Stakehold

to the wording currently used. We

continue to present information in this

section linked to the issues when

Lyme Disease has not resolved

spontaneously to present the fullest

range of experience.

Lyme Research UK	7 7	143 146- 147	You call symptoms that persist after treatment “post-infectious Lyme disease”: None of the Lyme borreliosis guidelines or articles in the medical literature refer to ‘post- infectious Lyme disease’, and we think it is not a good idea to introduce a new term that nobody else uses.	Thank you for your comment. We have deleted this phrase.
Lyme Research UK			You write “There is controversy over the existence of ‘chronic Lyme disease’ or ‘post Lyme disease’ syndrome”: We suggest that you delete this sentence. The British Infection Association (2011), the Infectious Diseases Society of America (Wormser et al, 2006) and the Centers for Disease Control and Prevention in the United States (2016b) now all recognize that some patients have persistent symptoms lasting for many months or years after the officially recommended treatment. See also the meta-analysis on this by Cairns et al (2005). It is debated whether this is a post-infectious syndrome or ongoing infection, although it is possible that some patients have a post-infectious syndrome while others have ongoing infection. The Centers for Disease Control and Prevention in the United States (2016b) writes: “Clinical studies are ongoing to determine the cause of PTLDS [post-treatment Lyme disease syndrome] in humans.” We think that a section on this should be included in the NICE Guideline, noting results from studies such as those by Bouquet et al (2016), Chandra et al (2010) and Fallon et al (2003), and any future results from the ongoing studies referred to by the Centers for Disease Control.	Thank you for your comment. We have changed ‘controversy’ to ‘uncertainty’ to reflect the ongoing discussion around this issue. The Guideline Committee will develop review questions and protocols based on the key areas as outlined in the scope. This is to ensure that the reviews follow good scientific practice and established NICE processes when identifying, synthesising and analysing the evidence. The references you provide may form part of literature to be reviewed depending on the specific content of the protocol developed by the guideline committee. Where appropriate. they may be used to inform the supporting introductory text to accompany any relevant review questions.
Lyme Research UK	7	158- 159	You write “Infection is more likely if the tick remains attached to the skin for more than 24 hours”: This may be taken by some to mean that an infection is very unlikely if the tick is attached for a short time. However, that is not the case. Infection can occur quickly and the minimum attachment time has never been established. Risk increases with attachment time with no evidence of a safe period (Cook, 2015), and a study indicates that removal of ticks after body searches on the day of exposure to ticks does not prevent significant risk of infection (Faulde et al, 2014). We think it would be better to replace the sentence with: "Infection risk increases with attachment time but there is no safe period and infection frequently occurs in less than 8-12 hours".	Thank you for your comment. We agree that the statement ‘An infection is more likely if a tick remains attached for longer periods’ Is not intended to imply that Lyme disease requires a tick to be attached for more than 24 hours in order to develop. We do not feel a change to the scope is required.
Lyme Research UK	7	165- 166	You write "those without a rash, but with symptoms suggestive of Lyme disease and at risk of tick exposure, have blood tests": As discussed in our general comments, test reliability is poor, with low sensitivities for the standard two-tier serological testing. Early use of antibiotics or steroids may also abrogate the immune response and produce false negative test results. Therefore we think that diagnosis should not be reliant on testing but experienced clinicians should be encouraged to make clinical diagnoses where clinical signs are strongly indicative of Lyme borreliosis. The diagnostic pathways should be amended to allow for clinical diagnoses even in the absence of a positive test result.	Thank you for your comment. We acknowledge the concerns about the diagnosis and treatment of Lyme disease. The development of this guideline will see recommendations being made based on the evidence identified through evidence reviews. This will include diagnostic tests for Lyme disease.
Lyme Research UK	8	179	You write “Experience of typical cases is limited”: We suggest you delete this sentence. With a few thousand diagnosed cases per year in the UK, around 300,000 per year in the U.S. (Centers for Disease Control, 2016c), and over 200,000 per year in Germany (Mueller et al, 2012), it seems that there must be quite a bit of experience. The term ‘typical case’ is best avoided, as Lyme borreliosis can present with many different symptoms (making it hard to diagnose). Or do you mean “Many GPs in the UK have limited experience with Lyme disease.”?	Thank you for your comment. We have deleted the sentence.
