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Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 The Primary Immune Deficiencies Macrophage T cell Immunodeficiency •Mechanisms •Presentations •When to suspect •How to treat • Definition – Immunodeficiency is the result of a diverse group of abnormalities of the immune system resulting primarily in an increased incidence of infection Pneumococcus • Primary Immunodeficiency – Congenital and hereditary Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI Professor of Medicine Chief of Allergy and Immunology Editor-In-Chief, Clinical Molecular Allergy Quillen College of Medicine James H. Quillen VA Medical Center • Secondary Immunodeficiency – Acquired on a transient or permanent basis August 10 Guha Krishnaswamy, M.D. 2 Innate-Adaptive Immunity Interactions Adaptive Immunity 8/2/2010 3 4 Disorders Diagnosed In Appalachia • Humoral – CVID, subclass defects, selective polysaccharide defects, selective IgM and IgE deficiency, Mixed defects • Cellular – SCID, HIGM, Ommen syndrome, DiGeorge’s syndrome • Complement – Component (C1, C4, C8), MBL, HAE/AAE • Phagocyte – CGD, Hyper-IgE, MPO defect • Secondary – Glucocorticoids, chemotherapy/mixed, paraproteinemias, DM, hematological dyscrazias, malignancies, iatrogenic (Gold, seizure medications), nephrosis, cirrhosis, ADEH • Structural and others 5 8/2/2010 – Immotile cilia syndrome Pathogen Patterns In Immune Deficiency Pathogen Type T-cell Defect B-cell Defect Granulocyte Defect Complement Defect Bacteria Bacterial sepsis Staphyloccus, Hemophilus Streptoccus Staphylococcus Pseudomonas Neisseria Pyogenic bacteria Virus CMV, EBV, VZ CEMA --- --- Fungi Candida --- Candida, Aspergillus --- Parasite PCP PCP, Giardia --- --- Acid Fast AFB --- Nocardia --- August 10 Guha Krishnaswamy, M.D. 6 1 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 Primary Immunodeficiency Cellular 10% Combined 20% Phagocytic 18% Complement 2% Antibody 50% • • • • Primary Immunodeficiency Disorders Frequency Italy 1:77,000 Japan p 1:200,000 , Switzerland 1:54,000 Sweden 1:55,000 B-cell disorders • Selective IgA deficiency (1:333) – XLA 1:100,000 – CVID 1:75,000 T cell disorders T-cell – SCID 1:100,00 Phagocytic disorders – CGD 1:200,000 Complement disorders – very rare Guha Krishnaswamy, M.D. 7 August 10 Case 1 Guha Krishnaswamy, M.D. 8 What is the single test that is most likely to confirm the underlying diagnosis? • A 16 year old girl presents with her third episode ankle arthritis with fever. Examination reveals l a rash. h Gram G stain i of the joint aspirate is shown in the slide A. Neutrophil count B. NBT assay C. Oxidative burst of neutrophil D CH50 D. E. IgG level C1q, C1r, C1s 0% ev el 0% O xi Ig G l ur s.. . 0% C H5 0 u. .. l c o Immune complex A. Stroke B. Premature coronary artery disease C. Paroxysmal cold hemoglobinuria D. Paroxysmal nocturnal hemoglobinuria E. Gram negative sepsis N BT ph i tro N eu Defects in DAF/CD55 and HRF/CD59 lead to: 0% as sa y 0% da t iv e b August 10 7 MBL,MASP1,MASP2 C2,C4 DAF/CD55 C1 inhibitor C3 e ro k 0% 0% 0% C5-C9 Homologous Restriction factor CD59 P re m at ur e c St 0% or o. P .. ar ox ys m al co P l. . ar . ox ys m al no G c.. ra . m n eg at ive .. . 