Detection of Borrelia burgdorferi sensu lato DNA in cerebrospinal fluid samples following pre-enrichment culture.

Molecular methods for diagnosing Lyme neuroborreliosis (LNB) have shown suboptimal diagnostic sensitivities. The objective of this study was to improve the clinical sensitivity of PCR detection of Borrelia burgdorferi sensu lato spirochetes by inoculating cerebrospinal fluid (CSF) from patients suspected of LNB directly into culture medium at the time of lumbar puncture, with this pursuing enrichment of Borrelia spirochetes before PCR analysis. Adult patients with symptoms suggestive of LNB were prospectively enrolled at two hospitals in the Region of Southern Denmark. The CSF-culture samples were incubated for at least eight weeks. During this period, culture sample aliquots were analysed for the presence of Borrelia DNA by separate PCR protocols in two independent clinical laboratories. The included patients were diagnosed with definite (n=12) or possible (n=2) LNB, and non-LNB (n=171) based on clinical and paraclinical findings. Patients in the LNB and the non-LNB group had a median duration from symptom onset to lumbar puncture of 40 days (IQR [23-90] days) and 120 days (IQR [32-365] days), respectively. Pre-enrichment growth of Borrelia spirochetes was accomplished from three patients (21 %) in the LNB group. The positive culture samples were confirmed by both the digital droplet PCR and the real-time PCR methods employed. All CSF samples were PCR negative in the non-LNB group. The results of this study do not support the use of Borrelia-specific PCR as a general routine diagnostic tool in adults. Still, they suggest it may prove of additional value in selected patients with a limited time from symptom onset to sample collection.

No correlation between symptom duration and intrathecal production of IgM and/or IgG antibodies in Lyme neuroborreliosis - a retrospective cohort study in Denmark.

OBJECTIVES: In Europe, a definite diagnosis of Lyme neuroborreliosis (LNB) requires intrathecally produced Borrelia-specific antibodies. We aimed to examine if the time from symptom debut to lumbar puncture (LP) correlated with findings of intrathecal production of Borrelia-specific IgM and/or IgG antibodies in LNB METHODS: A retrospective study of 544 patients with a positive Borrelia burgdorferi antibody index (Bb-AI) analysed at the Department of Clinical Microbiology, Odense University Hospital, Denmark, between 01.01.1995 and 31.12.2020 RESULTS: The delay from symptom onset to LP for patients with positive Bb-AI IgM was 30 days (IQR 14-95 days), IgG 24 days (IQR 11-62), IgM+IgG 24 days (IQR 14-48), P = 0.098. Ninety-three patients had a second LP after median 125 days (IQR 28-432) and 25 had a third LP after median 282 days (IQR 64-539). Most patients (66.7%) did not convert from their initial intrathecal antibody finding. The prevalence of different clinical manifestations differed significantly between the three Bb-AI groups. CONCLUSIONS: Intrathecal Borrelia-specific antibody production did not follow the typical immune response of initial IgM production followed by IgG production. Diagnosis of LNB stage should not be based on the type of antibodies found in the cerebrospinal fluid.

Fatigue and cognitive impairment in neuroborreliosis patients posttreatment-A neuropsychological retrospective cohort study.

BACKGROUND: The aim of this study was to determine the prevalence of fatigue and cognitive impairment in patients with neuroborreliosis (NB) posttreatment and to determine whether delayed treatment initiation led to higher levels of fatigue and cognitive impairment. METHODS: The study population consisted of 88 patients with NB included between October 10, 2014, and August 21, 2020, at the Clinical Center for Emerging and Vector-borne Infections at Odense University Hospital, Denmark. The Symbol Digit Modalities Test (SDMT) was used as a cognitive screening test, and the Modified Fatigue Impact Scale (MFIS) was used to assess the patients' level of fatigue over the course of a year. RESULTS: Overall, 14.3% of patients had an SDMT score indicative of cognitive impairment, and 38.8% of patients reported experiencing fatigue 12 months posttreatment. We found no statistically significant differences in fatigue or cognitive impairment when comparing the patients who had a treatment delay of ≤14 days and those with a treatment delay of >14 days (p > .05) 12 months posttreatment. A random effects regression model showed a significant positive correlation between longer treatment delay and higher MFIS scores, indicating higher levels of fatigue. CONCLUSIONS: The results of this study show that both the early and late treatment groups improved significantly over a 12-month period in terms of both cognitive symptoms and fatigue. However, it also showed that a substantial subgroup of patients with NB still suffer from fatigue and cognitive impairment 12 months posttreatment.

