Fatima Gutierrez M.D.. Learn when to Suspect an Immune Deficiency Important Aspects of History Taking Physical Exam Clues Initial Laboratory Work-up When.

Fatima Gutierrez M.D.

Learn when to Suspect an Immune Deficiency

Important Aspects of History Taking Physical Exam Clues Initial Laboratory Work-up When to get an Immune Consult Overview of Specialized Tests

8 or more new ear infections within one year

2 or more serious sinus infections within 1 year

Two or more months on antibiotics with little effect

2 or more pneumonias within 1 year

Failure of an infant to gain weight or grow normally

Recurrent, deep skin or or organ abscesses

Persistent thrush in mouth or elsewhere on skin, after age 1

Need for IV antibiotics to clear infections

2 or more deep-seated infections

Family history of Primary Immunodeficiency

Sinusitis/Pneumonia CF Allergic Rhinitis Anatomy

Low Antibody levels Protein-losing

entropathy, nephropathy

Severe eczema Burns

2° Immunodeficiency Malnourishment Diabetes Sickle Cell

Primary Immunodeficiencies Can Be Categories by their Defect: Cellular Immunity (T-Cells)

Humoral Immunity (B-Cell)

Phagocytes

Complement

Bone Marrow

B-lymphocytes

Stem Cell

Plasma cells

Immunoglobulins

T- cells

T-Cells directly Attack Foreign Antigens

Opportunistic infections Candida sp, Pneumocystis jiroveci

Persistent Thrush Diarrhea/Malabsorption Poor Growth/Failure to Thrive

Unable to make specific antibodies Multiple / Severe Bacterial Infections Persistent Upper Respiratory Tract

InfectionsStreptococcus, Haemophilis

Usually seen after 6 months when maternal antibodies lost

Growth usually normal unless patient with chronic infections

Natural Killer Cells – directly attack cells infected with Virus Phagocytes – ingest and kill microorganisms Chronic Granolomatous Disease –

- Infections caused by catalase + organisms

LAD No Pus Gingivitis/Periodontitis Skin Infections, Liver, GI Tract

Composed of 30 proteins Function in ordered integrated fashion to

defend against infection and produce inflammation

C5- C8 deficiency associated with autoimmune

C1-C4 deficiency Associated with Rheumatic Disorders Pyogenic Infections

C5-C9 Complement deficiency Neiserria Infections

Basic Screen – CH50 – measures function of alternate pathway

Immunodeficiency

Primary 1:500 – 1:100,000 -

All

1:500 IgA def 1:100,000 SCID 1:200,000 CGD

Secondary 1:300 - HIV

1:5 “unaware” of their HIV

History Infection HistorySexConsanguinityHistory of Miscarriage/ Death in InfantsPrimary Immune Deficiency in FamilyHistory of Autoimmune/Connective Tissue

d/oEnvironment (Smoke, allergies)Delayed Cord Separation (LAD)HIV risk factors

Eczema , Wiskott Aldrich or Hyper IgE?

Wiskott Aldrich Thrombocytopenia Small platelets

Hyper IgE -Job Syndrome Skin infections – Staph Sinusitis Coarse Facies Retain Primary Teeth

Look at MotherIncongentia Pigmenti

Conical Teeth

Nuclear Factor – kB Essential ModulatorX-LinkedDefect in Cellular Immunity

Variable Immunoglubulin levels Normal B-cell numbers

Recurrent bacterial sinopulmonary and oportunistic Infections

Ectodermal DysplasiaConical TeethTreatment Stem Cell Transplant

Lymphocyte countAbsolute Lymphocyte count Lymphopenia

Screen for B and T cell DeficienciesLymphocytosis

Omenn Syndrome, Leukocyte Adhesion Deficiency

Neutrophil CountLeukocyte Adhesion Deficiency -

>100,000/mm3 Platelet Size and Number

Wiskott Aldrich

WBC total x %lymphocytes = Absolute Lymphocyte Count (ALC)

Normal absolute lymphocyte count 10th-90th percentiles (#/μL) by age 0-3months 3400-76006-12months 3900-90001-2 years 3600-8900

Look at normal values based on Age!!

