Humoral and b-cell deficiencies Notes

Chapter 2 Acyanotic Defects NOTES HUMORAL & B-CELL DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES DIAGNOSIS ▪ Ineffective B-cell function → impaired antibody production, cellular immunity intact → recurrent, severe upper/lower respiratory tract infections, encapsulated bacteria LAB RESULTS CAUSES ▪ Clinical presentation ▪ Familial/sporadic, specific mutations SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Infections, recurrent fever, autoimmune diseases, allergic reactions, chronic diarrhea, hepatosplenomegaly, failure to thrive (FTT) ▪ Evaluate levels of immunoglobulins (Ig), specific antibodies, B-cells OTHER DIAGNOSTICS TREATMENT OTHER INTERVENTIONS ▪ Replacement of Ig OSMOSIS.ORG 195

COMMON VARIABLE IMMUNODEFICIENCY osms.it/common-variable-immunodeficiency PATHOLOGY & CAUSES ▪ Immune disorder characterized by hypogammaglobulinemia ▫ IgG,IgM, IgA; inherited/sporadic ▪ Defect in B-cell differentiation → impaired lymphocyte activation, function CAUSES ▪ Unclear ▪ Intrinsic defects in B-cells → antibody deficiency ▫ Impaired T-cell mediated activation ▫ Impaired differentiation into plasma cells → ↓ immunoglobulins ▪ Mutations in genes encoding B-cell activating factor (BAFF) cytokine receptor/ inducible costimulator (ICOS) COMPLICATIONS ▪ Autoimmune disorders ▫ Rheumatoid arthritis, autoimmune hemolytic anemia (AHA) ▪ Lymphoid malignancy, gastric cancer ▪ Bronchiectasis secondary to recurrent infections ▪ Granulomatous infiltration ▪ Poor immune response to immunizations SIGNS & SYMPTOMS ▪ Usually presents > two years old ▪ Variable presentation secondary to antibody deficiencies → recurrent infections (e.g. sinopulmonary pyogenic, meningoencephalitis) 196 OSMOSIS.ORG DIAGNOSIS LAB RESULTS ▪ Decreased serum IgG levels, marked decrease in IgM/IgA ▪ Lack of antibody immune response to protein antigens/immunization ▪ Genetic testing for mutations OTHER DIAGNOSTICS ▪ > four years old ▪ History of recurrent infections, positive family history ▪ Physical examination ▫ Peripheral lymphadenopathy ▪ Exclusion of other causes of hypogammaglobulinemia (e.g. X-linked agammaglobulinemia) TREATMENT MEDICATIONS ▪ Immunosuppressants to control autoimmune clinical features ▪ Antibiotics to treat chronic lung infections OTHER INTERVENTIONS ▪ Ig replacement therapy

Chapter 32 Humoral & B-Cell Deficiencies HYPER IGM SYNDROME osms.it/hyper-IgM-syndrome PATHOLOGY & CAUSES DIAGNOSIS ▪ Immune disorder; elevated levels of IgM; low to absent IgG, IgA, IgE ▫ X-linked/autosomal recessive ▪ Defect in B-cell antibody class switching → defective lymphocyte activation, function ▪ Predisposition to certain infections ▪ IgM antibodies can react with blood cells → autoimmune hemolytic anemia, thrombocytopenia, neutropenia ▪ In elderly, proliferation of plasma cells producing IgM can infiltrate gastrointestinal (GI) tract mucosa LAB RESULTS CAUSES MEDICATIONS ▪ Genetic defects ▫ Type 1 (most common): X-linked disease of CD40 ligand (CD40L) gene → affects T cell ability to stimulate, activate B cells ▫ Other subtypes: affect class switching, autosomal recessive diseases SIGNS & SYMPTOMS ▪ Recurrent severe pyogenic/opportunistic infections early in life ▪ Related to cause of infection ▫ Fungi: Pneumocystis jiroveci → pneumonia ▫ Protozoa: Cryptosporidium → infects biliary tract → diarrhea, malabsorption ▫ Viruses: Cytomegalovirus (CMV) → viral pneumonia/hepatitis ▫ Encapsulated bacteria: Streptococcus pneumoniae → otitis media, sinusitis, bacterial pneumonia ▪ No serum IgA, IgE, extremely low IgG ▪ Normal/elevated IgM ▪ Flow cytometry/genetic test ▫ Confirm mutation in CD40L OTHER DIAGNOSTICS ▪ History of recurrent infections, positive family history TREATMENT ▪ Prophylactic treatment with trimethoprim/ sulfamethoxazole for Pneumocystis jiroveci OTHER INTERVENTIONS ▪ Ig replacement therapy ▪ Individuals with persistent neutropenia may require granulocyte colony stimulating factor (G-CSF) ▪ Hematopoietic stem cell transplantation (HSCT) → bone marrow transplant (BMT)/ cord blood stem cell transplant OSMOSIS.ORG 197