Severe Bartonella henselae bone infection in a kidney transplanted young man.

We present a case of a young kidney transplanted man. He was admitted with lymphadenopathy, fluctuating fever and night sweats 2 months after a cat bite. After admission, he developed severe pain around his right hip. An 18F-fluorodeoxyglucose (FDG)-positron emission tomography/CT revealed intense FDG-uptake in lymph nodes, spleen and bone, suggestive of lymphoma. An extracted lymph node showed confluent granulomas, microabscesses with neutrophils and scattered multinucleated giant cells histologically. The patient had history of latent tuberculosis and proteinase 3 -anti-neutrophil cytoplasmic antibodies associated (PR3-ANCA) vasculitis, making differential diagnostic considerations complicated. Bartonella henselae antibodies was detected in blood and B. henselae DNA in a lymph node. He was started on doxycycline and rifampicin. Due to severe drug interactions with both tacrolimus and increasing morphine doses, rifampicin was changed to azithromycin. He received 12 days of relevant antibiotic treatment and responded well. He was discharged after 16 days with close follow-up and was still in habitual condition 12 months later.

An intervention in general practice to improve the management of Lyme borreliosis in Denmark.

BACKGROUND: Our objectives were to improve the following outcomes in patients with Lyme borreliosis (LB) through an educational intervention in general practice: (i) increase the number of hospital referrals on suspicion of LB, (ii) increase the number of cerebrospinal fluid (CSF) tests examined for Borrelia burgdorferi antibody index, (iii) decrease the number of serum-B. burgdorferi antibody tests ordered, (iv) shorten delay from symptom onset to hospital in Lyme neuroborreliosis (LNB) patients, (v) increase LB knowledge among general practitioners. METHODS: A prospective non-blinded non-randomized intervention trial on the island of Funen, Denmark. The intervention included oral and written education about LB and was carried out in areas with an LNB incidence ≥4.7/100.000 between 22 January 2019 and 7 May 2019. Results were compared between the intervention group (49 general practices) and the remaining general practices in Funen (71 practices) 2 years before and after the intervention. RESULTS: In the study period, 196 patients were referred on suspicion of LB, a 28.9% increase in the intervention group post-intervention, 59.5% increase in the control group (P = 0.47). The number of CSF-Borrelia-antibody index tests increased 20.8% in the intervention group, 18.0% in the control group (P = 0.68), while ordered serum-B. burgdorferi antibody tests declined 43.1% in the intervention group, 34.5% in the control group (P = 0.30). 25.1% had the presence of serum-B. burgdorferi antibodies. We found no difference in LNB pre-hospital delay before and after intervention or between groups (P = 0.21). The intervention group performed significantly better on a follow-up questionnaire (P = 0.02). CONCLUSION: We found an overall improvement in LB awareness and referrals among general practitioners but could not show any effect of the intervention on clinical outcomes of LNB.

Lyme neuroborreliosis with encephalitis; a systematic literature review and a Scandinavian cohort study.

