Controversies & Challenges in Treating Lyme and Other Tick-borne Diseases
By the International Lyme and Associated Diseases Society
I. Controversy over Diagnosis
The controversies in Lyme disease exist in a setting of incomplete scientific evidence around tick-borne diseases, including a lack of validated direct testing methods which can be applied across all stages of the disease to accurately distinguish infected from uninfected patients. Serologic testing, often held as a gold standard, has significant performance limitations. Lyme disease is a clinical diagnosis dependent on history, and physical examination, and supported by appropriate laboratory testing. The elements of diagnosis are placed in the context of the activities and experiences of the patient, environmental exposures and risk factors, and consideration of other diagnoses that may explain or impact the patient’s symptoms. At the heart of the controversy is the relative weight given to each element that contributes to the diagnosis. ILADS’ position is that no single data point, including serologic testing, automatically outweighs the contributions from all of the data in the patient’s presentation and evaluation.
ISSUES WITH DIAGNOSIS & DIAGNOSTICS
There is a distinction between diagnosis and diagnostics. A diagnosis encompasses the considered explanation for a patient’s symptoms based on the elements described above, as well as the process by which the diagnosis itself is reached. Diagnosticsrefers to laboratory and other test modalities used to aid in reaching a diagnosis. Challenges exist in both areas when considering Lyme disease.
Challenges in diagnosis occur in a setting of varied clinical presentations often appearing in the absence of a history of tick bite. Even the erythema migrans rash (EM), a hallmark of the disease, is not always present or remembered, and in its most common form does not resemble the classically described “bull’s eye” rash.3 The sometimes subtle physical findings and diversity of manifestations of Lyme borreliosis require awareness on the part of the examiner in order to discern this infection. Even in the case of Lyme arthritis with effusion, it has been reported that diagnosis in adults often takes longer than in children.4 In addition, since latency is a feature of this infection, some signs and symptoms do not develop for weeks, months or even years after the time of initial infection.5 6 7 All of these features contribute to diagnostic uncertainties and controversy.
Direct tests (culture, PCR) for Borrelia burgdorferi have performance limitations that must be considered when used in evaluating Lyme disease. These tests are not readily available; the slow growth characteristics of B. burgdorferi in culture and the sparse distribution of the bacteria in blood and tissues result in generally low sensitivities for these tests. The most successful cultures and PCRs have been on specimens from the leading edge of erythema migrans rashes8, a manifestation typically not requiring culture or PCR to clarify the diagnosis. When both culture and PCR have been performed on the same specimens, they have not necessarily given the same result.9 PCR in some studies is shown to perform fairly well in evaluating synovium of Lyme arthritis.10 11 In US studies, blood and CSF generally have very low yield on direct tests for Borrelia burgdorferi.12 Differences in testing methods, tissue and specimens being evaluated contribute to the challenges in direct testing. Emerging direct testing modalities, including a more promising method of culture, present new opportunities for addressing the challenges inherent in direct tests.13 14 As in all testing, interpretation of positives and negatives depends upon the clinical setting.
Serologic tests are the most commonly performed tests for investigating Lyme disease. These tests do not identify the presence or absence of B. burgdorferi, but rather detect the presence of an antibody response that may be attributable to exposure to this pathogen. Of the dozens of serologic tests available in the US market, none are FDA-approved. Rather, all are FDA-cleared, which means that the test compares favorably with and performs at least as well as other tests already in use, but has not been clinically validated in prospective studies. None has shown clear superiority in performance.
