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Dr Charu Chopra MRCP, FRCPath, PG Dip (Med Ed) Consultant Immunologist, Royal Infirmary Edinburgh

The effective use of the immunology/ allergy service in lothian (OR, Everything you wanted to ask about immunology testing but were too afraid to ask!!) GP Laboratory medicine update meeting January 2017. Dr Charu Chopra MRCP, FRCPath, PG Dip (Med Ed)

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Dr Charu Chopra MRCP, FRCPath, PG Dip (Med Ed) Consultant Immunologist, Royal Infirmary Edinburgh

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  1. The effective use of the immunology/ allergy service in lothian (OR, Everything you wanted to ask about immunology testing but were too afraid to ask!!)GP Laboratory medicine update meeting January 2017 Dr Charu Chopra MRCP, FRCPath, PG Dip (Med Ed) Consultant Immunologist, Royal Infirmary Edinburgh Honorary Clinical Senior Lecturer, University of Edinburgh

  2. Summary • Introduction • Immunology Service in Lothian • Focused talk on laboratory testing and key changes taking place • Changes to RefHelp guidelines for Neutropenia and Lymphopenia – ANA testing • Changes to OrderComms (CCP, ANA) • Other autoantibody testing • Allergy Testing • Discussion / Questions

  3. NHS Lothian is unique, in not having an already established clinical immunology service. I provide clinical oversight to patients with Primary Immunodeficiency and I also provide clinical input / direction to the diagnostic Immunology Lab No Allergy Service in Lothian Two-way communication is vital.. PLIG is great! But please telephone me rather than email me about specific patient queries..

  4. Immunology Testing Repertoire List (Updated Nov 2016) – Excluding sendaway tests..

  5. IgG subclasses – only useful to evaluate IgG4 disease (rare – secondary care). For myeloma screens, please request IgG/A/M (done in Biochemistry) Removal of IgG subclasses from order comms (planned) – But if you need it please call the lab and we can process!

  6. Anti-Nuclear Antibody (ANA) • One of the most frequently requested test in Immunology • Screened by IIF on HEp 2 cells (serum dilution 1:80) • All positive samples are then titred 1:160; 1:640 or > 1:640 • Total cost of ANA screen (~£6) and ANA titre (~£14)test; Total is ~£20

  7. From: Binding Site Hep 2 Patterns Atlas (Third Edition) Figure 1. Nuclear coarse speckled, nuclear homogeneous, nucleolar clumpy and centromere autoantibody patterns detected on HEp-2 cells(Left to right).

  8. Routine ANA testing • If ANA pos HOMO pattern then reflex dsDNA antibody done • If ANA pos at or >1:160 and SPECKLED, then reflex test ENA screen added (includes Sm, Ro, La, Sm/RNP, Scl70 and Jo-1). If screen positive then individual (ENA profile to ascertain specificity)

  9. When is an ana test useful? Consider for >1 clinical symptom/ sign: • Cutaneous rash (photosensitive/ malar/ facial), oral ulcers, alopecia, synovitis, serositis, renal disease, neurological features, blood dyscrasia • Immunological criteria – includes lupus anticoagulant/ Sm Ab/ ANA/dsDNA • Systemic Lupus Collaborating Clinics Criteria(SLICC) criteria (caveat:research tool) - Need 4 criteria POS (including 1 clinical and 1 immunological) for SLE diagnosis OR – renal biopsy evidence of Lupus nephritis

  10. NHS LOTHIAN RefHelp GUIDELINES – FOR PRIMARY CARE FIRST LINE INVESTIGATIONSNEUTROPENIA (2011)

  11. NHS LOTHIAN RefHelp GUIDELINES – FOR PRIMARY CARE FIRST LINE INVESTIGATIONS LYMPHOPENIA (2015)

  12. Neutropenia (and Lymphopenia) Guidelines (RefHelp NHS Lothian) Neutropenia (Accessed RefHelp NHS Lothian November 2016) Amended to only request if clinical context is appropritae (~ September 2016)

  13. The clinical utility of ana testing • ANA is not a useful screening test for CTD/ SLE • Clinical criteria are most important indicators of CTDs (as may have patients who have seronegative disease) • ANA is not specific for SLE (may be seen with drug therapies (penicillamine, OCP), in normal individuals (up to 20%), in infection and in autoimmune liver disease/ other inflammatory or autoimmune conditions) • Similarly CCP is probably not a useful screen for RA (note seronegative disease)

  14. Changes to gp order comms CCP antibody and ANA to be requested separately and not Together (Rheumatoid Arthritis testing is now CCP only) Note, ANA may be seen (commonly) in Rheumatoid Arthritris

  15. Other changes to order comms in the pipeline • Aim – to simplify test requesting, focus test requesting to the relevant tests • Allergy: specific IgE and Total IgE request layout • Change to certain order sets (e.g ANA / CCP) is under review OTHER RESOURCES: • Change to paper request form is also desirable... (on my ‘to do list’) • Test repertoire list and lab handbook (through NHS Lothian Lab Medicine website to be updated)

  16. Allergy service in lothian? Where is it? A comprehensive patient pathway: Clinical evaluation Testing, Skin testing, provocation/ challenge testing (Gold Standard) Desensitisation therapy / immunotherapy

