Stakehold

indicated 45% of infected ticks were co-infected with up to 5 pathogens (Moutailler et al,

2016). This has many implications including increased difficulty in diagnosis and

complications related to treatment. Whilst the guidelines relate to Lyme borreliosis they

should mention the confounding implications of co-infection.

Thank you for your comment. While people with co-infections will not be excluded from the evidence reviews, the focus of this guideline is the diagnosis and management of Lyme disease and the specific management of any co-infection will not be addressed. However, the guideline committee will give mention to any groups who require special consideration when linking evidence to recommendations.
Lyme Research UK	gener al	gene ral	Special patient groups: We think that the NICE guideline should include a section on special patient groups, including people who are immunocompromised, those who are more at risk of complications (e.g. the elderly and people with comorbid conditions), and pregnant women.	Thank you for your comment. As outlined in the equality impact assessment for this guideline, the guideline committee will review the evidence about diagnostic test accuracy and management strategies in pregnant women and immunocompromised people. It is anticipated that these populations will form sub-groups in each of our evidence reviews to ensure that, where evidence exists on these issues, the committee are able to make evidence-based recommendations to the NHS. These subgroups have been included in the equality impact assessment for this guideline.
Lyme Research UK	gener al	gene ral	Intravenous antibiotic treatment: We are very concerned that there are Lyme borreliosis patients who need but are not getting intravenous ceftriaxone or cefotaxime once the disease has progressed to later stages. They may not be getting this treatment because a diagnosis of their neuroborreliosis has not been made. Before treating Lyme borreliosis patients with intravenous antibiotics, a positive diagnosis of neuroborreliosis is necessary. The British Infection Association Position Statement (2011) says that serology testing for Lyme neuroborreliosis should include intrathecal specific antibodies and specific cerebrospinal fluid/serum antibody index. The guidelines from the European Federation of Neurological Societies guidelines (Mygland et al, 2010) state that antibody tests for cerebrospinal fluid “are useful” in the diagnosis of Lyme neuroborreliosis, but they do not state that a positive result is essential. Unfortunately, the sensitivity of the current tests of cerebrospinal fluid is relatively low. Djukic et al (2012) reported that, of 118 patients with acute neuroborreliosis, intrathecal immunoglobulin synthesis was found in the Reiber nomograms for IgM in 70.2% and for IgG in 19.5% of patients. Isoelectric focussing detected an intrathecal IgG synthesis in 70.3%. Elevation of the Borrelia burgdorferi antibody index in the cerebrospinal fluid was found in 82.2%. The sensitivity was particularly low in patients with a meningitis course (44.4% to 61.1%). Therefore many patients with Lyme neuroborreliosis who need intravenous antibiotics may not receive a positive diagnosis because the laboratory test is inadequate. We think that, until better diagnostic tools are available, the criteria for intravenous treatment should be relaxed and not require evidence of antibodies in the cerebrospinal fluid.	Thank you for your comment. The Guideline Committee will carefully consider the evidence when making recommendations on management strategies including the role of intravenous antibiotics.
Lyme Research UK	gener al	gene ral	Guideline scope: We would like to see NICE address uncertainty in existing knowledge (where relevant), and recommend what kind of research is needed to improve patient outcomes (Parliamentary Office of Science and Technology, 2004).	Thank you for your comment. The Guideline Committee will make research recommendations (if appropriate) at a later stage of the guideline development once the evidence reviews have been conducted and important gaps have been identified.
Lyme Research UK	gener al	gene ral	Lyme borreliosis: We think the term 'Lyme borreliosis' should be used rather than 'Lyme disease' to be consistent with the rest of Europe.	Thank you for your comment. We have decided to use the term Lyme disease as it is a widely accepted term which we feel is more accessible to non-healthcare professionals than Lyme borreliosis. In addition it directly reflects the commission received from NHS England.
