Meningitidis Infection Research Articles

Knowledge Levels and Attitudes of Pediatric Physicians Regarding Meningococcal Infections and Vaccines: A Cross-Sectional Study

Objective: Invasive meningococcal disease (IMD) clinically manifests as meningitis, meningococcemia, or a combination of both. Globally, approximately 1.2 million meningococcal cases are reported annually, resulting in 135,000 deaths. Despite meningococcal infections being a significant public health concern, widespread vaccination is not commonly practiced. The aim of this study is to evaluate the knowledge levels and attitudes of pediatric specialists and assistant doctors regarding meningococcal infections and associated vaccines. Material and Method: This descriptive cross-sectional study included pediatric specialists and assistant doctors working in Antalya. During the study period, 170 pediatricians were identified, and it was aimed to reach at least 80% of this population. A total of 150 participants, selected via snowball sampling, participated in the survey. Data collection was carried out through face-to-face interviews and online questionnaires. Results: Of the participants, 72.7% were pediatric specialists and 27.3% were assistant doctors. The conjugate meningococcal vaccine was recommended by 68% of the participants for all patients, by 20% for high-risk patients only, while 12% did not recommend the vaccine. The primary reasons for this hesitancy included the cost of the vaccine, concerns about adverse effects, perceptions of low vaccine efficacy, and the rarity of the disease. Additionally, 47.4% of the participants suggested that the conjugate meningococcal vaccine should be included in the national immunization schedule, followed by 39.3% who recommended the rotavirus vaccine and 13.3% who recommended the human papillomavirus (HPV) vaccine. Conclusion: Our study found that pediatric specialists and assistant doctors had sufficient knowledge and generally positive attitudes towards Neisseria meningitidis infections and vaccines. However, the most significant barriers to vaccine administration were identified as cost, concerns about adverse effects, and the perception of low vaccine efficacy. It is anticipated that improving the knowledge and awareness of pediatricians will positively influence vaccine acceptance.

THE ETIOLOGICAL PROFILE AND ALTERATIONS IN CEREBROSPINAL FLUID CHARACTERISTICS IN PATIENTS WITH BACTERIAL MENINGITIS

Currently, bacterial meningitis (BM) remains a form of life-threatening infectious pathology, with a mortality rate ranging from 4% to 35% and poor prognosis often accompanied by diverse specific and non-specific complications, including infectious toxic shock, cerebral edema, ventricular inflammation, hydrocephalus, acute cerebrovascular accidents, venous sinus thrombosis, disseminated intravascular coagulation (DIC) syndrome, respiratory distress syndrome (RDS) syndrome, inappropriate secretion of antidiuretic hormone, and systemic inflammatory response syndrome. In clinical practice, the early identification of the causative microorganism and the implementation of proper antibiotic treatment, as well as a comprehensive assessment of the patient's status and management, are crucial for minimizing a risk of related severe complications and mortality. The BM etiology is characterized by a highly variable nature, contingent upon a multitude of factors such as geographic location, temporal context, patient age, immunological status, and other variables. Over the past two to three decades, advancements in conjugate vaccines and the use implementation of antibiotic treatment have brought about alterations in the spectrum of pathogens responsible for meningitis. The objective of this study was to delve into the etiological profile and prognostic implications of cerebrospinal fluid (CSF) parameters among patients with diagnosed meningitis admitted to the Neuroinfectious Diseases Division of the Infectious Clinical Hospital №2 (Moscow) between 2022 and 2023. A retrospective analysis of medical records of meningitis patients admitted to the Infectious Clinical Hospital №2 during 2022–2023 was conducted. The data were analyzed using the k-means clustering algorithm implemented in the Loginom analytics software to create a scenario, as well as OLAP cubes. The study involved the analysis of medical records for 110 patients aged 18-89 years old. Among the BM pathogens identified, Neisseria meningitidis emerged as the most prevalent in this patient cohort, accounting for 68.2% of cases. Within the group of meningococcal meningitis cases, serovariants A and W135 were the most frequently detected, accounting for 49.3% and 33.3%, respectively. Significant alterations in cerebrospinal fluid parameters, characterized by elevated cell counts and lowered glucose levels, were observed among patients with purulent meningitis resulting from serogroup A Neisseria meningitidis infections. A combination of elevated baseline cell level along with high concentrations of proteins, and lactate, coupled with the presence of D-dimer in cerebrospinal fluid, has been associated with a severe disease progression and the emergence of critical and life-threatening sequelae.

