Journal of Infectious Diseases最新文献

Background: Our understanding of Mycobacterium tuberculosis (Mtb) natural history and infection dynamics is evolving, including recognition that many individuals previously infected with Mtb may clear their infections or experience substantially reduced progression risks with time since infection. Such dynamics suggest that recent transmission is more important in driving TB incidence in high-burden settings than previously estimated; thus, the impact of interventions to reduce transmission (e.g., community-based active case-finding) may also be greater than previously thought.

Methods: We constructed two models of Mtb transmission that differed only in that one model included a clearance mechanism while the other did not. We then calibrated these models independently to the same set of epidemiological data representative of a high-TB-burden setting (India) and compared metrics of infection dynamics absent intervention. Finally, we used the calibrated models to project the impact of illustrative biennial active case-finding campaigns (achieving 75% population coverage with 65% screening sensitivity).

Results: The estimated annual risk of Mtb infection and prevalence of recent infection were both substantially higher in the model that allowed for Mtb clearance, despite being fit to the same data. The model with clearance projected a greater impact of case-finding on the incidence of TB disease: 45% [95% uncertainty interval 28-57%] reduction compared to no intervention after 10 years, versus 11% [6-18%] in the model without a clearance mechanism.

Conclusions: Models that allow for Mtb clearance are supported by biological and epidemiological evidence and project greater impact from active case-finding than models that do not include these dynamics.

Background: High-dose rifampicin could potentially shorten tuberculosis preventive therapy (TPT) and improve outcomes. We aimed to characterize population pharmacokinetics of standard- and high-dose rifampicin for TPT among individuals with tuberculosis infection.

Methods: Intensive and sparse pharmacokinetic sub-studies were conducted in Indonesia, Canada, and Vietnam within the 2R2 randomized trial, which compared two months of high-dose rifampicin at 20 mg/kg/day (2R20) or 30 mg/kg/day (2R30) with four months of standard-dose rifampicin at 10 mg/kg/day (4R10) in adults and adolescents aged ≥10 years. Venous blood samples were collected after four weeks of treatment. Rifampicin pharmacokinetics were analyzed using nonlinear mixed-effects modeling.

Results: Among 1368 trial participants, 440 were included in model development (51 intensive, 389 sparse sampling), with 191 (43%) assigned to 4R10, 159 (36%) to 2R20, and 90 (20%) to 2R30. A one-compartment model with saturable hepatic extraction and transit-compartment absorption best described rifampicin pharmacokinetics. Disposition parameters were allometrically scaled using fat-free mass. Country-specific differences, particularly variation in drug formulation, were associated with lower bioavailability in Canada (-21.8% [95%CI -27.9 to -18.0%]) and Vietnam (-12.3% [95%CI -17.7 to -7.9%]) compared with Indonesia. The 24-hour area under the concentration-time curve increased more than proportionally with dose and was higher across treatment arms in Indonesia, followed by Vietnam and Canada.

Conclusion: High-dose rifampicin for TPT resulted in greater-than-proportional increases in exposure due to non-linear clearance at higher doses. Substantial between-country variability in exposure was observed, which may have been due to multiple factors, including differences in country-specific formulations, fat-free mass, and unmeasured confounders.

Background: Given concerns about the potential that influenza vaccine effectiveness (VE) might differ in recipients of repeated annual influenza vaccination, we aimed to estimate VE against influenza-associated hospitalization​ while investigating potential repeat vaccination effects.

Methods: We analyzed data from a test-negative design study conducted in three Hong Kong hospitals from ​​October 2015 through July 2025​​. Due to the absence of influenza circulation during the COVID-19 pandemic, the 2020/21 and 2021/22 seasons were excluded, leaving eight influenza seasons for subsequent analysis. PCR testing was used to identify influenza virus infections. We used conditional logistic regression to estimate influenza VE overall, by influenza type/subtype, and by influenza vaccination status in the preceding year (repeat vaccination status).

Results: We analyzed data on 34,237 children, among whom 5,245 (15.3%) tested positive for influenza. VE against influenza-associated hospitalization was 57.2% (95% confidence interval [CI]: 52.3%, 61.6%), with subtype-specific VE estimates of 67.7% (95% CI: 61.8%, 72.7%) for A(H1N1)pdm09, 60.6% (95% CI: 50.8%, 68.5%) for influenza B, and 37.2% (95% CI: 24.7%, 47.6%) for A(H3N2). The overall ΔVE (repeated VE - current only VE) was -13.6% (95% CI: -33.2%, 3.2%), indicating lower VE among repeatedly vaccinated children.

