tract to the middle ear in a child with recurrent bacterial meningitis) should be considered.
Identified infectious organisms may themselves suggest a defect in a particular compartment of the immune system. Several pathogens are discussed in depth at the end of this chapter. Children with primary antibody deficiencies are typically susceptible to infections caused by polysaccharide-encapsulated extracellular bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae ). In contrast, children with T-cell–mediated immune deficiencies often develop infections caused by unusual or opportunistic viruses, fungi, protozoa, and mycobacteria ( Table 67.1 ). Because of impaired T-cell–dependent antibody responses, bacterial infections may also be observed. Children with primary deficiencies of complement proteins can present with a history of recurrent neisserial infections, and patients with certain phagocyte deficiencies may have invasive infections due to catalase-positive bacterial (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens ) or fungal (e.g., Aspergillus spp.) organisms.
| Immunodeficiency | Common Pathogens |
|---|---|
| Antibody deficiencies | Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Mycoplasma, Salmonella, Shigella, Campylobacter, rotavirus, enteroviruses, Giardia |
| Combined immune deficiencies | Pathogens in antibody deficiencies plus: Mycobacteria, Candida, Pneumocystis jiroveci, herpesviruses, adenoviruses |
| Complement deficiencies | Neisseria, S. pneumoniae, H. influenzae |
| Phagocyte deficiencies | S. aureus, B. cepacia, Nocardia spp., Serratia, Klebsiella, enteric gram-negative bacilli, Aspergillus, P. aeruginosa |
Other elements of the clinical history may help to define the risk for and nature of a potential PIDD. Because young infants are afforded some protection against infections by the presence of maternal immunoglobulin (Ig) G, children with primary antibody deficiencies generally begin to develop infections between 3 and 18 months of age. In contrast, children with severe T-cell–mediated, complement, or phagocytic deficiencies may have onset of infections in the first days or weeks of life. Omphalitis, resulting in delayed detachment of the umbilical cord stump, and poor wound healing suggest phagocytic deficiency. Hypocalcemic seizures in the neonatal period and congenital heart disease should lead to suspicion for a diagnosis of DiGeorge syndrome. Severe infection from live vaccine strains after immunization (e.g., bacille Calmette-Guérin [BCG] lymphadenitis, measles, poliomyelitis, varicella, rotavirus) warrants screening for functional immunologic defects.
The family history can augment suspicion for the presence of a PIDD. A history of consanguinity, recurrent or unusual infections, or deaths from infection or from unexplained causes during infancy or early childhood in close relatives increases the likelihood for an inheritable immunologic defect. Many PIDDs have X-linked inheritance patterns ( Box 67.2 ), explaining the male-to-female ratio of 5 : 1 observed in children with PIDDs.
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X-linked agammaglobulinemia (Bruton disease)
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Immunodeficiency with hyper–immunoglobulin M (CD40 ligand deficiency)
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X-linked ectodermal dysplasia with immunodeficiency (NEMO deficiency)
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Immunodeficiency, polyendocrinopathy, enteropathy, X linked (IPEX)
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X-linked lymphoproliferative syndrome
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Severe combined immunodeficiency (common γ-chain deficiency)
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Properdin deficiency
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Wiskott-Aldrich syndrome
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X-linked chronic granulomatous disease
Physical Examination
In patients who are very young and have not been exposed to requisite pathogens to develop infections, the physical examination in many children with PIDDs often provides few clues pointing to an immune defect. A paucity of lymphoid tissues (e.g., tonsils, lymph nodes) may suggest impaired lymphocyte development at an early age. Other examples of helpful physical stigmata include the characteristic facial features ( Fig. 67.1 ) and cardiac malformations in children with DiGeorge syndrome.
In older children, physical examination findings may help to increase suspicion for the presence of a PIDD. Short stature with wasting or failure to thrive appear frequently, likely due to recurrent infections or other chronic issues, such as intestinal malabsorption associated with persistent or frequent diarrhea. Recurrent or recalcitrant oral candidiasis, omphalitis, or multiple skin abscesses can serve as signs of immune deficiency. Severe rash, hepatomegaly, and lymphadenopathy are observed in conditions such as Omenn syndrome. Telangiectasias of the bulbar conjunctivae ( Fig. 67.2 ), nasal bridge, ears, and flexor surfaces of the extremities, with or without ataxia, suggest a diagnosis of ataxia-telangiectasia. Chronic eczema can be observed in the hyperimmunoglobulinemia E (hyper-IgE) and Wiskott-Aldrich syndromes, and severe gingivitis with secondary loss of alveolar bone and dentition ( Fig. 67.3 ) can occur in children with leukocyte adhesion deficiency (LAD).