Real-world safety profile of eculizumab: an analysis of FDA adverse event reporting system and systematic review of case reports

ABSTRACT Background Most of the safety data regarding eculizumab came from clinical trials, while its safety information in the real world is still limited. Research design and methods The data of eculizumab in the FDA Adverse Event Reporting System (FAERS) database (from the first quarter of 2007 to the first quarter of 2023) was collected and analyzed. The case reports of adverse drug reactions (ADRs) related to eculizumab in PubMed, Embase and Web of Science before May 2023 were systematically reviewed. Results A total of 464 ADRs of eculizumab were identified in the FAERS database. The top five ADRs with the highest proportional reporting ratio (PRR) are total complement activity decreased, extravascular hemolysis, hemoglobinuria, total complement activity increased and breakthrough hemolysis. Fifty-one cases of ADR related to eculizumab were identified from 44 publications. The number of reported cases of eculizumab associated Neisseria gonorrhoeae infection in case reports was observed to be comparable to the number of cases of Neisseria meningitidis infection. Conclusions Clinicians must pay close attention to the risk of infections in patients receiving eculizumab, including severe N. meningitidis infection and other potentially fatal infections such as N. gonorrhoeae infection. In addition, The possible emergence of new ADRs should be vigilant during clinical medication.

Angiopoietin-like 4 protects against endothelial dysfunction during bacterial sepsis.

Loss of endothelial integrity and vascular leakage are central features of sepsis pathogenesis; however, no effective therapeutic mechanisms for preserving endothelial integrity are available. Here we show that, compared to dermal microvessels, brain microvessels resist infection by Neisseria meningitidis, a bacterial pathogen that causes sepsis and meningitis. By comparing the transcriptional responses to infection in dermal and brain endothelial cells, we identified angiopoietin-like 4 as a key factor produced by the brain endothelium that preserves blood-brain barrier integrity during bacterial sepsis. Conversely, angiopoietin-like 4 is produced at lower levels in the peripheral endothelium. Treatment with recombinant angiopoietin-like 4 reduced vascular leakage, organ failure and death in mouse models of lethal sepsis and N. meningitidis infection. Protection was conferred by a previously uncharacterized domain of angiopoietin-like 4, through binding to the heparan proteoglycan, syndecan-4. These findings reveal a potential strategy to prevent endothelial dysfunction and improve outcomes in patients with sepsis.

Serogroup B Invasive Meningococcal Disease in Older Adults Identified by Genomic Surveillance, England, 2022-2023.

We report a cluster of serogroup B invasive meningococcal disease identified via genomic surveillance in older adults in England and describe the public health responses. Genomic surveillance is critical for supporting public health investigations and detecting the growing threat of serogroup B Neisseria meningitidis infections in older adults.

The Diverse Spectrum of Invasive Meningococcal Disease in Pediatric and Adolescent Patients: Narrative Review of Cases and Case Series.

Invasive meningococcal disease (IMD) is a potentially life-threatening disease caused by Neisseria meningitidis infection. We reviewed case reports of IMD from newborns, infants, children, and adolescents, and described the real-life clinical presentations, diagnoses, treatment paradigms, and clinical outcomes. PubMed and Embase were searched for IMD case reports on patients aged ≤ 19years published from January 2011 to March 2023 (search terms "Neisseria meningitidis" or "invasive meningococcal disease", and "infant", "children", "paediatric", pediatric", or "adolescent"). We identified 97 publications reporting 184 cases of IMD, including 25 cases with a fatal outcome. Most cases were in adolescents aged 13-19years (34.2%), followed by children aged 1-5years (27.6%), children aged 6-12years (17.1%), infants aged 1-12months (17.1%), and neonates (3.9%). The most common disease-causing serogroups were W (40.2%), B (31.7%), and C (10.4%). SerogroupW was the most common serogroup in adolescents (17.2%), and serogroupB was the most common in the other age groups, including children aged 1-5years (11.5%). The most common clinical presentations were meningitis (46.6%) and sepsis (36.8%). IMD continues to pose a threat to the health of children and adolescents. While this review was limited to case reports and is not reflective of global epidemiology, adolescents represented the largest group with IMD. Additionally, nearly half of the patients who died were adolescents, emphasizing the importance of monitoring and vaccination in this age group. Different infecting serogroups were predominant in different age groups, highlighting the usefulness of multivalent vaccines to provide the broadest possible protection against IMD. Overall, this review provides useful insights into real-life clinical presentations, treatment paradigms, diagnoses, and clinical outcomes to help clinicians diagnose, treat, and, ultimately, protect patients from this devastating disease.

