An outbreak of nosocomial infection of neonatal aseptic meningitis caused by echovirus 18.

We describe an outbreak of echovirus 18 infection involving 10 patients in our neonatal intensive care unit (an attack rate of 33%). The mean age at the onset of illness was 26.8 days. Eighty percent were preterm infants. All were discharged home without sequelae. There were no differences in gestation age, birth weight, delivery mode, use of antibiotics, and parenteral nutrition between the enterovirus (EV) group and non-EV group, but the rate of breastfeeding was significantly higher in the EV group. Separation care and reinforcement of hand-washing seemed to be effective in preventing further spread of the virus. Visiting policy, hygiene practice, and handling of expressed breastmilk should be reinforced.

Molecular characterization of enterovirus detected in cerebrospinal fluid and wastewater samples in Monastir, Tunisia, 2014-2017.

BACKGROUND: Enteroviruses (EVs) are considered the main causative agents responsible for aseptic meningitis worldwide. This study was conducted in the Monastir region of Tunisia in order to know the prevalence of EV infections in children with meningitis symptoms. Detected EV types were compared to those identified in wastewater samples. METHODS: Two hundred CSF samples collected from hospitalized patients suspected of having aseptic meningitis for an EV infection between May 2014 and May 2017 and 80 wastewater samples collected in the same time-period were analyzed. EV detection and genotyping were performed using PCR methods followed by sequencing. Phylogenetic analyses in the 3'-VP1 region were also carried-out. RESULTS: EVs were detected in 12% (24/200) CSF and in 35% (28/80) wastewater samples. EV genotyping was reached in 50% (12/24) CSF-positive samples and in 64% (18/28) sewage. Most frequent types detected in CSF were CVB3, E-30 and E-9 (25% each). In wastewater samples, the same EVs were identified, but also other types non-detected in CSF samples, such as E-17,CVA9 and CVB1 from EV species B, and EV-A71 and CVA8 from EV-A, suggesting their likely lower pathogenicity. Phylogenetic analysis showed that within the same type, different strains circulate in Tunisia. For some of the EV types such as E-9, E-11 or CVB3, the same strains were detected in CSF and wastewater samples. CONCLUSIONS: Epidemiological studies are important for the surveillance of the EV infections and to better understand the emergence of certain types and variants.

The epidemiology of aseptic meningitis in New Zealand children from 1991 to 2020.

AIM: Aseptic meningitis, including culture negative and viral meningitis, contributes a significant health-care burden, including unnecessary antibiotic use and hospitalisation to treat possible bacterial meningitis. This study analysed aseptic meningitis hospitalisations in New Zealand (NZ) children over 29 years. METHODS: In this population-based study, aseptic meningitis hospitalisations in NZ children <15 years old were analysed from 1991 to 2020. Incident rate ratios were calculated using Poisson regression models. Variations in hospitalisations by age, year, sex, ethnicity, geographical region and socio-economic deprivation were analysed. RESULTS: There were 5142 paediatric aseptic meningitis hospitalisations from 1991 to 2020. Most were unspecified viral meningitis (64%), followed by enterovirus (29%). Hospitalisation rates varied annually with a median of 18.4/100 000 children including a peak in 2001 of 56.4/100 000 (51.7-61.6). From 2002 to 2019, rates increased by 8.4%/year (7.2-9.5%) in infants <90 days old but decreased in all other age groups. In 2020, a reduction in hospitalisations to 9.6/100 000 (7.9-11.8) occurred, and in infants <90 days old were 0.37 times expected. Hospitalisations were 1.50 times (1.49-1.68) higher in males than females; higher in children of Maori (P < 0.001) and Pacific (P < 0.001) versus European ethnicity; and higher for children living in the most (2.44 times, (2.16-2.75)) versus least deprived households; and in northern versus southern NZ. CONCLUSIONS: Aseptic meningitis hospitalisations increased in young infants during 29 years of surveillance, apart from 2020 when admissions reduced during the COVID-19 pandemic. In contrast, hospitalisations decreased in children aged >1 year. Further investigation into reasons for higher admissions by ethnic group, geographical location and increased deprivation are required.

Clinical and laboratory detection of nonpolio enteroviruses among different age groups of aseptic meningitis patients in Alexandria, Egypt.

BACKGROUND: Viral meningitis is the most common type of meningitis. Worldwide, nonpolio enteroviruses (NPEVs) account for 23%-60% of all cases of viral meningitis. We aimed to detect NPEV among aseptic meningitis cases using reverse transcription-polymerase chain reaction (RT-PCR) and evaluate molecular testing versus clinical and laboratory parameters. PATIENTS AND METHODS: A 2-year prospective study was conducted for all clinically suspected meningitis patients, who underwent lumbar puncture in Alshatby University and Alexandria Fever Hospitals. Clinical manifestations were reviewed; cytological, microbiological, and biochemical examinations were done. One-step RT-PCR for NPEV was introduced to a routine workflow using Pan-Enterovirus primers. RESULTS: Out of 2519 patients, 994 (40%) patients were found to have positive cerebrospinal fluid findings, out of which 716 (72%) patients had positive findings of aseptic meningitis. Ninety-four samples were randomly selected and divided across four age groups: neonates, infants, children, and adults. The significant difference was found among adult patients regarding fever, vomiting, headache, signs of meningeal irritation, cranial nerve affection, and focal neurological deficits (p ≤ .05). Seven cases (7.4%) were found to be NPEV positive by RT-PCR. Positive NPEV PCR samples were shown to be statistically significant among neonates (p ≤ .05). The statistical significance was found among the NPEV group regarding the length of hospital stay and duration of IV antibiotic intake while no statistical significance was found with any clinical or laboratory findings. CONCLUSION: RT-PCR was reliable to identify NPEV while clinical and laboratory findings were inconclusive. NPEV showed low incidence and slight seasonal variation which rings the bell to investigate other causes of viral meningitis throughout the year.

Molecular epidemiology of enteroviruses and predominance of echovirus 30 in an Iranian population with aseptic meningitis.

Human enteroviruses are the most prevalent causes of aseptic meningitis worldwide. However, despite such predominancy, defining the enteroviral etiology of aseptic meningitis remains a diagnostic dilemma for the clinician in Iran. Therefore, this study was conducted to characterize the prevalence and clinical significance of enteroviral aseptic meningitis as well as the predominant enterovirus serotypes among patients with aseptic meningitis in the South of Iran.Cerebrospinal fluid (CSF) specimens were obtained from 73 patients with aseptic meningitis (52.1% males and 47.9% females), ages ranging from 1 month to 88 years. Following the extraction of nucleic acid, the detection of enteroviruses was performed by RT-PCR, targeting the 5' untranslated region of the genome, and sequencing. Enteroviruses were found in 46.6% of samples (34/73). The most predominant serotype was echovirus 30, followed by coxsackievirus B5 and poliovirus type 1 Sabin strain. The enterovirus infections were more prevalent among female patients (58.8%) and those below 5 years of age (52.9%). Although enterovirus infections were observed throughout the year, the infections were more prevalent during autumn with fever as the predominant clinical symptom. The outcomes revealed that enteroviruses are significant causes of aseptic meningitis in the South of Iran, while suspected cases of aseptic meningitis are usually monitored by bacterial culture and biochemical testing of CSF samples. Therefore, the etiology remains unknown in most cases. Molecular detection of viral pathogens should be included as a common approach in the screening of patients with aseptic meningitis to prevent unnecessary treatment and to improve clinical management.

Temporal phylogeny and molecular characterization of echovirus 30 associated with aseptic meningitis outbreaks in China.

BACKGROUND: An outbreak of aseptic meningitis occurred from June to August 2016, in Inner Mongolia Autonomous Region, China. METHODS: To determine its epidemiological characteristics, etiologic agent, and possible origin, specimens were collected for virus isolation and identification, followed by molecular epidemiological analysis. RESULTS: A total of 363 patients were clinically diagnosed from June 1st to August 31st 2016, and most cases (63.1%, n = 229) were identified between June 22nd and July 17th, with children aged 6 to 12 years constituting the highest percentage (68.9%, n = 250). All viral isolates from this study belonged to genotype C of echovirus 30 (E30), which dominated transmission in China. To date, two E30 transmission lineages have been identified in China, of which Lineage 2 was predominant. We observed fluctuant progress of E30 genetic diversity, with Lineage 2 contributing to increased genetic diversity after 2002, whereas Lineage 1 was significant for the genetic diversity of E30 before 2002. CONCLUSIONS: We identified the epidemiological and etiological causes of an aseptic meningitis outbreak in Inner Mongolia in 2016, and found that Lineage 2 played an important role in recent outbreaks. Moreover, we found that Gansu province could play an important role in E30 spread and might be a possible origin site. Furthermore, Fujian, Shandong, Taiwan, and Zhejiang provinces also demonstrated significant involvement in E30 evolution and persistence over time in China.

Analysis of enterovirus genotypes in the cerebrospinal fluid of children associated with aseptic meningitis in Liaocheng, China, from 2018 to 2019.

BACKGROUND: Aseptic meningitis is most often caused by enteroviruses (EVs), but EVs associated with aseptic meningitis have not yet been reported in Liaocheng. The aim of this study was to determine the prevalence and genetic characteristics of EVs causing aseptic meningitis in children in Liaocheng. METHODS: We reviewed the epidemiological and clinical characteristics of 504 paediatric cases of aseptic meningitis in Liaocheng from 2018 to 2019 and analysed the phylogeny of the predominant EV types causing this disease. RESULTS: A total of 107 children were positive for EV in cerebrospinal fluid samples by nested PCR. Most of the positive patients were children 13 years old or younger and had symptoms such as fever, headache and vomiting (P < 0.05). The seasons with the highest prevalence of EV-positive cases were summer and autumn. The 107 EV sequences belonged to 8 serotypes, and echovirus types 18, 6 and 11 were the three dominant serotypes in Liaocheng during the 2-year study period. Phylogenetic analyses demonstrated that the E18 and E6 isolates belonged to subgenotype C2, while the E11 isolates belonged to subgenotype D5. VP1 analysis suggested that only one lineage of these three types was cocirculating in the Liaocheng region. CONCLUSIONS: This study demonstrated the diverse EV genotypes contributing to a large outbreak of aseptic meningitis in Liaocheng. Therefore, large-scale surveillance is required to assess the epidemiology of EVs associated with aseptic meningitis and is important for the diagnosis and treatment of aseptic meningitis in Liaocheng.

Cases of aseptic meningitis after vaccination against mumps in Russia (2009-2019).

OBJECTIVES: Mumps is a highly contagious viral infection prevented by immunization with live attenuated vaccines. Mumps vaccines have proven to be safe and effective; however, rare cases of aseptic meningitis (AM) can occur after vaccination. The range of meningitis occurrence varies by different factors (strain, vaccine producer, and so on). Monovaccines or divaccines (mumps-measles vaccine), prepared from the strain Leningrad-3 (L-3), are used in Russia. Meningitis occurrence after vaccination has been established previously as very low. Nevertheless, with the number of children being vaccinated every year, vaccine-associated AM cases still occur. There is no official statistics on AM incidence after mumps vaccines, and information on AM features as an adverse event of mumps vaccination is limited and mostly devoted to vaccines, prepared from strains other than L-3. STUDY DESIGN: The study included patients with AM who were vaccinated against mumps in the previous 30 days before the present disease onset during 2009-2019. METHODS: Patients admitted to Infectious Clinical Hospital No. 1, Moscow, Russia, with AM were observed by a pediatrician and were screened for etiological agents of meningitis. RESULTS: Seven patients were enrolled, and clinical features and the course of infection are presented. CONCLUSIONS: Detection of only 7 cases of AM associated with mumps vaccination during the 10-year period supports very low occurrence of this adverse event after immunization with the L-3 strain-based mumps vaccines. Nevertheless, the annual number of AM cases that occur after mumps vaccination remains unknown and poorly diagnosed in practice because of the low awareness of physicians of this adverse reaction. Detection and objective coverage of such cases can lead to a weakening of 'antivaccination' moods in a society and to restoration of confidence in the healthcare system.

Two clusters of Toscana virus meningo-encephalitis in Livorno Province and Elba Island, July-September 2018.

BACKGROUND: Toscana virus (TOSV) is an arbovirus transmitted to humans by Phlebotomus spp sandflies. It causes aseptic meningitis and meningoencephalitis with marked seasonality. Here we describe the clinical, microbiological and epidemiological features of two clusters of cases occurred in Tuscany in 2018. METHODS: A confirmed case was defined as the detection of anti-TOSV IgM and IgG in serum sample, in presence of typical clinical manifestations. We consulted hospital records of hospitalized patients to collect clinical information and obtained epidemiological information from the local health authority investigation report. We telephonically interviewed patients using a standard questionnaire for a 6 months follow-up. RESULTS: A total of 12 cases of TOSV meningo-encephalitis with onset between 4th of July and 12th of September accessed health care services in the province of Livorno. Eight cases were males with median age 41,5 and four were not resident in the area. Serological investigations confirmed a recent TOSV infection. Eight cases reported visiting Elba Island and four had a possible occupational-related exposure. CONCLUSIONS: This surge of infection emphasizes the need of information campaigns coupled with adequate surveillance and control interventions against TOSV that, among other arboviruses, is a growing issue of concern in Italy.

Drug-induced aseptic meningitis: 329 cases from the French pharmacovigilance database analysis.

AIMS: Drug-induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify suspected drugs. METHODS: Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All cases were initially analysed according to the French imputability method by institutional pharmacologists (clinicians or pharmacists). Further analyses of well documented cases were then performed. RESULTS: In this study, 329 cases of aseptic meningitis were retrieved from the French Pharmacovigilance Database for a total of 429 suspected drugs. Analysis of 203 well documented cases, including 282 drugs, showed that the main reported classes were intravenous polyvalent immunoglobulin, nonsteroidal anti-inflammatory drugs (NSAIDs), vaccines, antimicrobials, intrathecal antimetabolites, corticosteroids and antalgics/anaesthetics (except NSAIDs). Lymphocytic (33.0%) and purulent (44.8%) meningitis represented the majority of cases of aseptic meningitis. In other cases, the cerebrospinal fluid was mixed (45-55% of neutrophils +45-55% of lymphocytes) or data about cerebrospinal fluid composition were lacking. Most DIAM cases (96%) had a favourable reported outcome with full recovery or minimal residual symptoms. CONCLUSION: The most frequently involved drugs in DIAM were intravenous polyvalent immunoglobulin, NSAIDs, vaccines, and antimicrobials and this without being able to differentiate them in terms of biological characteristics. Although further studies are needed to better understand the pathophysiological mechanisms of DIAM, a continuous enrichment of pharmacovigilance databases is essential to identify new signals and to help clinicians in the understanding of DIAM.

Increased risk for aseptic meningitis after amoxicillin or amoxicillin-clavulanic acid in males: A signal revealed by subset disproportionality analysis within a global database of suspected adverse drug reactions.

