Combining antibiotic with anti-TLR2/TLR13 therapy prevents brain pathology in pneumococcal meningitis.

Despite effective antibiotic therapy, brain-destructive inflammation often cannot be avoided in pneumococcal meningitis. The causative signals are mediated predominantly through TLR-recruited myeloid differentiation primary response adaptor 88 (MyD88), as indicated by a dramatic pneumococcal meningitis phenotype of Myd88-/- mice. Because lipoproteins and single-stranded RNA are crucial for recognition of Gram-positive bacteria such as Streptococcus pneumoniae by the host immune system, we comparatively analyzed the disease courses of Myd88-/- and Tlr2-/- Tlr13-/- mice. Their phenotypic resemblance indicated TLR2 and -13 as master sensors of S. pneumoniae in the cerebrospinal fluid. A neutralizing anti-TLR2 antibody (T2.5) and chloroquine (CQ) - the latter applied here as an inhibitor of murine TLR13 and its human ortholog TLR8 - abrogated activation of murine and human primary immune cells exposed to antibiotic-treated S. pneumoniae. The inhibitory effect of the T2.5/CQ cocktail was stronger than that of dexamethasone, the current standard adjunctive drug for pneumococcal meningitis. Accordingly, TLR2/TLR13 blockade concomitant with ceftriaxone application significantly improved the clinical course of pneumococcal meningitis compared with treatment with ceftriaxone alone or in combination with dexamethasone. Our study indicates the importance of murine TLR13 and human TLR8, besides TLR2, in pneumococcal meningitis pathology, and suggests their blockade as a promising antibiotic therapy adjunct.

Characterization and diagnosis spectrum of patients with cerebrospinal fluid pleocytosis.

PURPOSE: There is an overlap in the cerebrospinal fluid (CSF) characteristics of patients presenting with different etiologies of CSF pleocytosis. Here, we characterized patients with CSF pleocytosis treated in a large hospital. METHODS: A retrospective cohort study of 1150 patients with an elevated CSF leukocyte count > 5 cells/µl treated at a university hospital in Germany from January 2015 to December 2017 was performed. Information on clinical presentation, laboratory parameters, diagnosis and outcome was collected. Clinical and laboratory features were tested for their potential to differentiate between bacterial meningitis (BM) and other causes of CSF pleocytosis. RESULTS: The most common etiologies of CSF pleocytosis were CNS infections (34%: 20% with detected pathogen, 14% without), autoimmune (21%) and neoplastic diseases (16%). CSF cell count was higher in CNS infections with detected pathogen (median 82 cells/µl) compared to autoimmune (11 cells/µl, p = 0.001), neoplastic diseases (19 cells/µl, p = 0.01) and other causes (11 cells/µl, p < 0.001). The CHANCE score was developed to differentiate BM from other causes of CSF pleocytosis: Multivariate regression revealed that CSF cell count > 100 cells/µl, CSF protein > 100 mg/dl, CRP > 5 mg/dl, elevated white blood cell count, abnormal mental status and nuchal rigidity are important indicators. The CHANCE score identified patients with BM with high sensitivity (92.1%) and specificity (90.9%) (derivation cohort: AUC: 0.955, validation cohort: AUC: 0.956). CONCLUSION: Overall, the most common causes for CSF pleocytosis include infectious, neoplastic or autoimmune CNS diseases in ~ 70% of patients. The CHANCE score could be of help to identify patients with high likelihood of BM and support clinical decision making.

A prospective longitudinal cohort study on risk factors for COVID-19 vaccination failure (RisCoin): methods, procedures and characterization of the cohort.

