Kluczowe do materiałów ID's - I Katedra Pediatrii · µµµµ, δδδδ= membrane IgM and IgD ......

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Immunodeficiencies

Wojciech Feleszko MD

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Respiratory

GastrointestinalCNS

Urinary Tract

Bones Skin0

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50

60

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100

WHY WE ?

WHY TODAY?

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Immunodeficiencies

● Congenital/Primarygenetic or developmental defect

● Acquired/Secondaryresult of disease or therapy

� In America alone, up to 1/2 million people suffer from one ofthe 100 known Primary Immunodeficiency diseases.

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How does the immune system work (1) ?

ThTh

NKNK

MMøø

BBNeuNeu

InterferonsInterferons

ComplementComplement

TcTc

YY

YY

YY

YY

YY

YY

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� Innate immunity runs first

� Acquired immunity:

– precise (specific for particular microorganism)

– requires more time (7-14 days)

– maturates in lymph nodes


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� Immune memory

� Control of opportunistic infections (natural barriers)

� „ This is the immune system , which eradicates infection, but not the antibiotic drug ”


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� Mechanisms of immunity mature slowly

– innate (barriers)

– acquired (thymus, immune memory)

� Other: narrow airways, weak cough reflex

Maturation of the IS (1)

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Are frequent infections in childhood an obligatory indication for diagnosis of immunodeficiency ??

0-166.08

0-186.17

0-136.26

0-187.45

2-157.64

1-157.83

0-158.12

1-178.31

0-156.7<1

Range (min to max)

Number of illnesses/year

Age

Dingle, J. H., Badger, G. F., & Jordan, W. S. (1964). Illness in the home. Cleveland, OH: The Press of Western Reserve University.

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Recurrent respiratory tract infections

(causes)

Normal

immunity

50%

Allergy

30%

Anatomic,

metabolic

abnormalities

10%

Immune-

deficiency

10%

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Are frequent infections in childhood an obligatory indication for diagnosis of immunodeficiency ??

5.68

6.77

6.36

5.55

5.24

4.53

Illnesses per person per year(respiratory)

Family size

Dingle, J. H., Badger, G. F., & Jordan, W. S. (1964). Illness in the home. Cleveland, OH: The Press of Western Reserve University.

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LYMPHOCYTE DIFFERENTIATION

THY

Ag

T ,T ,T ...H C S/R

Hematopoeiticstem cell

CommonLymphocyte

Precursor

Pre-B

Pre-T

B

T

IgM...

RBC

GranulocytesMonocytes

Platelets

CR

Ab-forming cells

T-effectorT - cells

CR

H,C,S

CR = complement receptor; µµµµ, δδδδ = membrane IgM and IgD

µµµµ δδδδ

Central/Congenital

Severe Combined Immunodeficiency

DiGeorge Syndrome, Thymic Aplasia

Bruton’s Agammaglobulinemia Chronic Granulomatous Disease

12Clinical symptoms suggesting Clinical symptoms suggesting immune deficiency immune deficiency (1)(1)

Eight or more new ear infections within 1 year

Two or more serious sinus infections within 1 year

Jeffrey Modell Foundation

13Clinical symptoms suggesting Clinical symptoms suggesting immune deficiency immune deficiency ((22))

Two or more months on antibiotics with little effect

Two or more pneumonias within 1 year


Failure of an infant to gain weight or grow normally

Recurrent, deep skin or organ abscesses (boils)


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

Need for intravenous antibiotics to clear infections


Two or more deep-seated infections

A family history of Primary Immunodeficency

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THY

Ag

T ,T ,T ...H C S/R


CommonLymphocyte

Precursor

Pre-B

Pre-T

B

T

IgM...

RBC


Platelets

CR

Ab-forming cells

T-effectorT - cells

CR

H,C,S


µµµµ δδδδ

Central/Congenital

Bruton’s Agammaglobulinemia

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Cellular &

Combined

deficiencies

26,2%

Phagocyte

deficiency

9,6%Complement

deficiency

2,2%

Other

3,7%

Humoral

deficiency

58,3%

PrimaryPrimary ImmuneImmune DeficienciesDeficiencies in in PolandPoland19801980 –– 20020077n n == 1 0271 027

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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

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THY

Ag

T ,T ,T ...H C S/R


CommonLymphocyte

Precursor

Pre-B

Pre-T

B

T

IgM...

