Lyme disease is the most common tick-borne illness in the United States. A recent study conducted by investigators at the Centers for Disease Control (CDC) estimated that approximately 300,000 new cases of Lyme disease are diagnosed in the United States each year (19). This represented a 10-fold increase over the previous CDC estimate of 30,000 cases per year (25). Although once believed to be primarily limited to the northeastern and upper midwestern areas of the United States where the disease is most common, recent studies have also revealed higher prevalence and risk of Lyme disease than previously believed throughout other areas of the United States (16,29), Europe (11,13), and Asia (18,26). Accordingly, Lyme disease is increasingly being recognized as a public health problem with international repercussions.
The disease is caused by the spirochete bacterium Borrelia burgdorferi (30). Symptoms of acute Lyme disease infection can include erythema migrans (“bull’s eye”) rash, fatigue, headache, and musculoskeletal pain. Diagnosis can be difficult because these symptoms may not initially occur in some patients and are often attributed to other causes even when they are present (2). Acute Lyme disease infection is usually treated successfully with oral antibiotics. However, some patients with acute Lyme disease either do not respond to antibiotic therapy or experience only transient resolution of symptoms. Furthermore, many patients whose Lyme disease was undiagnosed or untreated soon after infection go on to experience persistent symptoms. These symptoms are often systemic and can include disabling musculoskeletal pain, extensive neurological dysfunction, overwhelming fatigue, and poor health-related quality of life. Controversy surrounds the nomenclature of this constellation of persistent symptoms, with some groups referring to them as “post–Lyme disease syndrome” (35) and others as “chronic Lyme disease” (7). Regardless of their nomenclature, persistent symptoms of Lyme disease are common, as 42% of patients with Lyme disease have been shown to be symptomatic after 6 months and 12% are still symptomatic after 3 yr (20).
The treatment of patients with persistent symptoms of Lyme disease is even more controversial. Long-term antibiotic therapy is relatively common, although randomized controlled trials have revealed mixed results for this therapeutic approach, with both positive (6,14) and null findings (21–23,30). Even patients that benefit from long-term antibiotic therapy generally experience only partial resolution of their symptoms. Thus, many patients with persistent symptoms of Lyme disease also turn to nonpharmacological modalities such as acupuncture, nutritional supplements, and herbal medicine to attempt to improve their symptoms. Although there is anecdotal evidence and some qualitative reports of effectiveness for some of these therapies (1), there are no published trials assessing the effectiveness of any nonpharmacological therapies for the treatment of persistent symptoms of Lyme disease.
Consequently, there is a clear need for the evaluation of novel nonpharmacological therapies for patients experiencing persistent symptoms of Lyme disease. The investigators postulated that resistance exercise could be a promising therapy for reducing the persistent symptoms of Lyme disease for several reasons. Resistance exercise has been shown to be an effective modality for improving many of the persistent symptoms of Lyme disease and other medically unexplained symptoms occurring in other chronic disease populations, including musculoskeletal pain (32), neurological dysfunction (9), fatigue (12), low health-related quality of life (15), and fibromyalgia (5). In addition, a published case report of a patient experiencing persistent symptoms of Lyme disease 1 yr after diagnosis despite extensive antibiotic therapy demonstrated that a physical therapy intervention including resistance exercise improved the patient’s pain, fatigue, and quality of life (24). However, resistance exercise is not currently a part of the clinical practice guidelines offered by the CDC and Infectious Disease Society of America (35) nor is it recommended in the more comprehensive treatment guidelines of the International Lyme and Associated Diseases Society (7). Although it is plausible that resistance exercise might ameliorate some of the persistent symptoms of Lyme disease, it is currently unclear whether a resistance exercise program would be feasible, let alone efficacious, in this patient population.