The reliability of diagnostic testing is a function of accuracy and reproducibility. Accuracy is a test’s ability to detect disease when it is present, and not detect disease when it is absent. Reproducibility is the ability of a test to give the same result for a specimen on repeat testing. Highly accurate tests generate few false negatives and few false positives. Unfortunately, Lyme serology produces many false negatives and false positives. Additionally, investigators have repeatedly demonstrated that both ELISA and immunoblot tests for Lyme have poor reproducibility.15 16 17 18
When antibody testing is done too early or too late in infection, false negatives may result. Further, it has been shown that after an antibody response develops, it can wane or persist regardless of disease status.19 20 21 In Embers’ study of Bb-infected primates, some untreated animals had antibodies develop and then disappear over time, despite persistence of infection. Finally, some patients fail to develop antibody responses to this infection.22 23 Interpreting test results within the context of the patient’s clinical history is important in assessing the likelihood that a positive test represents the presence of the disease and that a negative test represents its absence.24 The occurrence of false negatives and false positives greatly contributes to the controversy over diagnosis.
Performance characteristics are not only affected by timing of testing but also by the particular disease manifestation being evaluated. Western blot testing, for example, has been found to perform very well in cases of arthritis (96% sensitivity) but less well in neurologic presentations (72% sensitivity).25 26 Note that even when the tests perform well, some cases will be missed if we rely solely on test results. In the vaccine trials, it may be noted that reliance on serology alone for the diagnosis of Lyme disease would have missed one third of cases.27
The ELISA quantitatively measures IgM, IgG or a combination of IgM and IgG antibodies in an automated format. ELISA sensitivities have been shown to vary by disease stage and manifestation.28 In early Lyme, sensitivities of ~40% have been reported, rising to as high as 82% in disseminated or late/convalescent samples. In a clinical setting consistent with Lyme disease, the likelihood that a positive ELISA is a true positive is high. However, in the same setting, the likelihood that a negative ELISA is a true negative is less certain.
Western Blot Interpretation
Western blots, either IgM or IgG, qualitatively measure antibody reactions across a range of more than 2 dozen B. burgdorferiantigens. The determination of which antibody reactions to include in establishing criteria for a positive Western blot has been the subject of much controversy. Dressler et al. developed criteria based on the frequency with which particular antibodies appeared in clinically well-characterized patients. They then applied statistical parameters to determine which particular antigens to include and the minimum number of antibody responses needed to achieve a test specificity of 99%.29 Of interest is the absence of 31 and 34 kDa proteins (ospA and ospB) which may occur infrequently but are significant for Bb, especially when occurring together.30, 31 Other investigators have proposed different criteria for Western Blot interpretation. Engstrom et al.’s proposed criteria for interpretation of IgM Western blot, and Dressler, et al.’s proposed criteria for IgG Western blot were adopted for standardization.32
The commonly recommended testing scheme for evaluating a person suspected of having Lyme disease calls for a first step using a highly sensitive ELISA, only followed by a Western Blot if the first step result is positive or equivocal.33 Negative samples by ELISA are not investigated further. Tests used in this strategy are subject to the confounders of testing described above, and because they are linked sequentially in the stated manner, those confounders are magnified, making the possibility of false negatives much greater.
This test strategy, like the interpretation parameters of the tests involved, was adopted for standardization of testing practices,34 35 which were deemed unreliable at the time. Primarily designed and intended to enhance testing specificity, the overall sensitivity of a sequence of this sort necessarily falls. Nevertheless, it was adopted by the CDC and the Association of State and Territorial Public Health Laboratory Directors “as a temporary measure,” despite objections, at the Second National Conference on Serologic Diagnosis of Lyme Disease held in Dearborn, Michigan in 1994.36 This test strategy has not been replaced.
Clinical practice necessarily places emphasis on identifying every infected patient in order to identify, treat, and prevent adverse consequences. Therefore, ILADS concludes that the two-tiered test strategy does not adequately serve clinician or patient.
THE ILADS POSITION ON DIAGNOSIS AND TESTING
Lyme disease is a clinical diagnosis based on the history and physical findings, and supported by appropriate laboratory tests when they are indicated. These elements must be considered in the context of the individual patient’s full story and with consideration of other diagnoses that may explain or confound the patient’s diagnosis. No single element of the diagnostic process outweighs the full and complete evaluation. The strengths and limitations of laboratory testing must be understood by the clinician in order to use testing modalities effectively and avoid some of the pitfalls of diagnosis that can result from over-reliance on laboratory testing to rule in or rule out an illness.
