Neoehrlichiosis associated with ocrelizumab in a patient with multiple sclerosis: A case report.

OBJECTIVE: To describe a case of neoehrlichiosis, an emerging opportunistic tick-borne infection, in a patient with multiple sclerosis (MS) treated with ocrelizumab. METHODS: This is a case study. RESULTS: Our patient developed clinical infection over several months while on ocrelizumab and was ultimately diagnosed with neoehrlichiosis, caused by the bacteria Neoehrlichia mikurensis. Resolution of symptoms began within a few days after the initiation of antibiotic treatment. CONCLUSION: We describe the first probable case of ocrelizumab-associated neoehrlichiosis in a patient with MS. Clinicians should be aware of this potentially debilitating and life-threatening infection in patients receiving CD20-depleting therapy.

Empiric treatment of healthcare-associated central nervous system infections in Denmark: do we need carbapenems?

BACKGROUND: Carbapenems are widely used for empiric treatment of healthcare-associated central nervous system (CNS) infections. We investigated the feasibility of a carbapenem-sparing strategy, utilising a third-generation cephalosporin (ceftriaxone or cefotaxime) (combined with vancomycin) for the empirical treatment of healthcare-associated CNS infections in Eastern Denmark. METHODS: The departments of neurosurgery and neuro-intensive care at Copenhagen University Hospital Rigshospitalet. First, we analysed local microbiological data (1st January 2020-31st August 2022) to identify microorganisms non-susceptible to third-generation cephalosporin. Subsequently, we assessed all carbapenem prescriptions over a three-month period for their indication and justification. RESULTS: In total, 25,247 bacterial cultures were identified, of which 2,563 CNS-related, were included in the analysis. The positivity rate was 10.5% (n = 257/2439) for cerebrospinal-fluid samples and 75.8% (n = 95/124) for brain parenchyma. CNS samples from five individual patients revealed bacteria non-susceptible to third generation cephalosporins (Enterobacter spp. (n = 3), Pseudomonas spp. (n = 2), Klebsiella spp. (n = 2), Citrobacter freundii (n = 1)). All five patients had been hospitalised for ≥10days at the time-point of antibiotic therapy. Out of 11,626 sets of blood cultures, a total of 10 individual patients had Gram-negative blood-stream infections with resistance to ceftriaxone and piperacillin/tazobactam. 140 days-of-therapy (32%) with carbapenem in 18 patients (36%) were definitively or possibly indicated according to guidelines, none were indicated for healthcare-associated CNS-infections. CONCLUSION: An empiric treatment strategy relying on a third-generation cephalosporin appears suitable for healthcare-associated CNS infections at our tertiary hospital, serving a population of 2.6 million. However, in patients with prolonged hospitalization (≥10 days), immunosuppression, prior broad-spectrum antibiotic use, or history of resistant Gram-negative bacteria, empirical prescription of carbapenem may be needed.

Neoehrlichia mikurensis is uncommon in rheumatological patients receiving tumour necrosis factor inhibitors and in blood donors: a retrospective cohort study.

INTRODUCTION: Neoehrlichia mikurensis is a tick-borne bacterium that primarily causes disease in immunocompromised patients. The bacterium has been detected in ticks throughout Europe, with a 0%-25% prevalence. N. mikurensis infection presents unspecific symptoms, which can easily be mistaken for inflammatory disease activity. We aimed to determine the prevalence of N. mikurensis in rheumatological patients receiving tumour necrosis factor inhibitors (TNFi) and a cohort of healthy individuals. MATERIALS AND METHODS: This retrospective cohort study included 400 rheumatological patients treated with TNFi and 400 healthy blood donors. Plasma samples were retrieved from the Danish Rheumatological Biobank and the Danish Blood Donor Study between 2015 and 2022. Age, sex, diagnosis and duration of TNFi treatment were recovered from the Danish Rheumatological Database, DANBIO. Data on age and sex were available for the blood donors. One plasma sample per individual was tested for N. mikurensis DNA-specific real-time PCR targeting the groEL gene. RESULTS: In the rheumatological patients, the median age was 61 years (IQR 55-68 years), 62% were women, and 44% had a diagnosis of seropositive rheumatoid arthritis. In total, 54% of the patients were treated with infliximab. The median time from TNFi initiation to blood sampling was 20 months (IQR, 5-60 months). N. mikurensis DNA was not detected in any samples from patients or blood donors. CONCLUSION: N. mikurensis infection does not appear to represent a prevalent risk in Danish rheumatological patients receiving TNFi or in blood donors.

