Abstract Background Ruxolitinib is a highly potent janus kinase inhibitor that places its users at risk for various bacterial infections and viral reactivation. However new reports are also emerging that suggest greater immunosuppression and risk for fungal disease. Case presentation We report the case of a 51 year-old veteran from Guam, treated with ruxolitinib for polycythemia vera, who developed disseminated histoplasmosis and concurrent cryptococcal meningitis. Conclusion This case draws attention to the degree of immunosuppression that may be seen with this drug and the need for heightened vigilance for opportunistic infections in those treated with inhibitors of janus kinase/signal transducers and activators of transcription (JAK/STAT) such as ruxolitinib.…

Shiri T, Loyse A, Mwenge L, et al.

AbstractBackgroundMortality from cryptococcal meningitis remains very high in Africa. In the ACTA trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2-week amphotericin-based regimens. However, many African settings treat with FLU monotherapy and the cost effectiveness of adding 5FC to FLU is uncertain. MethodsEffectiveness and costs of FLU+5FC were taken from ACTA, which included costing analysis at the Zambian site. Effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtraction of 5FC drug and monitoring costs.Cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analysis assessed uncertainties, and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER.ResultsMean costs per patient were US$847 (95%CI:776-927) for FLU+5FC, and US$628 (95%CI:557-709) for FLU. 10 week mortality was 35.1% (95%CI 28.9-41.7) with FLU+5FC and 53.8% (95%CI: 43.1–64.1) with FLU. At the current 5FC price of $US1.30 per 500mg tablet, the ICER of 5FC+FLU versus FLU alone was US$65 (95%CI: 28-208) per life year saved. Reducing 5FC cost to between US$0.80 and US$0.40 per 500mg resulted in an ICER between US$44 and US$28 per life year saved.Conclusions Addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and if made available widely could substantially reduce mortality rates among HIV-infected persons in Africa.

Houlihan, Catherine F.; Bharucha, Tehmina; Breuer, Judith

Purpose of review Central nervous system (CNS) infections present an ongoing diagnostic challenge for clinicians, with an aetiological agent remaining unidentified in the majority of cases even in high-income settings. This review summarizes developments in a range of diagnostic methods published in the past 18 months. Recent findings Several commercial assays exist for the detection of viral, bacterial and fungal pathogens using single multiplex PCR. Multicentre validation of the Biofire FilmArray panel illustrated high sensitivity for bacterial and fungal pathogens, but poor results for Cryptococcus species detection. The development of microarray cards for bacterial CNS pathogens shows promise but requires further validation. Few developments have been made in proteomics and transcriptomics, contrasted with significant increase in the use of metagenomic (or unbiased) sequencing. Novel viruses causing CNS infection have been described using this technique but contamination, cost, expertise and turnaround time requirements remain restrictive. Finally, the development of Gene Xpert and Ultra has revolutionized tuberculosis meningitis diagnostics with newly released recommendations for their use from the WHO. Summary Progress has been made in the clinical validation and international recommendation of PCR-based tests for CNS infections. Sequencing techniques present the most dynamic field, although significant ongoing challenges persist. Correspondence to Professor Judith Breuer, Division of Infection and Immunity, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK. Tel: +44 20 3108 2130 (internal 52130); fax: +44 20 3108 2123; e-mail: j.breuer@ucl.ac.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Abstract Background Purulent meningitis (PM) is a serious life-threatening infection of the central nervous system (CNS) by bacteria or fungi and associated with high mortality and high incidence of CNS sequelae in children. However, the conventional cerebrospinal fluid (CSF) culture method is time-consuming and has a low sensitivity. Methods Our study developed a real-time PCR-based purulent meningitis-TaqMan array card (PM-TAC) that targeted 21 PM-related pathogens and could produce results within 3 h. Primers and probes were adapted from published sources possibly. The performance of them were evaluated and optimized and then they were spotted on TAC. Results The PM-TAC showed a sensitivity and specificity of 95 and 96%, respectively. For all of the 21 targeted pathogens, the PM-TAC assay had a LOD ranging from 5 copies/reaction to 100 copies/reaction, an intra-assay variation of 0.07–4.45%, and an inter-assay variation of 0.11–6.81%. Of the 15 CSF samples collected from patients with PM after empiric antibiotic therapies, the positive rate was 53.3% (8/15) for our PM-TAC assay but was only 13.3% (2/15) for the CSF culture method. Of the 17 CSF samples showing negative CSF culture, the PM-TAC assay identified a case of Neisseria meningitidis infection. Furthermore, all of the 10 CSF samples from patients without CNS infection showed negative for the PM-TAC assay. Conclusions Our PM-TAC assay also demonstrated that the pathogen loads in the CSF samples correlated with the severity of PM. Thus, the PM-TAC may be helpful to improve the prognosis of PM and clinical outcomes from antibiotic therapies.…

