1 Immunodeficiencies. Wojciech Feleszko MD

Transcription

1 1 Immunodeficiencies Wojciech Feleszko MD

2 WHY TODAY? WHY WE? 2 30 Respiratory Gastrointestinal CNS Urinary Tract Bones Skin

3 3 Immunodeficiencies Congenital/Primary genetic or developmental defect Acquired/Secondary result of disease or therapy In America alone, up to 1/2 million people suffer from one of the 100 known Primary Immunodeficiency diseases.

4 How does the immune system work (1)? 4 Interferons Mø Th Neu Y Y Tc B Y Complement NK Y Y Y

5 How does the immune system work (2)? 5 Innate immunity runs first Acquired immunity: precise (specific for particular microorganism) requires more time (7-14 days) maturates in lymph nodes

6 How does the immune system work ( 3)? 6 Immune memory Control of opportunistic infections (natural barriers) This is the immune system, which eradicates infection, but not the antibiotic drug

7 7 Maturation of the IS (1) Mechanisms of immunity mature slowly innate (barriers) acquired (thymus, immune memory) Other: narrow airways, weak cough reflex

8 Are frequent infections in childhood an obligatory indication for diagnosis of immunodeficiency?? 8 Age < Number of illnesses/year Range (min to max) Dingle, J. H., Badger, G. F., & Jordan, W. S. (1964). Illness in the home. Cleveland, OH: The Press of Western Reserve University.

9 9 Recurrent respiratory tract infections (causes) Anatomic, metabolic abnormalities 10% Immunedeficiency 10% Allergy 30% Normal immunity 50%

10 Are frequent infections in childhood an obligatory indication for diagnosis of immunodeficiency?? 10 Family size Illnesses per person per year (respiratory) Dingle, J. H., Badger, G. F., & Jordan, W. S. (1964). Illness in the home. Cleveland, OH: The Press of Western Reserve University.

11 Central/Congenital 11 RBC Platelets Granulocytes Monocytes Ag CR CR µ δ IgM... B Hematopoeitic stem cell Pre-B Ab-forming cells Common Lymphocyte Precursor CR = complement receptor; µ, δ = membrane IgM and IgD Pre-T THY T H,C,S T,T,T... H C S/R T-effector T - cells LYMPHOCYTE DIFFERENTIATION Bruton s Agammaglobulinemia Chronic Granulomatous Disease DiGeorge Syndrome, Thymic Aplasia Severe Combined Immunodeficiency

12 Clinical symptoms suggesting 12 immune deficiency (1) Eight or more new ear infections within 1 year Two or more serious sinus infections within 1 year Jeffrey Modell Foundation

13 Clinical symptoms suggesting 13 immune deficiency (2) Two or more months on antibiotics with little effect Two or more pneumonias within 1 year

14 Clinical symptoms suggesting 14 immune deficiency (3) Failure of an infant to gain weight or grow normally Recurrent, deep skin or organ abscesses (boils)

15 Clinical symptoms suggesting 15 immune deficiency (4) Persistent thrush in mouth, or elsewhere on skin, after age 1. Need for intravenous antibiotics to clear infections

16 Clinical symptoms suggesting 16 immune deficiency (5) Two or more deep-seated infections A family history of Primary Immunodeficency

17 Central/Congenital 17 RBC Platelets Granulocytes Monocytes Ag CR CR µ δ IgM... B Hematopoeitic stem cell Pre-B Ab-forming cells Common Lymphocyte Precursor CR = complement receptor; µ, δ = membrane IgM and IgD Pre-T THY T H,C,S T,T,T... H C S/R T-effector T - cells LYMPHOCYTE DIFFERENTIATION Bruton s Agammaglobulinemia

18 Primary Immune Deficiencies in Poland n = Humoral deficiency 58,3% Cellular & Combined deficiencies 26,2% Other 3,7% Complement deficiency 2,2% Phagocyte deficiency 9,6%

19 19 Common Immune Deficiencies (1) Humoral: 1. 6 m. - otitis media ( 8/year), sinusitis, pneumonia, meningitis and sepsis (at least twice a year) Haemoplius, Staphylococci, Streptococci, viruses: Entroviruses (Polio, Echo) 2. IgA-deficiency transient infant hypogammaglobulinemia 3. To check IgA, IgG & IgM level Tx: Intravenous Ig therapy

20 Central/Congenital 20 RBC Platelets Granulocytes Monocytes Ag CR CR µ δ IgM... B Hematopoeitic stem cell Pre-B Ab-forming cells Common Lymphocyte Precursor CR = complement receptor; µ, δ = membrane IgM and IgD Pre-T THY T H,C,S T,T,T... H C S/R T-effector T - cells LYMPHOCYTE DIFFERENTIATION DiGeorge Syndrome, Thymic Aplasia

21 Primary Immune Deficiencies in Poland n = Humoral deficiency 58,3% Cellular & Combined deficiencies 26,2% Other 3,7% Complement deficiency 2,2% Phagocyte deficiency 9,6%