Thus, the investigators felt that a supervised and low-intensity resistance exercise program would be warranted in light of the clinical uncertainty regarding exercise in this population. The purpose of this pilot study was to assess the feasibility and efficacy of a resistance exercise intervention in patients with persistent symptoms of Lyme disease. The investigators hypothesized that the low-intensity nature of the exercise program and the supervision provided by an exercise professional would result in feasibility and moderate efficacy of the resistance exercise in improving symptoms in this physically compromised patient population.
METHODS
Study design
An uncontrolled pilot study was conducted to evaluate the feasibility and preliminary efficacy of a 4-wk supervised resistance exercise intervention among a sample of patients with persistent symptoms of Lyme disease. The institutional review board of the University of Maryland School of Medicine approved this study.
Study participants
Study participants were recruited through flyers posted in a community-based medical practice in Baltimore, MD. The Baltimore metropolitan area has a high prevalence of Lyme disease (17), and the medical practice from which participants were recruited treats many patients with persistent symptoms of the disease. Study eligibility was determined by a physician who is board certified in internal medicine. Eligibility criteria included the following: men or women age 18–60 yr, previous clinical diagnosis of Lyme disease, symptoms that had persisted for at least 3 months since clinical diagnosis of Lyme disease, and medical clearance for participation in a resistance exercise program. Patients with uncontrolled hypertension, chronic obstructive pulmonary disease, coronary heart disease, tachycardia, or other medical conditions that the investigators believed might cause potential safety concerns with participation in an exercise program were excluded from the study. Eligible participants were not currently participating in a resistance exercise program or any other concurrent clinical trials and agreed not to change their medications (unless deemed medically necessary by their physician) or any nutritional or herbal supplements during the 4-wk exercise intervention. An informed written consent was obtained from all participants by an institutional review board-approved research assistant before the beginning of the study.
Description of exercise intervention
The exercise intervention was supervised by a team of certified exercise trainers and was provided at an exercise facility in Baltimore, MD. Under an exercise trainer’s supervision, study participants performed one set of a varying number of repetitions of each of the following five resistance exercises: leg press (LP), seated row (SR), standing heel raise (HR), vertical chest press (CP), and supine abdominal crunch. The LP, SR, and CP were all performed on selectorized Cybex Eagle resistance machines (10). These machines are widely available at exercise facilities throughout the world and have been used extensively in previous research. The HR and abdominal crunch were performed using the participant’s body weight as the resistance.
In light of the substantial physical symptoms that patients in this trial were experiencing at the time of enrolment and the clinical uncertainty with respect to the feasibility of resistance exercise in this population, a novel exercise exertion scale (“Purvis effort continuum scale”) was developed and implemented to ensure participant safety and promote the feasibility of the exercise intervention. The number of repetitions for each set of exercise that the participant performed was based on this participant-reported RPE. The participant’s level of perceived exercise exertion was reported to the exercise trainer after each repetition of each exercise. The five-point participant-reported exertion scale pictured in Figure 1 was used by the participant to assess the level of exercise exertion and by the exercise trainer to assign the number of repetitions in each set that could be safely performed by the participant.
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FIGURE 1: Purvis effort continuum scale for low-intensity resistance exercise.
Before beginning the exercise intervention, the exercise trainer first performed an exercise-specific active range of motion assessment (29) for the participant on each exercise. In brief, this assessment allowed the exercise trainer to assess the participant’s range of motion that was safe for each exercise. The exercise trainer then adjusted each resistance exercise machine on the basis of this assessment to eliminate the potential risk associated with resistance applied beyond an active range of motion limit. The exercise trainer then performed a familiarization phase with the participant before each set to educate the participant on the operation of the exercise equipment, the use of the exercise exertion scale, and the tempo of the exercise.
