Assessment of three criteria to establish borrelial infection in suspected lyme neuroborreliosis.

PURPOSE: Diagnosis of (European) Lyme neuroborreliosis has been based on clinical presentation, cerebrospinal fluid (CSF) pleocytosis and demonstration of intrathecal borrelial antibody synthesis (ITBAS) to document Borrelia burgdorferi s. l. INFECTION: It is not known if other criteria to document Borrelia infection may contribute to the diagnosis. METHODS: We compared the sensitivity of three individual criteria (ITBAS, CSF Borrelia culture, and the presence of erythema migrans [EM]) to confirm the diagnosis of early Lyme neuroborreliosis in 280 patients ≥ 15 years of age evaluated at a Lyme borreliosis outpatient clinic in Slovenia. The patients had either radicular pain of new onset or involvement of a cranial nerve but without radicular pain, each in conjunction with CSF pleocytosis. Evaluation was of patients who had each of the three confirmatory criteria assessed, and for whom at least one criterion was positive. RESULTS: Analysis of 280 patients, 120 women and 160 men, median age 57 (range 15-84) years, revealed that ITBAS was the most frequently observed positive criterion (85.4%), followed by EM (52.9%), and by a positive CSF Borrelia culture (9.6%). Of the 280 patients, 154 (55%) met only one criterion (43.2% ITBAS only, 10.7% EM only, and 1.1% positive CSF culture only), whereas 42.1% met two criteria. Only 2.9% of patients were positive by all three criteria. CONCLUSION: Although ITBAS was the most frequent criterion for confirmation for Borrelia infection, the presence of EM alone confirmed an additional 10.7% of patients and a positive CSF Borrelia culture alone added another 1.1%.

Erythema Migrans in Patients with Post-Traumatic Splenectomy.

Information on asplenic Lyme borreliosis (LB) patients with erythema migrans (EM) is lacking. We compared the course and outcome of 26 EM episodes in 24 post-trauma splenectomized patients (median age 51 years) diagnosed at a single clinical center in Slovenia during 1994-2023 with those of 52 age- and sex-matched patients with EM but with no history of splenectomy. All patients were followed for one year. A comparison of pre-treatment characteristics revealed that EM in splenectomized patients was of shorter duration before diagnosis (4 vs. 8 days, p = 0.034) with a smaller EM diameter (10.5 vs. 14 cm, p = 0.046), and more frequently fulfilled criteria for disseminated LB (3/26, 11.5% vs. 0%, p = 0.034). Treatment failure occurred in 5/26 (19.2%) EM episodes in splenectomized patients versus 0/52 in non-splenectomized patients (p = 0.003). The five treatment failure cases were retreated with antibiotic regimens used to treat EM and had complete resolution of all symptoms/signs. In conclusion, our study showed that splenectomized adult patients with EM differ somewhat in presentation and more often have treatment failure compared with non-splenectomized patients with EM.

Genetic variability in the glucocorticoid pathway and treatment outcomes in hospitalized patients with COVID-19: a pilot study.

Introduction: Corticosteroids are widely used for the treatment of coronavirus disease (COVID)-19. Genetic polymorphisms of the glucocorticoid receptor, metabolizing enzymes, or transporters may affect treatment response to dexamethasone. This study aimed to evaluate the association of the glucocorticoid pathway polymorphisms with the treatment response and short-term outcomes in patients with severe COVID-19. Methods: Our pilot study included 107 hospitalized patients with COVID-19 treated with dexamethasone and/or methylprednisolone, genotyped for 14 polymorphisms in the glucocorticoid pathway. Results: In total, 83% of patients had severe disease, 15.1% had critical disease and only 1.9% had moderate disease. CYP3A4 rs35599367 was the major genetic determinant of COVID-19 severity as carriers of this polymorphism had higher risk of critical disease (OR = 6.538; 95% confidence interval = 1.19-35.914: p = 0.031) and needed intensive care unit treatment more frequently (OR = 10; 95% CI = 1.754-57.021: p = 0.01). This polymorphism was also associated with worse disease outcomes, as those patients had to switch from dexamethasone to methylprednisolone more often (OR = 6.609; 95% CI = 1.137-38.424: p = 0.036), had longer hospitalization (p = 0.022) and needed longer oxygen supplementation (p = 0.040). Carriers of NR3C1 rs6198 polymorphic allele required shorter dexamethasone treatment (p = 0.043), but had higher odds for switching therapy with methylprednisolone (OR = 2.711; 95% CI = 1.018-7.22: p = 0.046). Furthermore, rs6198 was also associated with longer duration of hospitalization (p = 0.001) and longer oxygen supplementation (p = 0.001). NR3C1 rs33388 polymorphic allele was associated with shorter hospitalization (p = 0.025) and lower odds for ICU treatment (OR = 0.144; 95% CI = 0.027-0.769: p = 0.023). GSTP1 rs1695 was associated with duration of hospitalization (p = 0.015), oxygen supplementation and (p = 0.047) dexamethasone treatment (p = 0.022). Conclusion: Our pathway-based approach enabled us to identify novel candidate polymorphisms that can be used as predictive biomarkers associated with response to glucocorticoid treatment in COVID-19. This could contribute to the patient's stratification and personalized treatment approach.

Microbiologic Findings in a Cohort of Patients with Erythema Migrans.

