Chronic Lyme Disease: A Working Case Definition

Corresponding Author: Raphael B. Stricker Union Square Medical Associates, San Francisco, CA, USA Email: rstricker@usmamed.com Abstract: Although Lyme disease is the most common tickborne illness in the USA and Eurasia, the pathophysiology and clinical course of chronic Lyme disease (CLD) have not been formally defined. The purpose of this paper is to present a working case definition of CLD based on analysis of more than 700 peer-reviewed publications. According to this definition, CLD is a multisystem illness with diverse musculoskeletal, neuropsychiatric and/or cardiovascular manifestations that result from ongoing infection with pathogenic members of the Borrelia spirochete complex often associated with other tickborne disease (TBD) pathogens. To qualify for the diagnosis of CLD, patients must have Lyme-compatible symptoms and signs that are either consistently or variably present for six or more months. Two subcategories of CLD include untreated chronic Lyme disease (CLD-U) and chronic Lyme disease following a limited course of antibiotic treatment (CLD-T). The symptom patterns and optimal therapy of CLD require further study.

We propose a working case definition of chronic Lyme disease (CLD) based on evidence that Bb and associated pathogens may cause persistent infection that correlates clinically with invasion of the diverse cells and tissues described above (Cameron et   . The resultant chronic illness may be found in patients with undiagnosed Lyme disease or in patients with an inadequate response to TBD treatment, as outlined below.

Length of Infection
In order to define the chronic form of Lyme disease, it is first necessary to define the minimum duration of the medical condition. Goodman et al. (2013) describe the lack of standardization for the definition of chronic medical diseases. The required duration of chronic illness has ranged from more than three months to more than twelve months (USDHHS, 2010a; Hwang et al., 2001;Warshaw, 2006;Friedman and Jiang, 2008;Anderson, 2017; USDHHS, 2010b) and some researchers have suggested that the medical condition needs to be permanent to qualify (Bernstein et al., 2003;McKenna and Collins, 2010). In the setting of infectious disease in general, the term "chronic" often implies a minimum duration of six months, and with chronic Pseudomonas and Mycobacterial infections the chronically infecting pathogens may be capable of "evading or subverting the immune response" to "establish chronic infection with a time course of years to decades, often resulting in persistent inflammation and disease" (Pressler et al., 2011;Behar et al., 2014). In the case of TBDs, this process often becomes established and persists after 3-6 months of untreated or inadequately treated infection (Cameron et al., 2014;. Therefore we define CLD as persistent TBD infection of at least six months' duration, although we emphasize that treatment should not be withheld for individuals presenting with all the criteria discussed in this study except for the duration. In addition, we recognize other challenges including the often uncertain nature of symptom onset and the variability of musculoskeletal, neuropsychiatric and cardiovascular symptoms and signs induced by TBDs (see section on Clinical Manifestations below).

Vector Exposure
The primary vectors of Lyme disease are members of the  Wang et al., 1999)). The role of associated TBD pathogens in patients with CLD is discussed below.

Laboratory Testing for Lyme Disease
As the CDC acknowledges, "The Lyme disease surveillance case definition was developed to standardize national public health surveillance and reporting of Lyme disease cases; it is not meant to be used as absolute criteria for clinical diagnosis" (Bacon et al., 2008). Criteria generated for epidemiologic surveillance purposes are often inadequate for the diagnosis of Lyme disease. In fact, the two-tiered testing paradigm of Enzyme-Linked Immunosorbent Assay (ELISA) or Immunofluorescent Assay (IFA) screen and Western blot confirmation is positive in less than 30% of patients with early Lyme disease and in only 46% of patients with Lyme disease for more than six weeks (Coulter et  Cook and Puri, 2016; Stricker and Johnson, 2009). The allegedly high sensitivity of two-tiered testing in late Lyme disease is based on circular reasoning, as discussed in detail elsewhere .
Seronegativity is well documented in late Lyme disease Chmielewski et al., 2003). In a study of 41 patients with active Bb infection shown by positive culture and/or PCR, 63.5% did not have reactive Lyme serologies despite the fact that 54% had been symptomatic for over a year . The authors concluded that "antibodies to B. burgdorferi often are present in only low levels or are even absent in culture-or PCR-positive patients" who have been suffering for years from symptoms of Lyme disease. In a second study of 32 patients hospitalized for late Lyme disease whose disease activity was confirmed by positive PCR, 56.3% were seronegative .

