The Bacterial Meningitis Epidemic in Banalia in the Democratic Republic of Congo in 2021.

BACKGROUND: The Banalia health zone in the Democratic Republic of Congo reported a meningitis epidemic in 2021 that evolved outside the epidemic season. We assessed the effects of the meningitis epidemic response. METHODS: The standard case definition was used to identify cases. Care was provided to 2651 in-patients, with 8% of them laboratory tested, and reactive vaccination was conducted. To assess the effects of reactive vaccination and treatment with ceftriaxone, a statistical analysis was performed. RESULTS: Overall, 2662 suspected cases of meningitis with 205 deaths were reported. The highest number of cases occurred in the 30-39 years age group (927; 38.5%). Ceftriaxone contributed to preventing deaths with a case fatality rate that decreased from 70.4% before to 7.7% after ceftriaxone was introduced (p = 0.001). Neisseria meningitidis W was isolated, accounting for 47/57 (82%), of which 92% of the strains belonged to the clonal complex 11. Reactive vaccination of individuals in Banalia aged 1-19 years with a meningococcal multivalent conjugate (ACWY) vaccine (Menactra®) coverage of 104.6% resulted in an 82% decline in suspected meningitis cases (incidence rate ratio, 0.18; 95% confidence interval, 0.02-0.80; p = 0.041). CONCLUSION: Despite late detection (two months) and reactive vaccination four months after crossing the epidemic threshold, interventions implemented in Banalia contributed to the control of the epidemic.

Invasive meningococcal disease in older adults: current perspectives and call for action.

PURPOSE: Invasive meningococcal disease (IMD) is a devastating condition. While most attention is directed towards disease in children and adolescents, IMD poses an important cause of morbidity and mortality in adults ≥60 years. While immunization is a critical component of healthy ageing strategies, meningococcal immunization is not routinely offered to older adults. The aim of this review was to summarize clinical and epidemiological aspects of IMD and available immunization strategies, with a particular focus on disease in older individuals, to emphasize the importance of this rather neglected area. METHODS: An expert working group was established to evaluate clinical and epidemiological data to raise awareness of IMD in older individuals, and develop suggestions to improve the existing burden. RESULTS: Routine child and adolescent meningococcal immunization has substantially reduced IMD in these targeted populations. Consequently, prevalence and proportion of IMD among those ≥60 years, mostly unvaccinated, is increasing in developed countries (accounting for up to 25% of cases). IMD-related mortality is highest in this age-group, with substantial sequelae in survivors. IMD due to serogroups W and Y is more prevalent among older adults, often with atypical clinical features (pneumonia, gastrointestinal presentations) which may delay timely treatment. CONCLUSIONS: IMD in older adults remains overlooked and greater awareness is required at clinical and societal levels. We encourage clinicians and immunization policy makers to reconsider IMD, with a call for action to remedy existing inequity in older adult access to protective meningococcal immunization.

Severe Meningococcal Meningitis Revealing a Novel Form of Properdin Deficiency in a Previously Healthy 13-year-old Child.

A 13-year-old boy was admitted with severe meningococcal meningitis. Immunologic workup revealed a properdin deficiency, and genetic sequencing of CFP identified a novel, private and predicted pathogenic variant in exon 8. The patient received broad immunizations and penicillin prophylaxis. Children with invasive meningococcal disease should be tested for complement deficiency.

Characterizing Neisseria meningitidis in Southern Vietnam between 2012 and 2021: A predominance of the chloramphenicol-resistant ST-1576 lineage.

