Plasma Concentrations of sTREM-1 as Markers for Systemic Adverse Reactions in Subjects Treated With Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection

doi:10.3389/fmicb.2022.821066

. 2022 Mar 3:13:821066.

doi: 10.3389/fmicb.2022.821066. eCollection 2022.

Plasma Concentrations of sTREM-1 as Markers for Systemic Adverse Reactions in Subjects Treated With Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection

Tsai-Yu Wang^{1

2}, Jia-Yih Feng^{3

4}, Chin-Chung Shu⁵, Susan Shin-Jung Lee^{4

6}, Chung-Yu Chen⁷, Yu-Feng Wei⁸, Chih-Bin Lin⁹, Wei-Chang Huang^{10

11

12

13}, Wei-Juin Su³, Shu-Min Lin^{1

2}

Affiliations

¹ Department of Thoracic Medicine, Chang Gung Memorial Hospital Linkou Main Branch, Taoyuan, Taiwan.
² School of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁴ Faculty of Medicine, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei, Taiwan.
⁵ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Division of Infectious Diseases, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁷ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
⁸ Division of Chest Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
⁹ Division of Chest Medicine, Department of Internal Medicine, Hualien Tzu Chi Hospital, Hualien, Taiwan.
¹⁰ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
¹¹ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
¹² Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
¹³ School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

PMID: 35308376
PMCID: PMC8927064
DOI: 10.3389/fmicb.2022.821066

Plasma Concentrations of sTREM-1 as Markers for Systemic Adverse Reactions in Subjects Treated With Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection

Tsai-Yu Wang et al. Front Microbiol. 2022.

. 2022 Mar 3:13:821066.

doi: 10.3389/fmicb.2022.821066. eCollection 2022.

Authors

Affiliations

¹ Department of Thoracic Medicine, Chang Gung Memorial Hospital Linkou Main Branch, Taoyuan, Taiwan.
² School of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁴ Faculty of Medicine, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei, Taiwan.
⁵ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Division of Infectious Diseases, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁷ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
⁸ Division of Chest Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
⁹ Division of Chest Medicine, Department of Internal Medicine, Hualien Tzu Chi Hospital, Hualien, Taiwan.
¹⁰ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
¹¹ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
¹² Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
¹³ School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

PMID: 35308376
PMCID: PMC8927064
DOI: 10.3389/fmicb.2022.821066

Abstract

Background: A regimen of once-weekly rifapentine plus isoniazid for 3 months (3HP) is an effective treatment for subjects with latent tuberculosis infection; however, no reliable biomarker exists for predicting systemic adverse reactions (SARs) to 3HP treatment.

Methods: This prospective, multi-center study evaluated the plasma concentrations of soluble triggering receptors expressed on myeloid cells (sTREM)-1 and sTREM-2 in subjects undergoing 3HP treatment and examined the associations between these biomarkers and SARs.

Results: This study enrolled 80 consecutive subjects receiving 3HP treatment, 25 of whom had SARs and 55 of whom did not. Subjects with SARs presented higher concentrations of sTREM-1 at baseline than those without SARs (240.1 ± 19.1 vs. 176.7 ± 9.4 pg/mL, P = 0.001). The area under the receiver operating characteristic curves revealed that day 1 plasma levels of sTREM-1 (0.708, 95% CI, 0.584-0.833, P = 0.003) and sTREM-2 (0.343, 95% CI, 0.227-0.459, P = 0.025) as well as the sTREM-1/sTREM-2 ratio (0.748, 95% CI, 0.638-0.858, P = 0.001) had modest discriminative power pertaining to the development of SARs. An sTREM-1 level exceeding the cut-off value (>187.4 pg/mL) (hazard ratio [HR], 6.15; 95% CI 1.67-22.70, P = 0.006) and a sTREM-2 below the cut-off value (<237.2 pg/mL) (HR, 4.46; 95% CI 1.41-14.1, P = 0.011) were independent predictors of SARs after controlling for other variables.

Conclusions: Plasma sTREM-1 and sTREM-2 levels are useful biomarkers for predicting SARs during 3HP treatment.

Clinical trial government: NCT04655794.

Keywords: LTBI; exacerbation; sTREM-1; sTREM-2; tuberculosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**FIGURE 1**
Serial sTREM plasma levels. (N = 12: systemic adverse reactions (SARs) group; N = 31: non-SARs group): **(A)** Mean sTREM-1 plasma levels were significantly higher in the SARs group (red circle) than in the non-SARs group (blue circle) on day 1 (P = 0.006). Mean sTREM-1 plasma levels were significantly higher on the day of SARs development (red circle) than that on day 1 (P = 0.003); **(B)** Mean sTREM-2 plasma levels in the SARs group (red circle) were not significantly higher than in the non-SARs group (blue circle) on day 1; **(C)** The sTREM-1/sTREM-2 ratio in the SARs group (red circle) was significantly higher than in the non-SARs group (blue circle) on day 1. *P < 0.05 versus day 1 of SAR group, ⁺P < 0.05 versus day 1 of Non-SAR group.