HYPERIMMUNOGLOBULIN E SYNDROME osms.it/hyper-IgE-syndrome PATHOLOGY & CAUSES ▪ Rare immunodeficiency; recurrent skin, respiratory infections, eczema, elevated serum IgE levels ▪ AKA Job syndrome ▪ Mostly sporadic DIAGNOSIS LAB RESULTS ▪ Markedly elevated serum IgE levels OTHER DIAGNOSTICS ▪ Clinical presentation TYPES Autosomal dominant (AD-HIES) ▪ More common Autosomal recessive (AR-HIES) ▪ Increased risk of developing fatal complications, infections, malignancies, autoimmune disorders SIGNS & SYMPTOMS ▪ Primary characteristics ▫ Newborn rash/eczema, first manifestation; impetigo, boils ▫ Recurrent staphylococcal skin abscesses, without typical signs of inflammation (“cold abscesses”) ▫ Recurrent respiratory infections → formation of lung cavities, pneumatoceles ▪ Ear, sinus infections; mucocutaneous candidiasis; facial, skeletal findings (e.g. hyperextensibility of joints, retained primary teeth, due to connective tissue, skeletal abnormalities); susceptibility to malignancies (esp. lymphomas), autoimmune diseases 198 OSMOSIS.ORG TREATMENT MEDICATIONS ▪ Prophylactic administration of trimethoprim-sulfamethoxazole ▪ Limited use of steroids for eczema SURGERY ▪ Incision, drainage for skin/lung abscesses OTHER INTERVENTIONS ▪ Skin care, antisepsis (prevent infections); prompt treatment of skin, respiratory infections; control of pulmonary complications; moisturizing creams ▪ HSCT

Chapter 32 Humoral & B-Cell Deficiencies IGG SUBCLASS DEFICIENCY osms.it/IgG-subclass-deficiency PATHOLOGY & CAUSES ▪ Decrease in serum concentration of ≥ one subclasses of IgG ▫ IgG1, IgG2, IgG3, IgG4 while total IgG concentration remains unchanged ▫ IgG1 accounts for 60–70% of total IgG; IgG1 deficiency presents with low total IgG ▫ IgG2/IgG3 deficiencies most common ▫ Low IgG4 alone insufficient evidence of antibody deficiency disorder ▪ IgG subclass deficiency ▫ Integral component of other primary immunodeficiency diseases (e.g. Wiskott–Aldrich syndrome) ▪ Individuals with IgG subclass deficiency have recurrent ear/sinus/lung infections ▪ In many children, deficiency resolves with age ▪ May develop into common variable immunodeficiency (CVID) DIAGNOSIS LAB RESULTS ▪ ≥ one low IgG subclasses with normal total IgG ▪ History of recurrent sinopulmonary infections ▪ Inadequate response to vaccination TREATMENT MEDICATIONS ▪ Antibiotic prophylaxis OTHER INTERVENTIONS ▪ Treatment of conditions predisposing to recurrent infections (e.g. asthma) ▪ Immunization with conjugate vaccines ▪ Long-term Ig replacement therapy SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Recurrent ear/sinus/pulmonary infections with encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae) ▪ Increased incidence of atopic disease, chronic airway disease, autoimmune disease (e.g. vasculitis) OSMOSIS.ORG 199