Laboratory Tests
Widely available, relatively inexpensive laboratory tests can be used to screen for the presence of a PIDD and exclude most of the severe disorders ( Table 67.2 ). The evaluation should be targeted to the type of immune deficiency (e.g., antibody deficiency vs. phagocyte deficiency) suspected by the medical history and physical examination findings. Laboratory test results must be interpreted against age-defined ranges because normal absolute lymphocyte counts, serum immunoglobulin levels, T-cell counts, and other immune parameters change physiologically with age. Tests to exclude secondary immune deficiency caused by HIV infection, malnutrition, or metabolic disorders should always be considered.
| Immunodeficiency | Screening Tests |
|---|---|
| All types | Complete blood cell count |
| Peripheral blood smear | |
| Antibody deficiency | Quantitative serum immunoglobulins: IgG, IgA, IgM, IgE |
| Postimmunization specific IgG antibody titers | |
| Isohemagglutinins | |
| T-cell deficiency | Delayed hypersensitivity skin tests or lymphocyte proliferation response to mitogens |
| Chest imaging studies for thymus size | |
| Lymphocyte subset phenotyping | |
| Complement deficiency | Total hemolytic complement (CH50) assay |
| Phagocyte deficiency | Dihydrorhodamine (DHR)-1,2,3 reduction by flow cytometry |
| Neutrophil CD18 and CD15 expression |
A complete blood count with manual differential provides an excellent screening test for PIDDs. Because 50% to 70% of circulating lymphocytes consist of T cells, children with defects in T-cell production (e.g., severe combined immunodeficiency [SCID], complete DiGeorge syndrome) can typically be recognized by absolute lymphopenia. Meanwhile children with Wiskott-Aldrich syndrome are characterized by reduced numbers of platelets that are small (decreased mean platelet volume), a feature that is specific for this syndrome and the related X-linked thrombocytopenia. Large neutrophil cytoplasmic granules are observed in children with Chédiak-Higashi syndrome. Furthermore a complete blood cell count can help to exclude congenital neutropenia. Children with LAD, on the other hand, typically exhibit markedly increased baseline neutrophil and total white blood cell counts. The presence of Howell-Jolly bodies, with or without thrombocytosis, suggests anatomic or functional asplenia.
Evaluation of Humoral Immunity
Screening assessments for antibody deficiency should include quantitative measurement of serum immunoglobulin levels and functional assessment of specific antibody responses. Evaluations of serum IgG, IgA, IgM, and IgE levels help to identify children with panhypogammaglobulinemia, IgA deficiency, hyper-IgM syndrome, hyper-IgE syndrome, and so forth. Functional antibody production should be tested by measuring antibody titers generated in response to immunization with vaccines, such as Diphtheria and tetanus toxoids. Antibody responses to polysaccharide antigens should be assessed separately using the 23-serotype pneumococcal polysaccharide vaccine after 24 months of age. Infants younger than 2 years are felt to have functional immaturity in the ability to respond to this class of antigens, although this assertion has been challenged. Alternatively, because ABO blood group antigens are polysaccharides, and cross-reacting environmental antigen epitopes exist ubiquitously, some antipolysaccharide antibody production may be assessed by measuring serum isohemagglutinin titers, taking into consideration the fact that children with blood type AB do not form isohemagglutinins. The 13-valent conjugated pneumococcal antigen and H. influenzae type b vaccines do not assess antipolysaccharide antibody responses because the immune response to the conjugated protein element drives antibody production to each target antigen. Patients vaccinated with the conjugated pneumococcal vaccine can still be evaluated for antipolysaccharide antibody production to the serotype antigens in the pneumococcal polysaccharide vaccine that are not present in the conjugated vaccine, however. Assessments of children whose screening tests indicate significant humoral immune abnormalities should be followed by enumeration of B-cell subsets in the peripheral blood.
Evaluation of T-Cell–Mediated Immunity
The screening evaluation for T-cell deficiency can begin without specialized immunologic testing. Assessments include measurement of the absolute lymphocyte count, delayed hypersensitivity skin tests, and, in the young infant, posteroanterior and lateral chest radiographs to assess the size of the thymus ( Fig. 67.4 ).
Delayed hypersensitivity skin tests are performed using vaccine or microbial antigens to which the child has had prior exposure. Commonly used antigens include tetanus toxoid and Candida albicans. The standard initial dilution is 1 : 100 for both antigens, but a C. albicans dilution of 1 : 10 may be more appropriate for children 5 years of age or younger who are less likely to have had repeated exposures to this antigen. The diluted antigen is administered intradermally, and the skin reaction is examined for the presence of wheal formation after 24 and 48 hours.
Specialized tests include enumeration of peripheral blood T cells, T-cell subset phenotyping (e.g., CD4 + or CD8 + T-cell counts), and mitogen- and antigen-induced lymphocyte proliferation studies.
Evaluation of the Complement System
Deficiencies of components of the classic complement pathway can be detected by the total serum hemolytic complement (CH50) assay. This test measures the ability of complement proteins in fresh patient serum to lyse antibody-coated sheep erythrocytes and reflects the activity of all components of the classic complement pathway from C1 through C9. Complete deficiency of any of these components results in very low CH50 values. Improper sample handling can produce low CH50 results. Thus assessments of single complement component levels and targeted functional testing should only be pursued when the CH50 value is zero or near zero. Measurement of serum levels of C3 and C4 is available in most clinical laboratories. The alternate complement pathway is assessed with a similar assay (AH50).
