Publications by authors named "Daša Stupica"

29 Publications

  • Page 1 of 1

Clinical manifestations and long-term outcome of early Lyme neuroborreliosis according to the European Federation of Neurological Societies diagnostic criteria (definite versus possible) in central Europe. A retrospective cohort study.

Eur J Neurol 2021 Jun 11. Epub 2021 Jun 11.

Institute for Microbiology and Immunology Ljubljana, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

Background And Purpose: The characteristics and long-term outcome of Lyme neuroborreliosis (LNB) according to diagnostic certainty (definite vs. possible) are incompletely understood.

Methods: In this retrospective cohort study of adults with definite or possible LNB, clinical and microbiological characteristics and long-term outcome over 12 months were evaluated at a single medical center. Severity of acute disease and long-term outcome were assessed using a composite clinical score encompassing clinical findings and symptoms and by the probability of incomplete recovery.

Results: Amongst 311 adult patients enrolled from 2008 to 2017, 139 (44.7%) had definite LNB and 172 (55.3%) had possible LNB. The most frequent LNB manifestation was cranial neuropathy with or without meningitis (53.4%). Patients with definite LNB more often had Bannwarth syndrome (53.2% vs. 18.6%), more severe disease (6 points vs. 4 points), longer pre-treatment duration (median 21 days vs. 13.5 days), higher cerebrospinal fluid pleocytosis (median 139 × 10 /L vs. 11 × 10 /L) and higher rate of Borrelia seropositivity (84.2% vs. 68.6%) than those with possible LNB. Ceftriaxone was prescribed more often than oral doxycycline in definite LNB than in possible LNB (96.4% vs. 65.7%). Unfavorable outcomes decreased during follow-up, being higher in patients with more severe disease at enrollment and in those with possible LNB, but were not associated with antibiotic therapy.

Conclusions: Early LNB, most often presenting as cranial neuropathy, was definitively diagnosed in less than half of cases. A better diagnostic approach is needed to confirm borrelial etiology. Ceftriaxone was not superior to doxycycline in the treatment of early LNB, regardless of diagnostic certainty. In this retrospective cohort study of 311 adults with Lyme neuroborreliosis (LNB), allocated according to diagnostic certainty, early LNB was definitively diagnosed in less than half of cases and the most frequent LNB manifestation was cranial neuropathy with or without meningitis. Patients with definite LNB more often had Bannwarth syndrome, more severe disease, longer pre-treatment duration, higher cerebrospinal fluid pleocytosis and higher rate of Borrelia seropositivity than those with possible LNB. A better diagnostic approach is needed to confirm borrelial etiology. Ceftriaxone was not superior to doxycycline in the treatment of early LNB, regardless of diagnostic certainty.
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http://dx.doi.org/10.1111/ene.14962DOI Listing
June 2021

Systemic immune responses in patients with early localized or early disseminated Borrelia afzelii lyme borreliosis.

Immun Inflamm Dis 2021 Jun 31;9(2):375-387. Epub 2020 Dec 31.

Faculty of Medicine Ljubljana, Ljubljana, Slovenia.

Introduction: The role of host immune responses in the pathogenesis of borrelial dissemination in early Lyme borreliosis (LB) in the form of multiple erythema migrans (MEM) or LB-associated symptoms is incompletely understood.

Methods: In this study, fifteen cytokine or chemokine levels, representative of innate, Th1, and Th17 immune responses, were assessed using a bead-based Luminex multiplex assay in acute sera from 76 adult patients with skin culture-positive Borrelia afzelii solitary erythema migrans (SEM) and 58 patients with MEM at a single-center university hospital. Differences between the groups were tested by modeling each cytokine or chemokine concentration by means of left-censored regression using the classic Tobit model.

Results: Mean serum cytokine or chemokine levels were low. When taking into account the proportion of patients with cytokine or chemokine concentrations below the lowest detectable limit, only levels of CXCL10 (p = .03) and CCL19 (p = .02), representatives of the Th1 immune response, differed between patients with SEM and those with MEM; however, the differences did not reach statistical significance when adjusted for multiple comparisons. In addition, we did not find differences in systemic inflammatory responses when comparing patients with and those without LB-associated constitutional symptoms.

Conclusion: No significant differences in systemic immune responses represented by selected cytokines or chemokines in serum samples of patients with EM infected with B. afzelii suggest that systemic mediators are not pivotal in the pathogenesis of dissemination of early infection in the form of MEM or LB-associated symptoms. Localized immune responses in the skin or other pathogenetic mechanisms may be more important in this regard.
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http://dx.doi.org/10.1002/iid3.398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127568PMC
June 2021

Five-Day vs 10-Day Postexposure Chemoprophylaxis With Oseltamivir to Prevent Hospital Transmission of Influenza: A Noninferiority Randomized Open-Label Study.

Open Forum Infect Dis 2020 Aug 19;7(8):ofaa240. Epub 2020 Jun 19.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Background: The efficacy and optimal duration of postexposure influenza prophylaxis with oseltamivir are undetermined in hospital settings, where immediate separation from index cases is not feasible.

Methods: In an open-label noninferiority randomized clinical trial in a single-center university hospital, the efficacy of 5-day vs 10-day postexposure prophylaxis with oseltamivir was compared in adult patients exposed to influenza who could not be immediately separated from index influenza cases. Influenza incidence was assessed for 10 days after discontinuing prophylaxis.

Results: Among 222 exposed patients (median age, 75 years; male 119; median Charlson Comorbidity Index, 5), 110 patients were assigned to 5 days of postexposure prophylaxis with oseltamivir, and 112 patients were assigned to the 10-day group. The median duration of exposure to influenza (interquartile range) was 2 (1-3) days. In the intention-to-treat analysis, the incidence of influenza was 2/110 (1.8%) in the 5-day group and 0/112 (0%) in the 10-day group (difference, 1.8 percentage points; 1-sided 95% CI, -1 to 4.9 percentage points;  = .77).

Conclusions: For patients exposed to influenza in a hospital setting and who were not immediately separated from index cases, postexposure prophylaxis with oseltamivir resulted in low incidence of nosocomial influenza transmission. Five-day postexposure prophylaxis was noninferior to 10-day regimen.

Clinicaltrialsgov Registration: NCT03899571.
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http://dx.doi.org/10.1093/ofid/ofaa240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397832PMC
August 2020

Antibiotic Use and Long-Term Outcome in Patients with Tick-Borne Encephalitis and Co-Infection with Sensu Lato in Central Europe. A Retrospective Cohort Study.