RBC


Platelets

CR

Ab-forming cells

T-effectorT - cells

CR

H,C,S


µµµµ δδδδ

Central/Congenital

DiGeorge Syndrome, Thymic Aplasia

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Cellular &

Combined

deficiencies

26,2%

Phagocyte

deficiency

9,6%Complement

deficiency

2,2%

Other

3,7%

Humoral

deficiency

58,3%


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� 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

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• Lower location of eyes• hypertelorism• Short philtrum• rethrognathia

Di George Syndrome

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Di George Syndrome

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4−6 weeks of gestation

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THY

Ag

T ,T ,T ...H C S/R


CommonLymphocyte

Precursor

Pre-B

Pre-T

B

T

IgM...

RBC


Platelets

CR

Ab-forming cells

T-effectorT - cells

CR

H,C,S


µµµµ δδδδ

Central/Congenital


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Cellular &

Combined

deficiencies

26,2%

Phagocyte

deficiency

9,6%Complement

deficiency

2,2%

Other

3,7%

Humoral

deficiency

58,3%


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1. overwhelming infections in first year of lifeabsence of functional T- or B -cells

- usually lethal before 2 nd y. 2. Early diagnosis - ESSENTIAL3. several genetic defects, including ADA (adenosi ne

deaminase), PNP (purine nucleotide phosphorylase), IL-2Rg (IL-2 receptor gamma, X -linked)

3. Complete cure� B.M. transplant

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David the “Bubble Boy”, born with SCID

● 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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● Phagocytic function, ADA & com-

plement close to normal.

● IgM low, no IgG, traces of IgA,

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● No response to keyhole limpet hemocyanin (KLH), either by

Ab or skin test (CMI).

● No Ab response to typhoid antigen

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● 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 10-16 months; poor or no

response to fungal skin tests.

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● 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

38David Vetter“Bubble Boy”

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GeneralizedGeneralized erythrodermiaerythrodermia in SCID in SCID patientpatient

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AcuteAcute GvHDGvHD afterafter BMT in a SCID BMT in a SCID patientpatient

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poorpoor generalgeneral conditioncondition, , failurefailure to to thrivethrive

disseminateddisseminated skin skin changeschanges mainlymainly on on lowerlower limbslimbs withwith puspus formationformation in in subcutaneoussubcutaneous layerlayer

locallocal reactionreaction on on vaccinationvaccination sitesite

osteomyelitisosteomyelitis ofof thetherightright palmarpalmar bonesbones

Disseminated BCG infection in SCID after BMTDisseminated BCG infection in SCID after BMT

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scarscar afterafter osteomyelitisosteomyelitis ofofsternumsternum

osteomyelitisosteomyelitis ofofmetatarsalmetatarsal bonesbones

fullfull recoveryrecovery afterafter antituberculousantituberculous treatmenttreatment

DisseminatedDisseminated BCG BCG infectioninfection in in patientpatient withwith interferon interferon γγγγreceptor receptor deficiencydeficiency

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� Phagocyte deficiency:

1. Shortly after birth: s tomatitis, 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?)

45Patients with CGD (17 years ofobservation )

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Boils in CGD patients

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

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

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Dgn. :Milliary TB ??

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Pneumonia in CGD

CT scan:

1.severe

volume loss

2.honeycomb

pattern (↓)

3.mosaic

attenuation

(right lung),

pleural

thickening

(*)

4.calcified

hilar lymph

nodes (�).

1. scarring in the lower lobe with hilar fibrosis (↑)

2. consolidation (�).

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ImmunodeficienciesSecondary to Disease

● Infectious disease (toxins, immuno-suppression; HIV)

●Malignancy (immunossupression, depression of hematopoiesis)

●Malnutrition (T-selective deficiencies)● Splenectomy (loss of filtration & phagocytic

cells; bacterial infections)

Acquired

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What to do when ID is suspected ? What to do when ID is suspected ? (1)(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)

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What to do when ID is suspectedWhat to do when ID is suspected ? ? (2)(2)

1. Do not vaccinate with living vaccines

2. Level of IgA, IgG, IgM & albumine

3. Cell count : T-cells (55-85%), B-cells (10-30%) & NK-

cells (5-20%) (FACS)

3. Blood cell count, NBT-test, chemiluminescence,

phagocyte migration activity

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Kluczowe do materiałów ID's - I Katedra Pediatrii · µµµµ, δδδδ= membrane IgM and IgD ......

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