An overview of primary immunodeficiency diseases 2014


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  • The primary feature of immunodeficiency is recurrent infection. The clinical features of infections in patients with primary immunodeficiency disorders are not only the increased frequency of infections but poor response to appropriate antimicrobial and/or surgical drainage of infections, unexpected complications such as mastoidsitis tissue damage, e.g. bronchiectasis.
  • Some common clinical findings the physician should keep in mind when evaluating a patient with suspected immunodeficiency are listed in this slide.
  • Rather than giving and encyclopedic listing of all primary immunodeficiency states, in the slides that follow, we will describe clinical disease states in which examples of defects in the four major host defense mechanisms (specific antibody, T-cell immunity, phagocytic cells, complement) are reviewed.
  • The next five slides review the approach to diagnosis of immunodeficiency. As in most diseases, the medical history and physical exam together with laboratory testing are important in diagnosis of these immune defects.
  • The age of presentation of symptoms for immunodeficiency states can give a clue to the diagnosis. The diagnosis of antibody immunodeficiency in infants is always complicated by the presence of maternal antibody for up to the first six months of life in the developing child.
  • Particular attention should be paid to evaluation of lymph node and tonsillar tissue, growth parameters, and skin rashes. All may be abnormal due to a primary defect in immunity.
  • The tests listed in this slide can be performed or are commercially available to most all medical laboratories. All of these tests are high-yield and can serve as the basis for more detailed testing when abnormal.
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  • An overview of primary immunodeficiency diseases 2014

    1. 1. In the Name of God the Merciful the Bneficient
    2. 2. Overview of Primary Immunodeficiency Disorders(PIDs) Mostafa Moin MD Professor of Allergy & Clinical Immunology Immunology, Asthma & Research Institute IAARI Tehran Univesity of Medical Sciences 1392- 2014
    3. 3. Key Roles of Immune System Prevent and control infection Prevent and control autoimmune diseases Prevent and control malignancy Prevent and control allergic diseases Prevent and control graft-versus-host (GVH)
    4. 4. Host Immune Defense Mechanisms Non-specific -Innate Barriers – Skin – Secretions (mucous, tears, saliva) – Mucociliary clearance, peristalsis Phagocytes – Neutrophils – Macrophages Complement Cytokines Specific - Acquired  Humoral (antibodies)  Cellular (lymphocytes)
    5. 5. Innate and Acquired Immunity Innate Acquired Ag specificity no yes Magnitude (10, 20) same higher (20 > 10) Memory no yes Key components PMN, NK T, B lymphocytes C’, barriers APCs Cytokines, Chemokines, Adhesion molecules
    6. 6. Types of Immuno-deficiencies Defects in some components of the immune system - Gene defect 6
    7. 7. Clinical Features of Primary Immunodeficiency Increased frequency, severity and duration of infection Unexpected complications or unusual manifestations of infection Infection with organisms normally considered of low pathogenicity Noninfectious manifestations in gastrointestinal, endocrinologic, hematologic organ systems
    8. 8. Clinical Findings in Primary Immunodeficiency Recurrent respiratory infection Persistent sinus infection Paucity of lymphoid tissue Failure-to-thrive in infants Skin lesions (rash, pyoderma, eczema, telangiectasia) Oral and perineal candidiasis Diarrhea and malabsorption
    9. 9. Accurate diagnosis and classification of PID is necessary WHY? To decide on appropriate clinical management To enable ininformed genetic counseling To permit the systematic collection of data on PID through registries that will facilitate further study of these rare diseases To highlight the advances in gene therapy 9
    10. 10. PIDs Prevalence     Texbooks report 1 in 10000 1999 U.S. Immunodeficiency Foundation Survey found 1 in 5000 2007 telephone survey of 27000 household members found 1 in 1200 Antibody deficiencies account for approximately 65% of PID cases
    11. 11. PID Classification:2011-IUIS International Union of Immunological Societies New York City, May 31-June 1, 2011 Table 1 | Combined immunodeficiencies Table 2 | Well-defined syndromes with immunodef. Table 3 | Predominantly antibody deficiencies Table 4 | Diseases of immune dysregulation Table 5 | Congenital defects of phagocyte number, function, or both Table 6 | Defects in innate immunity Table 7 | Autoinflammatory disorders Table 8 | Complement deficiencies