Conclusions: Current influenza vaccination programs provide substantial protection, but could be further improved by strategies that could mitigate repeat vaccination effects, and further research is needed to identify such strategies.

Background: Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants and those with RSV disease appear more likely to develop recurrent wheeze. We examined nasal airway gene expression and microbiome composition during acute primary RSV infection to test associations with illness severity and identify infants with recurrent wheeze.

Methods: Previously healthy infants with confirmed RSV infection were enrolled (Dec 2019 to Dec 2023). Clinical, demographic data, 2 anterior nasal swabs and a nasal wash were collected for metagenome and transcriptome sequencing. Disease severity was measured by the improved Global Respiratory Severity Score (iGRSS). Participants were followed for approximately 1 year after enrollment to identify recurrent wheeze. Multivariate regression models were developed to identify correlates and predictors of disease severity and recurrent wheeze, respectively.

Results: 100 (90 hospitalized) infants were enrolled (mean age 3.2±2.3 months; 61% male). 405 genes (false discovery rate 0.10) were significantly and consistently associated with illness severity (iGRSS), implicating Innate Immune and Interleukin Signaling pathways. An abundance of Dolosigranulum in the nares was inversely associated with iGRSS while the abundance of Haemophilus was directly associated with iGRSS. Predictive models using nasal gene expression during acute infection had the power to classify recurrent wheeze (in-sample AUC=0.992; cross-validated AUC=0.882) while metagenomic features did not improve predictive performance.

Conclusions: We prospectively followed infants with primary RSV infection and identified associations between nasal gene expression, microbiome composition/function and acute disease severity and recurrent wheeze. Host transcriptional profiles during infection were predictive of recurrent wheeze within the following year.

Background: Tuberculosis (TB) caused by the Mycobacterium tuberculosis complex (MTBC) is the leading cause of death from a single infectious agent worldwide. Current antibiotics fail against drug-resistant strains, highlighting the urgent need for novel therapies. Host-directed therapy (HDT), which enhances host immunity rather than targeting pathogens directly, offers a promising solution.

Methods: In this study, we use the in vitro cells infection assays and in vivo mouse infection model to identify the effects of a monovalent second mitochondria-derived activator of caspases (SMAC) mimetic named BI82 against mycobacterial infections.

Results: Here, we demonstrate that BI82 potently inhibits M. bovis growth in Raw264.7 macrophages, bone marrow-derived macrophages, and peripheral blood mononuclear cells, while exhibiting synergy with rifampicin. BI82 also significantly restricts M. tuberculosis growth in ex vivo whole-blood assays from both tuberculosis patients and healthy donors. Mechanistically, BI82 degrades cellular inhibitor of apoptosis protein 1 (cIAP1), promoting infected cell apoptosis as evidenced by elevated cleaved caspase-3 and phosphorylated MLKL levels. Caspase inhibition abrogates BI82's anti-mycobacterial effects, confirming apoptosis as the primary therapeutic pathway. In a mouse model, oral BI82 treatment degraded cIAP1, reduced M. bovis burden in lungs and spleens, alleviated lung lesions, and increased CD3⁺ T cells with elevated CD4/CD8 ratios. Notably, different SMAC mimetics showed pathogen-specific efficacy profiles, with monovalent compounds (BI82, LCL161) demonstrating superior activity compared to bivalent Birinapant against M. bovis.

Conclusions: This study highlights BI82's unique apoptosis-dependent mechanism and broad-spectrum potential against mycobacterial infections, including drug-resistant TB, positioning it as a promising HDT candidate.

Background: Diagnostics are essential for understanding hepatitis E epidemiology, but the field performance of available tests remains unclear. We evaluated the performance of polymerase chain reactions (PCR), IgM ELISA, and the Assure hepatitis E virus (HEV) IgM rapid diagnostic test (RDT) during a HEV genotype 1 outbreak and assessed the duration of viremia and antibodies responses.

Methods: We used data from enhanced surveillance at a health facility in Bentiu internally displaced persons camp, South Sudan (March-December 2022). As part of a vaccine effectiveness study, suspected hepatitis E cases underwent testing with all 3 diagnostics at enrollment with a follow-up sample. We used a latent class model to estimate test performance and accelerated failure time models to estimate time from jaundice onset to a negative test for PCR and ELISA.

