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Objectives Clofazimine is a promising drug for the treatment of nontuberculous mycobacterial (NTM) diseases. Accumulation of clofazimine to reach steady-state plasma concentrations takes months. A loading dose may reduce the time to steady-state-like concentrations. We evaluated the pharmacokinetics (PK), safety and tolerability of a loading dose regimen in patients with NTM disease. Methods Adult participants received a 4-week loading dose regimen of 300 mg clofazimine once daily, followed by a maintenance dose of 100 mg once daily (combined with other antimycobacterial drugs). Blood samples for PK analysis were collected on three occasions. A population PK model for clofazimine was developed and simulations were performed to assess the time to reach steady-state-like (target) concentrations for different dosing regimens. Results Twelve participants were included. The geometric mean peak and trough clofazimine concentrations after the 4-week loading phase were 0.87 and 0.50 mg/L, respectively. Adverse events were common, but mostly mild and none led to discontinuation of clofazimine. Our loading dose regimen reduced the predicted median time to target concentrations by 1.5 months compared to no loading dose (3.8 versus 5.3 months). Further time benefit was predicted with a 6-week loading dose regimen (1.4 versus 5.3 months). Conclusion A 4-week loading dose regimen of 300 mg once daily reduced the time to target clofazimine concentrations and was safe and well-tolerated. Extending the loading phase to 6 weeks could further decrease the time to target concentrations. Using a loading dose of clofazimine is a feasible strategy to optimize treatment of NTM disease. Clinical Trials Registration NCT05294146 [ABSTRACT FROM AUTHOR]

Background Hyponatremia is common in tuberculous meningitis (TBM), but its impact on disease severity and outcomes is unclear. Methods In a cohort of 864 adult patients with TBM in Indonesia, we assessed the prevalence and prognostic significance of hyponatremia, classified as moderate (120–130 mEq/L) or severe (<120 mEq/L). Patients received standard antituberculous therapy and corticosteroids and were followed for 1-year mortality. Results Hyponatremia occured in 86.8% of patients, with 26% classified as severe. Severe hyponatremia associated with male, younger age, a lower Glasgow Coma Scale (GCS), and markers of more severe disease (P <.05). One-year mortality was 46.5% and associated with older age, HIV infection, lower GCS, markers of neurologic severity, fever, and thrombocytosis. Severe hyponatremia predicted mortality in univariate analysis showed no impact in HIV-positive patients. Conclusions Hyponatremia reflects disease severity in TBM but does not independently predict mortality, suggesting limited benefit from agressive correction. [ABSTRACT FROM AUTHOR]

Objectives Rituximab (RTX) is a safe and effective treatment for RA. However, there are some concerns about infection risk and preliminary data suggest dose and time dependency. This study aims to determine the infection incidence in a large real-life population of RA patients using RTX, with special focus on (ultra-)low dosing and time since last infusion. Methods RA patients treated with 1000, 500 or 200 mg RTX per cycle between 2012 and 2021 at the Sint Maartenskliniek were included in a retrospective cohort study. Patient-, disease-, treatment- and infection characteristics were retrieved from electronic health records. Infection incidence rates, dose and time relations with RTX infusion were analysed using mixed-effects Poisson regression. Results Among 490 patients, we identified 819 infections in 1254 patient years. Most infections were mild and respiratory tract infections were most common. Infection incidence rates were 41, 54 and 71 per 100 patient years for doses of 200, 500 and 1000 mg. Incidence rate ratio (IRR) was significantly lower for 200 mg compared with 1000 mg (adjusted IRR 0.35, 95% CI 0.17, 0.72, P  = 0.004). In patients receiving 1000 or 500 mg RTX, infections seemed to occur more frequently within the first two months after infusion compared with later on in the treatment cycle, suggesting an association with peak concentration. Conclusion Ultra-low dosing (200 mg) of RTX is associated with a lower risk of infections in RA. Future interventions focusing on ultra-low dosing and slow release of RTX (e.g. by subcutaneous administration) may lower infection risk. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) can induce secondary hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory syndrome with high mortality. We integrated all published reports of adult HIV-negative TB-associated HLH (TB-HLH) to define clinical characteristics, diagnostic strategies, and therapeutic approaches associated with improved survival. Methods PubMed, Embase, and Global Index Medicus were searched for eligible records. TB-HLH cases were categorized into (1) patients with a confirmed TB diagnosis receiving antituberculosis treatment while developing HLH and (2) patients presenting with HLH of unknown cause later diagnosed with TB. We used a logistic regression model to define clinical and diagnostic parameters associated with survival. Results We identified 115 individual cases, 45 (39.1%) from countries with low TB incidence (<10/100 000 per year). When compared with patients with HLH and known TB (n = 21), patients with HLH of unknown cause (n = 94) more often had extrapulmonary TB (66.7% vs 88.3%), while the opposite was true for pulmonary disease (91.5% vs 59.6%). Overall, Mycobacterium tuberculosis was identified in the bone marrow in 78.4% of patients for whom examination was reported (n = 74). Only 10.5% (4/38) of patients tested had a positive result upon a tuberculin skin test or interferon-γ release assay. In-hospital mortality was 28.1% (27/96) in those treated for TB and 100% (18/18) in those who did not receive antituberculosis treatment (P <.001). Conclusions Tuberculosis should be considered a cause of unexplained HLH. TB-HLH is likely underreported, and the diagnostic workup of patients with HLH should include bone marrow investigations for evidence of Mycobacerium tuberculosis. Prompt initiation of antituberculosis treatment likely improves survival in TB-HLH. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. Methods Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. Results MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10−8) and IFN-γ (P = 2.3 × 10−6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03–1.49; P =.02), but not pulmonary tuberculosis (OR, 1.11, 95% CI,.98–1.25; P =.10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P =.005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P =.02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P =.06). Conclusions MUC5AC variants may contribute to immune changes that influence TBM outcomes. [ABSTRACT FROM AUTHOR]