The participant was instructed that each repetition of each exercise consisted of four distinct stages, stages I through IV. Stage I consisted of lifting the weight (“concentric”); stage 2, the transition between lifting the weight and lowering the weight (“isometric”); stage 3, lowering the weight (“eccentric”); and stage 4, the transition between lowering the weight and starting stage 1 of the next repetition (“unweighted”). The duration of stage I was 5 s; the duration of stage II was 1 s; the duration of stage III was 5 s; and the duration of stage IV was approximately 2 s or the time necessary for the subject to report their rating on the exercise exertion scale after having unloaded the resistance completely. The participants were instructed to count aloud for both stages I and III. The subjects were instructed to state “I’m holding” during stage II and report their current level of exertion to the exercise trainer during stage IV. The participant began a new repetition after reporting the level of exertion on the previous repetition unless the exercise trainer instructed the subject to terminate the exercise.
During the first session of the exercise intervention, the exercise trainer selected the appropriate level of resistance for each exercise so that the participant could perform the exercise at their lowest exertion level (level 1). The exercise trainer terminated the set when an increase in exertion level was reported by the participant (from level 1 to 2). After the first session, the participants then exercised at exertion level 2 for all exercises during the remainder of the intervention. The exercise trainer terminated the set when the participant reported an increase in exertion level (from level 2 to 3). In accordance with the low-intensity nature of the exercise intervention, exertion never exceeded level 3 for any participants. The exercise trainer also reserved the right to terminate the set at any time if participant safety was compromised.
Participants completed three sessions per week of the supervised resistance exercise intervention for 4 wk. Each session of the exercise intervention was approximately 45 min.
Study outcomes
Participant demographic data and a variety of outcomes assessing persistent symptoms of Lyme disease were collected by a research assistant at baseline. The same Lyme disease symptoms outcomes were also collected by the research assistant at the end of weeks 1, 2, 3, and 4 of the exercise intervention. Participant-reported severity and frequency during the past week of each the following persistent symptoms of Lyme disease were assessed: joint pain in the knees, joint pain in the hips, joint swelling in the knees, joint swelling in the hips, stiffness in the joints or back, back pain, muscle pain, muscle weakness, and fatigue. Symptom severity at each time point was reported as “none,” “mild,” “moderate,” or “severe”; symptom frequency at each time point was reported as “never,” “occasional,” “often,” and “constant.” This method of assessing persistent symptoms of Lyme disease was modeled after a set of treatment guidelines commonly used in clinical practice (4).
Three previously validated questionnaires were also administered to assess changes in health-related quality of life and overall vitality before and after the exercise intervention. The CDC Health-Related Quality of Life—Healthy Days Core Module (CDC HRQOL-4) and Healthy Days Symptoms Module (25) and the four-item Short Form-36 Vitality Subscale (SF-36 Vitality) (34) were administered by the research assistant at baseline and at the end of the 4-wk exercise intervention.
The exercise trainer recorded the number of repetitions and the amount of resistance for each exercise as well as any adverse events that occurred during each intervention session. Total exercise volume for each exercise was calculated by multiplying the number of repetitions by the amount of resistance. Exercise volume is a common measure of assessing exercise performance (27) and was used by the investigators to assess both the feasibility of the intervention and potential improvements in exercise performance throughout the course of the study.
Statistical analysis
Descriptive statistics were computed to characterize the study population at baseline. One-way ANOVA was conducted to assess changes over time in the study outcomes that were measured at three or more time points (exercise volume, exercise repetitions, SF-36 Vitality subscale, Lyme disease symptoms). To apply one-way ANOVA, the longitudinal data collected in this study were restructured so that each assessment point became a separate record with time point as an index variable. The post hoc tests (Fisher least significant difference) in one-way ANOVA enabled us to assess the statistical significance of the differences between each time point for each study outcome. Student’s t-test was used to assess pre- and postintervention changes in the study outcomes that were measured at just two time points (CDC HRQOL-4 and Healthy Days Symptoms Modules). Statistical significance was defined as a P value ≤ 0.05. All analyses were conducted in SPSS version 21.
