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Background Recurrent bacterial meningitis has been found to occur in about 5% of meningitis cases. Methods We analyzed adults with recurrent episodes in a prospective nationwide cohort study of community-acquired bacterial meningitis. Results Of 2264 episodes of community-acquired bacterial meningitis between 2006 and 2018, 143 (6%) were identified as recurrent episodes in 123 patients. The median age was 57 years (interquartile range [IQR], 43–66), and 57 episodes (46%) occurred in men. The median duration between the first and the current episode was 5 years (IQR, 1–15). For 82 of 123 patients (67%), it was the first recurrent episode, 31 patients had 2–5 previous episodes (25%), 2 had 6–10 episodes (2%), and 2 had >10 episodes (2%). Predisposing factors were identified in 87 of 118 patients (74%) and most commonly consisted of ear or sinus infections (43 of 120, 36%) and cerebrospinal fluid leakage (37 of 116, 32%). The most common pathogens were Streptococcus pneumoniae (93 of 143, 65%) and Haemophilus influenzae (19 of 143, 13%). The outcome was unfavorable (Glasgow outcome scale score, Recurrent meningitis occurs mainly in patients with ear or sinus infections and cerebrospinal fluid leakage. Predominant causative pathogens are Streptococcus pneumoniae and Haemophilus influenzae. The disease course is less severe, resulting in lower case fatality compared with nonrecurrent meningitis patients.

Contains fulltext : 287661.pdf (Publisher’s version ) (Closed access) BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO(2)/FiO(2) ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

We aimed to derive and validate a risk score to differentiate patients with bacterial meningitis from those with viral meningitis or encephalitis, among patients presenting with CSF leukocytosis and a negative Gram stain.We included adults with bacterial and viral meningitis or encephalitis, presenting with CSF leukocytes10 per mmDerivation was performed in 109 American patients with bacterial meningitis (median age 56 [interquartile range (IQR) 46-66], 46% female) and 194 with viral meningitis or encephalitis (median age 46 [IQR 33-60], 53% female). Serum leukocytes10.0 x10Our risk score may be able to rule out bacterial meningitis, among patients presenting with CSF leukocytosis and a negative Gram stain. However, it needs prospective testing prior to clinical implementation.

Background Cerebrospinal fluid (CSF) leakage is a risk factor for developing bacterial meningitis. Methods We analyzed episodes of community-acquired bacterial meningitis associated with CSF leakage from a prospective nationwide cohort study. Results CSF leakage was identified in 65 episodes of 2022 episodes (3%) in 53 patients. The cause of CSF leakage was identified in 49 of 65 episodes (75%), which most commonly consisted of ear-nose-throat surgery (19 of 49 episodes [29%]) and remote head trauma (15 of 49 episodes [23%]). The episode was a recurrent meningitis episode in 38 patients (59%). Of the recurrent episodes, 27 had known CSF leakage (71%) of whom 20 (53%) had previous surgery aiming to close the leak. Nine patients (38%) with known CSF leakage had been vaccinated (23-valent pneumococcal vaccine in 9 patients, meningococcal serogroup C vaccine in 2, meningococcal serogroup A and Haemophilus influenzae type b vaccine each in 1 patient). Streptococcus pneumoniae was cultured in 33 episodes (51%) and H. influenzae in 11 episodes (17%). The most common pneumococcal serotypes were 3 (4 episodes), 35B, 9N, 38, and 15C (each 2 episodes). Haemophilus influenzae was unencapsulated in all 10 episodes with known capsule type. The outcome was unfavorable in 8 episodes (12%) and no patient died. Conclusions Bacterial meningitis in patients with CSF leakage has a high recurrence rate, despite surgical repair or vaccination, and outcome is generally favorable. CSF leakage should be suspected in patients with bacterial meningitis presenting with liquorrhea, recurrent meningitis, or with disease caused by H. influenzae., Bacterial meningitis in patients with Cerebrospinal Fluid leakage has a high recurrence rate, despite surgery to repair the leak or vaccination, and outcome is generally favorable. Leakage should be suspected in patients with liquorrhea, recurrent meningitis, or with Haemophilus influenzae meningitis.

Background The epidemiology and treatment of pneumococcal meningitis has changed with the implementation of conjugate vaccines and the introduction of adjunctive dexamethasone therapy. Methods We analyzed episodes of community-acquired pneumococcal meningitis in adults (≥16 years) in the Netherlands, identified by the National Reference Laboratory for Bacterial Meningitis or treating physician between October 1, 1998, and April 1, 2002, and between January 1, 2006, and July 1, 2018. We studied incidence, pneumococcal serotypes, and clinical features. Predictors for unfavorable outcome (Glasgow Outcome Scale score 1–4) were identified in a multivariable logistic regression model. Two physicians independently categorized causes of death as neurological or systemic. Results There were 1816 episodes in 1783 patients. The incidence of 7- and 10−7-valent pneumococcal conjugate vaccine serotypes decreased (from 0.42 to 0.06, P = .001; from 0.12 to 0.03 episodes per 100 000 population per year, P = .014). Incidence of nonvaccine serotypes increased (from 0.45 to 0.68, P = .005). The use of adjunctive treatment with dexamethasone increased and was administered in 85% of patients in 2018. In-hospital death occurred in 363 episodes (20%) and unfavorable outcome in 772 episodes (43%). Delayed cerebral thrombosis occurred in 29 patients (2%), of whom 15 patients (52%) died. Adjunctive dexamethasone therapy was associated with favorable outcome (adjusted odds ratio 2.27, P Conclusion Implementation of conjugate vaccines and adjunctive dexamethasone therapy have changed the incidence and outcome of pneumococcal meningitis in adults over the last two decades. Despite recent advances pneumococcal meningitis remains associated with a residual high rate of mortality and morbidity.

