Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease.

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that (1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or (2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2, and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin, or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

Prospective Evaluation of the Frequency and Severity of Symptoms in Lyme Disease Patients With Erythema Migrans Compared With Matched Controls at Baseline, 6 Months, and 12 Months.

BACKGROUND: Erythema migrans is the most common clinical manifestation of Lyme disease. Despite antibiotic therapy, typically at least 10% of adult patients with erythema migrans experience persistence of at least 1 subjective symptom for ≥6 months (posttreatment Lyme disease symptoms [PTLDS]). METHODS: This study was designed to determine whether the frequency and severity (based on a visual analogue scale) of 12 particular symptoms in patients with erythema migrans (n = 52) differed from matched control subjects (n = 104) followed prospectively for 12 months. RESULTS: At baseline, patients with Lyme disease were more likely than controls to have at least 1 symptom (P = .006). Among symptomatic subjects, Lyme disease patients had a higher mean number of symptoms (P < .001) and a higher mean total symptom severity score (P < .001). At both 6 and 12 months, however, there were no significant differences for these variables and no significant differences in the frequency or severity of any of the 12 individual symptoms assessed. However, 10 patients were clinically assessed as having possible PTLDS. CONCLUSIONS: Patients with erythema migrans were more likely than matched control subjects to be symptomatic at baseline with a greater symptom severity score, but this was not found at ≥6 months. Use of symptom survey data alone, however, was less likely to identify patients with possible PTLDS compared with individual clinical assessments. Because it is very challenging to be certain that the presence of long-term symptoms in a particular patient is correctly attributable to having had Lyme disease, an objective biomarker would be highly desirable.

Patients with Erythema Migrans: Characterizing the Impact of Initiation of Antibiotic Therapy Prior to Study Enrollment.

Erythema migrans is the most common clinical manifestation of Lyme disease, with concomitant subjective symptoms occurring in ∼65% of cases in the United States. We evaluated the impact of having been started on antibiotic treatment before study enrollment on 12 particular symptoms for 38 subjects with erythema migrans versus 52 untreated subjects. There were no significant differences in the frequency of having at least one symptom or in the symptom severity score on study entry. However, the frequency of having at least one symptom was significantly greater for those who had received <7 days of antibiotic treatment than for those who had been treated for ≥7 days (23/24 [95.8%] versus 8/14 [57.1%], P = 0.006). In addition, the percentage of subjects who were males was significantly lower among the group on treatment than among the untreated study subjects (13/38 [34.2%] versus 34/52 [65.4%], P = 0.005). In conclusion, based on these findings, combining untreated and treated groups of patients with erythema migrans for research study analyses may have limitations and, depending on the study objectives, might not be preferred. Additional studies are warranted to better understand the day-to-day impact of antibiotic treatment on the presence, type, and severity of symptoms in patients with early Lyme disease.

Co-infections in Persons with Early Lyme Disease, New York, USA.

In certain regions of New York state, USA, Ixodes scapularis ticks can potentially transmit 4 pathogens in addition to Borrelia burgdorferi: Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and the deer tick virus subtype of Powassan virus. In a prospective study, we systematically evaluated 52 adult patients with erythema migrans, the most common clinical manifestation of B. burgdorferi infection (Lyme disease), who had not received treatment for Lyme disease. We used serologic testing to evaluate these patients for evidence of co-infection with any of the 4 other tickborne pathogens. Evidence of co-infection was found for B. microti only; 4-6 patients were co-infected with Babesia microti. Nearly 90% of the patients evaluated had no evidence of co-infection. Our finding of B. microti co-infection documents the increasing clinical relevance of this emerging infection.

Assessment of Duration of Tick Feeding by the Scutal Index Reduces Need for Antibiotic Prophylaxis After Ixodes scapularis Tick Bites.

Doxycycline is recommended for persons with Ixodes scapularis tick bites in certain geographic areas, if the tick had fed for at least 36 hours. Based on the scutal index, over 40% of I. scapularis tick bites from patients seen at the Lyme Disease Diagnostic Center did not warrant antibiotic prophylaxis.

Long-term Assessment of Post-Treatment Symptoms in Patients With Culture-Confirmed Early Lyme Disease.

