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Mashau RC, Meiring ST, Quan VC, et al. Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study. Lancet Infect Dis 2022; published online June 21. https://doi.org/10.1016/S1473-3099(22)00234-1. In this Article, a change has been made as follows. The statement in “Role of funding source” is incorrect and should be: The NICD conceived the study design, data collection, data analysis, data interpretation, and writing of the report.

Abstract

Purpose

In infections of the Central Nervous System (iCNS), rapid identification of causing pathogens is crucial for survival and to avoid long-term sequelae. Targeted therapy may reduce side effects and development of antibiotic resistance. New molecular-based syndromic tests such as the “meningitis/encephalitis panel” (MEP) allow accelerated pathogen identification from cerebrospinal fluid. We conducted a clinical study to evaluate the MEP’s efficacy in paediatric patients.

Methods

Cohort study in a unique clinical setting by comparing the outcome data of two neighbouring Children’s Hospitals in Germany which are comparable in size, catchment area and equipment but differ regarding availability of the MEP: study centre 1 (SC1): yes; SC2: no. The study population included 213 paediatric patients with a suspected iCNS (SC1: 106; SC2: 107), with comparable age, CRP at admission and frequency of intensive care. The primary outcome was total use of antibiotics.

Results

Total antibiotic use per patient was numerically lower in SC1 than in SC2 (SC1: median 2.83 days; SC2 3.67 days; p = 0.671). Multiple linear regression analysis did not show a relevant association between MEP-availability and total antibiotic use (ß = 0.1, 95% confidence interval [−1.46; +1.67], p = 0.897). In the subcohort with suspected meningoencephalitis (SC1: 18, SC2: 17), duration of acyclovir treatment was shorter in SC1 than in SC2 (median 1.3 days vs. 2.7 days, descriptive p = 0.0397).

Conclusions

The add-on use of the MEP in paediatric patients with suspected iCNS was associated with a non-significant reduction in total antibiotic use, and with a reduced exposure to acyclovir in treated patients.

…

To study the clinical features of bacterial meningitis in myeloma patients.

Fungal meningitis is typically diagnosed by culture, sometimes by molecular diagnosis or histology. However, cultures lack sensitivity and require several days to grow. A sensitive biomarker that could rapidly identify a fungal central nervous system (CNS) infection could be one step among several towards improving diagnosis and treatment.

Abstract

Purpose

In infections of the Central Nervous System (iCNS), rapid identification of causing pathogens is crucial for survival and to avoid long-term sequelae. Targeted therapy may reduce side effects and development of antibiotic resistance. New molecular-based syndromic tests such as the “meningitis/encephalitis panel” (MEP) allow accelerated pathogen identification from cerebrospinal fluid. We conducted a clinical study to evaluate the MEP’s efficacy in paediatric patients.

Methods

Cohort study in a unique clinical setting by comparing the outcome data of two neighbouring Children’s Hospitals in Germany which are comparable in size, catchment area and equipment but differ regarding availability of the MEP: study centre 1 (SC1): yes; SC2: no. The study population included 213 paediatric patients with a suspected iCNS (SC1: 106; SC2: 107), with comparable age, CRP at admission and frequency of intensive care. The primary outcome was total use of antibiotics.

Results

Total antibiotic use per patient was numerically lower in SC1 than in SC2 (SC1: median 2.83 days; SC2 3.67 days; p = 0.671). Multiple linear regression analysis did not show a relevant association between MEP-availability and total antibiotic use (ß = 0.1, 95% confidence interval [−1.46; +1.67], p = 0.897). In the subcohort with suspected meningoencephalitis (SC1: 18, SC2: 17), duration of acyclovir treatment was shorter in SC1 than in SC2 (median 1.3 days vs. 2.7 days, descriptive p = 0.0397).

Conclusions

The add-on use of the MEP in paediatric patients with suspected iCNS was associated with a non-significant reduction in total antibiotic use, and with a reduced exposure to acyclovir in treated patients.

…

Cryptococcal meningitis, a major cause of meningitis in adults living with HIV infection, accounts for 15% of global HIV-associated mortality.1 Treatment of cryptococcal meningitis involves three phases: induction, consolidation, and maintenance. The induction phase, which aims at reducing cerebral and meningeal fungal burden crucial for early survival, requires combination antifungal therapy and management of increased cerebrospinal fluid intracranial pressure. WHO in 2018 recommended at induction either 1-week amphotericin B deoxycholate plus flucytosine followed by high-dose fluconazole or 2-week oral fluconazole plus flucytosine.

In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit.

by Mariana Brena Souza, Maria Cecília Cergole-Novella, Delma Aparecida Molinari, Daniela Rodrigues Colpas, Andréia Moreira dos Santos Carmo, Vilma dos Santos Menezes Gaiotto Daros, Ivana Barros de Campos

Meningitis caused by Streptococcus pneumoniae is still a disease of great impact on Public health, which requires immediate diagnosis and treatment. However, the culture of clinical specimens is often negative and antibiotic susceptibility testing (AST) must be performed with isolated strains. Multiplex real-time polymerase chain reaction (qPCR) has high sensitivity and specificity, produces faster results to identify the pathogen, and it can also be an important tool to identify resistance antibiotic genes earlier than AST, especially in the absence of an isolated strain. This study developed a multiplex qPCR assay, using SYBR Green as a nonspecific dye, to detect antibiotic resistance genes to predict pneumococcal susceptibility/resistance in cerebrospinal fluid (CSF) samples from meningitis patients. From 2017 to 2020, CSF samples were cultured and analyzed by qPCR to detect the main three bacteria causing meningitis. Isolated and reference strains were applied in SYBR Green qPCR multiplex to detect pbp2b, ermB, and mef genes, and the results were compared with the AST. Pneumococcal-positive CSF samples (lytA-positive gene) without isolated strains were also tested to evaluate the antimicrobial susceptibility profile in the region from 2014 to 2020. From the received 873 CSF samples; 263 were cultivated, 149 were lytA-positive in the qPCR, and 25 produced viable isolated pneumococci strains, which were evaluated by AST. Melting temperature for each gene and the acceptance criteria were determined (pbp2b: 78.24–79.86; ermB: 80.88–82.56; mef: 74.85–76.34 ºC). A total of 48/51 strains presented a genetic profile in agreement with the AST results. Resistant strains to erythromycin and clindamycin were ermB-positive, and two were also mef-positive, indicating both resistance mechanisms were present. In the retrospective study of the genetic profile of resistance, 82 lytA-positive CSF samples plus 4 strains were applied in the SYBR Green qPCR multiplex: 51% of samples presented the wild genotype (pbp2b positive and ermB/mef negative); 15% were negative for all the three evaluated, indicating pneumococci resistant to penicillin; and 17% represented the multidrug-resistant pneumococci (pbp2b negative and ermB positive or pbp2b negative and ermB and mef positive). Therefore, SYBR Green qPCR multiplex proved to be a reliable tool to identify resistance genes in S. pneumoniae and would be less expensive than multiplex qPCR using specific probes. This could be easily introduced into the routine of diagnostic laboratories and provide a strong presumption of pneumococcal resistance, especially in the absence of isolated strains.

Streptococcus pneumoniae can cause Invasive pneumococcal disease (IPD) at a patient's sterile site, including the cerebrospinal fluid and blood, and commonly presents with septicemia, meningitis, and pneumonia (Dowell et al., 2003). In Japan, both children and the elderly receive public support for pneumococcal vaccination. Pneumococcal vaccine coverage has been increased since the launch of the vaccine program (Naito et al., 2020).

Abstract

Purpose

To investigate the prevalence of neuro-functional disability and its determinants 12 months after community-acquired bacterial meningitis (CABM) in adult patients.

Methods

In a prospective multicenter cohort study (COMBAT), all consecutive cases of CABM were enrolled and followed up for 12 months. Neuro-functional disability at 12 months was evaluated using a combination of the Glasgow Outcome Scale (functional disability), and the modified Rankin Disability Scale (physical disability). Factors associated with neuro-functional disability were identified by multivariate logistic regression.

Results

Among 281 patients, 84 (29.9%) patients exhibited neuro-functional disability at 12 months: 79 (28.1%) with functional disability and 51 (18.1%) with physical disability. Overall, 6 patients (2.1%) died during the follow-up. The most common pathogen identified was Streptococcus pneumoniae (131/272, 48.2%); 77/268 patients (28.7%) had a physical disability at hospital discharge. Factors independently associated with 12-month neuro-functional disability were a pneumococcal meningitis (adjusted OR = 2.8; 95% confidence interval (CI) = [1.3; 6.7]), the presence of a physical disability at hospital discharge (aOR = 2.3; 95%CI = [1.2; 4.4]) and the presence of behavioral disorders at hospital-discharge (aOR = 5.9; 95%CI = [1.6; 28.4]). Dexamethasone use was not significantly associated with neuro-functional disability (OR = 0.2; 95%CI = [< 0.1;1.3]).

Conclusion

Neuro-functional disability is frequently reported 12 months after CABM. Detailed neurological examination at discharge is needed to improve the follow-up.

Trial registration

NCT01730690.

…

Abstract

Purpose

To investigate the prevalence of neuro-functional disability and its determinants 12 months after community-acquired bacterial meningitis (CABM) in adult patients.

Methods

In a prospective multicenter cohort study (COMBAT), all consecutive cases of CABM were enrolled and followed up for 12 months. Neuro-functional disability at 12 months was evaluated using a combination of the Glasgow Outcome Scale (functional disability), and the modified Rankin Disability Scale (physical disability). Factors associated with neuro-functional disability were identified by multivariate logistic regression.

Results

Among 281 patients, 84 (29.9%) patients exhibited neuro-functional disability at 12 months: 79 (28.1%) with functional disability and 51 (18.1%) with physical disability. Overall, 6 patients (2.1%) died during the follow-up. The most common pathogen identified was Streptococcus pneumoniae (131/272, 48.2%); 77/268 patients (28.7%) had a physical disability at hospital discharge. Factors independently associated with 12-month neuro-functional disability were a pneumococcal meningitis (adjusted OR = 2.8; 95% confidence interval (CI) = [1.3; 6.7]), the presence of a physical disability at hospital discharge (aOR = 2.3; 95%CI = [1.2; 4.4]) and the presence of behavioral disorders at hospital-discharge (aOR = 5.9; 95%CI = [1.6; 28.4]). Dexamethasone use was not significantly associated with neuro-functional disability (OR = 0.2; 95%CI = [< 0.1;1.3]).

Conclusion

Neuro-functional disability is frequently reported 12 months after CABM. Detailed neurological examination at discharge is needed to improve the follow-up.

Trial registration

NCT01730690.

…

by Amene Saghazadeh, Nima Rezaei

Background Changes in endothelial function are implicated in the spread of tuberculosis (TB). Studies suggest a role for the vascular endothelial growth factor (VEGF) in TB-related endothelial function changes. However, the findings of studies investigating the VGEF profile in TB are not consistent, and no formal systematic review and meta-analysis exists summarizing these studies. Methods We did a meta-analysis of studies assessing VEGF levels in patients with TB. A systematic search on June 25, 2021, was conducted for eligible studies that made VEGF measurements in an unstimulated sample, e.g., a blood fraction (plasma or serum), cerebrospinal fluid (CSF), pleural effusion (PE), or bronchoalveolar lavage fluid, and ascites or pericardial fluid for patients with TB and controls without TB. Also, studies that made simultaneous measurements of VEGF in blood and PE or CSF in the same patients with TB were included. Longitudinal studies that provided these data at baseline or compared pre-post anti-tuberculosis treatment (ATT) levels of VEGF were included. The primary outcome was the standardized mean difference (SMD) of VEGF levels between the comparison groups. Results 52 studies were included in the meta-analysis. There were 1787 patients with TB and 3352 control subjects of eight categories: 107 patients with transudative pleural effusion, 228 patients with congestive heart failure (CHF)/chronic renal failure (CRF), 261 patients with empyema and parapneumonic effusion (PPE), 241 patients with cirrhosis, 694 healthy controls (with latent TB infection or uninfected individuals), 20 patients with inactive tuberculous meningitis (TBM), 123 patients with non-TBM, and 1678 patients with malignancy. The main findings are as follows: (1) serum levels of VEGF are higher in patients with active TB compared with healthy controls without other respiratory diseases, including those with latent TB infection or uninfected individuals; (2) both serum and pleural levels of VEGF are increased in patients with TPE compared with patients with transudative, CHF/CRF, or cirrhotic pleural effusion; (3) ascitic/pericardial fluid, serum, and pleural levels of VEGF are decreased in patients with TB compared with patients with malignancy; (4) pleural levels of VEGF are lower in patients with TPE compared with those with empyema and PPE, whereas serum levels of VEGF are not different between these patients; (5) both CSF and serum levels of VEGF are increased in patients with active TBM compared with controls, including patients with inactive TBM or non-TBM subjects; (6) post-ATT levels of VEGF are increased compared with pre-ATT levels of VEGF; and (7) the mean age and male percentage of the TB group explained large and total amount of heterogeneity for the meta-analysis of blood and pleural VEGF levels compared with healthy controls and patients with PPE, respectively, whereas these moderators did not show any significant interaction with the effect size for other analyses. Discussion The important limitation of the study is that we could not address the high heterogeneity among studies. There might be unmeasured factors behind this heterogeneity that need to be explored in future research. Meta-analysis findings align with the hypothesis that TB may be associated with abnormal vascular function, and both local and systemic levels of VEGF can be used to trace this abnormality.…

Introduction

Infant upper respiratory microbiota are derived partly from the maternal respiratory tract, and certain microbiota are associated with altered risk of infections and respiratory disease. Neisseria lactamica is a common pharyngeal commensal in young children and is associated with reduced carriage and invasive disease by Neisseria meningitidis. Nasal inoculation with N. lactamica safely and reproducibly reduces N. meningitidis colonisation in healthy adults. We propose nasal inoculation of pregnant women with N. lactamica, to establish if neonatal pharyngeal colonisation occurs after birth, and to characterise microbiome evolution in mother–infant pairs over 1 month post partum.

Methods and analysis

20 healthy pregnant women will receive nasal inoculation with N. lactamica (wild type strain Y92-1009) at 36–38 weeks gestation. Upper respiratory samples, as well as optional breastmilk, umbilical cord blood and infant venous blood samples, will be collected from mother–infant pairs over 1 month post partum. We will assess safety, N. lactamica colonisation (by targeted PCR) and longitudinal microevolution (by whole genome sequencing), and microbiome evolution (by 16S rRNA gene sequencing).

Ethics and dissemination

This study has been approved by the London Central Research Ethics Committee (21/PR/0373). Findings will be published in peer-reviewed open-access journals as soon as possible.

Trial registration number

NCT04784845.

…

by Aquino Albino Nhantumbo, Charlotte Elizabeth Comé, Plácida Iliany Maholela, Alcides Moniz Munguambe, Paulino da Costa, Mariana Mott, Gabriella Rosa Cunha, Lúcia Chambal, Cícero Dias, Vlademir Vicente Cantarelli, Eduardo Samo Gudo

Background Meningitis remains an important cause of morbi-mortality in adults in sub-Saharan Africa. Data on the etiological investigation of meningitis in adults in Mozambique is limited and most studies were conducted in southern Mozambique. Identification of the etiology of meningitis in adults are crucial to guide prevention and treatments strategies. In this study, we determine the burden of fungal and bacterial meningitis among adults at the three largest hospitals in Mozambique. Method We performed analysis of data from the routine sentinel surveillance system for meningitis in Mozambique from January 2016 to December 2017. Cerebrospinal fluid (CSF) samples were collected from eligible adults (≥18 years old) who met World Health Organization (WHO) case definition criteria for Meningitis. All samples were tested by cryptococcal antigen (CrAg) lateral flow assay (LFA), culture and triplex real-time polymerase chain reaction (qPCR) assay and all patients were tested for human immunodeficiency virus (HIV) using the national algorithm for HIV testing. Results Retrospective analysis of 1501 CSF samples from adults clinically suspected of meningitis revealed that 10.5% (158/1501) were positive for bacterial and fungal meningitis. Of these 158 confirmed cases, the proportion of Cryptococcal meningitis and pneumococcal meningitis was38.6% (95% CI: 31.0% to 46.7%) and 36.7% (95% CI: 29.2% to 44.7%), respectively. The other bacterial agents of meningitis identified include Neisseria meningitidis (8.9%; 14/158), Escherichia coli (6.3%; 10/158), Haemophilus influenzae (5.1%; 8/158) and S. aureus (4.4%; 7/158), which represent (24.7%; 39/158) of the total confirmed cases. Conclusion Altogether, our findings show a high burden of Cryptococcal meningitis among adults in Mozambique, especially in people living with HIV, followed by pneumococcal meningitis. Our findings suggest that rollout of CrAg Lateral Flow Assay in the health system in Mozambique for early detection of cryptococcus neoformans is necessary to improve overall patient care.…

Escherichia coli meningitis is frequent and has been widely described among newborns (1). The strains involved show an oligoclonal distribution within only a few sequence type complexes (STcs) and often harbor the K1 capsular antigen. Among adults, E. coli accounts for 0.5-3% of meningitis and has poor outcome, but data are scarce and genomic characteristics of responsible strains are often lacking (2). We conducted a multicentric retrospective study, including all cases referred for expertise to our national reference center between 2009 and 2020, and performed whole-genome sequencing to genetically characterize corresponding isolates as previously described (3).

Abstract

Objectives

With modern combination antiretroviral Treatment (cART) a normal life expectancy among people living with HIV (PLWH) has become reality if started early enough prior to the onset of more pronounced immunodeficiency. Therefore, prevention measures against other infectious diseases among this vulnerable group have gained increased attention. Indeed, the EACS guidelines recommend vaccinations against HAV, HBV, HPV, Influenza, Neisseria meningitidis, Streptococcus pneumoniae and VZV in HIV-infected adults.

Methods

All PLWH under cART attending our ID outpatient clinic between April to June 2018, were assessed during consultation for vaccination status regarding pneumococcus, Hepatitis A and B, influenza, varicella, meningococcus and HPV using a pre-defined questionnaire, vaccination certificates and medical records. In addition, the cohort database was screened for Hepatitis A and B serology and HIV surrogate markers.

Results

A total of 305 PLWH (82.3% male, 17.7% female) was included, median age was 48 years (IQR 47–51). Median CD4 + T cell count was 543 (IQR 304–770), and for 297 (97.4%) PLWH CD4 + T cell count was ≥ 200/ul. The viral load was undetectable (< 40 copies/ml) in 289 (94.8%) cases. Highest vaccination rates were observed for HAV (87.4%), Streptococcus pneumoniae (77.4%) and Influenza (76.5%). 64.3% PLWH got vaccinated against HBV, whereas VZV vaccination only played a minor role, in the context of the high rate of cleared infections (99.0%). Lowest vaccination rates were detected for HPV (0%) and Neisseria meningitidis (3.0%).

Conclusions

Our data suggest that vaccination rates among PLWH are higher compared to the general German population. Implementation of EACS guidelines into daily routine though is not fully executed and the need for improving vaccination rates has to be emphasized. Centrally organized vaccination registers as well as electronic medical records could be helpful tools to detect a lack of vaccination coverage and send digital vaccination reminders particularly among risk groups.

…

Abstract

Objectives

With modern combination antiretroviral Treatment (cART) a normal life expectancy among people living with HIV (PLWH) has become reality if started early enough prior to the onset of more pronounced immunodeficiency. Therefore, prevention measures against other infectious diseases among this vulnerable group have gained increased attention. Indeed, the EACS guidelines recommend vaccinations against HAV, HBV, HPV, Influenza, Neisseria meningitidis, Streptococcus pneumoniae and VZV in HIV-infected adults.

Methods

All PLWH under cART attending our ID outpatient clinic between April to June 2018, were assessed during consultation for vaccination status regarding pneumococcus, Hepatitis A and B, influenza, varicella, meningococcus and HPV using a pre-defined questionnaire, vaccination certificates and medical records. In addition, the cohort database was screened for Hepatitis A and B serology and HIV surrogate markers.

Results

A total of 305 PLWH (82.3% male, 17.7% female) was included, median age was 48 years (IQR 47–51). Median CD4 + T cell count was 543 (IQR 304–770), and for 297 (97.4%) PLWH CD4 + T cell count was ≥ 200/ul. The viral load was undetectable (< 40 copies/ml) in 289 (94.8%) cases. Highest vaccination rates were observed for HAV (87.4%), Streptococcus pneumoniae (77.4%) and Influenza (76.5%). 64.3% PLWH got vaccinated against HBV, whereas VZV vaccination only played a minor role, in the context of the high rate of cleared infections (99.0%). Lowest vaccination rates were detected for HPV (0%) and Neisseria meningitidis (3.0%).

Conclusions

Our data suggest that vaccination rates among PLWH are higher compared to the general German population. Implementation of EACS guidelines into daily routine though is not fully executed and the need for improving vaccination rates has to be emphasized. Centrally organized vaccination registers as well as electronic medical records could be helpful tools to detect a lack of vaccination coverage and send digital vaccination reminders particularly among risk groups.

…

Abstract

Background

Loop isothermal amplification (LAMP) has recently been proposed as a point-of-care diagnostic tool to detect acute infectious pathogens; however, this technique embeds risk of generating false-positive results. Whereas, with abilities to accurately recognize specific sequence, the CRISPR/Cas12a can forms complexes with cognate RNA sensors and cleave pathogen’s DNA targets complimerntary to its cognate RNA, afterward acquiring the collateral activity to unbiasedly cut nearby off-target fragments. Therefore, if relevant fluorescent-quencher-nucleic probes are present in the reaction, the non-specific cleavage of probes releases fluorescences and establish diagnostic read-outs.

Methods

The MetA gene of N. meningitidis was selected as target to optimize the LAMP reaction, whereas pseudo-dilution series of N. meningitidis gemonics DNA was used to establish the detection limit of LAMP/Cas12a combination assay. The diagnostic performance of established LAMP/Cas12a combination assay was validated in comparation with standard real-time PCR on 51 CSF samples (14 N. meningitidis confirmed patients and 37 control subjects).

Results

In relevant biochemical conditions, CRISPR-Cas12a and LAMP can work synchronously to accurately identify genetics materials of Nesseria menitigistis at the level 40 copies/reaction less than 2 h.

Conclusions

In properly optimized conditions, the CRISPR-Cas12a system helps to alleviate false positive result hence enhancing the specificity of the LAMP assays.

…

Group B streptococcus (GBS, Streptococcus agalactiae) is the most frequent cause of meningitis and a notable cause of sepsis in the first three months of life [1]. In adults, GBS is an occasional pathogen, mostly associated with genitourinary infection, but it can also cause invasive infections in those with certain predisposing conditions, particularly advanced age, diabetes, cancer, HIV, liver disease [2].

Abstract

Background

Loop isothermal amplification (LAMP) has recently been proposed as a point-of-care diagnostic tool to detect acute infectious pathogens; however, this technique embeds risk of generating false-positive results. Whereas, with abilities to accurately recognize specific sequence, the CRISPR/Cas12a can forms complexes with cognate RNA sensors and cleave pathogen’s DNA targets complimerntary to its cognate RNA, afterward acquiring the collateral activity to unbiasedly cut nearby off-target fragments. Therefore, if relevant fluorescent-quencher-nucleic probes are present in the reaction, the non-specific cleavage of probes releases fluorescences and establish diagnostic read-outs.

Methods

The MetA gene of N. meningitidis was selected as target to optimize the LAMP reaction, whereas pseudo-dilution series of N. meningitidis gemonics DNA was used to establish the detection limit of LAMP/Cas12a combination assay. The diagnostic performance of established LAMP/Cas12a combination assay was validated in comparation with standard real-time PCR on 51 CSF samples (14 N. meningitidis confirmed patients and 37 control subjects).

Results

In relevant biochemical conditions, CRISPR-Cas12a and LAMP can work synchronously to accurately identify genetics materials of Nesseria menitigistis at the level 40 copies/reaction less than 2 h.

Conclusions

In properly optimized conditions, the CRISPR-Cas12a system helps to alleviate false positive result hence enhancing the specificity of the LAMP assays.

…

by Liping Huang, Stéphane Fievez, Mélanie Goguillot, Lucile Marié, Stève Bénard, Anne Elkaïm, Myint Tin Tin Htar

Objective Invasive meningococcal disease (IMD) is life-threatening and associated with substantial morbidity and mortality. The study aimed to examine the clinical characteristics and hospital-based healthcare resource use and related costs following IMD diagnosis in France. Methods Patients admitted to hospitals due to IMD between 2014 and 2016 were selected from the French hospital discharge database (PMSI). Demographics, clinical outcomes and health utilization (HRU) during index hospitalization were described. HRU and costs during the follow-up period were also examined. A generalized linear model was applied to examine 1-year costs after index hospitalization adjusting for age, type of IMD and presence of sequelae at index hospitalization. Results A total of 1,344 patients were identified. About 30% cases were in children < 5 years old and 25% aged 10–24 years. Majority of patients presented as meningococcal meningitis (59%), 25% as meningococcaemia, and 9% both. The case fatality rate during the index hospitalization was 6%. About 15% of patients had at least one sequela at index hospital discharge. The median length of stay and the median cost of index hospitalization were 9 days and 8,045€, respectively. Patients with at least one sequela, with clinical manifestation as both meningitis and meningococcaemia, or aged 25 years and older were statistically significantly associated with higher costs than others. Conclusion IMD is unpredictable and can occur in all ages. The study highlights the severity and high health and economic burdens associated with the disease. The data underlines the importance of prevention against IMD through vaccination.…

by Luca G. Valente, Ngoc Dung Le, Melissa Pitton, Gabriele Chiffi, Denis Grandgirard, Stephan M. Jakob, David R. Cameron, Grégory Resch, Yok-Ai Que, Stephen L. Leib

Background Treatment failure in pneumococcal meningitis due to antibiotic resistance is an increasing clinical challenge and alternatives to antibiotics warrant investigation. Phage-derived endolysins efficiently kill gram-positive bacteria including multi-drug resistant strains, making them attractive therapeutic candidates. The current study assessed the therapeutic potential of the novel endolysin PlyAZ3aT in an infant rat model of ceftriaxone-resistant pneumococcal meningitis. Methods Efficacy of PlyAZ3aT was assessed in a randomized, blinded and controlled experimental study in infant Wistar rats. Meningitis was induced by intracisternal infection with 5 x 107 CFU/ml of a ceftriaxone-resistant clinical strain of S. pneumoniae, serotype 19A. Seventeen hours post infection (hpi), animals were randomized into 3 treatment groups and received either (i) placebo (phosphate buffered saline [PBS], n = 8), (ii) 50 mg/kg vancomycin (n = 10) or (iii) 400 mg/kg PlyAZ3aT (n = 8) via intraperitoneal injection. Treatments were repeated after 12 h. Survival at 42 hpi was the primary outcome; bacterial loads in cerebrospinal fluid (CSF) and blood were secondary outcomes. Additionally, pharmacokinetics of PlyAZ3aT in serum and CSF was assessed. Results PlyAZ3aT did not improve survival compared to PBS, while survival for vancomycin treated animals was 70% which is a significant improvement when compared to PBS or PlyAZ3aT (p<0.05 each). PlyAZ3aT was not able to control the infection, reflected by the inability to reduce bacterial loads in the CSF, whereas Vancomycin sterilized the CSF and within 25 h. Pharmacokinetic studies indicated that PlyAZ3aT did not cross the blood brain barrier (BBB). In support, PlyAZ3aT showed a peak concentration of 785 μg/ml in serum 2 h after intraperitoneal injection but could not be detected in CSF. Conclusion In experimental pneumococcal meningitis, PlyAZ3aT failed to cure the infection due to an inability to reach the CSF. Optimization of the galenic formulation e.g. using liposomes might enable crossing of the BBB and improve treatment efficacy.…

by Jacqueline Lim, Sureka Pavalagantharajah, Chris P Verschoor, Eric Lentz, Mark Loeb, Mitchell Levine, Marek Smieja, Lawrence Mbuagbaw, Dale Kalina, Jean-Eric Tarride, Tim O’Shea, Anna Cvetkovic, Sarah van Gaalen, Aidan Reid Findlater, Robin Lennox, Carol Bassim, Cynthia Lokker, Elizabeth Alvarez

Injection drug use poses a public health challenge. Clinical experience indicates that people who inject drugs (PWID) are hospitalized frequently for infectious diseases, but little is known about outcomes when admitted. Charts were identified from local hospitals between 2013–2018 using consultation lists and hospital record searches. Included individuals injected drugs in the past six months and presented with infection. Charts were accessed using the hospital information system, undergoing primary and secondary reviews using Research Electronic Data Capture (REDCap). The Wilcoxon rank-sum test was used for comparisons between outcome categories. Categorical data were summarized as count and frequency, and compared using Fisher’s exact test. Of 240 individuals, 33% were admitted to the intensive care unit, 36% underwent surgery, 12% left against medical advice (AMA), and 9% died. Infectious diagnoses included bacteremia (31%), abscess (29%), endocarditis (29%), cellulitis (20%), sepsis (10%), osteomyelitis (9%), septic arthritis (8%), pneumonia (7%), discitis (2%), meningitis/encephalitis (2%), or other (7%). Sixty-six percent had stable housing and 60% had a family physician. Fifty-four percent of patient-initiated discharges were seen in the emergency department within 30 days and 29% were readmitted. PWID are at risk for infections. Understanding their healthcare trajectory is essential to improve their care.

Abstract

Background

Streptococcus suis is an emerging zoonotic pathogen that mainly causes meningitis, sepsis, arthritis, endocarditis, and endophthalmitis in human. To the best of our knowledge, Spinal canal infection caused by Streptococcus suis has rarely been reported.

Case presentation

Here we report a case of spinal canal infection caused by Streptococcus suis in a 50-year-old male patient. The patient had a history of close contact with sick pigs days before disease onset. Initially he presented with headache and fever. After admission, the patient began to experience lower back pain, which led physicians to perform a lumber puncture. Meta-genomic next generation sequencing helped identify Streptococcus suis in the cerebrospinal fluid. MRI imaging indicated a spinal canal infection caused by Streptococcus suis.

Conclusions

Spinal canal infection is an uncommon disease of Streptococcus suis infection. This case report indicates that people presented with fever, headache and lower back pain should also be suspected as Streptococcus suis infection, especially for those who have had a history of sick pig contact.

…

Abstract

Background

Streptococcus suis is an emerging zoonotic pathogen that mainly causes meningitis, sepsis, arthritis, endocarditis, and endophthalmitis in human. To the best of our knowledge, Spinal canal infection caused by Streptococcus suis has rarely been reported.

Case presentation

Here we report a case of spinal canal infection caused by Streptococcus suis in a 50-year-old male patient. The patient had a history of close contact with sick pigs days before disease onset. Initially he presented with headache and fever. After admission, the patient began to experience lower back pain, which led physicians to perform a lumber puncture. Meta-genomic next generation sequencing helped identify Streptococcus suis in the cerebrospinal fluid. MRI imaging indicated a spinal canal infection caused by Streptococcus suis.

Conclusions

Spinal canal infection is an uncommon disease of Streptococcus suis infection. This case report indicates that people presented with fever, headache and lower back pain should also be suspected as Streptococcus suis infection, especially for those who have had a history of sick pig contact.

…

Abstract

Background

To analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing.

Methods

Paediatric IPD patients in our hospital were retrospectively collected from 2012 to 2017. Clinical manifestations, laboratory tests, antimicrobial susceptibility and serotype of isolates, and risk factors for mortality of IPD were analysed.

Results

Overall, 186 IPD cases were enrolled. The major manifestations were meningitis (76), pneumonia with bacteraemia (60), bacteraemia without focus (21), and pneumonia with empyaema (22). Of 72 cases with underlying diseases, leukaemia (18.0%), congenital heart disease (15.3%), primary immunodeficiency disease (12.5%), nephrotic syndrome (12.5%), and cerebrospinal fluid leakage (12.5%) were most common. In total 96.9% of isolates would have been covered by the pneumococcal conjugate vaccine (PCV13), including 19F (32.8%), 19A (23.4%), 4 (17.2%), and 23F (9.4%). Nonsusceptibility rates of penicillin, cefotaxime, and cefepime among nonmeningitis patients increased between 2012 and 2017; The mortality rate was 21.5%. Meningitis, respiratory failure, multiple organ failure, and white blood cell count < 4000 cells/μL were independent risk factors for mortality.

Conclusion

Meningitis was the most common clinical manifestation of IPD, and was frequently associated with death. Strains in the PCV13 vaccine would cover most of the cases, and so wider use of PCV13 should be considered.

…

Abstract

Background

To analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing.

Methods

Paediatric IPD patients in our hospital were retrospectively collected from 2012 to 2017. Clinical manifestations, laboratory tests, antimicrobial susceptibility and serotype of isolates, and risk factors for mortality of IPD were analysed.

Results

Overall, 186 IPD cases were enrolled. The major manifestations were meningitis (76), pneumonia with bacteraemia (60), bacteraemia without focus (21), and pneumonia with empyaema (22). Of 72 cases with underlying diseases, leukaemia (18.0%), congenital heart disease (15.3%), primary immunodeficiency disease (12.5%), nephrotic syndrome (12.5%), and cerebrospinal fluid leakage (12.5%) were most common. In total 96.9% of isolates would have been covered by the pneumococcal conjugate vaccine (PCV13), including 19F (32.8%), 19A (23.4%), 4 (17.2%), and 23F (9.4%). Nonsusceptibility rates of penicillin, cefotaxime, and cefepime among nonmeningitis patients increased between 2012 and 2017; The mortality rate was 21.5%. Meningitis, respiratory failure, multiple organ failure, and white blood cell count < 4000 cells/μL were independent risk factors for mortality.

Conclusion

Meningitis was the most common clinical manifestation of IPD, and was frequently associated with death. Strains in the PCV13 vaccine would cover most of the cases, and so wider use of PCV13 should be considered.

…

The introduction of vaccines against SARS-CoV-2 brought hope to end the pandemic, save lives, begin economic recovery, and restore social life. An unprecedented number of mass vaccination campaigns globally were initiated to curb transmission, prevent hospitalizations and deaths, and reestablish normalcy (Our World in Data, 2021). The mRNA-based BNT162b2 COVID-19 vaccine has demonstrated a high efficacy rate with an acceptable safety profile and was rapidly rolled out through several nationwide vaccination campaigns (Polack et al, 2021; Frenck et al., 2021; Our World in Data, 2021).

Abstract

Background

The impact of ventriculoperitoneal shunt on cerebrospinal fluid (CSF) biochemical profiles in HIV-associated cryptococcal meningitis (HCM) patients remains unclear.

Methods

Twenty-nine HCM patients who underwent ventriculoperitoneal shunt (the VPS group) and 57 HCM patients who did not undergo ventriculoperitoneal shunt (the non-VPS group) were enrolled in this propensity score matching analysis. Demographic characteristics, symptoms, CSF biochemical profiles, and adverse events were compared between the two groups. The Kaplan–Meier method was used to analyze the survival rate. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for increased CSF protein levels.

