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.

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.

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.

Differentiation of reinfection from relapse in recurrent Lyme disease.

BACKGROUND: Erythema migrans is the most common manifestation of Lyme disease. Recurrences are not uncommon, and although they are usually attributed to reinfection rather than relapse of the original infection, this remains somewhat controversial. We used molecular typing of Borrelia burgdorferi isolates obtained from patients with culture-confirmed episodes of erythema migrans to distinguish between relapse and reinfection. METHODS: We determined the genotype of the gene encoding outer-surface protein C (ospC) of B. burgdorferi strains detected in cultures of skin or blood specimens obtained from patients with consecutive episodes of erythema migrans. After polymerase-chain-reaction amplification, ospC genotyping was performed by means of reverse line-blot analysis or DNA sequencing of the nearly full-length gene. Most strains were further analyzed by determining the genotype according to the 16S-23S ribosomal RNA intergenic spacer type, multilocus sequence typing, or both. Patients received standard courses of antibiotics for erythema migrans. RESULTS: B. burgdorferi isolates obtained from 17 patients who received a diagnosis of erythema migrans between 1991 and 2011 and who had 22 paired episodes of this lesion (initial and second episodes) were available for testing. The ospC genotype was found to be different at each initial and second episode. Apparently identical genotypes were identified on more than one occasion in only one patient, at the first and third episodes, 5 years apart, but different genotypes were identified at the second and fourth episodes. CONCLUSIONS: None of the 22 paired consecutive episodes of erythema migrans were associated with the same strain of B. burgdorferi on culture. Our data show that repeat episodes of erythema migrans in appropriately treated patients were due to reinfection and not relapse. (Funded by the National Institutes of Health and the William and Sylvia Silberstein Foundation.).

Public health impact of strain specific immunity to Borrelia burgdorferi.

BACKGROUND: Lyme disease, caused by Borrelia burgdorferi, is the most common tick-borne infection in the United States. Although humans can be infected by at least 16 different strains of B. burgdorferi, the overwhelming majority of infections are due to only four strains. It was recently demonstrated that patients who are treated for early Lyme disease develop immunity to the specific strain of B. burgdorferi that caused their infection. The aim of this study is to estimate the reduction in cases of Lyme disease in the United States that may occur as a result of type specific immunity. METHODS: The analysis was performed based on three analytical models that assessed the effects of type specific immunity. Observational data on the frequency with which different B. burgdorferi strains cause human infection in culture-confirmed patients with an initial episode of erythema migrans diagnosed between 1991 and 2005 in the Northeastern United States were used in the analyses. RESULTS: Assuming a reinfection rate of 3 % and a total incidence of Lyme disease per year of 300,000, the estimated number of averted cases of Lyme disease per year ranges from 319 to 2378 depending on the duration of type specific immunity and the model used. CONCLUSION: Given the assumptions of the analyses, this analysis suggests that type specific immunity is likely to have public health significance in the United States.

Evidence for strain-specific immunity in patients treated for early lyme disease.

Lyme disease, caused by Borrelia burgdorferi, is the most commonly reported vector-borne disease in the United States. Many patients treated for early Lyme disease incur another infection in subsequent years, suggesting that previous exposure to B. burgdorferi may not elicit a protective immune response. However, identical strains are almost never detected from patients who have been infected multiple times, suggesting that B. burgdorferi exposure may elicit strain-specific immunity. Probabilistic and simulation models assuming biologically realistic data derived from patients in the northeastern United States suggest that patients treated for early Lyme disease develop protective immunity that is strain specific and lasts for at least 6 years.

Differences and similarities between culture-confirmed human granulocytic anaplasmosis and early lyme disease.

Lyme disease is transmitted by the bite of certain Ixodes ticks, which can also transmit Anaplasma phagocytophilum, the cause of human granulocytic anaplasmosis (HGA). Although culture can be used to identify patients infected with A. phagocytophilum and is the microbiologic gold standard, few studies have evaluated culture-confirmed patients with HGA. We conducted a prospective study in which blood culture was used to detect HGA infection in patients with a compatible clinical illness. Early Lyme disease was defined by the presence of erythema migrans. The epidemiologic, clinical, and laboratory features of 44 patients with culture-confirmed HGA were compared with those of a convenience sample of 62 patients with early Lyme disease. Coinfected patients were excluded. Patients with HGA had more symptoms (P = 0.003) and had a higher body temperature on presentation (P < 0.001) than patients with early Lyme disease. HGA patients were also more likely to have a headache, dizziness, myalgias, abdominal pain, anorexia, leukopenia, lymphopenia, thrombocytopenia, or elevated liver enzymes. A direct correlation between the number of symptoms and the duration of illness at time of presentation (rho = 0.389, P = 0.009) was observed for HGA patients but not for patients with Lyme disease. In conclusion, although there are overlapping features, culture-confirmed HGA is a more severe illness than early Lyme disease.