Increased Risk of Long-Term Disabilities Following Childhood Bacterial Meningitis in Sweden

Few studies have examined the incidence of long-term disabilities due to bacterial meningitis in childhood with extended follow-up time and a nationwide cohort. To describe the long-term risks of disabilities following a childhood diagnosis of bacterial meningitis in Sweden. This nationwide retrospective registry-based cohort study included individuals diagnosed with bacterial meningitis (younger than 18 years) and general population controls matched (1:9) by age, sex, and place of residence. Data were retrieved from the Swedish National Patient Register from January 1, 1987, to December 31, 2021. Data were analyzed from July 13, 2022, to November 30, 2023. A diagnosis of bacterial meningitis in childhood recorded in the National Patient Register between 1987 and 2021. Cumulative incidence of 7 disabilities (cognitive disabilities, seizures, hearing loss, motor function disorders, visual disturbances, behavioral and emotional disorders, and intracranial structural injuries) after bacterial meningitis in childhood. The cohort included 3623 individuals diagnosed with bacterial meningitis during childhood and 32 607 controls from the general population (median age at diagnosis, 1.5 [IQR, 0.4-6.2] years; 44.2% female and 55.8% male, median follow-up time, 23.7 [IQR, 12.2-30.4] years). Individuals diagnosed with bacterial meningitis had higher cumulative incidence of all 7 disabilities, and 1052 (29.0%) had at least 1 disability. The highest absolute risk of disabilities was found for behavioral and emotional disorders, hearing loss, and visual disturbances. The estimated adjusted hazard ratios (HRs) showed a significant increased relative risk for cases compared with controls for all 7 disabilities, with the largest adjusted HRs for intracranial structural injuries (26.04 [95% CI, 15.50-43.74]), hearing loss (7.90 [95% CI, 6.68-9.33]), and motor function disorders (4.65 [95% CI, 3.72-5.80]). The adjusted HRs for cognitive disabilities, seizures, hearing loss, and motor function disorders were significantly higher for Streptococcus pneumoniae infection (eg, 7.89 [95% CI, 5.18-12.02] for seizure) compared with Haemophilus influenzae infection (2.46 [95% CI, 1.63-3.70]) or Neisseria meningitidis infection (1.38 [95% CI, 0.65-2.93]). The adjusted HRs for cognitive disabilities, seizures, behavioral and emotional disorders, and intracranial structural injuries were significantly higher for children diagnosed with bacterial meningitis at an age below the median. The findings of this cohort study of individuals diagnosed with bacterial meningitis during childhood suggest that exposed individuals may have had an increased risk for long-term disabilities (particularly when diagnosed with pneumococcal meningitis or when diagnosed at a young age), highlighting the need to detect disabilities among surviving children.

Epidemiology and genetic diversity of invasive Neisseria meningitidis strains circulating in Portugal from 2003 to 2020