0% D,B,C3b,P 7 MAC CELL LYSIS 2 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 Complement Component Deficiency Case 2 • CTC is a 4 month old male admitted for a pneumonia • Prior hx: repaired imperforate anus, hydronephrosis • Lab reports show: • Early complement deficiency is associated with recurrent pyogenic infection and connective tissue disease (especially C2 and C4) • Complement deficiency of components 5 through 8 is associated with recurrent Neisseria species infection • Deficiency of the complement regulatory protein C1 esterase inhibitor associated with angiodema (hereditary angiodema) • Deficiency of DAF/CD55 and HRF/CD59 associated with PNH – – – – – – – – – – Blood sugar N Sodium 145 mmol/L (N) Calcium 6.1 mg/dL (9-11 N) Ionized calcium low 0.93L (N=1.12-1.32) Intact PTH 14 pg/ml (N=15-75) CD4+ T cells 688 (N=575-1070/cumm) CD8+ T cells 140 (N=190-860/cumm) WBC= 9600/cumm (N) ECHO: shows VSD, pulmonic stenosis IgG, A and M normal; poor vaccine response Typical finding in this disease is: Elevated PTH level Absence of a cleft palate Vitiligo Deletion of Tuple gene Elevated TRECs n o te d T f T 0% RE Cs u. .. go 0% ev a 7 El El ev 0% D el et io ce o f a c.. . 0% A bs en at ed P TH l. .. 0% V it i li A. B. C. D. E. CXR In DIGeorge Syndrome All the following defects are seen except: ar s pe d m ou th 0% sh ‐sh a th i Lo og na M icr 0% w se t e ow sh ad 0% a 0% Fi ce o f t h ym ic ex t ro ca rd i a 0% D C. D. E. Dextrocardia Absence of thymic shadow Micrognathia Low set ears Fish-shaped mouth A bs en A. B. 7 http://www.hawaii.edu/medicine/pe diatrics/pemxray/v2c02.html 8/2/2010 18 3 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 Fish del (22)(q11.2q11.2)(TUPLE1-) DiGeorge Anomaly Normal interphase Deleted interphase – Dysmorphic facies (micrognatia) – Hypocalcemia (lack of parathyroids) – Depressed T-cell immunity (absent thymus) – Congenital heart disease 11.2 13 22 Probes: • Defect in embryogenesis, 3rd and 4th pharyngeal pouches • Clinical features: 8/2/2010 TUPLE1 TUPLE1--22q11.2 (orange) ARSA--22q13.3(green) ARSA 19 Courtesy: Reid Myer, MAYO • Presents in first few days of life (tetany) • Diagnosed immediately by lateral chest x-ray (absence of thymic shadow) Case 3 DiGeorge Anomaly: Partial vs Complete Partial DGA • Most frequent • Thymic hypoplasia • Normal corticomedullary differentiation • Presence of Hassall Hassall’ss corpuscles • Normal thymic function • CD4 cells > 400/mm3 • T-cell function adequate • B-cell numbers and function normal • Usually free of infections Complete DGA Uncommon Thymic aplasia CD4 cells < 400/mm3 B-cell numbers normal Antibody response decreased • Susceptible to infections • Susceptible to GVHD • • • • • • Ataxia-telangiectasia (A-T) is characterized by CVID T cell dysregulation Low interferon gamma IgA g deficiency y Mannose binding lectin deficiency 0% en cy in di M an n os e b ic i de f Ig A gu ... rfe in te w Lo 0% – Progressive cerebellar ataxia • beginning between one and four years of age • – Oculomotor apraxia – Frequent infections – Choreoathetosis • – Telangiectasias of the conjunctivae – Patients with A-T are unusually sensitive to ionizing • radiation and malignancy n. .. 0% ro n. .. 