The primary objective of the RisCoin study was to investigate the interplay of genetic, metabolic, and lifestyle factors as well as stress levels on influencing the humoral immune response after at least two COVID-19 vaccinations, primarily with mRNAs, and the risk of SARS-CoV-2 breakthrough infections during follow-up. Here, we describe the study design, procedures, and study population. RisCoin is a prospective, monocentric, longitudinal, observational cohort study. Between October and December 2021, 4515 participants with at least two COVID-19 vaccinations, primarily BNT162b2 and mRNA-1273, were enrolled at the LMU University Hospital of Munich, thereof > 4000 healthcare workers (HCW), 180 patients with inflammatory bowel disease under immunosuppression, and 119 patients with mental disorders. At enrollment, blood and saliva samples were collected to measure anti-SARS-CoV-2 antibodies, their neutralizing capacity against Omicron-BA.1, stress markers, metabolomics, and genetics. To ensure the confidential handling of sensitive data of study participants, we developed a data protection concept and a mobile application for two-way communication. The application allowed continuous data reporting, including breakthrough infections by the participants, despite irreversible anonymization. Up to 1500 participants attended follow-up visits every two to six months after enrollment. The study gathered comprehensive data and bio-samples of a large representative HCW cohort and two patient groups allowing analyses of complex interactions. Our data protection concept combined with the mobile application proves the feasibility of longitudinal assessment of anonymized participants. Our concept may serve as a blueprint for other studies handling sensitive data on HCW.

[Influence of the COVID-19 pandemic on the occurrence of neurological infectious diseases]. / Einfluss der COVID-19-Pandemie auf das Auftreten neuroinfektiologischer Erkrankungen.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic a wide range of hygiene measures were implemented to contain the spread of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Besides a mitigation of SARS-CoV­2, a decline in the number of other respiratory tract infections could be observed. Interestingly, the numbers for some infections of the central nervous system (CNS) decreased as well. OBJECTIVE: This review article shows the development of important CNS infections in Germany during the COVID-19 pandemic. MATERIAL AND METHOD: This article is based on relevant literature on the epidemiology of CNS infections during the COVID-19 pandemic up to autumn 2022. RESULTS: During the COVID-19 pandemic the frequency of bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae significantly declined. The frequency of viral meningitis, particularly those caused by Enterovirus, decreased as well. In contrast, the number of patients suffering from tick-borne encephalitis significantly increased within the first year of the pandemic. DISCUSSION: During the pandemic there was a decrease in cases of bacterial and viral meningitis, most likely due to the general containment strategies and social contact restrictions. The increase of infections transmitted by ticks could be a consequence of changed leisure activities during the pandemic.

Cerebrospinal fluid analysis in emergency patients with suspected infection of the central nervous system.

BACKGROUND AND PURPOSE: Meningitis and encephalitis are potentially life-threatening diseases that require fast and accurate diagnostics and therapy. The value of polymerase chain reaction (PCR) multiplex testing in clinical practice is still a matter of debate. This study aims to evaluate its benefits and limitations in emergency patients. METHODS: We assessed the value of a meningoencephalitis PCR array in the clinical routine of an emergency department. RESULTS: Of 1578 emergency patients who received a lumbar puncture, 43% received it for a clinically suspected central nervous system (CNS) infection. After initial workup for cerebrospinal fluid (CSF) cell count, protein and glucose, a CNS infection was still considered likely in 307 patients. In these patients, further microbiologic workup was performed. A total of 230 samples were examined by PCR and a pathogen was detected in 66 of these samples. In the case of a positive microbiologic result, a comparison between PCR array and standard method was available for 59 samples, which demonstrated an overcall agreement of 80% (n = 47/59). Of interest, exclusively array-positive results were observed for patients with meningitis found to be positive for Streptococcus pneumoniae; four out of five patients had been treated with antibiotics before the lumbar puncture. In samples with normal CSF cell count only two positive array results were obtained, both for human herpesvirus 6, and these were not clinically relevant. CONCLUSION: Our data suggest that the array substantially contributes to a detection of pathogens in patients with suspected CNS infection and seems of particular interest in patients with acute bacterial meningitis under empiric antibiotic treatment. In CSF samples with normal cell count, it might be dispensable.

Patient disposition using the Emergency Severity Index: a retrospective observational study at an interdisciplinary emergency department.

