MAKE ANTIBODIES. Signs & Symptoms of Primary Immune Deficiency

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1 Signs & Symptoms of Primary Immune Deficiency MAKE ANTIBODIES Dr Jovanka King Department of Allergy & Immunology Women s & Children s Hospital, Adelaide

2 Overview Cook s tour of the immune system Signs & symptoms of PID Making a diagnosis of PID Patient examples

3 The Cook s Tour

4 The Immune System Complex arrangement of: Cells Body tissues/organs Messengers proteins & other molecules important for cell development & communication

5 Functions of the Immune System Protection from infection Bacteria Viruses Fungi Parasites Killing of tumour/cancer cells

6 Disorders of the Immune System Allergic Disease E.g., Eczema, hay fever, food allergy, asthma Autoimmune Disease E.g., Arthritis, lupus, thyroid disease, diabetes Immunodeficiency Primary Secondary / Acquired

7 Primary Immunodeficiency Diseases Over 200 identified diseases Relatively uncommon Recurrent, severe, unusual infections Other features PIDs may be grouped into various categories Antibody deficiencies T & B cell (combined) deficiencies Immune deficiency syndromes

8 Overview of the Immune System T Cell B Cell NK cell Antibodies Stem Cell Neutrophils Complement Macrophages Red Blood Cells Platelets Innate Adaptive

9

10 T cells (T Lymphocytes) T Cell B Cell Important for handling bacterial, viral, fungal infections Stem Cell NK cell Neutrophils Macrophages Red Blood Cells Absent / low numbers Disorders - Severe combined immunodeficiency (SCID) Platelets

11 B cells (B Lymphocytes) T Cell B Cell IgG IgA IgM IgE NK cell Antibodies Stem Cell Neutrophils Bacterial, some viral infections Macrophages Red Blood Cells Platelets Normal Disorders Specific antibody deficiency Absent / Low Disorders XLA HIGM THI CVID

12 Natural Killer (NK) Cells T Cell B Cell NK cell Important for handling viral infections Stem Cell Neutrophils Low numbers / defective activity Macrophages Red Blood Cells Increased susceptibility to viral infections Platelets

13 Neutrophils T Cell B Cell Important for handling bacterial, fungal infections NK cell Low numbers / defective function Stem Cell Neutrophils Increased risk of infections Macrophages Red Blood Cells Platelets Disorders - Neutropaenia - Chronic Granulomatous Disease

14 Complement System Increased bacterial infections Absence / defective function

15 Signs & Symptoms of PID

16 When do we suspect immune deficiency? Most children will become unwell with infections at some stage Viral infections, colds are common in young children When do we become suspicious for an underlying PID condition?

17 The 7 Warning Signs of PID

18 The 7 Warning Signs of PID

19 The 7 Warning Signs of PID

20 The 7 Warning Signs of PID Ear, sinus, chest infections (pneumonia) Sepsis (bloodstream infection), abscesses Fungal infections, thrush Unusual infections (TB-like) Chronic diarrhoea Needing many courses of antibiotics or IV antibiotics Adults: recurrent viral infections

21 Making the Diagnosis

22 The Immunologist s Toolbox History Infections Growth Family History Examination Specific findings Making a list Investigations Depend on history & examination findings Checking it twice

23 Patient Examples

24 Oliver 3 month old baby boy Severe eczema & nappy rash Diarrhoea Poor weight gain since birth Two episodes of pneumonia

25 Oliver Male infant Type of infection Bacterial (pneumonia) Possible viral infection (diarrhoea) Fungal (nappy rash) Other symptoms Poor growth Eczema

26 Oliver Investigations Low total lymphocyte count Absent T cells (T lymphocytes) Absent B cells Absent NK cells

27 Oliver : T cell disorder T Cell B Cell Important for handling bacterial, viral, fungal infections Stem Cell NK cell Neutrophils Macrophages Red Blood Cells Absent / low numbers Disorders - Severe combined immunodeficiency (SCID) Platelets

28 Lachlan 8 month old boy Always sick Multiple ear & chest infections Lots of antibiotics needed Grandfather has had lots of chest infections On examination No tonsils!

29 Lachlan Young male child Type of infections Upper respiratory tract & chest Bacterial Family history Specific finding on examination

30 Lachlan Investigations: Low Immunoglobulin levels What could it be?

31 Bousfiha et al., 2012 Low Antibody (Immunoglobulin) Levels

32 Lachlan Low (undetectable) Immunoglobulin levels IgG, IgA, IgM No B cells

33 B cells (B Lymphocytes) T Cell B Cell IgG IgA IgM IgE NK cell Antibodies Stem Cell Neutrophils Bacterial, some viral infections Macrophages Red Blood Cells Platelets Normal Disorders Specific antibody deficiency Absent / Low Disorders XLA HIGM THI CVID

34 Clin. Microbiol. Rev. July 2009 vol. 22 no Lachlan Likely diagnosis: X-linked (Bruton s) Agammaglobulinaemia Further Investigations: BTK protein analysis Genetic test for abnormal BTK gene

35 Diagnosing PID The process of making a diagnosis of PID What are the signs & symptoms? What are the examination findings? What are the possible diagnoses? Which tests will be helpful?