RESULTS
Eight eligible patients enroled and participated in the study. The sample was composed of five men and three women with a mean age of 44.8 yr (SD, 14.8 yr). Participants ranged in age from 25 to 60 yr at enrolment. All participants were of Caucasian race and had at least a college degree (five participants had a graduate degree). Five participants were married, and three were single. Work status varied in the study sample. Three participants were employed full time, one was employed part time, two were retired, one was a full-time student, and one was disabled and unable to work.
As per the study inclusion criteria, all participants had received a clinical diagnosis of Lyme disease (characterized most often by a combination of previous erythema migrans rash, accompanying symptoms, and possible history of exposure to infected black-legged ticks) at least 3 months before study enrolment. The mean time from Lyme disease diagnosis to study enrolment was 21.3 months (SD, 12.4 months). The time from diagnosis to study enrollment ranged from 4 to 41 months among study participants. In addition to a clinical diagnosis, six participants had a positive Western blot for Lyme disease, as verified in their medical records. All participants in the study had been experiencing some form of joint or muscle pain at the time of enrolment. All study participants had previously undergone antibiotic therapy for Lyme disease, and seven were currently taking an antibiotic at study enrolment. No participants changed their antibiotic regimen during the study.
The supervised exercise program was feasible in this population of patients with persistent symptoms of Lyme disease. All study participants attended each of the three exercise sessions per week (12 exercise sessions in total) and were able to perform all of the exercises in each session. There were no adverse events reported that were related to the exercise intervention.
Table 1 details the weekly changes in mean exercise volume (LP, vertical CP, SR) and mean number of repetitions (HR, supine crunch) for each of the five resistance exercises in the intervention. There was a week-to-week increase in mean weekly exercise volume and repetitions for each of the exercises across all study time points (week 1 to week 2, week 2 to week 3, and week 3 to week 4). The difference in exercise volume across all time points was statistically significant for SR (P < 0.0001) and vertical CP (P = 0.05). The increases in mean exercise volume and repetitions were greatest from week 1 to week 4: LP (1248.6 to 2036.9 pounds, 63% increase, P = 0.02), SR (358.1 to 1,123.6 pounds, 214% increase, P < 0.0001), vertical CP (114.3 to 443.6 pounds, 288% increase, P = 0.01), HR (19.5 to 29.8 repetitions, 53% increase, P = 0.06), and supine crunch (8.9 to 18.9 repetitions, 112% increase, P = 0.001).
TABLE 1: Changes in mean (SD) weekly exercise volumea or repetitionsb.
Table 2 presents the changes in the SF-36 Vitality subscale and the CDC Health-Related Quality of Life Healthy Days Core Module and Healthy Days Symptoms Module. With the exception of an increase in the number of days without enough rest or sleep, there were improvements in mean scores of all the measures of vitality and health-related quality of life from baseline to the end of the exercise intervention. The greatest improvements in mean scores were in number of days that pain made daily activities difficult (17.7 out of the past 30 d at baseline vs 11.0 out of the past 30 d at the end of the intervention), number of days feeling sad, blue, or depressed (9.1 out of the past 30 d at baseline vs 4.9 out of the past 30 d at the end of the intervention) and the number of days that participants felt healthy and full of energy (0.6 out of the past 30 d at baseline vs 4.5 days out of the past 30 d at the end of the intervention). However, the only statistically significant change was the number of days that participants felt healthy and full of energy (P = 0.05).
TABLE 2: Changes in mean (SD) vitality and health-related quality of life.
Table 3 provides data describing the changes throughout the intervention in the mean severity and frequency of some of the most common persistent symptoms of Lyme disease. Although there were reductions noted in both the severity and frequency of most of the symptoms, most notably in joint pain of the knee, hip, shoulder, and elbow, none of these changes reached statistical significance (P > 0.05).
TABLE 3: Changes in mean severitya and frequencyb of Lyme disease symptomsc.