Thao L, Wolbers M, Heemskerk A, et al.

AbstractBackgroundPre-treatment predictors of death from tuberculous meningitis (TBM) are well-established, but whether outcome can be predicted more accurately after the start of treatment by updated clinical variables is unknown. Hence, we developed and validated models that dynamically predict mortality using time-updated Glasgow coma score (GCS) and plasma sodium measurements, together with patient baseline characteristics.MethodsWe included 1048 adults from four TBM studies conducted in southern Vietnam from 2004-2016. We used a landmarking approach to predict death within 120 days after treatment initiation using time-updated data during the first 30 days of treatment. Separate models were built for patients with and without human immunodeficiency virus (HIV) infection. We used the area under the receiver operating characteristic curve (AUC) to evaluate performance of the models at day 10, 20 and 30 of treatment to predict mortality by 60, 90 and 120 days. Our internal validation was corrected for over-optimism using bootstrap. We provide a web-based application that computes mortality risk within 120 days.ResultsHigher GCS indicated better prognosis in all patients. In HIV-infected patients, higher plasma sodium was uniformly associated with good prognosis, whereas in HIV-uninfected patients the association was heterogeneous over time. The bias-corrected AUC of the models ranged from 0.82-0.92 in HIV-uninfected, and 0.81-0.85 in HIV-infected individuals. The models outperformed the previously published baseline models.ConclusionsTime-updated GCS and plasma sodium measurements improved predictions based solely on information obtained at diagnosis. Our models may be used in practice to define those with poor prognosis during treatment.

M. Rebelo et al.

Abstract Staphylococcus condimenti (S. condimenti) is a coagulase-negative bacterium, generally regarded as not pathogenic. Indeed, S. condimenti owes its name to having been isolated from starter cultures of fermented sausage, as well as from fish and soy sauces. To the best of our knowledge, only two cases of human infection caused by this bacterium have been reported. Here, we present a case of meningitis by S. condimenti in a 65-year-old woman who was brought to hospital after having been found unconscious at home. At her arrival, she had a Glasgow coma scale = 3, fever, and hypoxic–normocapnic respiratory failure. Examination of her cerebrospinal fluid showed a slightly increased white blood cell count, normal glucose and protein concentrations. Paired cultures on blood and liquor samples yielded S. condimenti. Targeted antibiotic treatment with ceftriaxone led to a complete recovery. This unique case expands our knowledge on S. condimenti as a pathogenic bacterium.…

Wang M, Wang L, Wu P, et al.

AbstractCronobacter sakazakii causes meningitis and necrotizing enterocolitis in premature infants. However, its virulence determinants, especially those specific for strains associated with neonate infections, remain largely unknown. Here, we performed a comparative genomic analysis of 209 C. sakazakii genomes, and eight clonal groups (CGs) were revealed. CG1 and CG2 were found to be significantly associated with neonate infections, and significantly prevalent genes in these two CGs were identified. Of these, a gene encoding the LysR-type regulator CklR, was shown to contribute to bacterial pathogenicity based on animal experiments. We found that CklR directly binds and activates the suf Fe-S cluster biosynthesis operon and high expression of the suf operon increases bacterial resistance to oxidative stress, which increases survival within the host. This leads to a high degree of bacteremia, which contributes to the development of meningitis. Our work revealed a novel virulence factor specific to predominant pathogenic C. sakazakii strains.

Chen T, Mwenge L, Lakhi S, et al.

AbstractBackgroundMortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses.MethodsParticipants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done.ResultsTotal costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91–1210) per life-year saved.ConclusionsBoth 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.

Hung-Chin Tsai, Yu-Hsin Chen, Chuan-Min Yen, Susan Shin-Jung Lee, Yao-Shen Chen

by Hung-Chin Tsai, Yu-Hsin Chen, Chuan-Min Yen, Susan Shin-Jung Lee, Yao-Shen Chen The 14-3-3 proteins are cerebrospinal fluid (CSF) markers of neuronal damage during infectious meningitis and Creutzfeldt-Jakob disease. Little is known about dynamic changes in the individual isoforms in response to parasitic eosinophilic meningitis. The purposes of this study were to determine the 14-3-3 protein isoform patterns, examine the kinetics and correlate the severity of blood brain barrier (BBB) damage with the expressions of these markers in mice with eosinophilic meningitis. Mice were orally infected with 50 A. cantonensis L3 via an oro-gastric tube and sacrificed every week for 3 consecutive weeks after infection. The Evans blue method and BBB junctional protein expressions were used to measure changes in the BBB. Hematoxylin and eosin staining was used to analyze pathological changes in the mice brains following 1–3 weeks of infection with A. cantonensis. The levels of 14-3-3 protein isoforms in serum/CSF and brain homogenates were analyzed by Western blot, and immunohistochemistry (IHC) was used to explore the different isoform distributions of 14-3-3 proteins and changes in BBB junctional proteins in the mice brain meninges. Dexamethasone was injected intraperitoneally from the seventh day post infection (dpi) until the end of the study (21 dpi) to study the changes in BBB junctional proteins. The amounts of Evans blue, tight junction and 14-3-3 protein isoforms in the different groups of mice were compared using the nonparametric Kruskal-Wallis test. There were significant increases in 14-3-3 protein isoforms β and γ in the CSF in the second and third weeks after infection compared to the controls and first week of infection, which were correlated with the severity of BBB damage in brain histology, and Evans blue extravasation. Using IHC to assess the distribution of 14-3-3 protein isoforms and changes in BBB junctional proteins in the mice brain meninges, the expressions of isoforms β, γ, ε, and θ and junctional proteins occludin and claudin-5 in the brain meninges increased over a 3-week period after infection compared to the controls and 1 week after infection. The administration of dexamethasone decreased the expressions of BBB junctional proteins occludin and claudin-5 in the mice brain meninges. Our findings support that 14-3-3 proteins β and γ can potentially be used as a CSF marker of neuronal damage in parasitic eosinophilic meningitis caused by A. cantonensis.