    12. 12. Immunopathologic Basis of PID
    13. 13. Four Major Host Defense Deficiencies 1. B-cell (humoral) immunodeficiencies 2. T-cell or combined immunodeficiencies 3. Phagocyte disorders 4. Complement disorders
    14. 14. IgG Antibody Levels Vary with Age
    15. 15. Deficient Serum Antibody Level  Rules of thumb: -Quantitative IgG< 1000 is abnormal -Quantitative IgM< 100 is abnormal -Quantitative IgA< 10 is abnormal
    16. 16. Symptoms of antibody deficiency  Recurrent upper and lower respiratory infections  Severe bacterial infections with polysaccharide encapsulated bacteria  Paucity of lymph nodes and tonsils  Immune cytopenias  Autoimmunity - arthritis, SLE  Diarrhea and malabsorption  Malignancies
    17. 17. Antibody Deficiency Infectious Organisms Bacteria: pneumococcus, H. flu, meningococcus, Staph aureus, Pseudomonas, Campylobacter Mycoplasma, ureaplasma Viruses: enteroviruses, rotavirus Protozoa: giardia, cryptosporidium Common organisms are still the most common - but typically more severe and difficult to treat
    18. 18. Primary Antibody Disorders Agammaglobinemias (XL,AR) Common Variable Immunodeficiency IgA deficiency IgG subclass deficiency Specific antibody deficiency Transient hypogammaglobinemia of infancy
    19. 19. Antibody def.-Bruton's disease  X-linked agammaglobulinemia (XLA)  Marked reduction in all Ig classes, B cell numbers & production of specific antibodies  Normal number and function of T cells  Defect in Bruton`s tyrosine kinase gene , B cell development “frozen” at early precursor stage  Beginning after 6 months of age,recurrent sino-pulmonary Infections
    20. 20. Antibody def.-Bruton's disease Diarrhea due to giardia, Invasive infections (sepsis, meningitis) due to encapsulated bacteria (pneumococcus, meningococcus)  Skin/soft tissue infections  Generally no increased severity of viral infections, but at risk for chronic multisystem inf. due to enteroviruses (including dermatomyositis- like synd. , hepatitis,meningoencephalitis) 
    21. 21. Antibody: Common variable immunodeficiency - CVID  Onset usually in 2nd to 4th decade of life Slow decline in all classes of immunoglobulin Recurrent sinopulmonary infections (usually bacterial in origin) Gastrointestinal, endocrine, hematologic and autoimmune disorders can be associated May follow Epstein-Barr infection Increased incidence of lymphoreticular malignancies Genetic defect?
    22. 22. Antibody: IgA deficiency        IgA< 5 mg/dl Most common (1:400- 1:1000) Often asymptomatic, may have recurrent sinopulmonary infections May co-exist with IgG subclass deficiency Allergy / autoimmunity No treatment (only for infections) Genetic defect?
    23. 23. Antibody deficiencies  - -  - - Transient hypogammaglobulinemia of infancy Maturational delay with low, persistent nadir in Ig production: normal event in preterm infants Usually recurrent sinopulmonary infections Usually normal B cell number and response to immunization IgG subclass deficiency Commonly overdiagnosed but may be significant if specific antibody production also low IgG2, 4-infection with encapsulated bacteria IgG3-recurrent respiratory infections May occur in association with IgA deficiency and evolve to common variable immunodeficiency
    24. 24. Antibody: Hyper IgM Syndrome         X-linked, defect in CD40 ligand expression (CD1540) 1: 500000, 90% by age 4 yrs old Recurrent sinopulmonary and invasive infections due to encapsulated bacteria Recurrent neutropenia associated with oral ulcers and perirectal abscesses Opportunistic infections caused by Pneumocystic jiroveci, CMV, adenovirus, Cryptococcus, and mycobacteria Chronic diarrhea due to Giardia or to Cryptosporidium, Salmonella, or Entamoeba histolytica Markedly reduced IgG & IgA; high or normal IgM Normal numbers of B and T cells
    25. 25. Secondary hypogammaglobulinemia       Medications, especially anticonvulsants Protein-losing enteropathy Nephrotic syndrome Iymphoproliferative disease Non-Hodgkin`s Iymphoma Multiple myeloma
    26. 26. T cells/combined immunodeficiency CD4+ cells: – DTH – Helper function for • Cellular cytotoxicity • Ig synthesis CD8+ cells: – T-cell cytotoxicity – T suppressor cell
    27. 27. T cells/combined immunodeficiency    -  T cells required for orchestrating adaptive immunity Loss of CD4 (helper) T cells results in combined cellular and humoral immunodeficiency, even if B cells are normal Deficiency results in infections with: viruses-particularly herpes group Intracellular bacteria-e.g., Mycobacteria, Listeria Protozoans-pneumocystis, toxoplasma, cryptosporidium, giardia Antibody production to newly encountered microbes also compromised
    28. 28. Functional Classification T cells/combined Id.