Results

After 24 weeks of treatment, the intracranial pressure was significantly lower in the VPS group than in the non-VPS group (mmH2O; 155.0 [120.0–190.0] vs. 200.0 [142.5–290.0]; P = 0.025), and the rate of neuroimaging improvement was significantly higher in the VPS group (16/17 [94.1%] vs. 2/10 [20%]; P < 0.001). Furthermore, the 24-week cumulative survival rates were also significantly higher in the VPS group (96.6% vs. 83.5%, P = 0.025). Notably, the CSF protein levels were higher in the VPS group than in the non-VPS group at each examination time, and the CSF glucose was lower in the VPS group than in the non-VPS group even at the 12-week follow-up. In the multivariate analysis, we found that VPS placement was an independent risk factor for increased CSF protein (odds ratio [OR]: 27.8, 95% confidence interval [95% CI] 2.2–348.7; P = 0.010).

Conclusions

VPS decreased the intracranial pressure, improved neuroimaging radiology and reduced the 24-week mortality in HCM patients. However, VPS significantly altered the CSF profiles, which could lead to misdiagnosis of tuberculous meningitis and some of them were diagnosed with immune reconstitution inflammatory syndrome. Physicians should be aware of these changes in the CSF profiles of patients with HCM undergoing VPS.

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Journal of Medical Virology, Accepted Article.

In Thailand, immunization against COVID-19 began in February 2021. The two major types of vaccines used are inactivated (CoronaVac or Sinovacࣨ) and viral vector (AstraZenecaࣨ). Globally, there have been a number of case reports of reactivation of varicella zoster infection within 28 days after immunization with mRNA COVID-19 vaccines (Chiu et al., 2021; Furer et al., 2021; Lee et al., 2021; McMahon et al., 2021; Psichogiou et al., 2021; Rodríguez-Jiménez et al., 2021). A few cases have also been reported after viral vector and inactivated COVID-19 vaccination (Aksu and Öztürk, 2021; Arora et al., 2021; Bostan and Yalici-Armagan, 2021; Chiu et al., 2021).

by Bongjin Lee, Hyun Jung Chung, Hyun Mi Kang, Do Kyun Kim, Young Ho Kwak

Serious bacterial infection (SBI) in children, such as bacterial meningitis or sepsis, is an important condition that can lead to fatal outcomes. Therefore, since it is very important to accurately diagnose SBI, SBI prediction tools such as ‘Refined Lab-score’ or ‘clinical prediction rule’ have been developed and used. However, these tools can predict SBI only when there are values of all factors used in the tool, and if even one of them is missing, the tools become useless. Therefore, the purpose of this study was to develop and validate a machine learning-driven model to predict SBIs among febrile children, even with missing values. This was a multicenter retrospective observational study including febrile children…

New England Journal of Medicine, Volume 386, Issue 12, Page 1109-1120, March 2022. …

New England Journal of Medicine, Volume 386, Issue 12, Page 1179-1181, March 2022. …

Abstract

Background

Mass gatherings can not only trigger major outbreaks on-site but also facilitate global spread of infectious pathogens. Hajj is one of the largest mass gathering events worldwide where over two million pilgrims from all over the world gather annually creating intense congestion.

Methods

We developed a meta-population model to represent the transmission dynamics of Neisseria meningitidis and the impact of Hajj pilgrimage on the risk of invasive meningococcal disease (IMD) for pilgrims population, local population at the Hajj site and country of origin of Hajj pilgrims. This model was calibrated using data on IMD over 17 years (1995–2011) and further used to simulate potential changes in vaccine policy and endemic conditions.

Results

The effect of increased density of contacts during Hajj was estimated to generate a 78-fold increase in disease transmission that impacts not only pilgrims but also the local population. Quadrivalent ACWY vaccination was found to be very effective in reducing the risk of outbreak during Hajj. Hajj has more limited impact on IMD transmission and exportation in the pilgrim countries of origin, although not negligible given the size of the population considered.

Conclusion

The analysis performed highlighted the amplifying effect of mass gathering on N. meningitidis transmission and confirm vaccination as a very effective preventive measure to mitigate outbreak risks.

…

Abstract

Background

Mass gatherings can not only trigger major outbreaks on-site but also facilitate global spread of infectious pathogens. Hajj is one of the largest mass gathering events worldwide where over two million pilgrims from all over the world gather annually creating intense congestion.

Methods

We developed a meta-population model to represent the transmission dynamics of Neisseria meningitidis and the impact of Hajj pilgrimage on the risk of invasive meningococcal disease (IMD) for pilgrims population, local population at the Hajj site and country of origin of Hajj pilgrims. This model was calibrated using data on IMD over 17 years (1995–2011) and further used to simulate potential changes in vaccine policy and endemic conditions.

Results

The effect of increased density of contacts during Hajj was estimated to generate a 78-fold increase in disease transmission that impacts not only pilgrims but also the local population. Quadrivalent ACWY vaccination was found to be very effective in reducing the risk of outbreak during Hajj. Hajj has more limited impact on IMD transmission and exportation in the pilgrim countries of origin, although not negligible given the size of the population considered.

Conclusion

The analysis performed highlighted the amplifying effect of mass gathering on N. meningitidis transmission and confirm vaccination as a very effective preventive measure to mitigate outbreak risks.

…

by Hannah Gora, Simon Smith, Ian Wilson, Annie Preston-Thomas, Nicole Ramsamy, Josh Hanson

Background The epidemiology of central nervous system (CNS) infections in tropical Australia is incompletely defined. Methods A retrospective study of all individuals in Far North Queensland, tropical Australia, who were diagnosed with a CNS infection between January 1, 2000, and December 31, 2019. The microbiological aetiology of the infection was correlated with patients’ demographic characteristics and their clinical course. Results There were 725 cases of CNS infection during the study period, meningitis (77.4%) was the most common, followed by brain abscess (11.6%), encephalitis (9.9%) and spinal infection (1.1%). Infants (24.3%, p<0.0001) and Aboriginal and Torres Strait Islander Australians (175/666 local residents, 26.3%, p<0.0001) were over-represented in the cohort.A pathogen was identified in 513 cases (70.8%); this was viral in 299 (41.2%), bacterial in 175 (24.1%) and fungal in 35 (4.8%). Cryptococcal meningitis (24 cases) was diagnosed as frequently as pneumococcal meningitis (24 cases). There were only 2 CNS infections with a S. pneumoniae serotype in the 13-valent pneumococcal vaccine after its addition to the National Immunisation schedule in 2011. Tropical pathogens–including Cryptococcus species (9/84, 11%), Mycobacterium tuberculosis (7/84, 8%) and Burkholderia pseudomallei (5/84, 6%)–were among the most common causes of brain abscess. However, arboviral CNS infections were rare, with only one locally acquired case—a dengue infection in 2009—diagnosed in the entire study period. Intensive Care Unit admission was necessary in 14.3%; the overall case fatality rate was 4.4%. Conclusion Tropical pathogens cause CNS infections as commonly as traditional bacterial pathogens in this region of tropical Australia. However, despite being highlighted in the national consensus guidelines, arboviruses were identified very rarely. Prompt access to sophisticated diagnostic and supportive care in Australia’s well-resourced public health system is likely to have contributed to the cohort’s low case-fatality rate.…