0% ys re T ce ll d C VI D 0% – a staggering gait – finger-nose incoordination Ataxia Telangiectasia The typical immune defect seen in these patients is: A. B. C. D. E. • A patient who has recurrent sinopulmonary infections demonstrates this ocular finding • He also has ATM gene: 11q22.3 Karyotype: 7;14 chromosomal translocation Alpha fetoprotein elevated in >90% of patients IgA deficient 7 4 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 Case 4 The best diagnostic test is: • A 16 year old male patient presents with recurrent purulent bronchitis and failure to thrive • HRTSCT chest h demonstrates saccular bronchiectasis • Sinus CT scan and CXR are shown in next slide A. Echocardiogram and endomyocardial biopsy B. Saccharin test C. IgG level D Transbronchial D. T b hi l bi biopsy and d electron microscopy E. Nasal biopsy N as al b io ps y l ... al ev e ch i Ig G l sb ro n ra n T ... gr am cc ha rd io C D1 1/ C D1 8 fl ev ph i N eu tro 0% ow .. . 0% l o xi. .. el 0% Ig G l Sa ho ca Ec • • • • • • • • CH50 CD4 cell count IgG level Neutrophil oxidative burst CD11/CD18 flow cytometry C H5 0 C D4 ce ll c ou nt 0% 7 Labs The best diagnostic test would be: 0% 0% • AS is a 11 month old Caucasian female admitted with fever, diarrhea, bilateral pneumonitis, bilateral otitis media and pansinusitis i ii • CXR is shown in adjoining picture • Bronchoscopy was carried out and cultures grew H. influenzae • This is her third bout of bacterial pneumonia • Dyskinetic cilia syndrome is the result of an abnormality in ciliary structure which results in abnormal ciliary motion. • The ultrastructural abnormality is related to a deficiency of the dynein arms (which are normally p for ciliary y bending), g) absent or short radial responsible spokes (which prevent buckling of the cilia), and absent central microtubules. • Patients have chronic rhinitis, sinusitis, otitis, recurrent bronchial infections, bronchiectasis, male sterility, and corneal abnormalities. • Situs inversus or dextrocardia is present in 50% of cases and this is the form originally described by Kartagener. 0% 0% Case 5 Kartageners Syndrome A. B. C. D. E. 0% rin te st 0% IgE undetectable IgG <200 mg/dL (L) IgM <30 mg/dL (L) I A <12 mg/dL IgA /dL (L) Serum protein and albumin are normal CD8 1656 cells/cumm (High) CD4 3373 cells/cumm (High) CD19 797 cells/cumm (High) 7 5 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 The next most important step is: The Most Likely Diagnosis is: A. Brutons disease B. Hyper-IgM syndrome C. Common variable immune deficiency D Nephrotic D. N h i syndrome d E. None of the above 0% 0% 0% 0% 0% 0% b. .. B ro nc ho sc M op ea y su re m en t o f St ... oo l f or al ph . St .. ar t in t ra ve M n. .. ea su re Ig G ha ... e a N on e of th iab sy nd tic hr o N ep 0% ... l.. . 0% va r C om m on s d ise gM sy r‐I ru to n H yp e B 0% nd ... as ... 0% A. Bronchoscopy B. Measurement of functional antibody response C. Stool for alpha-1 p antitrypsin yp D. Start intravenous immunoglobulin right away E. Measure IgG half life to monitor catabolism 7 7 Common Variable Immunodeficiency (Late-Onset Hypogammaglobulinemia) Predominantly Antibody Deficiencies • • • • • Onset usually in 2nd or 3rd decade of life We have seen several cases of infantile CVID 90% sporadic, 10% TACI/ICOS/BTK mutations 40% have T cell defects Recurrent sinopulmonary infections (usually bacterial in origin) and sepsis • Gastrointestinal, endocrine, hematologic disorders can be associated • May follow Epstein-Barr infection , sIgA-D, Iatrogens (Gold, Dilantin sodium) • Reduction in 2 or more isotypes and normal or low numbers of B lymphocytes – CVID (Variable inheritance) – ICOS deficiency (AR) mutation in ICOS – TACI deficiency* (AD/AR): mutation in TNFRF13B – CD19 deficiency (AR): mutation in CD19 – BAFF receptor deficiency (AR): mutation in TNFRF13C • Treated with IGIV infusions (IV or SQ) * Very common 8/2/2010 Management • • • • Diagnose ID by PCR or culture not serology IGIV 400-600 mg/Kg/month Avoid live vaccines No evidence for prophylactic or rotating antibiotics • Use higher IGIV dose for bronchiectasis or suppurative lung disease 33 August 10 Guha Krishnaswamy, M.D. 34 Case 6 • PC is a 9 year old male with a prior history of recurrent pneumonitis, otitis and sinusitis • He is admitted with the following CXR findings • Examination reveals a thin,, febrile male child • Thoracenthesis shows empyema and cultures grow Pneumococcus • A maternal uncle died of hypogammaglobulinemia and a cousin carried the diagnosis of cystic fibrosis 6 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 Laboratory Results 0% to ... x. .. .. . 0% ep es sio ec ll r ce T f . .. nd e in g o 0% C D4 0 m qu en c Se Se ru 0% ex pr 0% C D4 0 IgG <200 mg/dL IgA undetectable IgM g <40 mg/dL g (N ( >50-250)) Tetanus antibody “0” H. Influenza B low (<0.1) ESR 44 mm/hour Sweat chloride normal p ro t • • • • • • • lig a A. Serum protein electrophoresis B. Sequencing of BTK gene for mutation C CD40 ligand expression by C. flow D. CD40 expression by flow E. T cell receptor rearrangement study for clonality Immune CD4 1468 cells/cumm (H) CD8 1996 cells/cumm (H) CD3 3675 cells/cumm ((H)) CD19 0 cells/cumm (L) CD16/56 566 cells/cumm (N) WBC 8200 cells/cumm ei n ... Flow cytometry • • • • • • The confirmatory test of choice is: 7 X-Linked Agammaglobulinemia Predominantly Antibody Deficiencies • Gene defect chromosome location: Xq 21.3-22; B-cell tyrosine kinase deficiency • Infections begin at 4 - 6 months of life when maternal IgG wanes • Absent circulating mature B-cells • All major classes of immunoglobulin affected (IgG, IgM, IgA) • Lack of ability to make an antibody response to antigen • Pyogenic infections: Otitis, pneumonia, sinusitis • Post-vaccinal poliomyelitis We have summarized • Neutropenia in 25% Several leaky phenotypes • Enterovirus+++ (CEMA) Guha Krishnaswamy, M.D. 40 All the following facts about this condition are true except: 0% 0% 0% ie s i ss s ec t l de f he C la T 0% n f c ho ice .. 0% ex pr w itc es A ... h de ut os fe ct om is al s m ee od n es o f i nh .. . A. It is often X-linked B. The treatment of choice is gene therapy C. The defect lies in expression of either CD40 or its ligand on lymphocytes D. Class switch defect is seen E. Autosomal modes of inheritance may also be seen nk ed • RC is a 10 month old • Laboratory male admitted with – WBC 2600 cells/cumm fever, severe peri-rectal – ANC 270 cells/cumm and pharyngeal – IgG <200 mg/dL (L) ulceration, neutropenia, – IgA <6.0 mg/dL (L) and bibasilar pneumonia – IgM 89 mg/dL (N) • He has a prior history of pneumonia, otitis media – CH50 normal and one bout of severe pharyngitis August 10 tm en t o Case 7 39 X‐ li 8/2/2010 n Thymoma with Ig deficiency fte heavy chain deficiency (5%) 5 deficiency Ig deficiency Ig deficiency BLNK deficiency (B cell linker protein) ea AR he tr Btk phosphorylates PLC2 85% familial;; 15% spontaneous p mutation T Btk deficiency (XLA) 85% It is o • Severe reduction in all isotypes and decreased or absent B cells: AGAMMAGLOBULINEMIA 7 7 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 HIGM Syndrome • X-linked CD40L deficiency • Low IgG