DISCUSSION
This study revealed that a supervised and low-intensity resistance exercise program was safe and feasible in a sample of patients experiencing persistent symptoms of Lyme disease. There were no adverse events reported that were related to the exercise intervention, and participants experienced substantial improvements in their ability to perform the resistance exercises, as expressed by the statistically significant improvements in exercise volume and repetitions noted in this small sample of patients throughout the 4-wk intervention. This was the first exercise intervention of any type conducted among patients with persistent symptoms of Lyme disease. The feasibility and lack of adverse events associated with the exercise intervention is a clinically meaningful finding, as it was previously unclear whether patients experiencing persistent symptoms of Lyme disease are capable of safely participating in an exercise program. Despite the well-accepted health benefits associated with resistance exercise, none of the clinical practice guidelines for Lyme disease offered by the CDC, Infectious Disease Society of America, or International Lyme and Associated Diseases Society include any type of exercise. Our findings suggest that resistance exercise under the supervision of a qualified exercise professional may indeed be safe and feasible for patients with persistent symptoms of Lyme disease. Furthermore, although the small sample size of this pilot study may have contributed to the inability to detect statistically significant findings in most outcomes, improvements were noted in mean vitality and health-related quality of life scores and in the frequency and severity of joint and muscle pain.
There were several key strengths of this study. The participants were all screened for study eligibility by the same board-certified physician who specializes in treating patients with persistent symptoms of Lyme disease. Thus, there was consistency in the clinical diagnosis of the Lyme disease patients participating in this study. In addition, all participants were supervised by the same team of exercise trainers using an identical exercise protocol and rating system of perceived exercise exertion. Consequently, there was limited variability in the style of exercise training and exertion reporting that could potentially confound the true feasibility and effectiveness of the exercise program. The resistance exercises featured in this intervention used either the participant’s body weight alone (HR, supine crunch) or exercise machines (LP, SR, vertical CP) that are available and familiar to exercise professionals at most health clubs, fitness facilities, and physical therapist offices across the world. As a result, this intervention could potentially be replicated in a wide variety of exercise settings. The study participants were 100% compliant with both their participation in the exercise program and the instruction not to change medications during the course of the study. Thus, the potential for confounding due to concurrent changes in therapies other than the exercise program during the course of the intervention was minimized.
This study also introduced a novel scale of exercise exertion (“Purvis effort continuum scale”) for used in low-intensity resistance exercise programs for patients with persistent symptoms of Lyme disease. The investigators developed and used this scale because it was unknown whether the currently available ratings of perceived exercise exertion could be feasibly used in this exercise intervention and study population. The two most widely used ratings of perceived exercise exertion are the 20-point Borg scale (3) and the 10-point OMNI scale (33). The investigators noted several limitations to the use of these scales in this study. Chief among these concerns was the fact that there are few studies supporting their use in low-intensity resistance exercise interventions, as they have predominantly been used in higher-intensity endurance and aerobic exercise contexts. The low-intensity nature of this resistance exercise intervention was a key point of emphasis to promote safety and feasibility in this physically compromised study population. In addition, the investigators hypothesized that a new metric using a five-point Likert scale with a clearly delineated midpoint would provide a more intuitive framework for participants to quickly identify and verbally communicate to the exercise trainer their level of exertion between each repetition of exercise. The patients participating in this intervention were representative of many chronic disease populations in that they were not currently participating in an exercise program, and it was believed that the subtle differences between exertion scores on scales with many scoring options (20 options for Borg, 10 options for OMNI) might not be suitable for this study sample. The investigators believe that this simple and intuitive exercise exertion rating scale could be successfully used by physical therapists, exercise trainers, and other exercise professionals when working with patients with persistent symptoms of Lyme disease or other physically limiting conditions.