PURPOSE: Drug-induced aseptic meningitis (DIAM) is an inflammation of the membranes of the central nervous system caused by certain medications. It is a rare clinical entity whose risk factors are not yet fully elucidated. A local pattern of disproportionality within a global database of suspected adverse drug reactions (ADRs) revealed an increased reporting of aseptic meningitis and amoxicillin-clavulanic acid (AC) in males. The aim of this report is to explore the clinical probability of a higher risk in males to support the use of statistical methods to identify subgroups at risk for adverse drug reactions. METHODS: Disproportionality analysis was performed for all drug-adverse event (AE) pairs in the entire database and for the subsets of males and females. AC-aseptic meningitis was highlighted for an increased disproportionality in the male subgroup in the absence of an elevated disproportionality measure for the database overall. A clinical review was undertaken. RESULTS: Clinical review revealed a similar statistical pattern of gender difference observed for amoxicillin, evidence to suggest a delayed type 4 hypersensitivity reaction with Th1 cells as a mechanism for amoxicillin-aseptic meningitis, the existence of sex differences in immune responses (Th1/Th2), and an analogous increased risk of drug-induced liver injury by AC in males. CONCLUSIONS: Subgroup disproportionality analysis has revealed a larger than expected number of reports of aseptic meningitis after amoxicillin and AC in males. Evidence synthesis supports the statistical finding. Further exploration of spontaneous databases with more extensive analyses could usher in a new era of "precision pharmacovigilance."

Endoscopic endonasal skull base surgery for pediatric brain tumors.

PURPOSE: The utility of endoscopic endonasal skull base surgery (EES) in various pathologic entities in adults has been published in the literature. However, the role of EES in children has not been clearly elucidated. We evaluated the feasibility of EES in children with brain tumors. METHODS: We retrospectively reviewed clinical features, surgical outcomes, and complications in children who underwent EES for intracranial and skull base tumors at a single institution from July 2010 to October 2018. RESULTS: A total of 82 patients underwent EESs for 77 intracranial and 5 skull base bony tumors. The mean age at diagnosis was 11.4 years (range 4-18 years), and the mean follow-up period was 46.8 months. The most common tumors were craniopharyngioma in the intracranial tumor and chordoma in the skull base. Gross total resection was the goal of surgery in 55 patients and achieved in 90.9%. The vision was improved in 76.1% of patients with visual impairments. Preoperatively, various endocrinological deficiencies were revealed in 73.7% of 76 patients with hypothalamus-pituitary lesions, and the hyposomatotropism was most common. Endocrinological status was improved only in 10. Aseptic or bacterial meningitis (7.3%) was the most common surgical complication, and the cerebrospinal fluid leakage rate was 2.4%. CONCLUSIONS: EES provides favorable neurological outcomes with acceptable risk for children with brain tumors. The high incidence of endocrinological deficits in cases with hypothalamus-pituitary lesions emphasizes the importance of judicious pre- and postoperative evaluation.

Increased detection of enterovirus A71 infections, Germany, 2019.

We report on the increased circulation of enterovirus A71 in Germany in 2019. Strains were mainly identified in hospitalised patients with suspected aseptic meningitis/encephalitis. Molecular analysis showed co-circulation of EV-A71 sub-genogroups C1 and C4, a signal for physicians and public health authorities to include/intensify EV diagnostic in patients showing signs of aseptic meningitis, encephalitis or acute flaccid paralysis/myelitis.

Recombination analysis of coxsackievirus B5 genogroup C.

Coxsackievirus B5 (CVB5) is a member of the species Enterovirus B of the genus Enterovirus, family Picornaviridae. Based on its VP1 sequence, CVB5 is divided into four genogroups: A, B, C, and D. From 2002 to 2012, CVB5 serotype genogroup C caused an outbreak of aseptic meningitis in China. In order to study the evolution of CVB5 genogroup C, phylogenetic and recombination analysis was performed using the 399 available enterovirus B genome sequences in the GenBank database. The results indicated that 10 strains of CVB5 serotype genogroup C resulted from recombination between members of genogroup B and echovirus serotype E6, and another 5 strains resulted from recombination between members of genogroup C and serotype CVB4. These recombination events were confirmed by phylogenetic analysis.

Aseptic central nervous system infections in adults: what predictor for unknown etiological diagnosis?