II. Controversy over Treatment
Lyme disease is a complex illness with many variables. The severity of the infection and a person’s response to treatment may depend on 1) which species or strains of the bacteria the person has, 2) how long they have been ill, 3) which body systems are involved, 4) whether other tick-borne diseases are present, and 5) the person’s underlying health status. Commonly prescribed antibiotic regimens generally follow a one-size-fits-all approach using 30 or fewer days of antibiotic therapy, but several investigators37 38 39 have found that many people remain ill after receiving such care. ILADS maintains that in light of all of the potential variables, antibiotic treatment must be individualized.
ILADS members have treated tens of thousands of patients with Lyme and associated tick-borne diseases in the US and across the globe. Based on the collective work of its members, ILADS has a wealth of clinical expertise in treating complex and advanced cases of Lyme disease.
To determine the best possible course of action given the available data, ILADS convened a working group to conduct a thorough review of the literature with regards to managing blacklegged tick bites, treatment of EM rashes, and persistent (chronic) manifestations of Lyme disease. The team used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to evaluate and rate the quality of the evidence and the strength of ensuing recommendations. In reviewing the literature and making recommendations, ILADS placed a high value on preventing chronic infection, on not causing the abrogation of the immune response, and on the ability of the clinician to exercise clinical judgment.40
As of February 2018, ILADS’ treatment guidelines are the only Lyme disease guidelines available at the National Guideline Clearinghouse, an initiative of the Agency for Healthcare Research and Quality (AHRQ), under the umbrella of the US Department of Health and Human Services. These guidelines were developed with careful attention to the peer-reviewed scientific evidence presented in the Lyme research using a rigorous GRADE41 assessment of the pertinent trial evidence.
SUMMARY OF ILADS’ RECOMMENDATIONS
Generally speaking, treatment decisions hinge on the duration of the illness, the types of symptoms and signs the person has, and whether they were previously treated for this specific infection in the past.
- ILADS recommends that prophylaxis be discussed with all who have had a blacklegged tick bite. This is to prevent the onset of infection; technically speaking, antibiotic prophylaxis of a known bite is not treatment because the person is not yet ill.
- When the decision is made to use antibiotic prophylaxis, ILADS recommends 20 days of doxycycline (provided there are no contraindications). Additionally, ILADS recommends against single-dose doxycycline.
- ILADS recommends that most patients with erythema migrans receive an initial 4-6 weeks course of antibiotic therapy. Subsequent management decisions are based on whether the signs and symptoms remain or relapse.
- ILADS recommends that patients with persistent (chronic) signs and symptoms of Lyme disease receive individualized care that tailors antibiotic treatment to their specific situation. The duration of treatment and the choice of antibiotic or antibiotic combinations are clinical decisions to be made with several factors in mind. Long-term antibiotic therapy is not without risks, and should only proceed under close supervision.
Read the ILADS Treatment Guidelines for more detailed discussion of our treatment recommendations.
