Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Influence of Strongyloides stercoralis Coinfection on the Presentation, Pathogenesis, and Outcome of Tuberculous Meningitis.

BACKGROUND: Helminth infections may modulate the inflammatory response to Mycobacterium tuberculosis and influence disease presentation and outcome. Strongyloides stercoralis is common among populations with high tuberculosis prevalence. Our aim was to determine whether S. stercoralis coinfection influenced clinical presentation, cerebrospinal fluid (CSF) inflammation, and outcome from tuberculous meningitis (TBM). METHODS: From June 2017 to December 2019, 668 Vietnamese adults with TBM, enrolled in the ACT HIV or LAST ACT trials (NCT03092817 and NCT03100786), underwent pretreatment S. stercoralis testing by serology, stool microscopy, and/or stool polymerase chain reaction. Comparisons of pretreatment TBM severity, CSF inflammation (including cytokines), and 3-month clinical end points were performed in groups with or without active S. stercoralis infection. RESULTS: Overall, 9.4% participants (63 of 668) tested positive for S. stercoralis. Active S. stercoralis infection was significantly associated with reduced pretreatment CSF neutrophil counts (median [interquartile range], 3/µL [0-25/µL] vs 14 /µL [1-83/µL]; P = .04), and with reduced CSF interferon É£, interleukin 2, and tumor necrosis factor α concentrations (11.4 vs 56.0 pg/mL [P = .01], 33.1 vs 54.5 pg/mL [P = .03], and 4.5 vs 11.9 pg/mL [P = .02], respectively), compared with uninfected participants. Neurological complications by 3 months were significantly reduced in participants with active S. stercoralis infection compared with uninfected participants (3.8% [1 of 26] vs 30.0% [33 of 110], respectively; P = .01). CONCLUSIONS: S. stercoralis coinfection may modulate the intracerebral inflammatory response to M. tuberculosis and improve TBM clinical outcomes.

Tuberculous meningitis: where to from here?

PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in the last 2 years, since 1 January 2018, which we considered to have a major impact in advancing diagnosis, treatment and understanding of the pathophysiology of TBM meningitis in children and adults. RECENT FINDINGS: Studies have sought to identify a high sensitivity diagnostic test for TBM, with new data on modified Ziehl--Neelsen staining, urinary and cerebrospinal fluid (CSF) lipoarabinomannan and GeneXpert Ultra. Recent studies on CSF biomarkers provide a better understanding of the detrimental inflammatory cascade and neuromarkers of brain damage and suggest potential for novel host-directed therapy. Tryptophan metabolism appears to affect outcome and requires further study. Increased clinical trials activity in TBM focuses on optimizing antituberculosis drug regimens and adjuvant therapy; however, there are few planned paediatric trials. SUMMARY: Tuberculous meningitis still kills or disables around half of sufferers. Although some progress has been made, there remains a need for more sensitive diagnostic tests, better drug therapy, improved management of complications and understanding of host-directed therapy if outcomes are to improve.

In Vitro Digestion and Fermentation of Microencapsulated Tributyrin for the Delivery of Butyrate.

Butyrate possesses negative sensory qualities and is most effectively utilized in the intestine to provide energy to the colonocyte for the maintenance of intestinal health. Butyrate has also shown promise in the treatment of intestinal disorders and diseases such as short bowel syndrome, inflammatory bowel disease, and colon cancer. To modify sensory properties, intestinal release, and butyrate production capabilities, tributyrin (TB) was microencapsulated in whey protein isolate (WPI)-based and gamma-cyclodextrin (GC)-based materials. Using an in vitro digestion and fermentation model, microcapsules containing TB were monitored for their release and production of butyrate in vitro. All samples containing TB showed limited butyrate release (<5%) during oral and gastric stages. In the small intestinal phase, all microcapsules containing TB released approximately 75% of their total butyrate with no significant differences (P > 0.05) across formulations. During the fermentation phase, GC-based microcapsules produced significantly more butyrate (P < 0.001) on a molar basis than all WPI-based microcapsules. Butyrate production increased significantly (P < 0.001) over each time interval with GC-based microcapsules having the highest during the 12 h of fermentation. The GC-based TB encapsulation systems were able to effectively deliver butyrate to the small intestine and generate butyrate in the large intestine. These microcapsules may, therefore, be beneficial for the maintenance of intestinal health and improvement of disease states across all areas of the gastrointestinal tract.

