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.

Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity.

BACKGROUND: Lyme disease is transmitted by the bite of the Ixodes scapularis tick, which can also transmit Anaplasma phagocytophilum, the cause of human granulocytic anaplasmosis (HGA). Conflicting data exist on the frequency of coinfection and on whether Lyme-HGA coinfected patients have more symptoms than patients with Lyme disease alone. METHODS: Blood culture and serology were used to detect HGA infection in patients with early Lyme disease who presented with erythema migrans. The rate of coinfection was determined using different definitions. The clinical and laboratory features of Lyme-HGA coinfection were compared with that of the individual infections. RESULTS: Among 311 patients with erythema migrans, the frequency of coinfection with HGA varied from 2.3% to 10.0%, depending on the definition used (P < .001). Only 1 of 4 groups with presumed coinfection had significantly more symptoms than patients with Lyme disease alone P < .05. High fever and cytopenia were less common in Lyme-HGA coinfection than in patients with HGA alone. CONCLUSION: The results of this study indicate that how HGA is defined in patients with early Lyme disease has an impact on the apparent rate of coinfection and the severity of illness. The findings also suggest that HGA may be less severe than is usually believed, suggesting the existence of referral bias in testing patients preferentially who present with high fever or cytopenia.

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.).

Comparison of five diagnostic modalities for direct detection of Borrelia burgdorferi in patients with early Lyme disease.

Lyme disease, the most commonly reported tick-borne infection in North America, is caused by infection with the spirochete Borrelia burgdorferi. Although an accurate clinical diagnosis can often be made based on the presence of erythema migrans, in research studies microbiologic or molecular microbiologic confirmation of the diagnosis may be required. In this study, we evaluated the sensitivity of 5 direct diagnostic methods (culture and nested polymerase chain reaction [PCR] of a 2-mm skin biopsy specimen, nested PCR and quantitative PCR (qPCR) performed on the same 1-mL aliquot of plasma and a novel qPCR-blood culture method) in 66 untreated adult patients with erythema migrans. Results of one or more of these tests were positive in 93.9% of the patients. Culture was more sensitive than PCR for both skin and blood, but the difference was only statistically significant for blood samples (P<0.005). Blood culture was significantly more likely to be positive in patients with multiple erythema migrans skin lesions compared to those with a single lesion (P=0.001). Positive test results among the 48 patients for whom all 5 assays were performed invariably included either a positive blood or a skin culture. The results of this study demonstrate that direct detection methods such as PCR and culture are highly sensitive in untreated adult patients with erythema migrans. This enabled microbiologic or molecular microbiologic confirmation of the diagnosis of B. burgdorferi infection in all but 4 (6.1%) of the 66 patients evaluated.

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.

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.

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.

Long-term follow-up of patients with culture-confirmed Lyme disease.

PURPOSE: To determine the long-term outcome of patients with culture-confirmed Lyme disease. METHODS: We analyzed data collected prospectively on adult patients from a highly endemic area in New York State who were diagnosed with early Lyme disease between 1991 and 1994. Patients with culture-confirmed erythema migrans were evaluated at baseline, 7 to 10 days, 21 to 28 days, 3 months, 6 months, 1 year, and annually thereafter. All patients were treated with antibiotics at the time of diagnosis. RESULTS: We evaluated 96 cases on 709 separate occasions (median, eight evaluations per case). The erythema migrans rash resolved within 3 weeks in all of the 94 evaluable cases, none of whom developed an objective extracutaneous manifestation of Lyme disease. Of the 81 cases who were followed for >/=1 year, all but 8 (10%) were asymptomatic at their last visit, a mean (+/- SD) of 5.6 +/- 2.6 years into follow-up, and only 3 (4%) were symptomatic at every follow-up visit. Intercurrent tick bites were reported by 45 cases (47%), and 14 (15%) developed a second episode of erythema migrans. Four other cases who were asymptomatic seroconverted between years 2 and 5. CONCLUSION: The long-term outcome of patients with erythema migrans after antibiotic therapy was excellent, but patients from a highly endemic area in New York State remained at high risk of re-exposure to ticks and reinfection. Subjective symptoms during follow-up evaluations tended to be mild to moderate, intermittent, and associated with more symptomatic illness at the time of initial diagnosis.

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.