Summary of Study ST002845

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001780. The data can be accessed directly via it's Project DOI: 10.21228/M8MT5N This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002845
Study TitleMethylprednisolone therapy induces differential metabolic trajectories in severe COVID-19 patients
Study SummaryCorticosteroids have become a choice for managing severe COVID-19, but the molecular mechanisms behind the response after corticosteroid administration remain incompletely understood. In order to unravel this, comparisons between temporal metabolic profiles in the plasma samples of methylprednisolone (MP) - and placebo-treated COVID-19 patients were performed at different time points. The patient plasma samples used were obtained from a double blind, randomized, placebo-controlled Phase IIb clinical trial performed on severe COVID-19 patients in the Brazilian Amazon where the patients received placebo or 0.5 mg/kg MP intravenously twice daily for five days. The MP treatment reduced the number of metabolites in the plasma of patients during follow-up. The longitudinal changes in the MP-group was in eight metabolic pathways related to steroid hormones and eicosanoids. Direct comparison between the two groups, revealed differences at baseline, which peaked five days after initiation of MP treatment. The metabolic pathways differing between the two groups over time included galactose metabolism, glucose and gluconeogenesis, N-glycan metabolism, and prostaglandin formation from arachidonate. Deoxy-galactose, prostaglandin H2, sphingosine, and sphinganine exhibited differential trajectories by day 14 after initiating the MP treatment. Survival of MP-treated COVID-19 patients was associated with modulation of tryptophan metabolism. Network analysis revealed that MP treatment is highly associated with alterations in pathways reflecting eicosanoid metabolism, such as arachidonic acid and prostaglandins. Curiously, there is crosstalk between metabolomics, biochemistry and cytokine components. Treatment of systemic and inflammatory conditions induced by SARS-CoV-2 viral infections with methylprednisolone modulates metabolic activity associated with tryptophan and inflammatory lipids.
Institute
Federal University of Goiás
Last NameGardinassi
First NameLuiz Gustavo
AddressR. 235 s/n - Institute of Tropical Pathology and Public Health - Federal University of Goiás
Emailluizgardinassi@ufg.br
Phone+55 62 3209-6530
Submit Date2023-08-30
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2023-09-15
Release Version1
Luiz Gustavo Gardinassi Luiz Gustavo Gardinassi
https://dx.doi.org/10.21228/M8MT5N
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR001780
Project DOI:doi: 10.21228/M8MT5N
Project Title:Methylprednisolone therapy induces differential metabolic trajectories in severe COVID-19 patients
Project Type:Research
Project Summary:Corticosteroids have become a choice for managing severe COVID-19, but the molecular mechanisms behind the response after corticosteroid administration remain incompletely understood. In order to unravel this, comparisons between temporal metabolic profiles in the plasma samples of methylprednisolone (MP) - and placebo-treated COVID-19 patients were performed at different time points. The patient plasma samples used were obtained from a double blind, randomized, placebo-controlled Phase IIb clinical trial performed on severe COVID-19 patients in the Brazilian Amazon where the patients received placebo or 0.5 mg/kg MP intravenously twice daily for five days. The MP treatment reduced the number of metabolites in the plasma of patients during follow-up. The longitudinal changes in the MP-group was in eight metabolic pathways related to steroid hormones and eicosanoids. Direct comparison between the two groups, revealed differences at baseline, which peaked five days after initiation of MP treatment. The metabolic pathways differing between the two groups over time included galactose metabolism, glucose and gluconeogenesis, N-glycan metabolism, and prostaglandin formation from arachidonate. Deoxy-galactose, prostaglandin H2, sphingosine, and sphinganine exhibited differential trajectories by day 14 after initiating the MP treatment. Survival of MP-treated COVID-19 patients was associated with modulation of tryptophan metabolism. Network analysis revealed that MP treatment is highly associated with alterations in pathways reflecting eicosanoid metabolism, such as arachidonic acid and prostaglandins. Curiously, there is crosstalk between metabolomics, biochemistry and cytokine components. Treatment of systemic and inflammatory conditions induced by SARS-CoV-2 viral infections with methylprednisolone modulates metabolic activity associated with tryptophan and inflammatory lipids.
Institute:Federal University of Goiás
Last Name:Gardinassi
First Name:Luiz Gustavo
Address:R. 235 s/n Institute of Tropical Pathology and Public Health
Email:luizgardinassi@ufg.br
Phone:+55 62 3209-6530