36 Summary Primary Immunodeficiency Disorders should be considered in people who have recurrent, severe or unusual infections, or other features PIDs may be categorised according to the types of cells & cell systems affected Making a diagnosis depends on the person s medical history and examination findings, along with results of investigations

37 Questions?

38

39

40 Treatment Options for Primary Immune Deficiency Disorders CALL THE IMMUNOLOGIST Dr Jovanka King Department of Allergy & Immunology Women s & Children s Hospital, Adelaide

41 Overview Why is treatment of PID important? How do we decide on the ideal treatment? What treatment options are currently available, and when are they used?

42 Why is Treatment Important? Recurrent infections, feeling unwell, time missed from work/school Poor growth in children Complications of recurrent infection Ears Lungs Problems with other organ systems Heart/cardiovascular, gastrointestinal Increased risk of malignancy (cancers) & autoimmune disease

43 Treatment Options for Immune Deficiency Questions to consider What type of immune deficiency does the individual have? What is the best type of treatment for this disorder? What are the individual s symptoms? What are the risks vs. benefits? Are there any other considerations?

44 AVAILABLE TREATMENT OPTIONS FOR PID No Specific Treatment Anti-infective Therapies Immunoglobulin Replacement Disease-specific Therapy G-CSF Therapy Bone Marrow / Stem Cell Transplantation Gene Therapy

45 No Specific Treatment Mild symptoms Not significantly unwell Management Monitoring progress Regular review in clinics Blood investigations Health promotion

46 Anti-infective Therapy Antibiotics Active against bacterial infections DO NOT have activity against viruses Antibiotic choices vary Treatment for active infections Continuous preventative antibiotics Problems with antibiotics Side effects Resistance

47 Anti-infective Therapies Anti-fungal agents Eg. Fluconazole Specific preventative anti-infectives PCP prophylaxis - Bactrim Anti-viral agents Eg. Aciclovir

48 Conditions for which Antibiotics are used To treat active infections As sole therapy, e.g., Specific antibody deficiency Hypogammaglobulinaemia Additional to other therapies

49 Immunoglobulin Replacement Purified immunoglobulin (antibodies), collected from blood transfusions from multiple donors Modes of delivery Intravenous (~ monthly, in hospital) Subcutaneous (~ 1+ x per week, at home) Risks & Benefits Blood product Very effective in reducing infections Side effects

50 Immunoglobulin Replacement Antibody deficiencies Common variable immunodeficiency X-linked agammaglobulinaemia Specific antibody deficiency Hyper-IgM syndrome Combined immunodeficiencies Severe combined immunodeficiency Early therapy before definitive treatment

51 Other disease-specific therapies ADA-deficiency SCID (severe combined immunodeficiency) Enzyme replacement, injections of PEG-ADA Adenosine Lymphocytes do not survive ADA Enzyme Needed for T, B & NK cell development & survival Low levels of T, B, NK lymphocytes Deoxyadenosine ADA-deficiency SCID Severe, recurrent, unusual infections

52 G-CSF Low neutrophil counts are a feature of some PIDs G-CSF is a medication which increases the number of mature neutrophils produced & released by the bone marrow Given as injections, 1-2 x per week

53 One cell Many possibilities

54 One Cell Many Possibilities T Cell B Cell NK cell Antibodies Stem Cell Neutrophils Macrophages Red Blood Cells Platelets

55 Bone Marrow / Stem Cell Transplantation Patient Patient A suitable donor Bone Marrow / Stem Cell collection From the donor From umbilical cord blood Chemotherapy conditioning The donor cells are transplanted into the patient

56 Conditions for which BMT is used Primary immunodeficiency diseases Severe combined immunodeficiency (SCID) Combined immunodeficiency disorders (e.g., WAS) Hyper-IgM Syndrome (HIGM) Chronic granulomatous disease (CGD) Others Malignant diseases Metabolic diseases

57 Risks & Benefits of BMT Curative for many PIDs Best if performed as soon as possible after diagnosis in patients with SCID Risks vs Benefits Complications from conditioning procedure E.g., Infection Poor integration of donor cells ( engraftment ) Rejection Graft vs host disease

58 Genetic Material Mutations in genes can lead to disease Protein

59 Gene Therapy Gene therapy involves introducing a healthy copy of the faulty gene into the patient s cells Has been used for the treatment of SCID Most successful for ADA-SCID

60 Monitoring General health checkups Monitoring for known disease associations Monitoring for disease complications

61 What Else Can Be Done?

62 The Future : Screening for PID In many countries, newborn babies are screened for PID using the neonatal screening test (Guthrie card) Testing may pick up T and B cell deficiencies before symptoms occur Not yet available in Australia

63 Summary There are many different treatment options available for the management of PID Treatment choices depend upon the type of PID and individual factors General health care measures and monitoring are important

64 Recommended Resources

65 Questions?

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