Background Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (COVID-19). The tuberculosis BCG vaccine may provide heterologous protection against nontuberculous infections and has been proposed as a potential preventive strategy against COVID-19. Methods In this multicenter, placebo-controlled trial, we randomly assigned older adults (aged ≥60 years; n = 2014) to intracutaneous vaccination with BCG vaccine (n = 1008) or placebo (n = 1006). The primary end point was the cumulative incidence of respiratory tract infections (RTIs) that required medical intervention, during 12 months of follow-up. Secondary end points included the incidence of COVID-19, and the effect of BCG vaccination on the cellular and humoral immune responses. Results The cumulative incidence of RTIs requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio, 1.26 [98.2% confidence interval,.65–2.44]). In the BCG vaccine and placebo groups, 51 and 48 individuals, respectively tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with polymerase chain reaction (subdistribution hazard ratio, 1.053 [95% confidence interval,.71–1.56]). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokine responses after influenza, and also partially associated after SARS-CoV-2 stimulation. In patients diagnosed with COVID-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG vaccine. Conclusions BCG vaccination had no effect on the incidence of RTIs, including SARS-CoV-2 infection, in older adult volunteers. However, it improved cytokine responses stimulated by influenza and SARS-CoV-2 and induced stronger antibody titers after COVID-19 infection. Clinical trials registration EU Clinical Trials Register 2020-001591-15 ClinicalTrials.gov NCT04417335. [ABSTRACT FROM AUTHOR]

Background In previous studies, researchers have identified systemic lupus erythematosus (SLE) as a risk factor for tuberculosis (TB), but data from TB-endemic countries are still relatively scarce. We examined TB in a large cohort of SLE patients in Indonesia. Methods All patients registered in a lupus registry of the top referral hospital for West Java between 2008 and 2020 were included. Data on SLE characteristics and treatment were retrieved from the registry, and data on TB diagnosis, localization, and outcome were extracted from medical records. Cox-proportional hazard model was used to examine risk factors for development of TB. Results Among 1278 SLE patients observed over a total of 4804 patient-years, 131 patients experienced 138 episodes of TB, a median of 2 years (interquartile range, 0.6–5.4) after diagnosis of SLE. A total of 113 patients (81.9%) had pulmonary involvement and 61 (44.2%) had extrapulmonary involvement, with disseminated disease in 26 of 138 episodes (18.8%), and 13 of 131 patients (9.9%) died from TB. The estimated TB incidence was 2873 cases per 100 000 person years. In multivariate cox regression analysis, development of TB was associated with household TB contact (hazard ratio [HR], 7.20; 95% confidence interval [CI], 4.05–12.80), pulse methylprednisolone therapy (HR, 1.64; 95% CI, 1.01–2.67), and age ≤25 years old at SLE diagnosis (HR, 1.54; 95% CI, 1.00–2.35). Conclusions There is a high burden of TB in SLE patients in this TB-endemic setting, underlining the need for evaluation or implementation of TB preventive strategies. [ABSTRACT FROM AUTHOR]

