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Diagnosis of Primary Immunodeficiency Eli Eisenstein, M.D. Dept of Pediatrics

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Ways to Diagnose a Disease Sample the universe Pattern recognition Systematic approach

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Molecular Medicine, http://www.mm.interhealth.info

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Cerebellar ataxia Recurrent lung infections IgG2, IgA, IgE deficiency Lavin, Nat Rev Mol Cell Biol 2008

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Abnormal facies Congenital heart disease Hypocalcemia Lymphocytopenia

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A greatly over-simplified approach to primary immunodeficieny Humoral Cellular Phagocytic Complement

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Case 1 11 month old infant Recurrent fevers at least six episodes One episode of gastroenteritis, lasting six days Two episodes of otitis media

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Relevant history Growth Development Type of infections, and how documented Duration Response to therapy Other illnesses Family history- consanguinity ? Exposure

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PID ???

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Case 2 Three year old boy Recurrent lobar pneumonia beginning at six months of age One episode of sepsis caused by Strep. pneumoniae

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Relevant history Growth Development Type of infections, and how documented Duration Response to therapy Other illnesses Family history Exposure

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PID ???

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Humoral Cellular Phagocytic Complement

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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

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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

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Type:JPG. Cunningham-Rundles C et al 2005

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Clinical question What physical finding helps distinguish between B cell positive and B cell negative forms of hypogammaglobulinemia ?

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Case 3 Eight year old boy Second episode of meningitis caused by Neisseria meningitides

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PID ???

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Cellular Phagocytic Complement

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Complement Pathway Holers in: R Rich et al (eds) Clinical Immunology, 1986, p365

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Abbas et al, Cellular and Molecular Immunology, 6E

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Tests for Complement Deficiency Functional tests (e.g., CH50) Measure individual complement components

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Case 4 On month old boy Failure thrive Persistent diarrhea Pneumonia Pneumocystic jirovecii Sibling died at three months of age of presumed SIDS

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Cellular Phagocytic

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Fischer A, Nat Rev Immunol 2:615, 2002

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Evaluation of cellular immunity Total lymphocyte count (CBC) Presence of thymus Delayed hypersensitivty Flow cytometry Lymphocyte responses to mitogens

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http://crl.berkeley.edu/flow_cytometry_basic.html Always order a complete blood count with lymphocyte subset analysis.

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Molecular screening for SCID

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Phagocytic

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Three categories of phagocytic cell defects No cells Cells dont know where to go Cells dont know what to do when they get there

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No cells Several genetic forms including cyclic Diagnosis: complete blood count, peripheral blood smear, bone marrow examination Bacteremia No Pus !! GCSF BMT

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Cells dont know where to go: Leukocyte adhesion deficiency

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LAD-1 Clinical features Delayed umbilical cord separation Marked granulocytosis in peripheral blood

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Incompetent granulocytes Lymphpadenopathy, organomegaly Pneumonia Osteomyelitis Abscesses Staph, Aspergillus Radiographics, 25:1183, 1995

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NBT test Flow cytometry (DHR)

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Summary Humoral Complement Cellular Phagocytic

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Not to forget Molecular diagnosis important for early/prenatal diagnosis and genetic counseling Whole exome sequencing