Tick-borne encephalitis.

Tick-borne encephalitis (TBE) is a viral tick-borne infection occurring in many parts of Europe and Asia as described in this review. Increasing TBE case numbers have been reported over recent decades. In Denmark the infection is rare (1-14 annual cases). The rise in TBE in Denmark is mainly driven by microfoci outside of Bornholm, primarily North Zealand. Clinical illness has a bi-phasic presentation: "summer-flu" which may be followed by a neuroinfection. No specific treatment exists, and mortality is less-than 1%. A considerable percentage of patients may experience neurological sequelae. TBE is preventable through vaccination.

A typical case of tick-borne encephalitis.

Tick-borne encephalitis is a rare infection in Denmark. The infection has been endemic to the island of Bornholm for many years. During the past 10 years, transmission has occurred in other parts of Denmark, particularly North Zealand. This case report describes a typical tick-borne encephalitis case diagnosed in the first viraemic phase of the disease course. Clinical presentation and diagnostic criteria are described.

Neoehrlichia mikurensis-An emerging opportunistic tick-borne infection in immunosuppressed patients.

BACKGROUND: Neoehrlichia mikurensis (N. mikurensis) is a newly discovered tick-borne pathogen that can inflict life-threatening illness in immunocompromised patients. N. mikurensis infection is only detectable by polymerase chain reaction (PCR)-based methodologies. We describe three distinct clinical manifestations of N. mikurensis infection (neoehrlichiosis) in Danish patients receiving B-lymphocyte-depleting therapy, rituximab, for underlying hematological, rheumatological, or neurological disorders. All three patients went through a protracted pre-diagnostic period. METHODS: N. mikurensis DNA was detected and confirmed using two methods. Blood was tested by specific real-time PCR targeting the groEL gene and by 16S and 18S profiling followed by sequencing. Bone marrow was analyzed by 16S and 18S profiling. RESULTS: N. mikurensis was detected in blood samples in all three cases and in bone marrow from one of the three. The severity of the symptoms ranged from prolonged fever lasting more than 6 months to life-threatening hyperinflammation in the form of hemophagocytic lymphohistiocytosis (HLH). Interestingly, all patients presented with splenomegaly and two with hepatomegaly. After starting doxycycline therapy, symptoms were relieved within a few days, and biochemistry and organomegaly quickly normalized. CONCLUSION: We present three Danish patients recognized by the same clinician over a period of 6 months, strongly suggesting that many cases are going unrecognized. Second, we describe the first case of N. mikurensis-induced HLH and emphasize the potential severity of undetected neoehrlichiosis.

Cerebrospinal fluid levels of the macrophage-specific biomarker sCD163 are diagnostic for Lyme neuroborreliosis: An observational cohort study.

