Diederik van de Beek’s research while affiliated with Amsterdam University Medical Center and other places
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Introduction
We aimed to describe global sex-specific proportions and case fatality ratios of bacterial meningitis and to explore their associations with the Human Development Index (HDI) and Gender Inequality Index (GII).
Methods
Google Scholar and MEDLINE (via PubMed.gov) were searched in January 2022 using the terms “bacterial meningitis” and “mortality”. Studies with a mean observation period after the year 1940 and reporting ≥10 patients with community-acquired bacterial meningitis and their survival status were included, irrespective of the participants’ age. Studies that selected participants by specific risk factors, reported specific pathogens only, or had >10% missing outcomes were disregarded. Data were extracted by one researcher and validated by a second researcher. The main outcomes, sex-specific proportions and case fatality ratios, were analysed using random-effects models. Associations with HDI and GII were explored using metaregression.
Results
In this meta-analysis with metaregression, from 371 studies with 157 656 meningitis episodes, 217 (58%) reported the patients’ sex and 41 (11%) reported sex-specific outcomes. Proportion of males was 58% (95% CI 57%–59%, prediction interval (PI) 45%–71%). Case fatality ratios were slightly higher in females (male-to-female fatality ratio, 0.89, 95% CI 0.78 to 1.01, PI 0.53–1.49). The size of the male proportion was strongly associated with HDI (per index point, −0.64, 95% CI −0.88 to −0.40; R² 16%; p<0.001) and GII (per index point, 0.61, 95% CI 0.39 to 0.83; R² 19%; p<0.001). Sex-specific case fatality ratios were weakly associated with HDI (per index point, 0.53, 95% CI −0.19 to 1.25; R² 2%; p=0.15) and GII (per index point, −0.58, 95% CI −1.55 to 0.39; R² 7%; p=0.24).
Conclusion
Based on worldwide reporting from the last 80 years, we show that indicators of human development and gender inequality are associated with sex-based disparities and case fatality ratios in bacterial meningitis.
Background
Vilobelimab, a first in class C5a-specific monoclonal antibody, improved 28-day and 60-day mortality in intubated COVID-19 patients in PANAMO, a phase 3 randomised, double-blind, placebo-controlled multicentre study. All-cause mortality was pre-specified to be analysed pooling by region (western Europe, South America, South Africa/Russia).
Methods
Critically ill, invasively mechanically ventilated COVID-19 patients were randomised in a 1:1 ratio within 48 hours of intubation to receive vilobelimab treatment (six, 800 mg intravenous infusions) or placebo on top of standard of care. We analysed the efficacy and safety of vilobelimab based on prespecified geographic regions.
Results
368 patients were randomised and analysed: 177 in the vilobelimab group and 191 in the placebo group. In western Europe (n=209), 28-day all-cause mortality was significantly lower in the vilobelimab group (21%) compared with placebo (37%) (HR 0.51 (95% CI: 0.30, 0.87), p=0.014). In South America (n=126), mortality was similar between groups (40% vs 37%; HR 0.94 (95% CI: 0.53, 1.67), p=0.83). In South Africa/Russia (n=33), mortality was 69% in the vilobelimab group and 87% in the placebo group (HR 0.62 (95% CI: 0.28, 1.38), p=0.25). Within the Brazilian subpopulation (n=74), a significant age imbalance between the vilobelimab and placebo group was detected (median 53.5 years in the vilobelimab group vs 44.5 years in the placebo group). Occurrence of treatment-emergent adverse events between regions was similar.
Conclusion
The most apparent 28-day all-cause mortality benefit for vilobelimab was in western Europe. Age imbalance between treatment groups in Brazil may have resulted in a lower efficacy signal for vilobelimab in South America compared with other regions. Overall, vilobelimab demonstrated a favourable safety profile and reduced mortality in critically ill, intubated COVID-19 patients, with regional variations influencing outcomes.
Background
Various pre-clinical and clinical studies suggest an interplay between complement C5a/C5a receptor (R1) and interleukin 6 (IL-6) signaling. C5a boosts IL-6 levels and IL-6 increases C5aR1 in inflammation and sepsis models (Fig 1). Blocking IL-6 signaling, e.g. with tocilizumab (Toci), in patients with acute coronary artery disease and with antibodies in pre-clinical studies in different tissues significantly reduces C5aR1 expression. In addition, inhibiting C5a with vilobelimab (Vilo) in COVID-19 patients with acute respiratory distress syndrome (ARDS) also improves survival as shown in a multicenter, double-blind, randomized, placebo-controlled, phase 3 trial (PANAMO, NCT04333420). COVID-19 patients with ARDS who receive Toci in addition to Vilo may serve as a model for the interplay between IL-6 and the C5a/C5aR1 axis to improve survival in ARDS.Figure 1:C5a induction of IL-6 and IL-6 induction of C5aR1. Induction of IL-6 is blocked by vilobelimab binding to C5a and tocilizumab blocks IL-6 binding to IL-6 receptor decreasing induction of C5aR1.