Emergence of resistance to azithromycin-atovaquone in immunocompromised patients with Babesia microti infection.

BACKGROUND: Babesiosis is an emerging tickborne malaria-like infection principally caused by Babesia microti. This infection typically resolves either spontaneously or after administration of a 7-10-day course of azithromycin plus atovaquone or clindamycin plus quinine. Although certain highly immunocompromised patients may respond suboptimally to these drug regimens, unlike the situation with malaria there has been no reported evidence that the cause of treatment failure is infection with drug-resistant strains of B. microti. METHODS: Emergence of drug resistance in B. microti was defined as the development of a microbiologic relapse (recurrent parasitemia or a marked increase in parasitemia) in association with both clinical and laboratory abnormalities indicative of active babesiosis in a patient after 28 days of uninterrupted antibabesia drug therapy and while still receiving treatment. RESULTS: The clinical case histories of 3 highly immunocompromised patients who received a subcurative course of azithromycin-atovaquone associated with the eventual development of resistance to this drug regimen are described. One of the 3 patients died of complications related to babesiosis. CONCLUSIONS: B. microti may become resistant to azithromycin-atovaquone during the treatment of babesiosis with this combined drug regimen in highly immunocompromised patients. Although research is needed to determine the optimal therapy for highly immunocompromised patients with babesiosis, reducing the level of immunosuppression when possible would appear to be a desirable strategy.

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis.

BACKGROUND: The clinical value of antibiotic prophylaxis in preventing Lyme disease remains uncertain, owing to a meta-analysis lacking sufficient power to demonstrate efficacy and a more recent trial showing effectiveness but lacking precision. Our objective was to update our prior meta-analysis on antibiotic prophylaxis for the prevention of Lyme disease, to obtain a more precise estimate of treatment effect. METHODS: Clinical trials were identified by searching MEDLINE, Embase, the Cochrane Library and trial registries, and by an assessment of the bibliographies of retrieved articles and reviews. Trials were selected if their patients were randomly allocated to a treatment or placebo group within 72 h following an Ixodes tick bite and had no clinical evidence of Lyme disease at enrollment. Details of the trial design, patient characteristics, interventions and outcomes were extracted from each article. Study quality was assessed using the Jadad scale. RESULTS: Four placebo-controlled clinical trials were included for review. Among 1082 randomized subjects, the risk of Lyme disease in the placebo group was 2.2% [95% confidence interval (CI), 1.2%-3.9%] compared with 0.2% (95% CI, 0.0%-1.0%) in the antibiotic-treated group. Antibiotic prophylaxis significantly reduced the odds of developing Lyme disease compared with placebo (pooled odds ratio=0.084; 95% CI, 0.0020-0.57; P=0.0037). CONCLUSIONS: The available evidence to date supports the use of antibiotic prophylaxis for the prevention of Lyme disease in endemic areas following an Ixodes tick bite. Pooled data from four placebo-controlled trials suggests that one case of Lyme disease is prevented for about every 50 patients who are treated with antibiotics.

Blood cultures for patients with extracutaneous manifestations of Lyme disease in the United States.

Spirochetemia in US patients with extracutaneous manifestations of Lyme disease is not well documented. In this study, blood culture results were positive for 5 (19.2%; 95% confidence interval, 6.6%-39.4%) of 26 untreated adult patients with extracutaneous manifestations but only for patients with clinical evidence for a short duration of infection.

Management approaches for suspected and established Lyme disease used at the Lyme disease diagnostic center.

2015 marks the 27th year that the Lyme Disease Diagnostic Center, located in New York State in the United States, has provided care for patients with suspected or established deer tick-transmitted infections. There are five deer tick-transmitted infectious in this geographic area of which Lyme disease is the most common.For patients with erythema migrans, we do not obtain any laboratory testing. However, if the patient is febrile at the time of the visit or reports rigors and high-grade fevers, we consider the possibility of a co-infection and order pertinent laboratory tests.Our preferred management for Lyme disease-related facial palsy and/or radiculopathy is a 2-week course of doxycycline. Patients who are hospitalized for Lyme meningitis are usually treated at least initially with ceftriaxone. We have not seen convincing cases of encephalitis or myelitis solely due to Borrelia burgdorferi infection in the absence of laboratory evidence of concomitant deer tick virus infection (Powassan virus). We have also never seen Lyme encephalopathy or a diffuse axonal peripheral neuropathy and suggest that these entities are either very rare or nonexistent.We have found that Lyme disease rarely presents with fever without other objective clinical manifestations. Prior cases attributed to Lyme disease may have overlooked an asymptomatic erythema migrans skin lesion or the diagnosis may have been based on nonspecific IgM seroreactivity. More research is needed on the appropriate management and significance of IgG seropositivity in asymptomatic patients who have no history of Lyme disease.

