Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have been characterized in the context of malignancies. Here we show that PMN-MDSCs can restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G+ cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and interleukin-6 (IL-6), and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G+ cells or dysfunction of Ly6G+ cells through conditional ablation of STAT3 led to the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and lack of recovery from EAE. The frequency of CD138+ B cells in the cerebrospinal fluid (CSF) of human subjects with multiple sclerosis was negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells in the inflamed CNS.

Mutual regulation of CD4+ T cells and intravascular fibrin in infections.

Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin - CD4+ T cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T cell activation, which is initially triggered by IL- 12p40- and MHC-II dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the fibrinolysis inhibitor TAFI with fibrin whereby fibrin deposition is increased by TAFI in the absence but not presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1 dependent T helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development.

PCR-positive meningococcal CSF infection without pleocytosis but high IL-6 and IL-8.

BACKGROUND: Meningococcal meningitis is still a severe disease causing high mortality and morbidity rates. Early diagnosis is crucial to ensure prompt antibiotic therapy. However, identification of the pathogen can be challenging. CASE PRESENTATION: A 32-year-old male patient with systemic lupus erythematosus (SLE) presented to the emergency room with fever, nausea, vomiting, headache and lower back pain as well as multiple petechial bleedings. On suspicion of meningococcal infection, the emergency doctor had already administered one dose of ceftriaxone before arrival to the clinic. Blood works showed massive inflammation due to bacterial infection. Cerebrospinal fluid (CSF) analysis showed normal cell count, protein and glucose levels but PCR was positive for Neisseria meningitis and IL-6 as well as IL-8 were elevated. On antibiotic therapy with ceftriaxone, the patient's condition improved quickly. CONCLUSIONS: We present a rare case of meningococcal infection of the CSF in a SLE patient without further CSF abnormalities. We discuss the involvement of early antibiotic treatment and the role of the patient's immune status in the normal CSF findings of this case. Moreover, this case demonstrates the importance of early antibiotic therapy in bacterial meningitis for the clinical outcome.

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.

Pericytes are protective in experimental pneumococcal meningitis through regulating leukocyte infiltration and blood-brain barrier function.

BACKGROUND: Brain pericytes participate in the regulation of cerebral blood flow and the maintenance of blood-brain barrier integrity. Because of their perivascular localization, their receptor repertoire, and their potential ability to respond to inflammatory and infectious stimuli by producing various cytokines and chemokines, these cells are also thought to play an active role in the immune response to brain infections. This assumption is mainly supported by in vitro studies, investigations in in vivo disease models are largely missing. Here, we analysed the role of brain pericytes in pneumococcal meningitis, in vitro and in vivo in two animal models of pneumococcal meningitis. METHODS: Primary murine and human pericytes were stimulated with increasing concentrations of different serotypes of Streptococcus pneumoniae in the presence or absence of Toll-like receptor inhibitors and their cell viability and cytokine production were monitored. To gain insight into the role of pericytes in brain infection in vivo, we performed studies in a zebrafish embryo model of pneumococcal meningitis in which pericytes were pharmacologically depleted. Furthermore, we analyzed the impact of genetically induced pericyte ablation on disease progression, intracranial complications, and brain inflammation in an adult mouse model of this disease. RESULTS: Both murine and human pericytes reacted to pneumococcal exposure with the release of selected cytokines. This cytokine release is pneumolysin-dependent, TLR-dependent in murine (but not human) pericytes and can be significantly increased by macrophage-derived IL-1b. Pharmacological depletion of pericytes in zebrafish embryos resulted in increased cerebral edema and mortality due to pneumococcal meningitis. Correspondingly, in an adult mouse meningitis model, a more pronounced blood-brain barrier disruption and leukocyte infiltration, resulting in an unfavorable disease course, was observed following genetic pericyte ablation. The degree of leukocyte infiltration positively correlated with an upregulation of chemokine expression in the brains of pericyte-depleted mice. CONCLUSIONS: Our findings show that pericytes play a protective role in pneumococcal meningitis by impeding leukocyte migration and preventing blood-brain barrier breaching. Thus, preserving the integrity of the pericyte population has the potential as a new therapeutic strategy in pneumococcal meningitis.

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.

Quantitative proteomic analysis of cerebrospinal fluid from patients with idiopathic facial nerve palsy.

