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Primary Immunodeficiency Diseases( PID )
Dr. Li XiaoyuDepartment of Pediatrics
The 1st affiliated hospital of Sun Yat-sen University
Objectives
What will I learn?
Characteristics of immune development in children
classification and
clinical manifestation
Diagnosis
Treatment
D.Deorge
WiskottAldrich
Case Presentation
D. George is a 2 year old male brought in by his parents Wiskott and Aldrich because of concerns about recurrent infections. They state he has been sick many times over the last two years. He has been in the hospital twice with some sort of infection. He has also had frequent upper respiratory infections and has had Otitis Media 7 times in the last two years.
The parents of D. George are very concerned.
They wonder is there something wrong with him.
● Is it normal to have so many infections?
● Could there be something wrong with his
immune system?
● How are you going to figure this out?
● Does he need testing?
Questions
●What other information should we try to get from D. George and the family?
● Are there clues we could be missing in the history?
● Are there clues in the physical?
Immunology review (development and features of IM)
Organs of the Immune System
Immune system
Specific
Nospecific
ILs
IFNγ
TNFα
IgM
IgG1 ~ 4
IgA1 、 2
IgD 、 IgE
phagocytic cells
Macrophages(MC/MΦ)
Neutrophils
T cells
B cells
( organs, cells and molecules ) complement system
Immunology Review
● Have Lymphoid Progenitor for Lymphocytes– Becomes T cell in Thymus
• Important in Cellular Immunity
• Develop into CD4, CD8 or other cells
• Secretes cytokines, interleukins, etc.
• Assists B cells in making immunoglobulins
– Becomes B cell in Bone Marrow• Begins with IgM
• Matures to form other immunoglobulins – IgA, IgE, or IgG (with subclasses IgG1-4)
• Mature cell is Plasma cell
• Immunoglobulins used to surround antigens for phagocytosis
• Responsible for Specific immunity (and memory)
B Plasma IgM
B Plasma IgA
IgA
IgM
B Plasma IgG
IgG
B PlasmaIgE
IgE
CD19+
CD20 +
SLSC
ProBCFU
MØPMNPletRBC
PreB
PT T
THYRUM Epi.
BMCD3+
CD8+
CD4+TH1
TH2CTL
IFN-γ 、 IL-2
IL-4 、 5 、 8 、9 、 10 、 13
Development of Immune cell
More Immunology Review?
●Neutrophils and Macrophages
– Surround and gobble up organisms, often those
surrounded by immunoglobulins (Phagocytosis
and Opsonization).
– Part of natural or innate or nonspecific
immunity.
● Complement system
– Cascade of plasma proteins which aid in
chemotaxis and opsonization.
Characteristic of immune development in children
• T cell and cytokine CTL ↓ —— susceptibility to infections
TH2 ↑ —— allergic diseases • B cell and antibody antibody production↓ , all kinds of Ig↓
• MC/MΦ function insufficient
• PMN function insufficient
• Complement system
• Other immune molecules
Mannose-binding lectin
Development of Immunoglobulin
IgG from mother IgG of infant
6Mbirth
100%
IgG level of Infant
Age dependent changes of serum Igs levels(g/L)
Ages IgG IgA IgM
Neonate 6.46-17.74 0.004-0.017 0.05-0.27
1m- 2.75-7.50 0.05-0.60 0.10-0.70
4m- 3.70-8.30 0.14-0.50 0.33-1.25
7m- 3.50-8.90 0.06-0.54 0.36-1.20
1y- 5.52-11.46 0.06-0.74 0.60-2.12
3y- 4.95-12.74 0.33-0.89 0.65-2.01
7y- 6.09-12.85 0.52-2.16 0.67-2.46
12y- 6.98-14.26 0.92-2.50 0.56-2.18
15-18y 7.54-16.02 0.89-3.24 0.72-2.28
Schematic diagram of the exposure of microorganism during early life
fetus Full tern 6M Day care
pathogens
probiotics
Period of susceptible children
prematureFull term
6M Day care
Prevalence
●“The first cause of recurrent infections in children is childhood itself.”
● Average number of infections is 6-8 URI’s per year.