Untreated Chronic Lyme Disease (CLD-U)
Patients whose exposure was not clearly identified and thus have prolonged untreated infection.
CLD may be the consequence of diagnostic delays, and early recognition of the infection is frequently hindered by the failure to recognize or report a tick bite. For example, one study found that only 14% of patients recalled a tick bite at the site of an EM rash (Berger, 1989). Thus, while a history of potential exposure to Ixodes ticks is an important element in the definition of CLD, documentation of a known tick bite is not required.
Many patients may also be unaware of their exposure risks and clinicians will need to carefully inquire about potential exposures based on a patient's residential, occupational, recreational and travel history. As stated above, Ixodes ticks prefer wooded or brushy areas and exposure risk is correspondingly high in these areas (Kilpatrick et al., 2017;Eisen et al., 2009). Tick exposure may also occur through contact with reservoir animals or with other incidental tick hosts including deer, birds and pets.
Another problem is the variable incidence of the EM rash, which ranges from 27 to 70% in Lyme disease studies (Bingham et al., 1995;Stricker and Phillips, 2003). The CDC found that patients lacked an EM rash in 30% of cases that were diagnosed using the surveillance case definition (Bacon et al., 2008). The recognition of early Lyme disease may be delayed when the hallmark EM rash is absent or misidentified.

Chronic Lyme Disease Following Limited Antibiotic Treatment (CLD-T)
Patients who were diagnosed with Lyme disease and completed a limited course of antibiotic therapy, but whose symptoms persist.
This category differs from "Post-Treatment Lyme Disease Syndrome" (PTLDS), a research case definition proposed by the Infectious Diseases Society of America (IDSA) that excludes ongoing TBD infection as the cause of persistent CLD symptoms. In contrast, CLD-T requires that patients had been diagnosed with Lyme disease and treated with a limited course of antibiotic therapy (generally < four weeks), but that the treatment regimen was inadequate to resolve the infection and that the symptoms persisted or recurred within six months after completion of treatment without a new tick exposure. Clinicians and researchers have recognized that a substantial portion of patients remain ill following a limited course of antibiotic treatment for Lyme disease

