A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection

doi:10.1183/13993003.00459-2022

Multicenter Study

. 2022 Dec 15;60(6):2200459.

doi: 10.1183/13993003.00459-2022. Print 2022 Dec.

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection

Shahid Husain^{1

2

3}, Andrew T Sage^{2

3}, Lorenzo Del Sorbo^{2

3

4}, Marcelo Cypel^{2

3

5

6}, Tereza Martinu^{2

3

5

7}, Stephen C Juvet^{2

3

5

7}, Andrea Mariscal^{2

3}, Julie Wright⁸, Bonnie T Chao², Alaa A Shamandy^{9

10}, S Hossein Mousavi², Jin Ma¹¹, Bo Wang^{9

10

12

13}, Jerome Valero^{2

3}, Mingyao Liu^{2

3

5}, Megan Landes^{14

15}, Sharaniyaa Balachandran^{2

3}, Kimberley Hudson^{2

3}, Michelle Ngai⁸, Marialessia Capuano¹⁶, Maria Gelardi¹⁶, Enrico Lupia¹⁶, Daniel R Marinowic¹⁷, Frederico O Friedrich¹⁷, Carine R R Schmitz¹⁸, Leticya S M Dos Santos¹⁹, Florencia M Barbe-Tuana¹⁹, Marcus H Jones¹⁷, Kevin C Kain⁸, Tony Mazzulli²⁰, Sam Sabbah^{14

21}, Shaf Keshavjee^{22

3

5

6}

Affiliations

¹ Division of Infectious Diseases, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
² Toronto Lung Transplant Program and Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.
³ Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
⁴ Interdepartmental Division of Critical Care Medicine, Medical and Surgical Intensive Care Unit, University Health Network, University of Toronto, Toronto, ON, Canada.
⁵ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁶ Division of Thoracic Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
⁷ Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Tropical Disease Unit, Department of Medicine, University of Toronto, Sandra Rotman Centre for Global Health, University Health Network, Toronto General Hospital, Toronto, ON, Canada.
⁹ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
¹⁰ Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
¹¹ Biostatistics Research Unit, University Health Network, Toronto, ON, Canada.
¹² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹³ Vector Institute, Toronto, ON, Canada.
¹⁴ Department of Emergency Medicine, University Health Network, Toronto, ON, Canada.
¹⁵ Division of Emergency Medicine, Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
¹⁶ Division of Emergency Medicine and High Dependency Unit, Cittá della Salute e della Scienza di Torino Hospital-Molinette Site, Department of Medical Sciences, University of Turin, Turin, Italy.
¹⁷ School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
¹⁸ Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
¹⁹ School of Health, Sciences and Life, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
²⁰ Department of Microbiology, Mount Sinai Hospital, Toronto, ON, Canada.
²¹ Division of Emergency Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.
²² Toronto Lung Transplant Program and Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada shaf.keshavjee@uhn.ca.

PMID: 36104292
PMCID: PMC9753477
DOI: 10.1183/13993003.00459-2022

Multicenter Study

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection

Shahid Husain et al. Eur Respir J. 2022.

. 2022 Dec 15;60(6):2200459.

doi: 10.1183/13993003.00459-2022. Print 2022 Dec.

Authors

Affiliations

¹ Division of Infectious Diseases, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
² Toronto Lung Transplant Program and Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.
³ Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
⁴ Interdepartmental Division of Critical Care Medicine, Medical and Surgical Intensive Care Unit, University Health Network, University of Toronto, Toronto, ON, Canada.
⁵ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁶ Division of Thoracic Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
⁷ Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Tropical Disease Unit, Department of Medicine, University of Toronto, Sandra Rotman Centre for Global Health, University Health Network, Toronto General Hospital, Toronto, ON, Canada.
⁹ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
¹⁰ Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
¹¹ Biostatistics Research Unit, University Health Network, Toronto, ON, Canada.
¹² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹³ Vector Institute, Toronto, ON, Canada.
¹⁴ Department of Emergency Medicine, University Health Network, Toronto, ON, Canada.
¹⁵ Division of Emergency Medicine, Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
¹⁶ Division of Emergency Medicine and High Dependency Unit, Cittá della Salute e della Scienza di Torino Hospital-Molinette Site, Department of Medical Sciences, University of Turin, Turin, Italy.
¹⁷ School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
¹⁸ Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
¹⁹ School of Health, Sciences and Life, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
²⁰ Department of Microbiology, Mount Sinai Hospital, Toronto, ON, Canada.
²¹ Division of Emergency Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.
²² Toronto Lung Transplant Program and Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada shaf.keshavjee@uhn.ca.