Objectives: We aimed to derive and validate a risk score to differentiate patients with bacterial meningitis from those with viral meningitis or encephalitis amongst patients presenting with cerebrospinal fluid (CSF) leucocytosis and a negative Gram staining result. Methods: We included adults with bacterial and viral meningitis or encephalitis presenting with CSF leukocyte counts of >10 per mm3 and a negative Gram staining result from cohorts in Houston, Texas (2004–2019), and the Netherlands (2012–2021). Derivation and the first validation were performed in the American patients and further validation in the Dutch patients. Results: Derivation was performed in 109 American patients with bacterial meningitis (median age, 56 years; interquartile range [IQR], 46–66 years; 46% women) and 194 with viral meningitis or encephalitis (median age, 46 years; IQR, 33–60 years; 53% women). Serum leukocyte counts of >10.0 × 109/L, CSF leukocyte counts of >2000 per mm3, granulocyte counts of >1180 per mm3, protein levels of >2.2 g/L, glucose levels of 0 present). The first validation showed a sensitivity of 100% (95% CI, 96.6–100) and specificity of 34.0% (95% CI, 27.4–41.2). Further validation in 262 Dutch patients with bacterial meningitis (median age, 57 years; IQR 44–70 years; 45% women) and 68 with viral meningitis (median age, 34 years; IQR, 28–45 years; 60% women) showed a sensitivity of 99.6% (95% CI, 97.9–100) and specificity of 41.2% (95% CI, 29.4–53.7). Conclusions: Our risk score may be able to rule out bacterial meningitis amongst patients presenting with CSF leucocytosis and a negative Gram staining result. However, it needs prospective testing prior to clinical implementation.

Background Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19.Methods We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO(2)) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO2/FiO(2) in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420).Findings Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO2/FiO(2) assessments (irrespective of position). At day 5 after randomisation, the mean PaO2/FiO(2) (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO2/FiO(2) at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference -24% [95% CI -58 to 9], p=0.15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0.65 [95% CI 0.10-4.14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group vs seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group.Interpretation In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background: Severe coronavirus disease 2019 (Covid-19) is characterized by inflammation and coagulation in the presence of complement activation. Methods: We conducted an explorative phase 2 randomized, open label first part of an adaptive phase 2/3 trial of intravenous IFX-1, a monoclonal antibody selectively blocking the anaphylatoxin C5a, in adults with severe Covid-19. Patients were randomized between IFX-1 plus best supportive care (BSC) or BSC only. Results: 30 patients underwent randomization: 15 assigned to IFX-1 and 15 to BSC. PaO2/FiO2 ratio improvement on day 5, chosen as primary outcome parameter, did not show significant differences between groups. However, IFX-1 treatment was associated with consistent trends of improvement as evidenced by lower mortality rate, reduction in renal impairment, normalization of lymphocyte counts, and lowering of plasma lactate dehydrogenase concentrations. Kaplan-Meier estimates of mortality by 28 days were 13% for IFX-1 and 27% for BSC (HR for death, 0.56; 95%CI 0.09-3.74). Serious adverse events rates were comparable between groups but the rate of pulmonary embolisms was three-fold lower in the IFX-1 group (13%) compared to BSC group (40%). IFX-1 treatment was associated with significant increase of D-dimer levels suggesting a potential pro-fibrinolytic activity of anti-C5a treatment. Conclusion: In this exploratory part of the study, C5a inhibition with IFX-1 was shown to be safe in severe Covid-19. PaO2/FiO2 ratio at day five was comparable between groups, but consistent signals of benefit including a lower 28-day all-cause mortality rate, lower rate in impaired kidney function and a lower rate of pulmonary embolism warrant investigating C5a-inhibition with IFX-1 within a phase 3 trial. Trial Registration: This trial has been registered with the NIH, U.S. National Library of Medicine at ClinicalTrials.gov (NCT04333420). Funding Statement: The trial is funded by InflaRx GmbH. Declaration of Interests: NR and RG are founders, active officers and executive directors of InflaRx (InflaRx GmbH, InflaRx Pharmaceuticals Inc. and InflaRx N.V.) and hold shares and stock options in InflaRx. KP is Global Head of Clinical Development of InflaRx and holds stock options in InflaRx. SR is employee at Metronomia, a contracted statistical service provider for InflaRx. MW is supported by grants from the German Research Foundation, SFB-TR84 C6 and C9 and by the German Ministry of Education and Research in the framework of the CAPSyS (01ZX1304B) and the PROVID project (FKZ 01KI20160A). DvdB reports receiving departmental honoraria for serving on a scientific advisory board for InflaRx in 2017, paid to Amsterdam UMC. All other authors have no Conflict of Interest. Ethics Approval Statement: The study protocol was approved by the institutional review board of the Academic Medical Center, part of Amsterdam UMC, Amsterdam, the Netherlands (IRB: 2020_067#B2020179). If direct informed consent of patients was not feasible, patients could be included with a deferred consent procedure. All patients or their legally authorized representatives gave written informed consent for the study.