● Common triggers for more frequent URI’s.– Daycare
– Smoking
– Allergies and asthma
Prevalence
• Most children with recurrent infections
don’t have primary immunodeficiency
– 90% have secondary cause
Secondary Causes of Recurrent Infections
• HIV, HIV, and HIV• Anatomic
– Foreign Body– Central line– Eustacian Tube Obstruction– Sinus tract/fistula– Sacral Dimple– Cribiform Plate Disruption – Lung sequestration– Hypotonia causing
aspiration– Vesicoureteral Reflux
• Medications• Allergy or Asthma • Cystic Fibrosis• GERD• Malnutrition• Sickle Cell• Asplenia• Diabetes• Cancer• Colonization with resistant
organism (i.e. MRSA)
Primary Immunodeficiency Disease
• A group of disorders characterized by an impaired ability to produce normal immune response. Most of these disorders are caused by mutations in genes involved in the development and function of immune organs, cells, and molecules.
• Clinical features : Recurrent infection, high risk of autoimmune diseases, allergy and malignancy
50%
20%
10%
18%2%
Antibody
ComplementPhagocyte
Cell mediated
Combined
Distribution of PID
Up to 2007 more then 200 kinds of PID reported
Classification(new)
• Combined Immunodeficiency (B and T cells)
• Predominantly antibody deficiency (B cells and Ab)
• Predominantly T-cell deficiency (T cells)
• Immunodeficiency syndromes
• Phagocyte deficiency (PMN’s)
• Complement deficiency• Others
Note:-- There is significant overlap among syndromes. --Great variability in expression of disorders for all categories from mild to severe/fatal.
Combined immunodeficiencies ( 1 )
1. Severe combined immunodeficiency ( SCID )
X-linked (γc deficiency)
Autosomal recessive (Jak3 deficiency)
RAG1/RAG2 deficiency
Adenosine deaminase (ADA) deficiency Reticular dysgenesis
T T – – B +B +
T T - - B B --
Severe Combined Immunodeficiency , SCID (Bubble boy)
Combined immunodeficiencies ( 2 )
2. Hyper-IgM syndrome
3. Purine nucleoside phosphorylase
(PNP) deficiency
4. MHC class deficiencyⅡ
ADA & PNP deficiency
deaminization
inosine↓ ADAdeficiency
deoxyadenosine↑ dAMP↑
dADP↑
dATP↑dATP↑
ribonucleotide reductase↓
DNA synthsize↓blood
urineUric acid ↓
dGTP↑dGTP↑
dGDP↑
dGMP↑ deoxyguanosine ↑ PNP
deficiencyuridine↓
T/B cell mature compromised
Clinical features of combined immunodeficiency
• Onset age at early infants(4 - 5 months)
• Recurrent infection with fungi, virus, bacteria, mycobacterium, protozoa
• Opportunistic infections
• Poor prognosis, early infant deaths
• Severe infection after live virus vaccine and BCG
• GVHD after blood transfusion
• High risk of malignancy
Humoral / B-cell Defects
Predominantly antibody defects ● Panhypogammaglobulinemia
X-linked agammaglobulinaemia ( Bruton disease )
Common variable immunodeficiency ( CVID )
Transient hypogammaglobulinaemia of infancy
(ITHG)
● Selective Ig deficiency Ig heavy chain deficiency
IgA deficiency
Selective IgG subclass deficiency
—Bruton disease
— mutations in btk
—maturation disorder
of pre-B cell
CVID—variable (lack of signals from T cells)
ITHG—delayed maturation of TH function
Predominantly antibody defects
Common clinical manifestations:
● Recurrent bacterial infections (sepsis and meningitis)
● Viral ,fungal or protozoan infections rareViral ,fungal or protozoan infections rare
● Lymphatic system hypoplasia- Lymphatic system hypoplasia- tonsils, lymph node
( except CVID )
● Autoimmune disease
Predominantly antibody defects
Laboratory test
●Serum Ig ↓ (< 3 ~ 4g/L )● Natural antibody ↓ ( hemagglutinin titers < 1 4∶ )
● Common antibody ↓ ,> 2 A , ASO < 1 10∶
● Antibody responses to vaccine antigens ↓
● Circulating B cell ( CD19+、 CD20
+)↓,
bearing Ig cell ↓
.
