Approach of Primary Immune Deficiencies دکتر افشین شیرکانی فوق تخصص آسم و آلرژی و بیماری های نقص ایمنی استادیار دانشگاه عضو آکادمی آسم و آلرژی و ایمونولوژی آمریکا

Comparison of hypersensitivity reactions reactionLymphocyteEffector cells AntibodyAntigenTimeComple ment Diseases Type I BEosinophi ls and basophils IgEAllergen15-20 min-Asthma, atopic dermatitis urticaria Type II BPMNIgM, IgGSurface Ag?+Hemolytic disease of newborns Type III BPMNIgM, IgGSoluble Ag6-8 h+SLE Type IV TMacroph ages -Intracellul ar Ag h_Tuberculosis

Immunity Innate & Adaptive First line of defense Nonspecific Rapid onset No protective immunity No memory Phagocyte- mediated Activated Very specific Slower Protective immunity possible Memory possible Lymphocyte- mediated

Definition Any defect in the integrity of the immune systems – It may be congenital or late onset – It may be inherited or non hereditary – It may be in innate or adaptive parts of immune system

Components of Immunity Skin and mucosal barriers Innate immune system (nonspecific) – Phagocytic cells, NK cells, complement Adaptive immune system (specific) – T and B lymphocytes, antibodies

 Increasing susceptibility to infections  Increasing duration of infections  Increasing severity of infection  Continuous illness  Dependence to antibiotic s  Infection with opportunistic agent s  Unusual infection Characteristics of infections

Eight or more new ear infections within 1 year. Recurrent, deep skin or organ abscesses. Two or more serious sinus infections within 1 year. Persistent thrush in mouth or elsewhere on skin, after age 1. Two or more months on antibiotics with little effect. Need for intravenous antibiotics to clear infections. Two or more deep-seated infections. A family history of Primary Immunodeficiency. Two or more pneumonias within 1 year. Failure of an infant to gain weight or grow normally. The 10 Warning Signs Of Primary Immunodeficiency

Primary Immunodeficiency B cell (Antibody ) system T cell (cellular ) system Phagocyte (PMN and mononuclear ) Complement

Classification of Immunodeficiency 1.Humoral (B-cell) – quantitative or qualitative defects in antibody production account for more than 50% of defects. 2.Cellular (T-cell) – usually combined with humoral; account for 20-30%. 3.Phagocytic – defects in migration, or killing; account for ~18%. 4.Complement – account for ~2%

About %40 of cases are diagnosed in the first year  Another %40 by age 5 years  Another %15 by age 16  Only %5 in adulthood  About %10 of registered cases are adults  Late-onset Patients exhibit CVID

Common Risk Factors for Frequent Infections – Day-care, school – Second-hand smoke – Atopy – Anatomic abnormalities including ciliary defects – Retained foreign body – Gastroesophageal reflue – Cystic fibrosis

Children referred for evaluation for immuno deficiency  %50 Turn out to be normal  %30 have allergy  %10 have a serious but nonimmunologic disorder  Only %10 have an immunodeficiency

Allergic disorders in contrast to immunodeficiency  Absence fo fever  Clear nonpurulent discharge  Prior history of colic, food intolerance, ezema or other allergic symptoms  A Positive family history of allergy  A Characteristic seasonal or exposure pattern  Poor respons to antibiotic  Good respons to antihistamines or bronchodilators

Approach for Suspected Immune Deficiency are as following:

FAMILY HISTORY Consanguinity of the parents History of a sibling dying early in life of infections Family history of an X-linked or autosomal recessive inheritance of a primary immunodeficiency

GENERAL Complete blood count, including hemoglobin, differential white blood cell count(ALC, ANC) and morphology, and platelet count,ESR Radiographs to document infection in chest, sinus, mastoids, and long bones, if indicated by clinical history Cultures, if appropriate

History Our Guide Predominant B-Cell defects – Onset after maternal antibodies diminish, usually after 5-7 mos, later childhood to adulthood. – Bacteria: strep, staph, H.flu; Campylobacter, enteroviruses, giardia, cryptosporidia – Recurrent sinopulmonary infections, chronic GI symptoms, malabsorption, arthritis, viral meningoencephalitis – Autoimmunity, lymphoreticular malignancy; thymoma, lymphoma

SCREENING TESTS FOR B CELL IMMUNE FUNCTION Quantitative serum immunoglobulins Specific antibodies to vaccine responses Tetanus, diphtheria (IgG1) Pneumococcal and meningococcal polysaccharides (IgG2) Viral respiratory pathogens (IgG1 and IgG3) Other vaccines: hepatitis B, influenza, MMR, polio (killed vaccine) Isohemagglutinins (IgM antibodies to A and B blood group antigens) B cell quantitation by flow cytometry

Laboratory Evaluation Qualitative Evaluation of Antibodies – Isohemagglutins – Antibodies to ABO blood-group determinants – Antibodies to tetanus and diptheria glycoproteins and pneumococcal polysaccharides. If low titers, give booster, then repeat titers 4 weeks later.

History Our Guide Predominant T-Cell Defects – Early onset, usually 2-6 mos – Bacteria, mycobacteria, viruses: CMV, EBV, varicella; fungi, parasites, PCP, -intracellulare – FTT, diarrhea, extensive mucocutaneous candidiasis – GVHD caused by nonirradiated blood – Hypocalcemic tetany in infancy(DiGorje)

SCREENING TESTS FOR T CELL IMMUNITY Newborn screening for TREC analysis (not available in iran) Absolute lymphocyte count Chest radiograph for thymus shadow in newborns Delayed skin hypersensitivity to recall antigens Quantification of T cell subsets

History Our Guide for B and T cell defficiency ATAXIA TELLANGIECTASIA SCID WISKOTT- ALDERICHE SYNDROME

History Our Guide Granulocyte Defects – Early onset, delayed separation of cord (>8 weeks), poor wound healing(LAD) – Bacteria: staph, Pseudomonas, Serratia, Klebsiella; Fungi: Candida, Nocardia, Aspergillus(CGD) – Dermatitis, impetigo, cellulitis, abscesses, lymphadenitis, periodontitis, osteomyelits

History Our Guide Complement Defects – Late (C5-C9) – Neisserial infections: meningitidis, septic arthritis from gonorrhoeae. – Early (C1, C4, and C2) – autoimmune disease – C3 deficiency – overwhelming sepsis, especially with gram negative organisms

SCREENING TESTS FOR INNATE DEFENSE FACTORS Absolute granulocyte count, cell morphology Serum total hemolytic complement for classic pathway (CH50), alternative pathway hemolytic activity (AH50) Nitroblue tetrazolium (NBT) test or flow cytometry using dihydrorhodamine (DHR) « Staphylococcus aureus, Serratia marcescens, and Aspergillus” Flow cytometry for leukocyte adhesion molecules (CD11/CD18 and CD15a) IgE (JOB )

B Cell Immunodeficiencies B ruton Bruton’ s (X-linked) Agammaglobulinemia Autosomal Recessive Hyper-IgM Syndrome X-linked Lymphoproliferative Syndrome Transient Hypogammaglobulinemia of Infancy Common Variable Immunodeficiency (CVID) Selective IgA Deficiency IgG Subclass Deficiency

General Management of Patients with Immunodeficiency Av oid transfusions with blood products unless they are irradiated and cytomegalovirus-negative. Avoid live virus vaccines, especially in patients with severe T-cell deficiencies or agammaglobulinemia, and in household members. Use prophylaxis to Pneumocystis jiroveci (carinii) in T-cell immunodeficiency, and in X-linked hyper- IgM, consider antifungal prophylaxis in T-cell immunodeficiency. Follow pulmonary function in patients with recurrent pneumonia. Use chest physiotherapy and postural drainage in patients with recurrent pneumonia.

Consider using prophylactic antibiotics because minor infections can quickly disseminate. Examine diarrheal stools for Giardia lamblia and Clostridium difficile. Avoid unnecessary exposure to individuals with infection. Boil water for T-cell defects and hyper-IgM syndrome (Cryptosporidium risk). Use immunoglobulin for severe antibody deficiency states (400–600mg/kg q3–4 wk IV). BMT for T cell and Innate defect

 When IgG level are normal or near normal but Antibody deficiency is susceptible  IgG subclasses should be measured (IgG=70%, IgG 2 =20%, IgG3=7%, IgG4=3%)  Antibody function should be measured  In patient with selective IgA deficiency IgG subclasses should be measured  Many IgA deficiency patients have IgG2 subclass deficiency

 In older children and adults, a total Ig level above 800 mg/ dl with normal screening antibody test excludes antibody deficiency  Total Ig (IgG+IgM +IgA )< 400 or IgG level <200 mg /dl usually indicates antibody immunodeficiency