Objectives: Our goal was to describe Invasive Meningococcal Disease (IMD) in Southern Vietnam over the last 10 years. We characterized 109 Neisseria meningitidis strains in Southern Vietnam isolated between 1980s to 2021, that were collected from IMD (n = 44), sexually transmitted infections (n = 2), and healthy carriage (n = 63). Methods: IMD were confirmed by bacterial culture and/or real-time polymerase chain reaction at the national reference laboratory in Pasteur Institute of Ho Chi Minh City (PIHCM). Antimicrobial resistance was determined on 31 IMD and two sexually transmitted infection isolates with E-test for chloramphenicol (CHL), penicillin (PEN), ciprofloxacin (CIP), ceftriaxone (CRO), and rifampicin (RIF). Sequencing was performed for analyzing of multilocus-sequence-typing (MLST), porA, fetA, and antibiotic resistance genes, including gyrA, penA, and rpoB. Results: The incidence rate during this period was 0.02 per 100,000 persons/year. Serogroup B accounted for over 90% of cases (50/54). ST-1576 were mainly responsible for IMD, 27/42 MLST profiles, and associated with CHL resistance. Resistance was prevalent among IMD isolates. Thirteen were resistant to CHL (minimum inhibitory concentration [MIC] ≥16 mg/l), 12 were intermediate to PEN (MIC between 0.19 and 0.5 mg/l), and five were CIP-resistant (MIC between 0.19 and 0.5 mg/l). Particularly, one was non-susceptible to CRO (MIC at 0.125 mg/l), belonging to ST-5571 lineage. The resistance was due to carrying resistant alleles of penA and gyrA genes, and catP gene. Notably, seven isolates were resistant/non-susceptible to two or more antibiotics. Conclusion: Our results suggest the persistence of the circulating ST-1576 in Southern Vietnam, with a spread of antimicrobial resistance across the community.

Not Only Meningitis but Also Epiglottitis: An Emerging Clinical Presentation of Invasive Meningococcal Disease.

The rebound of invasive meningococcal disease cases in France since the fall of 2022 was accompanied by an increase in adult epiglottitis. These cases were provoked mainly by isolates of serogroup W belonging to the clonal complex 11 of Neisseria meningitidis. Awareness and surveillance should be reinforced.

Detection of CTX-M-15 ESBL in XDR Haemophilus parainfluenzae from a urethral swab.

OBJECTIVES: Haemophilus parainfluenzae is an opportunistic pathogen causing respiratory tract infection and sexually transmitted diseases. The emergence of multidrug resistance in this species is particularly worrisome, especially since the recent description of CTX-M-15 ESBL-producing isolates in Spain. The aim of this study was to characterize a CTX-M-15-producing H. parainfluenzae clinical isolate, HP01, obtained from a urethral swab. METHODS: MICs were determined with gradient strips for this isolate. Hydrolysis assays were performed with the ß LACTA test. Genomic DNA from HP01 was subjected to Illumina and Oxford Nanopore sequencing to investigate the genetic environment of blaCTX-M-15. Phylogenetic analysis was performed with available H. parainfluenzae genomes from the NCBI database, including CTX-M-15 producers. RESULTS: HP01, an XDR isolate, was resistant to penicillin, third-generation cephalosporins, fluoroquinolones, macrolides, cyclines and co-trimoxazole and susceptible only to carbapenems and rifampicin. HP01 carried blaTEM-1, blaCTX-M-15, tet(M), catS and mef(E)/mel and harboured amino acid substitutions in PBP3, PBP5, GyrA, ParC and FolA implicated in resistance. Genomic analysis revealed that blaCTX-M-15 was carried by a Tn3-like transposon inserted into a novel integrative and conjugative element (ICE), ICEHpaSLS, present on the chromosome and belonging to the ICEHin1056 family described in Haemophilus influenzae. The tet(M)-MEGA element was also detected on the chromosome. No plasmid was found. The phylogenetic analysis showed that four H. parainfluenzae producing CTX-M-15 clustered in the same clade. CONCLUSIONS: Here we report the description of an XDR H. parainfluenzae producing blaCTX-M-15 isolated from a urethral swab. The blaCTX-M-15 gene was inserted into an ICE structure similar to those recently described in CTX-M-15 producers in Spain. The emergence of XDR H. parainfluenzae producing blaCTX-M-15 is a matter of great concern. Careful surveillance is required to prevent its spread.

Meningococcal disease in the Middle East: A report from the Global Meningococcal Initiative.