Despite the availability of nucleic acid amplification tests (NAATs), most of aseptic acute meningitides, encephalitides, and meningoencephalitides (AAMEMs) in adults remain of unknown etiology so far. To shed light on such topic, we aimed to evaluate potential predictors for AAMEMs of unknown origin. We collected retrospectively data from all consecutive cases of AAMEMs in adults discharged from an Italian referral hospital, from January 2004 to December 2016. Laboratory analysis included common immunometric methods and NAATs. Potential predictors for unknown etiology (age, seasonality, serum C-reactive protein value, antibiotic use before lumbar puncture, immunodeficiency conditions, clinical symptoms and signs) were evaluated by a logistic regression analysis model. A p value ≤ 0.05 was considered to indicate statistical significance. The study included 92 patients (median age 39 years; 54.3% males) affected by meningitis (n = 57), encephalitis (n = 25), and meningoencephalitis (n = 10). The identified agents that cause AAMEMs were herpesviruses (20.7%), enteroviruses (5.4%), tick-borne encephalitis virus (3.3%), influenza virus A (2.2%), West Nile virus (1.1%), and parvovirus B19 (1.1%), while 66.3% of cases were of unknown etiology. No predictor was found to be significantly associated with AAMEMs of unknown etiology. We suggest that potential infectious agents causing undiagnosed cases should be investigated among non-bacterial, non-opportunistic, and non-seasonal organisms.

Upsurge in echovirus 30 detections in five EU/EEA countries, April to September, 2018.

An upsurge in Echovirus 30 (E30) infections, associated with meningitis/meningoencephalitis, has been observed in Denmark, Germany, the Netherlands, Norway and Sweden in the period April to September 2018, compared with 2015-2017. In total, 658 E30 infections among 4,537 enterovirus infections were detected in 15 countries between January and September 2018 and affected mainly newborns and 26-45 year-olds. National public health institutes are reminded to remain vigilant and inform clinicians of the ongoing epidemic.

Molecular characterization of environmental and clinical echovirus 6 isolates from Poland, 2006-2014.

The aim of this study was to investigate the genetic variability of echovirus 6 (E6) isolates from environmental samples and clinical cases of aseptic meningitis from 2006 to 2014. The analysis of the VP1 region showed the extensive diversity (up to 18.8%) and revealed that E6 circulating in Poland belong to four groups. Environmental strains clustered in three groups excepting the 2012 outbreak group, which shows the sudden introduction of new epidemic variant with Asiatic origin. Data from the study established relationships of E6 from Poland with previously characterized strains and confirmed the importance of both clinical and environmental surveillance. J. Med. Virol. 89:936-940, 2017. © 2016 Wiley Periodicals, Inc.

The spectrum of aseptic central nervous system infections in southern Germany - demographic, clinical and laboratory findings.

BACKGROUND AND PURPOSE: Aseptic infections of the central nervous system (CNS) are frequently observed in Germany. However, no study has systematically addressed the spectrum of aseptic CNS infections in Germany. METHODS: Data on 191 adult patients diagnosed from January 2007 to December 2014 with aseptic meningitis or encephalitis/meningoencephalitis at our hospital were collected by chart review and analyzed for demographic, clinical and laboratory findings. Patients were stratified according to the causative virus and findings were compared between groups. RESULTS: In our cohort, meningitis was caused in 36% by enterovirus (EV), 15% by herpes simplex virus (HSV), 12% by varicella zoster virus (VZV) and 5% by tick borne encephalitis (TBE). Encephalitis/meningoencephalitis was caused in 13% by HSV, 13% by VZV, and three out of 11 tested patients were positive for TBE. The highest incidence of EV infections was between 25 and 35 years and of HSV infections between 30 and 60 years. VZV infections had a bimodal distribution peaking below 30 and above 70 years. VZV and EV infections were more frequently observed during summer, whereas HSV infections showed no seasonal preference. Inflammatory changes in cerebrospinal fluid (CSF) were highest in HSV and lowest in EV infections. CONCLUSIONS: Polymerase chain reaction tests for HSV, VZV and EV in CSF and TBE serology determined the causative virus in over 60% of tested patients. The age of affected patients, seasonal distribution, disease course and inflammatory changes in CSF differ between groups of patients affected by the most common viral infections.