Transcript How to approach PID.ppt

Saleh Al-Muhsen, MD, FRCPC, FAAP
Assistant Professor of Pediatrics
Consultant Allergy and Immunology
King Khalid University Hospital, KSU &
King Faisal Specialist Hospital & Research Center
Riyadh, Saudi Arabia
WHAT DO WE NEED TO KNOW?
Q.1: WHAT DO WE MEAN BY PID?
Q.2: DOES THIS CHILD HAVE PID?
Q.3: WHAT TYPE OF PID HE MIGHT HAVE?
Q.4: ONCE SUSPECTED, WHAT SHOULD I DO?
Q
.1: WHAT DO WE
What is PID ?
MEAN BY PID?
• Genetic defect in immunity of the host.
• Not explained by secondary causes.
• Most are inherited disorders.
• Born with it but not always evident at birth.
• The first line of defense starts when the antigen is taken up by antigen presenting
cells (dendritic cells and phagocytes) and migrates to the primary lymphoid organs
(spleen and tonsils).
• These cells present to the T-lymphocytes, where T-cells proliferate to produce
effector (activated) cells and memory cells.
• The effector cells act as cytotoxic cell producing cytokines that act to kill the microorganism at site of infection.
• The T-lymphocyte also activate the B-lymphocyte to produce immunoglobulins.
• Once B cells are activated they will proliferate into plasma cells producing
immunoglobulin and memory cells.
• B-lymphocyte are normally programmed to produce IgM, IgD.
• It requires activation by T-lymphocytes via CD40 receptor, and CD40 ligand on Bcell to produce IgA, G, E.
• Ig bind to the antigen by complement fixation.
• Proliferation is the initial step in the activation process.
• Any defect in the previous sequence will lead to primary immunodeficiency.
Immune System Defect
• Normal immune response to infection
• Developmental
• Cell-to-Cell Communication
• Cell Function or Structure
Prevalence
• More than 100 known disorders.
• Relatively rare, increase with consanguinity (54% in SA) .
• In SA PID is more prevalent due to increased consanguinity that allows the
expression of AR diseases and blood disorders.
• No available local data !!
• Variable incidence according to the diseases:
– XL-SCID (severe combined immunodeficiency) 1:50,000
– CGD (chronic granulomatous disease)
1:200,000
– CVID (common variable immunodeficiency)
1:75,000
– Selective IgA deficiency 1:500 it’s the commonest form of PID.
Primary Immune Deficiency Diseases –
where we are now
Current estimates indicate that
as many as 70-90% of PI’s
are still undiagnosed
undiagnosed patients
These patients experience
unnecessary suffering and
depend heavily on healthcare
resources for the treatment of
lifelong complications and disabilities
that result from untreated PIDs
Complication
• Infections: chronic or recurrent.
• Autoimmune diseases.
• Malignancies.
• Unregulated inflammation.
Q.2: DOES THIS CHILD
HAVE PID?
It’s a clinical diagnosis that
depends on history
and examination.
HISTORY imp slide
1.
2.
3.
4.
Recurrent infections: Sino-pulmonary (Otitis media, Pneumonia, Sinusitis).
Deep organ or skin infections.
Severe and complicated infections (septicemia, meningitis, osteomyelitis).
Difficult to eradicate infection depite prolonged use of antibiotic for trivial
infections or use of I.V instead of oral antibiotics.
5. Persistent oral candidiasis (oral thrush) beyond infancy (normal during infancy).
6. Unexplained failure to thrive. Chronic diarrhea either due to infection by
salmonella or giardia that can’t be eradicated or due to an autoimmune process
causing inflammation and crohn’s-like diarrhea or due to malabsorption, the
diarrhea won't improve until the patient is immune competent.
7. Significant complication (infection) to vaccination (oral polio or BCG because
they’re both live attenuated).
8. Family history of immune deficiency (BM transplantation, recurrent infections),
early deaths.
Note: the most important is the type of infection for example CMV or Pneumocystis
jiroveci pneumonia infection (pneumocyctis carnii). In the absence of secondary
immunodeficiency, it is PID until proven other wise.
Q.3: WHAT TYPE OF
PID MIGHT THIS PATIENT
HAVE?
PYSICAL EXAMINATION
1.
2.
3.
Growth parameters.
Dysmorphic features: DiGeorge syndrome.
Lymph nodes and tonsils. They are absent in A-gamma-globinemia (x linked
disease) whith absent B-cells and no architecture of LN.
–
4.
5.
6.
7.
Homing of B-cells is in the tonsils and lymph nodes, while T-cells are circulating the blood.