    29. 29. Severe Combined Immunodeficiency(SCID)       Presentation usually< 6-12 mo age Opportunistis infections and recurrent pyogenic infections, chronic diarrhea , FTT, eczema Male: female 4:1 (most common form is X-linked) Often fatal befor 1 year of age if untreated Decreased number of T cells, variable numbers of B cells, poor proliferation to mitogens Low or absent IgG and IgA
    30. 30. Severe Combined Immunodeficiency(SCID)        Severe deficits in cellular and humoral immunity Classified by inheritance pattern and pattern of lymphocytes present X-linked: IL-2Rγ chain-more than half of all cases Same γ chain found in many interleukin receptors Autosomal recessive: RAG, ADA/PNP, JAK3, IL-7Ra, ZAP-70
    31. 31. Severe Combined Immunodeficiency(SCID)  X-linked  T- , NK, B+ phenotype  60% of SCID, gene identified in 1992  Defective gene encodes the cytokine common gamma chain  Mild lymphopenia (mean ALC 1500)  40% have a positive family history  Adenosine Dearninase (ADA) deficiency-AR  15% of all SCID  Early onset  Profound lymphopenia  Clinically heterogeneous  ADA is a widely expressed enzyme, involved in purine metabolism  Build up of toxic metabolic products toxic to T cell development
    32. 32. Severe Combined Immunodeficiency(SCID) RAG1 and RAG2 Deficiency- AR  T- , B-, NK+  10% of SCID genes identified in 1989  RAG1 and RAG2 form a heterodimer that is required to initiate VDJ recombination  Moderate lymphopenia (mean ALC 1000)  Amino acid substitutions can cause Omenn Syndrome (SCID with hyper-eosinophilia) JAK-3  T-, NK-, B+ phenotype  7% of SCID gene identified in 1994  Defective gene encodes a lyrosine kinase activated by the cytokine common gamma vhain  Mild lymphopenia (mean ALC 1500)
    33. 33. Other Forms of T cell/combined Immunodeficiency Purine nucleoside phosphorylase (PNP) deficiency –AR  Rare form of cellular deficiency associated with defective Ab production and autoimmunity  May present later in childhood  2/3 of patients develop progressive neurological manifestations Ataxia- Telangiectasia- AR  Mutation in protein required for DNA repair  Ocular telangiectasias, cerebellar ataxia  Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4 and Tcell deficits  Risk of Malignancy in patients and carriers
    34. 34. Other Forms of T cell/combined Immunodeficiency DiGeorge Syndrome  Developmental field defect of 3rd and 4th branchial arches due to chromosomal deletion (22q)  Cardiac/great vessel > parathyroid > thymic defect  Severe hypocalcemia  Charactristic facies: mandibular hypoplasia, hypertelorism  Great variability in the severity of T cell abnormality (<1% have thymic aplasia with absence of T cells)
    35. 35. Other Forms of T cell/combined Immunodeficiency  Wiskott-Aldrich Syndrome      X-linked partial combined immune deficiency Thrombocytopenia, eczema and recurrent infections Sinopulmonary, herpes group viruses and occasionally Pneumocystis Few, small platelets; elevated IgE, reduced IgM Defect in cytoskeletal organization by WaSp (wiskott Aldrich Syndrome protein)
    36. 36. X-linked lymphoproliferative disorder (XLP or Duncan Disease)      1 in 1000000 Avg age of onset: 2.5 yrs old, older reported Unique predisposition to uncontrolled infection with Epstein Barr virus EBV induces fatal/severe infectious mononucleosis Secondary agammaglobulinemia Lymphoma Bone marrow failure Defect in SAP- loss interferes with NK and CD8+ CTL function
    37. 37. Defects in Phagocytes  Defects in phagocytes generally associated with recurrent or severe/ unusual pyogenic infections  S.aureus, Serratia, Burkholderia, Nocardia, chromobacterium, fungi (esp, Aspergillus)  Tend to occur at interfaces between host and environment-skin, respiratory, Gl or GU tracts Failure to kill organism results in localized infection and abscess (CGD) Failure to mobilize WBCs to tissues (LAD,Chediak- Higashi) may result in rapid spread of infection systemically  
    38. 38. Defects in Phagocytes Chronic Granulomatous Disease (CGD) – 1: 200000 Due to genetic deficencies in NADPH oxidase for neutrophil oxidative burst required for intracellular killing X-linked most common (65-70%) also AR Mean age of presentation 0-8 yrs,older age possible Infections with catalase positive organaims (S.aureus, B.Cepacis, S.marcescens, aspergillus app.,Nocardia app)  Granulomatous inflammation-lymphadenitis,osteomyelitis, visceral abscess, pneumonia Prophylaxis with TMP-SMX,IFN-ү,Itraconazole