J Clin Med 2019 Oct 20;8(10). Epub 2019 Oct 20.

Department of Infectious Diseases, University Medical Center Ljubljana, Japljeva 2, Ljubljana 1525, Slovenia.

In this retrospective cohort study of patients with tick-borne encephalitis (TBE), the clinical outcome in relation to co-infection with sensu lato (s.l.) and, specifically, the effect of antibiotic treatment on clinical outcome in patients with TBE who were seropositive for borreliae but who did not fulfil clinical or microbiologic criteria for proven co-infection, were assessed at a single university medical center in Slovenia, a country where TBE and Lyme borreliosis are endemic with high incidence. Among 684 patients enrolled during a seven-year period from 2007 through 2013, 382 (55.8%) had TBE alone, 62 (9.1%) had proven co-infection with borreliae and 240 (35.1%) had possible co-infection. The severity of acute illness was similar in all the groups. The odds for incomplete recovery decreased during a 12-month follow-up but were higher in women, older patients, and in those with more severe acute illness. Incomplete recovery was not associated with either proven (odds ratio (OR) 1.21, 95% confidence interval (CI) 0.49-2.95; = 0.670) or possible co-infection (OR 0.95, 95% CI 0.55-1.65; = 0.853). Among patients with possible co-infection, older patients were more likely to be prescribed antibiotics, but the odds for incomplete recovery were similar in those who received antibiotics and those who did not (OR 0.82, 95% CI 0.36-1.87; = 0.630), suggesting that routine antibiotic treatment in patients with TBE and possible co-infection may not be warranted.
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http://dx.doi.org/10.3390/jcm8101740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832614PMC
October 2019

Clinical Course, Serologic Response, and Long-Term Outcome in Elderly Patients with Early Lyme Borreliosis.

J Clin Med 2018 Dec 2;7(12). Epub 2018 Dec 2.

Department of Infectious Diseases, University Medical Center Ljubljana, Japljeva 2, 1525 Ljubljana, Slovenia.

Infected elderly people often present with signs and symptoms that differ from those in younger adults, but data on the association between patient age and presentation of early Lyme borreliosis (LB) are limited. In this study, the association between patient age (18⁻44 years, young vs. 45⁻64 years, middle-aged vs. ≥ 65 years, elderly) and disease course, microbiologic characteristics, and the long-term outcome of treatment was investigated prospectively in 1220 adult patients with early LB manifesting as erythema migrans (EM) at a single-center university hospital. Patients were assessed at enrolment and followed-up for 12 months. Age was associated with comorbidities, previous LB, presenting with multiple EM, and seropositivity to borreliae at enrolment. The time to resolution of EM after starting antibiotic treatment was longer in older patients. At 12 months, 59/989 (6.0%) patients showed incomplete response. The odds for incomplete response decreased with time from enrolment (odds ratio (OR) of 0.49, 0.50, and 0.48 for 2-month vs. 14-days, 6-month vs. 2-month, and 12-month vs. 6-month follow-up visits, respectively), but were higher with advancing age (OR 1.57 for middle-aged vs. young, and 1.95 for elderly vs. young), in women (OR 1.41, 95% confidence interval (CI) 1.01⁻1.96), in patients who reported LB-associated constitutional symptoms at enrolment (OR 7.69, 95% CI 5.39⁻10.97), and in those who presented with disseminated disease (OR 1.65, 95% CI 1.09⁻2.51). The long-term outcome of EM was excellent in patients of all age groups. However, older patients had slower resolution of EM and higher odds for an unfavorable outcome of treatment (OR 1.57, 95% CI 1.05⁻2.34 for middle-aged vs. young; and OR 1.95, 95% CI 1.14⁻3.32 for elderly vs. young), manifested predominantly as post-LB symptoms. The presence of LB-associated constitutional symptoms at enrolment was the strongest predictor of incomplete response.
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http://dx.doi.org/10.3390/jcm7120506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306842PMC
December 2018

Impact of pre-existing treatment with statins on the course and outcome of tick-borne encephalitis.

PLoS One 2018 4;13(10):e0204773. Epub 2018 Oct 4.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Objectives: Although statins have anti-inflammatory and potentially also antimicrobial (including antiviral) activity, their therapeutic impact on infectious diseases is controversial. In this study, we evaluated whether pre-existing statin use influenced the course and outcome of tick-borne encephalitis.

Methods: To assess the influence of statin usage on the severity of acute illness and the outcome of tick-borne encephalitis, univariate and multivariable analyses were performed for 700 adult patients with tick-borne encephalitis of whom 77 (11%) were being treated with statins, and for 410 patients of whom 53 (13%) were receiving statins, respectively.

Results: Multivariable analyses found no statistically significant association between statin usage and having a milder acute illness. There was also no statistically significant benefit with respect to a favorable outcome defined by the absence of post-encephalitic syndrome (ORs for a favorable outcome at 6 months was 0.96, 95% CI: 0.46-2.04, P = 0.926; at 12 months 0.29, 95% CI: 0.06-1.33, P = 0.111; at 2-7 years after acute illness 0.44, 95% CI: 0.09-2.22, P = 0.321), by a reduction in the frequency of six nonspecific symptoms (fatigue, myalgia/arthralgia memory disturbances, headache, concentration disturbances, irritability) occurring during the 4 week period before the last examination, or by higher SF-36 scores in any of the eight separate domains of health as well as in the physical and mental global overall component. Furthermore, there were no significant differences between patients receiving statins and those who were not in the cerebrospinal fluid or serum levels for any of the 24 cytokines/chemokines measured.

Conclusions: In this observational study, we could not prove that pre-existing use of statins affected either the severity of the acute illness or the long-term outcome of tick-borne encephalitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204773PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171849PMC
March 2019

Doxycycline-induced photosensitivity in patients treated for erythema migrans.

BMC Infect Dis 2018 08 3;18(1):365. Epub 2018 Aug 3.

Department of Infectious Diseases, University Medical Centre Ljubljana, Japljeva 2, 1525, Ljubljana, Slovenia.

Background: Doxycycline is one of the recommended antibiotics for treating erythema migrans (EM). Since EM predominantly occurs during summer, the potential of doxycycline to induce photosensitivity is of concern. In studies on the efficacy of doxycycline for treating relatively small numbers of patients with EM, the reported frequency of photosensitivity has varied from none to 15%. The aim of this study was to elucidate the frequency and clinical symptoms of doxycycline-induced photosensitivity in a large cohort of patients with EM treated in a single medical centre.