Invasive meningococcal disease (IMD) continues to be a public health problem due to its epidemic potential, affecting mostly children. We aimed to present a detailed description of the epidemiology of IMD in Portugal, including insights into the genetic diversity of Neisseria meningitidis strains. Epidemiological analysis included data from the Portuguese National Reference Laboratory of Neisseria meningitidis during 2003 to 2020. Since 2012, N. meningitidis isolates have also been assessed for their susceptibility to antibiotics and were characterized by whole genome sequencing. During 2003–2020, 1392 confirmed cases of IMD were analyzed. A decrease in the annual incidence rate was observed, ranging from 1.99 (2003) to 0.39 (2020), with an average case fatality rate of 7.1%. Serogroup B was the most frequent (69.7%), followed by serogroups C (9.7%), Y (5.7%), and W (2.6%). Genomic characterization of 329 isolates identified 20 clonal complexes (cc), with the most prevalent belonging to serogroup B cc41/44 (26.3%) and cc213 (16.3%). Isolates belonging to cc11 were predominantly from serogroups W (77.3%) and C (76.5%), whereas cc23 was dominant from serogroup Y (65.7%). Over the past 4 years (2017–2020), we observed an increasing trend of cases assigned to cc213, cc32, and cc11. Regarding antimicrobial susceptibility, all isolates were susceptible to ceftriaxone and 61.8% were penicillin-nonsusceptible, whereas 1.4% and 1.0% were resistant to ciprofloxacin and rifampicin. This is the first detailed study on the epidemiology and genomics of invasive N. meningitidis infections in Portugal, providing relevant data to public health policy makers for a more effective control of this disease.

Erratum: Neisseria meningitidis Infection of Induced Pluripotent Stem-Cell Derived Brain Endothelial Cells.

An erratum was issued for:Neisseria meningitidis Infection of Induced Pluripotent Stem-Cell Derived Brain Endothelial Cells Larvae. The Authors section was updated from: Leo M. Endres1 Alexandra Schubert-Unkmeir1 Brandon J. Kim1,2 1Institute for Hygiene and Microbiology, University of Würzburg 2Department of Biological Sciences, University of Alabama to: Leo M. Endres1 Sarah F. Hathcock2 Alexandra Schubert-Unkmeir1 Brandon J. Kim1,2 1Institute for Hygiene and Microbiology, University of Würzburg 2Department of Biological Sciences, University of Alabama.

Accuracy of antigen tests for meningococcal meningitis in cerebrospinal fluid: A diagnostic meta-analysis.

Neisseria meningitidis is one of the major pathogens of meningitis in children worldwide and causes invasive meningococcal disease (IMD), which is a critical illness that mainly presents as meningitis and/or septicemia in children. Identification of N. meningitidis in cerebrospinal fluid (CSF) is the gold standard for the diagnosis of meningococcal meningitis, but antigen tests have advantages such as timely results, relatively low cost, and convenience. Yet, the diagnostic accuracy of antigen tests remains uncertain. Therefore, the aim of this meta-analysis was to evaluate the diagnostic accuracy of antigen tests for N. meningitidis in CSF. We searched the PubMed, Embase, and Cochrane Library databases for studies evaluating the diagnostic accuracy of antigen tests for N. meningitidis in CSF. We included studies that provided sufficient data to construct a 2 × 2 table on a per-sample basis. To determine the overall sensitivity and specificity of the antigen tests, we used polymerase chain reaction (PCR) as the reference standard and employed the hierarchical summary receiver operating characteristic model. Nine studies with 4533 CSF samples were included. The meta-analysis yielded a pooled sensitivity of 91.2% (95% confidence interval [CI]: 80.0%-100.0%) and a pooled specificity of 93.8% (95% CI: 83.9%-100.0%). A subgroup analysis of 2 studies that reported the outcomes of MeningoSpeed yielded a pooled sensitivity of 93.4% (95% CI: 90.0%-95.8%) and a pooled specificity of 91.9% (95% CI: 88.6%-94.4%). Antigen testing for the N. meningitidis serogroup X had a pooled sensitivity of 92.4% (95% CI: 85.2%-96.2%) and a pooled specificity of 99.2% (95% CI: 78.7%-100.0%). The studied antigen tests had high sensitivity and specificity for the diagnosis of meningococcal meningitis in CSF specimens. Antigen testing could serve as an accurate diagnostic method for assessing patients who have a suspected N. meningitidis infection.

The phosphoproteome of choroid plexus epithelial cells following infection with Neisseria meningitidis.