Oral cavity look for oral thrush (it’s worrisome beyond infancy).
Skin for erthroderma, nails for fungal infection.
Sino-pulmonary.
Others (BCG scar) the window for immunity is the BCG scar. If the patient gets
infection after vaccination as in cases of live OPV or BCG then it’s a sign of PID.
BCG vaccine is the first challenge to the immune system. Therefore, examine the
scar:
–
–
if it was absent, it indicates absent or defective immunity but not always.
If it is purulent, red, irritant scar, then definitely a defective immune response.
CLASSIFICATION
1.
PRIMARY CAUSES
The commonest is humoral because under it is the commonest type which is
selective IgA deficiency
Complement 2%
Phagocytic 18%
Humoral 50 %
Combined 25%
Humoral
Cellular
Combined
Phagocytes
Complement
Cellular 5%
Combined because whenever T-cells are affected B cells function will also be
affected; therefore, its called combined rather than T-cell cellular defect
MSMD (Mendelian susceptibility to mycobacterial disease): salmonella and
BCGitis.
• Secondary:
– Severe malnutrition.
– Metabolic disorders.
– Infections (HIV).
– Immunosuppressive therapy.
– Malignancy.
– Cystic Fibrosis.
– Burns.
WHAT TYPE OF PID MIGHT HE HAVE?
• Onset:
•
•
•
•
•
•
•
•
Combined (cellular) starts early in life because T cell immunity is required from day 1.
Humoral deficiency will start after 6 months due to the protective maternal immunoglobulins.
Phagocytic depends on when the child encounters infections, here in SA early in life due to BCG
vaccine; whereas, in the USA it may be variable and usually more prolonged because BCG is not a
routine vaccination.
Complement is variable.
Gender.
Organs Affected.
Infective Pathogens.
Associated Clinical Features:
•
–
–
–
–
–
–
•
Chronic Diarrhoea, FTT. With combined.
Sino-pulmonary (B-lymphocyte)
Deep seated infection and skin (phagocytic)
CNS meningitis (complement)
Oral thrush (combined B + T cell)
Skin rash
Thrombocytopenia
Dysmorphism and cardiac diseases. DiGeorge syndrome.
•
•
•
•
•
Sino-pulmonary (B-lymphocyte)
Deep seated infection and skin (phagocytic)
CNS meningitis (complement)
Oral thrush (combined B + T cell)
Skin rash
important
Organism
Antibody
deficiency
Cellular
Viruses
enteroviruses
Bacteria
S pneumoniae
H influenzae,
S aureus,
P aeruginosa,
Mycobacteria
No
Nontubercul
ous,
including
BCG
Fungi
NO
C albicans, As for
Aspergillus cellular
deficiency
Protozoa
G lamblia
deficiency
S typhi
Combined
deficiency
Phagocyte
defect
Complement
deficiency
All (CMV)
NO
NO
As for
antibody
deficiency
S aureus (the
most
common)
P aeruginosa,
S typhi,
As for
antibody
deficiency, esp
N meningitidis
Nontuberculo
us, including
BCG
Nontuberculo
us, including
BCG
No
A fumigatus,
C albicans
No
P carinii
No
P carinii,
T gondii
• Enterovirus in humoral deficiency because of the
absence of IgA which is secreted by the mucosa which
will lead to local rather than systemic infection.
• Giardia is a non invasive organism unless IgA is
deficient.
• CMV is pathognomonic for combined
immunodeficiency.
• Complement: meningitis, mainly encapsulated
organisms.
• Fungi are typically candida and PCP.
• Toxoplasmosis is rare.
• Phagocytic: most common infection is s. aureus.
Initial Testing
• CBC Differential
• Smear
• Immunoglobulins levels
• Antibody titers
• CH50, C3, C4
Complement blood count
• Neutrophil Count
– Primary
– Kostmann’s Syndrome.
– Cyclic neutropenia
– Secondary - Immunodeficiency Syndromes
• Eosinophils - Hyper IgE, SCID  GVHD
• Lymphocytes: <1,500 - 2,000 eg. SCID
• Platelets: Wiskott-Aldrich Syndrome
• Smear: Chediak-Hegashi, asplenia
Immunoglobulins
• IgG: (Hypogam).
• normal or  IgM, IgG, IgA, IgE  HIGM
• IgM   W.A.S (minor)
• IgA   Ataxia Telangactasia.
• IgE   hyper-IgE, WAS, Omenn syndrome
Specialized test
• IgG Subclasses/ Specific Antibody responses
– Antibody response to vaccine normally has a 4-fold
increase, if it decreases, it indicates a defective
immunity.