OBJECTIVES: We aimed to investigate levels of the macrophage-specific marker, sCD163, in cerebrospinal fluid and plasma in patients with Lyme neuroborreliosis. We tested the diagnostic value of CSF-sCD163 and ReaScan-CXCL13 and analyzed if plasma-sCD163 could monitor treatment response. METHODS: An observational cohort study: Cohort 1-Cerebrospinal fluid from adults with neuroborreliosis (n = 42), bacterial meningitis (n = 16), enteroviral meningitis (n = 29), and controls (n = 33); Cohort 2-Plasma from 23 adults with neuroborreliosis collected at diagnosis, three, and six months. sCD163 was determined using an in-house sandwich ELISA. ReaScan-CXCL13 measured semiquantitative concentrations of CXCL13, cut-off ≥ 250 pg/ml diagnosed neuroborreliosis. Receiver Operating Characteristics analyzed the diagnostic strength. A linear mixed model including follow-up as categorical fixed effect analyzed differences in plasma-sCD163. RESULTS: CSF-sCD163 was higher in neuroborreliosis (643 µg/l) than in enteroviral meningitis (106 µg/l, p < 0.0001) and controls (87 µg/l, p < 0.0001), but not bacterial meningitis (669 µg/l, p = 0.9). The optimal cut-off was 210 µg/l, area under the curve (AUC) 0.85. ReaScan-CXCL13 had an AUC of 0.83. Combining ReaScan-CXCL13 with CSF-sCD163 increased AUC significantly to 0.89. Plasma-sCD163 showed little variation and was not elevated during the 6 months of follow-up. CONCLUSION: CSF-sCD163 is diagnostic for neuroborreliosis with an optimal cut-off of 210 µg/l. Combining ReaScan-CXCL13 with CSF-sCD163 increases AUC. Plasma-sCD163 cannot monitor treatment response.

Neoehrlichia mikurensis in Danish immunocompromised patients: a retrospective cohort study.

BACKGROUND: The tick-borne bacterium, Neoehrlichia mikurensis (N. mikurensis) can cause severe febrile illness and thromboembolic complications in immunocompromised individuals. We investigated the presence of N. mikurensis DNA in retrospectively collected plasma from a well-characterized cohort of Danish immunocompromised patients. METHODS: Plasma samples from 239 patients with immune dysfunction related to hematological or rheumatological disease or due to immunosuppressive therapy, were retrieved from a transdisciplinary biobank (PERSIMUNE) at Rigshospitalet, Copenhagen, Denmark. Serving as immunocompetent controls, plasma samples from 192 blood donors were included. All samples were collected between 2015 and 2019. Real-time PCR targeting the groEL gene was used to detect N. mikurensis DNA. Sequencing was used for confirmation. Borrelia burgdorferi sensu lato IgG antibodies were detected by ELISA as a proxy of tick exposure. Prevalence was compared using Fisher's exact test. RESULTS: Neoehrlichia mikurensis DNA was detected in 3/239 (1.3%, 95% confidence interval (CI): 0.3 - 3.6%) patients, all of whom primarily had a hematological disease. Follow-up samples of these patients were negative. N. mikurensis DNA was not detected in any of the blood donor samples. IgG antibodies against B. burgdorferi s.l. were detected with similar prevalence in immunocompromised patients and blood donors, i.e., 18/239 (7.5%, 95% CI: 4.8-11.5%) and 11/192 (5.7%, 95%: CI 3.2-10.0%). CONCLUSION: In this study, patients with N. mikurensis were not identified by clinical indication and N. mikurensis may therefore be underdiagnosed in Danish patients. Further investigations are needed to explore the clinical significance and implications of this infection.

A case of imported West Nile encephalitis.

This is a case report of encephalitis and myeloradiculitis due to West Nile virus (WNV) with a fatal outcome in a 76-year-old male returning from a vacation in Serbia. In 2022 during transmission season, there was an outbreak of WNV infection in the southern part of Europe and the incidence is expected to increase globally in the future due to global warming. Currently, no antiviral treatments or vaccines against WNV are available for humans; hence, mosquito bite prevention is crucial in epidemic areas.

Neoehrlichiosis is a new tick-borne infection.

Neoeherlichiosis is an emerging tick-borne infection causing disease in individuals with inadequate B-cell responses because of haematologic cancer or treatment with B-cell depletion therapies such as rituximab. The infection has recently been found as a cause of prolonged fever among several patients receiving rituximab in Denmark. This review covers current knowledge on the clinical spectrum among healthy as well as immune compromised individuals, transmission, pathogenesis, diagnosis, and treatment.

3D blood-brain barrier-organoids as a model for Lyme neuroborreliosis highlighting genospecies dependent organotropism.