This review details recent findings from the Global Meningococcal Initiative's (GMI) recent meeting on the surveillance and control strategies for invasive meningococcal disease in the Middle East. The nature of case reporting and notification varies across the region, with many countries using bacterial meningitis as an IMD case definition in lieu of meningitis and septicaemia. This may overlook a significant burden associated with IMD leading to underreporting or misreporting of the disease. Based on these current definitions, IMD reported incidence remains low across the region, with historical outbreaks mainly occurring due to the Hajj and Umrah mass gatherings. The use of case confirmation techniques also varies in Middle Eastern countries. While typical microbiological techniques, such as culture and Gram staining, are widely used for characterisation, polymerase chain reaction (PCR) testing is utilised in a small number of countries. PCR testing may be inaccessible for several reasons including sample transportation, cost, or a lack of laboratory expertise. These barriers, not exclusive to PCR use, may impact surveillance systems more broadly. Another concern throughout the region is potentially widespread ciprofloxacin resistance since its use for chemoprophylaxis remains high in many countries.

Vaccine-preventable Pediatric Acute Bacterial Meningitis in France: A Time Series Analysis of a 19-Year Prospective National Surveillance Network.

BACKGROUND: In France, vaccination has been implemented against Hi serotype b (Hib), pneumococcus with pneumococcal conjugate vaccines (PCV), and Neisseria meningitidis serogroup C (MenC). These interventions with different coverage and uptake have disrupted the epidemiology of vaccine-preventable acute bacterial meningitis (ABM). METHODS: We analyzed data from a French prospective surveillance network of ABM in children ≤15 years old enrolled by 259 pediatric wards (estimated national coverage: 61%). From 2001 to 2020, the effect of vaccine implementation was estimated with segmented linear regression. RESULTS: We analyzed 7,186 cases, mainly due to meningococcus (35.0%), pneumococcus (29.8%), and Hi (3.7%). MenC ABM incidence decreased (-0.12%/month, 95% CI: -0.17 to -0.07, P < 0.001) with no change for the overall meningococcal ABM when comparing the pre-MenC vaccination and the post-MenC vaccination trends. Despite a decreasing MenB ABM incidence without a vaccination program (-0.43%/month, 95% CI: -0.53 to -0.34, P < 0.001), 68.3% of meningococcal ABM involved MenB. No change in pneumococcal ABM incidence was observed after the PCV7 recommendation. By contrast, this incidence significantly decreased after the switch to PCV13 (-0.9%/month, 95% CI: -1.6 to -0.2%, P = 0.01). After May 2014, a rebound occurred (0.5%/month, 95% CI: 0.3-0.8%, P < 0.001), with 89.5% of non-PCV13 vaccine serotypes. Hib ABM incidence increased after June 2017. CONCLUSIONS: PCV7 and MenC vaccine introduction in France, with slow vaccine uptake and low coverage, had no to little impact as compared to the switch from PCV7 to PCV13, which occurred when coverage was optimal. Our data suggest that MenB and next-generation PCVs could prevent a large part of the ABM incidence in France.

Biofilm formation by non-typeable Haemophilus influenzae confers resistance to complement-mediated clearance.

Biofilm formation is suggested to be associated with phenotype changes compared to planktonic form. We screened 1092 Haemophilus influenzae isolates for their genetic relationships and then selected 29 isolates from different genotypes and phenotypes and tested their ability to form biofilm. Our data showed a higher capacity of non-typeable isolates and particularly isolates from respiratory and genital infections to form biofilm compared to typeable isolates. This ability to form biofilm was also correlated with reduced deposition of the complement component C3b on biofilm-involved bacteria. These data suggest that the biofilm formation contributes to the virulence of non-typeable H. influenzae.

The rapid rebound of invasive meningococcal disease in France at the end of 2022.