The Gram-negative bacterium Neisseria meningitidis, which causes meningitis in humans, has been demonstrated to manipulate or alter host signalling pathways during infection of the central nervous system (CNS). However, these complex signalling networks are not completely understood. We investigate the phosphoproteome of an in vitro model of the blood-cerebrospinal fluid barrier (BCSFB) based on human epithelial choroid plexus (CP) papilloma (HIBCPP) cells during infection with the N. meningitidis serogroup B strain MC58 in presence and absence of the bacterial capsule. Interestingly, our data demonstrates a stronger impact on the phosphoproteome of the cells by the capsule-deficient mutant of MC58. Using enrichment analyses, potential pathways, molecular processes, biological processes, cellular components and kinases were determined to be regulated as a consequence of N. meningitidis infection of the BCSFB. Our data highlight a variety of protein regulations that are altered during infection of CP epithelial cells with N. meningitidis, with the regulation of several pathways and molecular events only being detected after infection with the capsule-deficient mutant. Mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD038560.

An Unusual Case of Neisseria Meningitidis Infection in Elderly Revealing a Primary Classic Pathway Complements Deficiency

Primary classic pathway complement deficiencies in older people are rarely reported in the literature. The link between classical pathway complement deficiencies and Neisseria Meningitidis infections is not clearly understood

National Burden of Encapsulated Bacterial Infections in Sickle Cell Disease

Introduction: Patients with sickle cell disease (SCD) are at much higher risk for infections from encapsulated organisms, particularly Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus), and Hemophilus influenzae. Vaccinations and prophylactic penicillin (for pneumococcus) have declined but not eliminated their incidence. We aim to study the SCD admissions with infections from above mentioned encapsulated organisms. Methods: We performed a retrospective analysis using the National Inpatient Sample (NIS) database from 2016 to 2019 to identify SCD hospitalizations with either S. pneumoniae, N. meningitidis, or H. influenzae infections using appropriate International Classification of Diseases, Tenth Revision, Clinical Modification (ICD 10-CM) codes. SCD included HbSS (D57.0x), HbSC (D57.2x) and others (D57.1, D57.4x and D57.8x). Infections from S. pneumoniae and H. influenzae included sepsis (A40.3, A41.3), pneumonia (J13, J14), meningitis (G00.1, G00.0), and others (M00.1x, B95.3, A49.2, B96.3, and J20.1). N. meningitidis infections were identified by ICD-10-CM code A39.x. Admissions were divided into pediatric (<18 years) and adult (≥18 years) age groups and descriptive analysis was performed to compare demographics, hospital characteristics, and comorbid conditions/complications. We also calculated the annual hospitalization rate for encapsulated organisms per 10,000 SCD admissions. The methodology provided by the HCUP (Healthcare Cost and Utilization Project) was utilized, and weights were applied to produce national estimates. Results: Out of 533,175 SCD admissions from 2016-2019, 830 (0.16%) had an infection from S. pneumoniae or H. influenzae. There were no admissions with N. meningitidis during our study period. The annual hospitalization rate for encapsulated bacterial infection per 10,000 SCD admissions ranged from 15.6/year to 40.6/year for the pediatric population and 11/year to 15.2/year among adults (Figure 1). Overall rate was 30 per 10,000 SCD admissions in pediatric population and 12 per 10,000 in adults (p <0.001). Among S. pneumoniae infections, hospitalizations were highest for children ≤5 years at 64 per 10,000 SCD admissions, followed by 14 per 10,000 in children aged >5 & <18 years and lowest in adults (≥18 years) at 12 per 10,000 (p <0.001). Among 695 SCD admissions with S. pneumoniae, 325 (46.8%) were HbSS, and 65 (9.4%) had HbSC disease. Furthermore, 260 (37.4%) were <18 years and 435 (62.6%) were ≥18 years. The median age for children was 5 (2-10) years and 34 (27-47) for adults (p <0.001). Most admissions were males (56.1%), without significant comorbidities (Charlson comorbidity index 0 in 59.7%) and belonged to lowest income communities (47.8%). More than a quarter of adults (26.4%) had tobacco use disorder, and 8.1% had HIV/AIDS. Incidence of acute respiratory failure and acute kidney failure was higher in adults than in children (25.3% vs. 1.9%; p <0.001 and 29.9% vs. 3.9%; p <0.001 respectively). The median length of stay was 6 (4-11) days for adults and 4 (3-7) days for <18-year-olds (p <0.001). There were 26.4% adults compared to 9.6% children with a length of stay >10 days (p 0.02). Median hospital charges and costs were also higher for adults compared to children. Whereas there were no pediatric discharges requiring home health care, 17.4% of adults had home health care arranged (p 0.01). All-cause-in-hospital mortality was 1.4%. Out of 145 H. influenzae admissions, 40 (27.6%) were <18 years, and 105 (72.4%) were ≥18 years. Like S. pneumoniae, the majority of SCD admissions with H. influenzae admissions were males (65.5%), belonged to the lowest income communities (51.7%), admitted to large (48.3%), teaching hospitals (89.7%), and had no significant comorbidities (Charlson comorbidity index 0 in 55.2%). Around 24.1% stayed in the hospital for >10 days, and 20.7% required invasive mechanical ventilation. The median length of stay was 7 (5-10) days, and all-cause-in-hospital mortality was 3.5% (Table 1). Conclusion: Despite vaccinations and prophylactic penicillin, the burden of encapsulated bacterial infections in pediatric SCD hospitalizations remains disproportionately higher than in adults. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Development of a multicellular in vitro model of the meningeal blood-CSF barrier to study Neisseria meningitidis infection