BACKGROUND AND PURPOSE: Idiopathic facial palsy (IFP) accounts for over 60% of peripheral facial palsy (FP) cases. The cause of IFP remains to be determined. Possible etiologies are nerve swelling due to inflammation and/or viral infection. In this study, we applied an integrative mass spectrometry approach to identify possibly altered protein patterns in the cerebrospinal fluid (CSF) of IFP patients. METHODS: We obtained CSF samples from 34 patients with FP. In four patients, varicella-zoster virus was the cause (VZV-FP). Among the 30 patients diagnosed with IFP, 17 had normal CSF parameters, five had slightly elevated CSF cell counts and normal or elevated CSF protein, and eight had normal CSF cell counts but elevated CSF protein. Five patients with primary headache served as controls. All samples were tested for viral pathogens by PCR and subjected to liquid chromatography tandem mass spectrometry and bioinformatics analysis and multiplex cytokine/chemokine arrays. RESULTS: All CSF samples, except those from VZV-FP patients, were negative for all tested pathogens. The protein composition of CSF samples from IFP patients with normal CSF was comparable to controls. IFP patients with elevated CSF protein showed dysregulated proteins involved in inflammatory pathways, findings which were similar to those in VZV-FP patients. Multiplex analysis revealed similarly elevated cytokine levels in the CSF of IFP patients with elevated CSF protein and VZV-FP. CONCLUSIONS: Our study revealed a subgroup of IFP patients with elevated CSF protein that showed upregulated inflammatory pathways, suggesting an inflammatory/infectious cause. However, no evidence for an inflammatory cause was found in IFP patients with normal CSF.

Community-acquired bacterial meningitis.

Progress has been made in the prevention and treatment of community-acquired bacterial meningitis during the past three decades but the burden of the disease remains high globally. Conjugate vaccines against the three most common causative pathogens (Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae) have reduced the incidence of disease, but with the replacement by non-vaccine pneumococcal serotypes and the emergence of bacterial strains with reduced susceptibility to antimicrobial treatment, meningitis continues to pose a major health challenge worldwide. In patients presenting with bacterial meningitis, typical clinical characteristics (such as the classic triad of neck stiffness, fever, and an altered mental status) might be absent and cerebrospinal fluid examination for biochemistry, microscopy, culture, and PCR to identify bacterial DNA are essential for the diagnosis. Multiplex PCR point-of-care panels in cerebrospinal fluid show promise in accelerating the diagnosis, but diagnostic accuracy studies to justify routine implementation are scarce and randomised, controlled studies are absent. Early administration of antimicrobial treatment (within 1 hour of presentation) improves outcomes and needs to be adjusted according to local emergence of drug resistance. Adjunctive dexamethasone treatment has proven efficacy beyond the neonatal age but only in patients from high-income countries. Further progress can be expected from implementing preventive measures, especially the development of new vaccines, implementation of hospital protocols aimed at early treatment, and new treatments targeting checkpoints of the inflammatory cascade.

In vivo proteomics identifies the competence regulon and AliB oligopeptide transporter as pathogenic factors in pneumococcal meningitis.

Streptococcus pneumoniae (pneumococci) is a leading cause of severe bacterial meningitis in many countries worldwide. To characterize the repertoire of fitness and virulence factors predominantly expressed during meningitis we performed niche-specific analysis of the in vivo proteome in a mouse meningitis model, in which bacteria are directly inoculated into the cerebrospinal fluid (CSF) cisterna magna. We generated a comprehensive mass spectrometry (MS) spectra library enabling bacterial proteome analysis even in the presence of eukaryotic proteins. We recovered 200,000 pneumococci from CSF obtained from meningitis mice and by MS we identified 685 pneumococci proteins in samples from in vitro filter controls and 249 in CSF isolates. Strikingly, the regulatory two-component system ComDE and substrate-binding protein AliB of the oligopeptide transporter system were exclusively detected in pneumococci recovered from the CSF. In the mouse meningitis model, AliB-, ComDE-, or AliB-ComDE-deficiency resulted in attenuated meningeal inflammation and disease severity when compared to wild-type pneumococci indicating the crucial role of ComDE and AliB in pneumococcal meningitis. In conclusion, we show here mechanisms of pneumococcal adaptation to a defined host compartment by a proteome-based approach. Further, this study provides the basis of a promising strategy for the identification of protein antigens critical for invasive disease caused by pneumococci and other meningeal pathogens.

