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

http://crl.berkeley.edu/flow_cytometry_basic.html

Always order a complete blood count with lymphocyte subset analysis.

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