Drug Reaction, Eosinophilia and Systemic Symptoms (DRESS) syndrome secondary to allopurinol with early lymphadenopathy and symptom relapse.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare condition with a mortality rate of up to 10%. Herein, we describe a case of DRESS syndrome secondary to allopurinol and which may have been precipitated by amoxicillin, the diagnostic challenge it represented and the successful treatment of the condition with corticosteroids.

Fatal fentanyl patch misuse in a hospitalized patient with a postmortem increase in fentanyl blood concentration.

Opioid-related mortality happens, even in healthcare settings. We describe serial postmortem fentanyl blood concentrations in a hospital inpatient who fatally abused transdermal fentanyl. This is a single-patient case report. A 42-year-old man with lymphoma was started on transdermal fentanyl therapy while hospitalized for chronic abdominal pain. The patient was last seen awake 1.3 h prior to being found apneic and cyanotic. During the resuscitation attempt, a small square-shaped film was removed from the patient's oropharynx. Femoral blood was collected 0.5 and 2 h postmortem, and the measured fentanyl concentration increased from 1.6 to 14 ng/mL. Study limitations include potential laboratory or collection errors and missing data. (i) Providers must be vigilant for signs of fentanyl patch abuse. (ii) Postmortem blood concentrations are not static postmortem, likely secondary to decreasing pH, increased aqueous solubility, and tissue redistribution, and are therefore unlikely to accurately represent antemortem blood concentrations.

Back pain, leg swelling and a cardiac arrest: an interesting case of endocarditis.

A 66-year-old woman with a history of tissue aortic valve replacement and chronic back pain presented to the emergency department with a suspected right leg deep vein thrombosis. A recent outpatient MRI had revealed discitis. A ventricular fibrillation cardiac arrest occurred in the emergency department. Cardiac output was restored on the fifth defibrillation. A transthoracic echocardiogram showed large aortic valve vegetations. Clinical impression was of infective endocarditis with cardiac arrest secondary to coronary artery embolisation. Peripheral blood cultures grew Cardiobacterium hominis, and appropriate intravenous antibiotic therapy was administered. The infected prosthetic valve was excised. The patient experienced postoperative complete heart block and a right hemisphere cerebrovascular accident, however she is now recovering well. This case describes an unusual case of infective endocarditis secondary to C. hominis, with disc, leg, coronary artery and brain septic embolisation. Infective endocarditis is an important differential diagnosis in multisystem presentations.

Selenium Adsorption onto Iron Oxide Layers beneath Coal-Mine Overburden Spoil.

A field experimental study to determine the feasibility of sequestering dissolved selenium (Se) leached from coal-mine waste rock used an iron (Fe)-oxide amendment obtained from a mine-drainage treatment wetland. Thirty lysimeters (4.9 × 7.3 m), each containing 57.7 t (1.2-1.8 m thickness) of mine-run carbonaceous shale overburden, were installed at the Hobet mine in southeastern West Virginia. The fine-grained Fe-oxide was determined to be primarily metal oxides (91.5% ferric and 4.37% aluminous), with minor (<3%) SO and Ca, perhaps as gypsum. The mineralogy of the Fe was goethite, although residual ferrihydrite may have been present. Various thicknesses of this amendment (0.0064, 0.057, 0.229, and 0.457 m, plus a zero-amendment control) were used, ranging from 0 to 2.2% weight percent of the spoil. The control and each treatment were replicated six times to estimate uncertainty due to compositional and hydrological variation. Infiltration of rainfall created leachate that drained to individual batch-collection tanks that were sampled 46 times at approximately 2-wk intervals from 2010 to 2012. Basal Fe-oxide layers in the three highest amendment categories removed up to 76.1% selenium (in comparison to unamended piles) from leachate by adsorption. Only lysimeters with very thin Fe-oxide layers showed no significant reduction compared with unamended piles. Reproducibility of replicates was within acceptable limits for amended and unamended lysimeters. Results indicate that in situ amendment using Fe-oxide obtained from treatment of mine water can sequester Se by adsorption on surfaces of goethite and possibly also ferrihydrite. This process is demonstrated to substantially reduce dissolved Se in leachate and improve compliance with regulatory discharge limits.