The impact of strain-specific immunity on Lyme disease incidence is spatially heterogeneous.

Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most common tick-borne infection in the US. Recent studies have demonstrated that the incidence of human Lyme disease would have been even greater were it not for the presence of strain-specific immunity, which protects previously infected patients against subsequent infections by the same B. burgdorferi strain. Here, spatial heterogeneity is incorporated into epidemiological models to accurately estimate the impact of strain-specific immunity on human Lyme disease incidence. The estimated reduction in the number of Lyme disease cases is greater in epidemiologic models that explicitly include the spatial distribution of Lyme disease cases reported at the county level than those that utilize nationwide data. strain-specific immunity has the greatest epidemiologic impact in geographic areas with the highest Lyme disease incidence due to the greater proportion of people that have been previously infected and have developed strain-specific immunity.

Brief communication: hematogenous dissemination in early Lyme disease.

BACKGROUND: Bloodstream invasion in Lyme disease has been difficult to study because until recently blood culture methods were too insensitive to detect spirochetemia. OBJECTIVE: To evaluate the clinical and laboratory features of spirochetemic patients. DESIGN: Cross-sectional study. SETTING: Lyme Disease Diagnostic Center in Valhalla, New York, 1997 to 2002. PATIENTS: 213 untreated adults with erythema migrans. INTERVENTION: Blood culture for Borrelia burgdorferi. MEASUREMENTS: Symptom scores and selected laboratory measures. RESULTS: Spirochetemia was found in 93 (43.7%) patients. Spirochetemic patients were more often symptomatic (89.2% vs. 74.2%; P = 0.006) and more often had multiple erythema migrans lesions (41.9% vs. 15.0%; P < 0.001) than patients without spirochetemia. However, 8 (22.9%) of the 35 asymptomatic patients with a single skin lesion nevertheless had a positive blood culture. Risk for spirochetemia was present the day the patient noticed the lesion and continued for more than 2 weeks. LIMITATIONS: Long-term outcome data were not available. CONCLUSIONS: The high rate, early onset, and prolonged duration of risk for spirochetemia explain why untreated patients with erythema migrans are at risk for dissemination of B. burgdorferi to anatomic sites beyond the lesion site. Differences in the strain of the infecting spirochete, as well as host factors, may be important determinants of hematogenous dissemination.

Microbiologic evaluation of patients from Missouri with erythema migrans.

BACKGROUND: Borrelia lonestari infects Amblyomma americanum, the tick species that is the most common cause of tick bites in southeast and south-central United States, and this spirochete has been detected in an erythema migrans (EM)-like skin rash in 1 patient. Therefore, B. lonestari is considered to be a leading candidate for the etiologic agent of EM in this region. METHODS: Skin biopsy specimens obtained from patients from the Cape Girardeau area of Missouri who had EM-like lesions were cultured in Barbour-Stoenner-Kelly medium and evaluated by polymerase chain reaction (PCR) targeting multiple genes. Serum specimens were tested by enzyme-linked immunosorbent assay for antibodies against sonicated whole-cell Borrelia burgdorferi. Results were compared with those obtained over the same period for patients from New York State who had EM. RESULTS: B. lonestari was not detected by PCR in any of 31 skin biopsy specimens collected from 30 Missouri patients. None of 19 cultures of Missouri skin samples that were suitable for evaluation were positive for B. burgdorferi, compared with 89 (63%) of 142 cultures of samples collected from New York State patients (P<.001). None of the 25 evaluable Missouri patients were seropositive for antibodies against B. burgdorferi, compared with 107 (75%) of 143 New York State patients (P<.001). CONCLUSIONS: Neither B. lonestari nor B. burgdorferi is likely to be the cause of EM-like skin lesions in patients from the Cape Girardeau area of Missouri. The etiology of this condition remains unknown.

Prospective clinical evaluation of patients from Missouri and New York with erythema migrans-like skin lesions.

BACKGROUND: The most common and most recognizable feature of Borrelia burgdorferi infection (Lyme disease) is the skin lesion erythema migrans (EM). An illness associated with an EM-like skin lesion, but which is not caused by B. burgdorferi, occurs in many southern states in the United States (southern tick-associated rash illness [STARI], also known as Masters disease). METHODS: Clinical features of 21 cases of EM-like skin lesions in 21 patients from Missouri were compared in a prospective study with those of 101 cases in 97 patients with EM-like skin lesions from New York. RESULTS: Among Missouri cases, the peak incidence of EM-like skin lesions occurred earlier in the year than it did among New York cases (P<.001). Case patients from Missouri were more likely to recall a tick bite than were case patients from New York (85.7% and 19.8%, respectively; P<.001), and the time period from tick bite to onset of the skin lesion was shorter among Missouri case patients (6.1+/-4.2 days and 10.4+/-6.1 days, respectively; P=.011). Missouri case patients were less likely to be symptomatic than were New York case patients (19.0% and 76.2%, respectively; P<.001), and Missouri case patients were less likely to have multiple skin lesions (4.8% and 26.7%, respectively; P=.042). EM-like lesions in Missouri cases were smaller in size than those in New York cases (8.3+/-2.2 cm and 16.4+/-11.5 cm, respectively; P<.001), more circular in shape (P=.004), and more likely to have central clearing (76.2% and 21.6%, respectively; P<.001). After antibiotic treatment, Missouri case patients recovered more rapidly than did New York case patients (P=.037). CONCLUSION: Cases of EM-like skin lesion in patients from Missouri and New York have distinct clinical presentations.

Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans.

BACKGROUND: Lyme disease has a wide spectrum of clinical manifestations. Diagnosis is usually based on the clinical and serologic picture rather than on microbiological confirmation. OBJECTIVE: To examine the clinical presentation and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. DESIGN: Observational cohort study. SETTING: 31 university-based or clinician-practice sites in 10 endemic states. PARTICIPANTS: 10 936 participants enrolled in a phase III trial of Lyme disease vaccine; 118 participants had erythema migrans in which Borrelia burgdorferi was detected by culture or polymerase chain reaction. MEASUREMENTS: Clinical characteristics and treatment outcome were noted. Skin biopsies of erythema migrans were performed for culture and detection of B. burgdorferi by polymerase chain reaction; serologic responses were determined by Western blot. RESULTS: The 118 patients with microbiologically confirmed erythema migrans presented a median of 3 days after symptom onset. Early erythema migrans commonly had homogeneous or central redness rather than a peripheral erythema with partial central clearing. The most common associated symptoms were low-grade fever, headache, neck stiffness, arthralgia, myalgia, or fatigue. By convalescence, 65% of patients had positive IgM or IgG antibody responses to B. burgdorferi. Most patients responded promptly to antibiotic treatment. CONCLUSIONS: In major endemic areas in the United States, Lyme disease commonly presents as erythema migrans with homogeneous or central redness and nonspecific flu-like symptoms. Clinical outcome is excellent if antibiotic therapy is administered soon after symptom onset.

Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Treatment of patients with early Lyme disease has trended toward longer duration despite the absence of supporting clinical trials. OBJECTIVE: To evaluate different durations of oral doxycycline treatment and the combination of oral doxycycline and a single intravenous dose of ceftriaxone for treatment of patients with early Lyme disease. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Single-center university hospital. PATIENTS: 180 patients with erythema migrans. INTERVENTION: Ten days of oral doxycycline, with or without a single intravenous dose of ceftriaxone, or 20 days of oral doxycycline. MEASUREMENTS: Outcome was based on clinical observations and neurocognitive testing. Efficacy was assessed at 20 days, 3 months, 12 months, and 30 months. RESULTS: At all time points, the complete response rate was similar for the three treatment groups in both on-study and intention-to-treat analyses. In the on-study analysis, the complete response rate at 30 months was 83.9% in the 20-day doxycycline group, 90.3% in the 10-day doxycycline group, and 86.5% in the doxycycline-ceftriaxone group (P > 0.2). The only patient with treatment failure (10-day doxycycline group) developed meningitis on day 18. There were no significant differences in the results of neurocognitive testing among the three treatment groups and a separate control group without Lyme disease. Diarrhea occurred significantly more often in the doxycycline-ceftriaxone group (35%) than in either of the other two groups (P < 0.001). CONCLUSIONS: Extending treatment with doxycycline from 10 to 20 days or adding one dose of ceftriaxone to the beginning of a 10-day course of doxycycline did not enhance therapeutic efficacy in patients with erythema migrans. Regardless of regimen, objective evidence of treatment failure was extremely rare.

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.