BackgroundBacterial meningitis is a life-threatening disease that occurs when pathogens such as Neisseria meningitidis cross the meningeal blood cerebrospinal fluid barrier (mBCSFB) and infect the meninges. Due to the human-specific nature of N. meningitidis, previous research investigating this complex host–pathogen interaction has mostly been done in vitro using immortalized brain endothelial cells (BECs) alone, which often do not retain relevant barrier properties in culture. Here, we developed physiologically relevant mBCSFB models using BECs in co-culture with leptomeningeal cells (LMCs) to examine N. meningitidis interaction.MethodsWe used BEC-like cells derived from induced pluripotent stem cells (iBECs) or hCMEC/D3 cells in co-culture with LMCs derived from tumor biopsies. We employed TEM and structured illumination microscopy to characterize the models as well as bacterial interaction. We measured TEER and sodium fluorescein (NaF) permeability to determine barrier tightness and integrity. We then analyzed bacterial adherence and penetration of the cell barrier and examined changes in host gene expression of tight junctions as well as chemokines and cytokines in response to infection.ResultsBoth cell types remained distinct in co-culture and iBECs showed characteristic expression of BEC markers including tight junction proteins and endothelial markers. iBEC barrier function as determined by TEER and NaF permeability was improved by LMC co-culture and remained stable for seven days. BEC response to N. meningitidis infection was not affected by LMC co-culture. We detected considerable amounts of BEC-adherent meningococci and a relatively small number of intracellular bacteria. Interestingly, we discovered bacteria traversing the BEC-LMC barrier within the first 24 h post-infection, when barrier integrity was still high, suggesting a transcellular route for N. meningitidis into the CNS. Finally, we observed deterioration of barrier properties including loss of TEER and reduced expression of cell-junction components at late time points of infection.ConclusionsHere, we report, for the first time, on co-culture of human iPSC derived BECs or hCMEC/D3 with meningioma derived LMCs and find that LMC co-culture improves barrier properties of iBECs. These novel models allow for a better understanding of N. meningitidis interaction at the mBCSFB in a physiologically relevant setting.

Outcomes of Extracorporeal Life Support in Children with Meningococcal Septicemia: A Retrospective Cohort Study.

Meningococcal disease is associated with high mortality despite aggressive antibiotic therapy and intensive care support. Patients may develop refractory hypotension and acute respiratory distress syndrome in which extracorporeal membrane oxygenation (ECMO) could serve as a life-saving rescue therapy. However, there is limited data regarding the outcomes of ECMO support in the setting of meningococcal disease. This retrospective analysis of prospectively collected data from Extracorporeal Life Support Organization registry (1989-2019) enrolled children (29 days-18 years old) with Neisseria meningitidis infection receiving ECMO for any support type and mode. A total of 122 patients underwent a single course of ECMO support, equating to 122 ECMO runs. The overall survival-to-discharge rate was 46.7%. Patients receiving pulmonary venovenous (VV) ECMO had the highest survival-to-discharge of 85.7%, while those receiving venoarterial (VA) ECMO for pulmonary indications had a survival of 32.4%. Patients receiving VA ECMO support for cardiac indications had a survival-to-discharge rate of 60.9%. Those needing extracorporeal cardiopulmonary resuscitation (ECPR) had a poor survival (14.3%). Hemorrhagic complications were common, occurring in 43.4% of patients, but not found to be associated with mortality (complication was present in 47.7% of deceased and 38.6% of survivors, p = 0.31). Multivariable logistic regression analysis revealed that neurologic complications were associated with increased odds of mortality (odds ratio: 44.11; 95% confidence interval: 4.95-393.08). ECMO can be utilized as rescue therapy in children with refractory cardiopulmonary failure in setting of meningococcemia. Patients who require pulmonary VV or cardiac ECMO have the best ECMO outcomes. However, the use of ECMO in those suffering cardiac arrest (ECPR) should be undertaken with caution.