Methods: Prospectively collected data on adverse events were analysed in adult patients with EM treated with doxycycline 100 mg twice daily for 10-15 days.

Results: Photosensitivity reactions ranging from itching and burning sensations to transient mild erythema of sun-exposed skin were documented in 16/858 (1.9, 95% CI 1.1-3.0%) patients and appeared from June to October with highest frequency in July. These adverse events were more frequent in patients treated for 14 or 15 days (16/750 [2.1%]; 95% CI 1.2-3.4%) than in those treated for 10 days (0/108 [0%]; 95% CI 0.0-3.4%); however, the difference was not significant (P = 0.24). Women were more often affected than men (13/475 [2.7%], 95% CI 1.5-4.6% versus 3/383 [0.8%], 95% CI 0.2-2.3%; P = 0.04). Of the 16 patients who developed photosensitivity, 13 did not adhere to the recommendation to avoid sun exposure. None of the patients had any long-term sequelae of photosensitivity.

Conclusions: Photosensitivity reactions in adult patients with EM treated with doxycycline 100 mg twice daily for 10-15 days occurred rarely, were not severe, and had no long-term sequelae.

Trial Registration: Registered at http://clinicaltrials.gov , Identifiers NCT00910715, May 28th 2009, NCT01163994, July 13th 2010 and NCT03584919, June 19th 2018 retrospectively registered.
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http://dx.doi.org/10.1186/s12879-018-3270-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090842PMC
August 2018

Comparison of Clinical Course and Treatment Outcome for Patients With Early Disseminated or Early Localized Lyme Borreliosis.

JAMA Dermatol 2018 09;154(9):1050-1056

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Importance: Multiple erythema migrans (MEM) has been suggested as a risk factor for unfavorable antibiotic treatment outcome compared with solitary erythema migrans (EM). However, no direct comparison of early Lyme borreliosis manifested as MEM with solitary EM has been undertaken.

Objective: To investigate the potential differences in clinical course and treatment outcome between MEM and solitary EM.

Design, Setting, And Participants: This prospective cohort study was conducted from June 1, 2010, to October 31, 2015, at the University Medical Center Ljubljana, Slovenia. Data were analyzed from June 1, 2017, to January 3, 2018. Of the 778 consecutive adult patients with early Lyme borreliosis evaluated, 200 patients with MEM and 403 patients with solitary EM were enrolled. Patients were asked to refer a family member or a friend of similar age (±5 years) without a history of Lyme borreliosis to serve as a control participant. Clinical course and posttreatment outcome of MEM were compared with those of solitary EM. Outcome was assessed at 14 days and at 2, 6, and 12 months after enrollment. At each visit, patients completed a written questionnaire about their symptoms; controls completed the same questionnaire. Nonspecific symptoms reported by patients and controls without a history of Lyme borreliosis were compared.

Main Outcomes And Measures: The proportion of patients with incomplete response at 12 months after enrollment and the associated 2-sided 95% CI for the difference between MEM and solitary EM were estimated using the normal approximation with continuity correction.

Results: A total of 200 patients with MEM and 403 patients with solitary EM were included. Among the 200 patients with MEM, 94 (47.0%) were males and 106 (53.0%) were females, with a median (interquartile range [IQR]) age of 47 (35-58) years. Among the 403 patients with solitary EM, 182 (45.2%) were males and 221 (54.8%) were females, with a median (IQR) age of 55 (42-62) years. Patients with MEM reported Lyme borreliosis-associated constitutional symptoms at enrollment more often than those with solitary EM (93 [46.5%]; 95% CI, 39.4-53.7 vs 96 [23.8%]; 95% CI, 19.7-28.3; P < .001). During the initial 6 months after treatment, the proportion of patients with incomplete response was higher in the MEM group than in the solitary EM group (14 days: 62 of 193 [32.1%] vs 72 of 391 [18.4%]; P < .001; 2 months: 38 of 193 [19.7%] vs 55 of 394 [14.0%]; P = .28; 6 months: 29 of 182 [15.9%] vs 31 of 359 [8.6%]; P = .02). However, at the 12-month visit, the outcome was comparable: 10 of 170 (5.9%) patients with MEM vs 20 of 308 (6.5%) patients with solitary EM showed incomplete response (-0.6; 95% CI, -5.5 to 4.3; P = .95). The frequency of nonspecific symptoms in patients was similar to that in controls.

Conclusions And Relevance: The long-term outcome at 12 months after treatment was comparable, regardless of dissemination. Follow-up of at least 12 months after treatment is thus recommended for future studies that investigate post-Lyme borreliosis symptoms.
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http://dx.doi.org/10.1001/jamadermatol.2018.2306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143036PMC
September 2018

Is the risk of early neurologic Lyme borreliosis reduced by preferentially treating patients with erythema migrans with doxycycline?

Diagn Microbiol Infect Dis 2018 Jun 2;91(2):156-160. Epub 2018 Feb 2.

Division of Infectious Diseases, New York Medical College, 40 Sunshine Cottage Rd, Valhalla, NY 10595, USA.

Doxycycline is highly effective treatment for early neurologic Lyme borreliosis (NLB). Nineteen studies were reviewed to determine if treatment of patients with erythema migrans with other oral antibiotics would increase the risk for developing NLB. In the eight studies that directly compared doxycycline to another antibiotic, the pooled difference indicated a 0.2% greater risk of developing NLB in doxycycline-treated patients (95% CI: -1.0%, +1.4%; P = 0.77), with an estimated heterogeneity of 0.0%, P = 0.58. Overall, in the 19 studies, NLB was reported in 8/828 (1.0%; 95% CI: 0.42%, 1.89%) doxycycline-treated patients versus 6/1022 (0.6%; 95% CI: 0.22%, 1.27%) patients treated with other antibiotics (P = 0.42). Based on the 95% CI calculation (-0.5%, +1.40%), patients receiving nondoxycycline treatment regimens collectively might have at most a 0.5% greater risk for developing NLB. Available data suggest that oral doxycycline is not superior to comparators for preventing NLB in patients receiving treatment for erythema migrans.
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http://dx.doi.org/10.1016/j.diagmicrobio.2018.01.025DOI Listing
June 2018

Oral doxycycline versus intravenous ceftriaxone for treatment of multiple erythema migrans: an open-label alternate-treatment observational trial.