Abstract Background Cryptococcosis is a common opportunistic infection in patients infected by Human Immunodeficiency Virus (HIV) and is the second leading cause of mortality in Acquired Immunodeficiency Syndrome (AIDS) patients worldwide. The most frequent presentation of cryptococcal infection is subacute meningitis, especially in patients with a CD4+ T Lymphocytes count below 100 cells/μL. However, in severely immunosuppressed individuals Cryptococcus neoformans can infect virtually any human organ, including the bone marrow, which is a rare presentation of cryptococcosis. Case presentation A 45-year-old HIV-infected male patient with a CD4+ T lymphocyte count of 26 cells/μL who presented to the emergency department with fever and pancytopenia. Throughout the diagnostic evaluation, the bone marrow aspirate culture yielded encapsulated yeasts in budding, identified as Cryptococcus sp. The bone marrow biopsy revealed a hypocellularity for age and absence of fibrosis. It was observed presence of loosely formed granuloma composed of multinucleated giant cells encompassing rounded yeast like organisms stained with mucicarmine, compatible with Cryptococcus sp. Then, the patient underwent a lumbar puncture to investigate meningitis, although he had no neurological symptoms and neurological examination was normal. The cerebrospinal fluid culture yielded Cryptococcus sp. The species and genotype identification step showed the infection was caused by Cryptococcus neoformans var. grubii (genotype VNI). The patient was initially treated with amphotericin B deoxycholate plus fluconazole for disseminated cryptococcosis, according to guideline recommendations. However, the patient developed acute kidney injury and the treatment was switched for fluconazole monotherapy. The symptoms disappeared completely with recovery of white blood cells and platelets counts. Cerebrospinal fluid cultures for fungi at one and two-weeks of treatment were negative. Conclusions Bone marrow infection caused by Cryptococcus neoformans is a rare presentation of cryptococcosis. The cryptococcal infection should be included for differential diagnosis in HIV-infected patients with fever and cytopenias, especially when CD4+ T lymphocytes count is below 100 cells/μL.…

Abstract Background Invasive Salmonella infections result in significant morbidity and mortality in developing countries. In Asia, typhoid and paratyphoid fever are reported to be the major invasive Salmonella infections, while invasive non-typhoidal Salmonella (iNTS) infections are believed to be uncommon. Data from Sarawak, in Malaysian Borneo, are limited. Methods A retrospective study identifying all children aged

Sühs K, Novoselova N, Kuhn M, et al.

AbstractBackgroundThe tryptophan-kynurenine-NAD+ pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in CNS infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers.MethodsWe measured concentrations of kynurenine (Kyn) and tryptophan (Trp) in 220 cerebrospinal fluid samples from patients with bacterial and viral (herpes simplex, varicella zoster, enteroviruses) meningitis/encephalitis, neuroborreliosis, autoimmune neuroinflammation (anti-NMDA-R encephalitis, multiple sclerosis), and noninflamed controls (Bell’s palsy, normal pressure hydrocephalus, Tourette syndrome).ResultsKyn concentrations correlated strongly with CSF markers of neuroinflammation (leukocyte count, lactate, and blood-CSF-barrier dysfunction) and were highly increased in bacterial and viral CNS infections, but were low or undetectable in anti-NMDA-R encephalitis, multiple sclerosis, and controls. Trp was decreased mostly in viral CNS infections and neuroborreliosis. Multiple logistic regression analysis revealed combinations of Kyn, Trp and Kyn/Trp ratio with leukocyte count or lactate as accurate classifiers for the clinically important differentiation between neuroborreliosis, viral CNS infections, and autoimmune neuroinflammation. ConclusionsThe Trp-Kyn-NAD+ pathway is activated in CNS infections and provides highly accurate CSF biomarkers, particularly when combined with standard CSF indices of neuroinflammation.

Lisa Malincarne, Elisabetta Schiaroli, Alessandra Ciervo, Vittoria Scaglione, Maurizio Paciaroni, Fabiola Mancini, Maria Grazia Paglia, Salvatore Cardaci, Maria Bruna Pasticci, Daniela Francisci, Franco Baldelli

Linder KA, Malani PN.

This JAMA Patient Page describes meningococcal meningitis, its causes, risk factors, and prevention measures.