Lyme Research UK	DQ1& 2		NICE questions 1 and 2 on definition of early and late Lyme borreliosis: The stages of Lyme borreliosis are defined by the British Infection Association (2011) and the Infectious Diseases Society of America (Wormser et al, 2006) according to the extent of disease, and not by time since tick bite. Patients can vary a lot in how quickly the infection spreads. The British Infection Association (2011) writes that late-stage disease can develop "months or years later”. They also write that the stages are “not clear-cut phases and should be regarded as a process". We therefore think it is better not to connect the stage with duration of infection, and better not to give a fixed cut-point of under or over 6 months. In fact, ‘early’ and ‘late’ are not useful descriptions of the stages of Lyme borreliosis since they imply durations of infection such as you have given. Better would be to use terms like ‘localised Lyme borreliosis’, ‘disseminated Lyme borreliosis’, and ‘neurological Lyme borreliosis’.	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.
Lyme Research UK	DQ3		NICE question 3 on range of clinical presentations: We think it is very important to point out that there is a large variety in the patterns of clinical presentation at each stage of the disease, making diagnosis difficult. Lyme borreliosis should be suspected in any patient that presents with a spectrum of the symptoms listed below. Studies of symptoms reported by patients with confirmed Lyme borreliosis include the following, and the patient will usually describe a number of these or many in a relapsing/remitting pattern. Symptoms in order of frequency of occurrence compiled from Aucott et al (2012), Djukic et al (2011), Strle et al (2006) and Trevejo et al  Arthritis/arthralgia (especially back, neck, knee, ankle)  Fatigue/malaise (frequently with headache)  Neurological symptoms (peripheral neuropathy, numbness, pins and needles, neuropsychiatric symptoms) Erythema migrans rash Cognitive dysfunction (short term memory problems, confusion, speech problems) Myalgia Chills Meningeal symptoms Radicular pain Sweats Tick bite  Facial palsy (more frequent in children)  Vision problems (floater, blurred/double vision)  Cardiac problems (chest pain, heart block)  Hearing problems (tinnitus, hearing loss)  Other (dizziness, vertigo, sleep disturbance, photophobia) Neuro-psychological symptoms are also part of the spectrum.	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.
	DQ4	DQ4	NICE question 4 on inclusion of strains of Borrelia: B. valaisiana has been detected in the UK, in addition to the Borrelia species that you list. Couper et al (2010) reported that 32% of infected ticks in south-west England had B. valaisiana, similar to the 35% in the New Forest reported by Kurtenbach et al (2001), while 58% of infected ticks had B. valaisiana in a study in northern England, north Wales and the Scottish Border region (Bettridge et al, 2013). B. valaisiana is considered pathogenic for humans (Venclíková et al, 2014), and it has been isolated in patients diagnosed with Lyme borreliosis (Pancewicz et al, 2015). We think B. valaisiana should therefore be included in your list. However, since infected ticks can be transported by birds, actually any species seen in the rest of Europe could be in ticks here too. Furthermore, people travel extensively and more than 10 million people per year vacation abroad, many of them camping and hiking. A relevant proportion of Lyme borreliosis infections seen England were caught abroad. This means that any species could be the cause in a case of Lyme borreliosis seen in the England. We think therefore you should not restrict your definition of Lyme borreliosis to three species. Species that are considered pathogenic include: B. afzelii, B. bissettii, B. garinii, B. burgdorferi s.s., B. valaisiana, B. lusitaniae, and B. spielmanii. (Venclíková et al, 2014; Stanek G et al, 2011). Plus there are 14 other similar Borrelia species and more than 20 Borrelia species associated with the relapsing fever group including B. miyamotoi which results in symptoms which match those of Lyme borreliosis (Wang G et al, 2014). Furthermore, although it is generally not known with which species a patient is infected, physicians need to know that patterns of presenting symptoms vary for the different species, i.e. there is no standard set of symptoms, and that the sensitivity of the laboratory tests differs for the different species, which is an area we think NICE should investigate further.	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.