III. Controversy over Chronic Lyme Disease
Chronic Lyme disease, which ILADS defines as an ongoing infection with any of the pathogenic bacteria in the Borrelia burgdorferi sensu lato group, is poorly understood and often mischaracterized. Although the infection was often described as “chronic” early in the history of Lyme disease, that terminology was abandoned by the Infectious Disease Society of America (IDSA) and many IDSA-affiliated researchers and clinicians in the late 1990s.42 The rationale for that switch is unclear, as the bacteria’s ability to cause a chronic and sometimes post-antibiotic persistent infection was already well documented in the scientific literature.43 44 The CDC generally maintains that Lyme disease is an acute infection and it does not readily acknowledge that the infection can persist following antibiotic treatment. Instead, the CDC recognizes other potential causes for ongoing symptoms. The CDC endorses the use of the term “Post-Treatment Lyme Disease Syndrome”(PTLDS) when symptoms persist for more than six months following antibiotic.45
ILADS agrees that for many patients, Lyme disease is strictly an acute infection. However, for many other individuals, the infection is chronic. Common symptoms include:
- Cognitive dysfunction
- Sleep disturbances
- Migratory myalgia and arthralgia
- Numbness and tingling
- Neuropathic pain
- Depression and anxiety
- Musculoskeletal problems.46
The diagnostic controversies discussed above also apply to patients with chronic Lyme disease, causing many medical providers to miss a Lyme diagnosis. As a result, patients can exhibit significant symptoms of Lyme disease for years and even decades that are misattributed to other entities — fibromyalgia, chronic fatigue syndrome, and depression are common misdiagnoses. Although Lyme symptoms overlap with the symptoms of these illnesses, a well-conducted meta-analysis demonstrated that persistent Lyme disease symptoms were a distinct set of symptoms that differed from those of other chronic, difficult-to-manage diseases.47 Additionally, in comparing the cerebrospinal fluid of patients with chronic, post-treatment manifestations of Lyme disease to that of patients with chronic fatigue syndrome, researchers found that the two groups could be distinguished from each other on the basis of proteins that were unique to a particular group.48
Patients with chronic Lyme disease may require prolonged treatment — i.e., additional courses of antibiotics. An unknown percentage of patients, with data ranging from 10 to more than 30%, report prolonged symptoms despite prior antibiotic treatment for Lyme disease.49 50 51 Given B. burgdorferi’s wide array of survival mechanisms, this statistic is not surprising. B. burgdorferi is notoriously adaptable, which enhances its survival. As noted in the ILADS guidelines, and by others, the bacteria can alter its morphology, engage in antigenic variation, invoke periods of dormancy, inhabit protective niches, and form biofilms that protect the bacteria from the immune system and the effects of antibiotics.52 53 These survival mechanisms allow for B. burgdorferi persistence following short-term antibiotic therapy. Repeated courses of antibiotics that do not address these bacterial protections are also likely to fail.
THE ILADS POSITION ON TREATING CHRONIC LYME DISEASE
Based on the extensive collective experience of ILADS members and a rigorous review of the broader scientific literature, ILADS maintains it is in the best interest of chronic Lyme disease patients for clinicians to offer additional treatment.54 Taking into account the strength of the evidence addressing the effectiveness of antibiotic retreatment, the burden of disease in this patient population, and the risks associated with various antibiotic options, ILADS concludes that the very real consequences of an untreated chronic Lyme infection far outweigh the potential consequences of long-term antibiotic therapy. Further, we assert that although it is too early to standardize restrictive protocols, effective treatment options are available for these patients.
IV. Controversy over Time of Attachment Before Transmission
Many professionals mistakenly believe that Lyme disease cannot be transmitted when a blacklegged tick has been attached for 24 to 48 hours. This is incorrect. Several animal studies have documented that although the risk of Lyme disease is quite low for attachment times under 24 hours, the risk is not zero.55 The length of attachment for transmission of other members of the Bb sensu lato complex pathogens to occur may differ from that of B. burgdorferi.56 ILADS recommends that patients with a known blacklegged tick bite of any duration should discuss the possibility of Lyme disease with their providers.
V. Other Challenges in Treating Lyme Disease
Other Tick-Borne Infections
Blacklegged ticks can transmit at least four other infections.57 The frequency of tick-borne co-infections in Lyme disease patients from endemic areas ranges from 4-45%.58 Not all providers appreciate the risks of acquiring co-infections nor the clinical significance of these pathogens. If co-infections are unidentified and unaddressed, a provider may treat Lyme disease effectively, yet have patients who remain ill.
Pressures on Clinicians
Medical providers face the challenge of these often complicated patients in practice settings that may impose time constraints and other limitations to their choices in diagnosis and treatment. The diagnostic possibilities are themselves complex and the requirements for follow-up and careful observation of progress and further decision-making significant. Placed in the context of a “controversial illness” and personal concerns about experience and expertise in this area of medicine, the pressure on individual clinicians can be substantial.