PMID: 36104292
PMCID: PMC9753477
DOI: 10.1183/13993003.00459-2022

Abstract

Background: Patients who present to an emergency department (ED) with respiratory symptoms are often conservatively triaged in favour of hospitalisation. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalisation in order to improve the precision of clinical decision making in the ED.

Methods: From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from EDs in an international multicentre study: Canada (n=310), Italy (n=131) and Brazil (n=200). Patients were followed prospectively for 28 days. Subgroup analysis was conducted on confirmed coronavirus disease 2019 (COVID-19) patients (n=245). An inflammatory profile was determined using a rapid, 50-min, biomarker panel (RALI-Dx (Rapid Acute Lung Injury Diagnostic)), which measures interleukin (IL)-6, IL-8, IL-10, soluble tumour necrosis factor receptor 1 (sTNFR1) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1).

Results: RALI-Dx biomarkers were significantly elevated in patients who required hospitalisation across all three sites. A machine learning algorithm that was applied to predict hospitalisation using RALI-Dx biomarkers had a mean±sd area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy) and 86±3% (Brazil). Model performance was 82±3% for COVID-19 patients and 87±7% for patients with a confirmed pneumonia diagnosis.

Conclusions: The rapid diagnostic biomarker panel accurately identified the need for inpatient care in patients presenting with respiratory symptoms, including COVID-19. The RALI-Dx test is broadly and easily applicable across many jurisdictions, and represents an important diagnostic adjunct to advance ED decision-making protocols.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: S. Keshavjee serves as Chief Medical Officer of Traferox Technologies and receives personal fees from Lung Bioengineering, outside the submitted work. A.T. Sage, M. Cypel, L. del Sorbo, B. Wang, J. Valero and S. Keshavjee are inventors of a patent licensed to SQI Diagnostics. The inventors fully adhere to a number of policies in place at the University Health Network that ensure academic integrity and management of potential conflicts of interest between authors and industry partners. For the purposes of regulatory application, SQI Diagnostics provided funding to support Brazil data collection and the work performed by D.R. Marinowic, F.O. Friedrich, C.R.R. Schmitz, L.S.M. dos Santos, F.M. Barbe-Tuana and M.H. Jones, but remained arms-length and blinded from the data analysis included in this study. All other authors report no conflicts of interest.

Figures

**FIGURE 1**
Schematic of patient outcomes following emergency department (ED) presentation in the Canada cohort. ICU: intensive care unit.

**FIGURE 2**
RALI-Dx biomarkers are associated with a) level of care provided (Kruskal–Wallis test) and b) 28-day mortality (Mann–Whitney U-test) in the Canada cohort. IL: interleukin; sTNFR1: soluble tumour necrosis factor receptor 1; sTREM1: soluble triggering receptor expressed on myeloid cells 1; ICU: intensive care unit. Box-and-whisker plots show median, interquartile range (IQR) and 1.5 times the IQR. *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001.

**FIGURE 3**
RALI-Dx biomarkers are elevated in hospitalised COVID-19 patients from Canada, Italy and Brazil. Box-and-whisker plots (median, interquartile range (IQR) and 1.5 times the IQR) for COVID-19 patients (n=245) that were discharged or hospitalised following emergency department presentation for: interleukin (IL)-6, IL-8, IL-10, soluble tumour necrosis factor receptor 1 (sTNFR1) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1). Mann–Whitney U-test. **: p<0.01; ****: p<0.0001.