AbstractBackgroundHistorically, antimicrobial resistance has been rare in US invasive meningococcal disease cases.MethodsMeningococcal isolates (n=695) were collected through population-based surveillance, 2012–2016, and national surveillance, 2015–2016. Antimicrobial susceptibility was assessed by broth microdilution. Resistance mechanisms were characterized using whole genome sequencing.ResultsAll isolates were susceptible to six antibiotics (cefotaxime, ceftriaxone, meropenem, rifampin, minocycline, and azithromycin). Approximately 25% were penicillin- or ampicillin-intermediate; among these, 79% contained mosaic penA gene mutations. Less than 1% of isolates were penicillin-, ampicillin-, ciprofloxacin-, or levofloxacin-resistant.ConclusionPenicillin- and ampicillin-intermediate isolates were common, but resistance to clinically relevant antibiotics remained rare.

AbstractBackgroundGroup B streptococcal (GBS) infection remains one of the most significant causes of late-onset sepsis and meningitis (LOGBS) among young infants. However, transmission routes and risk factors for LOGBS are not yet fully understood.MethodsWe conducted systematic reviews on clinical risk factors previously reported in the literature (prematurity, low birth weight [<2500 g], antenatal colonization, multiple-gestation pregnancy, maternal age <20 years, male infant sex, intrapartum fever, prolonged rupture of membranes) and meta-analyses to determine pooled estimates of risk.ResultsWe included 27 articles, reporting 5315 cases. Prematurity (odds ratio 5.66; 95% confidence interval [4.43-7.22]), low birth weight (6.73; [4.68-9.67]), maternal colonization (2.67; [2.07-3.45]), and multiple-gestation pregnancies (8.01; [5.19-12.38]) were associated with an increased risk of LOGBS.ConclusionsPrematurity/low birth weight and maternal colonization are major risk factors for LOGBS. Future GBS vaccine studies should try to establish the optimal time for vaccination during pregnancy to protect preterm infants.

Objectives

To describe the prevalence and severity of anaemia and to examine its associations with outcome in children with bacterial meningitis (BM).

Design

Secondary analysis of descriptive data from five randomised BM treatment trials.

Setting

Hospitals in Finland, Latin America and Angola.

Participants

Consecutive children from 2 months to 15 years of age admitted with BM and who had haemoglobin (Hb) measured on admission.

Outcome measures

Prevalence and degree of anaemia using the WHO criteria, and their associations with recovery with sequelae or death.

Results

The median Hb was 11.8 g/dL in Finland (N=341), 9.2 g/dL in Latin America (N=597) and 7.6 g/dL in Angola (N=1085). Of the children, 79% had anaemia, which was severe in 29%, moderate in 58% and mild in 13% of cases. Besides study area, having anaemia was independently associated with age <1 year, treatment delay >3 days, weight-for-age z-score <–3 and other than meningococcal aetiology. Irrespective of the study area, anaemia correlated with the markers of disease severity. In children with severe to moderate anaemia (vs mild or no anaemia), the risk ratio for death was 3.38 and for death or severe sequelae was 3.07.

Conclusion

Anaemia, mostly moderate, was common in children with BM, especially in Angola, in underweight children, among those with treatment delay, and in pneumococcal meningitis. Poor outcome was associated with anaemia in all three continents.

Trial registration number

The registration numbers of Angolan trials were ISRCTN62824827 and NCT01540838.

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by Michal Honskus, Zuzana Okonji, Martin Musilek, Pavla Krizova

Introduction The study presents the analysis of whole genome sequencing (WGS) data for Neisseria meningitidis serogroup Y isolates collected in the Czech Republic and their comparison to other countries. The aim of the study was to determine whether there are lineages of N. meningitidis serogroup Y in the Czech Republic genetically related to foreign ones that have been causing an increase of the morbidity and the mortality of invasive meningococcal disease (IMD) world-wide recently. Material and methods The WGS data of 43 Czech N. meningitidis Y isolates, 35 from IMD and 8 from healthy carriers were analysed. Due to the potential of meningococcal B vaccines to induce protection against non-B serogroups, the coverage of Czech isolates of N. meningitidis Y by these vaccines was studied. The WGS data of Czech, European and non-European isolates of N. meningitidis serogroup Y were compared. Results WGS assigned 36 isolates of N. meningitidis Y to five clonal complexes: cc23, cc92, cc167, cc103, and cc174, while seven isolates remained unassigned to any clonal complexes (ccUA). Eighteen invasive isolates belonged to clonal complex cc23, which was detected throughout the studied years. The occurrence of cc23 was recorded in all age groups of IMD patients, with the highest found in those aged 15–19 years. On the phylogenetic network isolates of cc23 form a separate lineage, distinct from all other isolates of N. meningitidis Y. The remaining isolates were assigned to other clonal complexes and have very low relatedness to cc23 isolates and to each other. The comparison with foreign WGS data showed that within the main genetic lineages, which are defined by clonal complexes, Czech isolates of N. meningitidis Y, similar to European ones, mostly cluster together and form geographical sublineages. Conclusions WGS analysis showed the population of Czech N. meningitidis Y isolates as relatively heterogeneous, containing a large number of genetic lineages. The Czech isolates of N. meningitidis Y follow the trend observed for European isolates. Our result was one of the bases for updating the recommended vaccination strategy in the Czech Republic.…