Misuse of Treatment Guidelines
Treatment guidelines were called for by the Institute of Medicine to assist clinicians by assembling the best available evidence from the medical literature as well as assessments of risks and benefits of treatments and alternatives in order to inform patient care. The IOM standards for guidelines development recommend that patients and others affected by a guideline be included in the development process as this would help assure that guidelines address and prioritize the issues most important to patients. Guidelines are not intended to supplant the judgment of a clinician in the care of individual patients. When insurers, employers, medical boards, or other entities treat guidelines as if they are laws, misusing them to determine payment, as performance measures, or for disciplinary purposes, it can undermine the utility of these works for clinicians.
Health insurance companies create policies for payment of benefits to guide in claims decisions. When these policies are narrowly determined, as they are when based on surveillance case definitions of Lyme disease, they may impede a patient’s recovery of benefits, and importantly, may prevent receipt of care. When cost assessments are performed, ILADS holds that they need to include the costs of non-treatment, the costs of other kinds of management that will be required if the underlying cause of illness is not treated, and the cost of disability as a result of the illness.
The Marginalization of Patients with Lyme Disease
While any patient, particularly one with a chronic illness, is at risk of marginalization,59 60 61 Lyme disease patients face a particularly intense set of challenges: the stigma associated with this controversial diagnosis; the polarization of medical providers concerning diagnosis and treatment; the challenges of obtaining insurance coverage for treatment beyond the acute phase of the disease; the potential to experience isolation because of the illness.
All of these factors and the controversies we have explored above contribute to the experiences of patients who struggle with the very real effects of Lyme disease. The medical uncertainties surrounding tick-borne diseases may lead some clinicians to take a hands-off approach to these illnesses, or to fail to coordinate with a Lyme-treating colleague. Patients experience mis- and missed diagnoses and, at times, their symptoms may be erroneously attributed to a psychiatric diagnosis or malingering. The cumulative effect is that many patients become marginalized.
The evidence regarding Lyme and other tickborne diseases continues to evolve. ILADS and ILADEF recognize that many in the greater medical community may not be sufficiently versed in the scientific evidence of Lyme disease and other tick-borne illnesses, giving rise to misconceptions about the disease. Evidence-based medicine is the integration of clinical research, clinical expertise and patient values and preferences. Given that the clinical evidence is limited and of low quality, clinical expertise and patient values take on increased importance. To assure the decisions about treatment and outcomes remain patient-centered and individualized, ILADS and ILADEF strongly encourage patients to be actively involved in decisions affecting their medical care.
1 The Centers for Disease Control website, https://www.cdc.gov/lyme/faq/index.html. Last visited 11/1/17.
2 Vector-borne diseases. European Environment Agency. Last visited 1/31/18.
3 Smith RP, Schoen RT, Rahn DW, et al. Clinical characteristics and treatment outcome of early lyme disease in patients with microbiologically confirmed erythema migrans. Annals of Internal Medicine. 2002;136(6):421–428. [PubMed]
4 Daikh, B. E., Emerson, F. E., Smith, R. P., Lucas, F. L. and McCarthy, C. A. (2013), Lyme Arthritis: A Comparison of Presentation, Synovial Fluid Analysis, and Treatment Course in Children and Adults. Arthritis & Rheumatism, 65: 1986–1990. doi:10.1002/acr.22086
5 Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. New Engl J of Med. 1990;323:1438-44.
6 Logigian EL, Steere AC. Clinical and electrophysiologic findings in chronic neuropathy of Lyme disease Neurology Feb 1992, 42 (2) 303; DOI: 10.1212/WNL.42.2.303
7 Steere AC, Levin RE, Molloy PJ, Kalish RA, Abraham JH 3rd, Liu NY, Schmid CH.Treatment of Lyme arthritis.Arthritis Rheum. 1994 Jun;37(6):878-88.