J Antimicrob Chemother 2018 05;73(5):1352-1358

Department of Infectious Diseases, University Medical Centre Ljubljana, Japljeva 2, 1525 Ljubljana, Slovenia.

Background: Several guidelines advocate the same treatment approaches for both early disseminated Lyme borreliosis, manifested as multiple erythema migrans (EM), and early localized Lyme borreliosis, manifested as solitary EM.

Methods: Oral doxycycline (100 mg q12h) was compared on a non-inferiority premise with intravenous ceftriaxone (2 g q24h) for 14 days in 200 adult European patients with multiple EM in an open-label alternate-treatment observational trial performed in a single-centre university hospital. Treatment outcome was assessed at 14 days and at 2, 6 and 12 months post-enrolment. Non-specific symptoms in patients and 192 control subjects without a history of Lyme borreliosis were evaluated and compared. This trial was registered at http://clinicaltrials.gov (identifier NCT01163994).

Results: At the 12 month visit, 4/82 (4.9%) multiple EM patients prescribed doxycycline and 6/88 (6.8%) multiple EM patients prescribed ceftriaxone showed incomplete response manifested predominantly as post-Lyme symptoms (1.9% difference, upper limit of 95% CI 5.1%). The upper limit of 95% CI for the difference in proportion of patients with incomplete response between doxycycline and ceftriaxone groups did not exceed the predetermined non-inferiority margin of 10%. The frequency of non-specific symptoms in patients was similar to that in controls.

Conclusions: The 14 day oral doxycycline was not inferior to the 14 day intravenous ceftriaxone in treatment of adult European patients with early disseminated Lyme borreliosis manifested as multiple EM. The frequency of non-specific symptoms in patients was similar to that in controls without a history of Lyme borreliosis.
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http://dx.doi.org/10.1093/jac/dkx534DOI Listing
May 2018

The long-term outcome of tick-borne encephalitis in Central Europe.

Ticks Tick Borne Dis 2018 02 6;9(2):369-378. Epub 2017 Dec 6.

Department of Infectious Diseases, University Medical Centre Ljubljana, Japljeva 2, 1525 Ljubljana, Slovenia.

Background: Information on the long-term outcome of tick-borne encephalitis (TBE) is limited.

Objectives: To assess the frequency and severity of post-encephalitic syndrome (PES) at different time points after TBE, and to determine the parameters associated with unfavourable outcome.

Methods: Adult patients diagnosed with TBE in Slovenia in the period 2007-2012 were followed-up for 12 months and also examined 2-7 years after TBE. Each patient was asked to refer a person of similar age without a history of TBE to serve as control.

Results: A total of 420 patients and 295 control persons participated in the study. The proportion of patients with PES (defined as the presence of ≥ 2 subjective symptoms that newly developed or worsened since the onset of TBE and which had no other known medical explanation, and/or ≥ 1 objective neurological sign) was higher (P < 0.001) at the follow-up visit 6 months after the acute illness (127/304, 42%, 95% CI: 36-47%) than at 12 months (68/207, 33%, 95% CI: 26-40%); the proportion at 12 months was the same as at 2-7 years after TBE (137/420, 33%, 95% CI: 28-37%). However, the proportion of severe PES at the last two time points differed (9.7% vs 4.3%, P = 0.008). Multivariate logistic regression showed that unfavourable outcome at 6 months was associated with CSF leukocyte count (OR = 1.003, 95% CI: 1.001-1.005%, P = 0.017), at 12 months with the disease outcome at 6 months (OR = 115.473, 95% CI: 26.009-512.667%, P < 0.001), and at the final visit with disease outcome at 6 months (OR = 3.808, 95% CI: 1.151-12.593%, P = 0.028) and 12 months (OR = 26.740, 95% CI: 8.648-82.680%, P < 0.001). Unspecific symptoms that occurred within the four weeks before the final examination were more frequent and more constant in patients than in the control group.

Conclusions: The frequency of PES diminished over time and stabilized 12 months after the acute illness, whereas the severity of PES continued to decline. Unfavourable outcomes at 12 months and at the final visit were strongly associated with the presence of PES at previous time points.
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http://dx.doi.org/10.1016/j.ttbdis.2017.12.001DOI Listing
February 2018

Should we consider faecal colonisation with extended-spectrum β-lactamase-producing Enterobacteriaceae in empirical therapy of community-onset sepsis?

Int J Antimicrob Agents 2017 Oct 12;50(4):564-571. Epub 2017 Jul 12.

Department of Infectious Diseases, University Medical Center Ljubljana, Japljeva 2, Ljubljana 1525, Slovenia. Electronic address:

In patients colonised with extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E), the preference for carbapenems (CRBs) over non-CRB antibiotics for empirical therapy of sepsis is questionable from an ecologic perspective. Moreover, how well colonisation predicts an ESBL-E aetiology of infection has been poorly investigated. The purpose of this retrospective observational study was to determine the positive predictive value (PPV) of ESBL-E faecal colonisation for ESBL-E sepsis aetiology and the impact of empirical therapy on treatment outcome. The study included 653 ESBL-E carriers with community-onset sepsis hospitalised at a single medical centre during a 5-year period. The PPV of ESBL-E colonisation for ESBL-E sepsis aetiology was significantly higher (62.6%) when sepsis originated from a urinary tract infection (UTI) than from a respiratory tract infection (24.5%), other known origins (27.1%) or an unidentified origin (21.4%). Among the 653 patients, 177 (27.1%) received CRBs empirically and 476 received non-CRBs, predominantly β-lactam/β-lactamase inhibitor combinations. Although univariate analysis suggested a higher 30-day mortality in the non-CRB versus CRB group (26.7% vs. 19.2%; OR = 1.53; P = 0.049), the estimated association was much smaller and was not significant (OR = 1.11, 95% CI 0.66-1.87; P = 0.68) in the multiple regression analysis adjusted for age, sex, Charlson comorbidity index, and severity, origin or aetiology of sepsis. The subgroup of 240 patients with unidentified sepsis aetiology also did not benefit from empirical CRB treatment. In non-critically ill ESBL-E carriers with community-onset sepsis, CRB-sparing empirical therapy seems appropriate, particularly if sepsis originates from a site other than a UTI.
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http://dx.doi.org/10.1016/j.ijantimicag.2017.06.019DOI Listing
October 2017

Comparison of MKP and BSK-H media for the cultivation and isolation of Borrelia burgdorferi sensu lato.

