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

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

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

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

7. Abnormal facies
Congenital heart disease
Hypocalcemia
Lymphocytopenia

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

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

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

11. PID ???

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

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

14. PID ???

15. Humoral
Cellular
Phagocytic
Complement

16. 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

17. 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

18. .
Type:
JPG
Cunningham-Rundles C et al 2005

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

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

21. PID ???

22. Cellular
Phagocytic
Complement

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

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

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

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

27. Cellular
Phagocytic

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

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

31. Always order a complete blood count with lymphocyte subset analysis.

32. Molecular screening for SCID

33. Phagocytic

34. 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

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

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

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

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

39. NBT test
Flow cytometry (DHR)

40. Summary
Humoral
Complement
Cellular
Phagocytic

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