{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T00:09:19Z","timestamp":1793664559737,"version":"4.5.1"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Higher Education and Scientific Research of Tunisia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Severe Coronavirus disease 2019 (COVID-19) is associated with abnormal innate and adaptive immune responses, as well as systemic alterations, including a shift in lipid network. A case\u2013control study was conducted to describe the systemic lipidomic profile in COVID-19 according to disease severity. Selected polyunsaturated fatty acids (PUFAs), oxylipins, and endocannabinoids were analysed using a targeted liquid chromatography coupled to mass spectrometry in tandem method. Multivariate receiver operating characteristic curve-based model evaluation was performed to define a lipidomic signature for the disease. A total of 135 hospitalized COVID-19 patients, of whom 85 had severe form, and 134 healthy individuals were included. Patients exhibited increased levels of free PUFAs, proinflammatory and pro-resolving oxylipins, and endocannabinoids compared to controls. A combination of five lipid mediators, i.e., prostaglandin D2, prostaglandin E2, thromboxane B2, lipoxin B4, and 2-archidonylglycerol, discriminates patients from control individuals with excellent accuracy [AUC, 0.977 (0.950\u20130.995)]. The severe form is characterized by an imbalance between proinflammatory and pro-resolving oxylipins and increased endocannabinoids. COVID-19 is associated with a lipid storm that conditions disease severity. Targeting lipid mediators-related metabolic and signalling pathways could be an interesting therapeutic option in severe forms.<\/jats:p>","DOI":"10.3390\/microorganisms13112622","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T10:02:13Z","timestamp":1763546533000},"page":"2622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["COVID-19 is Associated with a Lipid Storm that Worsens in Cases of Severe Pneumonia"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6423-8996","authenticated-orcid":false,"given":"Amani","family":"Bouabdallah","sequence":"first","affiliation":[{"name":"Faculty of Medicine of Tunis, University of Tunis El Manar, Jebbari, Tunis 1007, Tunisia"},{"name":"Laboratory of Biochemistry, Rabta Hospital, LR99ES11, Jebbari, Tunis 1007, Tunisia"},{"name":"Service of Infectious Diseases, Rabta Hospital, Jebbari, Tunis 1007, Tunisia"},{"name":"Department of Infectious Diseases and Tropical Medicine, H\u00f4pital Nord-Franche-Comt\u00e9, 90400 Belfort-Montb\u00e9liard, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Kacem","family":"Ben-Fradj","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis, University of Tunis El Manar, Jebbari, Tunis 1007, Tunisia"},{"name":"Laboratory of Biochemistry, Rabta Hospital, LR99ES11, Jebbari, Tunis 1007, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9391-3321","authenticated-orcid":false,"given":"Mohamed Bessem","family":"Hammami","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis, University of Tunis El Manar, Jebbari, Tunis 1007, Tunisia"},{"name":"Laboratory of Biochemistry, Rabta Hospital, LR99ES11, Jebbari, Tunis 1007, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rim","family":"Abdelmalek","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis, University of Tunis El Manar, Jebbari, Tunis 1007, Tunisia"},{"name":"Service of Infectious Diseases, Rabta Hospital, Jebbari, Tunis 1007, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifa","family":"Sanhaji","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis, University of Tunis El Manar, Jebbari, Tunis 1007, Tunisia"},{"name":"Laboratory of Biochemistry, Rabta Hospital, LR99ES11, Jebbari, Tunis 1007, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4334-9889","authenticated-orcid":false,"given":"Timoth\u00e9e","family":"Klopfenstein","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Tropical Medicine, H\u00f4pital Nord-Franche-Comt\u00e9, 90400 Belfort-Montb\u00e9liard, France"},{"name":"Clinical Research Unit, H\u00f4pital Nord-Franche-Comt\u00e9, 90400 Belfort-Montb\u00e9liard, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1585-4052","authenticated-orcid":false,"given":"Moncef","family":"Feki","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis, University of Tunis El Manar, Jebbari, Tunis 1007, Tunisia"},{"name":"Laboratory of Biochemistry, Rabta Hospital, LR99ES11, Jebbari, Tunis 1007, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","unstructured":"(2025, September 19). COVID-19 Deaths|WHO COVID-19 Dashboard. Available online: http:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lopes-Pacheco, M., Silva, P.L., Cruz, F.F., Battaglini, D., Robba, C., Pelosi, P., Morales, M.M., Neves, C.C., and Rocco, P.R.M. (2021). Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.593223"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Silva, M.J.A., Ribeiro, L.R., Gouveia, M.I.M., Marcelino, B.d.R., Santos, C.S.d., Lima, K.V.B., and Lima, L.N.G.C. (2023). Hyperinflammatory Response in COVID-19: A Systematic Review. Viruses, 15.","DOI":"10.3390\/v15020553"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101165","DOI":"10.1016\/j.plipres.2022.101165","article-title":"Polyunsaturated Fatty Acids and Fatty Acid-Derived Lipid Mediators: Recent Advances in the Understanding of Their Biosynthesis, Structures, and Functions","volume":"86","author":"Dyall","year":"2022","journal-title":"Prog. Lipid Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nri2294","article-title":"Resolving Inflammation: Dual Anti-Inflammatory and Pro-Resolution Lipid Mediators","volume":"8","author":"Serhan","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature13479","article-title":"Novel Pro-Resolving Lipid Mediators in Inflammation Are Leads for Resolution Physiology","volume":"510","author":"Serhan","year":"2014","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.2353\/ajpath.2010.100322","article-title":"Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation: To Resolve or Not?","volume":"177","author":"Serhan","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd1495","article-title":"The Endocannabinoid System and Its Therapeutic Exploitation","volume":"3","author":"Marzo","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cytogfr.2020.05.003","article-title":"The Cytokine Storm in COVID-19: An Overview of the Involvement of the Chemokine\/Chemokine-Receptor System","volume":"53","author":"Coperchini","year":"2020","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"329","DOI":"10.4049\/jimmunol.2001025","article-title":"Cutting Edge: Severe SARS-CoV-2 Infection in Humans Is Defined by a Shift in the Serum Lipidome, Resulting in Dysregulation of Eicosanoid Immune Mediators","volume":"206","author":"Schwarz","year":"2021","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1161\/CIRCRESAHA.121.319142","article-title":"Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in COVID-19","volume":"129","author":"Koenis","year":"2021","journal-title":"Circ. Res."},{"key":"ref_12","first-page":"6782","article-title":"Acute Severe SARS COVID-19 Patients Produce pro-Resolving Lipids Mediators and Eicosanoids","volume":"25","author":"Regidor","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"McReynolds, C.B., Cortes-Puch, I., Ravindran, R., Khan, I.H., Hammock, B.G., Shih, P.-A.B., Hammock, B.D., and Yang, J. (2021). Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.663869"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Palmas, F., Clarke, J., Colas, R.A., Gomez, E.A., Keogh, A., Boylan, M., McEvoy, N., McElvaney, O.J., McElvaney, O., and Alalqam, R. (2021). Dysregulated Plasma Lipid Mediator Profiles in Critically Ill COVID-19 Patients. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0256226"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"250","DOI":"10.4049\/jimmunol.2200079","article-title":"Acetylcholine, Fatty Acids, and Lipid Mediators re Linked to COVID-19 Severity","volume":"209","author":"Pimentel","year":"2022","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"155197","DOI":"10.1016\/j.metabol.2022.155197","article-title":"Machine Learning and Semi-Targeted Lipidomics Identify Distinct Serum Lipid Signatures in Hospitalized COVID-19-Positive and COVID-19-Negative Patients","volume":"131","author":"Iftimie","year":"2022","journal-title":"Metabolism"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Karu, N., Kindt, A., Lamont, L., van Gammeren, A.J., Ermens, A.A.M., Harms, A.C., Portengen, L., Vermeulen, R.C.H., Dik, W.A., and Langerak, A.W. (2022). Plasma Oxylipins and Their Precursors Are Strongly Associated with COVID-19 Severity and with Immune Response Markers. Metabolites, 12.","DOI":"10.3390\/metabo12070619"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"047103","DOI":"10.1088\/1752-7163\/acea3d","article-title":"Oxylipin Concentration Shift in Exhaled Breath Condensate (EBC) of SARS-CoV-2 Infected Patients","volume":"17","author":"Borras","year":"2023","journal-title":"J. Breath Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.freeradbiomed.2022.01.021","article-title":"MS-Based Targeted Profiling of Oxylipins in COVID-19: A New Insight into Inflammation Regulation","volume":"180","author":"Biagini","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1093\/infdis\/jiab632","article-title":"Serum Levels of Proinflammatory Lipid Mediators and Specialized Proresolving Molecules Are Increased in Patients with Severe Acute Respiratory Syndrome Coronavirus 2 and Correlate with Markers of the Adaptive Immune Response","volume":"225","author":"Turnbull","year":"2022","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ir\u00fan, P., Gracia, R., Piazuelo, E., Pardo, J., Morte, E., Pa\u00f1o, J.R., Boza, J., Carrera-Lasfuentes, P., Higuera, G.A., and Lanas, A. (2023). Serum Lipid Mediator Profiles in COVID-19 Patients and Lung Disease Severity: A Pilot Study. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-33682-2"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"de Carvalho, J.C.S., da Silva-Neto, P.V., Toro, D.M., Fuzo, C.A., Nardini, V., Pimentel, V.E., P\u00e9rez, M.M., Fraga-Silva, T.F.C., Oliveira, C.N.S., and Degiovani, A.M. (2023). The Interplay among Glucocorticoid Therapy, Platelet-Activating Factor and Endocannabinoid Release Influences the Inflammatory Response to COVID-19. Viruses, 15.","DOI":"10.3390\/v15020573"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Velasco, M., Posada-Ayala, M., P\u00e9rez-Fern\u00e1ndez, E., Loria, F., Amores, M., Ramos, J.M., Jaime, E., Guijarro, C., Romero, J., and Pazos, M.R. (2024). Circulating Endocannabinoid Levels in SARS-CoV-2 Infection and Their Potential Role in the Inflammatory Response. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-70172-5"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.amjms.2025.06.003","article-title":"Elevated Blood Anandamide Levels in Acute COVID-19 Pneumonia with Respiratory Failure","volume":"370","author":"Basu","year":"2025","journal-title":"Am. J. Med. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101276","DOI":"10.1016\/j.plipres.2024.101276","article-title":"Oxylipin Profiling for Clinical Research: Current Status and Future Perspectives","volume":"95","author":"Parchem","year":"2024","journal-title":"Prog. Lipid Res."},{"key":"ref_26","unstructured":"Ministry of Health of Tunisia (2025, August 10). [Situation Update in Tunisia\u2014Coronavirus]. Point de Situation en Tunisie\u2014Coronavirus. Available online: http:\/\/coronavirus.rns.tn\/point-de-situation-en-tunisie\/."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Farhan, A., Ayed, K., Zayati, S., Akrout, R., Dlala, A., Abouda, A., Zoghlami, N., Mahjoubi, H., Labbane, I., and Gati, A. (2025). Optimizing Clinical Management of COVID-19: A Predictive Model for Unvaccinated Patients Admitted to ICU. Pathogens, 14.","DOI":"10.3390\/pathogens14030230"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"110624","DOI":"10.1016\/j.virol.2025.110624","article-title":"Impact of the COVID-19 Pandemic on the Molecular Epidemiology of Respiratory Rhinoviruses and Enteroviruses in Tunisia","volume":"610","author":"Smaoui","year":"2025","journal-title":"Virology"},{"key":"ref_29","unstructured":"(2025, September 18). Guideline Clinical Management of COVID-19 Patients: Living Guideline. 18 November 2021. Available online: https:\/\/iris.who.int\/server\/api\/core\/bitstreams\/670e3b89-b4ae-429b-abee-7b0d3d54af49\/content."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"106741","DOI":"10.1016\/j.prostaglandins.2023.106741","article-title":"Altered Mucosal and Plasma Polyunsaturated Fatty Acids, Oxylipins, and Endocannabinoids Profiles in Crohn\u2019s Disease","volume":"168","author":"Serghini","year":"2023","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.athoracsur.2004.09.040","article-title":"Summary Receiver Operating Characteristic Curve Analysis Techniques in the Evaluation of Diagnostic Tests","volume":"79","author":"Jones","year":"2005","journal-title":"Ann. Thorac. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s10555-020-09889-4","article-title":"Inflammation Resolution: A Dual-Pronged Approach to Averting Cytokine Storms in COVID-19?","volume":"39","author":"Panigrahy","year":"2020","journal-title":"Cancer Metastasis Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.5114\/aoms\/135703","article-title":"Bioactive Lipid-Based Therapeutic Approach to COVID-19 and Other Similar Infections","volume":"19","author":"Das","year":"2021","journal-title":"Arch. Med. Sci. AMS"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nri3859","article-title":"Eicosanoid Storm in Infection and Inflammation","volume":"15","author":"Dennis","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12746","DOI":"10.1073\/pnas.1404372111","article-title":"Phospholipase A2 Regulates Eicosanoid Class Switching During Inflammasome Activation","volume":"111","author":"Norris","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41392-020-00443-w","article-title":"Metabolism Pathways of Arachidonic Acids: Mechanisms and Potential Therapeutic Targets","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ajcnut.2022.12.007","article-title":"Bioactive Omega-3 Fatty Acids are Associated with Reduced Risk and Severity of SARS-CoV-2 Infection","volume":"117","author":"Calder","year":"2023","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100942","DOI":"10.1016\/j.lanmic.2024.07.005","article-title":"Immune Responses to SARS-CoV-2 in Sub-Saharan Africa and Western Europe: A Retrospective, Population-Based, Cross-Sectional Study","volume":"6","author":"Mbow","year":"2025","journal-title":"Lancet Microbe"},{"key":"ref_39","first-page":"308","article-title":"Efficacy of Omega-3 Fatty Acids for Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"32","author":"Yue","year":"2023","journal-title":"Asia Pac. J. Clin. Nutr."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/11\/2622\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T10:22:51Z","timestamp":1763547771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/11\/2622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["microorganisms13112622"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13112622","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}