Clinical Manifestations of CLD
Lyme disease is a multisystem illness that is often referred to as the "new great imitator" due to the diversity of its clinical manifestations that are reminiscent of syphilis (Cruz et  . Recent studies suggest that the Jarisch-Herxheimer reaction is triggered by rapid uptake of damaged spirochetes by neutrophils and mononuclear cells with release of lipoproteins and pyrogens that increase inflammatory cytokines . To date, the complete mechanism of this phenomenon remains undefined. Since clinical features of Lyme disease may change following exposure to antimicrobials, we have proposed two categories for this working case definition of CLD, as outlined above. For CLD-U, the natural course without antimicrobial intervention has been described by Steere and colleagues in the USA (Steere et al., 1987;. Prior to recognition of the importance of antimicrobial therapy, untreated patients with EM rash displayed the following clinical characteristics over six years of follow-up: 62% developed intermittent or persistent arthritis; 18% developed arthralgias; 11% developed neurologic abnormalities; 4% developed cardiac complications; 33% developed fatigue; and 33% developed other symptoms and signs including headache, stiff neck, morning stiffness, myalgias and abdominal pain (Steere et al., 1987). Further characteristics of CLD-U In contrast to CLD-U, CLD-T is a term used to describe individuals who have been treated for TBDs with a limited course of antibiotics (generally < four weeks) and within six months develop persistent or recurrent and functionally significant fatigue, musculoskeletal pain, cardiovascular disease and/or neuropsychiatric dysfunction that persists for six months or more Stricker and Johnson, 2012). CLD-T acknowledges the extensive published evidence for persistent TBD infection despite a limited course of antibiotic therapy. In contrast, the research case definition for PTLDS proposed by IDSA includes the following statement: "There is no convincing biologic evidence for the existence of symptomatic chronic B. burgdorferi infection among patients after receipt of recommended treatment regimens for Lyme disease" (Wormser et al., 2006). Based on animal models and human studies, however, we propose that treatment with limited antibiotic regimens may not consistently clear the infection, and we have provided evidence to support potential mechanisms by which this persistent infection occurs (see above). Thus Lyme patients who remain symptomatic following a limited course of antibiotic therapy likely have an ongoing, active TBD infection similar to CLD-U patients. We characterize this group as having CLD-T.
Other conditions that can mimic the clinical presentation of CLD must be ruled out. However, the diagnosis of "idiopathic" conditions such as multiple sclerosis, motor neuron disease, fibromyalgia or chronic fatigue syndrome is insufficient to rule out the presence of CLD. We analyzed more than 700 peerreviewed publications featuring symptoms and signs associated with both forms of CLD from a MEDLINE search (Appendix A). From this list, we chose 16 studies that describe symptoms and signs in patients with CLD-U and 13 studies that describe symptoms and signs in patients with CLD-T (Appendix B). In these 29 studies, persistent Bb infection was documented by culture, PCR and/or microscopy, while other studies without this stringent documentation were excluded.  The symptom profiles in patients with persistent Bb infection are indicative of the protean manifestations of CLD. In our representative sample, patients with CLD-U appeared to have relatively more musculoskeletal and cardiovascular symptoms and signs, while patients with CLD-T appeared to have relatively more neuropsychiatric symptoms and signs (Table 1 and 2). The broader pathology in untreated patients versus more restricted pathology following limited treatment is reminiscent of the immunopathology patterns in untreated versus initially-treated syphilis (Gschnait et al., 1982). However the number of studies with stringent documentation of persistent Bb infection was too small to draw definitive conclusions about patterns of symptoms and signs in CLD patients. Further comparison of symptom profiles associated with the two forms of CLD is warranted.

Functional Impact of CLD
A community-based study of CLD patients found that the Quality of Life (QoL) of these patients was the same or worse compared to that of individuals with depression, diabetes, heart disease, osteoarthritis and rheumatoid arthritis . Using a CDC metric of health-related QoL, a second survey of more than 5,000 respondents with CLD supported this analysis, revealing that 71.6% rated their health as fair or poor. The functionality scores of CLD patients were worse than those of other chronic diseases including congestive heart failure, fibromyalgia, post-stroke syndrome, post-myocardial infarction, diabetes and multiple sclerosis .
Further support for the adverse health impact of CLD was recently provided by Adrion et al. (2015) Based on retrospective data from medical claims over five years in the USA, 52,795 individuals treated for Lyme disease were compared to 263,975 matched controls with no evidence of TBDs. The study found that as many as 63% of treated Lyme disease patients had persistent symptoms of CLD and that Lyme disease was associated with $2,968 higher total health care costs (95% CI: $2,807-$3,128, p<0.001) and 87% more outpatient doctor visits (95% CI: 86-89%, p<0.001) over a 12 month period compared to TBD-negative controls ; van den Wijngaard et al., 2017). A more recent study from the Netherlands found that the annual cost of treatment for CLD was €5700 (about $6300) per patient or a total of €19.3 million ($21 million) per year in that country .
We recognize that there may be other contributing and at times independent causes for persistent symptoms in CLD patients. In essence, not all patients who remain symptomatic after being treated for Lyme disease suffer from an active, ongoing infection. Proposed mechanisms of persistent symptoms include immune dysregulation of various types, tissue injury, infection-induced secondary conditions and unrelated diseases . Based on the clinical evidence, however, we assert that a potentially large number of individuals with CLD are adversely impacted by persistent TBD infection associated with significant functional limitations and financial burdens  . We hope that technological advances in the characterization of ongoing TBD infection will improve our ability to deal with this condition.