PLoS One 2017 7;12(2):e0171622. Epub 2017 Feb 7.

Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

The isolation of B. burgdorferi sensu lato requires the use of complex cultivation media. The aim of the study was to compare the usefulness of BSK-H (a commercial medium produced by HiMedia, India) and MKP medium. MKP and BSK-H media were prepared in accordance with the relevant protocols. Borrelia strains and skin culture biopsies were simultaneously inoculated into both media, incubated and checked for growth. Borrelial growth characteristics, isolation rates and characteristics of the isolated borreliae were analysed and compared. Initially, numbers of spirochaetes were higher in BSK-H than in MKP; however, in comparison with MKP, the strains subcultured in BSK-H medium were more frequently irregular, thin and non-motile, and rapidly died. In addition, the borrelial isolation rate from erythema migrans skin samples was higher in MKP than in BSK-H medium (108/171, 63.2% versus 70/171, 40.9%; p<0.0001). The far most frequently isolated species was Borrelia afzelii (92.9% and 97.2% strains isolated from BSK-H and MKP, respectively). Comparison of strains cultured from individual patients in both media showed differences in plasmid contents in 9/46 (19.6%) strain pairs, and protein profiles differed in 30/43 (69.8%) strain pairs, most often in the expression of OspC (in 27/28 patients OspC was expressed only in strains growing in MKP). BSK-H medium supports the growth of borrelial strains but MKP is superior with regard to the isolation rate, morphology and motility of strains. BSK-H medium supports fast initial growth of borreliae but this is followed by rapid deformation and death of the spirochaetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171622PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295711PMC
August 2017

Pathogenetic implications of the age at time of diagnosis and skin location for acrodermatitis chronica atrophicans.

Ticks Tick Borne Dis 2017 02 24;8(2):266-269. Epub 2016 Nov 24.

Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia. Electronic address:

Background: The pathogenesis of acrodermatitis chronica atrophicans (ACA) is not well understood.

Objective: The purpose of this study was to gain a better understanding of ACA by utilizing a large data set of adult Slovenian patients with Lyme borreliosis.

Methods: The age of 590 ACA patients was compared with that of patients with other manifestations of Lyme borreliosis. The location of the ACA lesion on the body was compared with that of erythema migrans (EM).

Results: Patients diagnosed with ACA were on average 14.3 years older than patients with EM (p<0.001). ACA patients were also significantly older than patients with Lyme neuroborreliosis or Lyme arthritis (p<0.001). The average delay in diagnosis of ACA was 1.6 years (range 0.1-20 years). For 572 (96.9%) of the ACA patients, the site of the skin lesion(s) was confined to an extremity vs. 79.6% for patients with EM, p<0.001. For the 20 ACA patients who reported a preceding untreated EM lesion at the same body site, the mean time between the development of the EM and the onset of ACA was 3.0±4.4 (median 1.3, range 0.1-15.0) years.

Conclusions: ACA is more likely to be diagnosed in older individuals than any other manifestation of Lyme borreliosis. ACA is more likely than EM to be localized anatomically to the extremities. Available data favor the hypothesis that ACA occurs most often on the extremities of older individuals because of predisposing age-related anatomic or physiologic changes, but more data are needed to define the latency period and other aspects of the pathogenesis of this skin condition.
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http://dx.doi.org/10.1016/j.ttbdis.2016.11.011DOI Listing
February 2017

Course and Outcome of Early European Lyme Neuroborreliosis (Bannwarth Syndrome): Clinical and Laboratory Findings.

Clin Infect Dis 2016 08 8;63(3):346-53. Epub 2016 May 8.

Department of Infectious Diseases, University Medical Center Ljubljana.

Background: Information on the course and outcome of early European Lyme neuroborreliosis is limited.

Methods: The study comprised 77 patients (38 males, 39 females; median age, 58 years) diagnosed with painful meningoradiculitis (Bannwarth syndrome) who were followed up for 1 year at a single center.

Results: Duration of neurological symptoms before diagnosis was 30 (interquartile range, 14-50) days. The most frequent symptoms/signs were radicular pain (100%), sleep disturbances (75.3%), erythema migrans (59.7%), headache (46.8%), fatigue (44.2%), malaise (39%), paresthesias (32.5%), peripheral facial palsy (PFP) (36.4%), meningeal signs (19.5%), and pareses (7.8%). Cerebrospinal fluid (CSF) analysis revealed lymphocytic/monocytic pleocytosis, elevated protein concentration, and intrathecal synthesis of borrelial immunoglobulin M and immunoglobulin G antibody in 100%, 81.1%, 63%, and 88.7% of patients, respectively. Borreliae (predominantly Borrelia garinii) were isolated from CSF, skin, and blood in 15.6%, 40.6%, and 2.7% of patients, respectively. The outcome after 14-day treatment with ceftriaxone was favorable in 87.8% of patients. Control CSF examination at 3 months showed decreased leukocyte counts in all patients; however, 23.3% still had pleocytosis (>10 × 10(6) cells/L). A model based on pretreatment data and the findings at the end of 14-day antibiotic treatment accurately predicted which patients would have an unfavorable outcome 6 or 12 months after treatment.

Conclusions: Our patients had fewer pretreatment neurological complications (PFP, pareses) than reported for Bannwarth syndrome decades ago, probably as the result of earlier recognition and prompt antibiotic treatment. Unfavorable outcome was rare and was predicted by the continued presence of symptoms 14 days after commencement of treatment.
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http://dx.doi.org/10.1093/cid/ciw299DOI Listing
August 2016

Differences in Genotype, Clinical Features, and Inflammatory Potential of Borrelia burgdorferi sensu stricto Strains from Europe and the United States.

Emerg Infect Dis 2016 May;22(5):818-27

Borrelia burgdorferi sensu stricto isolates from patients with erythema migrans in Europe and the United States were compared by genotype, clinical features of infection, and inflammatory potential. Analysis of outer surface protein C and multilocus sequence typing showed that strains from these 2 regions represent distinct genotypes. Clinical features of infection with B. burgdorferi in Slovenia were similar to infection with B. afzelii or B. garinii, the other 2 Borrelia spp. that cause disease in Europe, whereas B. burgdorferi strains from the United States were associated with more severe disease. Moreover, B. burgdorferi strains from the United States induced peripheral blood mononuclear cells to secrete higher levels of cytokines and chemokines associated with innate and Th1-adaptive immune responses, whereas strains from Europe induced greater Th17-associated responses. Thus, strains of the same B. burgdorferi species from Europe and the United States represent distinct clonal lineages that vary in virulence and inflammatory potential.
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http://dx.doi.org/10.3201/eid2205.151806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861522PMC
May 2016

Correlation of Culture Positivity, PCR Positivity, and Burden of Borrelia burgdorferi Sensu Lato in Skin Samples of Erythema Migrans Patients with Clinical Findings.