Abstract Background During fulminant meningococcal septicaemia, meningococci are often observed in the cerebrospinal fluid (CSF) although the patients have frequently no meningeal symptoms. Meningococcal meningitis, by contrast, usually features clinical meningeal signs and biochemical markers of inflammation with elevated white blood cell count (pleiocytosis) in the CSF. Cases of typical symptomatic meningitis without these biochemical features are uncommon in adults. Case presentation A 21-year-old male presented with meningococcal purpura fulminans and disseminated intravascular coagulation (DIC) associated with multiple organ dysfunction syndrome requiring hospitalization in the Intensive Care Unit. Despite typical meningeal clinical signs, lumbar puncture showed no pleiocytosis, normal glycorachia and normal proteinorachia, whereas the lactate concentration in the CSF was high (5.8 mmol/L). CSF culture showed a high inoculum of serogroup C meningococci. On day 2, after initial improvement, a recurrence of hypotension led to the diagnosis of acute meningococcal myocarditis, which evolved favourably within a week. During the hospitalization, distal ischemic and necrotic lesions were observed, predominantly on the fingertips, which were treated with local and systemic vasodilators. Conclusions We report a rare case of adult meningococcal disease characterized by an intermediate form of meningitis between purulent meningitis and meningeal inoculation from fulminant meningococcal septicaemia, without classical signs of biological inflammation. It highlights the diagnostic value of CSF lactate, which may warrant administration of a meningeal dosing regimen of beta-lactam antibiotics. This case also demonstrates the potential severity of meningococcal myocarditis; we discuss its pathophysiology, which is distinct from other sepsis-related cardiomyopathies. Finally, the observed effects of vasodilators on the meningococcal skin ischemia in this case encourages future studies to assess their efficacy in DIC-associated necrosis.…

Abstract Background Streptococcus agalactiae or Group B Streptococcus (GBS) is the leading cause of neonatal morbidity and mortality resulting in septicaemia, bacteraemia and meningitis. Long term problems in children range from loss of hearing to mental retardation. While Intrapartum Antibiotic Prophylaxis (IAP) has reduced the incidence of S. agalactiae infection, it still remains the leading cause of disease in neonates. GBS has ten capsular types whose distribution varies across the world. Therefore, this study sought to determine the prevalence of GBS in Namibia and South Africa amongst pregnant women between 35 and 37 weeks gestation and elucidate the capsular types. Methods Lower vaginal and rectal swabs were collected from pregnant women between 35 and 37 weeks gestation. Five hundred and thirty pregnant women were recruited into the study in Windhoek, Namibia while one hundred pregnant women were recruited in the Eastern Cape, South Africa. The swabs were cultured on 5% sheep blood agar (Biomerieux, New Jersey, USA) for isolation of GBS. Presumptive isolates were confirmed using both the Vitek (2) and molecular techniques targeting the scpB gene. Capsular typing was performed in a multiplex PCR with capsular specific primer pairs. Results The prevalence of GBS in Namibia was 13.6 and 37% in South Africa respectively. In both countries most women were dually colonised with GBS. Capsular types II, III and V were the most prevalent. Conclusions The prevalence of GBS in Namibia was lower than in South Africa in this study. The prevalence in both countries was not different from those reported in other African countries and around the world. The predominant capsular types in this study are the ones commonly associated with adverse maternal outcomes.…

Abstract Background Group B streptococcus (GBS) is reported as the leading cause of neonatal sepsis and meningitis. Newborns from GBS colonized pregnant women are at high risk of infection. Method A Hospital based cross-sectional study was conducted at Hawassa University Comprehensive Specialized Hospital from November 05, 2014 to March 25, 2015. A total of 280 pregnant women along with their newborns were screened for GBS using standard method recommended by Center of Disease Control and Prevention. GBS strains were serotyped by using serotype specific antisera. A structured questionnaire was used to collect sociodemographic, obstetrics and clinical data of pregnant women and newborns. Data was analyzed by using chi-square and logistic regression to determine factors associated with prevalence of GBS among pregnant women and newborns. Descriptive statistics was used to determine prevalence of GBS among pregnant women and newborns. P value less than 0.05 was considered statistically significant. Result Prevalence of GBS among pregnant women, newborns and vertical transmission rate at Hawassa University Comprehensive Specialized Hospital were 44(15.7%), 26(8.9%) and 59.1% respectively. Among 26 GBS colonized newborns one developed sign and symptoms of early onset disease. Serotype distribution of GBS isolates collected from pregnant women and newborns was Ia 13(18.6%), Ib 9(12.9%), II 24(34.3%), III 8(11.4%), V 14(20%), and NT 2 (2.9%). Conclusion In our study we found relatively high prevalence of GBS among pregnant women and vertical transmission rate. The most prevalent GBS serotypes identified in this study were serotype II followed by V, Ia and Ib. Therefore, appropriate prevention strategies such as intrapartum antibiotic prophylaxis and vaccine development should be considered.…

