{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:50:26Z","timestamp":1792018226050,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008903","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["MOHW104-CDC-C-114-114901"],"award-info":[{"award-number":["MOHW104-CDC-C-114-114901"]}],"id":[{"id":"10.13039\/100008903","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Science Council Grant","award":["NSC 102-2320-B-006\u2013049"],"award-info":[{"award-number":["NSC 102-2320-B-006\u2013049"]}]},{"name":"Ministry of Science and Technology","award":["MOST 103 - 2320 - B -006 - 030 - MY3"],"award-info":[{"award-number":["MOST 103 - 2320 - B -006 - 030 - MY3"]}]},{"name":"Ministry of Science and Technology","award":["MOST-106-2321-B-006 -012"],"award-info":[{"award-number":["MOST-106-2321-B-006 -012"]}]},{"name":"Ministry of Science and Technology","award":["MOST 107-2314-B-006 -063 -MY3"],"award-info":[{"award-number":["MOST 107-2314-B-006 -063 -MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A); dengue with warning signs (B); severe dengue (C); other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group; AUC = 0.944, H and OF group; AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group; AUC = 0.744, B and C group; AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.<\/jats:p>","DOI":"10.3390\/ijms22062879","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T11:56:55Z","timestamp":1615550215000},"page":"2879","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Cytokine Signature of Dengue Patients at Different Severity of the Disease"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0182-3768","authenticated-orcid":false,"given":"Irwin","family":"Puc","sequence":"first","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Chuan","family":"Ho","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko-Lun","family":"Yen","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Vats","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2226-8916","authenticated-orcid":false,"given":"Jih-Jin","family":"Tsai","sequence":"additional","affiliation":[{"name":"Tropical Medicine Center, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan"},{"name":"Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan"},{"name":"School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wen","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"},{"name":"Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chih","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guey Chuen","family":"Perng","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"},{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.envres.2016.07.026","article-title":"Dengue in a changing climate","volume":"151","author":"Ebi","year":"2016","journal-title":"Environ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Brady, O.J., Gething, P.W., Bhatt, S., Messina, J.P., Brownstein, J.S., Hoen, A.G., Moyes, C.L., Farlow, A.W., Scott, T.W., and Hay, S.I. (2012). Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based Consensus. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001760"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_4","unstructured":"WHO (2020, December 20). Dengue and Severe Dengue World Health Organization 2019. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dengue-and-severe-dengue."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hotta, S. (1952). Experimental Studies on Dengue: I. Isolation, Identification and Modification of the Virus. J. Infect. Dis., 90.","DOI":"10.1093\/infdis\/90.1.1"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rathakrishnan, A., Wang, S.M., Hu, Y., Khan, A.M., Ponnampalavanar, S., Lum, L.C.S., Manikam, R., and Sekaran, S.D. (2012). Cytokine Expression Profile of Dengue Patients at Different Phases of Illness. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052215"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16055","DOI":"10.1038\/nrdp.2016.55","article-title":"Dengue infection","volume":"2","author":"Guzman","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"999","DOI":"10.4269\/ajtmh.14-0628","article-title":"Dengue serotype-specific differences in clinical manifestation, laboratory parameters and risk of severe disease in adults, Singapore","volume":"92","author":"Yung","year":"2015","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"de Mello, C.P.P., Drusano, G.L., Rodriquez, J.L., Kaushik, A., and Brown, A.N. (2018). Antiviral Effects of Clinically-Relevant Interferon-\u03b1 and Ribavirin Regimens against Dengue Virus in the Hollow Fiber Infection Model (HFIM). Viruses, 10.","DOI":"10.3390\/v10060317"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1006\/smvy.1994.1050","article-title":"Cytokines in dengue virus infections: Role of cytokines in the pathogenesis of dengue hemorrhagic fever","volume":"5","author":"Kurane","year":"1994","journal-title":"Semin. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1016\/j.bbamcr.2014.05.014","article-title":"Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease","volume":"1843","author":"Turner","year":"2014","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.apjtm.2016.12.002","article-title":"Serodiagnosis of asymptomatic dengue infection","volume":"10","author":"Chatchen","year":"2017","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"172","DOI":"10.4269\/ajtmh.1988.38.172","article-title":"A Prospective Study of Dengue Infections in Bangkok","volume":"38","author":"Burke","year":"1988","journal-title":"Am. Soc. Trop. Med. Hyg."},{"key":"ref_14","first-page":"146","article-title":"Clinical and differential diagnosis: Dengue, chikungunya and Zika","volume":"81","year":"2018","journal-title":"Rev. M\u00e9d. Hosp. Gen. M\u00e9x."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Vogels, C.B.F., R\u00fcckert, C., Cavany, S.M., Perkins, T.A., Ebel, G.D., and Grubaugh, N.D. (2019). Arbovirus coinfection and co-transmission: A neglected public health concern?. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000130"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.3390\/v2122649","article-title":"The complexity of antibody-dependent enhancement of dengue virus infection","volume":"2","author":"Guzman","year":"2010","journal-title":"Viruses"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1126\/science.1185181","article-title":"Cross-reacting antibodies enhance dengue virus infection in humans","volume":"328","author":"Dejnirattisai","year":"2010","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/j.1574-695X.2000.tb01474.x","article-title":"Cytokine cascade in dengue hemorrhagic fever: Implications for pathogenesis","volume":"28","author":"Chaturvedi","year":"2000","journal-title":"FEMS Immunol. Med Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1128\/CMR.00035-09","article-title":"Dengue Virus Pathogenesis: An Integrated View","volume":"22","author":"Martina","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s00281-017-0625-1","article-title":"Immune-mediated cytokine storm and its role in severe dengue","volume":"39","author":"Srikiatkhachorn","year":"2017","journal-title":"Semin. Immunopathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1155\/2018\/8403937","article-title":"Serum Cytokine Profiles in Patients with Dengue Fever at the Acute Infection Phase","volume":"2018","author":"Huang","year":"2018","journal-title":"Dis. Markers"},{"key":"ref_22","first-page":"10","article-title":"Predictive Symptoms and Signs of Severe Dengue Disease for Patients with Dengue Fever: A Meta-Analysis","volume":"2014","author":"Zhang","year":"2014","journal-title":"BioMed. Res. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"180087","DOI":"10.1098\/rsob.180087","article-title":"Immune responses to dengue virus in the skin","volume":"8","author":"Rathore","year":"2018","journal-title":"Open Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Thein, T.-L., Gan, V.C., Lye, D.C., Yung, C.-F., and Leo, Y.-S. (2013). Utilities and Limitations of the World Health Organization 2009 Warning Signs for Adult Dengue Severity. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002023"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"183","DOI":"10.15562\/bmj.v8i1.1289","article-title":"Dengue hemorrhagic fever: The role of Soluble E-Selektin, Soluble Intra Cellular Adhesion Molecule-1 (Sicam-1) and Soluble Vascular Cellular Adhesion Molecule -1 (Svcam-1) in overweight children","volume":"8","author":"Juffrie","year":"2018","journal-title":"Bali Med. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e24","DOI":"10.1038\/emi.2015.24","article-title":"Serum levels of soluble vascular cell adhesion molecules may correlate with the severity of dengue virus-1 infection in adults","volume":"4","author":"Liao","year":"2015","journal-title":"Emerg. Microbes Infect."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e20180353","DOI":"10.1590\/0037-8682-0353-2018","article-title":"Upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in renal tissue in severe dengue in humans: Effects on endothelial activation\/dysfunction","volume":"52","author":"Vitoria","year":"2019","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chan, M., and Johansson, M.A. (2012). The Incubation Periods of Dengue Viruses. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050972"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Furuya-Kanamori, L., Liang, S., Milinovich, G., Magalhaes, R.J.S., Clements, A.C.A., Hu, W., Brasil, P., Frentiu, F.D., Dunning, R., and Yakob, L. (2016). Co-distribution and co-infection of chikungunya and dengue viruses. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-1417-2"},{"key":"ref_30","first-page":"36","article-title":"Pathologic patterns of interleukin 10 expression\u2014A review","volume":"25","author":"Miller","year":"2015","journal-title":"Biochem. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Malavige, G.N., Jeewandara, C., Alles, K.M.L., Salimi, M., Gomes, L., Kamaladasa, A., Jayaratne, S.D., and Ogg, G.S. (2013). Suppression of Virus Specific Immune Responses by IL-10 in Acute Dengue Infection. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002409"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e9713","DOI":"10.1097\/MD.0000000000009713","article-title":"Identifying protein biomarkers in predicting disease severity of dengue virus infection using immune-related protein microarray","volume":"97","author":"Soe","year":"2018","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/nri3014","article-title":"Immunity to dengue virus: A tale of original antigenic sin and tropical cytokine storms","volume":"11","author":"Rothman","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1365-2222.2004.01902.x","article-title":"Interleukin-4 increases the permeability of human endothelial cells in culture","volume":"34","author":"Kotowicz","year":"2004","journal-title":"Clin. Exp. Allergy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2149\/tmh.2014-09","article-title":"The association of cytokines with severe dengue in children","volume":"42","author":"Mangione","year":"2014","journal-title":"Trop. Med. Health"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Patro, A.R.K., Mohanty, S., Prusty, B.K., Singh, D.K., Gaikwad, S., Saswat, T., Chattopadhyay, S., Das, B.K., Tripathy, R., and Ravindran, B. (2019). Cytokine Signature Associated with Disease Severity in Dengue. Viruses, 11.","DOI":"10.3390\/v11010034"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"943","DOI":"10.4269\/ajtmh.19-0487","article-title":"Cytokine Expression in Dengue Fever and Dengue Hemorrhagic Fever Patients with Bleeding and Severe Hepatitis","volume":"102","author":"Imad","year":"2020","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hsieh, C.-C., Hong, M.-Y., Ho, T.-S., Liu, C.-C., Perng, G.-C., and Chuang, C.-C. (2019). Dynamic changes of soluble ST2 levels predicted fatality and were involved in coagulopathy in dengue fever in the elderly. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007974"},{"key":"ref_39","first-page":"5197592","article-title":"IL-10 and socs3 Are Predictive Biomarkers of Dengue Hemorrhagic Fever","volume":"2017","author":"Moreno","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1590\/S0074-02761999000300019","article-title":"Increased Pro-inflammatory Cytokines (TNF-a and IL-6) and Anti-inflammatory Compounds (sTNFRp55 and sTNFRp75) in Brazilian Patients during Exanthematic Dengue Fever","volume":"94","author":"Pinto","year":"1999","journal-title":"Mem\u00f3rias do Instituto Oswaldo Cruz"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1002\/(SICI)1096-9071(199911)59:3<329::AID-JMV12>3.0.CO;2-G","article-title":"Elevated plasma interleukin-10 levels in acute dengue correlate with disease severity","volume":"59","author":"Green","year":"1999","journal-title":"J. Med Virol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Peters, V.A., Joesting, J.J., and Freund, G.G. (2013). IL-1 receptor 2 (IL-1R2) and its role in immune regulation. Brain Behav. Immun., 32.","DOI":"10.1016\/j.bbi.2012.11.006"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 family in innate inflammation and acquired immunity","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nrd3800","article-title":"Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases","volume":"11","author":"Dinarello","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/imr.12614","article-title":"IL-1 and IL-1 regulatory pathways in cancer progression and therapy","volume":"281","author":"Mantovani","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3389\/fphar.2017.00278","article-title":"Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases","volume":"8","author":"Fenini","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_47","first-page":"1048","article-title":"Detection of interleukin-1 receptors in human epidermis. Induction of the type II receptor after organ culture and in psoriasis","volume":"145","author":"Groves","year":"1994","journal-title":"Am. J. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1007\/s00109-018-1684-z","article-title":"Regulation of IL-1 signaling by the decoy receptor IL-1R2","volume":"96","author":"Schelmbauer","year":"2018","journal-title":"J. Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Yeh, C.Y., Chen, P.L., Chuang, K.T., Shu, Y.-C., Chien, Y.-W., Perng, G.C., Ko, W.-C., and Ko, N.-Y. (2017). Symptoms associated with adverse dengue fever prognoses at the time of reporting in the 2015 dengue outbreak in Taiwan. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0006091"},{"key":"ref_50","unstructured":"WHO (2009). World Health Organization and the Special Programme for Research and Training in Tropical Diseases (TDR). Dengue Guidelines for Diagnosis, Treatment, Prevention and Control, WHO Press."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2879\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:37Z","timestamp":1760160877000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2879"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22062879"],"URL":"https:\/\/doi.org\/10.3390\/ijms22062879","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]}}}