Lyme neuroborreliosis (LNB), a tick-borne infection caused by spirochetes within the Borrelia burgdorferi sensu lato (s.L.) complex, is among the most prevalent bacterial central nervous system (CNS) infections in Europe and the US. Here we have screened a panel of low-passage B. burgdorferi s.l. isolates using a novel, human-derived 3D blood-brain barrier (BBB)-organoid model. We show that human-derived BBB-organoids support the entry of Borrelia spirochetes, leading to swelling of the organoids and a loss of their structural integrity. The use of the BBB-organoid model highlights the organotropism between B. burgdorferi s.l. genospecies and their ability to cross the BBB contributing to CNS infection.

Plasma neurofilament light significantly decreases following treatment in Lyme neuroborreliosis and is not associated with persistent symptoms.

BACKGROUND AND PURPOSE: Currently there is an unmet need for a highly standardized blood biomarker test to monitor treatment response in Lyme neuroborreliosis (LNB). Differentiating between active or past infection is challenged by the relatively high frequency of persistent symptoms after the end of antibiotic treatment (estimated 15%-20%), the variable clinical course and the long-lasting Borrelia burgdorferi antibodies. The aim was therefore to evaluate plasma neurofilament light chain (pNfL) as a marker for disease activity in LNB. METHODS: This was a prospective cohort of definite LNB (N = 36) with blood samples and clinical evaluation including Glasgow Outcome Score at treatment initiation and 3 and 6 months' follow-up. Consecutive plasma was retrospectively analysed for the content of neurofilament light chain by Quanterix® kits (Simoa® NF-light Kit). RESULTS: Plasma neurofilament light chain significantly decreased between treatment initiation and the 3-month follow-up (median 83 pg/ml vs. median 14 pg/ml (25 pairs), p < 0.0001). No significant change was observed between 3 and 6 months' follow-up (median 14 pg/ml vs. median 12 pg/ml (21 pairs), p = 0.33). At treatment initiation 90% had pNfL above the age-defined reference compared to only 23% and 7% respectively at 3 and 6 months' follow-up. Decreases in pNfL were mirrored by increasing Glasgow Outcome Score. Reporting persistent symptoms at the 6-month follow-up was not associated with pNfL (relative change from reference or actual values) at baseline or at 6 months' follow-up. CONCLUSION: Plasma neurofilament light chain decreases following antibiotic treatment in LNB and is not associated with reporting persistent symptoms. It was therefore speculated that it may prove useful as a treatment response biomarker in LNB.

Exploration of the induced cytokine responses in European Lyme neuroborreliosis: A longitudinal cohort study.

Lyme neuroborreliosis (LNB) is a prevalent tick-borne disease in Europe caused by Borrelia burgdorferi sensu lato complex. Slightly suppressed induced Th1- and Th17-responses are seen at diagnosis. The induced immune response following antibiotic therapy is unknown. We hypothesized that the immune responses normalize after completing antibiotic treatment. An observational longitudinal cohort study investigating the induced immune response in adult patients with LNB at diagnosis, three and six months after treatment. Whole blood was added to three TruCulture® (Myriad RBM, Austin, USA) tubes each containing one stimulation. An additional TruCulture® tube was without stimulation representing the in vivo activation of blood immune cells. Nine cytokines were measured using Luminex (LX200, R&D Systems, BIO-Teche LTD). Changes in immune response were analyzed with linear mixed model including follow-up as categorical fixed effect. A total of 21 patients with 55 samples were included. All had clinical improvement, but 5/21 patients reported residual symptoms after six months. The non-induced release of IL-17A and IL-1ß increased significantly from diagnosis to six month follow-up. Six months after treatment only IFN-α and TNF-α were below the reference range. Minor variations in the induced immune responses were seen during the study period. Th1- and Th17-responses continued to be low with low IFN-γ, IL-12p40, and IL-17A in multiple stimulations. Overall little dynamic was observed. The changes in the cytokine responses are most likely not linked to LNB pathogenesis and our results do not support the implementation of TruCulture® in the diagnostics or follow-up of LNB.

Antibiotic therapy of neuroborreliosis: A survey among infectious disease specialists and neurologists in Norway, Sweden, and Denmark.