Lyme Research UK	gener al	gene ral	REFERENCES CITED ABOVE: Aucott JN, Seifter A, Rebman AW (2012). Probable late lyme disease: a variant manifestation of untreated Borrelia burgdorferi infection. BMC Infect Dis 2012;12(1):173 Bettridge J, Renard M, Brown KJ, et al (2013). Distribution of Borrelia burgdorferi sensu lato in Ixodes ricinus populations across central Britain. Vector Borne and Zoonotic Diseases13(3):139–146 Bouquet J, Soloski MJ, Swei A et al (2016). Longitudinal transcriptome analysis reveals a sustained differential gene expression signature in patients treated for acute Lyme disease. mBio 7(1): e00100-16 British Infection Association (2011). The epidemiology, prevention, investigation and treatment of Lyme borreliosis in United Kingdom patients: A position statement by the British Infection Association. Journal of Infection 62:329-338 Cairns V, Godwin J (2005). Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int J Epidemiol 34:1340-1345 Centers for Disease Control and Prevention in the United States (2016a). Transmission. http://www.cdc.gov/lyme/transmission/index.html Centers for Disease Control and Prevention in the United States (2016b). Post-treatment Lyme disease syndrome. http://www.cdc.gov/lyme/postlds/ Centers for Disease Control and Prevention in the United States (2016c). How many people get Lyme disease? http://www.cdc.gov/lyme/stats/humancases.html Chandra A, Wormser GP, Klempner MS, et al (2010). Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms. Brain, Behavior and Immunity 24(6):1018-1024 Cook MJ (2015) Lyme borreliosis: a review of data on transmission time after tick attachment. Int J Gen Med 2015:8 1–8 Couper D, Margos G, Kurtenbach K, et al (2010). Prevalence of Borrelia infection in ticks from wildlife in south-west England. The Veterinary Record 167:1012-4 Djukic M, Schmidt-Samoa C, Lange P et al (2012). Cerebrospinal fluid findings in adults with acute Lyme neuroborreliosis. J Neurol 259(4):630-636 Djukic M, Schmidt-Samoa C, Nau R et al (2011). The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis--the experience from one year of a university hospital’s Lyme neuroborreliosis outpatients clinic. Eur J Neurol 18(4):547-55 Durovska J, Bazovska S, Ondrisova M et al (2010). Our experience with examination of antibodies against antigens of Borrelia burgdorferi in patients with suspected Lyme disease. Bratisl Lek Listy111(3):153-5 Elsner RA, Hastey CJ, Olsen KJ et al (2015). Suppression of long-lived humoral immunity following Borrelia burgdorferi infection. PLOS Pathog 11(7):e1004976 Fallon BA, Keilp J, Prohovnik I et al (2003). Regional blood flow and cognitive deficits in chronic Lyme disease. J Neuropsychiatry Clin Neurosci 15(3):326-32 Faulde MK, Rutenfranz M, Hepke J et al (2014). Human tick infestation pattern, tick-bite rate, and associated Borrelia burgdorferi s.l. infection risk during occupational tick exposure at the Seedorf military training area, northwestern Germany. Ticks Tick Borne Dis 5(5):594-9 Horowitz R (2016). Horowitz Lyme-MSIDS Questionnaire. http://lymeontario.com/wp-content/uploads/2015/03/Horowitz-Questionnaire.pdf Kurtenbach K, De Michelis S, Sewell HS, et al (2001). Distinct combinations of Borrelia burgdorferi sensu lato genospecies found in individual questing ticks from Europe. Applied and Environmental Microbiology 67(10):4926-4929 Lakos A, Solymosi N (2010). Maternal Lyme borreliosis and pregnancy outcome. Int J Infect Dis 14(6): e494 – e498 Leeflang MMG, Ang CW, Berghout J et al (2016). The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis. BMC Infect Dis 16:140 Lindgren E, Jaenson TGT (2006). WHO Report. Lyme borreliosis in Europe: influences of climate and climate change, epidemiology, ecology and adaptation measures. http://www.euro.who.int/__data/assets/pdf_file/0006/96819/E89522.pdf MacDonald AB, Benach JL, Burgdorfer W. (1987). Stillbirth