See this image and copyright information in PMC

Comment in

A leap towards personalised therapy of acute lung injury.
Witzenrath M, Welte T. Witzenrath M, et al. Eur Respir J. 2022 Dec 15;60(6):2201808. doi: 10.1183/13993003.01808-2022. Print 2022 Dec. Eur Respir J. 2022. PMID: 36522140 No abstract available.

Cited by

Insight into the lncRNA-mRNA Co-Expression Profile and ceRNA Network in Lipopolysaccharide-Induced Acute Lung Injury.
Shen Y, Gong L, Xu F, Wang S, Liu H, Wang Y, Hu L, Zhu L. Shen Y, et al. Curr Issues Mol Biol. 2023 Jul 24;45(7):6170-6189. doi: 10.3390/cimb45070389. Curr Issues Mol Biol. 2023. PMID: 37504305 Free PMC article.
Identification of two specific transcriptomic clusters of COVID-19 acute respiratory distress syndrome patients with different immune profiles and different outcomes.
Shindo Y, Dela Cruz CS, Witzenrath M. Shindo Y, et al. Eur Respir J. 2023 Jan 27;61(1):2202008. doi: 10.1183/13993003.02008-2022. Print 2023 Jan. Eur Respir J. 2023. PMID: 36517181 Free PMC article.

References

1. Canadian Institute for Health Information . Data Quality Documentation: National Ambulatory Care Reporting System – Current-Year Information 2018–2019. 2019. www.cihi.ca/sites/default/files/document/current-year-information-nacrs-... Date last accessed: 1 August 2022.
1. Lim WS, van der Eerden MM, Laing R, et al. . Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 377–382. doi:10.1136/thorax.58.5.377 - DOI - PMC - PubMed
1. Huang C, Wang Y, Li X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506. doi:10.1016/S0140-6736(20)30183-5 - DOI - PMC - PubMed
1. Herold T, Jurinovic V, Arnreich C, et al. . Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol 2020; 146: 128–136. doi:10.1016/j.jaci.2020.05.008 - DOI - PMC - PubMed
1. Del Valle DM, Kim-Schulze S, Huang HH, et al. . An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 2020; 26: 1636–1643. doi:10.1038/s41591-020-1051-9 - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

FRN 440205/CIHR/Canada

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

[1] Canadian Institute for Health Information . Data Quality Documentation: National Ambulatory Care Reporting System – Current-Year Information 2018–2019. 2019. www.cihi.ca/sites/default/files/document/current-year-information-nacrs-... Date last accessed: 1 August 2022.

[2] Canadian Institute for Health Information . Data Quality Documentation: National Ambulatory Care Reporting System – Current-Year Information 2018–2019. 2019. www.cihi.ca/sites/default/files/document/current-year-information-nacrs-... Date last accessed: 1 August 2022.

[3] Lim WS, van der Eerden MM, Laing R, et al. . Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 377–382. doi:10.1136/thorax.58.5.377 - DOI - PMC - PubMed

[4] Lim WS, van der Eerden MM, Laing R, et al. . Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 377–382. doi:10.1136/thorax.58.5.377 - DOI - PMC - PubMed

[5] Huang C, Wang Y, Li X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506. doi:10.1016/S0140-6736(20)30183-5 - DOI - PMC - PubMed

[6] Huang C, Wang Y, Li X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506. doi:10.1016/S0140-6736(20)30183-5 - DOI - PMC - PubMed

[7] Herold T, Jurinovic V, Arnreich C, et al. . Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol 2020; 146: 128–136. doi:10.1016/j.jaci.2020.05.008 - DOI - PMC - PubMed

[8] Herold T, Jurinovic V, Arnreich C, et al. . Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol 2020; 146: 128–136. doi:10.1016/j.jaci.2020.05.008 - DOI - PMC - PubMed

[9] Del Valle DM, Kim-Schulze S, Huang HH, et al. . An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 2020; 26: 1636–1643. doi:10.1038/s41591-020-1051-9 - DOI - PMC - PubMed

[10] Del Valle DM, Kim-Schulze S, Huang HH, et al. . An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 2020; 26: 1636–1643. doi:10.1038/s41591-020-1051-9 - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection

Affiliations

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous