Immune Deficiency Primary and Secondary. Dr Liz McDermott Immunology Department NUH

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1 Immune Deficiency Primary and Secondary Dr Liz McDermott Immunology Department NUH

2 Summary Different types of Immune Deficiency Why it is important to identify immune deficiency? Diagnostic delay Antibody deficiency Treatment of primary and secondary immune deficiency Immunoglobulin replacement

3 Primary Immune Deficiency genetics +/- environment Antibody deficiency XLA (X Linked Agammaglobulineamia) - (early) CVID (common Variable Immune Deficiency) Selective IgA deficiency Specific antibody deficiency Chronic Granulomatous Disease Combined immune deficiency Ataxia Telangiectasia Complement deficiencies

4 Secondary Immune Deficiency Malignancy Lymphoproliferative disease Uraemia Drugs steroids, immunosuppressants, anti-convulsants, Biologics HIV BMT Extremes of age Asplenia Malnutrition Burns Diabetes Protein losing enteropathy

5 Rituximab Anti-CD20 monoclonal antibody Figure from van Meerten and Hagenbeek.Seminars in Hematology 2010

6 Why Is It Important to Identify Immune Deficiency? In acute infections the investigation & management is different Unusual pathogens, persistent infection In Primary Immune Deficiency treatment is available in most cases e.g. Immunoglobulin replacement therapy Early Diagnosis improves clinical outcome Prevents organ damage e.g. bronchiectasis Life-saving

7 Diagnosis of Primary Immune Deficiency is often delayed - Why? Rare IgA deficiency 1 : CVID (Common Variable Immune Deficiency) 1 : Presents in a common way most patients with infections do not have immune deficiency A new type of immune deficiency identified every few months! Particularly with Next Generation Sequencing

8 How Can Diagnostic Delay Be Reduced? Any thoughts?...

9 When to Consider Immune Deficiency Need to differentiate between normal and immune deficiency pattern of infections Infections S evere P ersistent U nusual/opportunistic R ecurrent Associated problems: unusual inflammation, autoimmunity, granulomata,

10 Pattern of Infection Indicates Type of Primary Immune Deficiency 1) Recurrent sinopulmonary bacterial infections Antibody deficiency (Complement deficiency) (Phagocyte deficiency) 2) Recurrent Pyogenic infections +/- Fungal (Chest, lymphadenitis, skin, abscess) Phagocyte deficiency

11 How do you investigate recurrent sinopulmonary infections? Immunoglobulins Functional / Specific antibodies to tetanus, Hib, pneumococcus (with immunisation history)* T & B cell numbers (lymphocyte subsets) Complement screening (Immunology input) Not IgG subclasses as first choice *Sero-specific pneumococcal antibodies

12 Primary Antibody Deficiency 1:25000 Common Variable Immune Deficiency (CVID) X-Linked Agammaglobulinaemia (XLA) No mature B cells Specific antibody deficiency normal Igs, poor response to vaccination Selective IgA deficiency Most asymptomatic

13 Presenting Infections in Antibody Deficiency Respiratory infections Ear Sinus G I infections Cutaneous infections CNS/Meningitis Septic arthritis/osteomyelitis Ophthalmic

14 What are the roles of antibodies/immunoglobulins?

15 The role of immunoglobulins Opsonization: Cover microbes to help phagocytes & APCs to engulf them (extracellular bacteria), mainly IgG1 & IgG3 Neutralization: bind to antigen & then stops the antigen bind to the tissues, IgM>IgG (viruses, toxins) Activate the complement system: which assists phagocytosis, other roles of complement, mainly IgM, also IgG1 & IgG3 Antibody dependent cell cytotoxicity: helps cytotoxic action of NK cells (viral infected cells)

16 Phagocytosis assisted by IgG and complement

17 Half-life IgG 21 days IgA 10 days IgM 6 days

18 T & B cell Interaction CD40L CD40 T cell B cell cytokines

19 Treatment

20 Treatment in Primary and Secondary Immune Deficiency Prompt antibiotics & prolonged course in acute infections IV or SC Immunoglobulin replacement therapy (IVIG or SCIG) +/- prophylactic antibiotics Culture everything! Treat complications

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22 SCIG infusion in a Child

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26 Case Age 48 male Referred with recurrent chest infections Well as child/younger person Early 40s developed recurrent chest infections Admitted with pneumonia 18/12 ago Recent admission pneumonia, Strep Pneum

27 Case Winter months worst Often need 2 course of antibiotics to clear infection Weight loss recently (2 Kg) No nights sweats No family history No medications What immunology tests would you do?