Cell-Mediated/T cell Immunity
Predominantly T-cell defects
1. CD4+ deficiency
2. CD7+ deficiency
3. IL-2 deficiency
4. multiple cytokines deficiency
( IL-2 、 -4 、 -5 )Not completely understood
??
Destination serum Ig B-cells T-cells genetic defect clinical findings
● Wiskott- IgM↓ Normal Progressive↓ XL Thrombocytopenia
Aldrich Syn. Mutation in WAS eczema
lymphoma
● Ataxia- IgA, E, G↓ Normal ↓ ATM Ataxia,
Telangiectasia IgM ↑ telangiectasia
● DiGeorge Normal or ↓ Normal ↓or normal Deletion of Hypoparathyroidism
Syn. chromosome conotruncal defect
22q11.2-pter abnormal facies
Immunodeficiency syndrome
deficiencies
Wiskott-Aldrich Syndrome
• X-linked Recessive
• Gene defect of WAS protein
• B and T cell dysfunction
• Triad of – Thrombocytopenia
– Eczema
– Recurrent pyogenic infections
• Treatment – Stem cell or Bone Marrow transplant
• Prognosis - Average life expectancy 11 years
(( eczemeczemaa))
Ataxia-Telangiectasia
• Autosomal Recessive
• Have both B and T cell dysfunction – more characteristics of B cell dysfunction
• Associated Symptoms– Ataxia from early age – progressive
– Telangiectasia develop after 2 yrs
– High risk for various malignancies
– Endocrine abnormalities – many with Diabetes
– Liver Dysfunction
• Treatment – supportive
• Prognosis – death often in early childhood
Ataxia
telangiectasia
DiGeorge Syndrome
DiGeorge Syndrome• Deletion of chromosome 22q11.2
– Defective development of 3rd and 4th pharyngeal pouches
• Absence of Thymus– Therefore low or absent T cells
– No B cell abnormalities except in more severe forms.
• Associated Anomalies– Conotruncal Cardiac Defects
• VSD
• Tetralogy of Fallot
• Interrupted Aortic Arch
– Parathyroid Hypoplasia • Low Calcium
• Tetany
DiGeorge Syndrome
• Other Anomalies– Cleft Palate
– Velocardiofacial Syndrome
– Esophageal abnormalities
– Ocular anomalies
– Renal anomalies
– Increased incidence of Autoimmune disease
• Diagnosis – FISH– Will often have decreased CD3 T cells
• Treatment– IVIG and antibiotic prophylaxis
– Should be on TMP/SFA for PCP prophylaxis
– Thymic transplant or Bone marrow transplant
DiGeorge anormaly
HypertelorismHypertelorism
hooded eyelidshooded eyelids
short philtrum with
fish-mouth appearance ,
micrognathia
Low set earsLow set ears
telecanthus with short telecanthus with short
palpebral fissurespalpebral fissures
Facial features of children with DiGeorge syndrome
DiGeorge syndrome
Phagocytic Disorders
Congenital defects of phagocytic
number and/or function
● Severe congenital neutropenia ( SCN , Kostmann syndrome )
●Chronic granulomatous disease
● Chediak-Hiashi syndrome
Bacteria
phagosome
Bacteria
Phagosome
Neutrophil
NADPH H+NADPH H+
e- +O2
O2-
H+
H2O2
Normsal phagocyte Dysfunction of phagocyte
Chronic granulomatous disease
Chronic Granulomatous Disease
• Rare – 20 cases/year in the US
• Genetics– 70 % X-linked recessive
– Defect in NADPH oxidase
– Can’t form reactive oxygen species to destroy micro-organisms
• Symptoms– Pneumonia, Abscesses, Adenitis, Osteomyelitis
– Uniquely susceptible to Aspergillosis
Chronic Granulomatous Disease
• Associated Symptoms– Severe Acne
– Excessive Granulomata – often in GI tract
– Lupus
– Chorioretinitis
• Diagnosis – Nitroblue Tetrazolium Test (NBT)
• Treatment– Antibacterial and antifungal prophylaxis
– Interferon Gamma
– Stem cell or Bone Marrow Transplant
Complement Disorders
Complement deficiency
Defects Inheritance Clinical findings● Classical pathway Infections ,
(C1q 、 r 、 s 、 C2 、 C4) AR Autoimmune disease
C1 inhibitor AD Hereditary angioedema
● Alternaive pathway Recurrent pyogenic infection
(C3 、 FactorⅠ、 FactorH) AR
● Others Neisseria infection
(C5 ~ 8 、 properdin 、 factor D) AR Lupus-link syndrome
C9 AR Asymptomatic
Common clinical manifestationsPIDPID