IgG, IgM, IgA, IgE IgG in young infants less reliable –

largely maternal Lab Variations! Age Adjusted Normals Low IgG in Infant

Hypogammaglobulinemia of Infancy Undetectable IgA

Primary Immune Deficiency High Levels IgM + Absence of other Ig

Hyper IgM IgE

Atopic Disease or Parasitic Illness, Hyper IgE

Immunoglobulin Immunoglobulin DevelopmentDevelopment

•IgG nadir for infants is age 3 months to 1 year of life•Premature infants will lack adequate maternal IgG•Note in IgG at approximately 6 months of life (maternal vs infant sources)

•IgM production starts immediately after birth•IgA rate of synthesis is slowest

THYMUS!

May shrink in response to stress/surgery/infection

Thymus continues to grow until teens

Largest size relative to body weight at birth

No Thymus

T-cell Response Common Antigens

CandidaTrychophytonTetanusDiphtheriaPPD

Anergy (no response) Immune suppr. Meds-

Steroids Infants < 6 months / 2yrs Malnutrition Collagen Vascular Disease Fever- Leukocytosis

Reaction measured at 48 hours

HIV – DNA when IgG unreliable

ELISA tests IgG Infants have Maternal IgGSevere HypogammaglobulinemiasLiver Disease

Guidelines : www.aidsinfo.nih.gov

Measurement of Specific T, B,

NK and phagocytic

cells

Measurement of Specific T, B,

NK and phagocytic

cells

NK Cells

Tcells-

B-Cells

The Case of SCIDThe Case of SCID

Tests your Body’s Ability to Make Antibodies – Majority of Vaccines activate B-cells in the presence of T-cell

Tests your Body’s Ability to Make Antibodies – Majority of Vaccines activate B-cells in the presence of T-cell

Tests for Common Vaccines

DiphtheriaTetanusStreptococcus

Tests for Common Vaccines

DiphtheriaTetanusStreptococcus

Normal ResponseDiphtheria > 0.1Tetanus > 0.1

Or…4 fold increase of baseline

1 month after vaccine given

Normal ResponseDiphtheria > 0.1Tetanus > 0.1

Or…4 fold increase of baseline

1 month after vaccine given

Streptococcus – Note minimal responseStreptococcus – Note minimal response

Serotypes in Prevnar:4, 6B, 9V, 14, 18C, 19F, 23FSerotypes in Prevnar:4, 6B, 9V, 14, 18C, 19F, 23F

Serotypes in PCV13Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F

Serotypes in PCV13Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F

Measures the ability of lymphocytes to respond to mitogens and Specific

antigens

Measures the ability of lymphocytes to respond to mitogens and Specific

antigens

Strongly Mitogenic on T-Cells - PHA (Phytohemagluttin) - ConA (Concanavalin-A)

Stimulates T&B cells (Mitogen - Pokeweed

Strongly Mitogenic on T-Cells - PHA (Phytohemagluttin) - ConA (Concanavalin-A)

Stimulates T&B cells (Mitogen - PokeweedAntigens: - Candida -Tetanus - Dipthera

*Prior exposure required for response !! > 2yrs age

Antigens: - Candida -Tetanus - Dipthera

*Prior exposure required for response !! > 2yrs age

Minimal Response

Assay working well

Early Recognition of Primary Immune Deficiency – Many Primary Immune Deficiencies are Lethal!

Recognize Lab Value Diversity

Don’t forget to look for HIV

Noroski MD, L., Shearer MD, W. Short Screening for Primary Immunodeficiencies in the Clinical Immunology Laboratory. Clinical Immunology and Immunopathology. Vol. 86, No3, March pp. 2237-245, 1998

Fleisher, Shearer, Kotzin, Schroder. Clinical Immunology – Principles and Practice 2nd Ed. Rich, R.

Schmitz PhD, Folds PhD. Clinical and Laboratory Assesment of Immunity. Journal of Allergy and Immunology 2003: 111:S702-11

American Academy of Allergy Asthma and Immunology – www. aaai.org

Immune Deficiency Foundation – primaryimmune.org

Jeffrey Modell Foundation www. jfmworld.org