Evaluation of Phagocyte Function
Few assays are available for the assessment of phagocyte function. Children with chronic granulomatous disease (CGD) show abnormally reduced superoxide production in phagocytes in a flow cytometry analysis that detects using dihydrorhodamine-1,2,3 (DHR) as a fluorescent indicator. More sophisticated tests available in research laboratories include assays of chemotaxis, phagocytosis, and bactericidal activity, which may be performed when a high clinical suspicion of a phagocytic disorder exists. Assessment of CD18 and CD15 expression on white blood cells is indicated when a diagnosis of LAD is suspected.
Genetic Testing
More than 300 molecular defects have been identified as causes of PIDDs ( Table 67.3 ). Gene sequence testing for many of these defects is available in a few specialized laboratories and should be pursued when a PIDD with a known genetic defect is suspected. In patients for whom a PIDD is highly likely, and the clinical phenotype can be caused by a defect in one of several candidate genes, whole exome or genome sequencing may be considered. Genetic testing is recommended for patients who have a suspicious clinical history and abnormal immune function, for prenatal diagnosis of an unborn child who has a sibling with a known PIDD, and for an individual who may have inherited or who may be a carrier of a known PIDD gene defect. For some conditions, identification of the specific genetic defect may help to determine prognosis and therapeutic options. For example, it has been established that patients with SCID due to Artemis deficiency should not be given alkylator therapy during conditioning for hematopoietic stem cell transplantation because use of such agents is associated with poor growth, abnormal dental development, and late endocrinopathies after transplantation. Determination of the specific genetic defect is also necessary for genetic counseling, usually regarding the probability that the parents will have another child with the same condition.
| Immunodeficiency | Defect | Chromosome |
|---|---|---|
| Antibody Deficiency | ||
| Agammaglobulinemia | Heavy-chain immunoglobulin | 14q23 |
| Bruton tyrosine kinase | Xq22 | |
| Hyper-IgM syndrome | Activation-induced deaminase | 12p13 |
| CD40 ligand (CD40LG) | Xq26 | |
| Cellular Immunodeficiency | ||
| DiGeorge syndrome | Unknown | 22q11.2, 10p13 |
| Severe combined immunodeficiency disease | RAG1, RAG2 | 11p13 |
| JAK3 | 19p13.1 | |
| Adenosine deaminase | 20q13.11 | |
| Common γ-chain | Xq13.1 | |
| IL-7 receptor-α | 5p13 | |
| Ataxia-telangiectasia | ATM | 11q22.3 |
| Wiskott-Aldrich syndrome | WAS | Xp11.23 |
| Phagocyte Deficiency | ||
| Chronic granulomatous disease | p67 phox | 1q25 |
| p47 phox | 7q11.23 | |
| p22 phox | 16q24 | |
| gp91 phox | Xp21.1 | |
| Leukocyte adhesion deficiency type I | ITGB2 | 21q22 |
Neonatal Screening for T-Cell Deficiencies
In June 2010, the U.S. Department of Health and Human Services approved the addition of SCID to the list of diseases recommended for universal neonatal screening. Children with severe T-cell deficiencies, such as SCID, are born with absent or very low numbers of T-cell receptor excision circles (TRECs), which are DNA byproducts of T-cell receptor recombination. In 2005, Drs. Puck and Chan demonstrated that TREC levels can be measured using blood spots from Guthrie cards. Newborn screening for SCID was subsequently pioneered in Wisconsin in 2008 and continues to be rapidly implemented across the nation. As of July 2017, 44 states and the District of Columbia had active programs to screen all newborns for SCID, resulting in the testing of more than 10 million infants. An additional four states committed to begin screening before the end of 2017. The programs have shown notable success in identifying children with SCID and other PIDDs, resulting in excellent treatment outcomes. Thus all infants who have abnormal newborn screening results for SCID should be evaluated by a clinical immunologist according to the specific algorithm developed by the Health Department of that state. Newborn screening has also determined that the incidence of SCID in the United States is one per 58,000 live births. A similar approach for the diagnosis of B-cell deficiencies in the newborn is being developed.
Management
The immunodeficient patient requires specialized care according to the specific diagnosis and clinical condition. For example, hematopoietic stem cell transplantation is indicated for many PIDDs and needs careful individualized assessment of risks and benefits to provide a treatment protocol that ensures optimal outcomes.
Administration of intravenous or subcutaneous IgG (IVIG or SCIG, respectively) serves as a common therapeutic measure for patients who lack IgG antibody responses, whether isolated or as part of combined immune deficiency. Other recommendations specific to patients with PIDDs may include exclusion from contact with infectious illness and avoidance of live vaccines ; use of irradiated, leukocyte-depleted, cytomegalovirus-negative blood products when needed; antibiotic prophylaxis; and prompt diagnosis and treatment of infections. Aside from patients with severe T-cell deficiency awaiting hematopoietic stem cell transplantation, isolation in sterile environments is not recommended because the risk for infection must be balanced with the severe impact in psychosocial development induced by isolation. Instead the infection risk should be minimized using advances in the treatment and prevention of community-acquired infections ( Box 67.3 ).