Background Mycobacterium marinum is a nontuberculous mycobacterium that causes skin and soft tissue infections. Treatment consists of multiple antibiotics, sometimes combined with surgical debridement. There is little evidence for the choice of antibiotics, the duration of treatment, and the role of susceptibility testing. Methods We performed a retrospective cohort study of culture-confirmed M. marinum infections in the Netherlands in the 2011–2018 period. Clinical characteristics, in vitro susceptibility, extent of disease, treatment regimens, and outcomes were analyzed. Incidence was assessed from laboratory databases. Results Forty cases of M. marinum infection could be studied. Antibiotic treatment cured 36/40 patients (90%) after a mean treatment duration of 25 weeks. Failure/relapse occurred in 3 patients, and 1 patient was lost to follow-up. Antibiotic treatment consisted of monotherapy in 35% and 2-drug therapy in 63%. Final treatment contained mostly ethambutol–macrolide combinations (35%). Eleven patients (28%) received additional surgery. We recorded high rates of in vitro resistance to tetracyclines (36% of isolates). Tetracycline resistance seemed correlated with poor response to tetracycline monotherapy. The annual incidence rate was 0.15/100 000/year during the study period. Conclusions Prolonged and susceptibility-guided treatment results in a 90% cure rate in M. marinum disease. Two-drug regimens of ethambutol and a macrolide are effective for moderately severe infections. Tetracycline monotherapy in limited disease should be used vigilantly, preferably with proven in vitro susceptibility. [ABSTRACT FROM AUTHOR]

Background Medical and nursing students entering their clinical programmes are at increased risk for tuberculosis (TB) in TB-endemic settings. Relatively little is known about Mycobacterium tuberculosis infection among such students in high-endemic countries. Methods We examined M. tuberculosis infection among medical and nursing students starting clinical training in Bandung, Indonesia using interferon-γ release assay (IGRA) QuantiFERON-TB Gold Plus. IGRA-negative students had a repeat test after 1 y and logistic regression was used to identify factors associated with IGRA positivity or conversion. Results There were 379 students included in this study: 248 (65.4%) were medical students and 131 (34.6%) were nursing students. Of 379 students, 70 (18.5%) were IGRA positive at baseline. Of 293 IGRA-negative students with 1-y results, 26 (8.9%) underwent IGRA conversion. Being a medical student (adjusted relative risk [ARR] 5.15 [95% confidence interval {CI} 1.82 to 14.59], p=0.002) and participation in sputum collection or bronchoscopy were associated with IGRA conversion (ARR 2.74 [95% CI 1.29 to 5.79], p=0.008). Conclusions Medical and nursing students entering clinical training are at high risk of M. tuberculosis infection and need improved infection prevention and control strategies. [ABSTRACT FROM AUTHOR]

Background For malaria elimination efforts, it is important to better understand parasite transmission to mosquitoes and develop models for early-clinical evaluation of transmission-blocking interventions. Methods In a randomized open-label trial, 24 participants were infected by bites from Plasmodium falciparum 3D7-infected mosquitoes (mosquito bite [MB]; n = 12) or by induced blood-stage malaria (IBSM) with the same parasite line (n = 12). After subcurative piperaquine treatment, asexual parasite and gametocytes kinetics were assessed, and mosquito feeding experiments were performed. Results Study procedures were well tolerated. The median peak gametocyte density was 1304/mL (interquartile range, 308–1607/mL) after IBSM, compared with 14/mL (10–64/mL) after MB inoculation (P  < .001), despite similar peak asexual parasite densities (P  = .48). Peak gametocyte density was correlated with preceding pfap2-g transcripts, indicative of gametocyte commitment (ρ = 0.62; P  = .002). Direct feeding assays resulted in mosquito infections from 9 of 12 participants after IBSM versus 0 of 12 after MB inoculation (P  < .001). Conclusions We observed a striking effect of inoculation method on gametocyte production, suggesting higher gametocyte commitment after IBSM. Our direct comparison of MB and IBSM establishes the controlled human malaria infection transmission model, using intravenous administration of P. falciparum –infected erythrocytes as a model for early-clinical evaluation of interventions that aim to interrupt malaria transmission. Clinical Trial Registration NCT03454048 [ABSTRACT FROM AUTHOR]

In this retrospective cohort study, selected patients with disseminated Staphylococcus aureus bacteremia, but without endovascular infection on echocardiography and 18F-FDG-PET/CT, were free of relapse after IV-oral switch. Mortality was low and similar to patients who received prolonged intravenous treatment. IV-oral switch was associated with a shorter length of hospital stay. [ABSTRACT FROM AUTHOR]

