A comparison of host response strategies to distinguish bacterial and viral infection

Ross, Melissa H; Henao, Ricardo; Burke, Thomas W.; Ko, Emily R; McClain, Micah T.; Ginsburg, Geoffrey S.; Woods, Christopher W.; Tsalik, Ephraim L.

doi:10.1371/journal.pone.0261385

Cited by 6 publications

(3 citation statements)

References 48 publications

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“…A bovine experimentally induced mastitis model would be ideal for these types of experiments for multiple reasons. In this model, features of infection may be altered based on the pathogen(s) introduced, allowing for the study of various host-pathogen dialogs that determine the nature of the immune response ( 124 , 125 ). Non-invasive read outs such as somatic cell count and bacterial load in milk can be used to follow the course of infection/treatment in real time.…”

Section: Discussionmentioning

confidence: 99%

The mammosphere-derived epithelial cell secretome modulates neutrophil functions in the bovine model

Harman,

Sipka,

Oxford

et al. 2024

Front. Immunol.

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BackgroundInnovative therapies against bacterial infections are needed. One approach is to focus on host-directed immunotherapy (HDT), with treatments that exploit natural processes of the host immune system. The goals of this type of therapy are to stimulate protective immunity while minimizing inflammation-induced tissue damage. We use non-traditional large animal models to explore the potential of the mammosphere-derived epithelial cell (MDEC) secretome, consisting of all bioactive factors released by the cells, to modulate host immune functions. MDEC cultures are enriched for mammary stem and progenitor cells and can be generated from virtually any mammal. We previously demonstrated that the bovine MDEC secretome, collected and delivered as conditioned medium (CM), inhibits the growth of bacteria in vitro and stimulates functions related to tissue repair in cultured endothelial and epithelial cells.MethodsThe immunomodulatory effects of the bovine MDEC secretome on bovine neutrophils, an innate immune cell type critical for resolving bacterial infections, were determined in vitro using functional assays. The effects of MDEC CM on neutrophil molecular pathways were explored by evaluating the production of specific cytokines by neutrophils and examining global gene expression patterns in MDEC CM-treated neutrophils. Enzyme linked immunosorbent assays were used to determine the concentrations of select proteins in MDEC CM and siRNAs were used to reduce the expression of specific MDEC-secreted proteins, allowing for the identification of bioactive factors modulating neutrophil functions.ResultsNeutrophils exposed to MDEC secretome exhibited increased chemotaxis and phagocytosis and decreased intracellular reactive oxygen species and extracellular trap formation, when compared to neutrophils exposed to control medium. C-X-C motif chemokine 6, superoxide dismutase, peroxiredoxin-2, and catalase, each present in the bovine MDEC secretome, were found to modulate neutrophil functions.ConclusionThe MDEC secretome administered to treat bacterial infections may increase neutrophil recruitment to the site of infection, stimulate pathogen phagocytosis by neutrophils, and reduce neutrophil-produced ROS accumulation. As a result, pathogen clearance might be improved and local inflammation and tissue damage reduced.

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Section: Discussionmentioning

confidence: 99%

The mammosphere-derived epithelial cell secretome modulates neutrophil functions in the bovine model

Harman,

Sipka,

Oxford

et al. 2024

Front. Immunol.

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“…The test also worked equally well among participants with acute COVID-19. Although we did not assess the combined performance of the HR-B/V test and procalcitonin measurement, a previous study found no improvement vs HR-B/V testing alone.…”

Section: Discussionmentioning

confidence: 99%

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection

Henao

Frankey

et al. 2022

JAMA Netw Open

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Key Points Question What is the ability of a host gene expression test to accurately discriminate bacterial from viral infection among patients with acute respiratory illness? Findings In this diagnostic study involving analysis of 616 children and adults with febrile acute respiratory illness of 7 or fewer days’ duration, the host response bacterial/viral test had up to 90% sensitivity, 82% specificity, and 98% negative predictive value for bacterial infection, which was significantly better than procalcitonin measurement. Meaning The study’s findings suggest that an accurate point-of-need host response test with high negative predictive value may identify patients unlikely to have bacterial infection, offering a better antibiotic stewardship strategy than is currently available.

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“…Analysis of the secondary outcomes will involve similar regression models, depending on the type of the outcome variable. In a further secondary analysis with IV antibiotic duration as the outcome, we will test the interaction between treatment arm and biomarker subgroups, categorised according to the following criteria: MR-proADM high (≥ 0.7 nmol/l) or low (< 0.7 nmol/l) [ 27 ], ImmunoXpert score high (> 0.65), intermediate, or low (< 0.35) [ 29 , 31 ]. PRECISE secondary analyses will not be performed if analysis of the same outcome in the host trial fails to discover a significant treatment effect.…”

Section: Sub-studiesmentioning

confidence: 99%

Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study

Schoenbuchner

Huang

Waldron

et al. 2023

Trials

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Introduction The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study. Methods The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up. Results Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age. Conclusion We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up. Trial registration BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832. PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.

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A comparison of host response strategies to distinguish bacterial and viral infection

Cited by 6 publications

References 48 publications

The mammosphere-derived epithelial cell secretome modulates neutrophil functions in the bovine model

The mammosphere-derived epithelial cell secretome modulates neutrophil functions in the bovine model

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection

Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study

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