1. Primary Immunodeficiency Diseases
（PID）
Dr. Li Xiaoyu
Department of Pediatrics
The 1st affiliated hospital of Sun Yat-sen
University

2. Objectives
Characteristics of immune
development in children
What will I
learn? classification and
clinical manifestation
Diagnosis
Treatment

3. Aldrich Wiskott
D.Deorge

4. 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.

5. 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?

6. Questions
●What other information should we try to
get from D. George and the family?
● Arethere clues we could be missing in
the history?
● Are there clues in the physical?

7. Immunology review
(development and features of IM)

8. Organs of the
Immune System

9. ILs
T cells IFNγ
TNFα
Specific IgM
B cells IgG1～4
IgA1、2
Immune
system IgD、IgE
（organs, cells
and molecules ） complement system
Nospecific Macrophages
(MC/MΦ)
phagocytic cells
Neutrophils

10. 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)

11. Development of Immune cell
THYRUM
TH1 IFN-γ、IL-2
Epi. CD3+ CD4+
BM PT T
TH2 IL-4 、5 、8、
CD8+
SC CTL 9、10、13
SL
CD19+ IgM
CD20 + IgM
ProB PreB B Plasma
CFU IgG
B Plasma IgG
IgA
RBC MØ
Plet PMN B Plasma IgA
IgE
IgE
B Plasma

12. 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.

14. 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

15. Development of Immunoglobulin
IgG level of Infant
100%
IgG from mother IgG of infant
birth 6M

16. 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

17. Schematic diagram of the exposure
of microorganism during early life
pathogens
probiotics
fetus Full tern 6M Day care

18. Period of susceptible children
premature 6M Day care
Full term

19. 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

20. Prevalence
• Most children with recurrent infections
don’t have primary immunodeficiency
– 90% have secondary cause

21. Secondary Causes of Recurrent Infections
• HIV, HIV, and HIV • Medications
• Anatomic • Allergy or Asthma
– Foreign Body
• Cystic Fibrosis
– Central line
– Eustacian Tube Obstruction • GERD
– Sinus tract/fistula • Malnutrition
– Sacral Dimple
• Sickle Cell
– Cribiform Plate Disruption
– Lung sequestration • Asplenia
– Hypotonia causing • Diabetes
aspiration
– Vesicoureteral Reflux • Cancer
• Colonization with
resistant organism (i.e.
MRSA)

22. 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

23. Up to 2007 more then 200 kinds of PID
reported
Complement
Phagocyte
2%
18%
Cell mediated
10% Antibody
50%
Combined
20%
Distribution of PID

25. 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.

26. Combined immunodeficiencies（1）
1. Severe combined immunodeficiency（SCID）
X-linked (γc deficiency)
T –B +
Autosomal recessive (Jak3 deficiency)
RAG1/RAG2 deficiency
Adenosine deaminase (ADA) deficiency
Reticular dysgenesis T -B -

27. Severe Combined Immunodeficiency，SCID
(Bubble boy)

28. Combined immunodeficiencies （2）
2. Hyper-IgM syndrome
3. Purine nucleoside phosphorylase
(PNP) deficiency
4. MHC class Ⅱ deficiency

29. ADA ＆ PNP deficiency
deaminization
ADA deoxyadenosine↑ dAMP↑
inosine↓ deficiency
dADP↑
dATP↑
DNA
blood ribonucleotide
Uric acid ↓ synthsize↓ reductase↓
urine
dGTP↑
T/B cell mature compromised
dGDP↑
dGMP↑
uridine↓ PNP deoxyguanosine ↑
deficiency

30. 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

31. Humoral / B-cell Defects

32. 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

33. —Bruton disease
— mutations in btk
—maturation disorder
of pre-B cell

34. CVID—variable (lack of signals from T cells)
ITHG—delayed maturation of TH function

35. Predominantly antibody defects
Common clinical manifestations:
● Recurrent bacterial infections (sepsis and meningitis)
● Viral ,fungal or protozoan infections rare
● Lymphatic system hypoplasia- tonsils, lymph node
（except CVID）
● Autoimmune disease

36. 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 ↓

37. Cell-Mediated/T cell Immunity
.

38. 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

39. Immunodeficiency syndrome
deficiencies
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

40. 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

41. （eczema）

42. 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

43. Ataxia

44. telangiectasia

45. DiGeorge Syndrome

46. 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

47. 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

48. DiGeorge anormaly

49. Facial features of children with DiGeorge syndrome
Hypertelorism
hooded eyelids
short philtrum with
fish-mouth appearance ,
micrognathia
Low set ears
telecanthus with short
palpebral fissures

50. DiGeorge syndrome

51. Phagocytic Disorders

52. Congenital defects of phagocytic
number and/or function
● Severe congenital neutropenia
（SCN，Kostmann syndrome）
●Chronic granulomatous disease
● Chediak-Hiashi syndrome

53. Chronic granulomatous disease
Normsal phagocyte Dysfunction of phagocyte
Neutrophil
Bacteria Bacteria
phagosome Phagosome
NADPH H+ NADPH H+
e- +O2
O2-
H+
H2O2

54. 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

55. 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

56. Complement Disorders

57. 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

58. Common clinical manifestations
PID
● 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

59. Table 1. Characteristic infections of the primary immunodeficiencies
component primary pathogen primary site clinical example
intracellular, bacteria
T-cells non-specific SCID, DiGeorge
viruses, protozoa, fungi,
pneumococcus,
IgG, IgM deficiency
streptococcus, lung, skin, CNS
IgG, IgM deficiency
B-cells haemophilus
enteric bacteria and viruses GI, nasal, eye IgA deficiency
Chronic
Staphylococcal, Klebsiella lung, skin, regional
phagocytes granulomatous
Pseudomonas, lymph node
disease (CGD)
neisseria, Haemophilus, CNS
C3, Factors I and H,
complement pneumococcus, lung
late C omponents
streptococcus skin

60. Approach to the patients with
suspected immunodeficiency
● The medical history in immunodeficiency
● Physical examination
● Laboratory investigation

61. Key History
● Get history of infections
– Location
– Organism
– Frequency
– Response to therapy
– Seriousness (i.e. hospitalization)
● Family History – Including Consanguinity
● Growth Pattern

62. Characteristics of infections
 Increasing susceptibility to infections
 Increasing severity of infection
 Increasing duration of infections
 Unusual infection
 Infection with opportunistic agents
 Continuous illness
 Dependence to antibiotics

63. From INFO4PI.ORG

64. Physical finding
●Failure to thrive
● Dysmorphism(abnormal facial features)
● Skin and mucosa
– Eczema, petechiae
– Abscesses, pyoderma
– Telangiectasia
– Delayed umbilical separation
● Respiratory tract
• ………

65. 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

66. Initial and advanced laboratory tests for
immunodeficiency

68. Management of PID
● General treatment
● Replacement therapy
● Immune reconstruction
● Gene therapy

69. 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

70. Bubble Boy

71. 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

72. How to get out of the bubble ?

73. Specific treatment for cellular deficiency
● Bone marrow transplantation
● Replacement therapy
– Enzyme replacement
– Gene therapy
– Thymic hormones
– Cytokines
● Fetal thymus transplantation

74. A new hope for gene therapy of immunodeficency
how to get out of the bubble?

75. Specific treatment of phagocytic disorders
● Interferon gamma for CGD
● Granulocyte transfusion

76. 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.

77. 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?

80. Related website
http://www.info4pi.org/aboutPIin/
http://elearning.sysu.edu.cn