Coinfection

BackgroundTuberculous meningitis is often lethal, and many survivors have disabilities despite antimicrobial treatment and adjunctive glucocorticoid therapy. Standard-dose rifampin has limited central nervous system penetration. Whether high-dose rifampin could improve survival outcomes is unknown.MethodsWe performed a double-blind, randomized, placebo-controlled clinical trial involving adults with tuberculous meningitis in Indonesia, South Africa, and Uganda. We assigned persons with and those without human immunodeficiency virus (HIV) coinfection to receive standard daily isoniazid, rifampin (at a dose of 10 mg per kilogram of body weight), ethambutol, and pyrazinamide plus either additional rifampin (for a cumulative dose of 35 mg per kilogram; high-dose group) or matched placebo (standard-dose group) for 8 weeks; participants in both groups received standard therapy for the remainder of the 9-to-12-month treatment course. The primary outcome was 6-month mortality.ResultsA total of 499 participants were included in the intention-to-treat population (249 randomly assigned to the high-dose group and 250 to the standard-dose group), of whom 304 (60.9%) were persons living with HIV and 428 (85.8%) had definite or probable tuberculous meningitis. During 6 months of follow-up, 109 participants (Kaplan-Meier estimate, 44.6%) in the high-dose group and 100 participants (Kaplan-Meier estimate, 40.7%) in the standard-dose group died (hazard ratio, 1.17; 95% confidence interval, 0.89 to 1.54; P = 0.25). Among the participants who died within 6 months, the median time to death was 13 days (interquartile range, 4 to 39) in the high-dose group and 24 days (interquartile range, 6 to 56) in the standard-dose group. Drug-induced liver injury occurred in 8.0% of the participants in the high-dose group and in 4.4% of those in the standard-dose group, but no deaths from drug-induced liver injury occurred.ConclusionsAmong persons with tuberculous meningitis, no evidence of beneficial effect from high-dose rifampin was observed, and the potential for a harmful effect cannot be ruled out. (Funded by the U.K. Medical Research Council and others; ISRCTN Registry number, ISRCTN15668391.).

Acute respiratory infections (ARIs) in children present complex interactions between respiratory pathogens and host, contributing to high morbidity, hospitalization, and mortality. In this cross-sectional study, 2,044 pediatric in-patient samples were tested for 198 pathogens using targeted next-generation sequencing (tNGS). Pathogen spectrum and co-infection pattern were analyzed alongside blood-test results and clinical data. Pediatric ARIs presented staggered viral epidemics and age-specific infection patterns from 2022 to 2023. Viral infections were predominant in children under 3 years (67.5%). Specific viral-bacterial co-infections were associated with disease severity, including human metapneumovirus (HMPV)-Streptococcus pneumoniae (OR = 3.172, 95% CI: 1.257-8.009), human parainfluenza virus (HPIV)-Fusobacterium nucleatum (3.016, 1.051-8.653), and HPIV-S. pneumoniae (2.825, 1.007-7.927). Subnormal levels of prealbumin and creatinine served as biomarkers for homeostasis disruption in viral-bacterial co-infections. From June to December 2023, Mycoplasma pneumoniae (MP) became the dominant pathogen in preschool (31.3%) and school-age (45.3%) children. High MP loads were correlated with elevated eosinophil, IL-4, and IL-6 and decreased IgG and IL-2, linking to airway hyperreactivity and inflammation. At low MP loads, patients co-detected with human herpesvirus (HHV) (50.0%), or Haemophilus influenzae (40.0%) had a high proportion of severe cases. This study delineated the complex pathogen landscape of pediatric ARIs and highlighted the major role of viral-bacterial and MP-bacterial co-infections. Monitoring these pathogens through tNGS can aid in precise diagnosis and targeted treatment to improve clinical outcomes in children.IMPORTANCEMoving beyond the outdated "one germ, one disease" model, this study characterizes the etiological and epidemiological landscape and highlights co-infection patterns of virus-bacterium or MP-bacterium in 2044 pediatric respiratory in-patient children across three epidemic phases. Specific pathogen combinations are associated with clinical severity, as well as host immune and metabolic profiles. Our findings underscore the necessity of detecting pathogen-pathogen and host-pathogen dynamics, rather than individual pathogens, thereby informing precision diagnostics and targeted intervention strategies.

Trichomonas vaginalis (TV) infection is a common non-viral sexually transmitted infection, often combined with mixed vaginal infections. These mixed infections worsen inflammation, disrupt vaginal microbiota, and affect treatment. Currently, TV and its mixed infections are mainly diagnosed by wet mount microscopy, which has low sensitivity and cannot identify complex microbes well. This study compared microscopy with metagenomic sequencing to explore vaginal microbiota changes and improve diagnosis of TV-related mixed infections. We enrolled 30 participants: 20 TV-infected patients (diagnosed by wet mount microscopy) and 10 healthy controls (with Lactobacillus as dominant vaginal microbiota). Then tested by Gram staining, microscopy, and metagenomic sequencing. We analyzed microbial composition and identified different abundant taxa. We also measured clinical indices (Lactobacillus grade, vaginal pH, Nugent score for BV, Donders score for AV) to assess vaginal microecology. Among 20 TV patients, microscopy and clinical criteria found a 65% mixed infection rate (13/20), including TV+AV (5 cases), TV+BV+AV (7 cases), and TV+VVC (1 case). Metagenomic sequencing showed TV patients had higher alpha diversity (Shannon index: p=0.0276) and different beta diversity (ANOSIM, r=0.21, p=0.000167) than controls. At the genus level, TV patients had more anaerobic taxa (Fannyhessea, Atopobium, Peptostreptococcus, FDR<0.05) and less Lactobacillus (FDR<0.05) than controls. All TV patients were CST IV (low Lactobacillus, high mixed bacteria), including 12 cases of CST IV-C and 7 cases of CST IV-B. Microscopy and sequencing had low diagnostic consistency in diagnosing mixed infections, especially for mixed vaginitis. TV infection causes significant vaginal microecological imbalance (less Lactobacillus, more anaerobes, high mixed infection rate). Metagenomic sequencing is better than microscopy at identifying complex microbes and low-abundance pathogens, making it more accurate for diagnosing TV-related mixed infections. These results suggest molecular diagnostic methods should be used as complementary tools for precise analysis improve TV and its mixed infection diagnosis and treatment.