. 2024 Feb 27;28(1):63.

doi: 10.1186/s13054-024-04843-0.

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia

Chel Hee Lee¹, Mohammad M Banoei¹, Mariam Ansari¹, Matthew P Cheng², Francois Lamontagne³, Donald Griesdale⁴, David E Lasry², Koray Demir², Vinay Dhingra⁴, Karen C Tran⁵, Terry Lee⁶, Kevin Burns⁷, David Sweet⁸, John Marshall⁹, Arthur Slutsky¹⁰, Srinivas Murthy¹¹, Joel Singer⁶, David M Patrick¹², Todd C Lee², John H Boyd^{13

14}, Keith R Walley^{13

14}, Robert Fowler¹⁵, Greg Haljan¹⁶, Donald C Vinh², Alison Mcgeer¹⁷, David Maslove¹⁸, Puneet Mann¹⁹, Kathryn Donohoe¹⁹, Geraldine Hernandez¹⁹, Genevieve Rocheleau¹⁹, Uriel Trahtemberg^{20

21

22}, Anand Kumar²³, Ma Lou²³, Claudia Dos Santos²⁴, Andrew Baker²⁵, James A Russell^{13

14}, Brent W Winston²⁶; *ARBs CORONA I. Investigators

Collaborators, Affiliations

Collaborators

*ARBs CORONA I. Investigators:
J A Russell, K R Walley, J Boyd, T Lee, J Singer, D Sweet, K Tran, S Reynolds, G Haljan, M Cheng, D Vinh, T Lee, F Lamontagne, B Winston, O Rewa, J Marshall, A Slutsky, A McGeer, V Sivanantham, R Fowler, D Maslove, S Perez Patrigeon, K D Burns

Affiliations

¹ Department of Critical Care Medicine, University of Calgary, Alberta, Canada.
² Divisions of Infectious Diseases & Medical Microbiology, McGill University Health Center, McGill's Interdisciplinary Initiative in Infection and Immunity, Montreal, PQ, Canada.
³ University of Sherbrooke, Sherbrooke, QC, Canada.
⁴ Critical Care Medicine, Vancouver General Hospital and University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada.
⁵ Division of General Internal Medicine, Vancouver General Hospital and University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada.
⁶ Centre for Health Evaluation and Outcome Science (CHEOS), St. Paul's Hospital and University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
⁷ Department of Medicine, Division of Nephrology, Ottawa Hospital Research Institute, and University of Ottawa, 1967 Riverside Dr., Rm. 535, Ottawa, ON, K1H 7W9, Canada.
⁸ Critical Care Medicine and Emergency Medicine, Vancouver General Hospital and University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada.
⁹ Department of Surgery, St. Michael's Hospital and University of Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.
¹⁰ Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada.
¹¹ British Columbia Children's Hospital, University of British Columbia, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada.
¹² British Columbia Centre for Disease Control (BCCDC) and School of Population and Public Health, University of British Columbia, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada.
¹³ Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
¹⁴ Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.
¹⁶ Department of Medicine and Critical Care Medicine, Surrey Memorial Hospital, 13750 96th Avenue, Surrey, BC, V3V 1Z2, Canada.
¹⁷ Mt. Sinai Hospital and University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
¹⁸ Department of Critical Care, Kingston General Hospital and Queen's University, 76 Stuart Street, Kingston, ON, K7L 2V7, Canada.
¹⁹ Black Tusk, Vancouver, BC, Canada.
²⁰ Department of Critical Care, Galilee Medical Center, Nahariya, Israel.
²¹ Bar Ilan University, Ramat Gan, Israel.
²² Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
²³ Departments of Medicine and Medical Microbiology, University of Manitoba, Winnipeg, Canada.
²⁴ Department of Medicine and Interdepartmental Division of Critical Care, University of Toronto, Toronto, Canada.
²⁵ Departments of Critical Care and Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²⁶ Departments of Critical Care Medicine, Medicine and Biochemistry and Molecular Biology, University of Calgary, Health Research Innovation Center (HRIC), Room 4C64, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada. bwinston@ucalgary.ca.

PMID: 38414082
PMCID: PMC10900651
DOI: 10.1186/s13054-024-04843-0

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia

Chel Hee Lee et al. Crit Care. 2024.

. 2024 Feb 27;28(1):63.

doi: 10.1186/s13054-024-04843-0.

Authors

Collaborators

*ARBs CORONA I. Investigators:
J A Russell, K R Walley, J Boyd, T Lee, J Singer, D Sweet, K Tran, S Reynolds, G Haljan, M Cheng, D Vinh, T Lee, F Lamontagne, B Winston, O Rewa, J Marshall, A Slutsky, A McGeer, V Sivanantham, R Fowler, D Maslove, S Perez Patrigeon, K D Burns

