Metabolic Changes in Severe COVID-19 Patients: Implications for Pathophysiology and Disease Outcome


The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact worldwide, with millions of confirmed cases and deaths.

Despite the development and widespread administration of vaccines that have significantly reduced severe cases, it is expected that COVID-19 will persist and transition into an endemic state.

As the virus continues to evolve and affect millions, understanding the underlying molecular mechanisms of COVID-19 pathophysiology remains crucial for improved clinical management and identifying potential therapeutic targets.

COVID-19 Complexity and Post-Acute Sequelae

COVID-19 is a complex multisystemic disease that can lead to severe tissue damage and systemic immune responses. Even after recovery from the initial infection, around 20% of individuals may experience long-term symptoms, referred to as post-acute COVID-19 syndrome. T

his condition can result in various debilitating alterations, including neurological, gastrointestinal, pulmonary, and cardiovascular issues. Despite advancements in treatment, the molecular mechanisms underlying disease severity and post-acute symptoms are not yet fully understood.

Metabolomics: A System-Level Approach

Metabolomics, a central omics approach, plays a pivotal role in providing insights into the metabolic signature of organs and biological fluids under different conditions. This technique has been instrumental in understanding and managing other viral diseases such as Dengue, Chikungunya, SARS, and Zika.

The study of host energy, amino acid, and lipid metabolism alterations during viral infections is critical as viruses often manipulate these pathways for their own benefit and to modulate the host immune response.

Role of Host Lipid Metabolism in SARS-CoV-2 Replication

Coronaviruses, including SARS-CoV-2, are known to modulate host lipid metabolism, which is essential for viral RNA replication and assembly of viral particles. Accumulation of lipid droplets in monocytes isolated from COVID-19 patients has been observed, serving as assembly platforms for the virus.

SARS-CoV-2 non-structural protein 6 plays a crucial role in orchestrating lipid flow within cells, enabling viral replication and communication with lipid droplets. Understanding these lipid metabolic alterations could potentially lead to the development of targeted therapies.

Metabolic Alterations in COVID-19: Insights from Multi-Omics Studies

Several multi-omics studies have shed light on the metabolic alterations associated with COVID-19 severity. Proteomics and metabolomics analyses have revealed metabolic and immune dysregulation in mild and severe COVID-19 patients. Notably, more than 100 lipid species, including glycerophospholipids, fatty acids, and lipoproteins, were downregulated in COVID-19 patients compared to controls. Amino acid metabolism was also affected, with low levels of plasma tryptophan being associated with inflammation and COVID-19 severity.

Potential Markers for Fatal Outcomes

While the metabolic alterations associated with severe COVID-19 have been explored, the specific differences that may distinguish fatal cases have not been fully addressed. Therefore, this study aims to characterize in-depth the metabolic alterations associated with severe COVID-19, including survivors and non-survivors.

By employing advanced techniques such as 1H Nuclear Magnetic Resonance (NMR) spectroscopy and Liquid Chromatography-High-Resolution Mass spectrometry (LC-HRMS)-based metabolomics, a well-characterized prospective cohort of patients from Rio de Janeiro, Brazil, between April and July 2020 will be analyzed.

One-Carbon Metabolism, Lipid, and Amino Acid Metabolism

The study particularly focuses on investigating metabolites associated with one-carbon metabolism, lipid metabolism, and amino acid metabolism. These metabolic pathways have been implicated in COVID-19 pathophysiology, and understanding their alterations in severe cases may provide valuable insights into disease progression and potential biomarkers for fatal outcomes.

Implications for Post-Acute COVID-19 Syndrome

Given the high incidence of post-acute severe outcomes after hospital discharge, understanding acute pathophysiological mechanisms that may lead to post-acute COVID-19 syndrome is crucial. The metabolic alterations identified in this study may offer clues to monitor patients’ organ and tissue function and provide a better understanding of the underlying mechanisms that contribute to post-acute symptoms.

The Present Study

The present study aimed to investigate plasma metabolic changes in severe COVID-19 patients upon admission to the ICU and their association with mortality. The goal was to explore potential metabolic pathways involved in severe COVID-19 pathophysiology and disease outcome.

The researchers identified significant changes in various metabolites, indicating dysregulation in one-carbon, lipid, and amino acid metabolism, as well as lipoprotein dynamics.

Metabolites Associated with Uncontrolled Inflammation and Multi-Organ Dysfunction

In the study, higher plasma levels of creatine/creatinine, 4-hydroxyproline, gluconic acid, and N-acetylserine were observed in non-survivors compared to survivors and control groups.

These metabolites were associated with uncontrolled inflammation, multi-organ dysfunction, particularly affecting the liver and kidneys, and some degree of insulin resistance, all of which were linked to fatal COVID-19 outcomes.

Gluconic Acid and Oxidative Stress

Gluconic acid, previously linked to hyperglycemia and brain injury in ischemic stroke, was identified as a marker of oxidative stress in severe COVID-19 patients.

N-Acetylserine and Kidney Disease Progression

The presence of N-acetylserine, associated with SARS-CoV-2 infection and COVID-19 pathogenesis, was indicative of kidney disease progression in severe COVID-19 cases.

Creatine/Creatinine and Insulin Sensitivity

Higher levels of creatine/creatinine were associated with lower sensitivity to insulin, suggesting detrimental effects on metabolic health and immune responses due to SARS-CoV-2 infection.

4-Hydroxyproline and Liver Dysfunction

Elevated levels of 4-hydroxyproline indicated a disruption in the one-carbon metabolism pathway, leading to liver dysfunction and decreased availability of glycine.

Metabolic Alterations and Lipoprotein Dynamics

Severe COVID-19 significantly altered lipoprotein dynamics, as evidenced by lower total cholesterol and HDL- and LDL-cholesterol levels and higher VLDL and triacylglycerols in fatal cases. Choline-related metabolites, critical for one-carbon metabolism, played a protective role at ICU admission.

Implications of Altered Amino Acid Metabolism

Severe COVID-19 induced substantial changes in amino acid metabolism, including lower levels of alanine, BCAA, glutamine, tryptophan, glycine, and tyrosine. These changes may indicate increased amino acid catabolism to support viral replication and provide carbon and ATP.

Gender Differences in Metabolic Disturbances

Interestingly, the study revealed gender differences in metabolic alterations. While men are more vulnerable to severe COVID-19, women showed greater changes in key metabolites like choline metabolites, creatinine/creatinine, N-acetyl glycoproteins, and acetoacetate, suggesting potential sex-based differences in disease progression and post-acute COVID syndrome susceptibility.


This study shed light on the significant metabolic changes occurring in severe COVID-19 patients upon ICU admission. The identified metabolites associated with uncontrolled inflammation, multi-organ dysfunction, and insulin resistance offer potential prognostic biomarkers for assessing disease severity and outcomes.

Additionally, insights into one-carbon metabolism disruption, amino acid imbalances, and lipoprotein dynamics provide a better understanding of severe COVID-19 pathophysiology. Considering sex-based differences in metabolic responses could lead to more personalized and effective treatment strategies for COVID-19 patients. Further research in this area is essential to harness this knowledge for improved patient care and management during the ongoing pandemic and beyond.

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