CHAPTER 14: Immunology

Warning Signs for Immune Deficiency. Consider immune deficiency when two or more of the following are present (data from Jeffrey Modell Foundation).

• Recurrent otitis (≥8 episodes), sinusitis (≥2 episodes), or pneumonia (≥2 episodes) in 1 year (from Jeffrey Modell Foundation)

• Two or more invasive infections (meningitis, sepsis, osteomyelitis, etc.)

• Recurrent deep skin or organ abscesses

• Infections with unusual or opportunistic organisms

• Failure to thrive

• Persistent thrush in mouth or elsewhere on skin after 1 year of age

• Need for intravenous antibiotics to clear common infections

• Family history of immunodeficiency

The major categories of primary immune deficiencies reflect the various arms of the immune system (Tables 14-1 and 14-2).

A defect of B cell maturation, resulting in B cell and antibody deficiencies with recurrent bacterial infections.

EPIDEMIOLOGY

• Approximately 1/100,000–200,000

ETIOLOGY

• Btk (Bruton tyrosine kinase) gene, on Xp22

PATHOPHYSIOLOGY

• Btk is required for B cell maturation after the pre-B stage. As a result, patients with XLA have arrest of B cell development in the bone marrow at the pro-B to pre-B stage. Mature B cells and plasma cells do not develop, causing a deficiency of all antibody isotypes

• Btk is also expressed in myeloid stem cells so patients may also present with neutropenia

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: Autosomal recessive agammaglobulinemia (BLNK deficiency, Igα and Igβ deficiency, μ heavy-chain deficiency, and λ5 deficiency), CVID, hyper IgM syndrome, WHIM syndrome, transient hypogammaglobulinemia of infancy, GATA2 deficiency, dyskeratosis congenita

• Immunoglobulin loss: Nephrotic syndrome, severe burns, intestinal lymphangiectasia, severe enteropathy

• Prematurity: Maternal IgG is transferred to the fetus during third trimester

CLINICAL MANIFESTATIONS

• Bacterial respiratory tract infections such as sinusitis, otitis, pneumonia, and bronchitis with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) are very common

• Patients do not have difficulty with common viral respiratory infections

  • ✓ There is, however, an increased susceptibility to enterovirus infections (e.g., poliovirus, coxsackievirus, echovirus) which can cause chronic diarrhea, meningitis, or fatal disseminated infection

• Profound neutropenia is found in 10% of XLA patients at initial presentation (usually in the setting of acute infections). The neutropenia typically resolves after the infectious episode is treated. Sepsis, especially with Pseudomonas aeruginosa and Staphylococcus aureus, can occur during episodes of neutropenia

• Absence of lymphoid tissue (tonsils, adenoids, lymph nodes) is a classic finding

DIAGNOSTICS

• Low levels of IgG, IgA, and IgM antibodies in children beyond the first 6 months of life

  • ✓ IgG subclass evaluation is not necessary

  • ✓ T cell studies are not warranted if the clinical picture is highly suggestive of immunoglobulin deficiency

• Peripheral B lymphocyte counts are typically <1%

• Neutropenia can be seen during acute infectious episodes

• Absence of detectable Btk protein (by flow cytometry or western blotting) and genetic testing confirms the diagnosis

MANAGEMENT

• IVIG replacement (400–500 mg/kg every 3–4 weeks) is the cornerstone of therapy and helps to prevent serious infectious complications. IVIG provides passive immunity to common pathogens such as tetanus, diphtheria, pneumococcus, and hepatitis B

A heterogeneous group of disorders characterized by decreased antibody production and recurrent bacterial infections. Approximately 25% of patients also suffer from autoimmune complications.

EPIDEMIOLOGY

• 1/10,000–1/100,000 children affected

• Onset can occur at any age, but there are two peaks of presentation, the first and third decades of life

ETIOLOGY

• The exact genetic cause of most CVID cases remains unknown. This is likely a heterogeneous disorder with a common clinical phenotype. In recent years, a number of monogenic causes of CVID have been identified in a minority of patients, but this disorder is likely polygenic in most patients

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: XLA and autosomal recessive agammaglobulinemia, hyper IgM syndrome, WHIM syndrome, transient hypogammaglobulinemia of infancy, combined immunodeficiencies, X-linked lymphoproliferative disease

• Immunoglobulin loss: Nephrotic syndrome, severe burns, intestinal lymphangiectasia, and severe enteropathy

• Drug-induced: Antimalarial agents, captopril, carbamazepine, glucocorticoids, rituximab, phenytoin, sulfasalazine

• Malignancy: Chronic lymphocytic leukemia, thymoma, non-Hodgkin’s lymphoma, B cell malignancy