BACKGROUND: Invasive meningococcal disease (IMD) cases declined upon the implementation of non-pharmaceutical measures to control the COVID-19 pandemic. A rebound in IMD cases was feared upon easing these measures. METHODS: We conducted a retrospective descriptive study using the French National Reference Center Database for meningococci between 2015 and 2022. We scored serogroups, sex, age groups, and clonal complexes of the corresponding isolates. FINDINGS: Our data clearly show a decline in the number of IMD cases for all serogroups and age groups until 2021. This decline was mainly due to a decrease in IMD cases provoked by the hyperinvasive ST-11 clonal complex. However, since the fall of 2021, there has been an increase in IMD cases, which accelerated in the second half of 2022. This rebound concerned all age groups, in particular 16-24 years. The increase in cases due to serogroups B, W, and Y were mainly due to the expansion of isolates of the ST-7460, the clonal complex ST-9316 and the clonal complex ST-23, respectively. INTERPRETATION: IMD epidemiology changes constantly and profound epidemiological changes have been recently observed. The surveillance of IMD needs to be enhanced using molecular tools. Additionally, vaccination strategies need to be updated to acknowledge recent epidemiological changes of these vaccine-preventable serogroups.

Range of Clinical Manifestations Caused by Invasive Meningococcal Disease Due to Serogroup W: A Systematic Review.

INTRODUCTION: Invasive meningococcal disease (IMD) due to serogroup W meningococci (MenW) is consistently reported with atypical clinical manifestations, including gastrointestinal symptoms, bacteremic pneumonia, and septic arthritis. We undertook a systematic review of the literature for a comprehensive assessment of the clinical presentation of IMD caused by MenW. METHODS: PubMed and Embase databases were searched from inception to June 2022 using a combination of MeSH terms and free text for articles that reported symptoms and signs of MenW IMD, and associated manifestations. RESULTS: The most commonly reported symptoms identified included: fever (range 36-100% of cases), nausea and/or vomiting (range 38-47%), vomiting (range 14-68%), cough (range 7-57%), sore throat (range 13-34%), headache (range 7-50%), diarrhea (range 8-47%), altered consciousness/mental status (range 7-38%), stiff neck (range 7-54%), and nausea (range 7-20%). Sepsis (range 15-83% of cases) was the most commonly reported manifestation followed by meningitis (range 5-72%), sepsis and meningitis (range 6-74%), bacteremic pneumonia (range 4-24%), arthritis (range 1-15%), and other manifestations (e.g., pharyngitis/epiglottitis/supraglottitis/tonsillitis/conjunctivitis; range 1-24%). The case fatality rates ranged from 8-40%, and among the survivors 4-14% had long-term sequelae. CONCLUSIONS: Clinicians need to be aware of the nonspecific symptoms and signs of IMD, as well as of the atypical manifestations in regions where MenW is known to circulate to ensure timely diagnoses and treatment.

Characteristics of Meningococcal Invasive Disease in Neonates and Virulence of the Corresponding Isolates.

BACKGROUND: The highest incidence of invasive meningococcal disease (IMD) is observed in infants. However, its prevalence in neonates (≤28 days of age) and the characteristics of the corresponding isolates are less described. This report aimed to analyze meningococcal isolates from neonates. METHODS: We first screened the database of the national reference center for meningococci in France for confirmed neonatal IMD cases between 1999 and 2019. We then performed whole-genome sequencing on all cultured isolates, and we evaluated their virulence in a mouse model. RESULTS: Fifty-three neonatal cases of IMD (mainly bacteremia) were identified (50 culture-confirmed cases and 3 PCR-confirmed cases) of a total of 10,149 cases (0.5%) but represented 11% of cases among infants of under 1 year of age. Nine cases (17%) occurred among neonates of 3 days of age and younger (early onset). The neonate isolates were often of serogroup B (73.6%) and belonged to the clonal complex CC41/44 (29.4%) with at least 68.5% of coverage by vaccines against serogroup B isolates. The neonatal isolates were able to infect mice although to variable levels. CONCLUSION: IMD in neonates is not rare and can be of early or late onsets suggesting that anti-meningococcal vaccination can target women planning to have a baby.

Recent Evolution of Susceptibility to Beta-Lactams in Neisseria meningitidis.

