Lyme a 21 st century plague? Matthew Dryden Hampshire Hospitals Foundation Trust & Rare and Imported Pathogens Department, PHE

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1 Lyme a 21 st century plague? Matthew Dryden Hampshire Hospitals Foundation Trust & Rare and Imported Pathogens Department, PHE

2 Overview Epidemiology Diagnosis RIPL Lyme National Reference Lab Clinical presentation and treatment Chronic Lyme Research needs

3 Relative monthly volume of UK-based Google searches for Lyme disease in the last ten years. Data Source: Google Trends ( Lab samples Lyme Diagnostics in RIPL, Abbie Bown, 30 Nov 2015

4 PHE Confirmed Lyme approx 15,000 tests in

5 Traditional hotspots in England Forests are open woodland and heathland with undergrowth Lake District Ice Age Cumberland Westmorland Lancashire Northumberland Durham North Riding Yorkshire East Riding West Riding Lindsey Lake District & Scottish Highlands are low mountains with moorland, bracken & heather Cheshire Shropshire Hereford Stafford Derby Warwick Worcester Gloucester Wiltshire Notts Lincoln Kesteven Leicester Rutland Oxford Bucks Berks Huntingd on And Northants Peterbor West East ough Cambridge And Isle of Ely Suffolk Bedford Holland Hertford Greater London Essex Norfolk Thetford Forest Ancient Devon Somerset Dorset Hampshire Isle of Wight Surrey Sussex West East Kent Cornwall New Forest 1079

6 Muntjac Deer Increase in Lyme cases Fallow Deer Increase in UK Deer populations, Roe Deer Red Deer

7 No. cases Lyme Borreliosis rate in Winchester total 508 Total number of cases of Lyme Disease between Diagnosed at RHCH Winchester Year Dryden M, Saeed K, Ogborn S, Swales P. Lyme borreliosis in southern United Kingdom and a case for a new syndrome, chronic arthropod-borne neuropathy. Epidemiol. Infect., :1-12. doi: /s

8 Lyme Borreliosis rate in Winchester National rate: last accessed June 2013 Lyme Disease Annual Rate per 100,000 population Dryden M, Saeed K, Ogborn S, Swales P. Lyme borreliosis in southern United Kingdom and a case for a new syndrome, chronic arthropod-borne neuropathy. Epidemiol. Infect., :1-12. doi: /s

9 Rates in Europe Rates of Lyme disease in some European countries are much higher, with an estimated 206 per population in Slovenia (based on laboratory reports) 135 per population in Austria (based on physician surveys).

10 J Clin Microbiol March; 36(3):

11 Dryden M, et al. Epidemiol. Infect., :1-12. doi: /s

12 Dryden M, et al. Epidemiol. Infect., :1-12. doi: /s

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14 Tick bite 508 patients - Hampshire Dryden M, Saeed K, Ogborn S, Swales P. Lyme borreliosis in southern United Kingdom and a case for a new syndrome, chronic arthropod-borne neuropathy. Epidemiol. Infect.,

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16 What else could they B. burgdorferi B. garinii transmit? Anaplasma / Ehrlicia Babesia spp. Rickettsia spp. B. afzelii Francisella tularensis B.bavariensis, B. japonica, B. lusitaniae, B. sinica, B.spielmanii, B. tanukii, B. turdi, B.valaisiana, and B. yangtse, B. myamotoi Toxins? Coxiella spp. Viruses, TBE, CCHF

17 Prevalence rates of Borrelia in ticks Location Habitat Nymphs tested Prevalence Coed y Brenin, Gwynedd Mixed woodland 40 0 Dalby, Yorkshire Mixed woodland Glisland, Northumbria Conifer/grassland 55 0 Gisburn Forest, Lancashire Conifer/grassland Graig-fechan, Clwyd Moorland Hampsfell woos, Cumbria Decid woodland Harwood, Northumberland Conifer/grassland Kielder Forest, Northumberland Conifer/grassland Loch Doon, Ayrshire Conifer/grassland 8 - Madie Forest, Dumfries Decid woodland Mell Fell, Cumbria Decid woodland Naddle Forest, Cumbria moorland woodlands, Wiltshire Woodland Exmoor, Somerset Woodland woodlands, New Forest, Hants Woodland Richmond Park, London Parkland 83 0 Swinley, Surrey Pine woodland Salisbury, Wiltshire Urban fringe sites, Dartmoor, Devon Woodland/moorland Cirencester, Glos Woodland/ edge South Downs, Suffolk Woodland/ edge Thetford, Norfolk Woodland/ edge Wytham, Oxon Woodland/edge 9 0 Bettridge et al. 2013; Hansford et al. 2014; Layzell et al.