Methods
COVID-19 patients with ARDS in the Phase III PANAMO study (N=368) received up to six Vilo 800mg infusions or placebo (Plc) plus corticosteroids and anticoagulants (standard-of-care) within 48 hours of intubation over a 22-day period. A post-hoc Cox regression analysis was performed for 28- and 60-Day all-cause mortality in a subgroup of patients (n=60) who also received prior (within -7 days of Vilo administration) or concomitant Toci. Safety was also assessed.Figure 2:Kaplan Meier Survival Curve of COVID-19 Patients with ARDS Treated with Tocilizumab (Toci) prior (within 7 days) of Vilobelimab+SOC and Placebo+SOC. SOC= Standard-of-Care; corticosteroids and anticoagulants.
Results
Vilo+Toci (n=29) and Plc+Toci (n=31) showed point estimates for 28-Day all-cause mortality of 3.7% and 42.3% (HR 0.073; 95%CI:0.01-0.56, p=0.012), while 60-Day all-cause mortality point estimates were 15.9% and 49.1% (HR 0.245; 95%CI:0.08-0.74, p=0.013), respectively (Fig 2). Related TEAEs were similar in both groups (28.6% vs 25.8%). Serious TEAEs occurred in fewer patients receiving Vilo+Toci (42.9%) vs Plc+Toci (67.7%). Infections and infestations were slightly lower for Vilo+Toci (53.6%) vs Plc+Toci (64.5%).
Conclusion
This post-hoc analysis demonstrated that dual immunomodulator inhibition of the C5a/C5aR1 axis and IL-6 signaling improved survival in a subgroup of COVID-19 patients with ARDS without impacting safety. Dual immunomodulator treatment with vilobelimab and tocilizumab could potentially be used in different ARDS populations to produce a similar effect. Larger and well-controlled studies are warranted to test this hypothesis.
Disclosures
Roy F. Chemaly, MD/MPH, AiCuris: Advisor/Consultant|AiCuris: Grant/Research Support|Ansun Pharmaceuticals: Advisor/Consultant|Ansun Pharmaceuticals: Grant/Research Support|Astellas: Advisor/Consultant|Eurofins-Viracor: Grant/Research Support|InflaRX: Advisor/Consultant|Janssen: Advisor/Consultant|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck/MSD: Advisor/Consultant|Merck/MSD: Grant/Research Support|Moderna: Advisor/Consultant|Oxford Immunotec: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Roche/Genentech: Advisor/Consultant|Roche/Genentech: Grant/Research Support|Shinogi: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Tether: Advisor/Consultant Alexander Vlaar, MD, PhD, InflaRx GmbH: Advisor/Consultant Bruce P. Burnett, PhD, InflaRx Pharmaceuticals, InflaRx GmbH: Employee Camilla Chong, MD, InflaRx GmbH: Employee simon Rückinger, PhD, InflaRx GmbH: Advisor/Consultant Robert Zerbib, MSc, InflaRx GmbH: Advisor/Consultant Raymond M. Panas, PhD, InflaRx Pharmaceuticals, InflaRx GmbH: Employee Renfeng Guo, MD, InflaRx GmbH: Board Member|InflaRx GmbH: Chief Scientific Officer|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds (Public Company) Niels Riedemann, MD, PhD, InflaRx GmbH: Board Member|InflaRx GmbH: Chief Executive Officer|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds (Public Company) Diederik van de Beek, MD, PhD, InflaRx GmbH: Advisor/Consultant
Objective
We aimed to evaluate the diagnostic accuracy of heparin‐binding protein (HBP) in cerebrospinal fluid for the diagnosis of bacterial meningitis in patients with a suspected central nervous system infection.
Methods
This prospective multicenter cohort study determined the diagnostic accuracy of HBP in cerebrospinal fluid (CSF) for bacterial meningitis among a cohort of consecutive patients with a suspected central nervous infection. The final clinical diagnosis was considered the reference standard. The results were validated in a separate cohort.
Results
A total of 631 Dutch patients were evaluated for the current study, of which 73 (12%) had a final diagnosis of bacterial meningitis. For the differentiation of bacterial meningitis from all other disorders, diagnostic accuracy was high with an area under the curve (AUC) of 0.98 (95% confidence interval [CI] 0.96–1.00). With the proposed cutoff of 5.2 ng/ml, sensitivity was 97% with a specificity of 96%. In the population of patients with a CSF leukocyte count of 5‐1,000/mm ³ , the AUC was 0.96 (95% CI 0.87–1.00), outperforming CSF leukocytes (AUC 0.88 [95% CI 0.79–0.97]). Combining HBP with CSF C‐reactive protein (CRP) significantly increased accuracy in this population and reached a 100% sensitivity (AUC 1.00 [95% CI 0.99–1.00], cutoff 0.07, sensitivity 100%, specificity 96%). These results remained robust in an external validation cohort of 120 Danish patients (AUC 0.97 [95% CI 0.93–1.00]).
