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by Xanthi D. Andrianou, Flavia Riccardo, Maria Grazia Caporali, Cecilia Fazio, Arianna Neri, Paola Vacca, Luigina Ambrosio, Patrizio Pezzotti, Paola Stefanelli Enhanced laboratory-based surveillance of invasive meningococcal disease (IMD) in Italy was only assessed indirectly by numerically comparing surveillance data cases with hospital discharge records (HDR). In this study, we evaluated the completeness, timeliness and sensitivity of the IMD surveillance in Italy from 2015 to 2018. Completeness and timeliness were described at the national and subnational level. A capture-recapture analysis was conducted to evaluate the sensitivity and positive predictive value (PPV) using HDR as the external source with a combination of deterministic and probabilistic approaches. The characteristics of the unmatched vs. matched cases were compared using multivariable Poisson modeling. Overall, the completeness of data improved, except for specific variables. Timeliness of notifications also improved to a median of 4 days from onset to reporting. For the years 2015–2017, the sensitivity of the surveillance was estimated at 71.4% and the PPV at 77.5%, changing to 80.6% and 66.9% respectively after removing cases with a secondary meningitis diagnosis. We noted substantial sub-national differences. In 2018 sensitivity was 66.5% (135/203) and the PPV was 79.4% (135/170). The adjusted relative risk of being unmatched in 2015–2017 was higher in cases that were ≥60 years, had missing information or symptom onset in December. The IMD surveillance system overall performs well with completeness and timeliness improving in time. Specific challenges identified for individual variables should guide further improvement. Notwithstanding limitations posed by the comparison database, sensitivity and PPV are promising. The study highlights that promoting etiological ascertainment in people ≥60 years and addressing sub-national challenges are the main current challenges to address.

Abstract Background Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients’ prognosis. Case presentation Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients’ condition deteriorated rapidly and died in a short time. Conclusion The reason of patients’ poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients’ living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.…

TO THE EDITOR—We thank Pan and colleagues for their interest in our article. In response to the question about brain ischemic changes, we have found that this is not a common manifestation of cryptococcal meningoencephalitis in human immunodeficiency virus (HIV)–negative patients. In a study focused on magnetic resonance imaging findings in 45 HIV-negative patients with cryptococcal meningoencephalitis, none were found to have ischemic infarcts, although substantially more had basal ganglia lesions, hydrocephalus, ependymitis, and choroiditis, compared to their HIV-positive counterparts [1]. This data suggest that stroke is an uncommon complication in HIV-negative patients with cryptococcal meningitis. However, the picture can be sometimes convoluted by the fact that cryptococcomas may show restricted diffusion [2, 3], making it difficult to distinguish them from ischemic events, especially when they are small in size. Although infarcts associated with vasculitis have been described in central nervous system (CNS) cryptococcosis [4, 5], in our experience at the National Institutes of Health (NIH) clinical center, we have had only 1 patient presenting with multiple infarcts, which we attributed to extensive pachymeningeal inflammation involving the major arteries of the circle of Willis.

TO THE EDITOR—Marr and colleagues [1] report the results of a longitudinal follow-up of human immunodeficiency virus (HIV)–negative patients with cryptococcosis, and found substantial long-term neurological sequelae and morbidity in this multicenter cohort. This is a striking finding, because in patients living with HIV (PLHIV) presenting with cryptoccal meningitis, long-term neurological sequelae do not seem to be as prevalent if patients are treated promptly.

Purpose of review Neisseria meningitidis (Nm) is primarily associated with asymptomatic nasopharyngeal carriage and invasive meningococcal disease (sepsis and meningitis), but like N. gonorrhoea (Ng), Nm can colonize urogenital and rectal mucosal surfaces and cause disease. First noted in 2015, but with origins in 2011, male urethritis clusters caused by a novel Nm clade were reported in the USA (the US_NmUC). This review describes research developments that characterize this urogenital-tropic Nm. Recent findings The US_NmUC evolved from encapsulated Nm serogroup C strains. Loss of capsule expression, lipooligosaccharide (LOS) sialylation, genetic acquisition of gonococcal alleles (including the gonococcal anaerobic growth aniA/norB cassette), antimicrobial peptide heteroresistance and high surface expression of a unique factor-H-binding protein, can contribute to the urethra-tropic phenotype. Loss-of-function mutations in mtrC are overrepresented in clade isolates. Similar to Ng, repeat US_NmUC urethritis episodes can occur. The US_NmUC is now circulating in the UK and Southeast Asia. Genomic sequencing has defined the clade and rapid diagnostic tests are being developed for surveillance. Summary The US_NmUC emerged as a cause of urethritis due to acquisition of gonococcal genetic determinants and phenotypic traits that facilitate urogenital tract infection. The epidemiology and pathogenesis of this urogenital-tropic pathogen continues to be defined.