following maternal Lyme disease, N Y State J Med 87(11):615-6 Maheshwari P, Eslick GD (2015). Bacterial infection and Alzheimer's disease: a meta- analysis. J Alzheimers Dis 43(3):957-66 Middelveen MJ, Burke J, Sapi E et al (2015). Culture and identification of Borrelia spirochetes in human vaginal and seminal secretions [version 3; referees: 1 approved, 2 not approved]. F1000Research 2015, 3:309 Moutailler S, Valiente Moro C, Vaumourin E et al (2016). Co-infection of ticks: the rule rather than the exception. PLoS Negl Trop Dis10(3):e0004539 Mueller I, Freitag MH, Poggensee G, et al (2012). Evaluating Frequency, Diagnostic Quality, and Cost of Lyme Borreliosis Testing in Germany: A Retrospective Model Analysis. Clinical and Developmental Immunology 2012, Article ID 595427, Epub. Mygland A, Ljostad U, Fingerle V, et al (2010). EFNS on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurology 17:8-16 Pancewicz SA, Garlicki AM, Moniuszko-Malinowska A et al (2015). Diagnosis and treatment of tick-borne diseases. Recommendations of the Polish Society of Epidemiology and Infectious Diseases. Przegl Epidemiol 69:309-316) Parliamentary Office of Science and Technology (2004). Handling uncertainty in scientific advice. Postnote June 2004, Number 220. http://www.parliament.uk/documents/post/postpn220.pdf Preac-Mursic, Weber K, Pfister HW et al (1989). Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 17(6):355-359 Schlesinger PA, Duray PH, Burke BA et al (1985). Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Annals of Internal Medicine 103(1):67-68 Stanek G, Reiter M (2011). The expanding Lyme Borrelia complex-clinical significance of genomic species? Clin Microbiol Infect 17:487-93 Stricker RB, Middelveen MJ (2015). Sexual transmission of Lyme disease: challenging the tickborne disease paradigm. Expert Rev Anti Infect Ther 13(11):1303-6 Strle F, Nelson JA, Ruzic-Sabljic E, et al (1996). European Lyme borreliosis: 231 culture- confirmed cases involving patients with erythema migrans. Clin Infect Dis 23(1):61 – 65 Strle F, Ruzić-Sabljić E, Cimperman J (2006). Comparison of findings for patients with Borrelia garinii and Borrelia afzelii isolated from cerebrospinal fluid. Clin Infect Dis 43(6):704-10 Thorp AM, Tonnetti L (2006). Distribution and survival of Borrelia miyamotoi in human blood components. Transfusion 56(3):705-11 Trevejo RT1, Krause PJ, Sikand VK et al (1999). Evaluation of two-test serodiagnostic method for early Lyme disease in clinical practice. J Infect Dis 179(4):931-8 Tylewska-Wierzbanovska S, Chmielewski T (2002). Limitation of serological testing for Lyme borreliosis: evaluation of ELISA and western blot in comparison with PCR and culture methods. Wien Klin Wochenschr 114(113-14):601-5 Venclíková K, Betasova L, Sikutova S et al (2014). Human pathogenic borreliae in Ixodes ricinus ticks in natural and urban ecosystem (Czech Republic). Acta Parasitol 59(4):717-20 ViraMed Laboratory Diagnostics (2016). Borrelia ViraStripe® IgG, IgM Test Kit. http://www.viramed.de/en/bacteria/borrelia-species/borrelia-virastripe Wang G, Liverus D, Mukherjee P et al (2014). Molecular Typing of Borrelia burgdorferi. Weber K, Bratzke, HJ, Neubert U et al (1988). Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 7(4):286–289 Wormser GP, Dattwyler RJ, Shapiro EG, et al (2006). The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43:1089-1134	Thank you for your comment and the helpful list of references provided.
NHS England			Thank you for the opportunity to comment on the above Clinical Guideline. I wish to confirm that NHS England has no substantive comments to make regarding this consultation.	Thank you for your comment.
NHS England			Thank you for the opportunity to comment on the above Clinical Guideline. I wish to confirm that NHS England has no substantive comments to make regarding this consultation.	Thank you for your comment.