8 Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of lyme borreliosis. Clin Microbiol Rev. 2005 Jul;18(3):484-509. Review.
9 Smith, supra note 3
10 Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis.N Engl J Med. 1994 Jan 27;330(4):229-34.
11 Priem S, Burmester GR, Kamradt T, Wolbart K, Rittig MG, Krause A. Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy. Ann Rheum Dis. 1998 Feb;57(2):118-21.
12 Augero-Rosenfeld, supra note 6.
13 Sapi E, Pabbati N, Datar A, Davies EM, Rattelle A, Kuo BA. Improved culture conditions for the growth and detection of Borrelia from human serum. Int J Med Sci. 2013;10(4):362-76. doi: 10.7150/ijms.5698. Epub 2013 Feb 18.
14 Magni R, Espina BH, Shah K, et al. Application of Nanotrap technology for high sensitivity measurement of urinary outer surface protein A carboxyl-terminus domain in early stage Lyme borreliosis. Journal of Translational Medicine. 2015;13:346. doi:10.1186/s12967-015-0701-z.
15 Bakken LL, Callister SM, Wand PJ, Schell RF. Interlaboratory comparison of test results for detection of Lyme disease by 516 participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologists Proficiency Testing Program. Journal of Clinical Microbiology. 1997;35(3):537-543.
16 Ang CW, Notermans DW, Hommes M, Simoons-Smit AM, Herremans T. Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. European Journal of Clinical Microbiology & Infectious Diseases. 2011;30(8):1027-1032. doi:10.1007/s10096-011-1157-6.
17 Cook MJ, Puri BK. Commercial test kits for detection of Lyme borreliosis: a meta-analysis of test accuracy. International Journal of General Medicine. 2016;9:427-440. doi:10.2147/IJGM.S122313.
18 Leeflang MM, Ang CW, Berkhout J, Bijlmer HA, Van Bortel W, Brandenburg AH, et al.The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis. BMC Infect Dis. 2016 Mar 25;16:140. doi: 10.1186/s12879-016-1468-4. Review.
19 Embers ME1, Hasenkampf NR1, Jacobs MB1, Tardo AC1, Doyle-Meyers LA2, Philipp MT1, Hodzic E3. Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding.PLoS One. 2017 Dec 13;12(12):e0189071. doi: 10.1371/journal.pone.0189071. eCollection 2017.
20 Kalish RA, McHugh G, Granquist J, Shea B, Ruthazer R, Steere AC.Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10-20 years after active Lyme disease. Clin Infect Dis. 2001 Sep 15;33(6):780-5. Epub 2001 Aug 10.
21 Craft JE, Fischer DK, Shimamoto GT, Steere AC.Antigens of Borrelia burgdorferi recognized during Lyme disease. Appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness..J Clin Invest1986;78(4):934-939.
22 Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi.N Engl J Med. 1988 Dec 1;319(22):1441-6.
23 Dressler F, Whalen J, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease.. J Infect Dis. 1993;167:392-400.
24 Maloney EL The need for clinical judgment in the diagnosis and treatment of Lyme disease. J of Amer Phys and Surg. 2009;14(3):82-9.
25 Dressler, supra note 23
26 Maloney, supra note 24
7 Steere AC, Sikand VK, Meurice F, Parenti DL, Fikrig E, Schoen RT, Nowakowski J, Schmid CH, Laukamp S, Buscarino C, Krause DS.Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group. N Engl J Med. 1998 Jul 23;339(4):209-15.
28 Dressler, supra note 23
29 Dressler, supra note 23
30 Engstrom SM, Shoop E, Johnson RC.Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995; 33:419-27.
31 Ma B, Christen B, Leung D, Vigo-Pelfrey C. Serodiagnosis of Lyme borreliosis by western immunoblot: reactivity of various significant antibodies against Borrelia burgdorferi. J Clin Microbiol. 1992; 30(2):370-6.
