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  • 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.
  • 13. 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
  • 14. Development of Immunoglobulin IgG level of Infant 100% IgG from mother IgG of infant birth 6M
  • 15. 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
  • 16. Schematic diagram of the exposure of microorganism during early life pathogens probiotics fetus Full tern 6M Day care
  • 17. Period of susceptible children premature 6M Day care Full term
  • 18. 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
  • 19. Prevalence • Most children with recurrent infections don’t have primary immunodeficiency – 90% have secondary cause
  • 20. 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)
  • 21. 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
  • 22. Up to 2007 more then 200 kinds of PID reported Complement Phagocyte 2% 18% Cell mediated 10% Antibody 50% Combined 20% Distribution of PID
  • 23. 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.
  • 24. 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 -
  • 25. Severe Combined Immunodeficiency,SCID (Bubble boy)
  • 26. Combined immunodeficiencies (2) 2. Hyper-IgM syndrome 3. Purine nucleoside phosphorylase (PNP) deficiency 4. MHC class Ⅱ deficiency
  • 27. 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
  • 28. 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
  • 29. Humoral / B-cell Defects
  • 30. 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
  • 31. —Bruton disease — mutations in btk —maturation disorder of pre-B cell
  • 32. CVID—variable (lack of signals from T cells) ITHG—delayed maturation of TH function
  • 33. 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
  • 34. 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 ↓
  • 35. Cell-Mediated/T cell Immunity .
  • 36. 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
  • 37. 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
  • 38. 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
  • 39. (eczema)
  • 40. 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
  • 41. Ataxia
  • 42. telangiectasia
  • 43. DiGeorge Syndrome
  • 44. 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
  • 45. 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
  • 46. DiGeorge anormaly
  • 47. 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
  • 48. DiGeorge syndrome
  • 49. Phagocytic Disorders
  • 50. Congenital defects of phagocytic number and/or function ● Severe congenital neutropenia (SCN,Kostmann syndrome) ●Chronic granulomatous disease ● Chediak-Hiashi syndrome
  • 51. Chronic granulomatous disease Normsal phagocyte Dysfunction of phagocyte Neutrophil Bacteria Bacteria phagosome Phagosome NADPH H+ NADPH H+ e- +O2 O2- H+ H2O2
  • 52. 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
  • 53. 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
  • 54. Complement Disorders
  • 55. 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
  • 56. 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
  • 57. 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
  • 58. Approach to the patients with suspected immunodeficiency ● The medical history in immunodeficiency ● Physical examination ● Laboratory investigation
  • 59. Key History ● Get history of infections – Location – Organism – Frequency – Response to therapy – Seriousness (i.e. hospitalization) ● Family History – Including Consanguinity ● Growth Pattern
  • 60. 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
  • 61. From INFO4PI.ORG
  • 62. Physical finding ●Failure to thrive ● Dysmorphism(abnormal facial features) ● Skin and mucosa – Eczema, petechiae – Abscesses, pyoderma – Telangiectasia – Delayed umbilical separation ● Respiratory tract • ………
  • 63. 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
  • 64. Initial and advanced laboratory tests for immunodeficiency
  • 65. Management of PID ● General treatment ● Replacement therapy ● Immune reconstruction ● Gene therapy
  • 66. 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
  • 67. Bubble Boy
  • 68. 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
  • 69. How to get out of the bubble ?
  • 70. Specific treatment for cellular deficiency ● Bone marrow transplantation ● Replacement therapy – Enzyme replacement – Gene therapy – Thymic hormones – Cytokines ● Fetal thymus transplantation
  • 71. A new hope for gene therapy of immunodeficency how to get out of the bubble?
  • 72. Specific treatment of phagocytic disorders ● Interferon gamma for CGD ● Granulocyte transfusion
  • 73. 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.
  • 74. 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?
  • 75. Related website http://www.info4pi.org/aboutPIin/ http://elearning.sysu.edu.cn