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Diagnosis of Primary Immunodeficiency Eli Eisenstein, M.D. Dept of Pediatrics Ways to Diagnose a Disease • Sample the universe • Pattern recognition • Systematic approach Molecular Medicine, http://www.mm.interhealth.info •Cerebellar ataxia •Recurrent lung infections •IgG2, IgA, IgE deficiency Lavin, Nat Rev Mol Cell Biol 2008 •Abnormal facies •Congenital heart disease •Hypocalcemia •Lymphocytopenia A greatly over-simplified approach to primary immunodeficieny • Humoral • Cellular • Phagocytic • Complement Case 1 • • • • 11 month old infant Recurrent fevers – at least six episodes One episode of gastroenteritis, lasting six days Two episodes of otitis media Relevant history • • • • • • • • Growth Development Type of infections, and how documented Duration Response to therapy Other illnesses Family history- consanguinity ? Exposure • PID ??? Case 2 • Three year old boy • Recurrent lobar pneumonia beginning at six months of age • One episode of sepsis caused by Strep. pneumoniae Relevant history • • • • • • • • Growth Development Type of infections, and how documented Duration Response to therapy Other illnesses Family history Exposure • PID ??? • Humoral • Cellular • Phagocytic • Complement Hallmarks of Humoral Immune Deficiency • Respiratory tract infections: Pneumonia, otitis media, sinusitis • Encapsulated microorganisms: Pneumococcus, H. influenzae, Staph aureus • Chronic diarrhea, other infections, various complications depending on molecular variant • Begin after 6 months of age • Opportunistic infections uncommon Three Criteria for Diagnosis of Humoral Immune Deficiency • Characteristic recurrent infections • Low serum concentration of IgG (be sure to check age-appropriate norms) • Response to immunizations Type: JPG Cunningham-Rundles C et al 2005 Clinical question • What physical finding helps distinguish between B cell positive and B cell negative forms of hypogammaglobulinemia ? Case 3 • Eight year old boy • Second episode of meningitis caused by Neisseria meningitides • PID ??? • • Cellular • Phagocytic • Complement Complement Pathway Holers in: R Rich et al (eds) Clinical Immunology, 1986, p365 Abbas et al, Cellular and Molecular Immunology, 6E Tests for Complement Deficiency • Functional tests (e.g., CH50) • Measure individual complement components Case 4 • • • • • On month old boy Failure thrive Persistent diarrhea Pneumonia – Pneumocystic jirovecii Sibling died at three months of age of presumed SIDS • • Cellular • Phagocytic Fischer A, Nat Rev Immunol 2:615, 2002 Evaluation of cellular immunity • • • • • Total lymphocyte count (CBC) Presence of thymus Delayed hypersensitivty Flow cytometry Lymphocyte responses to mitogens Always order a complete blood count with lymphocyte subset analysis. http://crl.berkeley.edu/flow_cytometry_basic.html Molecular screening for SCID • • Phagocytic Three categories of phagocytic cell defects • No cells • Cells don’t know where to go • Cells don’t know what to do when they get there No cells • Several genetic forms including cyclic • Diagnosis: complete blood count, peripheral blood smear, bone marrow examination • Bacteremia • No Pus !! • GCSF • BMT Cells don’t know where to go: Leukocyte adhesion deficiency LAD-1 Clinical features • Delayed umbilical cord separation • Marked granulocytosis in peripheral blood Incompetent granulocytes • Lymphpadenopathy, organomegaly • Pneumonia • Osteomyelitis • Abscesses • Staph, Aspergillus Radiographics, 25:1183, 1995 • NBT test • Flow cytometry (DHR) Summary • • • • Humoral Complement Cellular Phagocytic Not to forget • Molecular diagnosis important for early/prenatal diagnosis and genetic counseling • Whole exome sequencing