Beta-lactams are the main antibiotics for the treatment of invasive meningococcal disease. However, reduced susceptibility to penicillin G is increasingly reported in Neisseria meningitidis and reduced susceptibility to third-generation cephalosporines (3GC) and the rare acquisition of ROB-1 beta-lactamase were also described. Modifications of penicillin-binding protein 2 (PBP2) encoded by the penA gene are the main described mechanism for the reduced susceptibility to penicillin and to other beta-lactams. penA modifications were analyzed using the sequences of all penA genes from cultured isolates between 2017-2021 in France (n = 1255). Data showed an increasing trend of reduced susceptibility to penicillin from 36% in 2017 to 58% in 2021. Reduced susceptibility to 3GC remained limited at 2.4%. We identified 74 different penA alleles and penA1 was the most frequent wild-type allele and represented 29% of all alleles while penA9 was the most frequently altered allele and represented 17% of all alleles. Reduced susceptibility to 3GC was associated with the penA327 allele. The amino acid sequences of wild-type and altered PBP2 were modeled. The critical amino acid substitutions were shown to change access to the active S310 residue and hence hinder the binding of beta-lactams to the active site of PBP2.

Changing patterns of invasive meningococcal disease and future immunization strategies.

Invasive meningococcal disease (IMD) is a life-threatening disease caused by Neisseria meningitidis and has high mortality rates. Survivors often exhibit long-term sequelae and reduced life expectancy. Disease incidence is highest in infants and toddlers, with a resurgence of cases in adolescents and older adults (>50 years of age). Substantial heterogeneity exists in the recommendations of meningococcal vaccines included in National Immunization Programs (NIPs) across countries. Recommendations are usually based on infant/toddler immunization, with some countries recommending immunization only for toddlers. While existing recommendations have led to a reduced incidence of IMD in children <5 years of age, there has been an increase in cases among adolescents and older adults. Currently, older adults are not included in the recommendations. The higher healthcare burden and the economic costs associated with IMD in these age groups suggest that it is time to consider including adolescents and older adults in NIPs to protect against IMD caused by the five most prevalent serogroups. Currently, the lack of equity of access to vaccines in the immunization programs is a glaring gap in the betterment of public health, and a broader meningococcal strategy is recommended to provide optimal protection for all age groups.

Invasive meningococcal diseases, which include meningitis, are rare and unpredictable, but may lead to very important/debilitating long-term sequelae, death, or reduced life expectancy. Vaccination is the best way to prevent them. Vaccination recommendations provided by national health agencies usually target infants (or toddlers), children, and adolescents. Older adults are only considered when they are at risk for invasive meningococcal diseases.Here, we analyzed the vaccination strategies for invasive meningococcal disease in different countries to identify the gaps preventing access to vaccination.We found that recommendations for invasive meningococcal disease vaccination vary markedly among countries. Vaccination programs target mainly infants and toddlers, and they successfully reduced the number of cases among them. However, we also observed that the disease now affects more adults. We also found that the lack of equitable access to vaccination prevents broader meningococcal protection for persons of any age.With this analysis, we suggest improving the current meningococcal vaccination guidelines to also provide adolescents and healthy older adults with access to vaccines. Promoting equal access to vaccination for everyone could reduce the impact on the healthcare system and help reduce social disparity. In order to do so, we advise universal recommendation of meningococcal vaccines, which would provide clear guidance to health-care practitioners.

Severe Bacterial Infection Initially Misdiagnosed as MIS-C: Caution Needed.

Working in the era of the novel coronavirus disease 2019 can predispose to cognitive bias. We present a case of life-threatening bacterial infection misdiagnosed as multisystem inflammatory syndrome in children. While multisystem inflammatory syndrome in children-related myocardial dysfunction is now a well-recognized complication of coronavirus disease 2019, a rigorous differential diagnosis approach, notably for infectious etiologies, is paramount.

Haemophilus influenzae drug resistance in France from 2017 to 2021: consideration for treatment of otitis media.

