Evidence for a specific anti-inflammatory metabolic signature in long-COVID

A recent research paper posted to the medRxiv* preprint server illustrated anti-inflammatory and hypo-metabolic fingerprints in long coronavirus disease (COVID) syndrome (LCS) using pan-omics plasma assessments.

Study: Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome – an exploratory study. Image Credit: Dmitry Demidovich / ShutterstockStudy: Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome – an exploratory study. ​​​​​​​Image Credit: Dmitry Demidovich / Shutterstock


Long COVID, also known as post-acute COVID syndrome (PACS), is a novel somatic illness group caused by the prolonged persistence of COVID-19 symptoms following acute infection.

Long COVID patients typically experience generalized fatigue, poor physical fitness and concentration, postural tachycardia, dyspnea, and a wide range of other clinical symptoms, significantly reducing the quality of life. Due to the high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection incidence globally, LCS prevalence might dramatically rise in the coming years, creating new long-term challenges for the health sector and adding to the burden of COVID-19.

Despite the increasing number of individuals with long COVID, the pathogenesis of the condition is still unknown, making diagnosis and treatment difficult and non-standardized.

About the study

Given the paucity of evidence regarding long COVID pathophysiological pathways, in the current work, the Austrian research team decided to conduct a large-scale exploratory investigation examining the lipidome, proteome, and metabolome among LCS patients. They recruited healthy people who had received COVID-19 vaccinations and people who had fully recovered from acute SARS-CoV-2 infection as control cohorts.

In a thorough exploratory screening analysis, the researchers used advanced post-genomic profiling techniques on blood plasma collected from three groups: 1) symptomatic COVID-19 patients at least three months following a SARS-CoV-2 infection, referred to as LCS patients in this study, 2) COVID-19 vaccinated healthy subjects lacking exposure to the whole virus, and 3) asymptomatic fully recovered COVID-19 patients about three months post-SARS-CoV-2 infection.

Besides, all study subjects were recruited from May to June 2021. The scientists enrolled PACS patients from the internal medicine's outpatient ward at the Medical University of Vienna, Austria. The sex and age-matched healthy/recovered and the vaccinated/healthy study cohorts were recruited among subjects following calls at the University of Applied Sciences, Vienna, Austria, and the Medical University of Vienna/Vienna General Hospital.


The scientists presented unambiguous proof of systemic anti-inflammatory conditions in PACS patients, contrary to the acute SARS-CoV-2 infection scenario. The proportions of cytokines, oxylipins, acute phase proteins, and metabolites in blood plasma were independently predominated by anti-inflammatory mediators and devoid of proinflammatory activity. Additionally, metabolomics investigations strongly suggested a mostly catabolic metabolism among LCS patients, possibly explaining the defining symptoms of chronic exhaustion (CFS).

Three indicators among the identified cytokines, chemokines, and soluble receptors: soluble tumor necrosis factor receptor II (TNF-RII), interleukin 18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1/CCL2), were considerably down-regulated among the LCS cohort. Acute-phase proteins were down-regulated in the proteome and were particularly obvious between the recovered and the LCS cohort. Notably, serpin family A member 5 (SERPINA5) levels were considerably lower in the LCS cohort than in the healthy and convalescent groups, revealing a distinctive characteristic of LCS.

Furthermore, since the most drastically down-regulated proteins in LCS patients directly influenced macrophage activity or were derived from macrophages, the identified proteome trends imply variable macrophage/monocyte polarization and function between the LCS and the recovered cohort. Independent proof of an anti-inflammatory condition was demonstrated by the patterns seen in the lipidome of LCS patients. Accordingly, the investigators discovered elevated amounts of docosahexaenoic acid (DHA), its metabolites, and other docosanoids among LCS patients.

The current metabolomics results showed a lack of inflammatory mechanisms in LCS. The PACS patients had significantly higher osmolyte taurine versus the other two groups. Hypaphorine or TrpBetaine was the metabolite that was up-regulated considerably in LCS patients. In contrast, the recovered group had significantly higher levels of hypoxanthine, accompanied by other signs of tissue hypoxia as seen in acute inflammation, while LCS patients had levels more in line with the healthy group.

The metabolome investigations revealed the first clues suggesting an abnormal amino acid metabolism in LCS, in addition to the overall pattern of anti-inflammation. In line with this, branched-chain amino acid levels, especially glucogenic and ketogenic amino acids, were markedly reduced in the PACS group. This finding provides evidence for higher protein breakdown-related energy consumption.

The present data also depicts the mechanisms of successful recovery following acute COVID-19. The symptom-free recovered subjects demonstrated variations in most measured metrics across the distinct biomolecular compartments relative to the healthy control cohort. These inferences showed that systemic mechanisms were still functioning in these people months after an acute infection. Therefore, long after symptomatic improvement, COVID-19 may still leave molecular traces, like infected macrophages.


Overall, the molecular patterns obtained from the current research offer initial insights into the pathophysiology of SARS-CoV-2 sequelae and also serve as a starting foundation for defining LCS-specific biomarkers. Unfortunately, the present large-scale analyses did not find a distinct and precise marker for PACS. However, numerous relevant molecular changes can be linked to the disease's recognizable symptoms. 

Additionally, a combination of currently described docosanoids (like high DHA), proteins (like low SERPINA5), and small metabolites (like high hypaphorine) among patients with characteristic anamnesis and symptoms might aid in the identification and improved definition of LCS. Indeed, more research is needed to evaluate the possible sensitivity and specificity of such ratings, considering various SARS-CoV-2 strains.

In summary, the present study provides evidence for a unique anti-inflammatory and highly distinctive metabolic fingerprint in long COVID, which may be beneficial for future diagnostic needs and support the development of logical treatment strategies in these patients.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study; Johannes J Kovarik, Andrea Bileck, Gerhard Hagn, Samuel M Meier-Menches, Tobias Frey, Anna Kaempf, Marlene Hollenstein, Tarik Shoumariyeh, Lukas Skos, Birgit Reiter, Marlene C Gerner, Andreas Spannbauer, Ena Hasimbegovic, Doreen Schmidl, Gerhard Garhoefer, Mariann Gyoengyoesi, Klaus G Schmetterer, Christopher Gerner. medRxiv preprint 2022, DOI: https://doi.org/10.1101/2022.07.11.22277499https://www.medrxiv.org/content/10.1101/2022.07.11.22277499v1
Shanet Susan Alex

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Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.


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