{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T13:52:23Z","timestamp":1782568343739,"version":"3.54.5"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T00:00:00Z","timestamp":1657065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"the Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["NSC 99-2314-B-040-018-MY3"],"award-info":[{"award-number":["NSC 99-2314-B-040-018-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"the Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["NSC 102-2314-B-040-016-MY3"],"award-info":[{"award-number":["NSC 102-2314-B-040-016-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"the Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 106-2314-B-040-015-MY3"],"award-info":[{"award-number":["MOST 106-2314-B-040-015-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"the Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 111-2314-B-371-001"],"award-info":[{"award-number":["MOST 111-2314-B-371-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Pleural effusions (PEs) are common in clinical practice and can be due to many different underlying diseases such as cancer, congestive heart failure, or pneumonia. An accurate differential diagnostic categorization is essential, as the treatment and prognosis of PEs largely depend on its cause. In this study, we tested the hypothesis that nitrite and nitrate concentrations in PEs are associated with the inflammation and infection conditions. We therefore measured the nitrite and nitrate levels in 143 PE samples using a sensitive liquid chromatography-tandem mass spectrometry method and investigated their diagnostic potential in differentiating PEs. The results showed that nitrite concentrations and nitrite\/nitrate ratios were higher in exudates than in transudates (NO2\u2212: 2.12 vs. 1.49 \u03bcM; NO2\u2212\/NO3\u2212: 23.3 vs. 14.0). Both the nitrite concentrations and the nitrite\/nitrate ratios were positively correlated with the three Light\u2019s criteria. Moreover, the receiver operating characteristic curve analysis revealed that the nitrite\/nitrate ratio with an area under the curve of 0.71 could be a potential diagnostic biomarker in separating infectious PEs (IPEs) from other types of PEs. Taken together, the nitrite\/nitrate ratio not only reflected the statuses of inflammation, but also the nitrate reduction by pathogenic bacteria infection in the pleural cavity. The nitrite\/nitrate ratio could be a better biomarker in the differential diagnosis of PEs than the nitrite concentration alone.<\/jats:p>","DOI":"10.3390\/antiox11071327","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T05:41:06Z","timestamp":1657086066000},"page":"1327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Elevated Nitrite\/Nitrate Ratio as a Potential Biomarker for the Differential Diagnosis of Pleural Effusions"],"prefix":"10.3390","volume":"11","author":[{"given":"Mu-Rong","family":"Chao","sequence":"first","affiliation":[{"name":"Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Jhe","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Ming","family":"Shih","sequence":"additional","affiliation":[{"name":"Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Lian","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Medical University, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Chieh","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4821-7500","authenticated-orcid":false,"given":"Chiung-Wen","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Public Health, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ccm.2021.07.003","article-title":"Pleural Fluid Analysis: Are Light\u2019s criteria still relevant after half a century?","volume":"42","author":"Porcel","year":"2021","journal-title":"Clin. Chest Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ccm.2012.11.006","article-title":"The light criteria: The beginning and why they are useful 40 years later","volume":"34","author":"Light","year":"2013","journal-title":"Clin. Chest Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ccm.2012.11.002","article-title":"Pleural fluid biomarkers: Beyond the Light criteria","volume":"34","author":"Porcel","year":"2013","journal-title":"Clin. Chest Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6648535","DOI":"10.1155\/2021\/6648535","article-title":"Diagnostic accuracy with total adenosine deaminase as a biomarker for discriminating pleural transudates and exudates in a population-based cohort study","volume":"2021","author":"Maranhao","year":"2021","journal-title":"Dis. Markers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1159\/000496396","article-title":"Simplified criteria using pleural fluid cholesterol and lactate dehydrogenase to distinguish between exudative and transudative pleural effusions","volume":"98","author":"Lepine","year":"2019","journal-title":"Respiration"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.ejim.2012.03.002","article-title":"Pleural fluid C-reactive protein contributes to the diagnosis and assessment of severity of parapneumonic effusions","volume":"23","author":"Porcel","year":"2012","journal-title":"Eur. J. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Watanabe, N., Ishii, T., Kita, N., Kanaji, N., Nakamura, H., Nanki, N., Ueda, Y., Tojo, Y., Kadowaki, N., and Bandoh, S. (2018). The usefulness of pleural fluid presepsin, C-reactive protein, and procalcitonin in distinguishing different causes of pleural effusions. BMC Pulm. Med., 18.","DOI":"10.1186\/s12890-018-0740-3"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1164\/rccm.200601-074OC","article-title":"The bacteriology of pleural infection by genetic and standard methods and its mortality significance","volume":"174","author":"Maskell","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7539780","DOI":"10.1155\/2016\/7539780","article-title":"The diagnostic value of the pleural fluid C-reactive protein in parapneumonic effusions","volume":"2016","author":"Izhakian","year":"2016","journal-title":"Dis. Markers"},{"key":"ref_10","first-page":"1211","article-title":"Diagnostic approach to pleural effusion in adults","volume":"73","author":"Porcel","year":"2006","journal-title":"Am. Fam. Physician"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2174\/1568010054526359","article-title":"Nitric oxide production and signaling in inflammation","volume":"4","author":"Korhonen","year":"2005","journal-title":"Curr. Drug Targets Inflamm. Allergy"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1080\/10715760500053651","article-title":"Methods of quantitative analysis of the nitric oxide metabolites nitrite and nitrate in human biological fluids","volume":"39","author":"Tsikas","year":"2005","journal-title":"Free Radic. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12814","DOI":"10.1073\/pnas.221381098","article-title":"Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action","volume":"98","author":"Lauer","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e003402","DOI":"10.1161\/JAHA.116.003402","article-title":"Dietary nitrate and the epidemiology of cardiovascular disease: Report from a national heart, lung, and blood institute workshop","volume":"5","author":"Ahluwalia","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.freeradbiomed.2019.08.005","article-title":"(15)N-labelled nitrite\/nitrate tracer analysis by LC-MS\/MS: Urinary and fecal excretion of nitrite\/nitrate following oral administration to mice","volume":"143","author":"Hu","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","first-page":"765","article-title":"Glutathione and nitrite levels in induced sputum at COPD patients and healthy smokers","volume":"6","author":"Turgut","year":"2014","journal-title":"J. Thorac. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1183\/09031936.02.00101202","article-title":"Elevated nitrite in breath condensates of children with respiratory disease","volume":"19","author":"Formanek","year":"2002","journal-title":"Eur. Respir. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.freeradbiomed.2021.08.237","article-title":"Serum nitrite and nitrate: A potential biomarker for post-COVID-19 complications?","volume":"175","author":"Wang","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1080\/10715762.2019.1587168","article-title":"Circulating markers of nitric oxide homeostasis and cardiometabolic diseases: Insights from population-based studies","volume":"53","author":"Bahadoran","year":"2019","journal-title":"Free Radic. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.clinbiochem.2009.09.011","article-title":"Reference values for serum nitric oxide metabolites in an adult population","volume":"43","author":"Ghasemi","year":"2010","journal-title":"Clin. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/INF.0000000000003353","article-title":"Pediatric parapneumonic effusion\/pleural empyema in Japan: A nationwide survey","volume":"41","author":"Hoshino","year":"2022","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1099\/00222615-25-4-253","article-title":"Nitrate- and nitrite-reducing bacteria in the achlorhydric stomach","volume":"25","author":"Forsythe","year":"1988","journal-title":"J. Med. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1128\/aem.63.3.924-930.1997","article-title":"Nitrate-reducing bacteria on rat tongues","volume":"63","author":"Li","year":"1997","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16652","DOI":"10.1038\/s41598-020-73479-1","article-title":"Nitrite-producing oral microbiome in adults and children","volume":"10","author":"Washio","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.freeradbiomed.2016.01.025","article-title":"Urinary nitrite\/nitrate ratio measured by isotope-dilution LC-MS\/MS as a tool to screen for urinary tract infections","volume":"93","author":"Chao","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1056\/NEJMcp010731","article-title":"Clinical practice. Pleural effusion","volume":"346","author":"Light","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"265","DOI":"10.4103\/2249-4863.154672","article-title":"Reliability of dipstick assay in predicting urinary tract infection","volume":"4","author":"Mambatta","year":"2015","journal-title":"J. Family. Med. Prim. Care"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1378\/chest.128.3.1436","article-title":"Childhood parapneumonic effusions: Biochemical and inflammatory markers","volume":"128","author":"Utine","year":"2005","journal-title":"Chest"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1080\/10715760400017327","article-title":"Adaptation of the Griess reaction for detection of nitrite in human plasma","volume":"38","author":"Giustarini","year":"2004","journal-title":"Free Radic. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"276","DOI":"10.3390\/s30800276","article-title":"Measurement of nitric oxide production in biological systems by using Griess Reaction assay","volume":"3","author":"Sun","year":"2003","journal-title":"Sensors"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4104","DOI":"10.1021\/pr5004856","article-title":"Pleural effusion lipoproteins measured by NMR spectroscopy for diagnosis of exudative pleural effusions: A novel tool for pore-size estimation","volume":"13","author":"Lam","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1159\/000070572","article-title":"Nitric oxide in experimental joint inflammation. Benefit or detriment?","volume":"174","author":"Wahl","year":"2003","journal-title":"Cells Tissues Organs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/s41423-021-00832-3","article-title":"Neutrophils in chronic inflammatory diseases","volume":"19","author":"Soehnlein","year":"2022","journal-title":"Cell Mol. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1055\/s-0036-1597577","article-title":"Nitric Oxide: Link between Inflammation and Endothelial Dysfunction in Rheumatoid Arthritis","volume":"26","author":"Garg","year":"2017","journal-title":"Int. J. Angiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.niox.2009.12.004","article-title":"Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall","volume":"22","author":"Zweier","year":"2010","journal-title":"Nitric Oxide"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1097\/00003246-199706000-00027","article-title":"Measurements of total plasma nitrite and nitrate in pediatric patients with the systemic inflammatory response syndrome","volume":"25","author":"Spack","year":"1997","journal-title":"Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1164\/ajrccm.158.1.9707096","article-title":"Total sputum nitrate plus nitrite is raised during acute pulmonary infection in cystic fibrosis","volume":"158","author":"Linnane","year":"1998","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1097\/INF.0b013e31828637b1","article-title":"Etiology of empyema thoracis and parapneumonic pleural effusion in Taiwanese children and adolescents younger than 18 years of age","volume":"32","author":"Lin","year":"2013","journal-title":"Pediatr. Infect. Dis. J."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/7\/1327\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:43:16Z","timestamp":1760139796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/7\/1327"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,6]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["antiox11071327"],"URL":"https:\/\/doi.org\/10.3390\/antiox11071327","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,6]]}}}