1. Immunodeficiency Paula O’Leary CP4004 Lecture Nov 2010

2. Immune Defence – the challenges Microbial Challenges –On us, in us, around us –Variable structure; activity; pathogenecity

3. Host defence – protective measures Non-Immunological –Physical –Functional –Chemical –Biological Immunological –Innate / Non-Specific recognition of non-self –Specific / Adaptive

4. Immune Defense Overview

5. Immunodeficiency / Immunocompromised States Primary –Intrinsic abnormality of one or more components of the Immune System >130 Conditions Characterised Individually, uncommon, but important to recognise Range from global, overwhelming immune failure ( SCID) to subtle defects in individual components of function Opportunistic; Disproportionately Severe; Recurring Infections; Immune dysregulation; Malignancies 1/ 10,000 live births

6. Primary Immunodeficiencies – type and causes SCID / CID – T cells (and B cells) –Il 2 common  R; ADA, AK RAG, CD40Ligand Antibody deficiencies – B cells –CVID, XLA; Hyper IgM; Specific Antibody Deficiency Immunodeficiency with Immune Dysregulation –APECED ( AIRE); IPEX; ALPS; Hyper IgE Innate Defects –Phagocyte (neutropaenia); CGD; LAD –Complement –Tlr defects –Il – 12 / IFN - gamma

7. Likely Deficiency B cells – pyogenic infections; resp tract; any age T cells – broad ranging; opportunistic; disseminated; early onset Neutrophils – skin; mucosae; bacterial and fungal; deep-seated abcesses Complement – Neisseria; pyogenic Cytokine defects – TB; disseminated intracellular bacteria

8. 8 or more ear infections within 1 year 2 or more serious sinus infections within 1 year 2 or more months on antibiotics without resolution 2 or more pneumonias within 1 year Failure to gain weight or grow normally Persistent candidiasis after the age of 1 year Need for I.V. antibiotic to clear infections 2 or more deep-seated infections A family history of Primary Immunodeficiency Recurrent, deep skin or organ abscesses 1 2 3 4 5 6 7 8 9 10 The Ten Warning Signs of Primary Immunodeficiency

9. Likely Deficiency and Investigation B cells – Igs, Electrophoresis, (BJP), IgG subclasses, Specific Antibodies; Immunisation challenges; Specialised studies T cells – total lymphocyte numbers, phenotyping; genetics; functional analysis Neutrophils – numbers; function assays Complement – CH50; individual components Cytokine defects – specialised studies - refer

10. PID - treatments Immunoglobulin replacement Bone Marrow Transplantation Gene-based therapies Antimicrobial management and prophylaxis Nutritional Support Patient Support Groups

11. Immunodeficiency / Immunocompromised States Secondary –Dysfunction of one or more components of the Immune System arising as a result of another process –Much more common; accumulation of defects leading to clinical immunocompromise –More difficult to measure in the laboratory

12. Infections HIV Pneumocystis jiroveci infection Mycobacterial Infections Toxoplasmosis CMV infection CNS lymphoma Kaposi Sarcoma Tissue Infection – GI; CNS

13. Haematological Malignancies Lymphoid –Multiple Myeloma –Chronic Lymhocytic Leukaemia –Lymphoma –Treatments for these disorders

14. Medical Treatments Corticosteroid therapy –Widely used in the management of inflammatory and autoimmune diseases; transplant patients Monocyte; Lymphocyte Inhibition and Prostaglandin Inhibition Infection more widespread and less clearcut in presentation

15. Medical Management cont./ “Crude” Immunosuppressants – AZA; MTX; 6-MP; Cyclophosphamide; Radiotherapy –Bone Marrow Suppression –Neutropaenia; Lymphopaenia –Careful dose calculation and patient monitoring Targeted cell Immunosuppressants – Cyclosporin, Tacrolimus –Opportunistic Infections; Malignancies Targetted Biologicals – Rituximab; Infliximab; CAMPath- 1H; Netalizumab –Risks specific to interrupted immune component

16. Medical States Splenectomy –OPSI; Malaria; Salmonellosis –Immunisation; Antibiotic Prophylaxis Poor Nutrition; Surgery / Trauma / ICU –Recognition and Correction Protein Losing States Renal Disease Extremes of Age

17. Care of Immunocompromised Patients Vigilance and Monitoring Prophylaxis –Pneumocystis prophylaxis; Immunisation Limitation of Immune-suppressing Agent Patient Education Medical Carer Education