● Infection recurrent
▼Age >50 % younger than 3 yrs
▼Location respiratory tract , GI tract…
▼Pathogen
▼Course
● Malignancy and autoimmune disease
● Tendency of inheritance <15yrs 80 % male
● Others
Table 1. Characteristic infections of the primary immunodeficiencies
component primary pathogen primary site clinical example
T-cells intracellular, bacteria viruses, protozoa, fungi,
non-specific SCID, DiGeorge
B-cells
pneumococcus,streptococcus, haemophilus
lung, skin, CNSIgG, IgM deficiencyIgG, IgM deficiency
enteric bacteria and viruses GI, nasal, eye IgA deficiency
phagocytesStaphylococcal, Klebsiella
Pseudomonas,lung, skin, regional
lymph node
Chronicgranulomatous disease (CGD)
complementneisseria, Haemophilus,
pneumococcus, streptococcus
CNSlungskin
C3, Factors I and H, late C omponents
Approach to the patients with suspected immunodeficiency
● The medical history in immunodeficiency
● Physical examination
● Laboratory investigation
Key History
● Get history of infections– Location
– Organism
– Frequency
– Response to therapy
– Seriousness (i.e. hospitalization)
● Family History – Including Consanguinity
● Growth Pattern
Increasing susceptibility to infections
Increasing duration of infections
Increasing severity of infection
Continuous illness
Dependence to antibiotics
Infection with opportunistic agents
Unusual infection
Characteristics of infections
From INFO4PI.ORG
Physical finding
●Failure to thrive
● Dysmorphism(abnormal facial features)
● Skin and mucosa
– Eczema, petechiae
– Abscesses, pyoderma
– Telangiectasia
– Delayed umbilical separation
● Respiratory tract
• ………
Diagnostic Work Up
● Antibody Defects– Quantitative - Immunoglobulin levels– Functional - Antibody Titers to immunizations
● T cell– Quantitative – CBC, Abs lymphocyte count– Functional – Skin tests for antigens (Mumps, candida, etc.)– Chest x-ray
● Phagocyte – Quantitative – CBC, Abs neutrophil count– Functional – NBT test
● Complement– Quantitative – C3, C4– Functional – CH50
Initial and advanced laboratory tests for immunodeficiency
From INFO4PI.ORG
Management of PID
● General treatment
● Replacement therapy
● Immune reconstruction
● Gene therapy
General management of PID
● Diet
● Avoidance of pathogens (“germ-free” care)
● Antibiotics
– Use in acute illness
– Prophylactic
● A void whole blood transfusion in combined
immunodeficiency disorder(GVHR)
● Avoid live virus vaccines and BCG
Bubble Boy
Immunoglobulin replacement
• Treatment of severe antibody disorders
●IVIG 400 ~ 600mg/kg/m iv drip
● Frozen plasma 10ml/kg/month
◎ Caution with administration of blood production
if selective IgA deficiency
How to get out of the bubble ?
Specific treatment for cellular deficiency
● Bone marrow transplantation
● Replacement therapy– Enzyme replacement
– Gene therapy
– Thymic hormones
– Cytokines
● Fetal thymus transplantation
A new hope for gene therapy of immunodeficency
how to get out of the bubble?
Specific treatment of phagocytic disorders
● Interferon gamma for CGD
● Granulocyte transfusion
Case Presentation
D. George is a 2 year old male brought in by
his parents Wiskott and Aldrich because of
concerns about recurrent infections. They
state he has been sick many times over the last
two years. He has been in the hospital twice
with some sort of infection. He has also had
frequent upper respiratory infections and has
had Otitis Media 7 times in the last two years.
Questions
●What other history should we get?
● Does the child need work up for
immunodeficiency?
– Depends on history
– What immunodeficiency should we worry
about?
– What work up should be done?
Related website
http://www.info4pi.org/aboutPIin/
http://elearning.sysu.edu.cn
Thanks you
for
your
attentio
n
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