OBJECTIVES: Early patient disposition is crucial to prevent crowding in emergency departments (EDs). Our study aimed to characterise the need of in-house resources for patients treated in the ED according to the Emergency Severity Index (ESI) and the presenting complaint at the timepoint of triage. DESIGN: A retrospective single-centre study was conducted. SETTING: Data of all patients who presented to the interdisciplinary ED of a tertiary care hospital in Munich, Germany, from 2014 to 2017 were analysed. PARTICIPANTS: n=113 694 patients were included. MEASURES: ESI Score, medical speciality according to the chief complaint, mode of arrival, admission rates and discharge destination from the ED were evaluated. RESULTS: Patient disposition varied according to ESI scores in combination with the chief complaint. Patients with low ESI scores were more likely to be admitted after treatment in the ED than patients with high ESI scores. Highly prioritised patients (ESI 1) mainly required admission to an intensive care unit (ICU, 27%), intermediate care unit (IMC, 37%) or immediate intervention (11%). In this critical patient group, 30% of patients with neurological or medical symptoms required immediate intensive care, whereas only 17% of patients with surgical problems were admitted to an ICU. A significant number of patients (particularly with neurological or medical problems) required hospital (and in some cases even ICU or IMC) admission despite high ESI scores. CONCLUSIONS: Overall, ESI seems to be a useful tool to anticipate the need for specialised in-hospital resources on arrival. Patients with symptoms pointing at neurological or medical problems need particular attention as ESI may fail to sufficiently predict the care facility level for this patient group.

Decline in the number of patients with meningitis in German hospitals during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated. RESULTS: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001). DISCUSSION: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis.

TSPO PET With 18F-GE-180 to Differentiate Variants of Multiple Sclerosis: Relapsing-Remitting Multiple Sclerosis, Tumefactive Demyelination, and Baló's Concentric Sclerosis.

PET targeting the translocator protein (TSPO) expression is an interesting approach to detect neuroinflammation, as TSPO is upregulated in activated macrophages and microglia. Considering the variable pathophysiology of multiple sclerosis (MS) variants, we compare TSPO PET using F-GE-180 in 3 different demyelinating diseases of the central nervous system: relapsing-remitting MS, tumefactive MS, and Baló's concentric sclerosis. Visualization of neuroinflammation and its PET patterns in addition to MRI may contribute to accurate distinction and monitoring of central nervous system demyelination.

Abundant glutamic acid decarboxylase (GAD)-reactive B cells in gad-antibody-associated neurological disorders.

High levels of antibodies against glutamic acid decarboxylase (GAD) are observed in patients with different neurological disorders, but cells producing these autoantibodies are largely unexplored. We detect circulating GAD-reactive B cells in peripheral blood that readily differentiate into antibody-producing cells. These cells are highly elevated in most patients with GAD-antibody-associated disorders (n = 15) compared to controls (n = 19). They mainly produce GAD65 antibodies of the IgG1 and IgG4 subclasses and are as abundant as B cells reactive for common recall antigens. Bone marrow cells represent an additional source of GAD antibodies. The identification of GAD-antibody-producing cells has implications for the selection of cell-specific biologics. ANN NEUROL 2019;85:448-454.

Impaired Consciousness in the Emergency Department.

BACKGROUND: The approach to unconscious patients in the emergency department (ED) is difficult, often depends on local resources and interests, and workup strategies often lack standardization. One reason for this is that data on causes, management, and outcome of patients who present to the ED with sudden onset unconsciousness of unknown cause is limited. OBJECTIVES: This study was performed to analyze the causes of acute impaired consciousness in patients in an interdisciplinary ED. METHODS: Here, we analyzed all patients who were admitted to the ED of a tertiary care hospital with the dominating symptom of "sudden onset unconsciousness" within 1 year (September 2014 until August 2015). Patients with a clear diagnosis at arrival that explained the altered state of consciousness or other dominating symptoms at the time of arrival were not included. RESULTS: A total of 212 patients were analyzed. In 88% of the patients, a final diagnosis could be established in the ED. Most common causes for unconsciousness were cerebrovascular diseases (24%), infections (14%), epileptic seizures (12%), psychiatric diseases (8%), metabolic causes (7%), intoxications (7%), transient global amnesia (5%), and cardiovascular causes (4%). The diagnoses were predominantly established by physical examination in combination with computed tomography (23%) and by the results of laboratory testing (25%). In-hospital mortality was 11%, and 59% of all patients were discharged with a Glasgow Outcome Score of 2-4. CONCLUSIONS: This analysis demonstrates a large variety of etiologies in patients with unknown unconsciousness of acute onset who are admitted to an ED. As neurological diagnoses are among the most common etiologies, neurological qualification is required in the ED, and availability of diagnostics such as cerebral imaging is indispensable and recommended as an early step in a standardized clinical approach.

