{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:39:52Z","timestamp":1792132792516,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Region Stockholm, Karolinska University Hospital","award":["H556916013"],"award-info":[{"award-number":["H556916013"]}]},{"name":"Hj\u00e4rt-Lungfonden","award":["H556916013"],"award-info":[{"award-number":["H556916013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Critically ill COVID-19 patients with pleural effusion experience longer hospitalization, multisystem inflammatory syndrome, and higher rates of mortality. Generally, pleural effusion can serve as a diagnostic value to differentiate cytokine levels. This study aimed to evaluate the pleural effusions of COVID-19 deceased patients for 182 protein markers. Olink\u00ae Inflammation and Organ Damage panels were used to determine the level of 184 protein markers, e.g., ADA, BTC, CA12, CAPG, CD40, CDCP1, CXCL9, ENTPD2, Flt3L, IL-6, IL-8, LRP1, OSM, PD-L1, PTN, STX8, and VEGFA, which were raised significantly in COVID-19 deceased patients, showing over-stimulation of the immune system and ravaging cytokine storm. The rises of DPP6 and EDIL3 also indicate damage caused to arterial and cardiovascular organs. Overall, this study confirms the elevated levels of CA12, CD40, IL-6, IL-8, PD-L1, and VEGFA, proposing their potential either as biomarkers for the severity and prognosis of the disease or as targets for therapy. Particularly, this study reports upregulated ADA, BTC, DPP6, EDIL3, LIF, ENTPD2, Flt3L, and LRP1 in severe COVID-19 patients for the first time. Pearson\u2019s correlation coefficient analysis indicates the involvement of JAK\/STAT pathways as a core regulator of hyperinflammation in deceased COVID-19 patients, suggesting the application of JAK inhibitors as a potential efficient treatment.<\/jats:p>","DOI":"10.3390\/diagnostics12112789","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T02:31:15Z","timestamp":1668479475000},"page":"2789","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Proteomic Analysis of Pleural Effusions from COVID-19 Deceased Patients: Enhanced Inflammatory Markers"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8771-998X","authenticated-orcid":false,"given":"Ali","family":"Razaghi","sequence":"first","affiliation":[{"name":"Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, SE-141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Szakos","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Alouda","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9la","family":"Boz\u00f3ky","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2831-3837","authenticated-orcid":false,"given":"Mikael","family":"Bj\u00f6rnstedt","sequence":"additional","affiliation":[{"name":"Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, SE-141 86 Stockholm, Sweden"},{"name":"Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laszlo","family":"Szekely","sequence":"additional","affiliation":[{"name":"Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, SE-141 86 Stockholm, Sweden"},{"name":"Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s11596-021-2395-1","article-title":"A Comprehensive Review of COVID-19 Virology, Vaccines, Variants, and Therapeutics","volume":"41","author":"Forchette","year":"2021","journal-title":"Curr. Med. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"558898","DOI":"10.3389\/fimmu.2020.558898","article-title":"COVID-19: In the Eye of the Cytokine Storm","volume":"11","author":"Borges","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Melo, A.K.G., Milby, K.M., Caparroz, A., Pinto, A., Santos, R.R.P., Rocha, A.P., Ferreira, G.A., Souza, V.A., Valadares, L.D.A., and Vieira, R. (2021). Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253894"},{"key":"ref_4","first-page":"391","article-title":"Review on therapeutic targets for COVID-19: Insights from cytokine storm","volume":"97","author":"Souza","year":"2020","journal-title":"Postgrad. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"101715","DOI":"10.1016\/j.redox.2020.101715","article-title":"Selenium and selenoproteins in viral infection with potential relevance to COVID-19","volume":"37","author":"Zhang","year":"2020","journal-title":"Redox Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1080\/00325481.2020.1855921","article-title":"JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy","volume":"133","author":"Satarker","year":"2021","journal-title":"Postgrad. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1177\/1403494820980264","article-title":"A comparison of COVID-19 epidemiological indicators in Sweden, Norway, Denmark, and Finland","volume":"49","author":"Cipriano","year":"2021","journal-title":"Scand. J. Public Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e07134","DOI":"10.1016\/j.heliyon.2021.e07134","article-title":"Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of COVID-19 death","volume":"7","author":"Szekely","year":"2021","journal-title":"Heliyon"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1155\/MI.2005.2","article-title":"The differential diagnostic values of cytokine levels in pleural effusions","volume":"2005","author":"Akarsu","year":"2005","journal-title":"Mediat. Inflamm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e14123","DOI":"10.1111\/ijcp.14123","article-title":"Pleural effusion as an indicator for the poor prognosis of COVID-19 patients","volume":"75","author":"Wei","year":"2021","journal-title":"Int. J. Clin. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Assarsson, E., Lundberg, M., Holmquist, G., Bjorkesten, J., Thorsen, S.B., Ekman, D., Eriksson, A., Rennel Dickens, E., Ohlsson, S., and Edfeldt, G. (2014). Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095192"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100287","DOI":"10.1016\/j.xcrm.2021.100287","article-title":"Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions","volume":"2","author":"Filbin","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tay, T.R., and Tee, A. (2013). Factors affecting pleural fluid adenosine deaminase level and the implication on the diagnosis of tuberculous pleural effusion: A retrospective cohort study. BMC Infect. Dis., 13.","DOI":"10.1186\/1471-2334-13-546"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/1479-5876-12-70","article-title":"Regulatory mechanisms of betacellulin in CXCL8 production from lung cancer cells","volume":"12","author":"Shi","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1080\/14756366.2021.1924165","article-title":"Is carbonic anhydrase inhibition useful as a complementary therapy of Covid-19 infection?","volume":"36","author":"Deniz","year":"2021","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_16","unstructured":"Heng, P. (2017). Characterisation of Macrophage Capping Protein as a Novel Inflammatory Mediator. [Ph.D. Thesis, University of Melbourne]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/ijlh.13516","article-title":"Platelets: \u2018multiple choice\u2019 effectors in the immune response and their implication in COVID-19 thromboinflammatory process","volume":"43","author":"Rolla","year":"2021","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.4049\/jimmunol.2001406","article-title":"CDCP1 on Dendritic Cells Contributes to the Development of a Model of Kawasaki Disease","volume":"206","author":"Lun","year":"2021","journal-title":"J. Immunol."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1093\/eurheartj\/eht310.4559","article-title":"Characterisation of familial idiopathic ventricular fibrillation linked to DPP6","volume":"34","author":"Postema","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.cell.2020.09.016","article-title":"The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19","volume":"183","author":"Consiglio","year":"2020","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1093\/ecco-jcc\/jjx058","article-title":"Expression of Ecto-nucleoside Triphosphate Diphosphohydrolases-2 and -3 in the Enteric Nervous System Affects Inflammation in Experimental Colitis and Crohn\u2019s Disease","volume":"11","author":"Moss","year":"2017","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nri1996","article-title":"Steady-state and inflammatory dendritic-cell development","volume":"7","author":"Shortman","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e002285","DOI":"10.1136\/jitc-2020-002285","article-title":"IL-6 modulation for COVID-19: The right patients at the right time?","volume":"9","author":"Ascierto","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"602395","DOI":"10.3389\/fimmu.2020.602395","article-title":"Interleukin-8 as a Biomarker for Disease Prognosis of Coronavirus Disease-2019 Patients","volume":"11","author":"Li","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Foronjy, R.F., Dabo, A.J., Cummins, N., and Geraghty, P. (2014). Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection. BMC Immunol., 15.","DOI":"10.1186\/s12865-014-0041-4"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fcvm.2019.00051","article-title":"Low Density Lipoprotein Receptor-Related Protein-1 in Cardiac Inflammation and Infarct Healing","volume":"6","author":"Potere","year":"2019","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1126\/science.abc6261","article-title":"Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans","volume":"369","author":"Arunachalam","year":"2020","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1093\/infdis\/jiab061","article-title":"Increased PD-L1 Expression May Be Associated With the Cytokine Storm and CD8(+) T-Cell Exhaustion in Severe COVID-19","volume":"223","author":"Chen","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/bs.acc.2020.02.003","article-title":"Chapter Three\u2014Pleiotrophin: Activity and mechanism","volume":"Volume 98","author":"Makowski","year":"2020","journal-title":"Advances in Clinical Chemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/j.bbamcr.2016.04.014","article-title":"Syntaxin 8 is required for efficient lytic granule trafficking in cytotoxic T lymphocytes","volume":"1863","author":"Bhat","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1038\/s41467-021-21085-8","article-title":"Efficacy and tolerability of bevacizumab in patients with severe Covid-19","volume":"12","author":"Pang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"L283","DOI":"10.1152\/ajplung.00337.2018","article-title":"Transitional human alveolar type II epithelial cells suppress extracellular matrix and growth factor gene expression in lung fibroblasts","volume":"317","author":"Correll","year":"2019","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"681516","DOI":"10.3389\/fimmu.2021.681516","article-title":"Cytokine Signature Associated With Disease Severity in COVID-19","volume":"12","author":"Guo","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"100043","DOI":"10.1016\/j.medidd.2020.100043","article-title":"COVID-19 lockdown: De-risking exit by protecting the lung with leukaemia inhibitory factor (LIF)","volume":"6","author":"Metcalfe","year":"2020","journal-title":"Med. Drug Discov."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1080\/09537104.2020.1852543","article-title":"Over time relationship between platelet reactivity, myocardial injury and mortality in patients with SARS-CoV-2-associated respiratory failure","volume":"32","author":"Campo","year":"2021","journal-title":"Platelets"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"695242","DOI":"10.3389\/fimmu.2021.695242","article-title":"PD-L1 Dysregulation in COVID-19 Patients","volume":"12","author":"Sabbatino","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3892\/ijo.2020.5159","article-title":"Immune-checkpoint inhibitors from cancer to COVID19: A promising avenue for the treatment of patients with COVID-19 (Review)","volume":"58","author":"Vivarelli","year":"2021","journal-title":"Int. J. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhang, C., Li, Z., Xu, L., Che, X., Wen, T., Fan, Y., Li, C., Wang, S., Cheng, Y., and Wang, X. (2018). CXCL9\/10\/11, a regulator of PD-L1 expression in gastric cancer. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4384-8"},{"key":"ref_40","first-page":"3351","article-title":"Oncostatin M treatment increases the responsiveness toward cisplatin-based chemoradiotherapy in cervical cancer cells in a STAT3-dependent manner","volume":"16","author":"Stroeder","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"36551","DOI":"10.1038\/srep36551","article-title":"IL-17 Promotes Angiogenic Factors IL-6, IL-8, and Vegf Production via Stat1 in Lung Adenocarcinoma","volume":"6","author":"Huang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.tips.2020.06.007","article-title":"Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19","volume":"41","author":"Luo","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"103","DOI":"10.21037\/tcr.2016.03.09","article-title":"Epidermal growth factor-like repeats and discoidin I-like domains 3: A multifaceted oncoprotein at the crossroad of MAPK and TGF-beta pathways in human hepatocellular carcinoma","volume":"5","author":"Calvisi","year":"2016","journal-title":"Transl. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1182\/blood.V95.12.3758.012k44_3758_3764","article-title":"CD40-ligand stimulates myelopoiesis by regulating flt3-ligand and thrombopoietin production in bone marrow stromal cells","volume":"95","author":"Solanilla","year":"2000","journal-title":"Blood"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/12\/11\/2789\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:17:59Z","timestamp":1760145479000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/12\/11\/2789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,14]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["diagnostics12112789"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics12112789","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,14]]}}}