Combined therapy with ceftriaxone and doxycycline does not improve the outcome of meningococcal meningitis in mice compared to ceftriaxone monotherapy.

BACKGROUND: Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10-20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM. METHODS: BALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi. RESULTS: Analysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX. CONCLUSIONS: Treatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.

Virulence Traits of a Serogroup C Meningococcus and Isogenic cssA Mutant, Defective in Surface-Exposed Sialic Acid, in a Murine Model of Meningitis.

In serogroup C Neisseria meningitidis, the cssA (siaA) gene codes for an UDP-N-acetylglucosamine 2-epimerase that catalyzes the conversion of UDP-N-acetyl-α-d-glucosamine into N-acetyl-d-mannosamine and UDP in the first step in sialic acid biosynthesis. This enzyme is required for the biosynthesis of the (α2→9)-linked polysialic acid capsule and for lipooligosaccharide (LOS) sialylation. In this study, we have used a reference serogroup C meningococcal strain and an isogenic cssA knockout mutant to investigate the pathogenetic role of surface-exposed sialic acids in a model of meningitis based on intracisternal inoculation of BALB/c mice. Results confirmed the key role of surface-exposed sialic acids in meningococcal pathogenesis. The 50% lethal dose (LD50) of the wild-type strain 93/4286 was about four orders of magnitude lower than that of the cssA mutant. Compared to the wild-type strain, the ability of this mutant to replicate in brain and spread systemically was severely impaired. Evaluation of brain damage evidenced a significant reduction in cerebral hemorrhages in mice infected with the mutant in comparison with the levels in those challenged with the wild-type strain. Histological analysis showed the typical features of bacterial meningitis, including inflammatory cells in the subarachnoid, perivascular, and ventricular spaces especially in animals infected with the wild type. Noticeably, 80% of mice infected with the wild-type strain presented with massive bacterial localization and accompanying inflammatory infiltrate in the corpus callosum, indicating high tropism of meningococci exposing sialic acids toward this brain structure and a specific involvement of the corpus callosum in the mouse model of meningococcal meningitis.

Challenges in HSV encephalitis: normocellular CSF, unremarkable CCT, and atypical MRI findings.

PURPOSE: Herpes simplex virus (HSV) encephalitis continues to be the most common form of sporadic lethal encephalitis worldwide. The wide spectrum of clinical presentations and laboratory findings often poses a diagnostic challenge for physicians which might delay administration of life-saving therapy with acyclovir. Atypical presentations of HSV encephalitis have become increasingly prevalent with better diagnostic techniques and have not been well studied. METHODS: We retrospectively evaluated all consecutive PCR-proven HSV encephalitis cases treated at the Hospital of the Ludwig-Maximilians-University in Munich, Germany from January 1, 2013 to February 28, 2018. RESULTS: We included 18 patients with PCR-proven HSV encephalitis. The most common clinical features were altered mental status (77.8%), focal neurologic deficits (72.2%) and fever (72.2%). Remarkably, four of these patients (22.2%) had a normocellular cerebrospinal fluid (CSF) on admission. Electroencephalography and magnetic resonance imaging abnormalities were highly sensitive for HSV encephalitis independent of CSF cell count. Striking atypical findings on MRI were extensive global brain swelling and severe brainstem involvement in single patients. Of note, initial CT scans were normal in 11 out of 16 patients (68.8%). All patients were treated with acyclovir. Three patients still developed a clinical deterioration under therapy with acyclovir with one patient requiring decompressive craniotomy due to bilateral space-occupying temporal lobe hemorrhage. 94.4% of the patients survived but only 38.9% were discharged with a good clinical outcome (Glasgow Outcome Score = 5). CONCLUSION: Atypical presentations of HSV encephalitis seem to be more common than previously thought and physicians should apply a high level of clinical suspicion and a low threshold to initiate life-saving acyclovir therapy in suspected cases.

Novel and preclinical treatment strategies in pneumococcal meningitis.

