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

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