Lyme borreliosis (LB) is a tick-borne multisystem infectious disease caused by Borrelia burgdorferi sensu lato.1,2 In United States, the etiologic agent of LB is B. burgdorferi sensu stricto, whereas in Europe, LB is caused by at least 3 different Borrelia species, namely, B. afzelii, B. garinii, and B. burgdorferi sensu stricto.3 Erythema migrans (EM) is the clinical hallmark of LB.1 Solitary EM (SEM) is the characteristic sign of early localized LB, whereas multiple EM (MEM) is one of the main characteristics of early disseminated stage of the disease.4 Published data on isolation of B. burgdorferi sensu lato from blood of the children with EM are scarce.5,6
The aim of our present study was to establish the frequency and characteristics of B. burgdorferi sensu lato bacteremia in Slovenian children with SEM and MEM.
PATIENTS AND METHODS
Between 1996 and 2004, the prospective clinical study was conducted at the Department of Infectious Diseases, University Medical Centre Ljubljana, Slovenia. The study was approved by the Medical Ethics Committee at the Ministry of Health of the Republic of Slovenia. Informed consent was obtained from parents or guardians of all patients. The study included consecutive patients younger than 15 years of age with previously untreated SEM or MEM. The diagnosis of EM was established according to the modified criteria proposed by Centers for Disease Control and Prevention.7 Data on basic demographic and clinical features were collected by a questionnaire, and microbiologic investigations were performed as reported previously.6 In each patient, 1 mL of blood was withdrawn before treatment and cultured in modified Kelly-Pettenkofer medium for the presence of Borrelia. Patients were treated with antibiotics according to the Slovenian recommendations for treatment of early LB in children.8 Patients with SEM and MEM received oral antibiotics and intravenous ceftriaxone, respectively.
Differences in categoric data were analyzed by Yates corrected χ2 or Fisher exact test, whereas differences in continuous data were assessed by Kruskal-Wallis test. All P values were 2-tailed; P < 0.05 was considered statistically significant.
B. burgdorferi sensu lato was isolated from blood in 133 of 1164 (11.4%) patients: in 47 of 619 (7.6%) with SEM and in 86 of 545 (15.8%) with MEM (P < 0.0001). B. afzelii was the predominant isolate, however, B. garinii was found more often in blood of patients with SEM than in patients with MEM. Patients with SEM were older, more often recalled a bite at the site of later EM and less often reported ring-like skin lesion (Table 1). In 26% of patients with SEM and in 1% of those with MEM homogenous red skin lesions were observed without central clearing. No central blistering was found. The median number of skin lesions in patients with MEM was 5.5, ranging from 2 to 58. Bacteremic patients with SEM more often reported associated local and/or systemic symptoms than bacteremic patients with MEM (55% vs. 17%, P = 0.0000). Headache and fever were more often reported in patients with SEM than in patients with MEM (17% vs. 5%, P = 0.0256 and 13% vs. 1%, P = 0.0079). However, at physical examination elevated body temperature >38°C and positive meningeal signs were comparable between the 2 groups (6% vs. 1%, P = 0.1262 and 0% vs. 2%, P = 0.5395).
B. burgdorferi sensu lato bacteremia was detected as early as the day of appearance of EM and as late as 39 days after the appearance of skin lesions (Fig. 1).
In 2001, a prospective clinical study was conducted in Slovenian children with SEM and isolation of B. burgdorferi sensu lato from blood.5 Comparison of bacteremic and nonbacteremic patients revealed no differences in pretreatment characteristics. Patients were treated orally with either penicillin V or cefuroxime axetil for 14 days and followed at least 12 months after initiation of therapy. No difference in post-treatment clinical course was found between the 2 groups. After 1 year, all patients were free of signs and symptoms of LB.
In 2003, a prospective analysis of a large group of European children with EM revealed several differences in demographic, clinical, and laboratory findings between children with SEM and MEM.6 MEM, younger age, and male sex were identified as risk factors for the isolation of B. burgdorferi sensu lato from blood.
In present study, we established the frequency and characteristics of B. burgdorferi sensu lato bacteremia in children with SEM and MEM. After an infected tick bite, B. burgdorferi sensu lato spreads from the site of inoculation to other parts of the body through bloodstream.1,4 The typical, clinical sign of early localized borrelia infection is SEM, whereas MEM is one of the main characteristics of early disseminated infection. The time point at which hematogenous dissemination occurs is not known. It is also not clear whether particular clinical or laboratory features are associated with spirochetemia.9 In the United States, B. burgdorferi sensu stricto is the only species of B. burgdorferi sensu lato complex causing disease in human beings. Wormser et al report that specific genetic subtypes of B. burgdorferi sensu stricto are significantly associated with spirochetemia in adult patients with EM.10 The high rate, early onset, and prolonged duration of risk for spirochetemia are found as possible explanations as to why untreated patients with EM are at risk for dissemination of B. burgdorferi sensu stricto to anatomic sites beyond the skin lesion site. Differences in the strain of infecting spirochete, as well as host factors, may be important determinants of hematogenous dissemination.9 In a study by Wormser et al, high-volume plasma blood cultures were performed and 43.6% of patients were found to be bacteremic; 54 of 156 (34.6%) with SEM and 39 of 57 (68.4%) with MEM. Of 213 patients, 57 (26.8%) had MEM lesions and 39 of them were bacteremic, while 156 (73%) patients had single EM lesion, and 54 of them were bacteremic, representing 68.4% and 34.6% of all bacteremic patients, respectively.9
In our study, B. burgdorferi sensu lato bacteremia was established in 11.4% patients. Among bacteremic patients, the proportion of patients with MEM and those with SEM was 64.7% (86 of 133) and 35.3% (47 of 133). We found almost the same proportion of positive blood cultures between patients with MEM and SEM as has been reported by Wormser et al; however, the rate of isolation of B. burgdorferi sensu lato was much lower in our than in US patients. Small amount of inoculated blood (1 vs. 18 mL), different culture medium (modified Kelly-Pettenkofer vs. antibiotic-free Barbour-Stoenner-Kelly II), and different etiology of EM in Europe and United States (B. afzelii vs. B. burgdorferi sensu stricto) may be the possible explanation for this finding.
In present study, 45% of our bacteremic patients with SEM and 83% of bacteremic patients with MEM were asymptomatic. This finding is in great contrast with the report of Wormser et al.9
In the study by Wormser et al, the risk for bacteremia in adult patients with EM is present from the day the patient notices the skin lesion and continues for more than 2 weeks.9 The results of our present study support such finding, because B. burgdorferi sensu lato bacteremia was detected as early as on the day of appearance of EM and as late as 39 days after the appearance of skin lesion. We agree with Wormser et al that bacteremia during LB is of early onset and of prolonged duration. Our results confirm this statement (Fig. 1).
Almost all isolates were B. afzelii; however, B. garinii was found more often in patients with SEM. No B. burgdorferi sensu stricto were isolated. In a report by Picken et al, 75% of isolates from Slovenian adult patients are typed as B. afzelii, 9% as B. garinii, and 16% as B. burgdorferi sensu stricto.11 No significant difference is reported between isolated species from skin of patients with SEM and MEM because B. afzelii and B. garinii were isolated in 4.5% and 5.8% of Slovenian adult patients with MEM, respectively.12
In conclusion, B. burgdorferi sensu lato bacteremia was established in 11.4% of Slovenian children with untreated EM. Blood cultures were more often positive in patients with MEM (15.8%) than in patients with SEM (7.6%). The risk for B. burgdorferi sensu lato bacteremia in children with untreated EM can last as long as 39 days after the onset of skin rash.
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