PATHOPHYSIOLOGY

• Defects in B cell differentiation or B cell co-stimulatory signaling result in impaired immunoglobulin production

CLINICAL MANIFESTATIONS

• > 90% of patients suffer from recurrent infections of the sinopulmonary tract (sinusitis and pneumonia)

• Autoimmune diseases are common (25%) and include autoimmune hemolytic anemia and immune thrombocytopenic purpura. Autoimmune complications can precede the onset of infections

• Patients are also at greater risk for developing certain malignancies including lymphoma (incidence, 8%) and gastric carcinoma (incidence, 2%)

• Gastrointestinal diseases, including inflammatory bowel disease and malabsorption are common; chronic infectious diarrhea (often Giardia lamblia or Campylobacter jejuni) can also occur

• Non-caseating granulomas of lungs, liver, and spleen can occur

DIAGNOSTICS

• Two of three immunoglobulin isotypes (IgG, IgA, IgM) are 2 SD below age-appropriate normal levels

• Poor antibody response to vaccine antigens at least 4 weeks postvaccination

• T and B cell enumeration by flow cytometry. A CD4 lymphopenia may be present in some patients. B cell numbers are typically normal but may be low in some patients. Patients with low or absent switched memory B cells appear to be at greatest risk for bronchiectasis and autoimmune complications

MANAGEMENT

• IVIG replacement every 3–4 weeks

• Prophylactic antibiotics can be considered as adjunctive therapy in patients with recurrent infections. The type of prophylaxis should be directed at the site of infection and offending pathogens (e.g., amoxicillin 20 mg/kg/day or azithromycin 10 mg/kg/week)

• Routine screening for autoimmune and infectious complications

  • ✓ CBC to monitor for autoimmune cytopenias (e.g., ITP hemolytic anemia)

  • ✓ Other testing should be guided by clinical symptoms

  • ✓ Routine or screening imaging studies are not recommended for detection of malignancy in the absence of suggestive signs or symptoms

A prolongation of the physiologic nadir of immunoglobulin production which typically occurs between 3 and 6 months of life.

EPIDEMIOLOGY

• Approximately .061 per 1000 live births

ETIOLOGY

• A maturational delay in endogenous IgG production

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: XLA and autosomal recessive agammaglobulinemia, CVID, hyper IgM syndrome, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), combined immunodeficiencies, X-linked lymphoproliferative disease

• Immunoglobulin loss: Nephrotic syndrome, severe burns, intestinal lymphangiectasia, and severe enteropathy

• Drug-induced: Antimalarial agents, captopril, carbamazepine, glucocorticoids, rituximab, phenytoin, sulfasalazine

• Malignancy: Chronic lymphocytic leukemia, thymoma, non-Hodgkin’s lymphoma, B cell malignancy

• Prematurity: Maternal IgG is transferred to the fetus during third trimester

PATHOPHYSIOLOGY

• Transplacental transfer begins during the second trimester of pregnancy and peaks during the third trimester; IgG measured in the infant at birth is almost entirely maternal. Maternal IgG gradually declines and a physiologic nadir is reached around 6 months of age, when the infant’s endogenous IgG production begins to develop

• Transient hypogammaglobulinemia is a delay in endogenous IgG production leading to prolonged hypogammaglobulinemia

CLINICAL MANIFESTATIONS

• Low IgG levels

• Normal vaccine antigen responses

• Many patients are asymptomatic and identified incidentally, but some may present with recurrent bacterial sinopulmonary infections

• Spontaneous improvement in IgG levels usually occurs by 18 months of age, but some may not have full recovery until 5 years of age

  • ✓ 67% normalize by 24 months of age

  • ✓ 100% normalize by 5 years of age

DIAGNOSTICS

• Low IgG levels with decreased or normal IgM and IgA levels

• Normal or low normal vaccine responses (in contrast to CVID patients who have low IgG and absent vaccine response). If vaccine antibody levels are low, patients should be revaccinated and have levels rechecked 4–6 weeks later

• Absolute T, B, and NK cells are normal

• Transient hypogammaglobulinemia remains a diagnosis of exclusion and the absence of other primary immunodeficiencies (XLA, HIGM, CVID) must be documented

MANAGEMENT

• No therapy is needed if patients are asymptomatic. Immunoglobulin levels and vaccine antibody responses should be rechecked every 6–12 months until resolution of hypogammaglobulinemia can be documented

• Antibiotic prophylaxis (e.g., amoxicillin 20 mg/kg divided twice daily) can be considered for those with recurrent sinopulmonary infections

• IVIG is typically not indicated for transient hypogammaglobulinemia of infancy unless patients continue to suffer from severe infections despite antibiotic prophylaxis. IVIG therapy should be stopped within 1–2 years to assess endogenous antibody levels and vaccine responses

The most common immunodeficiency, characterized by isolated undetectable serum IgA.