    39. 39. Defects in Phagocytes  Leukocyte adhesion deficiency - - Failure of neutrophil adhesion and migration to site of infection due to defect in CD18 (LAD1) Neutrophilla, recurrent life-threatening infections, little inflammation at site of inlection Delayed cord separation, severe periodontal disease  Myeloperoxidase deficiency - Failure to generale hypochlorous acid in neutrophil,AR Most common inherited neutrophil disorder Rarely develop serious infection-diabetics at risk for fungal infections - -
    40. 40. Defects in Phagocytes  Chediak-Higashi syndrome AR, results in abnormal neutrophil granule formation-abnormal chemotaxis and degranulation with delayed killing Recurrent cutaneous and respiratory infections, progresses to malignancy  IRAK4 deficiency Important signaling molecule in Toll-like receptor4 pathway in macrophages Deficiency leads to recurrent, life-threatening staphylococcal and pnemococcal infections
    41. 41. Defects in Phagocytes  Hyper-IgE syndrome (Job syndrome) - Classified as a phagocytic disorder, but most likely represents an abnormality of T cell function(dysregulated cytokine & IgE production) - Candida infections,occult infections due to pneumocystis, cryptocoocus - Recurrent pyogenic infections with massively elevated IgE levels - Recurrent sinopulmonary infections, pneumatoceles, severe atopic dermatitis - S.aureus most common pathogen
    42. 42. Defects in Complement  Defects in complement system lead to susceptibility to encapsulated organisms (S.pneumoniae, N.meningitidis) & autoimmunity (SLE)  Classical pathway: - Activated by IgE, IgM, CRP bound to a microbe  MBL pathway: - Activited by mannan binding lectin bound to a microbe  Alternative pathway: - Fluid phase activation, amplified on microbe
    43. 43. Defects in Complement Early classical complement deficiencies: May be associated with recurrent pyogenic infections and or collagen vascular disease(SLE)  Alternative pathway deficiencies: C3- collagen vascular disease and significant infections with encapsulated bacteria Properdin deficiency-X-linked, fulminanl/ fatal infections due to a N.meningitidis  MBL deficiency: Autoimmune, worse prognosis for other infections(AIDS), immunosuppressed patients, liver transplants  Terminal component deficiencies: - Associated with infections due to N.meningitidis and N.gonorrheae, chronic meningococcemla 
    44. 44. Complement- Acquired Def. Lack of synthesis: - Severe liver dysfunction  Increased consumption: - Immune complex mediated (SLE) DIC, endocarditis, disseminated gonococcal infection, hepatitis - Some glomerulonephritides- C3 nephritic factor causes C3 depletion  Loss: - Nephrotic syndrome 
    45. 45. Diagnosis of Primary Immunodeficiency Medical history Physical examination Laboratory testing
    46. 46. Primary Immunodeficiency: Infections
    47. 47. Diagnosis of Primary Immunodeficiency History of Symptoms Birth to 3 months – Phagocytic cell defects – Complement defects – DiGeorge syndrome 3 to 6 months – Severe combined immunodeficiency (SCID) 6 to 18 months – X-linked agammaglobulinemia 18 months through adulthood – Common variable immunodeficiency – Complement defects
    48. 48. Diagnosis of Primary Immunodeficiency Physical Examination Growth measurements Inspection of tonsils Palpation of lymph nodes Organomegaly Skin lesions
    49. 49. Diagnosis of Primary Immunodeficiency Screening Tests Antibody mediated immunity – Quantitative immunoglobulins – IgG subclass determination – Isohemagglutinins T-cell immunity – Total lymphocyte count – Lateral chest x-ray (infants) – Delayed hypersensitivity skin tests (individuals >2 years of age)
    50. 50. Diagnosis of Primary Immunodeficiency Screening Tests Neutrophil – White blood cell count and differential Complement – Total hemolytic complement test (CH50) – C3 and C4 concentration
    51. 51. Diagnosis of Primary Immunodeficiency Advanced Tests
    52. 52. Management of PID General treatment Replacement therapy Immune reconstruction Gene therapy
    53. 53. General Management of PID Diet Avoidance of pathogens (“germ-free” care) Antibiotics - use in acute illness - Prophylactic Avoid whole blood transfusion in combined immunodeficiency disorder (GVHR) Avoid live virus vaccines and BCG
    54. 54. Immunoglobulin replacement Treatment of severe antibody disorders IVIG 400~ 600 mg/kg/m iv drip SCIG Frozen plasma 10ml/kg/month Caution : with administration of blood products if selective IgA deficiency
    55. 55. Specific treatment for cellular deficiency Bone marrow transplantation Replacement therapy - Enzyme replacement - Gene therapy - Thymic hormones - Cytokines Fetal thymus transplantation Interferon gamma for CGD Granulocyte transfusion
    56. 56. ‫شكرم‬ THANKS