by Elburg Van Boetzelaer, Samiur Chowdhury, Berhe Etsay, Abu Faruque, Annick Lenglet, Anna Kuehne, Isidro Carrion-Martin, Patrick Keating, Martins Dada, Jorieke Vyncke, Donald Sonne Kazungu, Maria Verdecchia Background Following an influx of an estimated 742,000 Rohingya refugees in Bangladesh, Médecins sans Frontières (MSF) established an active indicator-based Community Based Surveillance (CBS) in 13 sub-camps in Cox’s Bazar in August 2017. Its objective was to detect epidemic prone diseases early for rapid response. We describe the surveillance, alert and response in place from epidemiological week 20 (12 May 2019) until 44 (2 November 2019). Methods Suspected cases were identified through passive health facility surveillance and active indicator-based CBS. CBS-teams conducted active case finding for suspected cases of acute watery diarrhea (AWD), acute jaundice syndrome (AJS), acute flaccid paralysis (AFP), dengue, diphtheria, measles and meningitis. We evaluate the following surveillance system attributes: usefulness, Positive Predictive Value (PPV), timeliness, simplicity, flexibility, acceptability, representativeness and stability. Results Between epidemiological weeks 20 and 44, an average of 97,340 households were included in the CBS per surveillance cycle. Household coverage reached over 85%. Twenty-one RDT positive cholera cases and two clusters of AWD were identified by the CBS and health facility surveillance that triggered the response mechanism within 12 hours. The PPV of the CBS varied per disease between 41.7%-100%. The CBS required 354 full-time staff in 10 different roles. The CBS was sufficiently flexible to integrate dengue surveillance. The CBS was representative of the population in the catchment area due to its exhaustive character and high household coverage. All households consented to CBS participation, showing acceptability. Discussion The CBS allowed for timely response but was resource intensive. Disease trends identified by the health facility surveillance and suspected diseases trends identified by CBS were similar, which might indicate limited additional value of the CBS in a dense and stable setting such as Cox’s Bazar. Instead, a passive community-event-based surveillance mechanism combined with health facility-based surveillance could be more appropriate.…

Tropical Medicine & International Health, Accepted Article.

Approximately 9.96 million new cases of tuberculosis (TB) were reported in 2019; these infections led to serious consequences, including ∼1.4 million deaths (World Health Organization, 2020). TB remains the most lethal of the infectious diseases and as such has a profound global impact (Donovan et al., 2020). Tuberculous meningitis (TBM), which accounts for 1%–5% of all new cases of TB, is among the most serious manifestations of this disease; TBM results in severe disability or death in nearly half of those infected (Cresswell et al., 2020).

Citing persistent quality issues at compounding facilities since a deadly 2012 national fungal meningitis outbreak, the FDA issued final guidance to help prevent contamination of compounded drug products.

Streptococcus suis (S. suis) serotype 2 is a crucial pathogenic cause of bacterial meningitis, a life-threatening disease with neurological sequelae and high rates of mortality. Inflammation triggered by S. suis infection must be precisely regulated to prevent further tissue damage. As a glucocorticoid anti-inflammatory mediator, Annexin A1 (AnxA1) mainly acts through formyl peptide receptor 2 (Fpr2) to alleviate inflammation in the peripheral system. In this research, we evaluated the roles of AnxA1 and Fpr2 in a mouse model of S. suis meningitis created via intracisternal infection in Fpr2-deficient (Fpr2–/–) and wild-type (WT) mice. We revealed that Fpr2–/– mice were highly susceptible to S. suis meningitis, displaying increased inflammatory cytokine levels, bacterial dissemination, and neutrophil migration compared with the findings in WT mice. Additionally, AnxA1 exerted anti-inflammatory effects through Fpr2, such as attenuation of leukocyte infiltration, inflammatory mediator production, and astrocyte or microglial activation in the brain. Importantly, we found that the anti-migratory function of AnxA1 decreases neutrophil adherence to the endothelium through Fpr2. Finally, an in vitro study revealed that AnxA1 potentially suppresses IL-6 expression through the Fpr2/p38/COX-2 pathway. These data demonstrated that Fpr2 is an anti-inflammatory receptor that regulates neutrophil migration in mice with S. suis meningitis and identified AnxA1 as a potential therapeutic option.…