NHS Highland	3	67 to 82	The key to ensuring that the NICE recommendations are clinically useful is to have clear and relevant clinical case definitions at each stage. European clinical case definitions (Stanek, G) are narrow including no category for a flu like illness, and stringent laboratory confirmation for neuroborreliosis (requiring lumber puncture). In my opinion these are too narrow. Suggest NICE guidance divides patients into clinically defined presentations, and makes testing and management recommendations for each presentation (presentation categories that should be included given below). I appreciate that ‘Flu like’ is not an ideal label and care should be taken defining the symptoms that would qualify for this presentation. 1/ Tick exposure, no symptoms 2/ Seropositive, no symptoms 3/ Chronic tick exposure non-specific chronic symptoms (fatigue, arthralgia, parasthesia) 4/ ECM, atypical rash 5/ Flu like presentation without respiratory component 6/Symptoms consistent with early neuroborreliosis including radiculitis, meningitis, cranial neuropathy and mononeuritis multiplex 7/Symptoms consistent with late neuroborreliosis including encephalomyelitis, encephalopathy, cerebral vasculitis (could be called late neuroborreliosis) *IDSA includes peripheral neuropathy in late neuroborreliosis, while European guidelines state peripheral neuropathy without achrodermatitis chronicum atrophicans is vanishingly rare – this needs to be addressed as peripheral neuropathy very common in the elderly and in endemic regions many of these people will be seropositive. Geography of exposure may influence recommendation. 8/Arthritis 9/Carditis 10/Lymphocytoma 11/Achrodermatitis chronicum atrophicans 12/Ocular manifestations	Thank you for your comment on the issue of the classification of Lyme disease as described in the consultation version of the scope. We now propose to present the guideline committee with the stakeholder feedback on this issue to allow them to determine the best approach for the guideline to take. As such, we have removed the detail linked to the definitions of Lyme disease from the final scope.
NHS Highland	3	69	Suggest delete ‘to confirm or rule out Lyme disease’.	Thank you for your comment. This has now been amended to ‘Diagnostic testing for Lyme disease’.
NHS Highland	3	71	Role of CSF tests in diagnosis of lyme neuroborreliosis. When are they indicated and how interpreted (my current practice is usually not to perform LP in borrelia seropositive radiculopathy or cranial nerve palsy in absence of meningitis)	Thank you for your comment. The Guideline Committee will consider relevant diagnostic tests and procedures in the context of differing clinical presentations when defining the review questions and protocols. We will ensure that they are informed of your comment.
NHS Highland	3	77	Delete ‘or without’ as not disease if asymptomatic	Thank you for your comment. We had intended for ‘without symptoms or signs’ to refer to the absence of either clinical signs or symptoms, and not the absence of both. For example a person could have a clinical sign (something than can be easily measured by someone else, e.g. a rash) but no symptoms (something that cannot be easily measured by someone else, e.g. feeling unwell or a headache) or vice versa. This was to reflect the issue around the difficulty of diagnosing or ruling out Lyme disease using clinical signs only. However, we now propose to present the guideline committee with the stakeholder feedback on the issue of clinical scenarios and presentations to allow them to determine the best approach for the guideline to take. As such, we have removed the detail linked to the definitions of different clinical scenarios and presentations.
NHS Highland	3	83	Management recommendations could be further targeted by dividing patients into Possible/probable/definite Lyme disease depending on strength of clinical presentation and test results. I appreciate that this adds complexity, but until lab diagnostics improve we will be operating in an area of diagnostic uncertainty and these labels make that explicit and allow physician and patient to appreciate the balance of risks between overtreatment and under- treatment. These distinctions become most helpful when discussing pros / cons of repeat courses of antibiotics where first line therapy has failed to improve symptoms	Thank you for your comment. Whilst we do not feel that any changes to the scope are required in this area, we will bring the detail of your comment to the committee’s attention when they draft their protocol for this question
NHS Highland	3	83	Management may also include referral to specialist (eg rheumatologist). Guidance on which presentations of suspected arthritis with positive Lyme serology should be referred would be useful.	Thank you for your comment. We acknowledge that where complications of Lyme disease occur referral for specialist NHS opinion may be desirable if the evidence supports this. Management strategies including specialist referral in different clinical scenarios/presentations will be explored in more detail by the Guideline Committee through the evidence reviews.