•
•
•
•
•
? Phagocytosis / Chemotaxis
Leukocyte Markers
Lymphocyte Blastogenesis
CH50 + AH50 Complement Components
NBT Test / oxidative burst by flow
Leukocyte markers
• Lymphocyte Population/distribution/activation
• CD3 (T-cells)
• CD4 (T-Helper)
• CD8 (T- Suppressor)
• CD19 (B-cells)
• CD16/56 (NK-cells)
• MHC class I and II
Q.3: WHAT TYPE OF PID
MIGHT HE HAVE?
ILLUSTRATED CASE (1)
• 2 years old boy presented with history of:
– Recurrent chest infection, 2 were documented in the last
year)
– 6 times URTI and Otitis media.
– No other significant infection.
– Growth parameters were on the 10%.
– Received vaccination at birth, 2, 4, 6, 12 months
– Parents are first degree relatives. Otherwise negative family
history.
• Physical exam: no tonsils or lymph nodes were
found, crepitation in chest exam
Humoral Immunodeficiency
•
•
•
•
Start at 6-12 months of age.
Recurrent OM, sinusitis, pneumonia (sino-pulmonary)
Diarrhea (enteroviruses and giardia).
Examples:
1. Transient hypogammaglobulinemia of infancy.
2. Selective IgA deficiency.
3. X-linked agammaglobulinemia.
4. Common Variable Immune deficiency.
5. Antibody poor response with normal Immunoglobulin.
6. Hyper IgM syndrome (AR types)- in this syndrome the activation of
B-cells by T-cells to switch to the production of IgG is inhibited.
Therefore its detected by high levels of IgM and not by absent levels
of IgG.
Note: early presentation: auto-immune Late: recurrent infection.
The highest level of IgG will be at 2 weeks or the
closest to birth, and it reflects maternal immunity.
X-linked Infantile
Agammaglobulinemia (XLA)
(Bruton’s Agammaglobulinemia)
The development of functional B cells depends upon the maturation of
pre-B stem cells.
XLA Defect
X-linked Infantile
Agammaglobulinemia (XLA)
(Bruton’s Agammaglobulinemia)
Selective IgA Deficiency
Hyper-IgM Syndrome
Humoral Immunodeficiency
• Diagnosis:
– Clinical (good history and physical examination).
– Immunoglobulin profile (IgG, IgA, IgM, IgE).
– Antibody response to vaccines. Normally immunoglobulin
should increase by 4 folds after vaccination if it failed to
rise then there is humoral defeciency.
– Lymphocyte markers.
• Treatment:
– Early diagnosis and treatment of infections (usually
parentral antibiotics)
– IVGG replacement therapy.
– ? Prophylactic antibiotics.
ILLUSTRATED CASE (2)
• 4 months old boy:
–
–
–
–
–
–
–
–
–
Chest infection one month ago, not resolved yet.
Diarrhea.
Received vaccination at birth.
His brother died at age of 6 months because of chest
infection. (this indicate severe infection and illness)
Skin rash.
Oral thrush.
Growth parameters below 5%.
Tachypneic and on O2 1L/min (indicating pneumocyctis
carnii infection)
CBC showed mild lymphopenia, platlets 100, Hb 90
Severe Combined immunodeficiency (SCID)
• Complete absence of normal lymphocyte
function.
• Usually start early in life (at birth)
• Recurrent and chronic respiratory infections.
• Opportunistic and disseminated infections
(PCP, BCGitis, CMV, Candidemia)
• Persistent oral thrush.
• Chronic diarrhea with failure to thrive.
• It Could be an X-linked or AR.
Severe Combined immunodeficiency (SCID)
• Examples:
– XL-SCID
– JAK3 deficiency.
– ADA deficiency
• Diagnosis:
– Clinical.
– CBC, Diff: lymphopenia , decreased T4 cells, B cells might
be normal or decreased in count, even if their count is
normal their function is abnormal.
– Lymphocytes markers.
– Immunoglobulins levels and function (function is measured
by comparing the count before and after stimulating their
proliferation
– Blastogenesis: function of T-cells.