INTRODUCTION: Neuroborreliosis (NB) is a prevalent tick-borne neuroinfection in Europe. To delineate current practice in antimicrobial management of adults with NB and to prioritize future trials needed to optimize treatment recommendations, a questionnaire-based survey was performed. METHODS: A self-administered Internet-based survey of NB treatment practices among specialists in infectious diseases and neurology based in Norway, Sweden, and Denmark was carried out between October 2021 and February 2022. The participants were also asked to prioritize four pre-defined research questions for randomized controlled trials (RCTs) on therapy for NB. RESULTS: In total, 290 physicians (45% female) from Norway (30%), Sweden (40%), and Denmark (30%) participated in the survey. Of the responders, 230 (79%) were infectious disease specialists and 56 (19%) were neurologists. The preferred antibiotic treatment for patients with early NB was oral doxycycline (n = 225, 78%). Intravenous (IV) penicillin, ceftriaxone, or cefotaxime for the full treatment course was favored by 12%. A preferred treatment duration of 10-14 days for patients with NB was reported by 245 respondents (85%), most common among participants from Sweden (97%). A total of 170 (59%) responders reported having local hospital guidelines on the treatment of NB, most often with recommendation of oral doxycycline (92%) for 10-14 days (90%) as first line treatment. The prioritization score for future RCTs was highest for adjunctive prednisone therapy in NB patients with facial palsy (median 5; IQR 4-6) and for placebo versus repeated antibiotics in patients with persistent symptoms after completed antibiotic therapy for NB (median 5, IQR 3-6). CONCLUSION: In Sweden, all respondents preferred treating NB with oral doxycycline for 10-14 days, whereas 5% in Norway and 19% in Denmark still treat NB with IV antibiotics for the entire treatment course. RCTs to define the role of adjunctive prednisolone in NB patients with facial palsy and repeated antibiotics in patients with persistent symptoms are prioritized for future research.

Neurofilament Light in Cerebrospinal Fluid is Associated With Disease Staging in European Lyme Neuroborreliosis.

Background: Drivers of differences in disease presentation and symptom duration in Lyme neuroborreliosis (LNB) are currently unknown. Objectives: We hypothesized that neurofilament light (NfL) in cerebrospinal fluid (CSF) would predict disease location and sequelae in a historic LNB cohort. Design: Using a cross-sectional design and archived CSF samples from 185 patients diagnosed with LNB, we evaluated the content of NfL in the total cohort and in a subgroup of 84 patients with available clinical and paraclinical information. Methods: Individuals were categorized according to disease location: a. Central nervous system (CNS) with stroke (N=3), b. CNS without stroke (N=11), c. Peripheral nervous system (PNS) with cranial nerve palsy (CNP) (N=40) d. PNS without CNP (N=30). Patients with hospital follow-up more than 6 months after completed antibiotic therapy were categorized as having LNB associated sequelae (N=15). Results: At diagnosis concentration of NfL exceeded the upper reference level in 60% (105/185), especially among individuals above 30 years. Age-adjusted NfL was not found to be associated with symptom duration. Age-adjusted NfL was significantly higher among individuals with CNS involvement. Category a. (stroke) had significantly higher NfL concentrations in CSF compared to all other categories, category b. (CNS involvement without stroke) had significantly higher values compared to the categories of PNS involvement. We found no significant difference between the categories with PNS involvement (with or without CNP). Significantly higher NfL was found among patients with follow-up in hospital setting. Conclusion: Comparison of NfL concentrations between the 4 groups of LNB disease manifestations based on clinical information revealed a hierarchy of neuron damage according to disease location and suggested evolving mechanisms with accelerated injury especially when disease is complicated by stroke. Higher values of NfL among patients with need of follow-up in hospital setting suggest NfL could be useful to identify rehabilitative needs.

Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART.