18 Borrelia burgdorferii sensu lato In the UK, 3 Borrelia spp. cause Lyme disease Borrelia burgdorfeii sensu stricto Borrelia garinii Borrelia afzelii Spirochaete 10-30µm in length Tick-borne Wide range of clinical presentations Lyme Diagnostics in RIPL, Abbie Bown, 30 Nov 2015

19 Anatomy of a professional p66 porin Outer membrane Inner membrane VlsE protein Borrelia membrane protein A OspC cell attachment protein Courtesy Tim Brooks Flagellin strands between membranes rotate to propel organism P83 surface protein P 17/ Decorin binding protein

20 Laboratory tests for direct detection Test Acute disease Late disease Benefits Limitations Direct microscopic visualisation Bacterial culture x Rapid Good PPV x Isolate strain PCR (from certain tissues/fluids) Rapid Higher sensitivity from skin biopsies of EM (69 Limited clinical utility, poor reliability Slow. Poor success rate (40% from skin biopsies, <5% from blood) Low numbers of organisms in samples

21 Laboratory tests for indirect detection Test Acute disease Late disease Benefits Limitations Immunofluorescent Assays (IFA) Visualisation of infected cells Whole cell ELISA Easy to use and automate Can lack specificity Subjective reading and interpretation Can lack specificity and sensitivity Specific peptide ELISA Western / line blots Two tier testing Easy to use and automate Useful for all strains Better sensitivity and specificity than ELISA and IFA Increase in specificity and high sensitivity Cross reactions Sample numbers Cross reactions Time to mount antibody response versus rash

22 Screen: Immunetics C6 ELISA Combined IgM and IgG C6 synthetic peptide High sensitivity Some false positives High throughput 75 % samples negative Positive / indeterminate blotted

23 Viramed Virastripe Borrelia immunoblot IgM and IgG Lineblots (Viramed Virastripe system) Purified antigens striped at different positions Automatic reader Consistency between users and over time Lyme Diagnostics in RIPL, Abbie Bown, 30 Nov 2015

24 Borrelia antigens flagellum Outer surface protein lipoprotein Guidelines: For IgM blot: Positive if 1 of 5 bands is > cut-off threshold IgG blot: Positive if 2 of 11 bands are > cut-off threshold

25 Limitations and interpretations IgM appear 2-3 weeks after onset (may persist for months/years) IgG produced several weeks to months after onset Band number and intensity generally increase over time. Antibiotics can suppress development Known cross reactions: - other spirochaetes - other bacteria with flagella - acute EBV cause polyclonal stimulation of Borrelia antibodies - autoimmune diseases

26 PCR Automated nucleic acid extraction Real time PCR Samples: fla flagellin gene target specific to Borrelia burgdoferii sensu lato Acute lyme: punch biopsy from EM rash Disseminated or chronic lyme: joint fluid, tissue, CSF and EDTA blood (after discussion with RIPL microbiologist) Blood samples rarely positive New assay under development to detect other Borrelia species eg those causing relapsing fever B. miyamotoi

27 Alternative tests why are NHS tests rubbish? The NHS uses the same tests as the rest of the world! Igenex labs USA Their own interpretation of blots, differs from CDC interpretation Armin/Infecto labs Germany & others Microscopy of blood films probably proteinacous fibrils Unconventional PCR Lyme ELISPOT MELISA Lymphocyte transformation test CD 57 assay

28 Early Infection Treat EM empirically Little advantage in doing serology and certainly should not wait for serology results 1st line: Doxycycline 100mg bd days or Amoxicillin 500mg tds for days 2 nd line Cefuroxime axetil 500mg bd days 3 rd line Azithromycin 500mg od 10 days (beware relapses)