To date, ceftazidime-avibactam (CAZ-AVI) neurotoxicity in patients with normal renal function has not been reported in the literature, and no data about its penetration into the CNS through the blood-brain barrier are available.We report the occurrence of severe encephalopathy in a patient with normal renal function, after the infusion of CAZ-AVI to treat a Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) sepsis.The radiological and clinical pictures of our patient, and particularly the encephalopathy resolution after drug discontinuation, support the hypothesis of a drug-induced aseptic meningitis (DIAM).

Abstract Background Bordetella bronchiseptica is a gram-negative, obligate aerobic coccobacillus known to cause disease in domesticated animals and pets. In humans, B. bronchiseptica commonly leads to respiratory infections like pneumonia or bronchitis, and animal contact usually precedes the onset of symptoms. Case presentation We report a case of post-traumatic B. bronchiseptica meningitis without recent surgery in the setting of immunosuppression with a monoclonal antibody. Our case concerns a 77-year-old male with ulcerative colitis on infliximab who sustained a mechanical fall and developed a traumatic cerebrospinal fluid leak complicated by meningitis. He received meropenem then ceftazidime during his hospital course, and temporary neurosurgical drain placement was required. His clinical condition improved, and he was discharged at his baseline neurological status. Conclusions B. bronchiseptica is an unusual cause of meningitis that may warrant consideration in immunocompromised hosts with known or suspected animal exposures. To better characterize this rare cause of meningitis, we performed a systematic literature review and summarized all previously reported cases.…

by Guocan Yu, Wuchen Zhao, Yanqin Shen, Pengfei Zhu, Hong Zheng Background Tuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis and its early diagnosis is very difficult leading to present with severe disability or die. The current study aimed to assess the accuracy of metagenomic next generation sequencing (mNGS) for TBM, and to identify a new test for the early diagnosis of TBM. Methods We searched for articles published in Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Data up to June 30, 2020 for studies that assessed the efficacy of mNGS for the diagnosis of TBM. Then, the accuracy between mNGS and a composite reference standard (CRS) in these articles was compared using the meta-analysis approach. Results Four independent studies with 342 samples comparing mNGS and a CRS were included in this study. The sensitivity of mNGS for TBM diagnosis ranged from 27% to 84%. The combined sensitivity of mNGS was 61%, and the I2 value was 92%. Moreover, the specificity of mNGS for TBM diagnosis ranged from 96% to 100%. The combined specificity of mNGS was 98%, and the I2 value was 74%. The heterogeneity between studies in terms of sensitivity and specificity was significant. The area under the curve (AUC) of the summary receiver operating characteristic curve (SROC) of mNGS for TBM was 0.98. Conclusions The sensitivity of mNGS for TBM diagnosis was moderate. Furthermore, the specificity was extremely high, and the AUC of the SROC indicated a very good diagnostic efficacy. mNGS could be used as an early diagnostic method for TBM, however, the results should be treated with caution for the heterogeneity between studies was extremely significant. Systematic review registration INPLASY202070100.…

Abstract Background Despite the profound impact of antiretroviral therapy in the control of AIDS mortality, central nervous system opportunistic infections remains a significant burden in AIDS patients. This retrospective study aims to elucidate the clinical characteristics, outcome and risk factors of cryptococcal meningitis (CM) poor prognosis in AIDS patients from a tertiary hospital in China. Methods Clinical data from 128 patients admitted in Beijing Ditan Hospital, Capital Medical University from November 2008 to November 2017 was collected. The cohort was stratified based on treatment outcome (effective 79%, and ineffective 21%), and Multivariate Logistic regression analysis used to identify risk factors of poor disease prognosis. Results Age, incidence of cerebral infarction, the proportion of consciousness disorder, and fasting plasma glucose was higher in the ineffective treatment group than the effective treatment group. The duration of treatment in the induction period of the ineffective group was significantly shorter than that of the effective group. Multivariate Logistic regression analysis indicated that the occurrence of cerebral hernia and consciousness disorder were risk factors for the prognosis of AIDS patients with CM infection, while the duration of treatment in the induction period was a indicative of a better prognosis in AIDS with CM infection complications. Finally, shunt decompression therapy correlated with a better disease outcome. Conclusions This retrospective study exposes the main risk factors associated with worse disease prognosis in AIDS patients with CM infection complications.…

The UNAIDS target to reduce HIV-related death to fewer than 500 000 deaths per year by 2020 will not be met.1 This statement might not be headline grabbing as this target was never as prominent as the 90-90-90 targets,2 the achievement of which is a necessary but not sufficient step towards ending AIDS mortality.

