{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:16:30Z","timestamp":1790356590349,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,11]],"date-time":"2020-01-11T00:00:00Z","timestamp":1578700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background and Aims: There has been a recent growing interest in the role of nasal nitric oxide (nNO) as a biomarker for osteomeatal complex obstruction in paranasal sinus diseases. By using meta-analysis, we systematically reviewed the literature to establish the possible link between nNO concentration and chronic rhinosinusitis with nasal polyps (CRSwNP) or without (CRSsNP). Methods: We systematically searched the EMBASE, PubMed, Scopus, and Web of Science databases for related studies. Differences between controls and cases were reported as standardized mean difference (SMD), with 95% confidence intervals (95% CI), using the random-effects method. Results: We selected 23 articles for the final analysis: 15 with data on 461 CRSwNP patients and 384 healthy controls, 10 with data on 183 CRSsNP patients and 260 controls, and 14 studies on 372 CRSwNP and 297 CRSsNP patients. CRSwNP patients showed significantly lower nNO values when compared to both healthy controls (SMD: \u22121.495; 95% CI: \u22122.135, \u22120.854; p &lt; 0.0001) and CRSsNP patients (SMD: \u22121.448; 95% CI: \u22122.046, \u22120.850; p &lt; 0.0001). Sensitivity and subgroup analyses confirmed the results, which were further refined by regression models. They showed that an increasing aspiration flow is related to a greater difference in nNO levels between cases and control subjects. We also documented lower nNO levels in CRSsNP patients with respect to controls (SMD: \u22120.696; 95% CI: \u22121.189, \u22120.202; p = 0.006), being this result no longer significant when excluding patients in therapy with intranasal corticosteroids. As shown by regression models, the increased Lund\u2013Mackay score indicates a high effect size. Conclusions: nNO levels are significantly lower in CRSwNP, especially when using higher aspiration flows. Additional studies are needed to define one single standardized method and normal reference values for nNO.<\/jats:p>","DOI":"10.3390\/jcm9010200","type":"journal-article","created":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T04:05:51Z","timestamp":1578888351000},"page":"200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Nasal Nitric Oxide in Chronic Rhinosinusitis with or without Nasal Polyps: A Systematic Review with Meta-Analysis"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9398-0428","authenticated-orcid":false,"given":"Pasquale","family":"Ambrosino","sequence":"first","affiliation":[{"name":"Cardio-Pulmonary Rehabilitation Dept, Istituti Clinici Scientifici Maugeri IRCCS, 82037 Telese Terme (BN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Molino","sequence":"additional","affiliation":[{"name":"Respiratory Division, Department of Respiratory Medicine, Federico II University, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio Alfredo","family":"Spedicato","sequence":"additional","affiliation":[{"name":"Unipol Group, 40128 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Parrella","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Rehabilitation Dept, Istituti Clinici Scientifici Maugeri IRCCS, 82037 Telese Terme (BN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Formisano","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Rehabilitation Dept, Istituti Clinici Scientifici Maugeri IRCCS, 82037 Telese Terme (BN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8643-658X","authenticated-orcid":false,"given":"Andrea","family":"Motta","sequence":"additional","affiliation":[{"name":"Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli (Naples), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8059-3819","authenticated-orcid":false,"given":"Matteo Nicola Dario","family":"Di Minno","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Federico II University, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-9921","authenticated-orcid":false,"given":"Mauro","family":"Maniscalco","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Rehabilitation Dept, Istituti Clinici Scientifici Maugeri IRCCS, 82037 Telese Terme (BN), Italy"},{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 4, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/327524a0","article-title":"Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor","volume":"327","author":"Palmer","year":"1987","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.4168\/aair.2019.11.3.367","article-title":"Nasal nitric oxide is correlated with nasal patency and nasal symptoms","volume":"11","author":"Ren","year":"2019","journal-title":"Allergy Asthma Immunol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/S1567-5769(01)00086-8","article-title":"Nitric oxide in immunity and inflammation","volume":"1","author":"Coleman","year":"2001","journal-title":"Int. Immunopharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s00011-006-6111-1","article-title":"Nitric oxide in upper airways inflammatory diseases","volume":"56","author":"Maniscalco","year":"2007","journal-title":"Inflamm. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1164\/rccm.9120-11ST","article-title":"An official ATS clinical practice guideline: Interpretation of exhaled nitric oxide levels (FENO) for clinical applications","volume":"184","author":"Dweik","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1164\/rccm.200905-0695OC","article-title":"Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma","volume":"181","author":"Dweik","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1164\/rccm.200906-0896OC","article-title":"Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program","volume":"181","author":"Moore","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1164\/ajrccm.153.2.8564142","article-title":"Expression of nitric oxide synthase in the human nasal mucosa","volume":"153","author":"Furukawa","year":"1996","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.1365-2362.2004.01384.x","article-title":"Humming-induced release of nasal nitric oxide for assessment of sinus obstruction in allergic rhinitis: Pilot study","volume":"34","author":"Maniscalco","year":"2004","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1034\/j.1398-9995.2003.00098.x","article-title":"Characterization of airway nitric oxide in allergic rhinitis: The effect of intranasal administration of L-NAME","volume":"58","author":"Palm","year":"2003","journal-title":"Allergy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1183\/09031936.97.10071683","article-title":"Exhaled and nasal nitric oxide measurements: Recommendations","volume":"10","author":"Kharitonov","year":"1997","journal-title":"Eur. Respir. J."