Yoon H, Nakouzi A, Chang C, et al.

AbstractBackgroundInitiation of antiretroviral therapy (ART) in HIV-infected individuals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated.MethodsWe compared plasma levels of immunoglobulins, Cryptococcus neoformans (CN) glucuronoxylomannan (GXM) capsule-specific and (Lam)inarin-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not and evaluated associations of these parameters with risk of C-IRIS.ResultsPrior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P=0.0003), Lam-IgM (P=0.0005), Lam-IgG (P=0.002), and GXM-IgM (P=0.002) independent of age, sex, HIV viral load, CD4+ T cell count and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells.DiscussionAntibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM, may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.

Abstract Background With a prevalence of 4.7–13% in Danish Ixodes ricinus ticks, Rickettsia helvetica is one of the most frequently detected tick-borne organisms in Denmark. Most reports of human exposure have described asymptomatic seroconversion or a mild, self-limiting flu-like illness but it has also been implicated as a cause of subacute lymphocytic meningitis. Because Borrelia burgdorferi sensu lato (Bbsl) and R. helvetica are both found in the same tick species, potential co-transmission is a possibility. We examined 1) the seroprevalence of anti-rickettsia antibodies in patients investigated for Lyme neuroborreliosis (LNB), and 2) the cerebrospinal fluid (CSF) and sera of same patients for the presence of Rickettsia DNA. Methods Ninety-nine sera and 87 CSF samples from patients with intrathecal synthesis of anti-Borrelia antibodies and 101 sera and 103 CSF samples from patients with no detectable intrathecal synthesis were retrospectively examined for this study. Sera were analyzed for antibodies against spotted fever group (SFG) rickettsiae and both the CSF and sera were tested for Rickettsia DNA using a genus-specific real-time PCR. Results Of the patients tested for LNB, 32% (64/200) had IgG antibodies against SFG rickettsiae. Among patients with confirmed intrathecal synthesis of Borrelia-specific antibodies, 38% (38/99) exhibited IgG antibodies. None of these values were statistically significant when compared with sera from healthy blood donors (p = 0.7 and 0.19). Rickettsia DNA was found in the CSF of 4% (8/190) of patients. Conclusion No statistically significant difference was found in the seroprevalence of anti-rickettsia antibodies in patients tested for LNB and healthy blood donors, indicative of a low rate of exposure in this group of patients. Eight patients showed evidence of Rickettsia DNA in the CSF, five of whom had LNB. However, cycle threshold (Ct) values were high, indicating low concentrations of DNA, and no apparent alteration in the clinical manifestations of LNB were noted in the medical records of these patients.

Depledge D, Cudini J, Kundu S, et al.

AbstractBackgroundVaricella zoster virus (VZV) may cause encephalitis, both with and without rash. Here we investigate whether viruses recovered from the central nervous system (CNS; encephalitis or meningitis) differ genetically from those recovered from non-CNS samples.MethodsEnrichment-based deep sequencing of 45 VZV genomes from cerebral spinal fluid (CSF), plasma, bronchoalveolar lavage (BAL), and vesicles was carried out with samples collected from 34 patients with and without VZV infection of the CNS.ResultsViral sequences from multiple sites in the same patient were identical at the consensus level. Virus from vesicle fluid and CSF in cases of meningitis showed low-level diversity. By contrast, plasma, BAL, and encephalitis had higher numbers of variant alleles. Two CSF-encephalitis samples had high genetic diversity, with variant frequency patterns typical of mixed infections with different clades.ConclusionsLow viral genetic diversity in vesicle fluid is compatible with previous observations that VZV skin lesions arise from single or low numbers of virions. A similar result was observed in VZV from cases of VZV meningitis, a generally self-limiting infection. CSF from cases of encephalitis had higher diversity with evidence for mixed clade infections in 2 cases. We hypothesize that reactivation from multiple neurons may contribute to the pathogenesis of VZV encephalitis.