EPIDEMIOLOGY

• The most common immunodeficiency, manifesting in 1/200–1/1000 among Caucasians

ETIOLOGY

• A selective deficiency in IgA production secondary to a B cell maturational defect

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: CVID, XLA, hyper IgM deficiency

• Maturational delay: Younger patients under the age of 4 years may have low IgA levels due to immaturity of the humoral immune system

PATHOPHYSIOLOGY

• The IgA is the predominant immunoglobulin found in mucosal surfaces

• IgA is normally concentrated in mucosal secretions (pulmonary secretions, saliva, tears, breast milk, GI secretions); its concentration in the serum is relatively low

• In IgA deficiency, a maturational defect in B cells leads to expression of immature IgA on the cell surface with co-expression of IgM and IgD. Development into IgA-secreting plasma cells is impaired

CLINICAL MANIFESTATIONS

• Most (85%) patients with selective IgA deficiency are asymptomatic and do not require treatment or regular follow-up

• A minority of patients, particularly those with concurrent IgG subclass deficiency, may present with sinopulmonary infections with encapsulated bacteria

• Autoimmune disorders (ITP, autoimmune hemolytic anemia, SLE, vitiligo), gastrointestinal disorders (giardiasis, inflammatory bowel disease), and atopic diseases (asthma, allergic rhinitis, atopic dermatitis, food allergy) are also increased in patients with IgA deficiency

• Very rarely, anaphylactic transfusion reactions to IgA containing blood products may occur

• Selective IgA deficiency may progress to CVID. Thus, patients who are symptomatic with sinopulmonary infections should be followed longitudinally to determine if CVID develops

DIAGNOSTICS

• Undetectable IgA levels, with normal IgG and IgM levels

• Normal antibody responses to vaccines

MANAGEMENT

• No treatment is required for asymptomatic patients who do not suffer from increased infections

• If patient suffers from recurrent infections, prophylactic antibiotics can be considered. These should be tailored to the pathogens and sites of repeated infections (e.g., amoxicillin 20 mg/kg/day, azithromycin 10 mg/kg/week)

• Patients with selective IgA deficiency are not candidates for IVIG

A heterogeneous group of disorders characterized by profound T cell dysfunction resulting in severe infections and death within the first year of life without stem cell transplantation.

EPIDEMIOLOGY

• Incidence between 1/50,000 and 1/70,000 live births

• Increased incidence in males (X-linked SCID is the most common form)

ETIOLOGY

• Although there are many different causes of SCID (more than 30 have been described to date), the unifying feature shared by all types is a complete absence of T cell development. Although some mutations allow for B cell development to occur, B cell function is invariably impaired due to the absence of T cell co-stimulatory signaling

• Classification of the different types of SCID based on the pattern of lymphocyte subpopulation depression is a useful strategy for determining the underlying genetic defect

  • ✓ T−B+NK+SCID: IL-7 receptor deficiency, CD3 deficiencies, CD45 deficiency

  • ✓ T−B+NK−SCID: IL-2 receptor gamma deficiency (X-linked SCID), ADA deficiency

  • ✓ T−B−NK+SCID: Rag1/2 deficiency, Artemis deficiency

  • ✓ T−B−NK−SCID: Adenosine deaminase (ADA) deficiency, purine nucleotide phosphorylase (PNP) deficiency, adenylate kinase 2 deficiency (reticular dysgenesis)

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: Wiskott–Aldrich syndrome, 22q deletion syndrome, MHC class I or II deficiency, cartilage hair hypoplasia

• HIV infection

PATHOPHYSIOLOGY

• The unifying feature shared by all types of SCID is a complete absence of T cell development. Some mutations allow for B cell development to occur, but B cell function is invariably impaired due to the absence of T cell co-stimulatory signaling

  • ✓ In common gamma chain receptor SCID, the gamma chain forms the functional signaling unit of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, thus affecting T and NK cell development

  • ✓ In ADA deficiency SCID, accumulation metabolites that are toxic to all types of lymphocytes results in a T−B−NK−SCID phenotype

CLINICAL MANIFESTATIONS

• SCID patients present during early infancy with pneumonia, diarrhea, otitis, sepsis, or skin infections. Recalcitrant oral candidiasis, Pneumocystis jiroveci lung infections, and severe viral respiratory infections are common

• Lymphoid tissue, including the thymus, is often decreased or absent

• Failure to thrive secondary to recurrent infections

• Patients can develop severe infections after receiving live virus vaccines (rotavirus, BCG, MMR, Varicella)