HIV-1 resistance towards integrase inhibitors is a potential threat of the success of HIV-1 combination treatment. G118R is a rare drug resistance mutation conferring pan-integrase resistance. Here, we describe the occurrence of G118R in a HIV-1 subtype-B-positive individual with major compliance problems, detected while the patient was on dolutegravir-based cART. We speculate the pre-selection of M184I/V aided the occurrence of G118R in this case, and discuss the robustness of dolutegravir-based therapies.

Mortality and cause of death in persons with chronic hepatitis B virus infection versus healthy persons from the general population in Denmark.

The study aimed to determine adjusted all-cause mortality and cause of death in persons with chronic hepatitis B virus (HBV) infection compared with age- and sex-matched persons from the general population. We used nationwide registers to identify persons aged ≥18 years with chronic HBV infection in 2002-2017 in Denmark and included 10 age- and sex-matched controls for each. Follow-up was from 6 months after diagnosis until death, emigration, or 31 December 2017. Mortality rate ratios (MRRs) adjusted for age, sex, employment, origin and comorbidity were calculated using Poisson regression. Unadjusted cause-specific mortality rate ratios with 95% confidence intervals were calculated assuming a Poisson distribution. A total of 6988 persons with chronic HBV infection and 69,847 controls were included. During a median follow-up of 7.7 years (range 0.0-15.5), 315 (5%) persons with-and 1525 (2%) without-chronic HBV infection died. The adjusted all-cause MRR was 1.5 (95% CI 1.2-2.0). Persons with chronic HBV infection had increased mortality due to liver disease including hepatocellular carcinoma (MRR 12.3 [8.6-17.7]), external causes (MRR 3.3 [2.5-4.7]), endocrine disease (MRR 3.2 [1.8-5.4]), genitourinary disease (MRR 3.2 [1.2-7.6]) and neoplasms (except hepatocellular carcinoma; MRR 1.6 [1.2-2.0]). In conclusion, this study showed an increased all-cause mortality in persons with chronic HBV infection in comparison with age- and sex-matched persons without chronic HBV infection which remained after adjustment for several confounding factors. Excess mortality was mainly associated with liver disease, but also external factors, endocrine disease, genitourinary disease and neoplasms (excluding hepatocellular carcinoma).

[Lyme neuroborreliosis in adults].

Lyme neuroborreliosis (LNB) caused by the spirochete bacteria Borrelia burgdorferi sensu lato complex is the most common bacterial neuroinfection in Denmark (180 cases per year). One of the main challenges to LNB is the diagnosis due to its variant manifestations often involving the skin, musculosceletal or nervous system affecting patient morbidity. Recent data shows a diagnostic delay of 21 days in laboratory-confirmed patients in Denmark. The aim of this review is to summarise current state of knowledge concerning clinical manifestations, diagnostic assessment, antibiotic therapy, and prognosis.

Using 18F-FDG PET/CT to rule out Richter transformation as cause of deterioration in a patient with chronic lymphatic leukemia and severe COVID-19: A case report.

RATIONALE: This case report demonstrates the use of flourine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) to rule out Richter transformation (RT) as the cause of clinical deterioration in a patient with chronic lymphatic leukemia (CLL) and severe COVID-19. 18F-FDG PET/CT can be used to establish the diagnosis of RT in patients with CLL, but the use of 18F-FDG PET/CT to exclude RT as the cause of clinical deterioration in patients with CLL and severe COVID-19 has not previously been described. PATIENT CONCERNS: A 61-year-old male with CLL and COVID-19 developed increased dyspnea, malaise and fever during hospitalization for treatment of severe and prolonged COVID-19. DIAGNOSES: 18F-FDG PET/CT ruled out RT and revealed progression of opacities in both lungs consistent with exacerbation of severe acute respiratory syndrome coronavirus 2 pneumonia. INTERVENTIONS: 18F-FDG PET/CT imaging. OUTCOMES: The patient was discharged at day 52 without the need of supplemental oxygen, with normalized infection marks and continued care for CLL with venetoclax. LESSONS: 18F-FDG PET/CT ruled out RT as the cause of deteriorations in a patient with CLL and severe COVID-19, enabling directed care of exacerbation of severe acute respiratory syndrome coronavirus 2 pneumonia.