32 Centers for Disease Control and Prevention and Association of State and Territorial Public Health Laboratory Directors (ASTPHLD).1994. Proceedings of the 2nd National Conference on Serologic Diagnosis of Lyme Disease (Dearborn, MI). ASTPHLD, Washington, D.C.
33 See, e.g., Two-Step Laboratory Testing Process. Centers for Disease Control. Last visited 1/31/18.
34 Dressler, supra note 23
35 Centers for Disease Control and Prevention, supra note 32
36 Centers for Disease Control and Prevention, supra note 32
37 Logigian EL, Kaplan RF, Steere AC Successful treatment of Lyme encephalopathy with intravenous ceftriaxone.J Infect Dis. 1999 Aug;180(2):377-83.
38 Aucott JN, Rebman AW, Crowder LA, Kortte KB. Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here? Qual Life Res (2013) 22:75–84
39 Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP, Duray PH, Larson MG, Wright EA, Ginsburg KS, Katz JN, Liang MH The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study.Ann Intern Med. 1994 Oct 15;121(8):560-7.
40 Cameron DJ, Johnson LB, Maloney EL.. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease.Expert Rev Anti Infect Ther. 2014 Sep;12(9):1103-35. doi: 10.1586/14787210.2014.940900. Epub 2014 Jul 30.Review.
41 The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system is a basis for evidence assessment and the development of recommendations to ensure a transparent and trustworthy guideline process.
42 Maloney, Elizabeth L. Controversies in Persistent (Chronic) Lyme Disease. Journal of Infusion Nursing 39.6 (2016): 369–375. PMC. Web. 22 Jan. 2018.
43 Cameron, supra note 40
44 Embers, supra note 19
45 CDC Website https://www.cdc.gov/lyme/faq/index.html. Last visited 9/20/17.
46 Cameron, supra note 40
47 Cairns V, Godwin J., Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int J Epidemiol 2005;34(6):1340-5[Crossref], [PubMed], [Web of Science].
48 Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH. Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome. PLoS One. 2011 Feb 23;6(2):e17287. doi: 10.1371/journal.pone.0017287.
49 Maloney, supra note 42
50 Shadick, supra note 39
51 Aucott, supra note 38
52 Cameron, supra note 40
53 Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. 2013 Apr 23;6:291-306. doi: 10.2147/IJGM.S44114. Print 2013.
54 Cameron, supra note 40
55 Michael J. Cook, Lyme borreliosis: a review of data on transmission time after tick attachment. Int J Gen Med. 2015; 8: 1–8.
56 Dolan MC, Breuner NE, Hojgaard A, Boegler KA, Hoxmeier JC, Replogle AJ, Eisen L.Transmission of the Lyme Disease Spirochete Borrelia mayonii in Relation to Duration of Attachment by Nymphal Ixodes scapularis (Acari: Ixodidae).J Med Entomol. 2017 Sep 1;54(5):1360-1364. doi: 10.1093/jme/tjx089.
57 Tick-Borne Diseases. Columbia University Medical Center. Available at http://www.columbia-lyme.org/patients/tick_borne.html. Last visited 1/28/18.
58 Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections Acquired from Ixodes ticks. Clin Microbiol Rev. 2006 Oct; 19(4): 708–727.
59 Ali A1, Vitulano L, Lee R, Weiss TR, Colson ER. Experiences of patients identifying with chronic Lyme disease in the healthcare system: a qualitative study.BMC Fam Pract. 2014 May 1;15:79. doi: 10.1186/1471-2296-15-79.
60 Johnson L1, Aylward A, Stricker RB. Healthcare access and burden of care for patients with Lyme disease: a large United States survey.Health Policy. 2011 Sep;102(1):64-71. doi: 10.1016/j.healthpol.2011.05.007. Epub 2011 Jun 14.
61 Institute of Medicine (US) Committee on Lyme Disease and Other Tick-Borne Diseases: The State of the Science. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington (DC): National Academies Press (US); 2011