• Graft-versus-host (GVHD) reactions from engrafted maternal T cells can result in severe cutaneous, gastrointestinal, and hematologic disease. Lymphadenopathy and hepatosplenomegaly can also occur

DIAGNOSTICS

• Newborn screening for SCID is now available in a number of states and is based on measuring T cell receptor excision circles (TRECs) which are by-products of T cell development. Patients with SCID typically have undetectable TREC values

• A CBC with differential typically reveals a low absolute lymphocyte count (<3000/mm³) but a normal CBC does not exclude SCID as a possibility

• Flow cytometry to enumerate T, B, and NK cells (T cell numbers are markedly reduced. B and NK cell numbers vary depending on the type of SCID)

• Immunoglobulin levels are markedly reduced (although IgG can be normal in young infants due to maternally transferred immunoglobulin)

• T cell proliferation in response to mitogens usually reveals poor T cell function

• Thymic tissue is typically absent on chest x-ray

• HIV DNA PCR to exclude HIV infection

MANAGEMENT

• Isolation—Minimize sick contacts

  • ✓ Contact and respiratory precautions should immediately be instituted. Hospitalization is often necessary

• Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis to prevent Pneumocystis jiroveci infections

• IVIG replacement therapy (400–600 mg/kg once monthly to maintain IgG levels greater than 800 mg/dL)

• Avoid all live virus vaccinations (rotavirus, BCG, varicella, MMR)

• All blood products must be irradiated, CMV-negative, and leukocyte reduced. Patients can develop GVHD from retained leukocytes and CMV infections from blood products

• Breastfeeding should be avoided to prevent transmission of CMV

• HLA-typing for the patient and any siblings for bone marrow transplantation. There is a 95% success rate (i.e., survival >10 years) for bone marrow transplantation performed within the first 3 months of life

A genetic disorder characterized by cardiac defects, hypocalcemia, developmental delay, facial dysmorphology, and variable T cell defects.

• DiGeorge syndrome, velocardiofacial syndrome, and similar syndromes involve deletions within the 22q region, but wide heterogeneity of the phenotype results from differing amounts of chromosomal loss

EPIDEMIOLOGY

• 1/3000–1/4000 live births

• Found in 8% of children with cleft palates and 1% of children with congenital heart disease

ETIOLOGY

• The most common deletion which causes this syndrome includes a region containing more than 35 genes. TBX1 gene has emerged as one of the most likely causes of the clinical phenotype

• Chromosome 10p deletions and CHD7 mutations (CHARGE syndrome) can result in a similar clinical phenotype

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: Other T cell and combined immunodeficiencies

• Genetic syndromes: CHARGE syndrome, chromosome 10p deletions

• HIV infection

PATHOPHYSIOLOGY

• Impaired embryogenesis of the 3rd and 4th pharyngeal arches results in thymic hypoplasia (which impairs T cell development), parathyroid hypoplasia (which results in hypocalcemia), conotruncal heart defects, and facial dysmorphology

CLINICAL MANIFESTATIONS

• Low T cell numbers are present in 80% of patients with 22q11.2 deletion syndrome. The decrease in T cell numbers is typically mild to moderate but with preservation of T cell function

• A severe form of this syndrome resulting from complete thymic aplasia (resulting in near total absence of T cells) occurs in approximately 1% of patients. Patients with this condition require a thymic transplant in order to survive

• Patients typically have normal B cell numbers and immunoglobulin levels

• Tetany and seizures from hypocalcemia is present in 10–30% of neonatal patients. The hypocalcemia is self-limiting; most children do not require calcium supplementation beyond 1 year

• 80–90% of patients have congenital heart disease. Most commonly—interrupted aortic arch, right arch, ventricular septal defect, aberrant right subclavian and internal carotid arteries, tetralogy of Fallot, and truncus arteriosus

• Speech delay, nonverbal learning disorders, and mild mental retardation (40–50%)

• Paranoid schizophrenia and depression in adolescence

• Autoimmune diseases occur in 9%. Most commonly—juvenile idiopathic arthritis, immune thrombocytopenic purpura, and autoimmune hemolytic anemia

• Characteristic facial features: Low set, cupped or folded ears, small mouth, short philtrum, hypertelorism, high-arched or cleft palate, micrognathia

DIAGNOSTICS

• Patients with heart disease, characteristic facial features, and hypocalcemia should immediately be screened for a 22q11.2 deletion

• Chromosome 22q11 deletions via FISH

• Genome Wide Array—This is fast becoming the preferred method for diagnosis because it has the ability to identify atypical deletions and other chromosomal abnormalities such as 10p deletions and CHD7 deletions

