Links To “Post-treatment Lyme Disease as a Model for Persistent Symptoms in Lyme Disease”

In this post, I link to and excerpt from Post-treatment Lyme Disease as a Model for Persistent Symptoms in Lyme Disease [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Front Med (Lausanne). 2020 Feb 25;7:57. Alison W Rebman 1, John N Aucott 1. Lyme Disease Research Center, Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States


Pathogenesis, Diagnosis and Treatment of Lyme and other Tick-borne Diseases View all 17 Articles.

All that follows is from the above resource.

It has long been observed in clinical practice that a subset of patients with Lyme disease report a constellation of symptoms such as fatigue, cognitive difficulties, and musculoskeletal pain, which may last for a significant period of time. These symptoms, which can range from mild to severe, have been reported throughout the literature in both prospective and population-based studies in Lyme disease endemic regions. The etiology of these symptoms is unknown, however several illness-causing mechanisms have been hypothesized, including microbial persistence, host immune dysregulation through inflammatory or secondary autoimmune pathways, or altered neural networks, as in central sensitization. Evaluation and characterization of persistent symptoms in Lyme disease is complicated by potential independent, repeat exposures to B. burgdorferi, as well as the potential for co-morbid diseases with overlapping symptom profiles. Antibody testing for B. burgdorferi is an insensitive measure after treatment, and no other FDA-approved tests currently exist. As such, diagnosis presents a complex challenge for physicians, while the lived experience for patients is one marked by uncertainty and often illness invalidation. Currently, there are no FDA-approved pharmaceutical therapies, and the safety and efficacy of off-label and/or complementary therapies have not been well studied and are not agreed-upon within the medical community. Post-treatment Lyme disease represents a narrow, defined, mechanistically-neutral subset of this larger, more heterogeneous group of patients, and is a useful definition in research settings as an initial subgroup of study. The aim of this paper is to review the current literature on the diagnosis, etiology, risk factors, and treatment of patients with persistent symptoms in the context of Lyme disease. The meaning and relevance of existing patient subgroups will be discussed, as will future research priorities, including the need to develop illness biomarkers, elucidate the biologic mechanisms of disease, and drive improvements in therapeutic options.


Lyme disease is a geographically expanding, vector-borne disease which is transmitted to humans through the bite of a tick infected with various genospecies of the spirochete bacteria B. burgdorferi sensu lato (12). The species of Ixodes ticks which transmit the disease are commonly found throughout temperate regions of North America, Europe, and Asia (2). Currently, the Centers for Disease Control and Prevention (CDC) estimate approximately 300,000 new cases of Lyme disease in the United States alone each year (3). However, due to climate change, shifting land use patterns, and the relative abundance and distribution of reservoir hosts, it is anticipated that the geographic range of the tick vector will continue to expand (45). For instance, the number of reported cases in Canada has increased six-fold over the past decade, with particular increases in the eastern provinces of Nova Scotia and Ontario (67).

Clinically, Lyme disease presents with dermatologic and/or viral-like signs and symptoms such as intermittent fever, sweats, chills, malaise, fatigue, and achiness during the acute phase, which can transition to neurologic, cardiac, and/or joint involvement in later stages of the infection as the bacteria disseminate hematogenously (8). Along with these objective signs, persistent and recurrent symptoms such as fatigue, sleep disruption, arthralgia, myalgia, and headache are also commonly present during later stages of untreated Lyme disease and may account for the majority of the patient symptom experience (9). For example, patients with intermittent bouts of late Lyme arthritis continued to have such symptoms present during the intervening intervals (10). Occasionally, symptoms without physical exam, laboratory, or other so-called “objective” findings remain the major or only manifestations of untreated Lyme disease infection (11). The use of direct tests such as culture, polymerase chain reaction (PCR) or antigen detection for B. burgdorferi to aid clinicians in diagnosis is extremely limited, and B. burgdorferi cannot be cultured in non-research settings. A two-tier antibody test is widely available and utilized despite significant sensitivity limitations, particularly in early infection and in the convalescent phase after antibiotic treatment of early Lyme disease (1213). All stages of Lyme disease are currently treated with antibiotics (14).

The majority of patients return to their pre-morbid health following recommended antibiotic treatment for Lyme disease. However, it has long been observed in clinical practice and in research settings that a subset of patients continue to report a constellation of largely patient reported, so-called “subjective” symptoms which may last for a significant period of time following treatment (1524). Nevertheless, the epidemiology, significance, etiology, and appropriate treatment of these persistent symptoms are not well-understood and as such, remain the subject of a great deal of scientific dispute and controversy within the medical community (2528). Patients who can be said to have post-treatment Lyme disease (PTLD) (also called post-treatment Lyme disease syndrome or post-Lyme disease syndrome) represent a narrow, highly specific subset of the broader population of patients with persistent symptoms (14). This specificity is important in research, but not always in clinical settings, as there are multiple pathways through which patients who may be suffering from on-going symptoms from Lyme disease may not meet these narrow criteria. The term PTLD is neutral to underlying disease mechanism and as such, we do not necessarily assume that patients with PTLD have achieved microbiologic cure with initial antibiotic therapy. The aim of this manuscript is to review the published literature from a variety of academic disciplines and perspectives on symptoms which persist or recur in the setting of Lyme disease. We acknowledge that this is a broad topic, and one limitation of our manuscript is that not all related concepts could be readily addressed due to space constraints.

Estimated Frequency

After Lyme disease was first identified in the United States in the late 1970’s, but before the pathogenic bacteria was recognized, it was noted that untreated patients with Lyme arthritis often also reported concurrent symptoms such as headache, fatigue, myalgia, and hyperesthesia (9). It was first reported in some of the earliest cases series of treated patients that these symptoms could persist following antibiotic therapy (2930). Among patients diagnosed and treated in the early to mid-1980’s, largely with penicillin and/or tetracycline, up to 50% experienced symptoms such as fatigue, musculoskeletal pain, memory impairment, and headache several years after treatment (293132). A large, population-based study on Nantucket Island found that 36% of those with Lyme disease contracted and treated in the late 1980’s had on-going symptoms six years later, and that they were significantly more likely than those without a history of Lyme disease to report fatigue, headache, cognitive complaints, sleep disturbance, and musculoskeletal pain, numbness and/or weakness (33).

As more effective antibiotic treatments and drug regimens were tested and identified in prospective studies and clinical treatment trials, other investigators reported estimates of 0 to 35% for persistent, non-specific symptoms following treatment (1524). These symptoms were often considered “minor” and classified independently from defined treatment failure; objective signs of neurologic, cardiac, or joint involvement which would indicate progression to later stages of the infection. This relatively broad range of estimates is likely a reflection of several of the study design challenges which are still relevant in the field today. First, inter-study variability in enrollment criteria may encompass factors directly related to risk of persistent symptoms (see section Risk Factors). For instance, studies which require an active erythema migrans (EM) rash at enrollment will by definition exclude patients with longer disease durations, a likely risk factor for persistent symptoms. Population-based studies may be more reflective of the community practice of medicine than those conducted in academic research centers, with a wider range of treatment regimens, a higher misdiagnosis rate, and longer duration of disease prior to appropriate antibiotic treatment. Finally, without an objective biomarker, there has been a lack of standardization in outcome ascertainment, with many studies relying on physician assessment and classification into subjective sub-categories.



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