Clinical Judgment
Until technological advances provide reliably sensitive and specific diagnostics, some patients will continue to have a diagnosis that remains unclear. Under these circumstances, the value of clinical judgment will remain an important component in treating these individuals. According to the American Medical Association Code of Medical Ethics, the primary responsibilities of clinical medicine are to alleviate patient suffering and prevent disease (AMA, 2017). As previously described by Johnson et al. (2014) and  patients with CLD are often quite ill and physicians are charged with finding balanced and effective management strategies for such patients.
Uncertainty about a CLD diagnosis may confound clinical decision making, but clinical uncertainty should not exclude that diagnosis. This process involves both inclusionary and exclusionary criteria. Patient care is dynamic and clinical judgment requires vigilance in assessing clinical outcomes. As described by Kienle and Kiene, "Clinical judgment is a central element of the medical profession, essential for the performance of the doctor" (Kienle and Kiene, 2011). Thus given the current absence of a "gold standard" test for Lyme disease, it is essential that healthcare providers should consider this condition if symptoms and/or clinical signs occur in patients with a history consistent with CLD, as summarized in the guidelines of the International Lyme and Associated Diseases Society (ILADS) (Cameron et al., 2014).

Proposed Diagnostic Criteria for CLD
The proposed diagnostic criteria for CLD are shown in Table 3. Table 3. Proposed Diagnostic Criteria for CLD The four levels of diagnostic criteria are as follows: 1.
Strongly supportive criteria (but not required) 3.
Additional criteria I. Required criteria 1. Presence of clinical symptoms and/or signs consistent with Bb infection and/or associated TBDs, as described in Table 1 and 2, that adversely impact patient quality of life. 2. Symptom duration greater than six months, either without antibiotic treatment (CLD-U)* or following a limited course of antibiotic treatment for Lyme disease (CLD-T)**. Individuals residing in a Lyme-endemic area may be exposed through: Work, recreation and daily activities 2. Individuals not residing in a Lyme-endemic area may be exposed through:

Conclusion
This is the first study that provides a working case definition of chronic Lyme disease (CLD) and its subcategories. We propose that CLD is the result of persistent, active infection by pathogenic members of the Borrelia spirochete complex often associated with other TBD pathogens. Infection with these organisms produces a wide array of symptoms and signs that may be expressed in a given individual during the course of the chronic illness (Cameron et al., 2014;Liegner, 2015). Whether due to delayed diagnosis (CLD-U) or as a result of persistence after a limited course of antibiotic treatment (CLD-T), these symptoms and signs may fluctuate but are required to have cumulatively persisted for at least six months.
At this time, clinically available diagnostic testing does not consistently allow for identification of the pathogen(s) affecting individuals with CLD. As such, a hallmark feature of our working case definition is reliance on clinical judgment. This process includes the use of supportive diagnostics, but it does not require laboratory confirmation in light of present technological limitations of TBD testing. We recognize that as diagnostic testing evolves, the ability to define this entity should improve.
We also recognize that other diagnoses may be responsible for symptoms and signs that are similar to CLD and need to be considered in CLD patients. We hope that this outline will provide the clinician with a framework to weigh management options for these often significantly debilitated patients. We also hope to provide additional impetus for public policy to recognize the growing risk of the Lyme disease epidemic. Lastly, we encourage researchers to use the proposed definition of CLD to improve laboratory methodology for identifying patients with this condition and to facilitate the development of new treatment options for CLD patients. Appendix A

Peer-Reviewed Evidence of Persistence of Lyme Disease Spirochete Borrelia burgdorferi and Other Tickborne Diseases
The following is a list of over 700 peer-reviewed articles that support the evidence for persistence of Lyme and other tickborne diseases. It is organized into different categories-general, neuropsychiatric, dementia and congenital/sexual transmission.
General: Persistence of Borrelia burgdorferi and Other Tickborne Diseases