Abstract Background To investigate the clinical characteristics of Epstein–Barr virus (EBV) infection in the pediatric nervous system (NS). Methods We retrospectively analyzed the clinical data and follow-up results of 89 children with neurological damage caused by EBV who were hospitalized in the children’s hospital of Chongqing Medical University from January 2008 to April 2019. Results EBV infection of the NS can occur at any time of the year. The highest incidence was seen in the age group of 0–4 years. Fever is the main clinical feature (74/89, 83.1%). The main clinical types were encephalitis/meningoencephalitis (64/89, 71.9%), acute myelitis (2/89, 2.2%), acute disseminated encephalomyelitis (ADEM) (3/89, 3.4%), Guillain–Barré Syndrome (GBS) (15/89, 16.9%), neurological damage caused by EBV-hemophagocytic lymphohistiocytosis (EBV-HLH) (4/89, 4.5%), and NS-post-transplant lymphoproliferative disorder (NS-PTLD) (1/89, 1.1%). Anti-N-methyl-D-aspartate receptor encephalitis was found during the convalescence of EBV encephalitis. EBV encephalitis/meningitis showed no symptoms of tonsillitis, lymph node enlargement, skin rash, hepatosplenomegaly. Acute motor axonal neuropathy is the chief complication in GBS caused by EBV. Conclusion There were significant differences in neurological complications caused by EBV. The prognosis of EBV infection in the NS is generally good. These illnesses are often self-limiting. A few cases may show residual sequelae.…

Abstract Background Malaria still represents a major health threat, in terms of both morbidity and mortality. Complications of malaria present a diversified clinical spectrum, with neurological involvement leading to the most serious related-conditions. The authors recently encountered a case of a 60-year old Italian man presenting with confusion, language disturbances and Parkinson-like syndrome 3 weeks after complete remission from severe Plasmodium falciparum cerebral malaria. Chemical and microbiological analysis revealed aseptic meningitis, diffuse encephalitis and abnormal immune-activation. Re-infection and recrudescence of infection were excluded. Further analysis excluded paraneoplastic and autoimmune causes of encephalitis. A diagnosis of Post-Malaria Neurological Syndrome (PMNS) was finally formulated and successfully treated with high dose of steroids. Methods A systematic research of current literature related to PMNS was performed. Results 151 cases of PMNS were included, the majority of which occurred after severe P. falciparum infections. Four main clinical pattern were identified: 37% of the cases presented as “classical” PMNS, 36% presented as delayed cerebellar ataxia (DCA), 18% resembled acute inflammatory demyelinating polyneuropathy (AIDP), and 8% presented as acute disseminated encephalomyelitis (ADEM)-like form. Differentiation between different forms was not always simple, as clinical and radiological findings frequently overlap. Overall, in almost all of the tested cases, cerebrospinal fluid was found pathological; EEG revealed nonspecific encephalopathy in 30% of classical PMNS and 67% ADEM; imaging tests were found abnormal in 92% of ADEM-like forms. Pathogenesis remains unclear. An autoimmune mechanism is the most corroborated pathogenic hypothesis. Overall, the majority of PMNS cases revert without specific treatment. In most severe forms, high dose steroids, intravenous immunoglobulins, and plasmapheresis have been shown to improve symptoms. Conclusions PMNS is a disabling complication of malaria. The overall incidence is not known, due to frequent misdiagnosis and under-reporting. Pathogenesis is not also fully understood, but rapid response to immune-modulating treatment along with similarities to auto-immune neurological disease, strongly support a dysregulated immunological genesis of this condition. The lack of randomized controlled studies regarding therapeutic approaches is a major unmet need in this setting. A systematic collection of all the PMNS cases would be desirable, in order to increase awareness of this rare condition and to prospectively investigate the most appropriate management.…

Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, most commonly presents as meningitis or septicemia (Rosenstein et al., 2001). Diagnosis is challenging because of rapid onset and lack of distinguishing clinical signs. Untreated, IMD has high mortality and morbidity (World Health Organization, 2018). Although IMD occurs across ages, the highest rate is in infants, with additional peaks among adolescents and the elderly (Borrow et al., 2017a).