Interpretation
HBP can correctly distinguish bacterial meningitis from other disorders. It can be of additional value to current diagnostics in cases where CSF leukocyte count is relatively low, particularly when combined with CSF CRP. ANN NEUROL 2025
... Today, scientists require a lot of relevant, innovative, and qualitative research, which cannot be done without a detailed study of the state of the scientific issue [9,10,11,12]. A full solution to this problem is impossible without a deep analytical review of the literature. ...
... This assay is attractive due to the rapid and highly reproducible PCR for DNA. It has shown proof of efficacy as well as being easy to use thus making it desirable for both clinical and environmental assessment of Naegleria fowleri (Olie, Andersen, van de Beek, & Brouwer, 2024). ...
... Early initiation of steroids is one strategy to reduce worsening edema and meningeal inflammation; delays in the administration of dexamethasone are associated with more severe neurologic impairments, such as hearing loss [17]. However, a large meta-analysis has failed to demonstrate that steroids confer a mortality benefit except in cases of Streptococcus pneumoniae [18]. Although reasonable to consider for undifferentiated bacterial meningitis, our patient had already been on antibiotics for 24 h, and the meningoencephalitis array panel rapidly identified a non-Streptococcus organism after meningitis was suspected. ...
... This audit aims to evaluate the effectiveness and consistency of NG tube placement and care practices to identify areas for improvement and ensure adherence to best-practice guidelines [9]. By conducting this audit, we seek to identify areas for improvement in NG tube placement and care practices, ensuring that patients receive the highest quality of care and minimizing the risk of associated complications. ...
... Although a definite diagnosis of encephalitis is made through histopathological examination of brain tissue, the clinical diagnosis is generally based on a combination of clinical symptoms and ancillary investigations, such as quantitative PCR [4]. Among patients with a clinical diagnosis of suspected infectious encephalitis, current microbiological investigations are able to identify a pathogen in~50% of patients [5,6]. This is probably because of factors such as varying assay sensitivity for different pathogens [7] and the potential presence of unknown pathogens. ...
... or low <0.55). 34 Risk of bias (quality) assessment. No data on trial results were collected; therefore, quality and bias appraisal were not necessary. ...
... However, emerging evidence suggests that even asymptomatic GBS colonization involves bacterial factors that can facilitate transmission and increase virulence [9]. GBS colonization is closely associated with infectious disease in both mothers and newborns [10,11] and increases the risk of preterm birth [12], premature rupture of membranes [13,14], neonatal infectious diseases [15,16], neonatal sepsis [17,18], neonatal pneumonia [8, 10,11,19], neonatal meningitis [20,21], and neonatal neurodevelopmental disorders [22]. Nevertheless, the pathogenesis of GBS colonization remains incompletely understood, particularly in terms of the mechanisms by which GBS transitions from a harmless commensal to a pathogenic organism. ...
... (1) A pesar de la eficacia de los antibióticos para eliminar las bacterias del líquido cefalorraquídeo (LCR), la meningitis bacteriana en adultos sigue causando una morbilidad y mortalidad significativas en todo el mundo. (2) La patogenia y la fisiopatología de la meningitis bacteriana implican una interacción compleja entre los factores de virulencia de los patógenos y la respuesta inmunitaria del huésped. (3,4) Se cree que gran parte del daño causado por esta infección es resultado de toxinas liberadas dentro del líquido cefalorraquídeo cuando el huésped desarrolla una respuesta inflamatoria. ...
... The methods have been previously described elsewhere in detail. 10,11 In short, all adult patients (≥16 years of age) who were suspected of having a CNS infection and underwent CSF examination were eligible for inclusion. Exclusion criteria consisted of recent head trauma or neurosurgery within the past 3 months, as well as patients with a neurosurgical device in situ and patients who underwent a lumbar puncture at the outpatient clinic. ...
... [1][2][3] This infection remains associated with a high risk of mortality (20%-30%) 1 4-14 and of brain damage, hearing loss or learning disabilities (30%). 2 4 15-20 These risks are modulated by the intensity of the bacteriolysis which in turn depends on the host's genetic profile, 21 22 excessive host response [23][24][25] the pneumococcal profile [26][27][28] and especially the bacterial load. [29][30][31][32] Treatment (dexamethasone and third-generation cephalosporin) should be started immediately. [33][34][35] Despite these guidelines, approximately half of patients with pneumococcal meningitis are left with a disability, and mortality was as high as 20%. 2 12 14 19 20 36 The decrease in sensitivity of pneumococcal strains to certain antibiotics 37 is a potential threat that could lead to different antibiotic therapy proposals, for instance, the addition of daptomycin due to the good in vitro interactions. ...