BACKGROUND: Lyme neuroborreliosis (LNB) presenting with encephalitis is rare and scarcely described. OBJECTIVES: To describe the available literature on LNB encephalitis and to characterize this patient group through a Scandinavian retrospective cohort study. DATA SOURCES: Medline, Embase, Scopus, Cochrane library. STUDY ELIGIBILITY CRITERIA: There was no discrimination on study type, time of publication or language. PARTICIPANTS: Review: All articles with definite LNB and confirmed/possible encephalitis. COHORT: LNB cohorts from Denmark, Sweden and Norway 1990-2019 were screened for patients with encephalitis. METHODS: Review: Adhering to PRISMA guidelines; two authors extracted reviews and assessed quality of studies. COHORT: Data on demography, symptoms, cerebrospinal fluid findings, differential diagnostic examinations, treatment, residual symptoms, 1-year mortality were registered. RESULTS: Review: 2330 articles screened on title/abstract, 281 full texts, yielding 42 articles (case reports/series or cohort studies), including 45 patients from 18 countries spanning 35 years. Altered mental status ranged from personality changes and confusion to unconsciousness. Common focal symptoms were hemiparesis, ataxia and dysarthria; seven patients had seizures. Median time from symptom onset to hospital was 2 weeks (IQR 2-90 days). Of 38 patients with available follow-up after median 12 months (IQR 5-13), 32 had fully or partially recovered, two had died. COHORT: Thirty-five patients (median age 67 years, IQR 48-76) were included. The encephalitis prevalence was 3.3% (95% CI 2.2-4.4%) among 1019 screened LNB patients. Frequent encephalitis symptoms were confusion, personality changes, aphasia, ataxia. EEGs and neuroimaging showed encephalitis in 93.8% and 20.6%, respectively. Median delay from symptom onset to hospital was 14 days (IQR 7-34), with further 7 days (IQR 3-34) delay until targeted therapy. At follow-up (median 298 days post-treatment; IQR 113-389), 65.6% had residual symptoms. None had died. CONCLUSIONS: This study shows that encephalitis is an uncommon, but likely overlooked clinical manifestation of LNB. As the high frequency of residual symptoms may be related to prolonged treatment delay, prompt LNB testing of patients with encephalitis in Borrelia burgdorferi-endemic areas should be considered.

SARS-CoV-2 viral load as a predictor for disease severity in outpatients and hospitalised patients with COVID-19: A prospective cohort study.

INTRODUCTION: We aimed to examine if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) cycle quantification (Cq) value, as a surrogate for SARS-CoV-2 viral load, could predict hospitalisation and disease severity in adult patients with coronavirus disease 2019 (COVID-19). METHODS: We performed a prospective cohort study of adult patients with PCR positive SARS-CoV-2 airway samples including all out-patients registered at the Department of Infectious Diseases, Odense University Hospital (OUH) March 9-March 17 2020, and all hospitalised patients at OUH March 10-April 21 2020. To identify associations between Cq-values and a) hospital admission and b) a severe outcome, logistic regression analyses were used to compute odds ratios (OR) and 95% Confidence Intervals (CI), adjusting for confounding factors (aOR). RESULTS: We included 87 non-hospitalised and 82 hospitalised patients. The median baseline Cq-value was 25.5 (interquartile range 22.3-29.0). We found a significant association between increasing Cq-value and hospital-admission in univariate analysis (OR 1.11, 95% CI 1.04-1.19). However, this was due to an association between time from symptom onset to testing and Cq-values, and no association was found in the adjusted analysis (aOR 1.08, 95% CI 0.94-1.23). In hospitalised patients, a significant association between lower Cq-values and higher risk of severe disease was found (aOR 0.89, 95% CI 0.81-0.98), independent of timing of testing. CONCLUSIONS: SARS-CoV-2 PCR Cq-values in outpatients correlated with time after symptom onset, but was not a predictor of hospitalisation. However, in hospitalised patients lower Cq-values were associated with higher risk of severe disease.

Clinical presentation and mortality in hospitalized patients aged 80+ years with COVID-19-A retrospective cohort study.

BACKGROUND: COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has great health implications in older patients, including high mortality. In general, older patients often have atypical symptom presentations during acute illness due to a high level of comorbidity. The purpose of this study was to investigate the presentation of symptoms at hospital admissions in older patients with COVID-19 and evaluate its impact on disease outcome. METHODS: This retrospective study included patients ≥80 years of age with a positive test for SARS-CoV-2, who were admitted to one of three medical departments in Denmark from March 1st to June 1st, 2020. RESULTS: A total of 102 patients (47% male) with a mean age of 85 years were included. The most common symptoms at admission were fever (74%), cough (62%), and shortness of breath (54%). Furthermore, atypical symptoms like confusion (29%), difficulty walking (13%), and falls (8%) were also present. In-hospital and 30-day mortality were 31% (n = 32) and 41% (n = 42), respectively. Mortality was highest in patients with confusion (50% vs 38%) or falls (63% vs 39%), and nursing home residency prior to hospital admission was associated with higher mortality (OR 2.7, 95% CI 1.1-6.7). CONCLUSIONS: Older patients with SARS-Cov-2 displayed classical symptoms of COVID-19 but also geriatric frailty symptoms such as confusion and walking impairments. Additionally, both in-hospital and 30-day mortality was very high. Our study highlights the need for preventive efforts to keep older people from getting COVID-19 and increased awareness of frailty among those with COVID-19.