There were also several notable limitations to this study. The most important limitation was the lack of control group in this pilot study. The improvements in vitality, health-related quality of life, and joint and muscle pain noted in this exercise intervention may have been due to regression to the mean or observation of the natural course of Lyme disease symptoms in the study sample. However, it is unlikely that these improvements were primarily attributable to the natural course of the disease because study participants had been diagnosed with Lyme disease a mean of 21.3 months before enrolment in the intervention and they also had widely varying times since their diagnosis (SD, 12.4 months). It is plausible that the clinical and quality of life improvements could be attributed primarily to the exercise intervention, as these types of symptoms have been improved in previous exercise interventions in populations with chronic disease (5,9,12,15,32). The small size of the study sample also limits the generalizability of our findings. Larger studies are necessary both to confirm the feasibility of the exercise intervention noted in this pilot study and to offer greater statistical power in the evaluation of its efficacy in improving persistent symptoms of Lyme disease. Another limitation is that two of the study participants did not have positive serologic results for Lyme disease. However, these patients had received both a clinical diagnosis of and treatment for Lyme disease symptoms that had persisted over at least 3 months. According to the CDC, the presence of the characteristic erythema migrans (“bull’s eye”) rash and accompanying symptoms alone warrants clinical diagnosis and treatment for Lyme disease (8). All study participants had received a clinical diagnosis of Lyme disease that met the diagnostic criteria of the CDC (8), IDSA (35), and ILADS (7). Nevertheless, future studies may consider limiting the study sample to patients with both a clinical diagnosis and positive serologic results.
The fact that seven of the eight study participants were receiving concurrent antibiotic therapy for Lyme disease may also limit the inference attributable to the exercise intervention on the improvements in vitality, quality of life, and persistent symptoms noted in this study. Several studies have found that antibiotic treatment can be beneficial for patients with persistent symptoms of Lyme disease (6,14). With these findings in mind, the investigators incorporated an inclusion criterion for this study that a participant agreed that no changes would be made to their antibiotic therapy during the 4-wk intervention unless it was medically necessary. This inclusion criterion was implemented to help the investigators better isolate the effects of the exercise intervention. Ultimately, none of the study participants changed their antibiotic therapy during the course of the intervention. Thus, the investigators do not believe that the improvements noted in this study were due solely to antibiotic therapy because all participants were experiencing symptoms of Lyme disease at enrolment and no changes were made to their antibiotic therapy. Nevertheless, the investigators believe that there could potentially be interaction between antibiotic therapy and resistance exercise in this population. Future studies should continue to take this potential interaction into account.
Although the novel exercise exertion scale introduced in this study was feasible in this population of patients with persistent symptoms of Lyme disease, it has not been subject to formal validation testing. Future studies should assess the sensitivity and reliability of this scale. Finally, this exercise intervention was supervised by exercise professionals and our findings cannot be generalized to the independent performance of a resistance exercise program in patients with persistent symptoms of Lyme disease. The investigators insisted upon the supervision and interaction with an exercise professional to ensure the safety of the study participants in light of the clinical uncertainty regarding exercise in this physically compromised population. Thus, it is unclear at this juncture whether patients experiencing persistent symptoms of Lyme disease can safely and feasibly perform this program exercise in an independent manner. Our findings are contingent upon the supervision of an exercise trainer, physical therapist, or other qualified exercise professional.
Although larger and controlled studies are needed to confirm the preliminary findings noted in this pilot study, our results suggest that a supervised resistance exercise program is safe, feasible, and may potentially help improve the symptoms, vitality, and quality of life among patients with persistent symptoms of Lyme disease.
The authors would like to acknowledge Brick Bodies Fitness Services for welcoming the conduct of the intervention in one of their exercise facilities, the staff at the University of Maryland for assisting in the implementation of the intervention, the study participants for their participation in the intervention, and the inspiration for this work provided by Colleen Medlin, D.P.T.
This study was funded by philanthropic support from an anonymous private donor.
The authors have no professional relationships with companies or manufacturers who will benefit from the results of this study, nor do they have any other conflicts of interest to report. The results of this study do not constitute endorsement by the American College of Sports Medicine.
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