Results and conclusions: Among 893 suspected cases, test sensitivity declined with time from jaundice onset. Within 30 days of jaundice onset, PCR sensitivity was 73% (95% Credible Interval [CrI] 27, 90), compared to 86% for RDT (95% CrI: 74, 93), and 95% for ELISA (95% CrI: 91, 98). Specificity was high across tests: PCR at 98% (95% CrI: 98, 99), RDT at 95% (95% CrI: 93, 96), and ELISA at 95% (95% CrI: 93, 96). Median time from jaundice onset to negative test was 19 days (95% CI: 17, 21) for PCR and 113 days (95% CI: 87, 163) for ELISA. The Assure IgM RDT showed higher sensitivity for identifying hepatitis E than PCR and similar specificity to IgM ELISA, supporting its use in surveillance. Care seeking delays can greatly influence the interpretation of diagnostic tests.

Soluble urokinase-type plasminogen activator receptor (suPAR) is an emerging critical illness biomarker. Circulating suPAR levels are elevated in severe malaria and are associated with mortality risk. The present study evaluated clinical predictors of elevated plasma suPAR (≥15 ng/mL). Elevated suPAR occurred in 22.1% of 1226 Ugandan children with severe malaria and was independently associated with severe acute kidney injury, hyperlactatemia, and coma, as well as biomarkers of immune and endothelial activation. An optimized clinical decision algorithm that prioritizes suPAR testing for children with clinical danger signs, including coma and kidney injury, could improve the identification of children at highest risk of death.

As investigations of low-biomass microbial communities have become more common, so too has the recognition of major challenges affecting these analyses. These challenges have been shown to compromise biological conclusions and have contributed to several controversies. Here, we review some of the most common and influential challenges in low-biomass microbiome research. We highlight key approaches to alleviate these potential pitfalls, combining experimental planning strategies and data analysis methods.

Background: Plasmodium falciparum circumsporozoite protein (CSP) is the target of multiple malaria vaccines that include only a part of the protein, such as RTS,S and R21. The monoclonal antibodies L9 and CIS43 are directed against key CSP junctional region epitopes not included in RTS,S and R21, and next-generation vaccine candidates attempt to elicit similar antibodies. Understanding the effectiveness of multiple antibody responses against CSP peptides will inform next-generation vaccines.

Methods: Using serum samples collected during controlled human malaria infection experiments that evaluated vaccine efficacy, we used a peptide array inclusive of CSP genetic variants to quantify anti-CSP antibody responses in unprotected adults who received a full-length recombinant CSP vaccine (rCSP), protected adults who received RTS,S, and unprotected adults who received RTS,S. We compared the breadth and intensity of responses to CSP variants between groups.

Results: Overall, rCSP recipients had lower CSP antibody responses compared with the protected RTS,S group. Compared with the unprotected groups, protected RTS,S vaccinees had higher breadth of responses to peptides in the junctional region, central repeat region, and C-terminal region. The protected RTS,S group also had higher intensity of responses to 2 C-terminal peptides, including part of Th3R. In addition, protected RTS,S recipients had higher breadth of immunoglobulin A responses to variants of the C-terminal epitope PNDPNRNV, identified as a dominant motif by motif recognition software, and to similar sequences in the junctional region.

Conclusions: Protection-associated antibody responses to the junctional region not contained in RTS,S suggest a cross-reactive, vaccine-induced response that provides additional benefit beyond antibodies targeting vaccine peptides.

Background: The frequent temporal recurrence of Clostridioides difficile infection (CDI) may be the result of relapse with the same strain or reinfection with a different strain. We used whole-genome sequencing (WGS) to assess the genetic diversity and molecular evolution of strains that caused recurrent or sequential CDI.

Methods: We analyzed data from active population- and laboratory-based surveillance of CDI in Minnesota, USA. We performed WGS on isolates collected from 306 patients with multiple CDI events during 2019-2021. We identified multi-locus sequence types (MLSTs), nucleotide variants, and putative mobile genetic elements (MGEs) from WGS data to study the genetic similarity and evolution of those C. difficile genomes.

Results: Among patients with multiple CDI events in the surveillance period, 198 (64.7%) had multiple infections of the same MLST, including 49.6% of patients with subsequent infections beyond the 8-week limit of the case definition for recurrent CDI Among 232 temporally defined events of recurrent CDI, 155 (66.8%) involved isolates of the same MLST. There were no statistically significant correlations between accumulated mutations and elapsed time between same-MLST CDI events. Analysis of sequential same-MLST C. difficile genomes showed evidence of gain or loss of putative mobile genetic elements (MGEs) in 45.6% of genome pairs.

Conclusions: Leveraging the largest CDI genomic dataset to date, our results confirm prior findings that recurrent CDI is a combination of reinfection and/or change in the ascendant strain in mixed infection, and relapse, while expanding knowledge on the evolution of pathogenic C. difficile strains in the human gastrointestinal tract.