NHS Highland	4	88	As for comment no. 4	Thank you for your comment. We had intended for ‘without symptoms or signs’ to refer to the absence of either clinical signs or symptoms, and not the absence of both. For example a person could have a clinical sign (something than can be easily measured by someone else, e.g. a rash) but no symptoms (something that cannot be easily measured by someone else, e.g. feeling unwell or a headache) or vice versa. This is to reflect the issue around the difficulty of diagnosing or ruling out Lyme disease using clinical signs only.
NHS Highland	4	90 to 96	These are important questions. Suggest may be helpful to divide symptoms into objective and subjective (indicated in some papers)	Thank you for your comment. We will ensure that this information is brought to the guideline committee’s attention when they are developing the review questions and protocols.
NHS Highland	4	Figu re	Cannot have Lyme disease without symptoms and signs (mentioned in both boxes of figure)	Thank you for your comment. We had intended for ‘without symptoms or signs’ to refer to the absence of either clinical signs or symptoms, and not the absence of both. For example a person could have a clinical sign (something than can be easily measured by someone else, e.g. a rash) but no symptoms (something that cannot be easily measured by someone else, e.g. feeling unwell or a headache) or vice versa. This is to reflect the issue around the difficulty of diagnosing or ruling out Lyme disease using clinical signs only.
NHS Highland	6	134	You state ‘Lyme disease can be asymptomatic’. I disagree. Infection with Borrelia burgdorferi can be asymptomatic, but I would reserve the term ‘Lyme disease’ for symptomatic infection.	Thank you for your comment. We have amended the text in the scope to distinguish between asymptomatic infection and Lyme disease as a symptomatic infection.
NHS Highland	7	141	Delete ‘frequently’ and replace with ‘can be’ and ‘resolves’ with ‘may resolve’.	Thank you for your comment. The wording of the scope has been altered.
NHS Highland	8	170	Repeat testing to assess for relapse is recommended by PHE but is controversial as antibody levels persist even when patient cured and therefore ongoing positive test not helpful. May be helpful in looking for re-infection in the re-exposed with new symptoms as different blot bands may be present. Suggest unhelpful to state that blood test can diagnose relapse.	Thank you for your comment. The ‘current practice’ section is a standard section in NICE guideline scopes and aims to describe current standard practice (in this case the PHE guidance) rather than critiquing the guidance. We acknowledge the concerns about repeat serological testing; however the aim of this section is to summarise the PHE guidance.
NHS Highland	DQ1& 2		Relating to guideline committee’s Q1 and 2 above. Distinction between early and late is only of importance if different management strategies are recommended on the basis of this distinction. Many patients have ongoing exposure and fluctuating symptoms making use of these timelines impractical. The time periods are arbitrary and cannot be definitive due to various factors (eg host factors, infectious dose, strain). Six month timeline is mentioned in literature and may be reasonable but the arbitrary nature of it must be stated.	Thank you for your response and detailed comments on our questions. We will bring the detail of your response to the Guideline Committee's attention. The information will be used to inform the Committee's decision making as they develop the review protocols that guide the searches for and review of the evidence for the questions outlined in the guideline scope.
NHS Highland	DQ3		Relating to guideline committee’s Q 3 above. (Use of BIA position paper to determine range of presentations). I would also like NICE to consider patients with ongoing tick exposure and : 1) Flu like illness as mentioned in comment no.1. 2) Fatigue and arthralgia 3) Peripheral neuropathy or mononeuritis multiplex 4) Objective memory loss but without tetraspastic syndrome, spastic-ataxic gait disorder and disturbed micturition I think these presentations should be included in the guidance as many people with these symptoms present for testing, and a proportion are seropositive. The committee may conclude that these presentations should not lead to testing, and if inadvertently tested, should not be treated for possible Lyme disease, even if seropositive. Guidance on this would be very useful.	Thank you for your response and detailed comments on our questions. We will bring the detail of your response to the Guideline Committee's attention. The information will be used to inform the Committee's decision making as they develop the review protocols that guide the searches for and review of the evidence for the questions outlined in the guideline scope.