Subject:

Subject ID:SU002957
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Gender:Male and female

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Time-point Treatment Sex
SA308405ID_34D11 MP F
SA308406ID_67D11 MP F
SA308407ID_3D11 MP F
SA308408ID_113D11 MP M
SA308409ID_63D11 MP M
SA308410ID_31D11 MP M
SA308411ID_116D11 MP M
SA308412ID_198D11 MP M
SA308413ID_99D11 MP M
SA308414ID_159D11 MP M
SA308415ID_201D11 MP M
SA308416ID_80D11 MP M
SA308417ID_14D11 MP M
SA308418ID_118D11 MP M
SA308419ID_137D11 Placebo F
SA308420ID_21D11 Placebo F
SA308421ID_204D11 Placebo M
SA308422ID_208D11 Placebo M
SA308423ID_78D11 Placebo M
SA308424ID_108D11 Placebo M
SA308425ID_180D11 Placebo M
SA308426ID_91D11 Placebo M
SA308427ID_173D11 Placebo M
SA308428ID_146D14 MP F
SA308429ID_165D14 MP F
SA308430ID_191D14 MP M
SA308431ID_188D14 MP M
SA308432ID_71D14 MP M
SA308433ID_27D14 MP M
SA308434ID_56D14 MP M
SA308435ID_11D14 MP M
SA308436ID_86D14 MP M
SA308437ID_51D14 MP M
SA308438ID_141D14 MP M
SA308439ID_1D14 MP M
SA308440ID_77D14 Placebo F
SA308441ID_167D14 Placebo F
SA308442ID_177D14 Placebo M
SA308443ID_124D14 Placebo M
SA308444ID_132D14 Placebo M
SA308445ID_156D14 Placebo M
SA308446ID_96D14 Placebo M
SA308447ID_172D1 MP F
SA308448ID_110D1 MP F
SA308449ID_181D1 MP F
SA308450ID_32D1 MP F
SA308451ID_101D1 MP M
SA308452ID_155D1 MP M
SA308453ID_176D1 MP M
SA308454ID_151D1 MP M
SA308455ID_145D1 MP M
SA308456ID_127D1 MP M
SA308457ID_107D1 MP M
SA308458ID_49D1 MP M
SA308459ID_20D1 MP M
SA308460ID_90D1 MP M
SA308461ID_85D1 MP M
SA308462ID_37D1 MP M
SA308463ID_6D1 Placebo F
SA308464ID_66D1 Placebo F
SA308465ID_75D1 Placebo F
SA308466ID_148D1 Placebo F
SA308467ID_25D1 Placebo M
SA308468ID_9D1 Placebo M
SA308469ID_16D1 Placebo M
SA308470ID_29D1 Placebo M
SA308471ID_161D1 Placebo M
SA308472ID_139D1 Placebo M
SA308473ID_135D1 Placebo M
SA308474ID_58D1 Placebo M
SA308475ID_73D1 Placebo M
SA308476ID_94D1 Placebo M
SA308477ID_83D1 Placebo M
SA308478ID_88D5 MP F
SA308479ID_7D5 MP F
SA308480ID_169D5 MP F
SA308481ID_115D5 MP F
SA308482ID_174D5 MP M
SA308483ID_209D5 MP M
SA308484ID_119D5 MP M
SA308485ID_98D5 MP M
SA308486ID_163D5 MP M
SA308487ID_194D5 MP M
SA308488ID_100D5 MP M
SA308489ID_183D5 MP M
SA308490ID_93D5 MP M
SA308491ID_123D5 MP M
SA308492ID_111D5 MP M
SA308493ID_81D5 MP M
SA308494ID_43D5 Placebo F
SA308495ID_131D5 Placebo F
SA308496ID_42D5 Placebo F
SA308497ID_153D5 Placebo F
SA308498ID_185D5 Placebo M
SA308499ID_166D5 Placebo M
SA308500ID_18D5 Placebo M
SA308501ID_39D5 Placebo M
SA308502ID_2D5 Placebo M
SA308503ID_190D5 Placebo M
SA308504ID_55D5 Placebo M
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Collection:

Collection ID:CO002950
Collection Summary:The COVID-19 infected participants in this study were drawn from the MetCOVID study, a parallel, double blind, randomized, placebo-controlled Phase IIb clinical trial, that assessed the efficacy of MP in treating hospitalized patients with suspected SARS-CoV-2 infection. Individuals with COVID-19 were admitted at the Hospital e Pronto-Socorro Delphina Rinaldi Abdel Aziz, in Manaus, Western Brazilian Amazon. The hospital was the largest public reference unit for the treatment of severe COVID-19 cases in the city. After confirmation of SARS-CoV-2 infection by RT-qPCR testing of nasopharyngeal swabs, blood was collected from patients and the separated plasma was stored at -80oC. The plasma samples were collected at the day of inclusion (D1) before treatment, and day five (D5), day seven (D7), day eleven (D11), and day fourteen (D14) after the start of treatment for metabolomic analysis.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR002966
Treatment Summary:The participants were administered with either intravenous sodium succinate MP (0.5 mg/kg) or placebo (saline solution) twice daily for 5 days. As per hospital protocol, all patients meeting acute respiratory distress syndrome criteria also preemptively received intravenous ceftriaxone (1g twice daily for 7 days) plus azithromycin (500 mg once a day for 5 days) or clarithromycin (500 mg twice daily for 7 days), starting on Day 1. At inclusion, adult patients were excluded if they had a history of hypersensitivity to MP, were living with human immunodeficiency virus or AIDS, had a history of chronic use of corticosteroids or immunosuppressive agents, were pregnant or breastfeeding, or had decompensated cirrhosis or chronic renal failure.

Sample Preparation:

Sampleprep ID:SP002963
Sampleprep Summary:Metabolites were extracted from plasma samples using acetonitrile (2:1, v/v). Stable isotopes caffeine-¹³C3 and progesterone-d9 were used as internal standards.

Combined analysis:

Analysis ID AN004663
Analysis type MS
Chromatography type Reversed phase
Chromatography system Agilent 1220 Infinity
Column Agilent Zorbax Eclipse Plus C18 (150 x 4.6mm,3.5um)
MS Type ESI
MS instrument type Orbitrap
MS instrument name Thermo Q Exactive Orbitrap
Ion Mode POSITIVE
Units intesity

Chromatography:

Chromatography ID:CH003509
Chromatography Summary:The binary mobile phases were water 0.5% formic acid with 5 mM of ammonium formate (A), and acetonitrile (B). Their gradient elution started with 20% (B) for 5 min, then linearly increased to 100% (B) in 30 min and kept constant for 8 min in 100% (B). The eluent was restored to the initial conditions in 4 minutes to re-equilibrate the column and held for the remaining 8 minutes. The flow rate was kept at 0.5 mL min-1. The injection volume for analysis was 3 μL, and the column temperature was set at 35 °C.
Instrument Name:Agilent 1220 Infinity
Column Name:Agilent Zorbax Eclipse Plus C18 (150 x 4.6mm,3.5um)
Column Temperature:35
Flow Gradient:gradient elution started with 20% (B) for 5 min, then linearly increased to 100% (B) in 30 min and kept constant for 8 min in 100% (B). The eluent was restored to the initial conditions in 4 minutes to re-equilibrate the column and held for the remaining 8 minutes.
Flow Rate:0.5 mL/min
Solvent A:100% water; 0.5% formic acid; 5 mM of ammonium formate
Solvent B:100% acetonitrile
Chromatography Type:Reversed phase

MS:

MS ID:MS004410
Analysis ID:AN004663
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The electrospray ionization was operating with the following settings: spray voltage 3.5 kV; capillary temperature: 269 °C; S-lens RF level 50 V; sheath gas flow rate at 53 L min-1; aux gas flow rate at 14 L min-1; sweep gas flow rate 3 L min-1. The high-resolution mass-spectrometry was obtained under full MS/dd-MS2 mode. The mass range in the full MS scanning experiments was m/z 80-1200. The max IT was set at 200 ms, and AGC target was set at 1 x 106. For fragmentation acquisition, the top 5 (TopN, 5, loop count 5) most abundant precursors were sequentially transferred into the C-Trap (AGC target 1 x 105; max IT 50 ms) for collision. The collision energy for target analytes was 20, 30 and 35 eV. Resolving power was set at 140,000 and 70,000 for full MS and dd-MS2 acquisitions, respectively.
Ion Mode:POSITIVE
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