Immune function : T- and B-cell number and function should be assessed periodically.
IgG replacement therapy : Infusions are indicated for patients with poor antibody responses to immunizations.
Immunizations : Live vaccines should not be administered to patients who have severe T-cell deficiencies unless they have received definitive treatment. Household contacts of children with immunodeficiency should not receive oral poliovirus vaccines because of the risk for transmission to the immunodeficient child. Other live vaccines (BCG, MMRV) may be administered to household contacts. If the vaccine recipient develops a rash, contact with the immunodeficient child should be avoided.
Blood products : When needed, patients with immune deficiencies should receive only irradiated, cytomegalovirus-negative, leukocyte-depleted blood products.
Antibiotic prophylaxis : T-cell–deficient patients should be given antibiotic prophylaxis to prevent Pneumocystis jirovecii infection. Antibiotic prophylaxis is recommended for dental and surgical procedures and should be considered for patients with recurrent infections.
Infectious diseases : Infections should be recognized promptly, and unusual pathogens should be considered. Antibiotic therapy should be started early and discontinued cautiously.
Diet and activity : Patients with immune deficiency should have a regular diet and lifestyle but should be instructed to avoid eating raw food and playing in environments potentially highly contaminated with pathogens, including daycare centers. Strict hand-washing precautions and reverse isolation may be indicated for patients with poor T-cell function.
Selected Primary Antibody Deficiencies
X-Linked Agammaglobulinemia
Clinical Features
Boys with X-linked agammaglobulinemia (XLA) are often healthy during the first months of life due to the protective presence of transplacentally acquired maternal IgG. As maternal immunoglobulin disappears from the infant, chronic or recurrent infections develop. The most common findings include recurrent otitis media, sinusitis, pneumonia, and diarrhea, but infections are not limited to mucosal surfaces: bacteremia, meningitis, and osteomyelitis may also occur. In a retrospective study of 201 patients with XLA, the mean age at diagnosis was 2.5 years in patients with a family history of the disease and 3.5 years when no family history was present. The most common bacterial pathogens identified in patients with XLA include S. pneumoniae, H. influenzae , S. aureus, and P. aeruginosa . Mycoplasma spp. infections also occur with increased frequency and have been implicated as a cause of a subacute, destructive arthritis. Gastrointestinal infections may be caused by Salmonella, Shigella, Campylobacter, or rotavirus. Chronic giardiasis with intestinal malabsorption has been observed. Patients with XLA also demonstrate increased risk for enteroviral infections, particularly viral meningoencephalitis.
Pathogenesis
The defective gene (BTK) maps to the midportion of the long arm of the X chromosome. The gene encodes a cytoplasmic tyrosine kinase, BTK, which is a signal transducer necessary for B-cell survival during maturation. As a consequence, blood, lymph nodes, and bone marrow contain markedly diminished numbers of B cells and plasma cells, resulting in agammaglobulinemia. BTK also plays a role in viral immunity within macrophages and dendritic cells, perhaps explaining the enteroviral susceptibility.
Diagnosis
Because of the presence of transplacentally acquired maternal IgG, a normal level of serum IgG in a male infant during the first 6 months of life does not exclude the diagnosis of XLA. IgA, IgM, and IgE levels may be low as well, but defining values that clearly differentiate infants with the disease from normal infants has remained difficult. Diagnosis can be better obtained by immunophenotyping, using flow cytometry analysis to demonstrate absence of B cells in peripheral blood. After an infant with XLA reaches 6 months of age, serum IgG concentrations usually fall below 100 mg/dL, and levels of other immunoglobulin isotypes remain low or undetectable. No isohemagglutinins are present, and specific antibodies are not produced in response to immunization or natural infection. Recurrent infections or early mortality in male family members may suggest the characteristic X-linked pattern of inheritance. Definitive diagnosis is obtained by identifying functionally deleterious mutations in the BTK gene.
Treatment and Prognosis
Lifetime IgG replacement therapy is needed for all patients with XLA. It decreases the frequency of severe infections, reduces the need for hospitalization, and helps to prevent the development of chronic lung disease with progressive decline in pulmonary function. The dose and frequency of administration of IVIG or SCIG should be adjusted to minimize the frequency of infections. Some patients receiving IVIG will require serum IgG trough levels of 800 to 1300 mg/dL to achieve this goal. Most patients receive IVIG at a dose of 400 to 600 mg/kg every 3 or 4 weeks or SCIG at 140 to 200 mg/kg weekly. Patients who are given SCIG should have steady-state serum IgG levels measured periodically (SCIG administration does not produce trough serum IgG levels). SCIG recipients should maintain steady state serum IgG levels higher than the serum IgG trough level targeted by IVIG administration in order to achieve a comparable pharmacokinetic area under the curve.