  17. The clinical spectrum of Type 1 Hypersensitivity Reactions URTICARIA ANGIOEDEMA By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9444861 http://www.documentingreality.com/forum/f149/angioedema-82249/

  18. Definitions... ANAPHYLAXIS • NICE: ‘a severe, life threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing, life threatening problems involving: airway (pharyngeal or laryngeal oedema) and/or breathing (bronchospasm with tachypnoea) and/ or circulation (hypotension and/or tachycardia).’ (NICE Clinical Guideline 134. NICE,2011) • NICE (2016) Quality Standard 119 ‘People who have emergency treatment for suspected anaphylaxis are referred to a specialist allergy service’

  19. Allergy - Diagnosis Clinical History – THE MOST IMPORTANT ‘ALLERGY TEST’

  20. Patient Evaluation • Medical history • Timing of reaction related to exposures • Confirmation of diagnosis of anaphylaxis (∆∆ panic disorder, acute asthma exacerbation, vasovagal syncope, cardiac arrhythmia - and more!) • Seriel rise in mast cell tryptase (may still be within ‘normal’ range) – the only useful blood test in the acute setting (retrospective diagnosis – don’t delay treatment) • Response to therapy (adrenaline, antihistamines) • Previous reactions? • Dietary history (avoidance of any classes of food)

  21. Allergy ‘tests’ - to detect specific IgE • Skin prick tests – aeroallergens (HDM, pollens, moulds), some foods (egg, wheat), latex • Fresh prick-to-prick (fruits, latex, fish/shellfish, nuts) • Intradermal skin tests - drugs (penicillins), anaesthetic agents, • Specific IgE (blood tests) • All interpretation of testing depends on careful clinical correlation / context • Placebo controlled (blinded) food / drug challenge – GOLD STANDARD • Specific IgG tests (York tests) have NO evidence based role in evaluating patients with Type 1 hypersensitivity reactions

  22. Specific ige blood tests in evaluating allergy • Clinical utility really depends on pre-test probability of Type 1 reaction / clinical context • Presence of specific IgE to an allergen is evidence of SENSITISATION • SENSITISATION ≠ ALLERGY • Other reasons for presence of specific IgE: eczema (high total IgE and therefore low positive specific IgE to multiple allergens; cross reactivity of specific IgE)

  23. Type 1 hypersensitivity

  24. Cross-reactivity of IgE Specific IgE recognises >1 allergen because of shared epitopes Shrimp – house dust mite Latex fruit syndrome Birch pollen food allergy syndrome or "oral allergy syndrome" Therefore specific IgE test may be positive for both allergens and diagnosis of allergy depends on clinical history, as may or may not be allergic

  25. CLINICAL UTILITY OF SPECIFIC IgE TESTS • Useful to confirm clinical suspicion of food allergy from the clinical history • Useful to evaluate patients with rhinosinusitis / conjunctivitis for allergic causes (pets/ exposures) • Not useful as ‘screen’ for food allergies • Total IgE done concomitantly is useful for a ratio of specific IgE to total IgE. • Negative specific IgE does not exclude diagnosis of allergy (may need skin testing and provocation/ challenge testing) particularly for foods and drugs. • Interpretation of Specific IgE tests requires careful clinical correlation • Testing does not replace a specialist Allergy evaluation (elephant again......)

  26. Pernicious Anaemia • Low serum Vitamin B12 • Reflexed by lab to have Intrinsic Factor Antibody test (automated ELISA test) • Intrinsic Factor Antibodies, if present, are highly specific for pernicious anaemia, but may be absent in up to ~30% of patients with pernicious anaemia.

  27. Gastric parietal cell antibodies • Tested for along with liver antibodies on a rodent tissue block (Immunofluorescence) • Liver Kidney Microsomal (LKM), Mitochondrial, Smooth Muscle antibodies tested together • Parietal Cell antibody has poor specificity and is seen following infection, in patients with other autoimmune conditions (in particular thyroid autoimmunity), and in normal individuals...

  28. COMPOSITE TISSUE BLOCK: RODENT STOMACH, LIVER AND KIDNEY FOR TISSUE AUTOANTIBODY TESTING Figure 6.2. SMA on rat stomach (left), liver (centre) and kidney (right). Note staining of interglandular actin fibres and muscularis mucosae in the stomach, muscle layer around blood vessels in the liver, mesangial cells of the glomeruli and intracellular fibrils of the renal tubule and peritubular areas in the kidney.

  29. Figure 7.1. GPC antibodies on rat (left) and monkey (right) stomach.

  30. Parietal cell antibody • May be useful in some cases where serum B12 is low and Intrinsic Factor Antibody is negative • Diagnosis of Pernicious Anaemia means intramuscular Vitamin B12 (and not oral B12) as therapy

  31. my future aims for the clinical immunology service • Robust testing platforms for all autoimmune serology • Updated testing repertoire, newer tests. • Faster turn around times (ANA within 10 days, vasculitis screen within 3-5 working days) • Clinical interpretation and clinical validation of all tests and testing strategies • 2- way communication – if in doubt please call the lab/ myself! • Efficiency • Please give us feedback!– either directly or through PLIG

  32. Feedback/ Discussion/Questions charuchopra@nhs.net

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