Erythema migrans (EM) is the initial and the most frequent clinical manifestation of Lyme borreliosis (LB). Herein, we report on the capacity of culture and serology for the demonstration of Borrelia infection in a cohort of 292 patients diagnosed with typical EM at a single medical center. The median duration of EM at diagnosis was 12 days, and the largest diameter was 16 cm; 252 (86.3%) patients presented with solitary EM, whereas 40 (13.7%) had multiple EM. A total of 95/292 (32.5%) patients had positive IgM, and 169 (57.9%) had positive IgG serum antibodies; the Borrelia isolation rate was 182/292 (62.3%). The most frequent species by far was B. afzelii (142/148, 95.9%) while B. garinii (2.7%) and B. burgdorferi s.s. (1.4%) were rare. IgM seropositivity was associated with a younger age, multiple EM and the absence of underlying chronic illness; IgG seropositivity was associated with the duration of EM at diagnosis, the diameter of the EM, having had a previous episode of LB and the absence of symptoms at the site of the EM. Furthermore, the Borrelia isolation rate was statistically significantly lower in patients with positive Borrelia IgM antibodies. Although microbiologic analyses are not needed for the diagnosis of typical EM, they enable insights into the etiology and dynamics of the immune response in the course of early LB.

Elevated levels of serum muscle enzymes in the initial phase of tick-borne encephalitis.

PURPOSE: Since some patients with tick-borne encephalitis (TBE) have pronounced myalgias, and since myositis is reported in Flavivirus diseases such as dengue, we performed systematic search for abnormalities of muscle enzymes in a group of patients in whom the presence of tick-borne encephalitis virus (TBEV) RNA in the first phase of the disease was demonstrated and who developed second phase of TBE. METHODS: Total leukocyte and platelet blood counts were determined routinely at the initial examination during the first and the second phase of TBE. Activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), myoglobin and troponin was determined from the available stored serum specimens; the first and second phase disease specimens were tested simultaneously. RESULTS: Of 24 patients with biphasic course of TBE, 83% had leukopenia, 65% thrombocytopenia, 83% elevated AST and 4% elevated ALT level. Furthermore, 33% had elevated serum CK, 26% myoglobin and 22% troponin activity; at least one of the muscle enzymes was elevated in 42% of patients. Leukopenia, thrombocytopenia, elevated liver enzymes and elevations of CK and myoglobin were present in the initial phase but resolve later, while troponin abnormalities were also found in the second phase of TBE. CONCLUSIONS: The present study exposes that in addition to previously known leukopenia, thrombocytopenia and increased liver enzymes activity, the initial phase of TBE is relatively often associated also with elevated muscle enzymes. Clinical relevance of these findings remains to be determined.

Why Is the Duration of Erythema Migrans at Diagnosis Longer in Patients with Lyme Neuroborreliosis Than in Those without Neurologic Involvement?

In prior studies, the skin lesion erythema migrans (EM) was present for a longer time period before diagnosis of concomitant borrelial meningoradiculoneuritis (Bannwarth's syndrome) compared to EM patients without neurologic symptoms. To determine if this observation pertains to other manifestations of Lyme neuroborreliosis (LNB), we compared EM characteristics in patients with borrelial meningoradiculoneuritis (n = 122) to those with aseptic meningitis without radicular pain (n = 72 patients), and to patients with EM but without neurologic involvement (n = 12,384). We also assessed factors that might impact duration. We found that the duration of EM at diagnosis in patients with borrelial meningoradiculoneuritis was not significantly different compared with those with LNB without radicular pain (34 vs. 26 days; p = 0.227). The duration of EM for each of these clinical presentations of LNB, however, was significantly longer than in patients with EM without LNB (10 days; p < 0.001). Contributing factors to this difference might have been that patients with LNB failed to recognize that they had EM or were unaware of the importance of not delaying antibiotic treatment for EM. In conclusion, the duration of the EM skin lesion in EM patients with LNB is longer than in patients with just EM, irrespective of the type of LNB.

Poor virus-specific T-cell responses early after tick-borne encephalitis virus infection correlate with disease severity.

Tick-borne encephalitis virus (TBEV) infection may cause acute central nervous system inflammation varying in clinical manifestations and severity. A possible correlation of TBEV-specific antibody and cell-mediated immune responses, shortly after infection, with clinical manifestations, severity and long-term outcome has been poorly investigated. In a cohort of thirty early tick-borne encephalitis (TBE) patients, we assessed the magnitude, specificity and functional properties of TBEV-specific T-cell and antibody responses. These responses early during disease were assessed in view of clinical manifestations, severity and long-term outcome. TBEV-specific T-cell responses to C, E, NS1, and NS5 proteins were significantly lower in patients with severe acute illness than in patients with mild TBE. Lower T-cell responses to E, NS1, and NS5 proteins also correlated with the development of meningoencephalomyelitis. Virus-specific antibody titres early after infection did not correlate with disease severity, clinical manifestations, or long-term outcome in this study, possibly due to the small number of patients of which matching serum and peripheral blood mononuclear cells were available. The findings suggest that virus-specific T cells afford a certain degree of protection against the development of severe TBEV-induced disease.

Tick-borne encephalitis vaccine breakthrough infections induce aberrant T cell and antibody responses to non-structural proteins.

Tick-borne encephalitis virus (TBEV) vaccine breakthrough (VBT) infections are not uncommon in endemic areas. The clinical and immunological outcomes have been poorly investigated. We assessed the magnitude and specificity of virus-specific antibody and T cell responses after TBE in previously vaccinated subjects and compared the results with those of unvaccinated TBE patients and study subjects that received vaccination without VBT infection. Symptomatic TBEV infection of unvaccinated study subjects induced virus-specific antibody responses to the E protein and non-structural protein 1 (NS1) as well as T cell responses to structural and other non-structural (NS) proteins. After VBT infections, significantly impaired NS1-specific antibody responses were observed, while the virus-specific T cell responses to the NS proteins were relatively strong. VBT infection caused predominantly moderate to severe disease during hospitalization. The level of TBEV EDIII- and NS1-specific antibodies in unvaccinated convalescent patients inversely correlated with TBE severity and neurological symptoms early after infection.