Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + APPROACH TO PRIMARY IMMUNODEFICIENCY Download Section PDF Listen +++ ++ 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 + MAJOR CATEGORIES Download Section PDF Listen +++ ++ The major categories of primary immune deficiencies reflect the various arms of the immune system (Tables 14-1 and 14-2). ++Table Graphic Jump LocationTABLE 14-1 Classification of Primary Immune Deficiencies View Table||Download (.pdf) TABLE 14-1 Classification of Primary Immune Deficiencies Category Select Conditions B cell disorders X-linked agammaglobulinemia (XLA) Common variable immune deficiency (CVID) Transient Hypogammaglobulinemia of Infancy (THI) IgA deficiency Combined B and T cell disorders Severe combined immune deficiency (SCID) 22q11.2 deletion syndrome Wiskott–Aldrich syndrome Ataxia-Telangiectasia Phagocyte disorders Chronic granulomatous disease (CGD) Leukocyte adhesion deficiency (LAD) Severe congenital neutropenia (SCN) Hyper IgE syndrome ++Table Graphic Jump LocationTABLE 14-2 Features and Diagnostic Approach for Primary Immune Deficiencies View Table||Download (.pdf) TABLE 14-2 Features and Diagnostic Approach for Primary Immune Deficiencies General Features Diagnostic Approach B cell (antibody/humoral) disorders Usually present after 3–6 months of age after maternal antibodies decrease; exception is common variable immunodeficiency (CVID), which can present at any age including adulthood. Predisposition for infections of the upper and lower respiratory tract with encapsulated bacteria (Streptococcus pneumoniae and Haemophilus influenzae). Mycoplasma spp. and Ureaplasma spp. infections can cause pneumonia and destructive septic arthritis. Enterovirus infections (polio, coxsackie, echo virus) can cause chronic diarrhea, meningitis, or fatal disseminated infections in patients with X-linked agammaglobulinemia. The cornerstone of therapy is immunoglobulin replacement therapy to reduce the frequency of infections. Quantitative measures: Serum immunoglobulin levels (IgG, IgA, IgM), flow cytometry B cell enumeration Functional measures: IgG responses to vaccinations—pneumococcal serotype-specific antibodies after pneumococcal conjugate (Prevnar) or polysaccharide (Pneumovax) vaccination, tetanus and diphtheria antibodies after DTaP vaccination T cell and combined (T and B cell) disorders Present at birth or in early infancy Failure to thrive, chronic diarrhea Develop prolonged and severe respiratory viral infections Predisposition for fungal infections and opportunistic infections such as Pneumocystis jiroveci (formerly Pneumocystis carinii) Association with autoimmune diseases Severe combined immune deficiency (SCID) is characterized by a complete absence of T cells and is fatal in the first year of life without bone marrow transplantation. Milder forms of T cell deficiencies include 22q11.2 deletion syndrome and ataxia-telangiectasia. Quantitative measures: Absolute lymphocyte count (ALC) on CBC with differential (80% of the ALC is comprised of T cells) Flow cytometry for T cell subset enumeration Many states now have a TREC assay newborn screen—this test result is near zero for patients with SCID Functional measures: Mitogen proliferation assay Phagocyte disorders Present in early childhood Predisposition to skin infections, pneumonia, lymphadenitis, and osteomyelitis from catalase-positive organisms Staphylococcus aureus, Burkholderia cepacia, Nocardia asteroides, Serratia marcescens, Aspergillus fumigatus Poor wound healing, delayed separation of the umbilical cord, and omphalitis Quantitative measures: Absolute neutrophil count (ANC) on CBC with differential Functional measures: Neutrophil oxidative burst (DHR assay) Complement disorders Extremely rare Early complement component defects: predisposition for bacterial respiratory tract infections and immune complex disease (systemic lupus erythematosus) Terminal complement component defects: predisposition for recurrent meningococcal disease CH50 is typically near zero for affected patients + SPECIFIC IMMUNODEFICIENCIES Download Section PDF Listen +++ + X-LINKED AGAMMAGLOBULINEMIA (XLA) Download Section PDF Listen +++ ++ 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 + COMMON VARIABLE IMMUNODEFICIENCY (CVID) Download Section PDF Listen +++ ++ 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 + TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY Download Section PDF Listen +++ ++ 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 + IgA DEFICIENCY Download Section PDF Listen +++ ++ 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 + SEVERE COMBINED IMMUNODEFICIENCY (SCID) Download Section PDF Listen +++ ++ 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 + 22q11.2 DELETION SYNDROME Download Section PDF Listen +++ ++ 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 + WISKOTT–ALDRICH SYNDROME (WAS) Download Section PDF Listen +++ ++ 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 + ATAXIA-TELANGIECTASIA Download Section PDF Listen +++ ++ 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 + CHRONIC GRANULOMATOUS DISEASE (CGD) Download Section PDF Listen +++ ++ 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 + LEUKOCYTE ADHESION DEFICIENCY (LAD) Download Section PDF Listen +++ ++ 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 + SEVERE CONGENITAL NEUTROPENIA (SCN) Download Section PDF Listen +++ ++ 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 + HYPER-IgE SYNDROME (STAT3 DEFICIENCY) Download Section PDF Listen +++ ++ 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