When (and How) Should I Evaluate My Patient for Immunodeficiency? Workshop Update in Infectious Diseases April 27, 2012 Antoine E. Azar, M.D. Division of Immunology University of Iowa Hospitals and Clinics Take Home Points! Primary Immunodeficiency (PID): Is not rare May present at any age Does not always present with severe infections Early diagnosis and treatment are essential in order to avoid significant morbidity and mortality Outline 1. Outline of the Immune System 2. Overview of Primary Immunodeficiency 3. When to Evaluate for Immunodeficiency 4. How to Evaluate for Immunodeficiency Outline 1. Outline of the Immune System 2. Overview of Primary Immunodeficiency 3. When to Evaluate for Immunodeficiency 4. How to Evaluate for Immunodeficiency The Players in the Immune system Innate Immunity Adaptive Immunity Innate Immunity Epithelial Barriers Phagocytic cells Mononuclear phagocytes Neutrophils Natural Killer (NK) cells Complement Cell Receptors e.g. Toll-like receptors Receptors of Innate Immunity Toll Like receptors “Pattern recognition receptors” (PRRs) recognize components specific to certain microbes Toll-like receptors (TLRs) are transmembrane PRRs found on and within cells of the innate immune system Adaptive Immunity B lymphocytes Antibodies Humoral Helper CD4+ Regulatory T reg T lymphocytes Cellular Th1,Th2,Th17 CD8+ Cytotoxic IgM IgD Class Switching Naive B IgA IgE IgG Plasma Cells IgM IgG IgA IgE Helper T cells: TH1 vs TH2 e.g. Mycobacterium leprae Tuberculoid leprosy Granulomas Lepromatous TH2 leprosy Destructive lesions TH1 CD4 Specificity Memory Outline 1. Outline of the Immune System 2. Overview of Primary Immunodeficiency 3. When to Evaluate for Immunodeficiency 4. How to Evaluate for Immunodeficiency Tolerate “Self” Eliminate “Non-Self” Manifestations of Immunodeficiency Primary Immunodeficiency (PID) Genetically heterogeneous group of disorders Affect distinct components of the immune system (innate, adaptive) > 120 responsible genes identified > 150 different forms of PID identified Primary Immunodeficiency (PID) Prevalence ~ 1:1200 in US Boyle JM, Buckley RH. RH J Clin Immunol. 2007;27(5):497 Selective IgA Deficiency ~ 1:500 Most common PID Modell V. et al. Immunol Res (2011) 51:61–70 Modell V. et al. Immunol Res (2011) 51:61–70 Age at Diagnosis with PID 50% Immune Deficiency Foundation (IDF) survey 2003, N = 1499 Current Age of Patients with PID 60% Times Hospitalized Before Diagnosis IDF survey 2003, N = 1526 Cost Savings After PID diagnosis Modell V. et al. Immunol Res (2011) 51:61–70 Outline 1. Outline of the Immune System 2. Overview of Primary Immunodeficiency 3. When to Evaluate for Immunodeficiency 4. How to Evaluate for Immunodeficiency Recurrent infections… “Host” vs. Anatomical abnormalities 2ry Immunodeficiency 1ry Immunodeficiency “Hostility” Increased exposure “Aggressive” organisms Host factors Anatomical abnormality; e.g.: Pneumonia: bronchial obstruction; aspiration; Cystic fibrosis UTI: urinary tract obstruction; stones/tumors; reflux; neurogenic bladder Cellulitis: lymphedema, venous insufficiency; scarring from prior cellulitis Immune deficiency Secondary Primary When to Suspect an Immunodeficiency? History Family History Physical Exam History of Present Illness Infection history Site, frequency, complications Hospitalization, ICU stay Treatment IV antibiotics? Multiple antibiotics? More than one course of antibiotics? Non-Infectious clues Premature loss of dentition Recurrent aphthous ulcers Poor/delayed wound healing Multiple autoimmune disorders Extensive skin warts Chronic diarrhea Bronchiectasis Family History Immunodeficiency Early deaths Recurrent infections Children’s health during the first 6 months Consanguinity Autoimmune disorders Rheumatoid arthritis, SLE, pernicious anemia, ITP, thyroid disease, … Physical Exam HEENT Aphthous ulcers, thrush Tympanic membrane scarring/perforation Lungs: Crackles, rhonchi Abdomen: Hepatosplenomegaly Lymphadenopathy Skin Warts; abscesses; onychomycosis Scars: nature and extent Joint deformities How many infections are too many? 1. More than 3 episodes of bacterial sinusitis in one year, or chronic sinusitis 2. Pneumonia twice over any time period 3. More than 4 ear infections in one year after age 4 4. More than 2 courses of antibiotics per year (adults); more than 4 per year (children) 5. Any unusually severe infection 6. Infections caused by organisms that do not usually cause problems in most people at the patient's age AAAAI, April 2007 “6 Warning Signs for PID in Adults” 1. Four or more infections