BACKGROUND: Lyme disease patients with erythema migrans are said to have post-treatment Lyme disease symptoms (PTLDS) if there is persistence of subjective symptoms for at least 6 months following antibiotic treatment and resolution of the skin lesion. The purpose of this study was to characterize PTLDS in patients with culture-confirmed early Lyme disease followed for >10 years. METHODS: Adult patients with erythema migrans with a positive skin or blood culture for Borrelia burgdorferi were enrolled in a prospective study beginning in 1991 and followed up at 6 months and annually thereafter to determine the long-term outcome of this infection. The genotype of the infecting strain of B. burgdorferi was evaluated in subjects with PTLDS. RESULTS: One hundred twenty-eight subjects with culture-confirmed early Lyme disease, of whom 55% were male, were followed for a mean ± SD of 14.98 ± 2.71 years (median = 15 years; range = 11-20 years). Fourteen (10.9%) were regarded as having possible PTLDS, but only 6 (4.7%) had PTLDS documented at their last study visit. Nine (64.3%) had only a single symptom. None of the 6 with PTLDS at their last visit was considered to be functionally impaired by the symptom(s). PTLDS was not associated with a particular genotype of B. burgdorferi. CONCLUSIONS: PTLDS may persist for >10 years in some patients with culture-confirmed early Lyme disease. Such long-standing symptoms were not associated with functional impairment or a particular strain of B. burgdorferi.

Long-term assessment of health-related quality of life in patients with culture-confirmed early Lyme disease.

The health-related quality of life of 100 subjects with culture-confirmed early Lyme disease enrolled in a prospective study with annual follow-up visits was evaluated using the 36-Item Short Form General Health Survey version 2 (SF-36v2) questionnaire at 11-20 years after diagnosis. The mean summary scores of physical and mental health were similar to those of the general population.

A Prospective Study to Characterize Symptoms and Symptom Severity in Adult Patients with Extracutaneous Manifestations of Lyme Disease.

BACKGROUND: Systematic assessments of the presence and severity of particular symptoms over time are relatively uncommon for Lyme disease patients in the United States, and especially for Lyme disease patients with extracutaneous manifestations (ECLD). METHODS: Symptoms and symptom severity of 12 particular symptoms were evaluated in a prospective study at baseline and at 12 months for 35 adult Lyme disease patients with ECLD, 91.4% of whom were already started on antibiotic therapy, and compared with 52 adult Lyme disease patients with erythema migrans, who were untreated at study entry. RESULTS: No significant difference in the frequency of having at least 1 symptom of the 12 evaluated was found between the 2 groups at either the baseline visit or the 12-month evaluation. Demographic variables were also similar between the 2 study groups, except that the ECLD patients were significantly less likely to be Caucasian: 24/35 (68.6%) of the ECLD cases vs 48/52 (92.3%) of the erythema migrans cases; P = .008. CONCLUSION: Lyme disease patients with ECLD had a similar frequency of symptoms at baseline compared with patients with erythema migrans. ECLD subjects, however, were significantly less likely to be Caucasian, raising the question of whether a preceding erythema migrans skin lesion may have been missed in persons with a darker skin color. An important limitation of our study, however, is that we did not record skin color per se, which should be considered for future studies.

Evaluation of selected variables to determine if any had predictive value for, or correlated with, residual symptoms at approximately 12 months after diagnosis and treatment of early Lyme disease.

Subjective symptoms may persist after antibiotic treatment of patients with erythema migrans. Selected baseline variables were evaluated to determine if any correlated with symptom persistence to 12 months (PTLDS). Tingling or an abnormal skin sensation were reported by 5 (71.4%) of the 7 PTLDS cases at the baseline visit versus 4 (13.3%) of the 30 initially symptomatic subjects without PTLDS (P= 0.005). The frequency of having a total score of ≥17, when the Beck Depression Inventory score was added to the number of pain sites that the subject reported at the baseline visit, also showed a significant difference: 71.4% versus 10%, P= 0.002. All but 1 of the 7 subjects with possible PTLDS had either a total score of at least 17 on these 2 measures combined or had a score of ≥2 on the stress event questionnaire used. Clinical investigations should be conducted to validate these findings with other patient cohorts.

Efficacy of a 14-day course of amoxicillin for patients with erythema migrans.