	DQ5		NICE question 5 on appropriate diagnostic tests for consideration: There are problems with current testing. All tests used in the UK depend on detecting antibodies. All tests can generate false negatives for the following reasons: a) Poor laboratory practice and quality control. UK Lyme testing laboratories are not accredited to ISO 15189. All laboratories should (as soon as possible) be accredited to the ISO standard to meet acceptable laboratory quality management practice. b) Intrinsic insensitivity of the tests. Data from 43 independent studies selecting for commercial test kits and reporting specificity greater than 90% gives a sensitivity of 64.5% with samples that were confirmed positive using a prior serology test or culture positive (full set of references available from Lyme Research UK). Data from 78 studies shows test sensitivities as low as 15% and analysis of all studies with specificity 90% or greater the mean sensitivity is 70.9% (Leeflang et al, 2016). Since most evaluation of test kits use serum panels or samples with well characterised disease state, the results do not reflect the sensitivity when used for clinically derived samples. c) the early stages of disease, and the response can be affected by prior use of antibiotics, immune system suppression due to use of steroids, a compromised immune system, and the normal variation of the immune system due to age, stress, diet and pregnancy, as well as effects of the Borrelia spirochaete (Elsner et al, 2015; Strle et al, 1996; Preac-Mursic et al, 1989; Tylewska-Wierzbanovska et al, 2002; Durovska et al, 2010). d) Western Blot tests used in England are based on native antigens from 2 species plus recombinant VlsE (ViraMed Laboratory Diagnostics, 2016). It requires cross reactivity with antigens from other species for them to be detected with unknown and reduced sensitivity. e) The use of a screening test followed by a confirmatory test (2-tier test) was chosen as a method to reduce false positive tests at the Second National Conference on Serologic Diagnosis of Lyme Disease 27-29 Oct 1994. It was based on poor specificity of the early ELISA tests with resulting false positives. ELISA test manufacturers now ensure that the test specificity is close to 99%. Western blot tests also have a specificity close to 99%. Combining the test in the 2-tier sequential process reduces overall sensitivity and increases false negatives. Alternative tests to aid diagnosis: SeraSpot Elispot Lymphocyte Transformation Test  Any laboratory that is fully approved and validated by international laboratory certification protocols.  Culture is widely accepted for other pathogens but requires skilled microscopists. Probably not for use in mainstream laboratories but should not be excluded.  Molecular detection methods including: Polymerisation Chain Reaction PCR and variants o PCR/Electrospray Ionisation-Mass spectrometry. o Fluorescence in situ DNA Hybridization. o Other fluorescence systems.  Other molecular detection systems. There should be funding for study of new testing technologies and evaluation, with rapid implementation of superior methods.  An example is microscopy using digital filters and pattern recognition as developed by XRAPID for detection of malaria.  Next Generation Sequencing	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. The human antibody response is slow to develop making tests highly unreliable in
Lyme Research UK	gener al	gene ral	Misdiagnosis of Lyme borreliosis: In a WHO report (Lindgren et al, 2006), the authors noted that many Lyme borreliosis infections go undiagnosed. We are concerned that many undiagnosed Lyme borreliosis patients are actually misdiagnosed and so then are never tested for Lyme borreliosis. Patients with Lyme borreliosis in the later stages frequently have profound fatigue as well as notable cognitive problems. Many may thus be misdiagnosed as having chronic fatigue syndrome or Alzheimer's disease. See for example the publication by Maheshwari et al (2015) showing a 10-fold increased diagnosis of Alzheimer's disease when there is detectable evidence of spirochaetal infection. We would like to see it addressed how patients, before receiving a diagnosis of chronic fatigue syndrome or Alzheimer's disease, might be evaluated and tested for Lyme borreliosis, keeping in mind the relatively high rate of false negatives from the laboratory tests. Many Lyme borreliosis patients believe that the Multiple Systemic Infectious Disease Syndrome (MSIDS) differential diagnosis scoring system published by Horowitz (2016) would help clinicians diagnose Lyme borreliosis and co-infections.	Thank you for your comment. This guideline will cover in whom Lyme disease should be suspected and the assessment and diagnosis of Lyme disease. The Guideline Committee will carefully consider which assessment and diagnostic strategies can be included in the evidence reviews and will make recommendations based on the identified evidence. We would like to draw your attention to a NICE guideline on symptoms with unknown causes that has not yet been commissioned, which may cover differential diagnostic processes for conditions with unknown causes.
Lyme Research UK	gener al	gene ral	Coinfections as far as they impact on Lyme borreliosis: Ticks can carry other infections and patients are frequently infected by other organisms at the same time as Lyme borreliosis. We think that there should be some mention of coinfections in the guideline. In addition to Borrelia, ticks can carry over 100 other human pathogens. The proportion of infected ticks co-infected by other pathogens is very high. A recent study in France