PLoS One 2015 9;10(9):e0136600. Epub 2015 Sep 9.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Background: Limited data are available regarding the relationship of Borrelia burden in skin of patients with erythema migrans (EM) and the disease course and post-treatment outcome.

Methods: We studied 121 adult patients with EM in whom skin biopsy specimens were cultured and analyzed by quantitative PCR for the presence of Borreliae. Evaluation of clinical and microbiological findings were conducted at the baseline visit, and 14 days, 2, 6, and 12 months after treatment with either amoxicillin or cefuroxime axetil.

Results: In 94/121 (77.7%) patients Borrelia was detected in skin samples by PCR testing and 65/118 (55.1%) patients had positive skin culture result (96.8% B. afzelii, 3.2% B. garinii). Borrelia culture and PCR results correlated significantly with the presence of central clearing and EM size, while Borrelia burden correlated significantly with central clearing, EM size, and presence of newly developed or worsened symptoms since EM onset, with no other known medical explanation (new or increased symptoms, NOIS). In addition, the logistic regression model for repeated measurements adjusted for time from inclusion, indicated higher Borrelia burden was a risk factor for incomplete response (defined as NOIS and/or persistence of EM beyond 14 days and/or occurrence of new objective signs of Lyme borreliosis). The estimated association between PCR positivity and unfavorable outcome was large but not statistically significant, while no corresponding relationship was observed for culture positivity.

Conclusions: Higher Borrelia burden in EM skin samples was associated with more frequent central clearing and larger EM lesions at presentation, and with a higher chance of incomplete response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136600PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564201PMC
May 2016

medplot: a web application for dynamic summary and analysis of longitudinal medical data based on R.

PLoS One 2015 2;10(4):e0121760. Epub 2015 Apr 2.

Institute for Biostatistics and Medical Informatics, University of Ljubljana, Slovenia.

In biomedical studies the patients are often evaluated numerous times and a large number of variables are recorded at each time-point. Data entry and manipulation of longitudinal data can be performed using spreadsheet programs, which usually include some data plotting and analysis capabilities and are straightforward to use, but are not designed for the analyses of complex longitudinal data. Specialized statistical software offers more flexibility and capabilities, but first time users with biomedical background often find its use difficult. We developed medplot, an interactive web application that simplifies the exploration and analysis of longitudinal data. The application can be used to summarize, visualize and analyze data by researchers that are not familiar with statistical programs and whose knowledge of statistics is limited. The summary tools produce publication-ready tables and graphs. The analysis tools include features that are seldom available in spreadsheet software, such as correction for multiple testing, repeated measurement analyses and flexible non-linear modeling of the association of the numerical variables with the outcome. medplot is freely available and open source, it has an intuitive graphical user interface (GUI), it is accessible via the Internet and can be used within a web browser, without the need for installing and maintaining programs locally on the user's computer. This paper describes the application and gives detailed examples describing how to use the application on real data from a clinical study including patients with early Lyme borreliosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121760PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383594PMC
March 2016

Tick borne encephalitis without cerebrospinal fluid pleocytosis.

BMC Infect Dis 2014 Nov 18;14:614. Epub 2014 Nov 18.

Institute of Pathophysiology, Faculty of Medicine Ljubljana, Zaloška 4, 2211, Ljubljana, Slovenia.

Background: Tick borne encephalitis is the most frequent vector-transmitted infectious disease of the central nervous system in Europe and Asia. The disease caused by European subtype of tick borne encephalitis virus has typically a biphasic clinical course with the second phase presenting as meningitis, meningoencephalitis, or meningoencephalomyelitis. Cerebrospinal fluid pleocytosis is considered a condition sine qua non for the diagnosis of neurologic involvement in tick borne encephalitis, which in routine clinical practice is confirmed by demonstration of serum IgM and IgG antibodies to tick borne encephalitis virus.

Case Presentation: Here we present a patient from Slovenia, an area highly endemic for tick borne encephalitis, with encephalitis but without cerebrospinal fluid pleocytosis in whom tick borne encephalitis virus infection of the central nervous system was demonstrated.

Conclusion: Cerebrospinal fluid pleocytosis is not mandatory in encephalitis caused by tick borne encephalitis virus. In daily clinical practice, in patients with neurologic symptoms/signs compatible with tick borne encephalitis and the risk of exposure to ticks in a tick borne encephalitis endemic region, the search for central nervous system infection with tick borne encephalitis virus is warranted despite the lack of cerebrospinal fluid pleocytosis.
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http://dx.doi.org/10.1186/s12879-014-0614-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240899PMC
November 2014

Are patients with erythema migrans who have leukopenia and/or thrombocytopenia coinfected with Anaplasma phagocytophilum or tick-borne encephalitis virus?

PLoS One 2014 24;9(7):e103188. Epub 2014 Jul 24.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA) are endemic in central part of Slovenia. We tested the hypothesis that patients with erythema migrans (EM) from this region, who have leukopenia and/or thrombocytopenia (typical findings in HGA and in the initial phase of TBE but not in patients with LB) are coinfected with Anaplasma phagocytophilum and/or with TBE virus, i.e. that cytopenia is a result of concomitant HGA or the initial phase of TBE. Comparison of clinical and laboratory findings for 67 patients with EM who disclosed leukopenia/thrombocytopenia with the corresponding results in sex- and age-matched patients with EM and normal blood cell counts revealed no differences. In addition, patients with typical EM and leukopenia and/or thrombocytopenia tested negative for the presence of IgM and IgG antibodies to TBE virus by ELISA as well as for the presence of specific IgG antibodies to A. phagocytophilum antigens by IFA in acute and convalescent serum samples. Thus, none of 67 patients (95% CI: 0 to 5.3%) with typical EM (the presence of this skin lesion attests for early Lyme borreliosis and is the evidence for a recent tick bite) was found to be coinfected with A. phagocytophilum or had a recent primary infection with TBE virus. The findings in the present study indicate that in Slovenia, and probably in other European countries endemic for LB, TBE and HGA, patients with early LB are rarely coinfected with the other tick-transmitted agents.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103188PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110002PMC
January 2016

Reply to Seligman et Al.