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33 Lyme

34 Lyme

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37 Lyme

38 And more!!

39 Seronegative Lyme

40 Presenting symptoms 508 patients Dryden M, et al. Epidemiol. Infect., :1-12. doi: /s

41 Neurological presentation Dryden M, et al. Epidemiol. Infect., :1-12. doi: /s

42 Disseminated infection Antibody pattern Mycocarditis is rare All antibodies may appear OspC antibodies decline early IgM slowly disappears leaving variable patterns of IgG responses Pattern may correlate to species in some cases VlsE dominates Neuroborreliosis PCR occasionally positive IgM in CSF Arthritis PCR Negative Acrodermatitis chronica atrophicans PCR may be positive

43 Later Infection -Treatment Serology should be positive British Infection Association. The epidemiology, prevention, investigation and treatment of Lyme borreliosis in United Kingdom patients: a position statement by the British Infection Association. Journal of Infection 2011; 62:

44 Lyme myelitis Dryden MS, O'Connell S, Samuel W, Iannotti F. Lancet; 348: 642.

45 Chronic Lyme: The Parallel Universe

46 The controversy Lyme disease means different things to different people Occurs focally and is transmitted by infected ticks Presents with objective clinical findings Requires a laboratory test to confirm diagnosis Responds to antibiotic treatment for days Is insidious and ubiquitous Presents with non-specific symptoms alone Diagnosis based on clinical judgement Requires antibiotics for months or years Lyme literate doctors

47 Chronic Lyme What is it?- lack of clinical definition. Persisting symptoms after confirmed Lyme (PLDS) Persisting Borrelia burgdorferi infection Co-existing or another infection Babesia, Anaplasma /Ehrlichia Rickettsia spp. Another pathology Post infectious inflammation Autoimmune damage Immune system activation CFS, ME, fibromyalgia Psychiatric component Patients often receive prolonged and repeated courses of antibiotics Conventional diagnostic tests are negative but unvalidated research tests are positive

48 How should these be managed? pragmatic clinical Positive serology and no previous treatment treat. How long? High likelihood, negative or equivocal serology, consider empirical treatment PLDS or CAN are thought not to be improved by antibiotics ME/CFS management for the rest.

49 What Lyme Looks Like: Photos Of Some Of My 2 Years Of Lyme Treatment This is what 2 years of Lyme treatment looks like for most with chronic lyme disease. This photo is only some of my meds, injections and a small portion of IV stuff.

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51 Outside IDSA 2013

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54 Recommendations from Australian government Lyme commission. The report has three themes Chapter 1. Putting patients first. Chapter 2. Testing for the infection. Chapter 3. Treating the illness. increase funding for research into tick-borne pathogens as a matter of urgency establish a clinical trial of treatment guidelines developed by ACIIDS with the aim of determining a safe treatment protocol for patients with tick-borne illness develop a consistent, national approach to addressing tick-borne illness. undertake an epidemiological assessment of the prevalence of suspected tick-borne illness in Australia consistently adopt a patient-centric approach that focusses on individual patient symptoms, rather than a disease label; and remove 'chronic Lyme disease', 'Lyme-like illness' and similar 'Lyme' phrases from diagnostic discussions. the Australian Government Department of Health work closely with the Australian Medical Association and Royal Australian College of General Practitioners to ensure that general practitioners have a better understanding of how to treat patients who present with complex symptoms.

55 Updated information on Updated PHE tick awareness leaflets

56 Summary Currently /yr laboratory confirmed cases in England & Wales Does not include clinically diagnosed EM New test methodologies under investigation Host & Pathogen markers Proteomics, metabolomics, molecular techniques Fundamental questions on disease pathogenesis need answering Tick distribution varies widely across UK From woodland to gardens So does carriage rate in ticks and Borrelia species distribution Trials need infrastructure & sufficient numbers Publicity and policy changes underway. NICE committee producing guidelines

57 Thank you Acknowledgements RIPL team Tim Brooks Abbi Brown Andy Simpson Emma Aarons Amanda Semper, Jenny Warner, Jackie Duggan, Dan Bailey Jolyon Medlock & Maaike Pietzsch MEZE