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.

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 × 106 /L vs. 11 × 106 /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.

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

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.

Doxycycline-induced photosensitivity in patients treated for erythema migrans.

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.

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

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.

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

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.

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

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.

Tick borne encephalitis without cerebrospinal fluid pleocytosis.

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.

SARS-CoV-2 Vaccination and Clinical Presentation of COVID-19 in Patients Hospitalized during the Delta- and Omicron-Predominant Periods.

Evidence suggests that monovalent vaccine formulations are less effective against the Omicron SARS-CoV-2 than against previous variants. In this retrospective cohort study of hospitalized adults with PCR-confirmed COVID-19 during the Delta (October-November 2021) and Omicron (January-April 2022) variant predominant periods in Slovenia, we assessed the association between primary vaccination against SARS-CoV-2 and progression to critically severe disease (mechanical ventilation or death). Compared with the 529 patients hospitalized for acute COVID-19 during the Delta period (median age 65 years; 58.4% men), the 407 patients hospitalized during the Omicron period (median age 75 years; 50.6% men) were older, more often resided in long-term care facilities, and had higher Charlson comorbidity index scores. After adjusting for age, sex, the Charlson comorbidity index, the presence of immunocompromising conditions, and vaccination status, the patients admitted during the Omicron period had comparable odds of progressing to critically severe disease to those admitted during the Delta period. The 334/936 (35.7%) patients completing at least primary vaccination had lower odds of progression to critically severe disease and shorter hospital stay than unvaccinated patients; however, the protective effect of vaccination was less pronounced during the Omicron than during the Delta period. Although the Omicron variant appeared to better evade immunity induced by monovalent vaccines than the Delta variant, vaccination against SARS-CoV-2 remained an effective intervention to decrease morbidity and mortality in COVID-19 patients infected with the Omicron variant.

Treatment of erythema migrans with doxycycline for 7 days versus 14 days in Slovenia: a randomised open-label non-inferiority trial.

BACKGROUND: Lyme borreliosis is the most prevalent vector-borne disease in Europe and the USA. Doxycycline for 10 days is the primary treatment recommendation for erythema migrans. To reduce potentially harmful antibiotic overuse by identifying shorter effective treatments, we aimed to assess whether oral doxycycline for 7 days is non-inferior to 14 days in adults with solitary erythema migrans. METHODS: In this randomised open-label non-inferiority trial, we enrolled patients with a solitary erythema at the University Medical Centre in Ljubljana, Slovenia. Patients were excluded if they were pregnant or lactating, immunosuppressed, allergic to doxycycline, or had received antibiotics with anti-borrelial activity within 10 days preceding enrolment or had additional manifestations of Lyme borreliosis Adults were randomly allocated 1:1 to receive oral doxycycline 100 mg twice a day for 7 days or 14 days. The primary efficacy endpoint was the difference in proportion of patients with treatment failure, defined as persistent erythema, new objective signs of Lyme borreliosis, or borrelial isolation on skin re-biopsy at 2 months, in a per-protocol analysis (the population that completed the assigned doxycycline regimen according to the study protocol and did not receive any other antibiotics with anti-borrelial activity until the 2-month visit). The non-inferiority margin was 6 percentage points. Safety was assessed in all randomly assigned patients who followed the study protocol and were evaluable at the 14-day visit. This study is registered with ClinicalTrials.gov, NCT03153267. FINDINGS: Between July 3, 2017, and Oct 2, 2018, we enrolled 300 patients (150 per group: median age 56 years [IQR 47-65]; 126 [45%] of 300 male; skin culture positive 72 [30%] of 239 assessed). 295 patients completed antibiotic therapy as per protocol and 294 (98%) patients were evaluable 2 months post-enrolment. Five (3%) of 147 patients from the 7-day group versus 3 (2%) of 147 patients from the 14-day group (one patient did not attend the 2-month visit and was unreachable by telephone) had treatment failure manifesting as persistence of erythema (difference 1·4 percentage points; upper limit of one-sided 95% CI 5·2 percentage points; p=0·64). No patients developed new objective manifestations of Lyme borreliosis during follow-up or had positive repeat skin biopsies. Two (1%) of 150 patients in the 7-day and one (1%) of 150 patients in the 14-day group discontinued therapy due to adverse events. INTERPRETATION: Our data support 7 days of oral doxycycline for adult European patients with solitary erythema migrans, permitting less antibiotic exposure than current guideline-driven therapy. FUNDING: Slovenian Research Agency and the University Medical Centre Ljubljana.

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

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.

The Impact of SARS-CoV-2 Primary Vaccination in a Cohort of Patients Hospitalized for Acute COVID-19 during Delta Variant Predominance.

Vaccine breakthrough SARS-CoV-2 infections necessitating hospitalization have emerged as a relevant problem with longer time interval since vaccination and the predominance of the Delta variant. The aim of this study was to evaluate the association between primary vaccination with four SARS-CoV-2 vaccines authorized for use in the European Union-BNT162b2, ChAdOx-1S, mRNA-1273 or Ad.26.COV2.S-and progression to critically severe disease (mechanical ventilation or death) and duration of hospitalization among adult patients with PCR-confirmed acute COVID-19 hospitalized during the Delta variant predominance (October-November 2021) in Slovenia. Among the 529 enrolled patients hospitalized with COVID-19 (median age, 65 years; 58.2% men), 175 (33.1%) were fully vaccinated at the time of symptom onset. Compared with 345 unvaccinated patients, fully vaccinated patients with breakthrough infections were older, more often immunocompromised, and had higher Charlson comorbidity index scores. After adjusting for sex, age, and comorbidities, fully vaccinated patients had lower odds for progressing to critically severe disease and were discharged from the hospital earlier than unvaccinated patients. Vaccination against SARS-CoV-2 remains an extremely effective intervention to alleviate morbidity and mortality in COVID-19 patients.

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

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.

Association between statin use and clinical course, microbiologic characteristics, and long-term outcome of early Lyme borreliosis. A post hoc analysis of prospective clinical trials of adult patients with erythema migrans.

BACKGROUND: Statins were shown to inhibit borrelial growth in vitro and promote clearance of spirochetes in a murine model of Lyme borreliosis (LB). We investigated the impact of statin use in patients with early LB. METHODS: In this post-hoc analysis, the association between statin use and clinical and microbiologic characteristics was investigated in 1520 adult patients with early LB manifesting as erythema migrans (EM), enrolled prospectively in several clinical trials between June 2006 and October 2019 at a single-center university hospital. Patients were assessed at enrollment and followed for 12 months. RESULTS: Statin users were older than patients not using statins, but statin use was not associated with Borrelia seropositivity rate, Borrelia skin culture positivity rate, or disease severity as assessed by erythema size or the presence of LB-associated symptoms. The time to resolution of EM was comparable in both groups. The odds for incomplete recovery decreased with time from enrollment, were higher in women, in patients with multiple EM, and in those reporting LB-associated symptoms at enrollment, but were unaffected by statin use. CONCLUSION: Statin use was not associated with clinical and microbiologic characteristics or long-term outcome in early LB.

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

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; P = .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.

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

In this retrospective cohort study of patients with tick-borne encephalitis (TBE), the clinical outcome in relation to co-infection with B. burgdorferi 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; p = 0.670) or possible co-infection (OR 0.95, 95% CI 0.55-1.65; p = 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; p = 0.630), suggesting that routine antibiotic treatment in patients with TBE and possible co-infection may not be warranted.