and IgA • Normal or high IgM • Neutropenia • Autoimmunity • Opportunistic infections • Rx IGIV • BMT HIGMS: Molecular Defect • AR CD40 deficiency – Same as XL • AR AID deficiency – Adenopathy/T cell intact – Milder Mild disease di • AR UNG deficiency – Adenopathy/T cell intact – Milder disease AID=Activation induced cytosine deaminase UNG=Uracil N-glycosylase Both required for Ig CSR/somatic hypermutation 44 http://emedicine.medscape.com/article/889104-media Selective IgA Deficiency Predominantly Antibody Deficiencies • Most frequently occurring immunodeficiency • Serum IgA concentration <5 mg / dL. No other isotype immunoglobulin deficiency • 15% of cases associated with IgG subgroup deficiency g deficiencyy are • Some ppatients with IgA asymptomatic • Associated with recurrent sinopulmonary infections and autoimmune, GI tract, and endocrine disorders • Development of anti-IgA antibodies may lead to severe anaphylactic reactions with blood transfusions • Isotype or light chain deficiencies with normal B cells – IgG heavy chain mutations/deletions* (AR): absent IgG and/or IgA subclasses and IgE – Isolated IgG subclass deficiency – Selective IgA deficiency – Selective IgM deficiency – Selective IgE deficiency – Transient hypogammaglobulinemia of infancy – Specific antibody deficiency with normal Ig concentrations and normal B cells* * Relatively common 45 8/2/2010 August 10 Guha Krishnaswamy, M.D. 46 IgG Subclass Deficiency • IgG antibody can be divided into subclasses - IgG1, IgG2, IgG3, IgG4 • Deficiency in IgG subclasses has been reported in some individuals • Recurrent pyogenic infection has been associated with IgG subclass deficiency in some individuals – IgG2 and IgG4: capsulated pathogens – IgG1 and IgG3: Viral pathogens • Individuals with IgG subclass deficiency also found to be asymptomatic • Relationship of IgG2 deficiency to IgA deficiency • Clinical significance of IgG subclass deficiency is variable August 10 Guha Krishnaswamy, M.D. 47 August 10 Guha Krishnaswamy, M.D. 48 8 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 Case 8 • Baby N is a 2 day old child, sibling of a baby diagnosed with JAK3 SCID • Due to family history of SCID, we were consulted by Dr. Devoe • There is no diarrhea, pneumonia or opportunistic infection Immune Tests STAT LABS drawn CD4 20 cells/cumm CD8 275 cells/cumm WBC 22,400 cells/cumm Hgb 18 18.5 5 g/dL MPV 7.2 fl (L) IgG 780 mg/dL IgM <25 mg/dL PAN T CD3 % < 1* % (58-69) CD3 #/CUMM < 17* #/cumm (1700-3600) T HELPER CD4 % < 1* % (30-50) T HELPER CD4 #/CUMM < 17* #/cumm (1000-2800) CD8(CD3+)/CD45 % < 1* % (18-32) C 8(C 3 )/C 4 #/C CD8(CD3+)/CD45 #/CUM < 17* 1 * #/cumm #/ (800-1500) (800 1 00) CD16+56 (NK) % 13 % (8-17) CD16+56 #/CUMM 218 #/cumm (200-700) PAN B CD19 % 82* % (19-31) CD19 #/CUMM 1378 #/cumm (500-1500) T-cell Dysfunction : Clinical Characteristics The most likely diagnosis is: A. DiGeorge syndrome B. Severe combined immunodeficiency (SCID) C. Sarcoidosis D HIV D. 0% H IV Sa rc oi do s is ro m e sy nd 0% co m bi n rg e 0% Se ve re D iG eo ed im m u. .. 