FC057: Incidence of Infections in the Avacopan Group Versus Prednisone Group in Anca-Associated Vasculitis, Results from the Phase 3 Advocate Study

Abstract BACKGROUND AND AIMS Standard therapy for ANCA-associated vasculitis (AAV) includes glucocorticoids (GC), which are associated with increased infections. Avacopan is an orally administered selective inhibitor of the C5a receptor recently approved for treatment of AAV. The phase 3 ADVOCATE study tested daily avacopan as a substitute for a standard, scheduled, daily oral GC tapered regimen (all with standard background therapy), resulting in a 63% mean reduction in overall GC load for the avacopan group. At week 26, the avacopan group achieved a comparable remission rate to prednisone (72.3% versus 70.1%) and superior sustained remission at Week 52 (65.7% versus 54.9%; one-sided P = 0.0066) (1). The present analysis compared infections in avacopan and prednisone groups in the ADVOCATE trial. METHOD ADVOCATE, a phase 3, randomized, double-blind, controlled trial in 330 patients, evaluated the efficacy and safety of avacopan. AAV patients (new onset or relapsing disease) were randomized to receive avacopan 30 mg twice daily, or a standard 20-week oral prednisone taper, plus matching placebos. Both groups had background therapy of either cyclophosphamide (followed by azathioprine) or rituximab, and additional GC exposure from premedication for rituximab, from taper of pre-randomization GC, and as required per investigator judgment. Patients were on blinded study drug for 52 weeks. Infections occurring from first dose of blinded study drug through day 56 after last dose were analyzed. RESULTS Total mean GC use during the first 26 weeks of the study was 1073 mg with avacopan and 3193 mg with prednisone groups, and in the last 26 weeks, 296 and 489 mg, respectively. Infections were higher in the prednisone group than with avacopan: 291 events (prednisone) versus 233 (avacopan), with a 75.6% incidence (124/164) with prednisone versus 68.1% (113/166) with avacopan (Table 1). During the prednisone taper period (first 20 weeks), infection incidence was 54.9% in prednisone group versus 49.4% for avacopan, and after the first 20 weeks 52.4% in prednisone group versus 44.0% avacopan. Fewer patients in the avacopan group experienced serious AEs of infection (13.3%/25 events) versus prednisone group (15.2%/31 events); also serious opportunistic infections (3.6% versus 6.7%), life-threatening AEs of infection (0.6% versus 1.2%), and infections resulting in death (0.6% versus 1.2%) were fewer with avacopan (Table 1). No Neisseria meningitidis infections occurred in any patient in the trial. CONCLUSION In the ADVOCATE trial, the mean dose of GCs from all sources was 63% lower in the avacopan group than the prednisone group (1349 versus 3655 total mg, respectively). The avacopan group had a numerically lower incidence of infections, including serious, life-threatening, fatal and serious opportunistic infections compared with the prednisone group.

Changes in Invasive Neisseria meningitidis and Haemophilus influenzae Infections in France during the COVID-19 Pandemic.

