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 ID	ST002845
Study Title	Methylprednisolone therapy induces differential metabolic trajectories in severe COVID-19 patients
Study 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 - Federal University of Goiás
Email	luizgardinassi@ufg.br
Phone	+55 62 3209-6530
Submit Date	2023-08-30
Raw Data Available	Yes
Raw Data File Type(s)	mzML
Analysis Type Detail	LC-MS
Release Date	2023-09-15
Release Version	1

Select appropriate tab below to view additional metadata details:

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
SA308405	ID_34	D11 \| Treatment:MP \| Sex:F
SA308406	ID_67	D11 \| Treatment:MP \| Sex:F
SA308407	ID_3	D11 \| Treatment:MP \| Sex:F
SA308408	ID_113	D11 \| Treatment:MP \| Sex:M
SA308409	ID_63	D11 \| Treatment:MP \| Sex:M
SA308410	ID_31	D11 \| Treatment:MP \| Sex:M
SA308411	ID_116	D11 \| Treatment:MP \| Sex:M
SA308412	ID_198	D11 \| Treatment:MP \| Sex:M
SA308413	ID_99	D11 \| Treatment:MP \| Sex:M
SA308414	ID_159	D11 \| Treatment:MP \| Sex:M
SA308415	ID_201	D11 \| Treatment:MP \| Sex:M
SA308416	ID_80	D11 \| Treatment:MP \| Sex:M
SA308417	ID_14	D11 \| Treatment:MP \| Sex:M
SA308418	ID_118	D11 \| Treatment:MP \| Sex:M
SA308419	ID_137	D11 \| Treatment:Placebo \| Sex:F
SA308420	ID_21	D11 \| Treatment:Placebo \| Sex:F
SA308421	ID_204	D11 \| Treatment:Placebo \| Sex:M
SA308422	ID_208	D11 \| Treatment:Placebo \| Sex:M
SA308423	ID_78	D11 \| Treatment:Placebo \| Sex:M
SA308424	ID_108	D11 \| Treatment:Placebo \| Sex:M
SA308425	ID_180	D11 \| Treatment:Placebo \| Sex:M
SA308426	ID_91	D11 \| Treatment:Placebo \| Sex:M
SA308427	ID_173	D11 \| Treatment:Placebo \| Sex:M
SA308428	ID_146	D14 \| Treatment:MP \| Sex:F
SA308429	ID_165	D14 \| Treatment:MP \| Sex:F
SA308430	ID_191	D14 \| Treatment:MP \| Sex:M
SA308431	ID_188	D14 \| Treatment:MP \| Sex:M
SA308432	ID_71	D14 \| Treatment:MP \| Sex:M
SA308433	ID_27	D14 \| Treatment:MP \| Sex:M
SA308434	ID_56	D14 \| Treatment:MP \| Sex:M
SA308435	ID_11	D14 \| Treatment:MP \| Sex:M
SA308436	ID_86	D14 \| Treatment:MP \| Sex:M
SA308437	ID_51	D14 \| Treatment:MP \| Sex:M
SA308438	ID_141	D14 \| Treatment:MP \| Sex:M
SA308439	ID_1	D14 \| Treatment:MP \| Sex:M
SA308440	ID_77	D14 \| Treatment:Placebo \| Sex:F
SA308441	ID_167	D14 \| Treatment:Placebo \| Sex:F
SA308442	ID_177	D14 \| Treatment:Placebo \| Sex:M
SA308443	ID_124	D14 \| Treatment:Placebo \| Sex:M
SA308444	ID_132	D14 \| Treatment:Placebo \| Sex:M
SA308445	ID_156	D14 \| Treatment:Placebo \| Sex:M
SA308446	ID_96	D14 \| Treatment:Placebo \| Sex:M
SA308447	ID_172	D1 \| Treatment:MP \| Sex:F
SA308448	ID_110	D1 \| Treatment:MP \| Sex:F
SA308449	ID_181	D1 \| Treatment:MP \| Sex:F