Infections should be treated aggressively in patients with XLA. Routine middle ear, sinus, and skin infections usually respond to oral antibiotics. Therapy for pneumonia and other significant focal or systemic infections should start with intravenously administered antibiotics. Empirical antibiotic therapy should be directed against common bacterial pathogens, including S. pneumoniae, H. influenzae, and S. aureus. If possible, a causative pathogen should be identified, particularly in severe or chronic infections. Additional doses of IVIG are indicated for treatment of pneumonia or invasive infections. Because chronic pulmonary disease with bronchiectasis represents a significant cause of mortality in patients with XLA, defined periods of antibiotic therapy, similar to strategies employed in patients with cystic fibrosis, may be helpful for certain patients.
Immunoglobulin Deficiency With Increased IgM
Clinical Features
About 70% of patients with immunoglobulin deficiency with increased IgM (i.e . , hyper-IgM syndrome) are male, associated with X-linked inheritance of the condition, while the remainder display an autosomal recessive inheritance pattern. Patients with this disorder develop recurrent pyogenic infections during infancy as transplacentally acquired maternal IgG wanes. Recurrent respiratory tract infections and chronic diarrhea with failure to thrive occur; patients can develop septicemia, meningitis, and other invasive infections as well. Patients who have hyper-IgM syndrome due to defects in the CD40 and NF-κB signaling pathways carry increased risk for opportunistic infections, such as Pneumocystis jiroveci pneumonia.
Other clinical manifestations can also arise. Almost two-thirds of patients with hyper-IgM syndrome have a history of neutropenia, which typically appears intermittently but without the precise periodicity of cyclic neutropenia. Patients frequently develop aphthous ulcers; perirectal ulcers and abscesses have also been reported. Lymphoid hyperplasia can develop in patients who have defects in enzymes responsible for isotype switching and somatic hypermutation. Intestinal nodular lymphoid hyperplasia may lead to malabsorption and protein-losing enteropathy. Patients also demonstrate increased risk for malignancy and autoimmune disease, including arthritis and nephritis, compared to normal children. Male patients with mutations in IKBKG may but do not necessarily have anhidrotic ectodermal dysplasia and conical teeth ( Fig. 67.5 ).
Pathogenesis
Several genetic defects have been identified as causes of hyper-IgM syndrome. Most boys with hyper-IgM syndrome have mutations in CD40LG , a gene on the X chromosome that encodes the T-cell ligand for CD40. CD40 is a signaling molecule that is expressed on the surface of B cells; several patients with hyper-IgM syndrome due to CD40 deficiency have also been reported. Engagement of CD40 by CD40 ligand is essential for B-cell proliferation, isotype switching, and terminal differentiation into antibody-secreting plasma cells. Most cases of autosomal recessive hyper-IgM syndrome occur due to mutations in the activation-induced cytidine deaminase (AICDA) and the uracil DNA glycosylase (UNG) genes. Hyper-IgM syndrome can also be caused by defects in NEMO, encoded by IKBKG on the X chromosome, and IKBα, which both play key roles in modulation of NF-κB signaling. Most mutations in IKBKG are lethal for male fetuses, and female carriers of these mutations may have incontinentia pigmenti.
Diagnosis
Various laboratory test findings can help to establish the diagnosis. Most patients with hyper-IgM syndrome have a characteristic increase in serum IgM level with low to absent concentrations of serum IgA and IgG. Serum IgM concentrations may exceed 1000 mg/dL. However, they can also exist within the normal range, especially in younger children. Patients have normal numbers of circulating IgM + B cells but few B cells that express surface IgA or IgG. Antibody responses to immunization may be present but consist predominantly or exclusively of IgM antibodies because isotype switching does not occur. Evaluation of boys with suspected hyper-IgM syndrome should include assessment of CD40 ligand expression in activated T cells by flow cytometry and genetic sequencing of CD40LG .
Treatment and Prognosis
Patients with hyper-IgM syndrome must be followed closely. All affected individuals require IgG replacement therapy. Patients with defects in the CD40 and NF-κB signaling pathways should receive antibiotic prophylaxes against a limited number of opportunistic pathogens, such as Pneumocystis or atypical mycobacteria, as well. Males with CD40LG defects have increased morbidity and mortality compared with patients with autosomal forms of hyper-IgM syndrome, likely related to the fact that CD40LG deficiency affects both T and B cells. Significant causes of long-term mortality include invasive infections, liver failure, and malignancy. Hepatic diseases include sclerosing cholangitis, cirrhosis, and hepatocellular carcinoma and are associated with Cryptosporidium parvum infection. Thus patients should be warned against trips to water parks and drinking of tap water. Human leukocyte antigen (HLA)-identical bone marrow transplantation has been successful in treating this condition and should be considered early after diagnosis before severe complications occur. Administration of recombinant CD40 ligand or agonistic anti-CD40 antibodies has also been reported to improve immune responses in these patients.