Abstract Background The WHO guidelines for the management of advanced HIV disease recommend a package of care consisting of rapid initiation of antiretroviral therapy (ART), enhanced screening and diagnosis of tuberculosis (TB) and cryptococcal meningitis, co-trimoxazole prophylaxis, isoniazid preventive therapy (IPT), fluconazole pre-emptive therapy, and adherence support. The goals of this study were to determine the prevalence of advanced HIV disease among individuals initiating ART in Senegal, to identify predictors of advanced disease, and to evaluate adherence to the WHO guidelines. Methods This study was conducted among HIV-positive individuals initiating ART in Dakar and Ziguinchor, Senegal. Clinical evaluations, laboratory analyses, questionnaires and chart review were conducted. Logistic regression was used to identify predictors of advanced disease. Results A total of 198 subjects were enrolled; 70% were female. The majority of subjects (71%) had advanced HIV disease, defined by the WHO as a CD4 count

Laura V. Cooper, Anna Robson, Caroline L. Trotter, Abraham Aseffa, Jean‐Marc Collard, Doumagoum Moto Daugla, Aldiouma Diallo, Abraham Hodgson, Jean‐François Jusot, Babatunji Omotara, Samba Sow, Musa Hassan‐King, Olivier Manigart, Maria Nascimento, Arouna Woukeu, Daniel Chandramohan, Ray Borrow, Martin C. J. Maiden, Brian Greenwood, on behalf of James M. Stuart, the MenAfriCar Consortium, Oumer Ali, Ahmed Bedru, Tsehaynesh Lema, Tesfaye Moti, Yenenesh Tekletsion, Alemayehu Worku,

Abstract Objective To investigate potential risk factors for acquisition in seven countries of the meningitis belt. Methods Households were followed up every 2 weeks for 2 months, then monthly for a further 4 months. Pharyngeal swabs were collected from all available household members at each visit and questionnaires completed. Risks of acquisition over the whole study period and for each visit were analysed by a series of logistic regressions. Results Over the course of the study, acquisition was higher in: (i) 5‐to 14‐year olds, as compared with those 30 years or older (OR 3.6, 95% CI 1.4–9.9); (ii) smokers (OR 3.6, 95% CI 0.98–13); and (iii) those exposed to wood smoke at home (OR 2.6 95% CI 1.3–5.6). The risk of acquisition from one visit to the next was higher in those reporting a sore throat during the dry season (OR 3.7, 95% CI 2.0–6.7) and lower in those reporting antibiotic use (OR 0.17, 95% CI 0.03–0.56). Conclusions Acquisition of meningococcal carriage peaked in school age children. Recent symptoms of sore throat during the dry season, but not during the rainy season, were associated with a higher risk of acquisition. Upper respiratory tract infections may be an important driver of epidemics in the meningitis belt.

Mukaremera, L., McDonald, T. R., Nielsen, J. N., Molenaar, C. J., Akampurira, A., Schutz, C., Taseera, K., Muzoora, C., Meintjes, G., Meya, D. B., Boulware, D. R., Nielsen, K.

Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet Cryptococcus factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the strain genotype and degree of antigen shedding, are associated with clinical outcome but the underlying biology remains elusive. In this study, we examined factors determining disease outcome in HIV-infected cryptococcal meningitis patients infected with C. neoformans strains with the same multi-locus sequence type (MLST). Both patient mortality and survival were observed during infections with the same sequence type. Disease outcome was not associated with patient CD4 count. Patient mortality was associated with higher cryptococcal antigen levels, CSF fungal burden by quantitative culture, and low CSF fungal clearance. Virulence of a subset of clinical strains with the same sequence type were analyzed using the mouse inhalation model of cryptococcosis. We showed a strong association between human and mouse mortality rates, demonstrating the mouse inhalation model recapitulates human infection. Similar to human infection, the ability to multiply in vivo, demonstrated by high fungal burden in the lung and brain tissues, was associated with mouse mortality. Mouse survival time was not associated with single C. neoformans virulence factors in vitro or in vivo; rather, a trend in survival time correlated with a suite of traits. These observations show that MLST-derived genotype similarities between C. neoformans strains do not necessarily translate into similar virulence either in the mouse model or in human patients. In addition, our results show that in vitro assays do not fully reproduce in vivo conditions that influence C. neoformans virulence.…

Bloch, Karen C.; Bailin, Samuel S.

Purpose of review Fungal infections of the central nervous system (CNS) are relatively uncommon but associated with significant morbidity and mortality. We reviewed recent literature highlighting new approaches to management of these complex patients. Recent findings Fungal infections are increasingly recognized as important causes of CNS disease in both immunocompromised and immunocompetent hosts. Globally, cryptococcal meningitis remains a leading cause of death in HIV-infected persons in resource-limited settings. Emerging fungal pathogens with increased virulence and resistance to numerous classes of antifungal agents have been identified and represent a management challenge. Newer diagnostic techniques focused on antigen detection or molecular amplification of fungal pathogens offer promise in the expediated diagnosis and treatment of CNS fungal infections. Summary Meningitis and brain abscess because of invasive fungal pathogens are frequently fatal infections. Newer laboratory tests allowing antigen detection or molecular amplification from cerebrospinal fluid are more sensitive than culture and allow earlier initiation of effective therapy. Correspondence to Karen C. Bloch, MD, MPH, FIDSA, FACP, Associate Professor, Medicine (Infectious Diseases) and Health Policy, Vanderbilt University School of Medicine, A-2200 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Tel: +1 615 322 2035; fax: +1 615 343 6160; e-mail: Karen.bloch@vumc.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Colicchio, R., Pagliuca, C., Ricci, S., Scaglione, E., Grandgirard, D., Masouris, I., Farina, F., Pagliarulo, C., Mantova, G., Paragliola, L., Leib, S. L., Koedel, U., Pozzi, G., Alifano, P., Salvatore, P.

In serogroup C Neisseria meningitidis, the cssA (siaA) gene codes for an UDP-N-acetylglucosamine 2-epimerase that catalyzes the conversion of UDP-N-acetyl-α-D-glucosamine into N-acetyl-D-mannosamine and UDP in the first step in sialic acid biosynthesis. This enzyme is required for the biosynthesis of the (α2->9)-linked polysialic acid capsule and for lipooligosaccharide (LOS) sialylation. In this study, we have used a reference serogroup C meningococcal strain and an isogenic cssA knockout mutant to investigate the pathogenetic role of surface-exposed sialic acids in a model of meningitis based on intracisternal inoculation of BALB/c mice. Results confirmed the key role of surface-exposed sialic acids in meningococcal pathogenesis. The 50% lethal dose (LD50) of the wild type strain 93/4286 was about four orders of magnitude lower than that of the cssA mutant. Compared to the wild type strain, the ability of this mutant to replicate in brain and spread systemically was severely impaired. Evaluation of brain damage evidenced a significant reduction in cerebral hemorrhages in mice infected with the mutant in comparison with those challenged with the wild type strain. Histological analysis showed the typical features of bacterial meningitis, including inflammatory cells in the subarachnoid, perivascular and ventricular spaces especially in animals infected with the wild type. Noticeably, 80% of mice infected with the wild type strain presented with massive bacterial localization and accompanying inflammatory infiltrate in the corpus callosum, indicating high tropism of meningococci exposing sialic acids toward this brain structure and a specific involvement of the corpus callosum in the mouse model of meningococcal meningitis.…