Low mortality of hospitalised patients with COVID-19 in a tertiary Danish hospital setting.

OBJECTIVES: We aimed to describe clinical characteristics and outcomes of admitted COVID-19 patients in a Danish hospital setting where an early active government intervention was taken. METHODS: Prospective cohort study including all admitted patients to the COVID-19 unit at Odense University Hospital from March 10 to April 21, 2020. Patients were assessed by a multidisciplinary team at admission. Outcome parameters were development of acute respiratory distress syndrome (ARDS), intensive care unit (ICU) admission, death and admission time. RESULTS: We included 83 patients (median age 62 years, 62.7% male). At hospitalization, 31.3% needed oxygen supplementation and the median National Early Warning Score was four. Median admission time was 7 days (Interquartile ranges (IQR) 3-12). In total, ARDS was diagnosed in 33.7% (28/83) of the patients corresponding to an incidence rate of 7.1 per 100 person days (95% CI: 4.1-10.2). Overall 13 patients (15.7%) were transferred to the ICU of whom 11 (84.6%) received corticosteroids.. No patients died while admitted to the ICU. Four patients (4.8%) died during admission. CONCLUSION: Despite similar patient characteristics compared to those reported by others, we found a low overall mortality of < 5%.

Spatial and temporal patterns of Lyme Neuroborreliosis on Funen, Denmark from 1995-2014.

In Europe, Lyme neuroborreliosis (LNB) is the most severe manifestation of Lyme borreliosis and has recently been added to the communicable disease surveillance list for EU/EEA by the European Commission. In Northern Europe, LNB is primarily caused by the spirochete Borrelia garinii and transmitted by the tick Ixodes ricinus. This Danish observational epidemiologic case-control study includes every identified LNB patient (n = 401) on Funen, Denmark, from 1995-2014. We display spatial and temporal LNB incidence variation, seasonal distribution of cases and local spatial case clustering. Seasonal patterns show LNB symptom-onset peaking in July and a significant seasonal difference in number of cases (p < 0.01). We found no significant change in seasonality patterns over time when dividing the study period into 5-year intervals. We identified a significant local geographical hot-spot of cases with a relative risk of 2.44 (p = 0.013). Analysis revealed a significantly shorter distance to nearest forest for cases compared with controls (p < 0.001). We present a novel map of the focal geographical distribution of LNB cases in a high endemic borreliosis area. Continued studies of case clustering in the epidemiology of LNB are of key importance in guiding intervention strategies.

Lyme neuroborreliosis in adults: A nationwide prospective cohort study.