28 Investigations IgG 1.02 ( ) mg/l IgA 0.20 (0.8-4) mg/l IgM 0.12 ( ) mg/l No paraprotein No Bence Jones protein

29 Functional Antibodies Pneumococcal abs <1.50 mg/l (>40) Tetanus abs 0.15 IU/mL (>0.15) H. influenzae b (Hib) abs 0.03 mg/l (>1.0) Pneumo & Hib very low Pneumovax II & Hib immunisations given & then retest after 4 weeks Test Immunisation

30 Post-Vaccination Levels Pneumo abs < mg/l Hib abs mg/l Should see about 3 fold increase and be in normal range

31 Other Investigations Lymphocyte subsets (markers): normal T & B cell numbers but low class switched memory B cells (CD19/IgG/CD27) HRCT scan chest: bronchiectasis RLL Bone Marrow: normal CT chest/abdo/pelvis: few small abdominal lymph nodes, nil suspicious of lymphoma

32 Diagnosis Primary antibody deficiency Most likely CVID (Common Variable Immune Deficiency) Diagnosis of exclusion - Negative genetic tests for other causes: X Linked Agammaglobulinaemia, X Linked Lymphoproliferative disease, etc.

33 Treatment Treat IVIG replacement Chest physio Prompt antibiotics for acute infections & double usual length course Microbiology specimens wherever possible

34 IVIG Mechanism of action Replacement therapy Immuno-modulatory DOH demand management plan Prescribing IVIG IVIG database

35 Immunoglobulin replacement therapy IgG purified from plasma pool from ,000 donor units Highly processed to reduce blood borne infection Replacement: g/Kg/month, adjusted to response IVIG given 3 weekly, SCIG given weekly No clonal expansion, so no focussing to current infection Immunomodulatory: high doses, one off

36 How does it work? Complex! In Immune deficiency replaces absent/poor quality IgG High dose has immuno-modulatory effects on adaptive & innate immune system

37 DOH National Guidelines for the appropriate use of Immunoglobulin Clinical Indications Red Blue Grey Black Priority Highest Priority Reasonable evidence base but other treatment options available Lowest priority. Weak evidence base Evidence to suggest immunoglobulin is not appropriate

38 RED Priority- HIGH BLUE Priority - MEDIUM GREY & UNLISTED Priority -LOW BLACK IVIG Not Indicated Available at all times Automatic approval Reduced use in times of shortage Panel approval required Selection Criteria Case by case basis. Panel and PCT funding approval Automatic rejection by panel IVIG given IVIG given IVIG given if Panel and commisioners approval IVIG is NOT given Outcome Measures identified

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40 Selective IgA Deficiency Absent IgA but normal IgG & IgM Normal functional antibodies Common, 1: What problems are associated? Majority asymptomatic Increased risk autoimmunity & atopy Rarely, recurrent respiratory/gi infections

41 Selective IgA Deficiency IgA based tests for Coeliac disease are noninformative IgA anti tissue transglutaminase IgA anti endomysial antibodies IgG based tests for Coeliac disease less sensitive or specific so less helpful Serology alone may miss Coeliac disease in IgA deficiency

42 Chronic Granulomatous Disease (CGD) Rare inherited disorder of phagocytes 1 in Failure of respiratory burst due to defect/deficiency of component of NADPH oxidase complex in phagosome Membrane-bound components gp 22 & gp91 Cytosolic components p47, p67, p40 & p21 X-linked or Autosomal recessive Leads to ineffective intracellular killing

43 Phagocytosis assisted by IgG and complement

44 CGD Susceptible to serious, life-threatening infections Problems with Catalase-positive bacteria e.g. Staph aureus, Salmonella, Klebsiella Fungi e.g. Aspergillus Main sites of infection: lungs, skin, lymph nodes Chronic granulomatous inflammation Colitis, mimics Crohn s disease Obstruction of hollow organs Oesophageal/Urinary tract/gastric outlet obstruction

45 Diagnosis NBT (Nitro blue tetrazolium) Test Yellow dye Turns purple when reduced 1. Activate neutrophils and add dye neutrophils ingest dye and produce superoxide radicals 2. View down microscope to see colour change (absent in CGD)

46 Unstimulated Unstimulated Unstimulated Stimulated Stimulated Stimulated Control CGD Patient CGD Carrier

47 Treatment CGD Prophylactic CoTrimoxazole Prophylactic antifungals BMT / gene therapy better outcome in younger age Acute infections use antibiotics with good cell penetrance e.g. Cipro, Tazocin

48 Summary Think Immunodeficiency primary or secondary Secondary Immune deficiency becoming more common Infections: SPUR Look for unusual pathogens Treat more aggressively Discuss with Immunologist early