BackgroundSince the appearance of COVID-19 in January 2020, invasive bacterial infections have decreased significantly worldwide. However, alterations in age and sex distributions, clinical forms, phenotypes, and genotypes of isolates have not been analyzed. Our goal is to present and discuss these data considering the current COVID-19 pandemic situation. Methods: The data of the national reference center for meningococci and Haemophilus influenzae in France were mined to examine the above aspects of invasive bacterial infection before (2018–2019) and after (2020–2021) the COVID-19 pandemic. Detailed epidemiological, clinical, and microbiological data were collected, and whole genome sequencing was carried out on meningococcal isolates (n = 1466). Results: In addition to the overall decline in the number of cases, various changes in age, sex, and phenotypes of isolates were also noted. As for N. meningitidis, more cases were observed in adults, as well as more invasive pneumopathies. Furthermore, fewer hyperinvasive meningococcal genotypes have circulated since COVID-19 emerged. The situation has been different for H. influenzae, as the number of invasive cases among adults decreased due to a reduction in non-typeable isolates. In contrast, cases due to serotypeable isolates, particularly serotypes a and b, increased in children <5 years-old. Conclusions: It is possible that measures implemented to stop COVID-19 may have reduced the circulation of N. meningitidis and H. influenzae isolates, but to a variable extent. This may be due to differences in circulation between these two species according to age groups. Vaccination schedules against these two species may have also influenced the evolution of these invasive bacterial infections since the emergence of the COVID-19 pandemic.

Estrogen Suppresses Cytokines Release in cc4821 Neisseria meningitidis Infection via TLR4 and ERβ-p38-MAPK Pathway.

Estrogen has long been known to possess immune-modulatory effects in diseases, and multiple pathological conditions show great sex disparities. However, the impact of estrogen in Neisseria meningitidis infection has not been determined. The present study aimed to investigate the role of estrogen in N. meningitidis infection and the molecular mechanism. We selected 35 N. meningitidis isolates representing different clonal complexes (cc), serogroups, and isolation sources to infect the HBMEC cell line. Results showed that the expression of estrogen receptor (ER) β in N. meningitidis-infected cells was downregulated compared with that in normal cells. The expression of ERβ induced by invasive isolates was lower than that in carriers. Serogroup C isolates induced the lowest expression of ERβ compared with serogroup A and B isolates. We used four cc4821 N. meningitidis isolates to infect two kinds of host cells (human brain microvascular endothelial cells and meningeal epithelial cells). The results showed that 17 β-estradiol (E2) could inhibit the release of inflammatory factors interleukin (IL)-6, IL-8, and tumor necrosis factor-α after N. meningitidis infection via TLR4. E2 could inhibit the activation of the p38-MAPK signal pathway induced by N. meningitidis infection through binding to ERβ, and significantly inhibit the release of inflammatory factors in N. meningitidis-infected host cells. This study demonstrated that estrogen plays a protective role in N. meningitidis infection. ERβ is potentially associated with the release of inflammatory cytokines in N. meningitidis infection, which sheds light on a possible therapeutic strategy for the treatment of invasive diseases caused by N. meningitidis.

Update on the Neisseria Macrophage Infectivity Potentiator-Like PPIase Protein.

Neisseria pathogens express a Macrophage Infectivity Potentiator Protein (MIP), which belongs to the FK506 binding protein (FKBP) family of proteins that exhibit peptidyl-prolyl cis/trans isomerase (PPIase) activity. Neisseria MIP proteins are potential candidates for inclusion into vaccines for gonorrhoea caused by N. gonorrhoeae infection, and meningitis/sepsis caused by M. meningitidis infection. Neisseria MIP proteins are also potential targets for directed drug treatments, although this remains relatively unexplored. In this mini-review, we provide an update into the vaccine potential of Neisseria MIP and the few published drug targeting studies, and explore further the diversity of this protein amongst both pathogenic and commensal Neisseria spp.

Avacopan: An Oral Complement 5a Inhibitor for ANCA-associated Vasculitis

The oral complement 5a receptor antagonist, avacopan, was recently studied in phase II and III clinical trials in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This article summarizes the study findings and considers the implications for future care of patients with AAV. Avacopan was proven to be safe and noninferior to glucocorticoids for AAV in a study where patients with severe newly diagnosed or relapsing AAV were initially treated with either rituximab or cyclophosphamide. Greater improvement in the glomerular filtration rate, reduced numbers of relapses and better health-related quality of life were observed in the avacopan group compared with the prednisone group. Patients in the avacopan group also had fewer glucocorticoid-associated adverse events and, despite complement inhibition, there were no cases of Neisseria meningitidis infection reported in either group. Future studies should address the long-term safety of avacopan and whether it can completely replace glucocorticoids in AAV-induction protocols and for the management of minor disease relapses.