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TREM-1, TREM-2 and their association with disease severity in patients with COVID-19.
Fan R, Cheng Z, Huang Z, Yang Y, Sun N, Hu B, Hou P, Liu B, Huang C, Liu S. Fan R, et al. Ann Med. 2023;55(2):2269558. doi: 10.1080/07853890.2023.2269558. Epub 2023 Oct 17. Ann Med. 2023. PMID: 37848000 Free PMC article.

References

1. Bassyouni I. H., Fawzi S., Gheita T. A., Bassyouni R. H., Nasr A. S., El Bakry S. A., et al. (2017). Clinical association of a soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with systemic lupus erythematosus. Immunol. Invest. 46 38–47. 10.1080/08820139.2016.1211140 - DOI - PubMed
1. Bliven-Sizemore E. E., Sterling T. R., Shang N., Benator D., Schwartzman K., Reves R., et al. (2015). Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI. Int. J. Tuberc. Lung Dis. 19 1039–1044, i–v. 10.5588/ijtld.14.0829 - DOI - PMC - PubMed
1. Brooks K. M., George J. M., Pau A. K., Rupert A., Mehaffy C., De P., et al. (2018). Cytokine-mediated systemic adverse drug reactions in a drug-drug interaction study of Dolutegravir with once-weekly Isoniazid and Rifapentine. Clin. Infect. Dis. 67 193–201. 10.1093/cid/ciy082 - DOI - PMC - PubMed
1. Cancer Therapy Evaluation Program (2020). Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Available online at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs... (accessed November 27, 2017).
1. Cao C., Gu J., Zhang J. (2017). Soluble triggering receptor expressed on myeloid cell-1 (sTREM-1): a potential biomarker for the diagnosis of infectious diseases. Front. Med. 11:169–177. 10.1007/s11684-017-0505-z - DOI - PubMed

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[1] Bassyouni I. H., Fawzi S., Gheita T. A., Bassyouni R. H., Nasr A. S., El Bakry S. A., et al. (2017). Clinical association of a soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with systemic lupus erythematosus. Immunol. Invest. 46 38–47. 10.1080/08820139.2016.1211140 - DOI - PubMed

[2] Bassyouni I. H., Fawzi S., Gheita T. A., Bassyouni R. H., Nasr A. S., El Bakry S. A., et al. (2017). Clinical association of a soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with systemic lupus erythematosus. Immunol. Invest. 46 38–47. 10.1080/08820139.2016.1211140 - DOI - PubMed

[3] Bliven-Sizemore E. E., Sterling T. R., Shang N., Benator D., Schwartzman K., Reves R., et al. (2015). Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI. Int. J. Tuberc. Lung Dis. 19 1039–1044, i–v. 10.5588/ijtld.14.0829 - DOI - PMC - PubMed

[4] Bliven-Sizemore E. E., Sterling T. R., Shang N., Benator D., Schwartzman K., Reves R., et al. (2015). Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI. Int. J. Tuberc. Lung Dis. 19 1039–1044, i–v. 10.5588/ijtld.14.0829 - DOI - PMC - PubMed

[5] Brooks K. M., George J. M., Pau A. K., Rupert A., Mehaffy C., De P., et al. (2018). Cytokine-mediated systemic adverse drug reactions in a drug-drug interaction study of Dolutegravir with once-weekly Isoniazid and Rifapentine. Clin. Infect. Dis. 67 193–201. 10.1093/cid/ciy082 - DOI - PMC - PubMed

[6] Brooks K. M., George J. M., Pau A. K., Rupert A., Mehaffy C., De P., et al. (2018). Cytokine-mediated systemic adverse drug reactions in a drug-drug interaction study of Dolutegravir with once-weekly Isoniazid and Rifapentine. Clin. Infect. Dis. 67 193–201. 10.1093/cid/ciy082 - DOI - PMC - PubMed

[7] Cancer Therapy Evaluation Program (2020). Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Available online at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs... (accessed November 27, 2017).

[8] Cancer Therapy Evaluation Program (2020). Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Available online at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs... (accessed November 27, 2017).

[9] Cao C., Gu J., Zhang J. (2017). Soluble triggering receptor expressed on myeloid cell-1 (sTREM-1): a potential biomarker for the diagnosis of infectious diseases. Front. Med. 11:169–177. 10.1007/s11684-017-0505-z - DOI - PubMed

[10] Cao C., Gu J., Zhang J. (2017). Soluble triggering receptor expressed on myeloid cell-1 (sTREM-1): a potential biomarker for the diagnosis of infectious diseases. Front. Med. 11:169–177. 10.1007/s11684-017-0505-z - DOI - PubMed

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Plasma Concentrations of sTREM-1 as Markers for Systemic Adverse Reactions in Subjects Treated With Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection

Affiliations

Plasma Concentrations of sTREM-1 as Markers for Systemic Adverse Reactions in Subjects Treated With Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection

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Abstract

Conflict of interest statement

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