Abstract Background Raised intracranial pressure (ICP) and insufficient antifungal regimens are the two main factors result to unsatisfactory outcomes in non-HIV cryptococcal meningitis (CM) patients. In this study, we try to discuss that whether triple therapy of amphotericin B (AmB), fluconazole, 5-flucytosine (5-FC) plus ventriculoperitoneal shunts (VPS) is superior to AmB, 5-FC, fluconazole plus intermittent lumbar puncture in induction therapy in non-HIV CM patients with increased ICP. Methods We reviewed 66 clinical records from non-HIV CM patients with increased ICP. The demographic and clinical characteristics, BMRC staging, cerebrospinal fluid profiles (CSF), brain magnetic resonance imaging, treatment, and outcomes of these individuals were retrospectively analyzed. All non-HIV CM patients with increased ICP (≥ 25 cmH2O) were divided into two groups, including 27 patients treated with triple antifungal agents and 39 patients treated with the same triple therapy plus VPS. Results Triple therapy plus VPS group had more satisfactory outcomes, more CSF sterilization at 10 weeks follow-up, lower CSF opening pressure, lower BMRC staging scores one week after VPS, less CSF C. neoformans counts and CSF culture positive. Besides, these patients had shorter hospital stay than triple therapy group. Conclusions Triple antifungal agents combined with VPS could effectively reduce ICP, had faster rate of clearance of C. neoformans counts, more improved neurological function, shorten hospitalization time and better outcomes in non-HIV CM patients with increased ICP. Our study indicated that triple therapy plus early VPS may be an optimal treatment for non-HIV CM patients with increased ICP.…

Herpes simplex virus 2 (HSV-2) is a common virus, which causes genital herpes (Groves, 2016). It is known to cause neurological complications (i.e. meningitis, sacral radiculopathy, transverse myelitis) and is often reactivated, especially in immunocompromised patients (Nardone et al., 2017; Venkatesan et al., 2019). However, it has not been well described in the literature that such neurological complications occur secondary to the reactivation. Moreover, several studies showed that sepsis may induce immunosuppression and cause reactivation of several viruses including HSV, especially in critically ill patients (Hotchkiss et al., 2013; Luyt et al., 2007).

H. Alburkat et al.

Tropical Medicine & International Health, Accepted Article.

Abstract Background The pathogenic fungus Schizophyllum sp. can cause allergic fungal rhinosinusitis and allergic bronchopulmonary mycosis in humans. Sinus and lung infections due to Schizophyllum sp. have been reported globally; however, no case of hypertrophic pachymeningitis due to this pathogen has been reported yet. Herein, we describe for the first time, a case of hypertrophic pachymeningitis due to Schizophyllum sp. Case presentation A 69-year-old woman visited the hospital with chief complaints of headache, right trigeminal neuralgia (third branch), ataxic gait, and deafness in the right ear. Magnetic resonance imaging revealed a tumor in the right sphenoidal sinus and thickening of the dura mater surrounding the right porus acusticus internus. Endoscopic sinus surgery and neuroendoscopic biopsy were performed to remove sinus lesions and intracranial lesions, respectively. Both pathological specimens showed findings indicative of filamentous fungi on Grocott’s staining. DNA sequencing with the sinus specimen revealed Schizophyllum sp. as the causative pathogen, consistent with the diagnosis of fungal sinusitis and hypertrophic pachymeningitis. Intravenous liposomal amphotericin B was started, but owing to lack of improvement, the treatment was switched to intravenous voriconazole. We observed improvements in both radiological findings and symptoms. However, the symptoms exacerbated again when the trough level of voriconazole decreased. Upon increasing the voriconazole dose, a higher trough level was obtained and the symptoms improved. Conclusion Our study suggests that when symptoms of central nervous system infection due to Schizophyllum sp. do not improve with liposomal amphotericin B, voriconazole can be administered at high trough levels to improve the symptoms.…

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and are currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. One-hundred Vietnamese children with TBM were treated with an 8-month anti-tuberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs, and to simulate different dosing strategies. The pharmacokinetic properties of rifampicin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. CSF penetration of rifampicin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampicin, were sufficient to achieve target exposures. Ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampicin dosing at 50 mg/kg/day would be required to achieve the target exposure. Moreover, low rifampicin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampicin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.…