ISOLATED PRIMARY IMMUNOGLOBULIN M DEFICIENCY osms.it/isolated-primary-IgM-deficiency PATHOLOGY & CAUSES ▪ Rare immune disorder; decreased IgM antibodies in bloodstream ▪ AKA selective IgM immunodeficiency (SIgMD) ▪ Unclear etiology ▫ Rapid degradation of B cells after being secreted ▫ B cells unable to mature, produce free IgM ▪ Associated with recurrent infections, allergic conditions, Bloom’s syndrome, celiac disease, systemic lupus erythematosus (SLE), malignancy COMPLICATIONS ▪ Infections may progress to meningitis, sepsis SIGNS & SYMPTOMS ▪ Start in infancy, vary widely ▫ May be asymptomatic; recurrent severe infection (e.g. sinusitis, diarrhea, skin infections); allergic reactions (e.g. atopic dermatitis) 200 OSMOSIS.ORG DIAGNOSIS LAB RESULTS ▪ Decreased levels of IgM antibodies OTHER DIAGNOSTICS ▪ History of recurrent infections TREATMENT MEDICATIONS ▪ Prophylactic antibiotics for severe recurrent infections ▪ Antibiotics to treat infections

Chapter 32 Humoral & B-Cell Deficiencies SELECTIVE IMMUNOGLOBULIN A DEFICIENCY osms.it/selective-IgA-deficiency PATHOLOGY & CAUSES ▪ Most common primary immunodeficiency; isolated deficiency of IgA in blood, secretions ▪ IgA deficiency (primarily in mucosal surface secretions) → infections, GI disorders, autoimmune diseases, allergic reactions ▪ Unknown etiology; associated with several non-causative genetic alterations RISK FACTORS ▪ Family history of IgA deficiency/CVID SIGNS & SYMPTOMS ▪ May be asymptomatic; may present significant clinical problems (less common) ▪ Susceptibility to infections (e.g. sinopulmonary, ear infections) ▪ Autoimmune diseases ▫ Rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura ▪ GI disorders (e.g. diarrhea); Giardia lamblia infections ▪ Allergic disorders (e.g. asthma) ▪ Anaphylactic reactions to blood products DIAGNOSIS LAB RESULTS ▪ Individual > four years old ▫ Undetectable levels of IgA OTHER DIAGNOSTICS ▪ Clinical presentation ▪ Exclude other causes of hypogammaglobulinemia, IgA deficiency secondary to medications TREATMENT MEDICATIONS ▪ Antibiotics to treat infections/long-term antibiotic prophylaxis to prevent them ▪ Anti-inflammatory drugs, steroids, monoclonal antibodies for autoimmune diseases ▪ Antihistamines, anti-inflammatory drugs, steroids for allergies OSMOSIS.ORG 201

TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY osms.it/infant/hypogammaglobulinemia PATHOLOGY & CAUSES ▪ Temporary decrease in circulating Ig during first months of life ▫ Maternal IgG pass fetus through placenta in sixth month of pregnancy → maternal IgG slowly diminishes, disappears six months after birth ▫ By 3–6 months of age, healthy infants begin making IgG as maternal IgG levels fall ▫ If severe/prolonged beyond six months of age → THI ▪ More common in individuals who are biologically male (2:1) ▪ Most individuals with THI have adequate antibody responses to infections/ immunizations → usually not susceptible to infections ▪ Serum Ig levels should return by age four years, may persist for few more years ▪ Severe, life-threatening infections rare SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Recurrent infections ▫ Upper respiratory, ear, sinus ▪ Atopic manifestations ▫ Asthma, eczema, food allergy ▪ GI difficulties 202 OSMOSIS.ORG DIAGNOSIS LAB RESULTS ▪ IgG level < two standard deviations below age-appropriate mean, with/without diminished levels of other serum Ig, on at least two occasions ▪ Ig must normalize during childhood/rarely during adolescence OTHER DIAGNOSTICS ▪ Diagnosis of exclusion; other permanent forms of hypogammaglobulinemia must be excluded first TREATMENT MEDICATIONS ▪ Antibiotics ▫ If persistent infections occur OTHER INTERVENTIONS ▪ Immunoglobulin replacement therapy if infections severe/persistent