NHS Highland	DQ4		Relating to guideline committee’s Q 4 above. Borrelia spielmanii, Borrelia bavariensis, Borrelia bissettii, Borrelia lusitaniae, Borrelia kutchenbachii and Borrelia valaisiana also have pathogenic potential (see Borchers A, journal autoimmunity for useful table). Review of evidence to assess relevance to diagnostics of some of these may be worthwhile.	Thank you for your response and detailed comments on our questions. We will bring the detail of your response to the Guideline Committee's attention. The information will be used to inform the Committee's decision making as they develop the review protocols that guide the searches for and review of the evidence for the questions outlined in the guideline scope.
NHS Highland	DQ4		Relating to guideline committee’s Q4 above. Diagnostic test should include tests and testing strategies. All tests should be included: EIA, IF, Immunoblot, western blot, CSF/serum parallel testing by EIA/Blotting, lymphocyte transformation test, PCR and culture (joint fluids, skin biopsy, CSF, urine), direct microscopy and non-specific tests such as CXCL13, CD57+, CSF biochemistry and cytology. The committee may find many of these tests lack standardisation, sensitivity and specificity but it is still useful to have them assessed.	Thank you for your response and detailed comments on our questions. We will bring the detail of your response to the Guideline Committee's attention. The information will be used to inform the Committee's decision making as they develop the review protocols that guide the searches for and review of the evidence for the questions outlined in the guideline scope.
Royal College of Genera Practitioner s (RCGP)	2	43	The RCGP hopes that the medications recommended in the guideline are those that a) Experts recommend (even if not licensed). If the guideline recommends a medication that is contrary to expert opinion then that severely will undermine the entire guideline. b) Are (where clinically appropriate) medications that are familiar to GPs- most of these patients will present to primary care. If these are medications that generally speaking GPs won’t feel confident with then it will mean more referral to secondary care with the delay and cost that that entails. (MJ) c)	Thank you for your comment. The Guideline Committee will consider which medications should be included in the evidence review. As stated in the scope, recommendations are generally only made within their licensed indications unless there is strong evidence for an unlicensed indication. The Guideline Committee will also consider any potential issues around prescribing (such as the lack of familiarity in prescribing that you outline) in various settings when formulating recommendations.
Royal College of Genera Practitioner s (RCGP)	2	51	There is clearly a link being made between chronic fatigue syndrome and Lyme disease by the support groups for suffers of chronic fatigue. Some GPs have seen a few patients who are desperate to pursue a diagnosis of Lyme disease to explain their fatigue symptoms. The RCGP feels that it would be invaluable if this guideline helped to differentiate on clinical grounds those fatigue suffers who need further investigation and those that we can reassure without recourse to blood tests, investigations and/or referrals. (MJ)	Thank you for your comment. This guideline only covers Lyme disease. We acknowledge that the clinical presentations of Lyme disease and chronic fatigue syndrome (CFS) can be very similar and that it can be difficult to make a definitive diagnosis of one or the other. Following systematic review of the evidence available in the scope areas of assessment diagnosis and management, the Guideline Committee will make recommendations in regards to Lyme disease and may wish to cross-refer to other guidelines if appropriate. The reference to the CFS / myalgic encephalomyelitis (or encephalopathy) NICE guideline (CG53) is included as an example of another available NICE guideline and will not be covered by this Lyme disease guideline.
Royal College of Genera Practitioner s (RCGP)	6	147 (que stion 2)	What is the role of epitope mapping of antibodies to VlsE protein of Borrelia burgdorferi in post-Lyme disease syndrome. (MH)	Thank you for your response and detailed comments on our questions. We will bring the detail of your response to the Guideline Committee's attention. Where relevant the information will be used to inform the Committee's decision making as they develop the review protocols that guide the searches for and review of the evidence for the questions outlined in the guideline scope.
Royal College of Genera Practitioner s (RCGP)	Gener al	Gen eral	The draft scope is an excellent working document and covers the essential areas and difficulties. (PS) and points 1-5 in the first page all seem reasonable. (MJ)	Thank you for your comment.