Phenotypic classification of SCID
NK+
IL-7R DEFICIENCY
CD3 deficiency
NK-
c deficiency
JAK 3 deficiency
NK+
RAG 1/2 deficiency
Artemise deficiency
? other
B+
T-
BNK-
ADA deficiency
Reticular dysgenesis
Mechanism of SCID
A Fischer, Immunological Review, 20
18.0
15
12.0
9.0
6.0
3.0
1.5
0
0
2
4
6
8
10
12
Age (months)
Absolute lymphocyte counts in infants with ( SCID)
SEVERE COMBINED
IMMUNODEFICIENCY (SCID)
•
Treatment:
1. NO LIVE VACCINES! (live vaccines are given at birth and at the
age of 1 (BCG) and these should not be given in cases of immune
deficiency. If discovered late, oral polio vaccine (live) should not be
given to avoid poliomyelitis infection. Nowadays, oral polio isonly
found in remote areas.
2. Blood transfusion should be irradiated (to get rid of T lymphocytes)
and CMV ( even very small particles can produce infection ). RBC
are not problematic because they are enucleated but the blood
product might contain some lymphocytes that will trigger the
immune response and may cause a mortality rate of up to 80% and a
morbidity of 100%.
3. Prevent contact with sick patients
4. Treat infection aggressively.
5. IVGG replacement therapy.
6. Prophylactic antibiotic (Septra).
7. Stem cell transplantation. ( bone marrow transplant has a cure rate of
85% )
8. Screen the family (newly born)
MANAGEMENT: BUBBLE!!
MANAGEMENT:
STEM CELL TRANSPLANTATION
STEM CELL TRANSPLANTATION
STEM CELL TRANSPLANTATION
DONOR
RECEPIENT
Stem cell transplantation in PID:
local experience:1993-2004
70
60
50
40
30
20
10
0
ADA def Omenn
Other
SCID
BLS
WAS
Neut
defect
Stem Cell transplantation in SCID
KFSH Experience 1993-2004
10 (11%)
4 (4%)
4 (4%)
T-,B- SCID
Omenn Syndrome
ZAP-70 Deficiency
9 (10%)
ADA Deficiency
T-,B+ SCID
62 (71%)
Distribution according to SCID phenotype
STEM CELL TRANSPLANTATION IN SCID 19932004
LOCAL EXPERIENCE
Overall Survival:Immune Deficiency
Pediatric Allogeneic Transplant 1993-2004
Mean survival time=99.6 months .Survival 79.82%
1.0
.9
.8
Cum Survival
.7
.6
.5
.4
.3
.2
Survival Function
.1
0.0
0
20
40
60
80
Time in months
100
120
140
STEM CELL TRANSPLANTATION IN SCID
1993-2004
LOCAL EXPERIENCE
Overall Survival Immune Deficiency
SCIDS 1993-2004
1.0
.9
.8
Cum Survival
.7
.6
.5
.4
.3
.2
Survival Function
.1
0.0
Censored
0
20
40
60
80
Time in months
100
120
140
MANAGEMENT:
GENE THERAPY TRIALS
GENE THERAPY: PRINCIPLE
Replication deficient virus with transgene in genome
Viral DNA is joined to cell chromosome
Transgene product is expressed
Viral DNA replicates with the
chromosome and is inherited by
progeny cells
Ex vivo gene transfer
Remove cells from patient
Transduce cells in culture
Select cells expressing
transgene
Replace cells in patient
COMBINED IMMUNODEFICIENCY
• MHC-II deficiency (Bare Lymphocyte syndrome) the
crucial point is chronic diarrhea and recurrent infection.
• Wiskott-Aldrich syndrome (WAS).
• Ataxia-telangiectasia (A-T).
• DiGeorge syndrome (22q11 chromosome deletion).
• The X-linked hyper-IgM syndrome.
• X-linked lymphoproliferative disorder (XLP).
Bare Lymphocyte syndrome
(MHC deficiency)imp
• Significant AR (?severe) combined immune defect
– Class I (CD8)
--Class II (CD4).
--Combined
•
•
•
•
•
Recurrent infection (opportunistic).
Chronic diarrhea (cryptosporidium)& Failure to thrive
Lethal on the first decade if not treated.
Dx: Lymphocyte markers and Blastogenesis
Rx:
– IVGG
-- Septra Px.
– Bone marrow transplantation
T cell recognition of a peptide-MHC
complex
MHC CLASS I and II
T
Lymphocyte
APC
STEM CELL TRANSPLANTATION IN MHC II
DEFICIENCY
LOCAL EXPERIENCE 1993-2004
Overall Survival Immune Deficiency
Barelymphocyte Syndrome 1993-2004
1.00
Cum Survival
.80
.60
.40
.20
Survival Function
0.00
Censored
0
20
40
60
80
Time in months
100
120
140
ILLUSTRATED CASE
• 7 years old boy:
• Chest infection at age of 3yrs and last year, prolonged
hospitalization and IV antibiotic course.