0% Infections with intracellular microorganisms – Viruses (HSV, V-Z, CMV, EBV) – Protozoa (Cryptosporidium, toxoplasma) – Mycobacteria – Fungal (Candida, pneumocistis carinii) – Bacteria, gram negative enteric (T-cell) – Bacteria, polysaccharide encapsulated (Bcell) 7 T-cell Dysfunction: Clinical Characteristics Severe Combined Immunodeficiency Designation • Anergy to recall antigens • Graft versus host disease • Failure to thrive (especially with diarrhea)) • Increased B-cell malignancies • Eosinophilia, thrombocytopenia • Eczema, alopecia Inh Ig Phenotype Reticular dysgenesis c chain deficiency AR XL JAK3 deficiency AR Swiss type AR IL-7R deficiency AR Adenosine deaminase deficiency ZAP 70 deficiency Omenn syndrome AR T-NKB T-NK B T-NK B T,NK B T, nlNK nl B TB AR AR NI MHC Class II deficiency AR Comments stem cell defect IL-2R, IL-4R, IL-7R, IL-9R, IL-15R Janus kinase 3 defect RAG 1/2 deficiency in some ADA in RBC CD8 nl T-NK-B RAG 1/2 defect T, IgE, eosinophilia NK B class II transactivator RF-X defects nl T-B 9 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI Severe Combined Immunodeficiencies • IVIG JAK3 deficiency • Avoidance live viral vaccines • Irradiation blood products • Prophylactic antibiotics IL--7R IL 7R deficiency Omenn The diagnosis is best established by: Fl ow cy to HIES • Three variants : • AD/Job syndrome- High IgE, poor antibody functional response, pneumatoceles, coarse facies, scoliosis, osteoporosis and mutations t ti iin STAT3 • AR-HIES: Elevated IgE, no skeletal disease, TYK2 mutation, mycobacterial and viral infection • AR-HIES: DOCK8 mutation, severe atopy, skin viral and staphylococcal infection 0% hy ... 0% 0% 0% C . . D4 . , C D8 an d N. .. 0% ns fo r A. Flow cytometry for Tolllike receptor B. IgE level C. PCR for staphylococcus aureus D. Mutations for Btk E. CD4, CD8 and NK cell counts m et ry ... • A 12 year old girl has recurrent lung infections with staphylococcus aureus and her CXR is shown. • She has had skin infections and cutaneous abscesses • Spine films show scoliosis and osteoporosis. c - chain deficiency tio Case 9 Rag 1 and 2 recombination deficiency • Enzyme replacement (PEGADA) XL SCID) • Gene therapy (ADA, XL-SCID) M ut a NK NK--cells + Rag 1 and 2 deficiency ve l B B--cells low • BMT/Stem cell transplantation Ig E le T-cells + Syndrome (clonal) NK NK--cells + ADA deficiency st ap B-cells + NK NK--cells – Reticular dysgenesis fo r T-cells – NK NK--cells + Severe Combined Immunodeficiency Treatment P CR B-cells – NK NK--cells – 08/01/2010 7 Case 10 • A patient presents with high fever, sinusitis, pneumonitis and sterile skin abscesses • He has poor healing after injury • Severe S periodontitis i d i i has h been b a problem (Figure) • The mother claims he had an infected umbilical stump for 2 months after childbirth • Infections are characterized by severe leukemoid reactions 10 Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI 08/01/2010 Leukocyte Adhesion Deficiency The diagnosis is best established by: • Absent beta subunit (CD18) of 3 cell surface glycoproteins (CD11 family) • Gene defect chromosome location: 21q22.3; gene product: CD18 • Neutrophils cannot migrate toward i fl inflammatory t stimuli ti li or adhere dh to t vascular endothelium • Diagnosis suggested by: 0% – – – – 0% ss ay ai n fo r m ye l. . . m et ry ... 0% St G 6P D a o. .. t u m fo r Fl ow cy to A ss ay 0% m et ry ... 0% Fl ow cy to A. Assay for tumor necrosis factor B. Flow cytometry for CD18 C. Flow cytometry for NFkappaB D. G6PD assay E. Stain for myeloperoxidase 7 Recurrent soft tissue infections Delayed umbilical cord separation Severe peridontal disease No pus formation despite high white blood cell counts T-B Interactions and Defects 8/2/2010 63 11