SA308450	ID_32	D1 \| Treatment:MP \| Sex:F
SA308451	ID_101	D1 \| Treatment:MP \| Sex:M
SA308452	ID_155	D1 \| Treatment:MP \| Sex:M
SA308453	ID_176	D1 \| Treatment:MP \| Sex:M
SA308454	ID_151	D1 \| Treatment:MP \| Sex:M
SA308455	ID_145	D1 \| Treatment:MP \| Sex:M
SA308456	ID_127	D1 \| Treatment:MP \| Sex:M
SA308457	ID_107	D1 \| Treatment:MP \| Sex:M
SA308458	ID_49	D1 \| Treatment:MP \| Sex:M
SA308459	ID_20	D1 \| Treatment:MP \| Sex:M
SA308460	ID_90	D1 \| Treatment:MP \| Sex:M
SA308461	ID_85	D1 \| Treatment:MP \| Sex:M
SA308462	ID_37	D1 \| Treatment:MP \| Sex:M
SA308463	ID_6	D1 \| Treatment:Placebo \| Sex:F
SA308464	ID_66	D1 \| Treatment:Placebo \| Sex:F
SA308465	ID_75	D1 \| Treatment:Placebo \| Sex:F
SA308466	ID_148	D1 \| Treatment:Placebo \| Sex:F
SA308467	ID_25	D1 \| Treatment:Placebo \| Sex:M
SA308468	ID_9	D1 \| Treatment:Placebo \| Sex:M
SA308469	ID_16	D1 \| Treatment:Placebo \| Sex:M
SA308470	ID_29	D1 \| Treatment:Placebo \| Sex:M
SA308471	ID_161	D1 \| Treatment:Placebo \| Sex:M
SA308472	ID_139	D1 \| Treatment:Placebo \| Sex:M
SA308473	ID_135	D1 \| Treatment:Placebo \| Sex:M
SA308474	ID_58	D1 \| Treatment:Placebo \| Sex:M
SA308475	ID_73	D1 \| Treatment:Placebo \| Sex:M
SA308476	ID_94	D1 \| Treatment:Placebo \| Sex:M
SA308477	ID_83	D1 \| Treatment:Placebo \| Sex:M
SA308478	ID_88	D5 \| Treatment:MP \| Sex:F
SA308479	ID_7	D5 \| Treatment:MP \| Sex:F
SA308480	ID_169	D5 \| Treatment:MP \| Sex:F
SA308481	ID_115	D5 \| Treatment:MP \| Sex:F
SA308482	ID_174	D5 \| Treatment:MP \| Sex:M
SA308483	ID_209	D5 \| Treatment:MP \| Sex:M
SA308484	ID_119	D5 \| Treatment:MP \| Sex:M
SA308485	ID_98	D5 \| Treatment:MP \| Sex:M
SA308486	ID_163	D5 \| Treatment:MP \| Sex:M
SA308487	ID_194	D5 \| Treatment:MP \| Sex:M
SA308488	ID_100	D5 \| Treatment:MP \| Sex:M
SA308489	ID_183	D5 \| Treatment:MP \| Sex:M
SA308490	ID_93	D5 \| Treatment:MP \| Sex:M
SA308491	ID_123	D5 \| Treatment:MP \| Sex:M
SA308492	ID_111	D5 \| Treatment:MP \| Sex:M
SA308493	ID_81	D5 \| Treatment:MP \| Sex:M
SA308494	ID_43	D5 \| Treatment:Placebo \| Sex:F
SA308495	ID_131	D5 \| Treatment:Placebo \| Sex:F
SA308496	ID_42	D5 \| Treatment:Placebo \| Sex:F
SA308497	ID_153	D5 \| Treatment:Placebo \| Sex:F
SA308498	ID_185	D5 \| Treatment:Placebo \| Sex:M
SA308499	ID_166	D5 \| Treatment:Placebo \| Sex:M
SA308500	ID_18	D5 \| Treatment:Placebo \| Sex:M
SA308501	ID_39	D5 \| Treatment:Placebo \| Sex:M
SA308502	ID_2	D5 \| Treatment:Placebo \| Sex:M
SA308503	ID_190	D5 \| Treatment:Placebo \| Sex:M
SA308504	ID_55	D5 \| Treatment:Placebo \| Sex: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.

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