Background Diabetes mellitus (DM) patients are three times more likely to develop tuberculosis (TB) than the general population. Active TB screening in people with DM is part of a bidirectional approach. The aim of this study was to conduct pragmatic active TB screening among DM patients in four countries to inform policy. Methods DM patients were recruited in Indonesia (n=809), Peru (n=600), Romania (n=603) and South Africa (n=51). TB cases were diagnosed using an algorithm including clinical symptoms and chest X-ray. Presumptive TB patients were examined with sputum smear and culture. Results A total of 171 (8.3%) individuals reported ever having had TB (South Africa, 26%; Indonesia, 12%; Peru, 7%; Romania, 4%), 15 of whom were already on TB treatment. Overall, 14 (0.73% [95% confidence interval 0.40 to 1.23]) TB cases were identified from screening. Poor glucose control, smoking, lower body mass index, education and socio-economic status were associated with newly diagnosed/current TB. Thirteen of the 14 TB cases diagnosed from this screening would have been found using a symptom-based approach. Conclusions These data support the World Health Organization recommendation for routine symptom-based screening for TB in known DM patients in high TB-burden countries. DM patients with any symptoms consistent with TB should be investigated and diagnostic tools should be easily accessible. [ABSTRACT FROM AUTHOR]

Background People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further. [ABSTRACT FROM AUTHOR]

Background Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents. Methods Within the multicenter Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) study, pregnant women living with HIV and using dolutegravir once daily (50 mg, with food) underwent 24-hour pharmacokinetic profiling in their third trimester and postpartum. Dolutegravir exposure in the third trimester was considered adequate if geometric mean unbound, pharmacologically active, minimal plasma concentrations (Cmin, unbound) and ≥90% of individual Cmin, unbound levels were >0.85 µg/L, the proposed 90% inhibitory concentration for unbound dolutegravir. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) for comparison of total and unbound pharmacokinetic parameters in the third trimester and postpartum were calculated, including the metabolic ratio for dolutegravir-glucuronide. Safety and virological data were collected. Results Seventeen women (76% black) were enrolled (25 evaluable pharmacokinetic profiles; 15 in the third trimester, 10 in postpartum). In the third trimester, geometric mean (coefficient of variation, %) Cmin, unbound was 2.87 (87) µg/L and 93% of individual Cmin, unbound levels were >0.85 µg/L. The GMR (90% CI) in the third trimester vs postpartum was 0.86 (.68–1.10) for area under the curve (AUC0-24h), and for Cmax, 0.93 (.77–1.13). GMR (90% CI) for the trough concentrations was 0.71 (.49–1.02), based on total dolutegravir concentrations. Four serious adverse events were reported, unlikely related to dolutegravir. The HIV polymerase chain reaction test was negative in 14/17 infants (result unknown for 3 infants). Conclusions Pharmacokinetic changes for dolutegravir in late pregnancy are not clinically relevant and support the use of dolutegravir 50 mg once daily with food in pregnancy. Clinical Trials Registration NCT00825929. [ABSTRACT FROM AUTHOR]

Background Tuberculous meningitis (TBM) is a medical emergency, yet there are no standardized treatment guidelines for the medical or neurosurgical management of these patients and little data on neurocritical care. We conducted an international survey to understand current medical and neurosurgical TBM management and resource availability to provide baseline data needed for future multicenter trials addressing unanswered clinical research questions and the establishment of standardized guidelines. Methods An online survey of 77 questions covering medical and neurosurgical TBM management aimed at clinicians/nurses treating TBM was distributed as an anonymous link through email invitation, international organizations' membership distribution, and direct links on organizational webpages or social media. The survey remained open for 5 months. Data were summarized with frequencies and percentages. Results The survey had 222 responses from 43 countries representing 6 continents. Most respondents were from tertiary care facilities, with broad access to medical and neurosurgical resources. There was significant heterogeneity in general supportive care, and TBM-specific management demonstrated considerable divergence from current standard-of-care practices. The lack of standardized guidelines was identified as a major challenge in TBM management. General and neurocritical care were largely absent. Resources for bedside supportive care and noninvasive monitoring were broadly accessible. Conclusions These findings suggest that current TBM management could be improved by the establishment of internationally accepted treatment guidelines based on available evidence, and that numerous centers have resources available to participate in future multicenter trials, even for basic interventions, that may further improve patient outcomes globally. [ABSTRACT FROM AUTHOR]

