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Diagnosis of Primary Immunodeficiency

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

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Diagnosis of Primary Immunodeficiency

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

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

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

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

  5. Abnormal facies Congenital heart disease Hypocalcemia Lymphocytopenia

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

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

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

  9. PID ???

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

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

  12. PID ???

  13. Humoral • Cellular • Phagocytic • Complement

  14. 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

  15. 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

  16. . Cunningham-Rundles C et al 2005

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

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

  19. PID ???

  20. Cellular • Phagocytic • Complement

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

  22. Abbas et al, Cellular and Molecular Immunology, 6E

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

  24. Case 4 • On month old boy • Failure thrive • Persistent diarrhea • Pneumonia – Pneumocysticjirovecii • Sibling died at three months of age of presumed SIDS

  25. Cellular • Phagocytic

  26. Fischer A, Nat Rev Immunol 2:615, 2002

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

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

  29. Molecular screening for SCID

  30. Phagocytic

  31. 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

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

  33. Cells don’t know where to go:Leukocyte adhesion deficiency

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

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

  36. NBT test • Flow cytometry (DHR)

  37. Summary • Humoral • Complement • Cellular • Phagocytic

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

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