Interleukin-22 is elevated in lavage from patients with lung cancer and other pulmonary diseases.

BACKGROUND: Interleukin-22 (IL-22) is involved in lung diseases such as pneumonia, asthma and lung cancer. Lavage mirrors the local environment, and may provide insights into the presence and role of IL-22 in patients. METHODS: Bronchoscopic lavage (BL) samples (n = 195, including bronchoalveolar lavage and bronchial washings) were analysed for IL-22 using an enzyme-linked immunosorbent assay. Clinical characteristics and parameters from lavage and serum were correlated with lavage IL-22 concentrations. RESULTS: IL-22 was higher in lavage from patients with lung disease than in controls (38.0 vs 15.3 pg/ml, p < 0.001). Patients with pneumonia and lung cancer had the highest concentrations (48.9 and 33.0 pg/ml, p = 0.009 and p < 0.001, respectively). IL-22 concentration did not correlate with systemic inflammation. IL-22 concentrations did not relate to any of the analysed cell types in BL indicating a potential mixed contribution of different cell populations to IL-22 production. CONCLUSIONS: Lavage IL-22 concentrations are high in patients with lung cancer but do not correlate with systemic inflammation, thus suggesting that lavage IL-22 may be related to the underlying malignancy. Our results suggest that lavage may represent a distinct compartment where the role of IL-22 in thoracic malignancies can be studied.

Interleukin-22 is frequently expressed in small- and large-cell lung cancer and promotes growth in chemotherapy-resistant cancer cells.

INTRODUCTION: In lung cancer, interleukin-22 (IL-22) expression within primary tissue has been demonstrated, but the frequency and the functional consequence of IL-22 signaling have not been addressed. This study aims at analyzing the cellular effects of IL-22 on lung carcinoma cell lines and the prognostic impact of IL-22 tissue expression in lung cancer patients. METHODS: Biological effects of IL-22 signaling were investigated in seven lung cancer cell lines by Western blot, flow cytometry, real-time polymerase chain reaction, and proliferation assays. Tumor tissue specimens of two cohorts with a total of 2300 lung cancer patients were tested for IL-22 expression by immunohistochemistry. IL-22 serum concentrations were analyzed in 103 additional patients by enzyme-linked immunosorbent assay. RESULTS: We found the IL-22 receptor 1 (IL-22-R1) to be expressed in six of seven lung cancer cell lines. However IL-22 signaling was functional in only four cell lines, where IL-22 induced signal transducer activator of transcription 3 phosphorylation and increased cell proliferation. Furthermore, IL-22 induced the expression of antiapoptotic B-cell lymphoma 2, but did not rescue tumor cells from carboplatin-induced apoptosis. Cisplatin-resistant cell lines showed a significant up-regulation of IL-22-R1 along with a stronger proliferative response to IL-22 stimulation. IL-22 was preferentially expressed in small- and large-cell lung carcinoma (58% and 46% of cases, respectively). However, no correlation between IL-22 expression by immunohistochemistry and prognosis was observed. CONCLUSION: IL-22 is frequently expressed in lung cancer tissue. Enhanced IL-22-R1 expression and signaling in chemotherapy-refractory cell lines are indicative of a protumorigenic function of IL-22 and may contribute to a more aggressive phenotype.