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 ID: 1036579
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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 2017Dr Charu Chopra MRCP, FRCPath, PG Dip (Med Ed)Consultant Immunologist, Royal Infirmary EdinburghHonorary Clinical Senior Lecturer, University of Edinburgh
2. SummaryIntroductionImmunology Service in LothianFocused talk on laboratory testing and key changes taking placeChanges to RefHelp guidelines for Neutropenia and Lymphopenia – ANA testingChanges to OrderComms (CCP, ANA)Other autoantibody testingAllergy Testing Discussion / Questions
3. NHS Lothian is unique, in not havingan already established clinical immunology service.I provide clinical oversight to patientswith Primary Immunodeficiency and Ialso 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 ImmunologyScreened by IIF on HEp 2 cells (serum dilution 1:80)All positive samples are then titred 1:160; 1:640 or > 1:640Total cost of ANA screen (~£6) and ANA titre (~£14)test; Total is ~£20
7. Figure 1. Nuclear coarse speckled, nuclear homogeneous, nucleolar clumpy and centromere autoantibody patterns detected on HEp-2 cells(Left to right).From: Binding Site Hep 2 Patterns Atlas (Third Edition)
8. Routine ANA testingIf ANA pos HOMO pattern then reflex dsDNA antibody doneIf 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/dsDNASystemic Lupus Collaborating Clinics Criteria(SLICC) criteria (caveat:research tool) - Need 4 criteria POS (including 1 clinical and 1 immunological) for SLE diagnosisOR – 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)Primary care investigationsAssess patient for symptoms e.g. recurrent infections, mouth ulcers etc.Establish if patient is of an ethnic background known to be associated with lower neutrophil counts (See “Who not to refer” below).Review medication (see additional notes)Examine for lymphadenopathy and splenomegalyRepeat FBC. If neutrophil >1 then repeat at 6 weeks. If neutrophil count <1 repeat at 1 weekFor persistent neutropenia do the following tests:Blood filmB12 and folate, Ferritin. Treat if deficiency is detectedHIV, HBV, HCV serologyIf additional clinical features to suggest a diagnosis of SLE, RA or other connective tissue disorder check CCP, ANF, dsDNA (if ANF positive)Neutropenia (Accessed RefHelp NHS Lothian November 2016)Amended to only request if clinical context is appropritae (~ September 2016)
13. The clinical utility of ana testingANA is not a useful screening test for CTD/ SLEClinical 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 commsCCP 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 pipelineAim – to simplify test requesting, focus test requesting to the relevant testsAllergy: specific IgE and Total IgE request layoutChange to certain order sets (e.g ANA / CCP) is under reviewOTHER 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 evaluationTesting, Skin testing, provocation/ challenge testing (Gold Standard)Desensitisation therapy / immunotherapy
17. The clinical spectrum of Type 1 Hypersensitivity ReactionsURTICARIAANGIOEDEMABy James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9444861http://www.documentingreality.com/forum/f149/angioedema-82249/
18. Definitions... ANAPHYLAXISNICE: ‘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 EvaluationMedical historyTiming of reaction related to exposuresConfirmation 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 IgESkin prick tests – aeroallergens (HDM, pollens, moulds), some foods (egg, wheat), latexFresh 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 / contextPlacebo controlled (blinded) food / drug challenge – GOLD STANDARDSpecific IgG tests (York tests) have NO evidence based role in evaluating patients with Type 1 hypersensitivity reactions
22. Specific ige blood tests in evaluating allergyClinical utility really depends on pre-test probability of Type 1 reaction / clinical contextPresence of specific IgE to an allergen is evidence of SENSITISATIONSENSITISATION ≠ ALLERGYOther 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 Latex fruit syndromeBirch pollen food allergy syndrome or "oral allergy syndrome"Shrimp – house dust mite Specific IgE recognises >1 allergen because of shared epitopes Therefore specific IgE test may be positive for both allergens and diagnosis of allergy dependson clinical history, as may or may not be allergic
25. CLINICAL UTILITY OF SPECIFIC IgE TESTSUseful to confirm clinical suspicion of food allergy from the clinical historyUseful to evaluate patients with rhinosinusitis / conjunctivitis for allergic causes (pets/ exposures) Not useful as ‘screen’ for food allergiesTotal 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 correlationTesting does not replace a specialist Allergy evaluation(elephant again......)
26. Pernicious AnaemiaLow serum Vitamin B12Reflexed 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 antibodiesTested 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. 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.COMPOSITE TISSUE BLOCK: RODENT STOMACH, LIVER AND KIDNEYFOR TISSUE AUTOANTIBODY TESTING
29. Figure 7.1. GPC antibodies on rat (left) and monkey (right) stomach.
30. Parietal cell antibodyMay be useful in some cases where serum B12 is low and Intrinsic Factor Antibody is negativeDiagnosis of Pernicious Anaemia means intramuscular Vitamin B12 (and not oral B12) as therapy
31. my future aims for the clinical immunology serviceRobust testing platforms for all autoimmune serologyUpdated 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 strategies2- way communication – if in doubt please call the lab/ myself!EfficiencyPlease give us feedback! – either directly or through PLIG
32. Feedback/ Discussion/Questionscharuchopra@nhs.net