requiring antibiotics within one year (otitis, bronchitis, sinusitis, pneumonia) 2. Recurring infections or infection requiring prolonged antibiotic therapy 3. Two or more severe bacterial infections (osteomyelitis, meningitis, septicemia, cellulitis) 4. Two or more radiologically proven pneumonia within 3 years 5. Infection with unusual localization or unusual pathogen 6. PID in the family European Society for Immunodeficiencies (ESID) When to Suspect an Immunodeficiency? frequency severity Infections with UNUSUAL: duration complications organisms Non-infectious clues Autoimmunity Poor wound healing Premature loss of dentition Unexplained bronchiectasis Chronic diarrhea or malabsorption “Failure to thrive” Outline 1. Outline of the Immune System 2. Overview of Primary Immunodeficiency 3. When to Evaluate for Immunodeficiency 4. How to Evaluate for Immunodeficiency Document all infections Etiologic organisms (microbiology) Will guide the workup Imaging (sinusitis, bronchiectasis) Treatment Complications Secondary Immunodeficiency Malnutrition HIV Malignancy Splenectomy Vitamin and mineral deficiencies Immunosuppressive drugs Immunomodulatory agents Rituximab, infliximab, etanercept, adalimumab, anakinra Secondary Immunodeficiency (cont’d) Drug-induced hypogammaglobulinemia Protein loss Nephrotic syndrome, protein-losing enteropathy, severe burns Metabolic disease Anti-epileptics (e.g. diphenylhydantoin, carbamazepine, valproate) Diabetes mellitus, severe liver disease, uremia Impaired barriers Cystic fibrosis, immotile cilia syndromes, severe burns Lab Screening for 2ry immunodeficiency CBC with differential and smear Creatinine, liver function tests, blood glucose Total serum protein, albumin Urinalysis HIV (ELISA or PCR) Lab evaluation of PID Microbiology and clinical picture guide the workup Azar A, Ballas Z. Am J Med 2007; 120(9):764-8 Humoral Immunity (B cells) Infections Complications Upper and lower respiratory tract - Bacterial Gastroenteric – Giardia, Campylobacter Bronchiectasis Granulomatous disease (lungs, skin, liver, spleen, GI) Autoimmune disorders (ITP, hemolytic anemia) Inflammatory bowel disease (Crohn’s, ulcerative colitis) Malignancy (lymphoma, GI tract) False negative serologic tests (HAV, HBV, HCV, HIV…) Humoral Immunity (B cells) X-linked Agammaglobulinemia (XLA) Common Variable Immunodeficiency (CVID) ↓ IgG ↓ IgA and/or IgM Selective IgA deficiency (incidence ~ 1:500) No B cells, no Immunoglobulins Undetectable IgA Normal IgG, IgM Functional Antibody Deficiency Normal Immunoglobulins Abnormal antibody response to vaccines Evaluation of Humoral Immunity Quantity IgG, IgA, IgM B cell numbers (Flow cytometry) CD19, CD20 * Immunoelectrophoresis is semiquantitative and should not be used to evaluate antibody deficiency Evaluation of Humoral Immunity (2) Function Response to immunization Polysaccharide: 23-valent Pneumococcal vaccine 4-fold ↑ in titers to > 70% of serotypes Polypeptide: Tetanus/Diphtheria vaccine IgG Isohemagglutinins = naturally occurring Ig to ABO blood group antigens 70% of infants by age 1 have positive isohemagglutinin titers IgG IgA IgM Differential Diagnosis ↓ N • Selective IgA deficiency (IgA undetectable) • Anti-epileptics N • Protein loss (nephrotic syndrome, proteinlosing enteropathy) • Antibody deficiency with low IgG N ↓ ↓ ↓ N-↑ N ↓-N ↓-N ↓ ↓ N-↑ ↓ • Common variable immunodeficiency (CVID) • Monoclonal gammopathy - Waldenstrom, MGUS, multiple myeloma • Hyper-IgM syndrome • Monoclonal IgG production • CVID on IG replacement therapy Azar A, Ballas Z. Am J Med 2007; 120(9):764-8 Cellular Immunity (T cells) Opportunistic infections Viruses Fungi Mycobacteria Usually severe, early in life Cellular Immunity (T cells) Quantity T cell numbers (Flow cytometry) CD3, CD4, CD8 Function Delayed-Type Hypersensitivity skin testing Tetanus, Candida, PPD ≥ 5 mm In vitro lymphocyte function Proliferation: Mitogens, alloantigen, recall antigens Differentiation: Interleukin-2 secretion Natural Killer cells Quantity NK cell numbers (Flow cytometry) CD3, CD16, CD56 Function Cytotoxic assays in vitro Phagocytes Bacterial/ fungal infections Skin Periodontal tissue Lymph nodes Lung Liver Bone Phagocytes Quantity CBC/Differential Multiple time points Function Superoxide generation Dihydrorhodamine assay (DHR) Chemotaxis (neutrophil movement) Complement C1 C4 Classical pathway C2 C3 Alternative pathway C5 C 5,6,7,8,9 MAC (Membrane attack complex) Complement Total hemolytic complement assay Alternative hemolytic complement assay CH50 AH50 Individual complement components