The goal of this paper is to characterize the clinical presentation, serological results, current antibiotic treatment practice, including compliance with current European guidelines, and outcome in adults with Lyme neuroborreliosis (LNB) diagnosed at departments of infectious diseases in Denmark. Using a nationwide prospective cohort of patients with central nervous system infections, we identified all adults (≥ 18 years of age) treated for LNB at departments of infectious diseases in Denmark from 2015 through 2017. The database contains information on baseline demographics, history of tick bite, erythema migrans, clinical presentation, laboratory results of blood samples, and cerebrospinal (CSF) biochemistry (e.g. specific Borrelia burgdorferi sensu lato (s.l.) antibodies in serum, B. burgdorferi s.l. intrathecal antibody index) as well as antibiotic therapy. Outcome was assessed by the Glasgow Outcome Scale (GOS) and the presence of residual symptoms at follow-up one month after discharge. We included 194 LNB patients with a median age of 59 years (range 18-85 years, interquartile range [IQR] 47-69 years). The female-to-male ratio was 0.8. A total of 177 of 191 (93 %) of patients had early (second stage) LNB. A history of tick bite or erythema migrans was registered in 75 (39 %) and 49 (25 %) patients, respectively. The median duration of neurological symptoms before first hospital contact was 21 days (range 0-600 days, IQR 10-42 days). Predominant symptoms consisted of radicular pain in 135 of 194 (70 %), cranial nerve paresis in 88 of 194 (45 %), headache in 71 of 185 (38 %), and extremity paresis in 33 of 194 (17 %) patients. Serum-B. burgdorferi s.l. IgM and/or IgG antibodies were detectable in 166 of 181 (92 %) patients at the time of first CSF investigation. Median duration of antibiotic treatment was 14 days (range 10-35 days, IQR 14-21 days) and 59 (39 %) of the patients received intravenous ceftriaxone and/or benzylpenicillin G throughout treatment. At the 1-month follow-up, GOS was unfavorable (< 5) in 54 of 193 (28 %) patients. An unfavorable GOS score was more often registered in patients with ≥ 45 days of symptom duration (20 of 45 (44 %) vs. 34 of 145 (23 %); P = 0.006). In conclusion, a European cohort of adult patients with LNB diagnosed between 2015-2017 presented with classic symptoms and CSF findings. However, a substantial diagnostic delay was still observed. In disagreement with current guidelines, a substantial part of LNB patients were treated with antibiotics longer than 14 days and/or intravenously as route of administration.

The predictive value of CXCL13 in suspected Lyme neuroborreliosis: a retrospective cross-sectional study.

The role of CXCL13 as a marker of Lyme neuroborreliosis (LNB) is under investigation, and CXCL13 is not part of routine diagnostics in suspicion of LNB. Our aim was to find the optimal cut-off value of CXCL13 for LNB in a Danish population and to investigate the role of CXCL13 both in early LNB and as a discriminatory marker between LNB and other neuroinflammatory disorders. We conducted a retrospective cross-sectional study including all patients with a cerebrospinal CXCL13 test performed at the Department of Clinical Immunology, Odense University Hospital, Denmark, between 1 January 2015 and 31 December 2018. We included 619 patients, of which 51 had definite LNB, 14 patients had possible LNB with neurological symptoms suggestive of LNB and pleocytosis but no intrathecal Borrelia antibodies, eight patients had prior LNB and 546 had no LNB. With an optimal CXCL13 cut-off of 49 ng/L we found a sensitivity of 100% and specificity of 94% (AUC 0.988, 95% CI 0.980-0.996) when patients treated with antibiotics prior to lumbar puncture were excluded (n = 130). All patients with possible LNB had a CXCL13 value above the cut-off value; 18/546 patients (3.3%) without LNB had a CXCL13 value ≥ 50 ng/L. While CXCL13 cannot be used as a stand-alone test, it can be used as a reliable additional marker in treatment-naive patients suspected of LNB. CXCL13 can be used to monitor treatment response in LNB patients.

Characteristics and Clinical Outcome of Lyme Neuroborreliosis in a High Endemic Area, 1995-2014: A Retrospective Cohort Study in Denmark.

BACKGROUND: Despite a well-described symptomatology, treatment delay and sequelae are common in patients with Lyme neuroborreliosis (LNB). The aim of this study was to contribute to the knowledge about the symptomatology and epidemiology of LNB. METHODS: We conducted a retrospective study of all LNB cases verified by a positive Borrelia intrathecal antibody index test performed at the Department of Microbiology, Odense University Hospital, Denmark, from 1995 through 2014. RESULTS: The study included 431 patients; 126 were children. The mean incidence was 4.7 per 100 000 inhabitants per year. The median delay from neurological symptom debut to first hospital contact was 20 days and significantly longer for patients with symptom debut in the winter/early spring. The most common clinical symptoms were painful radiculitis (65.9%), cranial nerve palsy (43.4%), and headache (28.3%). A total of 30.6% were seen in >1 hospital department, and 85.6% were admitted during their course of treatment. Serum Borrelia immunoglobulin M and immunoglobulin G at the time of positive Borrelia intrathecal antibody index test were negative in 67 patients (15.5%). We found a median treatment delay of 24 days, with no improvement in our 20-year study period. Residual symptoms following treatment were found in 28.1% of patients, and risk of residual symptoms was significantly associated with delay from symptom debut to initiation of treatment. CONCLUSIONS: The association between treatment delay and residual symptoms and the lack of improvement in treatment delay during the study period highlight the need for standardized diagnostic routines and a better follow-up for LNB patients. Our findings disprove that all patients with LNB develop positive serum Borrelia antibodies within 6 weeks after infection.