• Serum calcium levels (including ionized calcium)

• Parathyroid hormone level (frequency depends on initial levels as some patients never develop hypocalcemia)

• Echocardiography, ECG, and chest x-ray to identify conotruncal or other cardiovascular abnormalities in all infants with a high degree of clinical suspicion

• Flow cytometry for T cell and B cell subsets (along with CBC)

  • ✓ Low T cell numbers may result from thymic hypoplasia

  • ✓ T cell numbers may be normal if the thymus is well-developed

• Immunoglobulin levels and antibody responses to vaccinations

  • ✓ Low IgG levels and poor specific antibody response to pneumococcal, diphtheria, and tetanus occur in 5% of patients

MANAGEMENT

• Live viral vaccines are generally given to patients who have a CD8 T cell count >300 cells/mm³ and normal specific antibody responses to non-live viral vaccine antigens

• Thymic transplant is indicated for patients with complete thymic aplasia resulting in complete absence of T cells and severe immunodeficiency

• Antibody deficiency can be present in rare patients who would therefore require IVIG therapy

• Calcium supplementation if necessary

A combined T and B cell immunodeficiency associated with thrombocytopenia (small platelets), eczema, susceptibility to opportunistic infections, and increased risk for B cell lymphoma.

EPIDEMIOLOGY

• WAS occurs in 1/250,000 live male births

• Case reports of heterozygotic females due to inactivation of the unaffected X-chromosome

ETIOLOGY

• Defect in the WAS gene (Xp11.23)

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: Severe T cell and combined immunodeficiencies (SCID)

• HIV infection

• Immune thrombocytopenia purpura (ITP); ITP typically has normal to large platelet size

• Inherited thrombocytopenias (May–Hegglin, Fechter syndrome, Bernard–Soulier, Sebastian syndrome, gray platelet syndrome, Montreal platelet syndrome); these typically have giant platelets

PATHOPHYSIOLOGY

• WASP protein functions to enhance actin polymerization and branching allowing cells to rearrange their actin cytoskeleton. Cytoskeletal rearrangement is vital for a number of key functions in immune cells such as endocytosis, exocytosis, chemotaxis, and formation of the immunologic synapse

CLINICAL MANIFESTATIONS

• 30% have classic triad of thrombocytopenia, eczema, and chronic sinopulmonary infections

• Recurrent otitis media, sinusitis, and pneumonia. Other infections include sepsis, meningitis, severe viral infections, and opportunistic infections (including Pneumocystis jiroveci)

• Infants often present with petechiae and bleeding (e.g., bloody diarrhea, epistaxis, or prolonged bleeding after circumcision), especially if platelet counts are less than 10,000/mm³

• Mild to severe eczema develops in a majority of patients with WAS. The eczema is often complicated by superinfection with bacterial and viral (e.g., HSV) pathogens

• Malignancies develop in 13% of patients and occur during adolescence or adulthood (most commonly EBV-positive B cell lymphoma and leukemia)

• Autoimmune disease (e.g., autoimmune cytopenia, vasculitis, colitis) occurs in 40% of patients

DIAGNOSTICS

• Thrombocytopenia (typically <70,000/mm³) with small platelets (mean platelet volume, 3.8–5.0 fL)

• T cell lymphopenia and reduced lymphocyte proliferation to mitogens

• Normal IgG, reduced IgM, and increased IgA and IgE levels

• Assess antibody responses to protein and polysaccharide vaccine antigens as these can be decreased

  • ✓ Diphtheria and tetanus (DTaP if age <2 years)

  • ✓ Pneumococcus (13-valent conjugate pneumococcal vaccine if age <2 years and 23-valent polysaccharide pneumococcal vaccine if age >2 years)

• Reduced WASP protein expression (by flow cytometry or western blot). Protein expression can be normal in some patients

• Genetic testing for mutations in the WAS gene can confirm the diagnosis

MANAGEMENT

• WAS patients with antibody deficiency benefit from IVIG replacement therapy (400–600 mg/kg once each month)

• Pneumocystis jiroveci prophylaxis with TMP-SMX

• While splenectomy may improve thrombocytopenia, the risk of future invasive bacterial infections increases significantly. Therefore, splenectomy is not recommended

• Patients with severe disease who have an HLA-identical donor are good candidates for bone marrow transplantation. This therapy can cure both the immunological and hematological abnormalities seen in patients. Five-year survival following fully matched transplantation is 90% (survival for haploidentical transplants is approximately 50%). Outcomes are significantly better when transplant occurs before 5 years of age

Combined T and B cell immunodeficiency with neurocutaneous findings and a predisposition for malignancy.