Clin Infect Dis 2014 Sep 7;59(5):747-8. Epub 2014 May 7.

Department of Infectious Diseases, University Medical Center Ljubljana, Slovenia.

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http://dx.doi.org/10.1093/cid/ciu343DOI Listing
September 2014

Reply to Parvu and Parvu.

Clin Infect Dis 2014 Apr 26;58(8):1200. Epub 2014 Jan 26.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston.

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http://dx.doi.org/10.1093/cid/ciu062DOI Listing
April 2014

Clinical characteristics associated with Borrelia burgdorferi sensu lato skin culture results in patients with erythema migrans.

PLoS One 2013 26;8(12):e82132. Epub 2013 Dec 26.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Clinical characteristics associated with isolation of Borrelia burgdorferi sensu lato from skin have not been fully evaluated. To gain insight into predictors for a positive EM skin culture, we compared basic demographic, epidemiologic, and clinical data in 608 culture-proven and 501 culture-negative adult patients with solitary EM. A positive Borrelia spp. skin culture was associated with older age, a time interval of >2 days between tick bite and onset of the skin lesion, EM ≥ 5 cm in diameter, and location of the lesion on the extremities, whereas several other characteristics used as clinical case definition criteria for the diagnosis of EM (such as tick bite at the site of later EM, information on expansion of the skin lesion, central clearing) were not. A patient with a 15-cm EM lesion had almost 3-fold greater odds for a positive skin culture than patients with a 5-cm lesion. Patients with a free time interval between the tick bite and onset of EM had the same probability of a positive skin culture as those who did not recall a tick bite (OR=1.02); however, the two groups had >3-fold greater odds for EM positivity than patients who reported a tick bite with no interval between the bite and onset of the lesion. In conclusion, several yet not all clinical characteristics used in EM case definitions were associated with positive Borrelia spp. skin culture. The findings are limited to European patients with solitary EM caused predominantly by B. afzelii but may not be valid for other situations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082132PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873257PMC
September 2014

Elevated levels of IL-23 in a subset of patients with post-lyme disease symptoms following erythema migrans.

Clin Infect Dis 2014 Feb 11;58(3):372-80. Epub 2013 Nov 11.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston.

Background: The causes of post-Lyme disease symptoms are unclear. Herein, we investigated whether specific immune responses were correlated with such symptoms.

Methods: The levels of 23 cytokines and chemokines, representative of innate and adaptive immune responses, were assessed in sera from 86 antibiotic-treated European patients with erythema migrans, 45 with post-Lyme symptoms and 41 without symptoms, who were evaluated prior to treatment and 2, 6, and 12 months thereafter.

Results: At study entry, significant differences between groups were observed for the type 1 helper T cell (TH1)-associated chemokines CXCL9 and CXCL10, which were associated with negative Borrelia cultures, and the type 17 helper T cell (TH17)-associated cytokine interleukin 23 (IL-23), which was associated with positive cultures and the development of post-Lyme symptoms (P ≤ .02). Moreover, of the 41 patients with detectable IL-23 levels, 25 (61%) developed post-Lyme symptoms, and all 7 with IL-23 levels ≥ 230 ng/mL had such symptoms. Furthermore, antibody responses to the ECGF autoantigen were more common in patients with post-Lyme symptoms (P = .07) and were correlated directly with IL-23 levels (P = .02). Despite the presence of post-Lyme symptoms, all posttreatment culture results were negative, antiborrelial antibody responses declined, and there were no objective signs of disseminated disease, suggesting that spirochetal eradication had occurred with treatment in all patients.

Conclusions: High TH1-associated responses correlated with more effective immune-mediated spirochetal killing, whereas high TH17-associated immune responses, often accompanied by autoantibodies, correlated with post-Lyme symptoms, providing a new paradigm for the study of postinfectious symptoms in a subset of patients with Lyme disease.
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http://dx.doi.org/10.1093/cid/cit735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890340PMC
February 2014

Gender disparity between cutaneous and non-cutaneous manifestations of Lyme borreliosis.

PLoS One 2013 30;8(5):e64110. Epub 2013 May 30.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Cutaneous manifestations of Lyme borreliosis in Europe include erythema migrans (EM) and acrodermatitis chronica atrophicans (ACA); the most common non-cutaneous manifestations are Lyme neuroborreliosis (LNB) and Lyme arthritis. The purpose of this study was to evaluate the gender distribution of patients with these clinical manifestations of Lyme borreliosis. Data on gender were obtained from the clinical records of patients with Lyme borreliosis aged ≥15 years who had been evaluated at the University Medical Center Ljubljana, Ljubljana, Slovenia. Among 10,539 patients diagnosed with EM, 6,245 (59.3%) were female and among 506 ACA patients 347 (68.6%) were female. In contrast, among the 60 patients with Lyme arthritis only 15 (25%) were female (p<0.0001 for the comparison of gender with EM or ACA) and among the 130 patients with LNB only 51 (39.2%) were females (p<0.0001for the comparison of gender with EM or ACA). Although the proportion that was female in the LNB group was greater than that of patients with Lyme arthritis, this difference did not reach statistical significance (p = 0.10). Although older individuals are more likely to be female in the general Slovenian population, the age of patients with cutaneous versus non-cutaneous manifestations was not the explanation for the observed differences in gender. In conclusion, patients with cutaneous manifestations of Lyme borreliosis were predominantly female, whereas those with non-cutaneous manifestations were predominantly male. This provocative finding is unexplained but may have direct relevance to the pathogenesis of Lyme borreliosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064110PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667797PMC
January 2014

Quantitative detection of Borrelia burgdorferi sensu lato in erythema migrans skin lesions using internally controlled duplex real time PCR.

PLoS One 2013 16;8(5):e63968. Epub 2013 May 16.

Vaccine R&D, Baxter Bioscience, Orth/Donau, Austria.