Chapter 32 Humoral & B-Cell Deficiencies WISKOTT–ALDRICH SYNDROME osms.it/wiskott-aldrich_syndrome PATHOLOGY & CAUSES ▪ Rare syndrome; classic triad of microthrombocytopenia, eczema, recurrent pyogenic infections ▪ AKA eczema-thrombocytopeniaimmunodeficiency syndrome ▪ X-linked recessive inheritance pattern; can also result from spontaneous DNA mutation affecting hematopoietic cells ▪ Most commonly presents in individuals who are male, > two years old ▪ Progressive loss of T lymphocytes in peripheral blood, lymph nodes → impairment of T-cell mediated, humoral immunity CAUSES ▪ Mutation in Wiskott–Aldrich syndrome protein (WASP) gene at Xp11.23 ▫ Encodes for hematopoietic cellular proteins involved in cytoskeletal architecture COMPLICATIONS ▪ Increased risk of infections, bleeding, autoimmune disease, malignancy SIGNS & SYMPTOMS ▪ Thrombocytopenia → petechiae, bruising, epistaxis, severe bleeding ▪ Eczema, atopic symptoms ▪ Recurrent sinopulmonary/opportunistic infections caused by ▫ Encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) ▫ Fungi (e.g. Pneumocystis jirovecii, Candida albicans) ▫ Viruses (e.g. molluscum contagiosum, varicella zoster, cytomegalovirus) DIAGNOSIS LAB RESULTS Low to normal IgG, IgM High IgA, IgE Decreased number, function of T cells Peripheral blood smear ▫ Fewer, smaller platelets secondary to cytoskeletal remodeling ▪ Genomic DNA sequencing ▪ Flow-cytometry ▫ Screening test, determine presence of WASP ▪ ▪ ▪ ▪ OTHER DIAGNOSTICS ▪ History of bleeding, recurrent infections, eczema ▪ Clinical presentation, positive family history TREATMENT MEDICATIONS ▪ Prophylactic antimicrobials ▪ IVIG for recurrent infections SURGERY ▪ Splenectomy for severely low platelets OTHER INTERVENTIONS ▪ Platelet transfusions for severely low platelets ▪ Blood transfusions for severe bleeding ▪ HSCT ▫ Potentially curative OSMOSIS.ORG 203

X-LINKED AGAMMAGLOBULINEMIA osms.it/x-linked_agammaglobulinemia PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Immunodeficiency disorder; severe hypogammaglobulinemia, deficiency of all classes of antibodies → increased susceptibility to infection ▪ AKA Bruton’s disease ▪ Familial/sporadic mutation in BTK gene on X-chromosome → X-linked recessive genetic condition ▫ Manifests as disease in individuals who are biologically male ▫ Individuals who are biologically female only carriers ▪ Ineffective Bruton’s tyrosine kinase (BTK) enzyme → B-lymphocyte precursors fail to mature into B lymphocytes, plasma cells → differentiation stops at pre-B cell stage → absence of B-cells in circulation → deficiencies of all Ig → high risk of developing infections ▫ Bacterial (e.g. acute/chronic pharyngitis, sinusitis, otitis media, bronchitis, pneumonia), viral (e.g. enteroviruses, polio, coxsackievirus), protozoal intestinal parasitosis (e.g. giardia lamblia) ▪ T-cell mediated immunity remains intact; some viral, fungal, protozoal infections still cleared ▪ Newborns typically asymptomatic; after six months transplacentally-delivered Ig no longer present → prone to develop infections ▪ Infections frequently occur at mucous membranes, can also involve bloodstream, spread to internal organs, bones, joints, brain (e.g. otitis media, pharyngitis, bronchitis) ▪ Small/absent tonsils, lymph nodes DIAGNOSIS LAB RESULTS ▪ Serum Ig levels ▫ All Ig markedly reduced/absent ▪ Number of B-cells in peripheral blood ▫ Nearly absent (most characteristic finding) OTHER INTERVENTIONS ▪ Clinical presentation ▫ Any child with recurrent/severe bacterial infections ▪ Genetic testing ▫ Absence of BTK protein/presence of BTK mutation TREATMENT OTHER INTERVENTIONS ▪ Lifelong IVIG can be given to replace missing Ig ▪ Complete, prompt treatment of infections ▪ Avoid live viral vaccines (e.g. polio vaccine) 204 OSMOSIS.ORG