Background Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis. Methods An individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750–1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models. Results Pharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%–6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3–2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival. Conclusions Higher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials. [ABSTRACT FROM AUTHOR]

Background: A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed "early clearance."Methods: Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive.Results: Among 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae.Conclusions: Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity. [ABSTRACT FROM AUTHOR]

Background: Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance.Methods: Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point.Results: Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83-.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40-.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04).Conclusions: A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development. [ABSTRACT FROM AUTHOR]

Background Data regarding the incidence of tuberculosis (TB) among people living with diabetes (PLWD) in TB-endemic settings are scarce. We examined TB incidence among PLWD in Indonesia who had previously been screened for latent TB infection (LTBI) and TB disease. Methods PLWD (≥18 y of age) in an urban setting were examined a mean 3.4 y after they had been screened for active TB and LTBI. Data on subsequent TB diagnosis were collected by interview and with chest X-ray, sputum smear and Mycobacterium tuberculosis culture. TB incidence rates were stratified for baseline LTBI status, as determined by the QuantiFERON interferon-gamma release assay (IGRA). Results Of 590 PLWD, 101 had died and 163 could not be contacted or refused. Among the 326 who were re-examined, 6 (1.8%; 95% confidence interval [CI] 0.7 to 4.0) reported being diagnosed already and a further 5 were diagnosed with active TB (1.5%; 95% CI 0.50 to 3.5). The TB incidence rate was 9.85 (95% CI 4.03 to 15.68) per 1000 person-years. TB incidence was higher among PLWD with baseline LTBI (17.13; 95% CI 5.25 to 29.00/1000 person-years) compared with those without LTBI (4.79; 95% CI −0.63 to 10.21), with an incidence rate ratio of 3.57 (95% CI 0.86 to 20.92; p=0.054). Conclusions PLWD with LTBI in Indonesia and similar settings are likely to benefit from TB preventive therapy. [ABSTRACT FROM AUTHOR]

Background Certain vaccines, such as Bacille Calmette-Guérin (BCG), have nonspecific effects, which modulate innate immune responses and lead to protection against mortality from unrelated infections (trained immunity). In contrast, in spite of the disease-specific effects, an enhanced overall mortality has been described after diphtheria-tetanus-pertussis (DTP) vaccination in females. This randomized trial aimed to investigate the nonspecific immunological effects of BCG and DTP-containing vaccines on the immune response to unrelated pathogens. Methods We randomized 75 healthy, female, adult volunteers to receive either BCG, followed by a booster dose of tetanus-diphtheria-pertussis inactivated polio vaccine (Tdap) 3 months later; BCG and Tdap combined; or Tdap followed by BCG 3 months later. Blood was collected before vaccination, as well as at 1 day, 4 days, 2 weeks, and 3 months after the first vaccination(s), plus 2 weeks after the second vaccination. Ex vivo leukocyte responses to unrelated stimuli and pathogens were assessed. Results Tdap vaccination led to short-term potentiation and long-term repression of monocyte-derived cytokine responses, and short-term as well as long-term repression of T-cell reactivity to unrelated pathogens. BCG led to short-term and long-term potentiation of monocyte-derived cytokine responses. When given together with Tdap or after Tdap, BCG abrogated the immunosuppressive effects of Tdap vaccination. Conclusions Tdap induces immunotolerance to unrelated antigens, which is partially restored by concurrent or subsequent BCG vaccination. These data indicate that the modulation of heterologous immune responses is induced by vaccination with Tdap and BCG, and more studies are warranted to investigate whether this is involved in the nonspecific effects of vaccines on mortality. Clinical Trials Registration NCT02771782. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population.Objectives: To compare exposure to TB drugs in Tanzanian TB patients with and without DM.Patients and Methods: A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs.Results: A trend was shown for 25% lower total exposure (AUC0-24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC0-24 and peak concentration (Cmax) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC0-24 and Cmax values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid.Conclusions: There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM. [ABSTRACT FROM AUTHOR]