OBJECTIVES: Haemophilus influenzae is a prevalent agent of respiratory infections, including acute otitis media (AOM), that lead to high antibiotic prescription and may contribute to the development of bacterial resistance to antibiotics. The objective of this work was to describe and analyse antibiotic resistance of H. influenzae from 2017 to 2021 in France. METHODS: We characterized H. influenzae isolates transmitted to the French national reference centre for H. influenzae between 2017 and 2021. We included all the 608 non-invasive respiratory isolates. Resistance rates to the main antibiotics were described. The relationship between resistance rate, age, and sex of patients and germ serotype was investigated. RESULTS: Isolates were mainly from alveolar lavage (29.3%), expectoration (22.9%), or sputum (15%). Resistance to amoxicillin (61.4%), amoxicillin/clavulanic acid (47.4%), and cefotaxime (39.3%) was high and correlated with the presence of ß-lactamase and/or modifications of the ftsI gene encoding penicillin-binding protein 3. Resistance to sulfamethoxazole/trimethoprim (33.2%) was more moderate. There were no significant differences according to serotype, age, or gender. CONCLUSIONS: The benefit/risk balance of first choice use of amoxicillin and even of amoxicillin/clavulanic acid in AOM is questionable in view of the significant resistance to H. influenzae. The use of sulfamethoxazole/trimethoprim could be an alternative but may still need further evaluation.

Meningococcal disease in North America: Updates from the Global Meningococcal Initiative.

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of ß-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI.

Immunogenicity and safety of the meningococcal B recombinant (4CMenB) vaccine in allogeneic hematopoietic cell transplantation recipients.

OBJECTIVES: Despite a high risk of invasive meningococcal (Men) disease, there is no published data on any MenB vaccine after hematopoietic cell transplantation (HCT). We investigated the immunogenicity and safety of the 4CMenB recombinant vaccine (Bexsero) in adult HCT recipients. METHODS: Patients were eligible from 6 months post-HCT to receive 2 4CMenB doses at 2-month intervals. Sera were collected at baseline, 1 month after the second dose, and 12 months after enrolment. The serum bactericidal activity (SBA) using human complement (hSBA) was assessed against fHbp, NadA, PorAP1.4, and NHBA antigens. The vaccine response was defined by one criterion for one vaccine antigen: (1) in patients with a hSBA titer <4 at baseline: a titer ≥4; (2) in patients with a hSBA titer ≥4 at baseline: at least a 4 time increase. RESULTS: Forty (40) patients were included at a median of 2.14 (0.57-13.03) years posttransplant. At baseline, most patients (32/40, 80%) had hSBA titers <4 for all vaccine antigens. After 2 vaccine doses, the proportion of patients with a titer ≥4 was significantly increased for fHbp (23/40, 57.5%), NadA (25/40, 62.5%), and PorA (31/40, 77.5%) but not for NHBA for which only 6 of 40 (15%) patients responded. Of patients, 36 out of 0 (90%) were responders to ≥1 antigen. However, 9 months later, only 23 out of 37 (62.2%) patients were still seroprotected. No severe adverse event was observed. DISCUSSION: The response rate of 90% for ≥1 vaccine antigen and our safety data supports the 4CMenB vaccination of HCT recipients from 6 months after transplant with 2 doses.

Impact of mandatory vaccination against serogroup C meningococci in targeted and non-targeted populations in France.

Since January 2018, mandatory vaccination against meningococci serogroup C has been implemented in France for children <2 years with a recommended catch-up vaccination until the age of 24 years. We aimed to analyse the impact of mandatory vaccination on populations not targeted by it (2-24 years old). We used the database of the national reference centre for meningococci to collect the number of invasive meningococcal disease (IMD) cases before (2016-2017) and after (2018-2019) the mandatory vaccination. The cultured isolates were sequenced and submitted for genomic comparison. The total number of cases was 1706, including 376 cases of IMD serogroup C. Mandatory vaccination correlated with a significant decrease among the <2 years old and a decreasing trend among the 2-14 years old group but not among 15-25 years of age. This observation may be explained by the vaccine coverage that is still low among adolescents and young adults. Moreover, the genomic analysis revealed the co-circulation of two major genotypes belonging to the clonal complex ST-11 whose distribution differed across the age groups in accord with cyclic variations of genotypes. It is important to increase specific knowledge on meningococcal epidemiology and vaccination to involve them in establishing the vaccination strategy.