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

Recurrent lung infections IgG2, IgA, IgE deficiency 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