Affiliations

¹ Department of Critical Care Medicine, University of Calgary, Alberta, Canada.
² Divisions of Infectious Diseases & Medical Microbiology, McGill University Health Center, McGill's Interdisciplinary Initiative in Infection and Immunity, Montreal, PQ, Canada.
³ University of Sherbrooke, Sherbrooke, QC, Canada.
⁴ Critical Care Medicine, Vancouver General Hospital and University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada.
⁵ Division of General Internal Medicine, Vancouver General Hospital and University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada.
⁶ Centre for Health Evaluation and Outcome Science (CHEOS), St. Paul's Hospital and University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
⁷ Department of Medicine, Division of Nephrology, Ottawa Hospital Research Institute, and University of Ottawa, 1967 Riverside Dr., Rm. 535, Ottawa, ON, K1H 7W9, Canada.
⁸ Critical Care Medicine and Emergency Medicine, Vancouver General Hospital and University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada.
⁹ Department of Surgery, St. Michael's Hospital and University of Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.
¹⁰ Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada.
¹¹ British Columbia Children's Hospital, University of British Columbia, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada.
¹² British Columbia Centre for Disease Control (BCCDC) and School of Population and Public Health, University of British Columbia, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada.
¹³ Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
¹⁴ Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.
¹⁶ Department of Medicine and Critical Care Medicine, Surrey Memorial Hospital, 13750 96th Avenue, Surrey, BC, V3V 1Z2, Canada.
¹⁷ Mt. Sinai Hospital and University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
¹⁸ Department of Critical Care, Kingston General Hospital and Queen's University, 76 Stuart Street, Kingston, ON, K7L 2V7, Canada.
¹⁹ Black Tusk, Vancouver, BC, Canada.
²⁰ Department of Critical Care, Galilee Medical Center, Nahariya, Israel.
²¹ Bar Ilan University, Ramat Gan, Israel.
²² Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
²³ Departments of Medicine and Medical Microbiology, University of Manitoba, Winnipeg, Canada.
²⁴ Department of Medicine and Interdepartmental Division of Critical Care, University of Toronto, Toronto, Canada.
²⁵ Departments of Critical Care and Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²⁶ Departments of Critical Care Medicine, Medicine and Biochemistry and Molecular Biology, University of Calgary, Health Research Innovation Center (HRIC), Room 4C64, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada. bwinston@ucalgary.ca.

PMID: 38414082
PMCID: PMC10900651
DOI: 10.1186/s13054-024-04843-0

Abstract

Rationale: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair.

Objective: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis.

Methods: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms.

Results: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms.

Conclusion: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Keywords: Acute respiratory distress syndrome; H1N1; Metabolomics; Pneumonia; SARS-CoV-2.

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Conflict of interest statement

The authors declare no conflicts of interest, financial or otherwise, except Dr. James Russell who discloses the following: COI: DR. JAMES A. RUSSELL AB, MD, FRCPC FINANCIAL DISCLOSURE (last 36 months). Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to (1) the use of PCSK9 inhibitor(s) in sepsis, (2) the use of vasopressin in septic shock, and (3) a patent owned by Ferring for the use of selepressin in septic shock. Dr. Russell is an inventor on these patents. Dr. Russell was a founder, Director, and shareholder in Cyon Therapeutics Inc. (now closed) and is a shareholder in Molecular You Corp. Dr. Russell is a Senior Research Advisor of the British Columbia, Canada Post COVID—Interdisciplinary Clinical Care Network (PC-ICCN). Dr. Russell is no longer actively consulting for any industry. Dr. Russell reports receiving consulting fees in the last three years from: (1) SIB Therapeutics LLC (developing a sepsis drug). (2) Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). (3) Dr. Russell was a funded member of the Data and Safety Monitoring Board (DSMB) of an NIH-sponsored plasma trial in COVID-19 (PASS-IT-ON) (2020–2021). (4) PAR Pharma (sells prepared bags of vasopressin). Dr. Russell reports receiving an investigator-initiated grant from Grifols (entitled "Is HBP a mechanism of albumin's efficacy in human septic shock?") that was provided to and administered by UBC. Dr. Russell has received grants for COVID-19 research: 4 from the Canadian Institutes of Health Research (CIHR) and three from the St. Paul's Foundation (SPF). Dr. Russell was a non-funded Science Advisor and member of the Government of Canada COVID-19 Therapeutics Task Force (June 2020–2021).

Figures

**Fig. 1**
The heatmap shows the difference in metabolomic profile using the most differentiating metabolites (VIP > 1.0) over five study groups. C19/A = SARS-CoV-2-induced ARDS patients admitted to ICU, C19/P = SARS-CoV-2-infected patients not sick enough to be admitted to ICU, H1N1/A = H1N1-induced ARDS patients admitted to ICU, PNA/A = bacterial pneumonia-induced ARDS patients admitted to ICU, CTL = non-ARDS ventilated control patients admitted to ICU. Relative metabolite concentrations are shown as indicated by a scale between −4 and + 4

**Fig. 2**
A A PCA (principal component analysis) score plot of the first two principal components (PC1 and PC2). Patients are grouped by causes of ARDS indicated by the labels (and color). B The score plot from a multi-class PLS-DA model. Patients are grouped by causes of ARDS (indicated by label and color) using the metabolomic signature. The signature consists of 54 metabolites whose variable importance score on projection is greater than 1. The metabolites are listed in Table 2. A model is run with 25 patients in each group. C19/A = COVID-19-induced ARDS patients admitted to ICU, H1N1/A = H1N1-induced ARDS patients admitted to ICU, CTL = non-ARDS ventilated control patients admitted to ICU, PNA/A = bacterial pneumonia-induced ARDS patients admitted to ICU. VIP = variable importance on projection

**Fig. 3**
Side-by-side boxplot of biomarker quantification over study groups. CTL = non-ARDS ventilated control patients admitted to ICU, H1N1/A = H1N1-induced ARDS patients admitted to ICU, PNA/A = bacterial pneumonia-induced ARDS patients admitted to ICU, C19/A = COVID-19-induced ARDS patients admitted to ICU (C19/A)

**Fig. 4**
Metabolite and pathway illustration. Pathways included are those affected according to specific plasma metabolite changes in C19/A, H1N1/A, and PNA/A infections. Specific metabolites are included if they significantly changed in the group of interest compared to CTL, while they were not significantly different among the rest of the groups. The illustration of pathways is presented using KEGG pathway model descriptions

See this image and copyright information in PMC

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Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia

Collaborators

Affiliations

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

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LinkOut - more resources

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