Although a 14-day treatment course with amoxicillin is in wide clinical usage to treat early Lyme disease, only a few published studies exist to validate its efficacy and safety, with none in the United States. In this study, we reviewed the records of 24 prospectively followed adult patients with erythema migrans who were prescribed a 14-day course of amoxicillin, 500 mg 3 times daily. Treatment with amoxicillin was well tolerated and uniformly successful in resolving the erythema migrans skin lesion and in preventing the development of an objective neurologic, cardiac, or rheumatologic manifestation. Although the study was relatively small and only involved a single center, the findings provide additional evidence that a 14-day course of 500 mg amoxicillin given 3 times per day is highly effective therapy for patients with early Lyme disease.

Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition.

BACKGROUND: The Beck Depression Inventory (BDI-II) may be used to evaluate individuals for symptoms of depression. METHODS: In a 1-year prospective study, 52 adult Lyme disease patients with erythema migrans and 104 matched control subjects were clinically assessed and completed the BDI-II at study entry and approximately 6 and 12 months later following antibiotic treatment. RESULTS: The mean BDI-II score was significantly higher at the baseline visit among Lyme disease patients compared with controls (P = .002), but no significant differences between the groups were observed at either the 6- or 12-month study visits. Over the course of the study, the mean BDI-II scores decreased an average of approximately 0.22 points per month (P < .0005) for Lyme disease patients, whereas the mean scores changed very little for controls (mean change = -0.02 per month, P = .50). The total number of somatic symptoms, of the 12 symptoms evaluated, strongly and directly correlated with the BDI-II scores at the baseline visit for the Lyme disease patients. CONCLUSIONS: The mean BDI-II scores of patients with early Lyme disease significantly exceeded that of matched controls at study entry, but by 6 months the values did not differ significantly. There was a good-to-excellent direct correlation between the BDI-II score and the total number of symptoms, suggesting that the BDI-II scores were reflecting somatic rather than affective depressive symptoms. When using the BDI-II as an assessment tool of patients with Lyme disease, infection-related somatic symptoms per se need to be considered in the interpretation of the results.

Post-treatment Lyme disease symptoms score: Developing a new tool for research.

Some patients have residual non-specific symptoms after therapy for Lyme disease, referred to as post-treatment Lyme disease symptoms or syndrome, depending on whether there is functional impairment. A standardized test battery was used to characterize a diverse group of Lyme disease patients with and without residual symptoms. There was a strong correlation between sleep disturbance and certain other symptoms such as fatigue, pain, anxiety, and cognitive complaints. Results were subjected to a Logistic Regression model using the Neuro-QoL Fatigue t-score together with Short Form-36 Physical Functioning scale and Mental Health component scores; and to a Decision Tree model using only the QoL Fatigue t-score. The Logistic Regression model had an accuracy of 97% and Decision Tree model had an accuracy of 93%, when compared with clinical categorization. The Logistic Regression and Decision Tree models were then applied to a separate cohort. Both models performed with high sensitivity (90%), but moderate specificity (62%). The overall accuracy was 74%. Agreement between 2 time points, separated by a mean of 4 months, was 89% using the Decision Tree model and 87% with the Logistic Regression model. These models are simple and can help to quantitate the level of symptom severity in post-treatment Lyme disease symptoms. More research is needed to increase the specificity of the models, exploring additional approaches that could potentially strengthen an operational definition for post-treatment Lyme disease symptoms. Evaluation of how sleep disturbance, fatigue, pain and cognitive complains interrelate can potentially lead to new interventions that will improve the overall health of these patients.

Outcome of facial palsy from Lyme disease in prospectively followed patients who had received corticosteroids.

Although a short course of corticosteroid therapy has been shown to improve the outcome of idiopathic facial nerve palsy (Bell's palsy), it is unclear whether corticosteroids, in addition to antibiotic therapy, are beneficial, are harmful, or have no impact on the outcome of facial palsy from Lyme disease (LDFP). From 2011 through 2016, 14 patients with LDFP were enrolled into a prospective study to determine the outcome of Lyme disease over the ensuing 12 months. Eleven (78.6%) had received corticosteroids in addition to oral antibiotics and entered the study within 24 days after onset of the LDFP (median 14 days, range 2-24 days). Overall, 6 of the corticosteroid-treated patients (54.5%, 95% C.I.: 28.0% to 78.7%) had evidence of residual dysfunction of the facial nerve at the last evaluation, which occurred at a mean of 13.1 months after the baseline visit (range 9.6-19.6 months). In conclusion, although corticosteroids are frequently prescribed for LDFP, the efficacy of this therapy has not been established. Like another recent report, our study raises concern about the safety of adjunctive corticosteroid treatment for LDFP. A well-designed, prospective clinical trial is needed to determine the risk-to-benefit ratio of corticosteroid therapy for LDFP.