Royal College of Genera Practitioner s (RCGP)	Gener al	Gen eral	Overall there seems to be an increasing awareness amongst the population of this condition and yet a great deal of uncertainty amongst non-specialist clinicians as to how to diagnose and treat. Therefore the RCGP feels that this guideline is much needed. The scope seems appropriate and focussed. (MJ)	Thank you for your comment.
Royal College of Nursing			This is just to inform you that the feedback I have received from nurses working in this area of health suggests that there are no comments to submit on behalf of the Royal College of Nursing to inform on the consultation of the draft scope of Lyme Disease.	Thank you for your comment.
Royal College of Nursing			This is just to inform you that the feedback I have received from nurses working in this area of health suggests that there are no comments to submit on behalf of the Royal College of Nursing to inform on the consultation of the draft scope of Lyme Disease.	Thank you for your comment.
Royal College of Paediatrics and Child Health			Thank you for inviting the Royal College of Paediatrics and Child Health to comment on the Lyme Disease draft scope. We have not received any responses for this consultation.	Thank you for your comment.
The British Society for Antimicrobi al chemothera py (BSAC)			Members of The British Society for Antimicrobial Chemotherapy (BSAC) have no comments for this Guideline on Lyme disease.	Thank you for your comment.
VIRAS Vector- borne Infection, Research – Analysis - Strategy	DQ1& 2		VIRAS response to NICE request for comments on 6 month ‘phase’ (including observations on why this might have been suggested): “1) Is the time period of ‘< than 6 months since tick bite or first symptoms or signs’ an acceptable interpretation for ‘early Lyme borreliosis’? 2) Is the time period of ‘> 6 months since tick bite or first symptoms or signs’ or an acceptable interpretation for ‘late Lyme borreliosis’?” Pertains to Draft Scope document Page 3. Lines 74 to 77 Abbreviations CFS, Chronic Fatigue Syndrome GDG Guideline Development Group HPA, Health Protection Agency (now part of PHE) IDSA, Infectious Disease Society of America ILADS, International Lyme and Associated Diseases Society LB, Lyme Borreliosis NHS, UK National Health Service PHE, Public Health England M.E., Myalgic Encephalomyelitis NICE, National Institute for Health and Care Excellence An arbitrary time limit deemed to be a transformation point from one Lyme borreliosis phase to another has no medical or scientific logic. Miklossy (2012) states in The Open Neurology Journal: “Late Lyme neuroborreliosis is accepted by all existing guidelines in Europe, US and Canada. The terms chronic and late are synonymous and both define tertiary neurosyphilis or tertiary Lyme neuroborreliosis. The use of chronic and late Lyme neuroborreliosis as different entities is inaccurate and can be confusing. Further pathological investigations and the detection of spirochetes in infected tissues and body fluids are strongly needed.” In Lyme borreliosis, the time between infection (or re-infection) and the appearance of symptoms/signs which a patient or physician might associate with LB is highly variable and could be months or years. The U.S. Library of Medicine, MedlinePlus (2015) states: “Symptoms of early disseminated Lyme disease (stage 2) may occur weeks to months after the tick bite, and may include …” “Symptoms of late disseminated Lyme disease (stage 3) can occur months or years after the infection. The most common symptoms are muscle and joint pain…” Clearly the stages of LB infection do not conform to a predetermined timescale. Different stages depend upon variables impossible to compute and more rationally deduced by careful evaluation of each individual patient’s symptoms and laboratory tests, if indeed a physician considers determination of a ‘stage’ or ‘phase’ to be a worthwhile exercise. What purpose is served by attempting to define the progression of a disease by a fixed time period and how would it help doctors in making their clinical decisions? It seems unlikely that re-labelling patients at 6 months is considered a useful way to suggest the best tests for a patient’s infection. According to Public Health England (2014), the weaknesses they acknowledge for their tests relate to cross reactivity with other infections and “antibody tests in the first few weeks of infection may be negative”. These problems would not be improved by a 6 month deadline. Once a patient has been diagnosed and treated, further standard NHS two-tier testing is rendered useless because as West (2014) states: “Both IgM and especially IgG antibodies can remain positive for years