EPIDEMIOLOGY

• Incidence between 1/100,000 and 1/300,000, equal across races

ETIOLOGY

• Ataxia-telangiectasia mutated (ATM) protein (gene on chromosome 11q22.3)

• Autosomal recessive inheritance

PATHOPHYSIOLOGY

• ATM protein functions to detect double-stranded DNA breaks and to initiate cell cycle checkpoint arrest—This delay in cell cycle progression allows for the repair of DNA damage

DIFFERENTIAL DIAGNOSIS

• Other DNA breakage syndromes: Nijmegen breakage syndrome, Bloom syndrome

• Other T cell or combined immunodeficiencies

CLINICAL MANIFESTATIONS

• Although walking develops normally by 1 year of life, progressive ataxia develops, and patients are generally wheelchair bound after 10 years of age. Other neurologic abnormalities include oculomotor apraxia, dysarthria, and choreoathetosis

• The onset of ataxia precedes the development of cutaneous telangiectasias which are present by 3–5 years of age

  • ✓ Telangiectasias typically develop on the bulbar conjunctiva, ear pinna, and nose

• Patients suffer from recurrent sinopulmonary infections at high frequency, but opportunistic infections are rare. Aspiration pneumonia secondary to dysfunctional swallowing is common

• There is an increased risk of malignancy in patients with ataxia-telangiectasia; approximately one-third of patients develop non-Hodgkin’s lymphoma, leukemia, or solid malignancies

• Diminished large-fiber sensation

DIAGNOSTICS

• Definitive diagnosis is established by identification of mutations in the ATM gene

• Elevated serum alpha-fetoprotein (AFP) after 1 year of age; AFP can normally be elevated in infants

• Brain MRI may reveal cerebellar atrophy in older children with ataxia-telangiectasia

• B cell abnormalities include low immunoglobulin levels and low antibody responses to vaccinations

• T cell abnormalities include low T cell numbers via T cell enumeration and reduced T cell function via T cell proliferation in response to mitogens

MANAGEMENT

• IVIG supplementation for hypogammaglobulinemia (400–600 mg/kg once monthly with a goal IgG level >800 mg/dL)

• x-rays and ionizing radiation should be avoided to minimize the risk of future malignancies

A phagocyte immune deficiency resulting from impaired activation of key proteolytic enzymes in the neutrophil phagosome.

EPIDEMIOLOGY

• Prevalence varies by mutation (e.g., genes for gp91, a component of the NADPH oxidase complex, have mutations as follows: CYBB 1/250,000; CYBA 1/2,000,000)

• 65–70% X-linked inheritance; remainder autosomal recessive

ETIOLOGY

• Mutations affecting the NADPH oxidase complex

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiency: Hyper IgE syndrome, leukocyte adhesion deficiency, severe congenital neutropenia

PATHOPHYSIOLOGY

CGD is caused by defects in the NADPH oxidase system, which consists of six proteins (two membrane bound and four cytosolic). Upon cellular activation, the cytosolic components assemble with the membrane bound components to form the active complex.

Oxygen and NADPH+H are reduced by NADPH oxidase to produce NADP+ and superoxide radical. This stimulates an influx of potassium cations into the cell which then activates the release of neutrophil proteases (neutrophil elastase and cathepsin G).

CLINICAL MANIFESTATIONS

• Patients present within the first few years of life with severe deep-seated infections: Pneumonia (79%), skin or visceral abscesses (68%), lymphadenitis (53%), and osteomyelitis (25%)

• Patients are susceptible to catalase positive organisms: Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia spp., and Aspergillus fumigatus

• Inflammatory bowel disease resulting in malabsorption may occur, particularly in X-linked CGD. Obstructive GI tract and urinary tract granulomas are problematic complications

DIAGNOSTICS

• Flow cytometry for dihydrorhodamine 123 (DHR) dye conversion to rhodamine 123 is more sensitive and specific than the historically used nitroblue tetrazolium (NBT) test. It can be used to detect carrier status and can differentiate X-linked CGD from other forms in a majority of cases

MANAGEMENT

• Long-term prophylaxis with TMP-SMX and itraconazole to reduce severe bacterial and fungal infections

• Interferon-gamma prophylaxis has also been shown to reduce the frequency of infectious complications

  • ✓ Side effects such as fever and flu-like symptoms limit use of this medication

• Bone marrow transplantation (BMT) is a viable curative therapy

  • ✓ BMT should be considered as soon as possible for patients with X-linked CGD and those with autosomal recessive CGD with severe symptoms

  • ✓ CGD patients with autosomal recessive CGD with little or no reactive oxygen intermediate (ROI) production have greatly reduced long-term survival compared with patients with residual production of ROI

An autosomal recessive phagocyte immunodeficiency resulting from a defect in neutrophil migration leading to recurrent bacterial infections (neutrophil number and function are normal).