Fatigue in patients with erythema migrans.

Fatigue is a common symptom in patients with Lyme disease. The purpose of this study was to characterize fatigue in untreated adult patients presenting with erythema migrans. Selected variables were assessed to determine if any correlated with the presence or severity of fatigue. Fatigue was assessed on the day of the evaluation by a Visual Analogue Scale (VAS), over the past 14days by the 11-item Fatigue Severity Scale (FSS-11) and over the past 28days based on a question from the 36-item Short Form General Health Survey version 2. Fifty-one patients with erythema migrans whose mean age was 49.8years, and 33 (64.7%) of whom were male, were evaluated in this study. The 3 measures of fatigue were positively correlated with one another (P≤0.01). Twenty-six (51%) had fatigue based on a VAS score above 0. Ten (19.6%) had severe fatigue based on an FSS-11 score of ≥4. The strongest correlate for higher fatigue scores was having a greater total number of symptoms. Based on the FSS-11 assessment tool, approximately 20% of early Lyme patients have severe fatigue. Having a high total number of symptoms was associated with both the presence and severity of fatigue. Because prior studies have demonstrated the presence of elevated levels of proinflammatory cytokines and other molecules in the serum of highly symptomatic patients with erythema migrans, the symptom of fatigue in early Lyme disease may be a component of what has been referred to as the acute sickness response.

Long-term assessment of fatigue in patients with culture-confirmed Lyme disease.

BACKGROUND: Fatigue is a common symptom with numerous causes. Severe fatigue is thought to be an important manifestation of post-treatment Lyme disease syndrome. The frequency with which severe fatigue occurs as a long-term sequela in prospectively followed patients with Lyme disease is unknown. METHODS: Patients with culture-confirmed Lyme disease who originally presented with erythema migrans have been evaluated annually in a prospective study to determine their long-term outcome. In 2011-2013, subjects were evaluated for fatigue using an 11-item Fatigue Severity Scale (FSS-11) that has been used in studies of post-treatment Lyme disease syndrome. An FSS-11 score of ≥4.0 is indicative of severe fatigue. RESULTS: A total of 100 subjects were assessed, 52% of whom were male; the mean age was 64.9 years (range, 42-86 years). The mean duration of follow-up was 15.4 years (range, 11-20 years). Nine subjects had severe fatigue but in none as a consequence of Lyme disease. Only 3 subjects were thought to possibly have persistent fatigue from Lyme disease. The FSS-11 value for these 3 individuals was less than 4, averaging 2.27, and none had functional impairment. CONCLUSIONS: Severe fatigue was found in 9 patients (9%) with culture-confirmed early Lyme disease at 11 to 20 years after presentation, but was due to causes other than Lyme disease. Fatigue of lesser severity was possibly due to Lyme disease, but was found in only 3% of 100 patients, and therefore is rarely a long-term complication of this infection.

Long-Term Assessment of Fibromyalgia in Patients with Culture-Confirmed Lyme Disease.

Background: Fibromyalgia occurs in 2% to 8% of the general population. One of the triggers may be Lyme disease. Methods: Patients with culture-confirmed Lyme disease who originally presented with erythema migrans have been evaluated annually in a prospective study to determine their long-term outcome. In 2011-2013, subjects were evaluated for fibromyalgia by interview and tender point examination. Results: 100 subjects were assessed, 52% of whom were male; the mean age was 64.9 years (median 64 years, range 42-86 years). The mean duration of follow-up was 15.4 years (median 16 years, range 11-20 years). At least twenty-four (24%) subjects had experienced a second episode of erythema migrans before the evaluation for fibromyalgia. One patient (1%, 95% C.I.: 0.025 to 5.4%) met criteria for fibromyalgia. The symptoms consistent with fibromyalgia began more than 19 years after Lyme disease was diagnosed. Conclusions: Fibromyalgia was observed in only 1% of 100 patients with culture-confirmed early Lyme disease, a frequency consistent with that found for the general population. This article is protected by copyright. All rights reserved.