Common Variable Immunodeficiency Disease
Clinical Features
Common variable immunodeficiency disease (CVID) includes a heterogeneous group of antibody-deficient disorders with similar clinical manifestations, such as recurrent infections and a propensity for autoimmune conditions. Although the diagnosis is often given indiscriminately, CVID is strictly defined using diagnostic criteria established by the European Society for Immunodeficiencies ( Box 67.4 ). Onset can occur at any age. A study of more than 2200 European patients with CVID has demonstrated two peaks for diagnosis: during childhood and between 30 and 40 years of age.
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At least one of the following:
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Increased susceptibility to infection
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Autoimmune manifestations
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Granulomatous disease
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Unexplained polyclonal lymphoproliferation
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Affected family member with antibody deficiency
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And marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; <2 standard deviations below the normal levels for age)
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And at least one of the following:
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Poor antibody response to vaccines (and/or absent isohemagglutinins)
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Low switched-memory B cells (<70% of the age-related normal value)
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And secondary causes of hypogammaglobulinemia have been excluded
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And diagnosis is established after the fourth year of life (although symptoms may present before that age)
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And no evidence of severe T-cell deficiency, defined as two of the following:
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CD4 + cells/mm 3 : 2–6 years old, <300; 6–12 years old, <250; >12 years, <200
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Naive CD4 + %: 2–6 years old, <25; 6–16 years old, <20; >16 years, <10
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Significantly decreased T-cell proliferation to stimulation
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Ig, Immunoglobulin.
CVID typically manifests with susceptibility to infections in a similar manner to XLA and hyper-IgM syndrome. Patients develop recurrent bacterial infections of the respiratory tract or invasive bacterial infections. Bronchiectasis and chronic lung disease from recurrent pneumonias remain significant causes of long-term morbidity and mortality. The most common infectious organisms isolated from the respiratory tract include S. pneumoniae and H. influenzae . Many individuals with CVID develop chronic diarrhea and intestinal malabsorption associated with gastrointestinal infections by Giardia, Campylobacter, and Salmonella . The inflammation induced by these infections can result in protein-losing enteropathy, which may exacerbate the underlying hypogammaglobulinemia. Patients are also susceptible to infections of the genitourinary tract, joint tissues, and lungs by Ureaplasma spp.
Patients with CVID can demonstrate increased risk for noninfectious complications. They are known to have increased prevalence for ulcerative colitis, Crohn disease, other enteropathies, atrophic gastritis with achlorhydria, and cholelithiasis. Almost 30% of individuals with CVID develop autoimmunity, which includes chronic arthritis resembling rheumatoid arthritis, scleroderma, lupus-like disease, hypothyroidism, autoimmune chronic hepatitis, and autoimmune cytopenias. Abnormal lymphoid proliferation, granulomas, and malignancies, such as lymphoma and gastric carcinoma, appear over time in some patients. They can develop a pseudolymphoma syndrome in the lungs (i.e., lymphoid interstitial pneumonia) and intestines (i.e., nodular lymphoid hyperplasia), splenomegaly, or mediastinal adenopathy.
Pathogenesis
No single genetic defect has been widely identified as the cause of CVID. Instead the diagnosis of CVID encompasses a number of different genetic defects that result in loss of antibody secretion. B-cell phenotyping studies have demonstrated a variety of maturational defects in patients with CVID. Decreased or absent numbers of switched memory B cells is associated with disease severity and development of autoimmune disorders and malignancies. A variety of T-cell functional abnormalities also have been reported. They include decreased lymphocyte proliferation to mitogens and antigens and reduced expression of cytokines. Overall, polymorphisms or mutations in the TNFRSF13B, ICOS, MSH5, TNFRSF13C, CD27, CD81, CD19, MS4A1, CR2 , NFKB2, and LRBA genes have all been individually associated with disease in several families or individuals with CVID.
Diagnosis
The diagnosis should be established according to defined criteria (see Box 67.4 ). The clinical history must support a diagnosis of CVID. In terms of laboratory studies, the serum IgG and IgA levels must be less than 2 standard deviations below the normal ranges for age, and patients with CVID will typically have a serum IgG level persistently below 250 to 300 mg/dL. Patients must also demonstrate either impaired antibody responses to immunizations or low numbers of switched memory B cells; some patients will have both abnormalities. Secondary causes of hypogammaglobulinemia and severe T-cell deficiency must be excluded. The diagnosis of CVID is not generally given to patients under 4 years of age.
Treatment and Prognosis
No therapies are currently recommended for definitive treatment of CVID. Hematopoietic stem cell transplantation has been demonstrated to result in survival of less than 50%. Thus patients must be given lifelong IgG replacement therapy to minimize the frequency of infections, particularly of the lungs. Some patients require IVIG doses to maintain serum IgG trough levels of 500 to 1700 mg/dL or SCIG doses to achieve pharmacokinetically equivalent levels of steady-state serum IgG in order to accomplish this goal. Patients with CVID who have enteric protein loss due to enteropathy may require remarkable doses of IVIG or SCIG to maintain protective serum IgG concentrations. Limited antibiotic prophylaxis may be needed as an adjunctive measure in patients who continue to develop infections, especially in sites primarily protected by secretory IgA (e.g., the sinuses), despite appropriate serum IgG levels. Patients who have low serum IgM levels carry significantly increased risk for developing bronchiectasis. Overall, however, morbidity and mortality in patients with CVID are equally associated with either infectious (e.g., chronic lung disease with bronchiectasis) or noninfectious (e.g., autoimmunity, lymphoid hyperplasia) complications.
IgA Deficiency
Clinical Features
IgA deficiency is the most common PIDD. Its prevalence varies by ethnicity but ranges from one in 155 individuals to one of every 18,550. In Caucasians, it appears at a frequency of one in 300 to one in 1200 persons. The vast majority of individuals with IgA deficiency are clinically asymptomatic. Some patients develop recurrent infections of the respiratory tract, gastrointestinal tract (e.g., by Giardia ), or other tissues. IgA deficiency is associated with increased risk for autoimmunity, such as SLE, rheumatoid arthritis, pernicious anemia, autoimmune thyroid disease, type 1 diabetes, or celiac disease. Lymphoid and gastrointestinal malignancies may occur more frequently than in the general population. An association with increased atopy has been suggested but remains controversial.
Pathogenesis
The pathogenesis of IgA deficiency has not been determined. Of interest, some individuals with selective IgA deficiency subsequently develop CVID, and variations in TNFRSF13B and ICOS genes have been found in families with members that have either of these conditions. Genetic variations within the major histocompatibility complex (MHC) III region on chromosome 6 have also been associated with the development of selective IgA deficiency and CVID, further arguing that these two disorders may be related. In particular, the MSH5 gene falls within this region, and mutations in this gene have been implicated as a cause of CVID. Certain HLA haplotypes, such as 8.1, undeniably play a role, and associated candidate genes near or within the MHC class II and II regions are being investigated. Mutations in other genes outside of MHC regions have also been proposed as causes of IgA deficiency. Associated genes include IFIH1, CLEC16A, TNFAIP3, PVT1, FAS, CDH23 , and TM7SF3 .
Diagnosis
International consensus defines selective IgA deficiency as the presence of serum IgA levels of less than 7 mg/dL with normal IgG and IgM levels in individuals 4 years of age or older. Normal serum IgA concentrations can vary in children under the age of 4 and can even be undetectable in healthy infants younger than 6 to 9 months of age. In fact, more than 20% of children who meet criteria for a diagnosis of IgA deficiency between 4 and 10 years of age no longer have serum IgA levels of less than 7 mg/dL when they become adolescents, arguing that the diagnosis should be given very carefully in the pediatric population.
Treatment and Prognosis
IVIG and SCIG therapies are not indicated for the treatment of patients with selective IgA deficiency. Respiratory tract infections in individuals with selective IgA deficiency may require prolonged courses of antibiotic therapy. Antibiotic prophylaxis for respiratory tract infections should be considered if infections recur frequently. Parenteral antibiotics may be needed for refractory cases of sinusitis or pneumonia. IgA-deficient patients carry a small risk for development of IgE-mediated anaphylaxis if sensitized to IgA and given a blood product that contains IgA. The incidence of this kind of reaction is estimated to range between one in 20,000 and one in 47,000 transfusions. Broad, routine restriction of IgA-deficient patients against receiving IgA-containing blood products is not recommended.
Transient Hypogammaglobulinemia of Infancy
Clinical Features
Infants with transient hypogammaglobulinemia of infancy (THI) come to medical attention because of recurrent respiratory tract infections (e.g., otitis media, sinusitis) and serum immunoglobulin levels below laboratory normal ranges. Septicemia, meningitis, skin infections, and other invasive infections very rarely occur.
Pathogenesis
THI is caused by delayed physiologic maturation of immunoglobulin synthesis, resulting in prolongation of the relative hypogammaglobulinemia (“physiologic nadir”) observed in most normal infants at 3 to 6 months of age as maternal IgG is cleared from the circulation. No molecular etiology has been identified and confirmed. Patients with THI are able to produce protective specific antibody responses.
Diagnosis
The diagnosis can be made with certainty only in retrospect. More than 80% of children with THI recover to normal immunoglobulin levels by 3 years of age. In some children, however, serum immunoglobulin concentrations may remain low until the children are several years of age. Demonstration of normal specific antibody responses can help to support the diagnosis.
Treatment and Prognosis
Infants with suspected THI should be followed clinically, and serial measurements of serum immunoglobulin levels should be performed. Initial immunoglobulin levels may help to predict which infants will recover more quickly. Some children are eventually diagnosed with CVID, selective IgA deficiency, or another immunodeficiency disease. Because THI is self-limited and specific antibody production is normal, IgG replacement therapy is not indicated. Antibiotic prophylaxis may be considered in selected cases for recurrent respiratory tract infections.
IgG Subclass “Deficiency”
Four subclasses of IgG are known to exist. IgG1 constitutes 60% of total IgG, IgG2 accounts for 25%, and IgG3 and IgG4 are present in smaller quantities (10% and 5%, respectively). Normal ranges of serum levels for each subclass vary by age and must be considered when interpreting clinical laboratory data. The prevalence of IgG subclass deficiency has been reported at between 4.8% and 24% for different patient groups. Although various roles for each subclass have been proposed, the exact function of each subclass is not fully understood in immune processes. Thus the importance of isolated IgG subclass deficiency as a PIDD remains debatable.
In general, patients gain little benefit from measurements of IgG subclass levels and assignment of a diagnosis of IgG subclass deficiency as part of the initial evaluation for suspected PIDD. First, the clinical relevance of “low” levels of IgG2, IgG3, or IgG4 remains dubious. Individuals have been reported with complete lack of various subclasses who yet remain entirely asymptomatic. In fact, IgG subclass deficiencies may be present in 1% to 3% of healthy persons. Patients with allergic diseases in particular can have IgG subclass deficiencies yet do not merit a diagnosis of humoral immune deficiency. Thus inappropriate measurements of IgG subclass levels can lead to overdiagnosis or misdiagnosis and improper treatment. Second, the levels of IgG subclasses provide no information about humoral function. Most children with low IgG subclass levels demonstrate normal antibody responses against protein and polysaccharide antigens, indicating normal humoral immune function. The rest may have selective antibody deficiency, a separate diagnosis that remains controversial, or another PIDD. In either case, testing of responses to vaccines is required, indicating that assessments of specific antibody function and not measurements of IgG subclass levels should be performed in the initial evaluation for suspected PIDDs. Finally, some patients with IgG subclass deficiencies have other clinically relevant PIDDs (most commonly IgA deficiency) that can be identified through routine screening tests of immune function. Measurements of IgG subclass levels play no role in establishing the proper diagnosis in these patients.
Most patients with low IgG subclass levels should be managed with reassurance. Routine bacterial infections should be treated with antibiotics. Limited antibiotic prophylaxes against sinopulmonary tract infections may be offered to some patients. Immunoglobulin replacement therapy is not indicated, except perhaps in abbreviated courses for patients who have abnormally poor antibody responses to immunizations and a demonstrated propensity for frequent or chronic infections.
Selected Primary Combined Immune Deficiencies
Severe Combined Immunodeficiency Disease
Clinical Features
Most infants with SCID appear completely healthy at birth. Thus infants identified by newborn screening programs may not exhibit any clinical abnormalities other than lack of palpable lymph nodes and tonsils. In the absence of newborn screening, infants with SCID can typically be recognized during the first few months of life by the appearance of recurrent or severe infections. These infections include recurrent otitis media or pneumonia and persistent or severe viral infections caused by respiratory syncytial virus, parainfluenza virus, adenovirus, or rhinovirus. Infants with SCID may also develop a severe, disseminated infection from cytomegalovirus, especially if accompanied by very high plasma viral load and hemolytic anemia. Infections occur from attenuated virus strains in immunizations, including disseminated varicella after varicella or measles-mumps-rubella-varicella (MMRV) vaccine administration and persistent infection with vaccine strains of rotavirus, oral poliovirus, rubella, or measles virus. Infants with SCID can also develop disseminated infection with BCG after BCG immunization. Other signs of SCID include recurrent or recalcitrant oral and cutaneous candidiasis, septicemia, and other invasive bacterial infections. Patients demonstrate increased susceptibility to routine pathogens (e.g., S. pneumoniae, H. influenzae ), unusual organisms, and opportunistic pathogens, such as P. jiroveci . Other signs of SCID include chronic diarrhea and failure to thrive associated with onset of infections. In the neonatal period, a rash may appear that is produced by a graft-versus-host reaction induced by maternal T lymphocytes.
Pathogenesis
SCID represents a heterogeneous group of genetic disorders that share the ability to produce profound failure of both T and B cell function. At least 16 molecular defects have been confirmed to cause SCID ( Table 67.4 ). In the United States, the most prevalent cause of SCID is a defect in the γ chain of the IL-2 receptor, identified in 36% of patients with SCID. Because the molecule is encoded by the IL2RG gene on the X chromosome, all of these patients are male, and the defect is inherited in an X-linked recessive pattern. This protein is a functional component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 and is essential for development of human T cells and natural killer cells. All of the other known causes of SCID are inherited in an autosomal recessive pattern. IL-7 receptor α-chain deficiency produces the second most common cause of SCID in the United States and is followed in frequency by defects in recombinase activating genes 1 and 2 (RAG1 and RAG2), adenosine deaminase (ADA) deficiency, Janus kinase 3 (JAK3) deficiency, and Artemis deficiency. In more than 30% of patients, the molecular cause remains unknown.
