Immunodeficiency Paula O’Leary CP4004 Lecture Nov 2010

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

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

Immune Defense Overview

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

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

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 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 The Ten Warning Signs of Primary Immunodeficiency

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

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

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

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

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

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

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

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

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