PURPOSE OF REVIEW: Pneumococcal meningitis is the most frequent form of bacterial meningitis in Europe and the United States. Although early antimicrobial and adjuvant therapy with dexamethasone have helped to improve disease outcome in adults, mortality and morbidity rates remain unsatisfactorily high, emphasizing the need for additional treatment options. Promising targets for adjuvant therapy have been identified recently and will be the focus of this review. RECENT FINDINGS: Brain disease in pneumococcal meningitis is caused by direct bacterial toxicity and excessive meningeal inflammation. Accordingly, promising targets for adjuvant therapy comprise limiting the release of toxic bacterial products and suppressing inflammation in a way that maximally protects against tissue injury without hampering pathogen eradication by antibiotics. Among the agents tested so far in experimental models, complement inhibitors, matrix-metalloproteinase inhibitors, and nonbacteriolytic antibiotics or a combination of the above have the potential to more efficiently protect the brain either alone (e.g., in children and outside the high-income settings) or in addition to adjuvant dexamethasone. Additionally, new protein-based pneumococcal vaccines are being developed that promise to improve disease prevention, namely by addressing the increasing problem of serotype replacement seen with pneumococcal conjugate vaccines. SUMMARY: Pneumococcal meningitis remains a life-threatening disease requiring early antibiotic and targeted anti-inflammatory therapy. New adjuvant therapies showed promising results in animal models but need systematic clinical testing.

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.

Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. METHODS: We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. RESULTS: Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. CONCLUSIONS: DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.

Lyme neuroborreliosis.

PURPOSE OF REVIEW: Lyme disease is a multistage and multisystem disease. Neurological manifestations [termed Lyme neuroborreliosis (LNB)] occur in about 10% of patients with Lyme disease. Diagnostics and treatment of early and late LNB are widely established. However, the management of persistent symptoms is still fraught with controversies, and therefore is the focus of this review. RECENT FINDINGS: The incidence of Lyme disease seems to be much higher than previously assumed. Laboratory methods (namely serological tests) are essential for diagnosing LNB, but only when performed according to the guidelines of scientific medical societies. Most patients treated for LNB have good outcomes. However, some patients remain with nonspecific symptoms despite conventional therapy, a syndrome called posttreatment Lyme disease syndrome (PTLDS). IDSA has provided a formal definition of PTLDS, but its pathogenesis and even its existence remains to be clarified. Of note, there is evidence that these patients do not suffer from persistent Borrelia burgdorferi infection and do not benefit from additional antibiotic therapy. SUMMARY: Acute and late LNB are well established disorders. The existence of PTLDS as a disease entity is still unclear and needs further investigation. Unorthodox alternative therapies advertised to patients with Lyme disease on the Internet are not proven to be effective and well tolerated.

The role of host and microbial factors in the pathogenesis of pneumococcal bacteraemia arising from a single bacterial cell bottleneck.

The pathogenesis of bacteraemia after challenge with one million pneumococci of three isogenic variants was investigated. Sequential analyses of blood samples indicated that most episodes of bacteraemia were monoclonal events providing compelling evidence for a single bacterial cell bottleneck at the origin of invasive disease. With respect to host determinants, results identified novel properties of splenic macrophages and a role for neutrophils in early clearance of pneumococci. Concerning microbial factors, whole genome sequencing provided genetic evidence for the clonal origin of the bacteraemia and identified SNPs in distinct sub-units of F0/F1 ATPase in the majority of the ex vivo isolates. When compared to parental organisms of the inoculum, ex-vivo pneumococci with mutant alleles of the F0/F1 ATPase had acquired the capacity to grow at low pH at the cost of the capacity to grow at high pH. Although founded by a single cell, the genotypes of pneumococci in septicaemic mice indicate strong selective pressure for fitness, emphasising the within-host complexity of the pathogenesis of invasive disease.

Dramatic reduction of mortality in pneumococcal meningitis.

BACKGROUND: Acute bacterial meningitis is still a life threatening disease. METHODS: We performed a retrospective observational study on the clinical characteristics of consecutively admitted patients with acute pneumococcal meningitis in a single tertiary care center in central Europe (from 2003 until 2015). Data were compared with a previously published historical group of 87 patients treated for pneumococcal meningitis at the same hospital (from 1984 until 2002). RESULTS: Fifty-five consecutive patients with microbiologically proven pneumococcal meningitis were included. Most striking, mortality was down to 5.5 %, which was significantly lower than in the historical group where 24.1 % of the patients did not survive. Intracranial complications during the course of the disease were common and affected half of the patients. Unlike in the historic group, most of the intracranial complications (except ischemic stroke) were no longer associated with a low Glasgow Outcome Score at discharge. CONCLUSION: The drastic reduction of mortality proves there have been important advances in the treatment of pneumococcal meningitis. Nevertheless, the fact that only 44.2 % of survivors had a full recovery indicates that the search for new adjunctive treatment options must be ongoing.