Esayas Kebede Gudina, Markos Tesfaye, Andreas Wieser, Hans-Walter Pfister, Matthias Klein

by Esayas Kebede Gudina, Markos Tesfaye, Andreas Wieser, Hans-Walter Pfister, Matthias Klein Background The mortality and neurologic sequelae associated with acute bacterial meningitis (ABM) remain high despite advances in medical care. The main aim of this study was to evaluate short-term outcome in patients treated as bacterial meningitis at a teaching hospital in Ethiopia to identify factors that could be focused on to improve outcome in this setting. Methods A hospital based longitudinal study was conducted at Jimma University Hospital in southwest Ethiopia from March 1, 2013 to December 31, 2015. Participants of this study were patients of age 18 years and older who were treated as confirmed or possible cases of ABM. Patients were followed throughout their hospital stay for change in their clinical course and predefined end points. A multivariable analysis was done to identify factors associated with unfavorable outcomes. Result 90 patients admitted with diagnosis of acute bacterial meningitis were included in the study; cerebrospinal fluid was analysed for 85 (94.4%) of them. Causative bacteria were isolated in 26 (28.9%) patients only; most of these isolates (84.6%) were either Streptococcus pneumoniae or Neisseria meningitidis. Patients managed as cases of ABM at the hospital suffered from a high rate of unfavorable outcome (36.7%) and an overall mortality rate of 22.2%. Impaired level of consciousness (AOR = 0.766, 95% CI = 0.589–0.995), dexamethasone therapy (AOR = 4.676, 95% CI = 1.12–19.50) and fever persisting after two days of admission (AOR = 24.226, 95% CI = 5.24–111.96) were found to be independently associated with unfavorable outcome. Conclusion Outcome in patients treated for ABM at the hospital was found to be poor. Impaired mentation, treatment with adjunctive dexamethasone and persistent fever were found to be associated with poor outcome. Thus, development of clinical guidelines for treatment of ABM that suit the local context is essential to improve patient management and outcome.

Jean-Philippe Auger, Dominic Dolbec, David Roy, Mariela Segura, Marcelo Gottschalk

by Jean-Philippe Auger, Dominic Dolbec, David Roy, Mariela Segura, Marcelo Gottschalk Streptococcus suis serotype 2 is an important porcine bacterial pathogen and zoonotic agent responsible for sudden death, septic shock, and meningitis. However, serotype 2 strains are heterogeneous, composed of a multitude of sequence types (STs) whose distribution greatly varies worldwide. Of the virulence factors presently described for S. suis, the capsular polysaccharide (CPS) is a critical factor implicated in a multitude of functions, including in impairment of phagocytosis and innate immune cell activation by masking underlying bacterial components. However, these roles have been described using Eurasian ST1 and ST7 strains, which greatly differ from North American ST25 strains. Consequently, the capacity of the CPS to mask surface antigens and putative virulence factors in non-Eurasian strains remains unknown. Herein, the role of the S. suis serotype 2 CPS of a prototype intermediate virulent North American ST25 strain, in comparison with that of a virulent European ST1 strain, with regards to interactions with dendritic cells, as well as virulence during the systemic phase of infection, was evaluated. Results demonstrated that the CPS remains critical for virulence and development of clinical disease regardless of strain background, due to its requirement for survival in blood. However, its role in the interactions with dendritic cells is strain-dependent. Consequently, certain key characteristics associated with the CPS are not necessarily applicable to all S. suis serotype 2 strains. This indicates that though certain factors may be important for S. suis serotype 2 virulence, strain background could be as determining, reiterating the need in using strains from varying backgrounds in order to better characterize the S. suis pathogenesis.

Wiederhold, N. P., Najvar, L. K., Garvey, E. P., Brand, S. R., Xu, X., Ottinger, E. A., Alimardanov, A., Cradock, J., Behnke, M., Hoekstra, W. J., Schotzinger, R. J., Jaramillo, R., Olivo, M., Kirkpatrick, W. R., Patterson, T. F.

Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with C. neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28 after which mice were monitored off-therapy until day 30 or day 60, respectively, to assess survival. Fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg once daily. VT-1129 at doses of ≥ 0.3 mg/kg/day and each dose of fluconazole significantly reduced brain tissue fungal burden compared to control after both 7 and 14 days of dosing. Fungal burden was also undetectable in most mice treated with dose of ≥ 3 mg/kg/day, even ≥ 20 days after dosing had stopped in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.

Jarvis J, Harrison T.

Mukap, M., Sprod, C., Tefuarani, N., Laman, M., Page-Sharp, M., Salman, S., Moore, B. R., Batty, K. T., Davis, T. M. E., Manning, L.

Background: Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children from Papua New Guinea (PNG) with severe illness, a setting in which healthcare resources are limited and anemia is common.Methods: Using a previously validated liquid chromatography-mass spectroscopy (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5-10 years with acute bacterial meningitis or severe pneumonia. The concentration-time data were incorporated into population PK models.Results: Ten children were recruited with an admission hematocrit of 0.22-0.52. Raw data demonstrated good correlation between plasma and DBS concentrations (Spearman rs =0.94 [95% confidence interval 0.91-0.97], P