},{"key":"ref_12","first-page":"2104","article-title":"Recommendations for standardized procedures for online and offline measurementt of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children","volume":"160","author":"Slutsky","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1164\/rccm.200406-710ST","article-title":"ATS\/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005","volume":"171","author":"Exhaled","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.2174\/0929867323666160627115335","article-title":"Recent advances on nitric oxide in the upper airways","volume":"23","author":"Maniscalco","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1183\/09031936.00088614","article-title":"Nasal nitric oxide screening for primary ciliary dyskinesia: Systematic review and meta-analysis","volume":"44","author":"Collins","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.2500\/ajra.2014.28.3984","article-title":"Nasal and exhaled nitric oxide in chronic rhinosinusitis with polyps","volume":"28","author":"Jeong","year":"2014","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3109\/00016489709118001","article-title":"Nitric Oxide (NO) production in the upper airways is decreased in chronic sinusitis","volume":"117","author":"Lindberg","year":"1997","journal-title":"Acta Oto-Laryngol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/alr.21598","article-title":"Nasal nitric oxide as a marker of sinus mucosal health in patients with nasal polyposis","volume":"5","author":"Lee","year":"2015","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.alit.2018.09.005","article-title":"Reduced nasal nitric oxide levels in patients with eosinophilic chronic rhinosinusitis","volume":"68","author":"Yoshida","year":"2019","journal-title":"Allergol. Int. Off. J. Jpn. Soc. Allergol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fu, C.H., Tseng, H.J., Huang, C.C., Chang, P.H., Chen, Y.W., and Lee, T.J. (2017). Nasal nitric oxide in unilateral sinus disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171965"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/lary.23594","article-title":"Nasal nitric oxide levels do not allow for discrimination between olfactory loss due to various etiologies","volume":"123","author":"Gupta","year":"2013","journal-title":"Laryngoscope"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., and Altman, D.G. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_23","unstructured":"Wells GA, S.B., O\u2019Connell, D., Peterson, J., Welch, V., Losos, M., and Tugwell, P. (2019, December 01). Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomized Studies in Meta-Analyses. Available online: http:\/\/www.ohri.ca\/programs\/clinical_epidemiology\/oxford.htm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1136\/bmj.323.7304.101","article-title":"Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis","volume":"323","author":"Sterne","year":"2001","journal-title":"BMJ"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/j.0006-341X.2000.00455.x","article-title":"Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis","volume":"56","author":"Duval","year":"2000","journal-title":"Biometrics"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Alexandersson, C., Tuomi, L., and Olin, A.C. (2019). Measurement of nasal nitric oxide in chronic rhinosinusitis and its relationship to patient-reported outcome: A longitudinal pilot study. Ear Nose Throat J., 145561319880624.","DOI":"10.1177\/0145561319880624"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1034\/j.1399-3003.1999.13b15.x","article-title":"Nasal nitric oxide concentration in paranasal sinus inflammatory diseases","volume":"13","author":"Arnal","year":"1999","journal-title":"Eur. Respir. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1080\/02770903.2017.1332203","article-title":"Combined measurements of fractional exhaled nitric oxide and nasal nitric oxide levels for assessing upper airway diseases in asthmatic patients","volume":"55","author":"Asano","year":"2018","journal-title":"J. Asthma"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S1081-1206(10)60310-9","article-title":"Nasal nitric oxide concentration in suspected chronic rhinosinusitis","volume":"101","author":"Bommarito","year":"2008","journal-title":"Ann. Allergy Asthma Immunol. Off. Publ. Am. Coll. Allergy Asthma Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4193\/Rhin17.111","article-title":"Exhaled and nasal nitric oxide in chronic rhinosinusitis patients with nasal polyps in primary care","volume":"56","author":"Frendo","year":"2018","journal-title":"Rhinology"},{"key":"ref_32","first-page":"234","article-title":"Analysis of nasal and exhaled nitric oxide concentration in nasal polyposis","volume":"119","author":"Gilain","year":"2002","journal-title":"Ann. Otolaryngol. Chir. Cervicofac."