kluczowe do materiałów id's - i katedra pediatrii · µµµµ, δδδδ= membrane igm and...
TRANSCRIPT
1
Immunodeficiencies
Wojciech Feleszko MD
2
Respiratory
GastrointestinalCNS
Urinary Tract
Bones Skin0
10
20
30
40
50
60
70
80
90
100
WHY WE ?
WHY TODAY?
3
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.
4
How does the immune system work (1) ?
ThTh
NKNK
MMøø
BBNeuNeu
InterferonsInterferons
ComplementComplement
TcTc
YY
YY
YY
YY
YY
YY
5
� Innate immunity runs first
� Acquired immunity:
– precise (specific for particular microorganism)
– requires more time (7-14 days)
– maturates in lymph nodes
How does the immune system work (2) ?
6
� Immune memory
� Control of opportunistic infections (natural barriers)
� „ This is the immune system , which eradicates infection, but not the antibiotic drug ”
How does the immune system work (3) ?
7
� Mechanisms of immunity mature slowly
– innate (barriers)
– acquired (thymus, immune memory)
� Other: narrow airways, weak cough reflex
Maturation of the IS (1)
8
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.
9
Recurrent respiratory tract infections
(causes)
Normal
immunity
50%
Allergy
30%
Anatomic,
metabolic
abnormalities
10%
Immune-
deficiency
10%
10
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.
11
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
14Clinical symptoms suggesting Clinical symptoms suggesting immune deficiency immune deficiency ((33))
Failure of an infant to gain weight or grow normally
Recurrent, deep skin or organ abscesses (boils)
15Clinical symptoms suggesting Clinical symptoms suggesting immune deficiency immune deficiency ((44))
Persistent thrush in mouth, or elsewhere on skin, after age 1.
Need for intravenous antibiotics to clear infections
16Clinical symptoms suggesting Clinical symptoms suggesting immune deficiency immune deficiency ((55))
Two or more deep-seated infections
A family history of Primary Immunodeficency
17
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
Bruton’s Agammaglobulinemia
18
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
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
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
DiGeorge Syndrome, Thymic Aplasia
21
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
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
• Lower location of eyes• hypertelorism• Short philtrum• rethrognathia
Di George Syndrome
24
Di George Syndrome
25
4−6 weeks of gestation
26
27
28
29
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
30
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
31
Severe Combined Immunodeficiency
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
32
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).
33
34
● Phagocytic function, ADA & com-
plement close to normal.
● IgM low, no IgG, traces of IgA,
35
● No response to keyhole limpet hemocyanin (KLH), either by
Ab or skin test (CMI).
● No Ab response to typhoid antigen
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 10-16 months; poor or no
response to fungal skin tests.
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
38David Vetter“Bubble Boy”
39
GeneralizedGeneralized erythrodermiaerythrodermia in SCID in SCID patientpatient
40
AcuteAcute GvHDGvHD afterafter BMT in a SCID BMT in a SCID patientpatient
41
42
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
43
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
44
Common Immune Deficiencies (3)
� 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 )
46
Boils in CGD patients
47
Brain abscesses in an 8-year-old patient with known CGD
48
Osteomyelitis (32 m) with a history of recurrent subcutaneous abscesses on his leg.
49
Dgn. :Milliary TB ??
50
51
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 (�).
54
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
55
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)
56
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