[Clinical manifestations, diagnosis and treatment of Lyme borreliosis].

Lyme borreliosis is an infection caused by the Borrelia burgdorferi sensu lato complex and transmitted by Ixodes ricinus ticks in Denmark. It can manifest itself in several different forms of which erythema migrans is the most common and is diagnosed by clinical assessment of the characteristic erythema. Laboratory support for the clinical diagnosis of other manifestations rests on the measurement of Borrelia-specific antibodies. Treatment is straight-forward with antibiotics such as penicillin. This paper reviews the clinical manifestations, diagnosis and treatment of this infection.

Pontine abscess with initial treatment failure following infectious endocarditis with Streptococcus salivarius.

We present a case report of a 65-year-old man admitted to the department of infectious diseases on suspicion of meningitis with headache, fever and double vision. A cerebral MRI revealed a 17×30 mm pontine abscess with surrounding oedema. The patient had, 2 months prior to admission, been treated for Streptococcus salivarius aortic valve endocarditis. The abscess was not suitable for surgery, and the patient received multidrug antibiotic treatment for 4 weeks. The patient initially responded well clinically, but was readmitted 4 weeks after discontinuation of treatment, with headache and dizziness. A new cerebral MRI showed progression of the abscess. He received an additional 8 weeks of broad spectrum antibiotic treatment, followed by 12 weeks of oral treatment with pivampicillin. His symptoms resolved and a cerebral MRI at discontinuation of treatment showed regression of the abscess to 7.5 mm.

Characteristics of patients with community-acquired bacteremia who have low levels of C-reactive protein (≤20 mg/L).

OBJECTIVES: To characterize patients presenting with community-acquired bacteremia and a low C-reactive protein (CRP) plasma level at date of bacteremia. METHODS: Population-based cohort study. Patient characteristics were compared for three CRP groups (≤20 mg/L, 21-100 mg/L and >100 mg/L) using chi-square test and oneway anova. The 30-day mortality rates were compared using logistic regression analyses. RESULTS: Of the 2017 patients included, 193 (9.6%) had a CRP ≤20 mg/L. These patients were younger, more likely to be male, overrepresented in the intensive care unit and had more comorbidities. In blood cultures from the low CRP group hemolytic streptococci and coagulase-negative staphylococci were found relatively more common, whereas Streptococcus pneumoniae or Staphylococcus aureus were found relatively less common compared to the other CRP groups. The majority of patients with an initial low CRP mounted a CRP response the following days. The 30-day mortality rate was lower in the low CRP group (13.5%) than in the group with CRP >100 mg/L (20.6%). CONCLUSIONS: A considerable proportion of patients with community-acquired bacteremia has a normal or low initial CRP level. The plasma CRP level should not be used to rule out serious infection or withhold antibiotic therapy.

[Duodenal biopsy is the most important examination when diagnosing Whipple's disease]. / Tyndtarmsbiopsi er den vigtigste undersøgelse ved diagnosticering af Whipples sygdom.

Whipple's disease is a rare disease caused by the bacteria Tropheryma whipplei. It can present with different disease patterns including arthritis, gastrointestinal symptoms with abdominal pain and diarrhoea, malnutrition, anaemia and neurological symptoms. We present a case of a 71-year-old man who underwent a six-month long, thorough investigation before reaching the right diagnosis. After sufficient treatment the symptoms remitted. Physicians should be vigilant of this differential diagnosis in medical patients who have uncharacteristic symptoms consistent with Whipple's disease.