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1111\/j.1398-9995.2008.01892.x","article-title":"United airways again: High prevalence of rhinosinusitis and nasal polyps in bronchiectasis","volume":"64","author":"Guilemany","year":"2009","journal-title":"Allergy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"026009","DOI":"10.1088\/1752-7155\/7\/2\/026009","article-title":"Nasal nitric oxide is a marker of poor asthma control","volume":"7","author":"Heffler","year":"2013","journal-title":"J. Breath Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"389","DOI":"10.2500\/ajra.2017.31.4480","article-title":"Role of exhaled nasal nitric oxide in distinguishing between chronic rhinosinusitis with and without nasal polyps","volume":"31","author":"Liu","year":"2017","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"255","DOI":"10.2500\/ajra.2012.26.3772","article-title":"Monitoring of oral and nasal exhaled nitric oxide in eosinophilic chronic rhinosinusitis: A prospective study","volume":"26","author":"Noda","year":"2012","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_37","first-page":"969","article-title":"Airborne nitric oxide and nasal cytology in patients with chronic rhinosinusitis and nasal polyps","volume":"29","author":"Torretta","year":"2015","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_38","first-page":"102","article-title":"Nasal nitric oxide measurements in the assessment of nasal allergen challenge","volume":"22","author":"Tworek","year":"2012","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_39","first-page":"23","article-title":"Nasal fractional exhaled nitric oxide analysis with a novel hand-held device","volume":"46","author":"Weschta","year":"2008","journal-title":"Rhinology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.anai.2010.05.014","article-title":"Relationship between fractional exhaled nitric oxide and nasal nitric oxide in airways disease","volume":"105","author":"Williamson","year":"2010","journal-title":"Ann. Allergy Asthma Immunol. Off. Publ. Am. Coll. Allergy Asthma Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jaci.2013.12.480","article-title":"Measurement of nasal and exhaled nitric oxide in chronic rhinosinusitis and its comparison according to the presence of nasal polyps","volume":"133","author":"Bae","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e187","DOI":"10.2500\/ajra.2015.29.4249","article-title":"Nasal nitric oxide in relation to quality-of-life improvements after endoscopic sinus surgery","volume":"29","author":"Fu","year":"2015","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1111\/j.1398-9995.2006.01044.x","article-title":"Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy","volume":"61","author":"Ragab","year":"2006","journal-title":"Allergy"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1002\/alr.22087","article-title":"Nasal ventilation is an important factor in evaluating the diagnostic value of nasal nitric oxide in allergic rhinitis","volume":"8","author":"Hou","year":"2018","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Vlad, D., and Albu, S. (2019). Arginase isoform expression in chronic rhinosinusitis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8111809"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1007\/s004050050231","article-title":"Immunolocalization of inducible nitric oxide synthase and 3-nitrotyrosine in the nasal mucosa of patients with rhinitis","volume":"257","author":"Kang","year":"2000","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1097\/00005537-199912000-00023","article-title":"Increased expression of inducible nitric oxide synthase in nasal epithelial cells in patients with allergic rhinitis","volume":"109","author":"Kawamoto","year":"1999","journal-title":"Laryngoscope"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/00016489850182161","article-title":"Localization of nitric oxide synthase in human nasal mucosa with nasal allergy","volume":"539","author":"Kawamoto","year":"1998","journal-title":"Acta Oto-Laryngol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"210","DOI":"10.2500\/aap.2013.34.3660","article-title":"Inflammometry in pediatric asthma: A review of fractional exhaled nitric oxide in clinical practice","volume":"34","author":"Mahr","year":"2013","journal-title":"Allergy Asthma Proc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/S0954-6111(98)90308-0","article-title":"Effect of topical steroids on nasal nitric oxide production in children with perennial allergic rhinitis: A pilot study","volume":"92","author":"Baraldi","year":"1998","journal-title":"Respir. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"93","DOI":"10.2332\/allergolint.11-OA-0318","article-title":"Measurements of nasal fractional exhaled nitric oxide with a hand-held device in patients with allergic rhinitis: Relation to cedar pollen dispersion and laser surgery","volume":"61","author":"Takeno","year":"2012","journal-title":"Allergol. Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1046\/j.1365-2222.2002.01379.x","article-title":"Paradoxical low nasal nitric oxide in nasal polyposis","volume":"32","author":"Colantonio","year":"2002","journal-title":"Clin. Exp. Allergy"},{"key":"ref_53","first-page":"723","article-title":"Nasal NO measurement by direct sampling from the nose during breathhold: Aspiration flow, nasal resistance and reproducibility","volume":"263","author":"Struben","year":"2006","journal-title":"Eur. Arch. Otorhinolaryngol. Head Neck"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1080\/00016489950181035","article-title":"Aerodynamic influences on nasal nitric oxide output measurements","volume":"119","author":"Djupesland","year":"1999","journal-title":"Acta Oto-Laryngol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"261","DOI":"10.2217\/bmm.13.11","article-title":"Exhaled nasal nitric oxide during humming: Potential clinical tool in sinonasal disease?","volume":"7","author":"Maniscalco","year":"2013","journal-title":"Biomark. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/1\/200\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:19:31Z","timestamp":1760361571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/1\/200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,11]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["jcm9010200"],"URL":"https:\/\/doi.org\/10.3390\/jcm9010200","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,11]]}}}