B. burgdorferi sensu stricto, B. afzelii, B. garinii and B. bavariensis are the principal species which account for Lyme borreliosis (LB) globally. We have developed an internally controlled duplex quantitative real time PCR assay targeting the Borrelia 16S rRNA and the human RNAseP genes. This assay is well-suited for laboratory confirmation of suspected cases of LB and will be used to assess the efficacy of a vaccine against LB in clinical trials. The assay is highly specific, successfully detecting DNA extracted from 83 diverse B. burgdorferi sensu lato strains representing all major species causing LB, while 21 unrelated microbial species and human genomic DNA tested negative. The assay was highly reproducible and sensitive, with a lower limit of detection of 6 copies per PCR reaction. Together with culture, the assay was used to evaluate paired 3 mm skin biopsy samples taken from 121 patients presenting with solitary erythema migrans (EM) lesion. PCR testing identified more positive biopsy samples than culture (77.7% PCR positive versus 55.1% culture positive) and correctly identified all specimens scored as culture positive. OspA-based typing identified the majority of isolates as B. afzelii (96.8%) and the bacterial load was significantly higher in culture positive biopsies than in culture negative biopsies (P<0.001). The quantitative data also enabled relationships between Borrelia burden and patient symptoms to be evaluated. The bacterial load was significantly higher among patients with systemic symptoms than without (P = 0.02) and was significantly higher for biopsies retrieved from patients with EM lesions with central clearing (P<0.001). 16S copy numbers were moderately lower in samples from patients reporting a history of LB (P = 0.10). This is the first quantitative PCR study of human skin biopsies predominantly infected with B. afzelii and the first study to demonstrate a clear relationship between clinical symptoms in B. afzelii-infected patients and Borrelia burden.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655952PMC
December 2013

Treatment of erythema migrans with doxycycline for 10 days versus 15 days.

Clin Infect Dis 2012 Aug 20;55(3):343-50. Epub 2012 Apr 20.

Department of Infectious Diseases, University Medical Center Ljubljana, Slovenia.

Background: The efficacy of 10-day doxycycline treatment in patients with erythema migrans has been assessed in the United States but not in Europe. Experts disagree on the significance of post-Lyme borreliosis symptoms.

Methods: In a noninferiority trial, the efficacies of 10 days and 15 days of oral doxycycline therapy were evaluated in adult European patients with erythema migrans. The prevalence of nonspecific symptoms was compared between patients with erythema migrans and 81 control subjects without a history of Lyme borreliosis. The efficacy of treatment, determined on the basis of clinical observations and microbiologic tests, was assessed at 14 days and at 2, 6, and 12 months. Nonspecific symptoms in patients and controls were compared at 6 months after enrollment.

Results: A total of 117 patients (52%) were treated with doxycycline for 15 days, and 108 (48%) received doxycycline for 10 days. Twelve months after enrollment, 85 of 91 patients (93.4%) in the 15-day group and 79 of 86 (91.9%) in the 10-day group had complete response (difference, 1.6 percentage points; upper limit of the 95% confidence interval, 9.1 percentage points). At 6 months, the frequency of nonspecific symptoms in the patients was similar to that among controls.

Conclusions: The 10-day regimen of oral doxycycline was not inferior to the 15-day regimen among adult European patients with solitary erythema migrans. Six months after treatment, the frequency of nonspecific symptoms among erythema migrans patients was similar to that among control subjects.

Clinical Trials Registration: NCT00910715.
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http://dx.doi.org/10.1093/cid/cis402DOI Listing
August 2012

Comparison of erythema migrans caused by Borrelia burgdorferi and Borrelia garinii.

Vector Borne Zoonotic Dis 2011 Sep 25;11(9):1253-8. Epub 2011 May 25.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Background: A comparison of patients with erythema migrans due to Borrelia garinii versus Borrelia burgdorferi has not been reported.

Patients And Methods: One hundred nineteen patients from New York State with erythema migrans caused by B. burgdorferi were compared with 116 patients from Slovenia with erythema migrans due to B. garinii infection.

Results: Patients with B. garinii infection were older, more often reported a tick bite, and developed larger lesions (median largest diameter: 18 and 14  cm, respectively; p = 0.01) that more often had central clearing (61.2% compared with 35.3%; p < 0.0001). Patients infected with B. burgdorferi, however, more often had systemic symptoms (68.9% vs. 37.1%; p < 0.0001), including fatigue (p < 0.0001), arthralgia (p = 0.0003), myalgia (p < 0.0001), headache (p = 0.0008), fever and/or chills (p < 0.0001), and stiff neck (p < 0.0001), and more often had abnormal physical findings (57.1% compared with 11.2%; p < 0.0001), such as fever (p = 0.0002) or regional lymphadenopathy (p < 0.0001). There was a trend for more patients with B. burgdorferi infection to have multiple erythema migrans skin lesions (13.4% compared with 5.2%; p = 0.051), and among patients with multiple erythema migrans the number of lesions was greater in B. burgdorferi-infected patients (median: 5.5 compared with 2.0; p = 0.006).

Conclusions: The results of the present study indicate that in patients with erythema migrans the clinical features vary according to whether infection is caused by B. garinii or B. burgdorferi.
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http://dx.doi.org/10.1089/vbz.2010.0230DOI Listing
September 2011

Comparison of post-Lyme Borreliosis symptoms in erythema migrans patients with positive and negative Borrelia burgdorferi sensu lato skin culture.

Vector Borne Zoonotic Dis 2011 Jul 17;11(7):883-9. Epub 2010 Nov 17.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.

Purpose: Limited data exist on differences of erythema migrans patients with either positive or negative Borrelia burgdorferi sensu lato skin culture.

Methods: We analyzed 252 adult patients with erythema migrans in whom skin biopsy specimen was cultured for the presence of B. burgdorferi sensu lato. Evaluations of epidemiological, clinical, and microbiological findings were conducted at baseline, 14 days, 2, 6, and 12 months after treatment with either doxycycline or cefuroxime axetil.

Results: One hundred fifty-one (59.9%) patients had positive skin culture (86.9% B. afzelii, 8.0% B. garinii, 5.1% B. burgdorferi sensu stricto) and 101 (40.1%) had negative skin culture. Patients in the culture-positive and culture-negative groups were comparable for the basic demographic, epidemiological, clinical, and laboratory characteristics at presentation. Statistically significantly worse selected treatment outcome parameters in the culture-positive group compared with the culture-negative group were established during follow-up. Treatment failure was documented in two patients who were culture positive and in none in the culture-negative group.

Conclusions: Although findings for the pretreatment characteristics were comparable between the erythema migrans skin culture-positive and culture-negative patients, some parameters indicate that borrelia skin culture positivity may predict a less-favorable treatment outcome.
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http://dx.doi.org/10.1089/vbz.2010.0018DOI Listing
July 2011
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