Background: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis.Methods: We investigated in vitro and in vivo effects of metformin in humans.Results: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1β but increased phagocytosis activity and reactive oxygen species production.Conclusion: Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Rewiring cellular metabolism is important for activation of immune cells during host defense against Mycobacterium tuberculosis. Glutamine has been implicated as an immunomodulatory nutrient, but its role in the response to M. tuberculosis is unknown.Methods: We assessed expression of glutamine pathway genes in M. tuberculosis-infected macrophages and blood transcriptomic profiles of individuals with latent M. tuberculosis infection or tuberculosis. Subsequently, we studied the effect of blocking glutaminolysis on M. tuberculosis-induced cytokines. Finally, we examined whether polymorphisms in genes involved in the glutamine pathway influence M. tuberculosis-induced cytokines in a cohort of 500 individuals.Results: Glutamine pathway genes were differentially expressed in infected macrophages and patients with tuberculosis. Human peripheral blood mononuclear cells stimulated with M. tuberculosis displayed decreased cytokine (ie, interleukin 1β, interferon γ, and interleukin 17) responses when medium was devoid of glutamine. Specific inhibitors of the glutamine pathway led to decreased cytokine responses, especially T-cell cytokines (ie, interferon γ, interleukin 17, and interleukin 22). Finally, genetic polymorphisms in glutamine metabolism genes (including GLS2, SLC1A5, and SLC7A5) influenced ex vivo cytokine responses to M. tuberculosis, especially for T-cell cytokines.Conclusions: Cellular glutamine metabolism is implicated in effective host responses against M. tuberculosis. Targeting immunometabolism may represent new strategies for tuberculosis prevention and/or treatment. [ABSTRACT FROM AUTHOR]

Background: Bacteriological confirmation of tuberculous (TB) meningitis is difficult. Culture is slow and microscopy has insufficient sensitivity. We evaluated real time PCR targeting insertion sequence IS6110 among 230 consecutive adult patients with subacute meningitis in a referral hospital in Indonesia. Methods: Cerebrospinal fluid (CSF) samples were examined using microscopy, solid and liquid culture, and real time IS6110- PCR with a fluorescence-labeled probe using DNA extracted from CSF. CSF samples from 40 non-infectious neurology patients were used as negative controls. IS6110-PCR results were linked with clinical and CSF characteristics. Results: Most patients presented with subacute meningitis, after a median of 14 days of symptoms (range 7-30). After exclusion of cryptococcal and bacterial meningitis, 207 patients were classified as definite or probable TB meningitis; 17.9% with HIV infection. Among this group IS6110-PCR gave the highest positivity rate (68%, 95% CI 62-74%) compared with microscopy of ZN-stained slides (11%, 95% CI 7-15%), and mycobacterial culture using solid (36%, 95% CI 29-42%) and liquid (44%, 95% CI 37-51%) media. IS6110-PCR was positive in 92% of patients with culture-positive and 42% of patients with culture-negative probable TB meningitis. Among culture-negative patients, a positive PCR was associated with a history of TB treatment, a longer duration of illness, a higher CSF cell count and protein, and a lower CSF glucose. IS6110- PCR was negative in all CSF samples from non-meningitis control patients. Conclusions: Real time IS6110-PCR is a quick, sensitive, and specific test for diagnosing of TB meningitis in this setting. Its performance in other (less-developed) settings needs further study. [ABSTRACT FROM AUTHOR]

The Beijing strain is one of the most successful genotypes of Mycobacterium tuberculosis worldwide and appears to be highly homogenous according to existing genotyping methods. To type Beijing strains reliably we developed a robust typing scheme using single nucleotide polymorphisms (SNPs) and regions of difference (RDs) derived from whole-genome sequencing data of eight Beijing strains. SNP/RD typing of 259 M. tuberculosis isolates originating from 45 countries worldwide discriminated 27 clonal complexes within the Beijing genotype family. A total of 16 Beijing clonal complexes contained more than one isolate of known origin, of which two clonal complexes were strongly associated with South African origin. The remaining 14 clonal complexes encompassed isolates from different countries. Even highly resolved clonal complexes comprised isolates from distinct geographical sites. Our results suggest that Beijing strains spread globally on multiple occasions and that the tuberculosis epidemic caused by the Beijing genotype is at least partially driven by modern migration patterns. The SNPs and RDs presented in this study will facilitate future molecular epidemiological and phylogenetic studies on Beijing strains. [ABSTRACT FROM AUTHOR]

Corrigendum to: A Randomized Clinical Trial to Compare Plasmodium falciparum Gametocytemia and Infectivity After Blood-Stage or Mosquito Bite-Induced Controlled Malaria Infection. [Extracted from the article]

The article offers information on development of Vietnam model which aims at predicting mortality of tuberculous meningitis (TBM). It mentions that CSF neutrophil counts, low cerebrospinal fluid (CSF) to blood glucose ratio, CSF culture positivity, blood neutrophilia, and fever to be associated with higher mortality.