after successful therapy with antibiotics.” So the determination of treatment success or failure by standard testing would not be helped by a 6 month time limit. There are no tests for LB at any stage which can reliably exclude infection or confirm that treatment or time has eradicated an infection. If such a test (or combination of tests) existed, it is certain that PHE, the CDC, the IDSA and others would have used the test in support of their opinion that persistent infection does not occur beyond what they claim is ‘adequate’ treatment. In contrast, the scientists and doctors of ILADS (2012) who declare that persistent LB infection does occur, provide a list of 700 peer-reviewed scientific papers indicating persistence, in ‘Peer Reviewed Evidence of Persistence of Lyme Disease Spirochete Borrelia burgdorferi and Tick-Borne Diseases’. Furthermore, treatment considerations are guided by disease manifestations and sometimes supported by laboratory test results. E.g., neuroborreliosis is a diagnosis of the spread of LB spirochaetes to the central nervous system (CNS). It is suspected by symptoms, supported by examination and testing of cerebrospinal fluid (CSF) and treated by intravenous antibiotics. Neuroborreliosis can occur at any time in infected individuals because it relates to the spread of the infection. If the bacteria’s 6 month ‘VISA’ runs out, that would not prevent it crossing the barrier into the CNS. Therefore determining the choice of tests or treatment cannot be the motive for trying to determine the phase of a patient’s infection according to a calendar. A 6 month phase could not apply to an infant born infected or an infant with an immature immune system that becomes infected. How would 6 months apply to a child which is quite simply, a much smaller mammal than an adult human? Would the transformation from ‘early’ to ‘late’ infection happen at the same time in a person initially infected with a few spirochaetes compared to someone infected via multiple heavily infected tick bites which also transmitted ehrlichia and bartonella? In some regions, 10% to 20% of healthy blood donors are seropositive for Lyme antibodies. If they become ill in the future, will that be ‘early’ or ‘late’ Lyme? (Mygland, Skarpaas and Ljøstad, 2006; Hjetland et al 2014) Dr Willy Burgdorfer, who discovered the borrelia burgdorferi spirochaete in 1982, stated (Under Our Skin, 2007): “I am a believer in persistent infections because people suffering with Lyme disease, ten or fifteen or twenty years later, get sick [again]. Because it appears that this organism has the ability to be sequestered in tissues and [it] is possible that it could reappear, bringing back the clinical manifestations it caused in the first place.” When asked about the similarities between Borrelia burgdorferi and syphilis, Dr. Burgdorfer stated: “The similarities that I know of are associated with the infection of the brain, the nervous system. The syphilis spirochete, Treponema pallidum has an affinity for nerve tissues. The Borrelia burgdorferi spirochete very likely has that too. Children are especially sensitive to Borrelia burgdorferi. The Lyme disease spirochete is far more virulent than syphilis.” (Under Our Skin, 2007). Since early and late stages for Lyme borreliosis reflect similarities with syphilis, they must recognise that stages are determined by the spread and manifestation of the infection and not by a calendar. NHS Choices, (2014) remarks on Syphilis: Primary syphilis: “The initial symptoms of syphilis can appear any time from 10 days to three months after you have been exposed to the infection.” Secondary syphilis: “The symptoms of secondary syphilis will begin a few weeks after the disappearance of the sore.” Latent phase: “The latent stage can continue for many years (even decades) after you first become infected.” Tertiary syphilis: “The symptoms of tertiary syphilis can begin years or even decades after initial infection.” Specifying a 6 month or other arbitrary time-point between phases is so illogical, that one could be excused for questioning the motives behind even contemplating such a notion. Perhaps it is a coincidence that the CDC/Fukuda (1994) criteria for a diagnosis of Chronic Fatigue Syndrome requires 6 months of symptoms with fatigue criteria (which is common in LB). There is evidence which suggests that Public Health England intend that chronic LB patients should be re-diagnosed as having CFS or some other contrived ‘syndrome’, e.g., ‘chronic arthropod neuropathy syndrome’. The HPA (now part of PHE) informed the Health and Safety Executive (2012) of their plans: “RIPL and HPA staff will discuss with Simon Wesseley’s [sic] group and other interested