EPIDEMIOLOGY

• Extremely rare with less than 400 cases of LAD 1 reported in the United States

• LAD 2 reported primarily in Middle East

ETIOLOGY

• LAD 1: Deficiency or defect in the common beta chain of the beta 2-integrin family CD18

• LAD 2: Mutations in the gene encoding GDP-fucose transporter 1 (FUCT1)

• LAD 3: Mutations in the gene for KINDLIN3, which is a protein involved in integrin activation

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: Severe congenital neutropenia, cyclic neutropenia, CGD, hyper IgE syndrome

• Leukemoid reaction

PATHOPHYSIOLOGY

• Patients with LAD have normal absolute neutrophil counts and normal neutrophil function. However, their neutrophils are unable to adhere to the endothelium of vessels and migrate to sites of active infection or inflammation

  • ✓ LAD 1: Defective firm adhesion of neutrophils to endothelium

  • ✓ LAD 2: Defective leukocyte rolling but intact firm adhesion

  • ✓ LAD 3: Normal integrin expression and structure but impaired integrin activation (and thus binding)

CLINICAL MANIFESTATIONS

• LAD 1—This is the most common form of LAD and is characterized by markedly elevated WBC count (50,000–100,000/μL) even in the absence of infection, delayed separation of the umbilical cord with omphalitis, recurrent bacterial skin infections, impaired wound healing and pus formation, and pneumonia with staphylococcus and gram negative bacilli. Patients with severe forms of LAD 1 often die during infancy without bone marrow transplantation

• LAD 2—This is characterized by a milder phenotype than LAD 1. Patients develop mild leukocytosis (10,000–40,000/μL) and have reduced (but not absent) pus formation. Bacterial skin and lung infections are typically not life-threatening. Patients have severe mental, growth, and motor retardation as well as microcephaly

• LAD 3—The clinical phenotype is identical to patients with LAD 1

DIAGNOSTICS

• Marked leukocytosis in the absence of infection

• Decreased or absent expression of CD18 via flow cytometry in LAD 1 (normal in LAD 2 and LAD 3)

• Absence of CD15a on leukocytes on LAD 2 (flow cytometry)

• Gene sequencing—ITGB2 (LAD 1), SLC35C1 (LAD 2), or KINDLIN 3 (LAD 3)

MANAGEMENT

• LAD 1: Bone marrow transplantation should be a consideration for patients with severe forms of LAD 1. BMT has a success rate of 80% when a matched donor is available and 50% in cases of haploidentical transplants

• LAD 2: Aggressive treatment of infections and prophylactic antibiotics. Fucose supplementation as early as possible to help prevent psychomotor retardation

• LAD 3: As with LAD 1, early intervention with bone marrow transplantation is a consideration

A heterogeneous group of immunodeficiencies characterized by persistent severe neutropenia and severe recurrent bacterial infections.

EPIDEMIOLOGY

• The exact prevalence of SCN is difficult to determine but there appears to be at least 6 cases per million inhabitants

ETIOLOGY

• SCN is a genetically heterogeneous disease with autosomal dominant (ELANE and GFI-1), autosomal recessive (HAX1), and X-linked (WAS) forms of inheritance reported

  • ✓ An underlying genetic defect has not been elucidated in up to 40% of patients

DIFFERENTIAL DIAGNOSIS

• Primary immunodeficiencies: X-linked hyper IgM syndrome, XLA, WHIM syndrome, reticular dysgenesis, cyclic neutropenia, Chediak–Higashi syndrome, Shwachman–Diamond syndrome, Griscelli syndrome type 2, Hermansky–Pudlak type 2, dyskeratosis, congenital, Fanconi pancytopenia

• Metabolic diseases associated with neutropenia: Glycogen-storage disease type 1b, propionic acidemia; methylmalonic acidemia

• Infection: HIV, parvovirus, hepatitis viruses, malaria

• Immune-mediated: Autoimmune neutropenia, Felty syndrome

• Nutrition: Vitamin B₁₂, transcobalamin II, copper, or folate deficiency

• Hematologic diseases: Aplastic anemia, myelodysplastic syndromes

• Drug-induced: Chloramphenicol, penicillin, sulfonamides, aspirin, acetaminophen, phenylbutazone, barbiturates, benzodiazepines, chlorpromazine, phenothiazines, levamisole

PATHOPHYSIOLOGY

Pathophysiology varies depending on the genetic mutation causing the disease.