22 22 Common Immune Deficiencies(2) Cellular : 1. Shortly after birth: eczema, thrush, diarrhea, interstitial pneumonia, severe viral infections (HSV, CMV, Varicella) 2. Di George syndrome 3. To check T, B & NK-cells count Tx: supportive therapy, or thymic epithelial transplant

23 23 Di George Syndrome Lower location of eyes hypertelorism Short philtrum rethrognathia

24 Di George Syndrome 24

25 4 6 weeks of gestation 25

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29 Central/Congenital 29 RBC Platelets Granulocytes Monocytes Ag CR CR µ δ IgM... B Hematopoeitic stem cell Pre-B Ab-forming cells Common Lymphocyte Precursor CR = complement receptor; µ, δ = membrane IgM and IgD Pre-T THY T H,C,S T,T,T... H C S/R T-effector T - cells LYMPHOCYTE DIFFERENTIATION Severe Combined Immunodeficiency

30 Primary Immune Deficiencies in Poland n = Humoral deficiency 58,3% Cellular & Combined deficiencies 26,2% Other 3,7% Complement deficiency 2,2% Phagocyte deficiency 9,6%

31 31 Severe Combined Immunodeficiency 1. overwhelming infections in first year of life absence of functional T- or B-cells - usually lethal before 2 nd y. 2. Early diagnosis - ESSENTIAL 3. several genetic defects, including ADA (adenosine deaminase), PNP (purine nucleotide phosphorylase), IL-2Rg (IL-2 receptor gamma, X- linked) 3. Complete cureb.m. transplant

32 David the Bubble Boy, born with SCID 32 Born in 1971; older brother had died of SCID (Pneumocystis) one year earlier. Expected potential problem; 50% male, 50% diseased Germ-free birth, reverse isolation chamber. (Not truly germ-free, 35 species of microorganism identified at age 6).

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34 Phagocytic function, ADA & complement close to normal. IgM low, no IgG, traces of IgA, 34

35 No response to keyhole limpet hemocyanin (KLH), either by Ab or skin test (CMI). No Ab response to typhoid antigen 35

36 Lymphocytes ~400/cmm (~10% of normal), ~1/3 sig+, ~2/3 ERFC Minimal lymphocyte response to PHA, PWM, MLC. Transfer Factor (colostrum-derived) given at months; poor or no response to fungal skin tests. 36

37 Bone marrow transplant in 1983 at age 12 (treated with mab to reduce T-cells) from 15-year-old sister. Died 4 months later with a poorly understood pathology 37

38 David Vetter Bubble Boy 38

39 Generalized erythrodermia in SCID patient 39

40 Acute GvHD after BMT in a SCID patient 40

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42 Disseminated BCG infection in SCID after BMT 42 poor general condition, failure to thrive disseminated skin changes mainly on lower limbs with pus formation in subcutaneous layer local reaction on vaccination site osteomyelitis of the right palmar bones

43 Disseminated BCG infection in patient with interferon γ receptor deficiency 43 scar after osteomyelitis of sternum osteomyelitis of metatarsal bones full recovery after antituberculous treatment

44 44 Common Immune Deficiencies(3) Phagocyte deficiency: 1. Shortly after birth: stomatitis, lymphadenitis, prolonged wound healing pus-forming bacteria (Pseudomonas, Staphylococci) pneumonia caused by fungi (Aspergillus, Candida) 2. Chronic granulomatous disease (CGD) primary neutropenias 3. blood cell count, NBT TX: antibiotics (& B.M. transplant?)

45 Patients with CGD (17 years of 45 observation)

46 Boils in CGD patients 46

47 Brain abscesses in an 8-year-old patient with known CGD 47

48 Osteomyelitis (32 m) with a history of recurrent subcutaneous abscesses on his leg. 48

49 49 Dgn. : Milliary TB??

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51 51 Pneumonia in CGD

52 CT scan: 1.severe volume loss 2.honeycomb pattern ( ) 3.mosaic attenuation (right lung), pleural thickening (*) 4.calcified hilar lymph nodes ().

53 1. scarring in the lower lobe with hilar fibrosis ( ) 2. consolidation ().

54 Acquired Immunodeficiencies Secondary to Disease 54 Infectious disease (toxins, immuno-suppression; HIV) Malignancy (immunossupression, depression of hematopoiesis) Malnutrition (T-selective deficiencies) Splenectomy (loss of filtration & phagocytic cells; bacterial infections)

55 55 What to do when ID is suspected? (1) 1. Exclude other problems of respiratory tract: - CF - dyskinetic cilia syndrome - foreign body - third tonsil - bronchial tree malformations 2. Exclude other: - drugs (steroids, cytostatics) - AIDS, EBV, CMV - neoplasia - protein loss (renal, skin, gut) - phagocyte loss (splenectomy)

56 What to do when ID is suspected? (2) Do not vaccinate with living vaccines 2. Level of IgA, IgG, IgM & albumine 3. Cell count: T-cells (55-85%), B-cells (10-30%) & NKcells (5-20%) (FACS) 3. Blood cell count, NBT-test, chemiluminescence, phagocyte migration activity

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