• Aspergillus was isolated from lung biopsy.(either
combined or phagocytic)
• Gluteal and axillary abscess.
• Chronic diarrhoea with bloody stool. (25% of them
present with crohns like disease)
• Positive family history of similar problem brother and
uncle).
• Failure to thrive.
• Enlarged cervical and axillary lymph nodes.
Phagocytes defect
• Chronic Granulomatous Disease:
– Defective neutrophils killing. (the defect is not in the engulfing but in
producing the killing burst)
– Extreme susceptibility to infection with catalase producing organisms:
(S aureus and Aspergillus).
– Granulomatous inflammation that may affect any organ system (not
only infection also inflammation)
– X-linked or AR.
– Diagnosis:
• Clinical.
• Nitro Blue Tetrazolium they don’t oxidize the dye.
• Oxidative burst by flowcytometry.
– Treatment:
• Treat infection aggressively.
• Prophylactic antibiotic and antifungal.
• Bone marrow transplant ± IFN-γ
Cytoplasmic space
ACTIVATION
P
p47phox
???, lipid
mediated via
Phospholipase D
RhoGDI
Rac
p47phox
Second Activation
signal sequence
MEMBRANE
TRANSLOCATION
NADPH
P NADP
P
+
P
RhoGDI
GDP
Rac
P
p47phox
GTP
Rac
Phagocytic Cell Membrane
GTP
P
P
P
FAD
heme 1
p22phox
NO
NO 2
ClCl
Insufficient
Inhibition
H
O
H 2 O2
OH OH
O2OOON OOON
O2
HOCl
HOCl
2
???, phosphatidic acid
arachidonic acid,
phosphatidylinisitols
Vaculolar and/or
Extracelluar space
2
2
-
-
Defective
gp91phox
e-
Pathogens in CGD
Bacterial
Presentation
Staphylococcus aureus
Soft tissue infection, lymphadenitis,
liver abscess, osteomyelitis, pneumonia,
sepsis
Burkholderia species
Pneumonia, sepsis
Serratia marcescens
Pneumonia, osteomyelitis, sepsis, soft
tissue infection
Nocardia species
Chromobacterium
violaceum
Mycobacteria
Pneumonia, osteomyelitis, brain
abscess
Soft tissue infection, sepsis
BCGitis, dissaminated infection,
osteomyelitis
Pathogens in CGD
Fungal
Presentation
Aspergillus species
Pneumonia, osteomyelitis, brain
abscess
Paecilomyces species
Pneumonia, soft tissue infection,
osteomyelitis
Phaeohyphomycete species
(dark-walled fungi)
Pneumonia, soft tissue infection
Penicillium species
Pneumonia, soft tissue infection
Miscellaneous filamentous fungi
and yeasts
(Zygomycete, Acremonium,Candida )
Sepsis, soft tissue infection, liver
abscess
CGD
• 25% of patients with CGD have crohn’s like
diarrhea. The defect is not in phagocytosis but
in the oxygen burst.
CGD patient with skin infections due to Serratia marcescens
Barium swallow:
Esophageal involvement
in CGD. Esophageal
strictures caused by
granuloma formation
NBT
TEST
PATIENT
NORMAL
CARRIER
Previous photos
• You see clumps of blue back dye, meaning
that the NBT has been chemically
reduced, and you haven’t gotten rid of all
it.
• NBT dyes encounter the peroxide and will
turn blue black and this is when you will
see the dye inside the neutrophil. This
does not occur in chronic granulatmoas
disease.
Other phagocytic defects
• Neutropenia:
– Cyclic neutropenia.
– Kostmann disease.
• Leukocytes adhesion defect. There is failure of
migration to the site of infection and there will be
nodulated area with no pus production.
• Chediak-Higashi syndrome.
• Hyper IgE syndrome.
Omphalitis in LAD-I
B
A
C
Complement deficiencies
• Very rare.
• Early complement (C1q, C1r, C2, and C4).
– lead to autoimmune inflammatory pathology resembling
systemic lupus erythematosus.
• Terminal complement components (C5 -C8).
– Associated with both recurrent infections ( N meningitidis)
as well as rheumatic disease.
• hereditary angioedema:
–
–
–
–
AD disorder.
C1 esterase inhibitor deficiency.
Recurrent swelling and abdominal pain.
Life-threatening events.
Q.4: ONCE SUSPECTED
WHAT TO DO NEXT?
–NO LIVE VACCINES.
–Blood transfusion should be
irradiated and CMV negative.
–Prevent contact with sick patients
–Treat infection aggressively.
–Prophylactic antibiotic (Septra).
–Screen the family (newly born)