• ELANE (AD): ELANE (also known as ELA2) encodes for the protein neutrophil elastase (a serine protease synthesized during the early stages of primary granule production in promyelocytes). Heterozygous mutations in this gene account for 50–60% of autosomal dominant SCN cases. Mutations in ELANE are also known to cause cyclic neutropenia

• HAX1 (AR): Mutations in the HAX1 gene cause a form of autosomal recessive neutropenia. HAX1 appears to be critical for maintaining the inner mitochondrial membrane potential and protecting against neutrophil apoptosis

• WAS (XL): Missense mutations in the cdc42 binding site of the WAS gene can result in X-linked neutropenia without other clinical findings associated with WAS (eczema, thrombocytopenia, and T cell immunodeficiency)

• GFI-1 (AD): Heterozygous mutations in the growth factor-independent 1 (GFI-1) gene cause a rare autosomal dominant form of SCN. GFI-1 is a transcription factor which regulates key genes for neutrophil differentiation

CLINICAL MANIFESTATIONS

• Typically present during the first year of life with neutropenia (ANC <500/mm³) leading to recurrent, occasionally life-threatening, bacterial infections

• Staphylococcus aureus is the most common cause of infectious complications, including cellulitis, skin abscesses, omphalitis, oral ulcers, and pneumonia

• Neurologic disorders including developmental delay and epilepsy have been associated with patients with SCN due to HAX1 mutations

• Increased risk of developing myelodysplastic syndrome and acute myeloid leukemia

• Patients with cyclic neutropenia have a milder clinical course

DIAGNOSTICS

• CBC with differential 2 times per week for 6 weeks to diagnose or exclude cyclic neutropenia

• Anti-neutrophil antibody levels

• Bone marrow examination typically reveals arrest of neutrophil development at the promyelocyte stage

• Genetic testing should be performed to confirm the diagnosis of SCN

MANAGEMENT

• Recombinant G-CSF therapy is the cornerstone of therapy for patients with SCN. This therapy increases the neutrophil count and decreases the number of serious infections. Patients who require higher doses of G-CSF (>8 μg/kg/day) are at markedly increased risk for death from infections and malignancy; thus these patients are strong candidates for early bone marrow transplantation

A primary immunodeficiency characterized by invasive bacterial skin and lung infections, dermatitis, elevated IgE levels, and musculoskeletal abnormalities.

EPIDEMIOLOGY

• Incidence unknown, but rare; equal incidence in males and females, and across races

ETIOLOGY

• Autosomal dominant mutations in the STAT3 gene

DIFFERENTIAL DIAGNOSIS OF ELEVATED IgE

• Primary immunodeficiencies: Omenn syndrome (an SCID variant characterized by erythroderma, lymphadenopathy, and hepatosplenomegaly), WAS, Netherton syndrome, IPEX syndrome, DOCK8 deficiency

• Infections: HIV, malaria, parasitic infections

• Atopy, eczema, allergic bronchopulmonary aspergillosis

PATHOPHYSIOLOGY

• Mutations in STAT3 impair differentiation and function of IL-17 secreting (Th17) cells. IL-17 secreted by Th17 cells stimulate granulopoiesis through induction of G-CSF, recruit neutrophils to the site of infection through induction of IL-8, and stimulate production of antimicrobial peptides such as β-defensins

CLINICAL MANIFESTATIONS

• Eczematous rash in infancy or early childhood

• Retained primary teeth (60–70%) often requiring dental extraction

• Recurrent bacterial infections, including upper and lower respiratory tract infection (90%). Pneumatoceles following pneumonias are common. Organisms include Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and Aspergillus fumigatus

• Skin infections are common, including abscesses (hot and cold)

• Mucocutaneous fungal infections including thrush, esophageal candidiasis, and onychomycosis in 80% of patients

• Pathologic fractures following minor trauma (60–70%)

• Characteristic facial features: Coarse facies—wide nose, deep-set eyes, prominent chin and forehead. High arched palate

DIAGNOSTICS

• Elevated IgE greater than 2000 IU/mL (100%), although this can fluctuate

• Elevated eosinophil count greater than 2 SD above normal (93% of patients)

• Dental x-rays: Delayed development and retained primary teeth

• Abnormal neutrophil chemotaxis assay

• Antibody responses to pneumococcus, diphtheria, and tetanus should be assessed as some patients have impaired antibody responses to vaccine antigens

• Low Th17 cell numbers

• Genetic testing to identify mutations in the STAT3 gene can confirm the diagnosis

MANAGEMENT

• Anti-staphylococcal antibiotic prophylaxis (usually TMP-SMX at a dose of 2.5 mg/kg/day of the trimethoprim component)

• IVIG for patients with impaired antibody immunity