{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T23:20:37Z","timestamp":1789600837646,"version":"build-2803163510"},"reference-count":33,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"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: The effects of immunomodulators in patients with Coronavirus Disease 2019 (COVID-19) pneumonia are still unknown. We investigated the cellular inflammatory and molecular changes in response to standard-of-care + pidotimod (PDT) and explored the possible association with blood biomarkers of disease severity. Methods: Clinical characteristics and outcomes, neutrophil-to-lymphocyte ratio (NLR), plasma and cell supernatant chemokines, and gene expression patterns after SARS-CoV-2 and influenza (FLU) virus in vitro stimulation were assessed in 16 patients with mild-moderate COVID-19 pneumonia, treated with standard of care and PDT 800 mg twice daily (PDT group), and measured at admission, 7 (T1), and 12 (T2) days after therapy initiation. Clinical outcomes and NLR were compared with age-matched historical controls not exposed to PDT. Results: Hospital stay, in-hospital mortality, and intubation rate did not differ between groups. At T1, NLR was 2.9 (1.7\u20134.6) in the PDT group and 5.5 (3.4\u20137.1) in controls (p = 0.037). In the PDT group, eotaxin and IL-4 plasma concentrations progressively increased (p &lt; 0.05). Upon SARS-CoV-2 and FLU-specific stimulation, IFN-\u03b3 was upregulated (p &lt; 0.05), while at genetic transcription level, Pathogen Recognition Receptors (TRLs) were upregulated, especially in FLU-stimulated conditions. Conclusions: Immunomodulation exerted by PDT and systemic corticosteroids may foster a restoration in the innate response to the viral infection. These results should be confirmed in larger RCTs.<\/jats:p>","DOI":"10.3390\/jcm10245765","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T21:46:58Z","timestamp":1639086418000},"page":"5765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Anti-Inflammatory Effects of Immunostimulation in Patients with COVID-19 Pneumonia"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-8253","authenticated-orcid":false,"given":"Pierachille","family":"Santus","sequence":"first","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"},{"name":"Division of Respiratory Diseases, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9013-3418","authenticated-orcid":false,"given":"Dejan","family":"Radovanovic","sequence":"additional","affiliation":[{"name":"Division of Respiratory Diseases, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Garziano","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, Via Francesco Sforza 35, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3084-4365","authenticated-orcid":false,"given":"Stefano","family":"Pini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"},{"name":"Division of Respiratory Diseases, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Croce","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"},{"name":"Division of Respiratory Diseases, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Fuccia","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"},{"name":"Division of Respiratory Diseases, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Spitaleri","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"},{"name":"Division of Respiratory Diseases, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3671-4235","authenticated-orcid":false,"given":"Mara","family":"Biasin","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-6191","authenticated-orcid":false,"given":"Mario","family":"Clerici","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, Via Francesco Sforza 35, 20122 Milan, Italy"},{"name":"Don Carlo Gnocchi Foundation, IRCCS, 20148 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-3359","authenticated-orcid":false,"given":"Daria","family":"Trabattoni","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (DIBIC), Universit\u00e0 degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106323","DOI":"10.1016\/j.rmed.2021.106323","article-title":"Characteristics and outcomes in hospitalized COVID-19 patients during the first 28 days of the spring and autumn pandemic waves in Milan: An observational prospective study","volume":"178","author":"Radovanovic","year":"2021","journal-title":"Respir. Med."},{"key":"ref_2","first-page":"915","article-title":"Characteristics, outcomes and global trends of respiratory support in patients hospitalized with COVID-19 pneumonia: A scoping review","volume":"87","author":"Radovanovic","year":"2021","journal-title":"Minerva Anestesiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1001\/jama.2020.5394","article-title":"COVID-19 Lombardy ICU Network. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy","volume":"323","author":"Grasselli","year":"2020","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41579-020-00459-7","article-title":"Characteristics of SARS-CoV-2 and COVID-19","volume":"19","author":"Hu","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-020-0311-8","article-title":"The trinity of COVID-19: Immunity, inflammation and intervention","volume":"20","author":"Tay","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41392-021-00679-0","article-title":"The signal pathways and treatment of cytokine storm in COVID-19","volume":"6","author":"Yang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1136\/thoraxjnl-2012-202291","article-title":"Novel insights into immune and inflammatory responses to respiratory viruses","volume":"68","author":"Schwarze","year":"2013","journal-title":"Thorax"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12948-015-0012-1","article-title":"Pidotimod: The state of art","volume":"13","author":"Ferrario","year":"2015","journal-title":"Clin. Mol. Allergy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.pupt.2017.03.005","article-title":"Immunomodulatory effects of pidotimod in adults with community-acquired pneumonia undergoing standard antibiotic therapy","volume":"44","author":"Trabattoni","year":"2017","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1186\/s12967-015-0649-z","article-title":"Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia","volume":"13","author":"Esposito","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"260","DOI":"10.2174\/1570162X18666210111102046","article-title":"Pidotimod and Immunological Activation in Individuals Infected with HIV","volume":"19","author":"Ucciferri","year":"2021","journal-title":"Curr. HIV Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2020048","DOI":"10.4084\/mjhid.2020.048","article-title":"Pidotimod in Paucisymptomatic SARS-CoV2 Infected Patients","volume":"12","author":"Ucciferri","year":"2020","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e043651","DOI":"10.1136\/bmjopen-2020-043651","article-title":"Severity of respiratory failure at admission and in-hospital mortality in patients with COVID-19: A prospective observational multicentre study","volume":"10","author":"Santus","year":"2020","journal-title":"BMJ Open"},{"key":"ref_14","first-page":"2526","article-title":"ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin definition","volume":"307","author":"Ranieri","year":"2012","journal-title":"JAMA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1164\/rccm.201908-1581ST","article-title":"Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America","volume":"200","author":"Metlay","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"ofaa421","DOI":"10.1093\/ofid\/ofaa421","article-title":"Prolonged Low-Dose Methylprednisolone in Patients with Severe COVID-19 Pneumonia","volume":"7","author":"Salton","year":"2020","journal-title":"Open Forum Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1007\/s40121-021-00487-7","article-title":"Clinical Management of Adult Patients with COVID-19 Outside Intensive Care Units: Guidelines from the Italian Society of Anti-Infective Therapy (SITA) and the Italian Society of Pulmonology (SIP)","volume":"10","author":"Bassetti","year":"2021","journal-title":"Infect. Dis. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2001935","DOI":"10.1183\/13993003.01935-2020","article-title":"Helmet CPAP treatment in patients with COVID-19 pneumonia: A multicentre cohort study","volume":"56","author":"Aliberti","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Radovanovic, D., Rizzi, M., and Pini, S. (2020). Helmet CPAP to Treat Acute Hypoxemic Respiratory Failure in Patients with COVID-19: A Management Strategy Proposal. J. Clin. Med., 9.","DOI":"10.3390\/jcm9041191"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1186\/s13054-021-03627-0","article-title":"Predictors of weaning from helmet CPAP in patients with COVID-19 pneumonia","volume":"25","author":"Radovanovic","year":"2021","journal-title":"Crit. Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.ajem.2020.12.069","article-title":"Neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio and platelet to lymphocyte ratio to predict the severity of COVID-19","volume":"45","author":"Seyit","year":"2020","journal-title":"Am. J. Emerg. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"106504","DOI":"10.1016\/j.intimp.2020.106504","article-title":"The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients","volume":"84","author":"Yang","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1186\/s13054-020-03007-0","article-title":"Neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ARDS in severe COVID-19 patients","volume":"24","author":"Ma","year":"2020","journal-title":"Crit. Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1186\/s13054-020-03374-8","article-title":"Predictive values of neutrophil-to-lymphocyte ratio on disease severity and mortality in COVID-19 patients: A systematic review and meta-analysis","volume":"24","author":"Li","year":"2020","journal-title":"Crit. Care"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s41392-020-0211-1","article-title":"Temporal profiling of plasma cytokines, chemokines and growth factors from mild, severe and fatal COVID-19 patients","volume":"5","author":"Xu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","unstructured":"Foti, M., and Locati, M. (2017). Eosinophil Cytokines in Allergy. Cytokine Effector Functions in Tissues, Academic Press\u2014Elsevier Science Publishing Co. Inc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e01324-20","DOI":"10.1128\/mSphere.01324-20","article-title":"Interplay of Antibody and Cytokine Production Reveals CXCL13 as a Potential Novel Biomarker of Lethal SARS-CoV-2 Infection","volume":"6","author":"Horspool","year":"2021","journal-title":"mSphere"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104296","DOI":"10.1016\/j.phrs.2019.104296","article-title":"Current and future targeted therapies for severe asthma: Managing treatment with biologics based on phenotypes and biomarkers","volume":"146","author":"Santus","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"18689","DOI":"10.1038\/s41598-020-75659-5","article-title":"IL-4\/IL-13 remodeling pathway of COVID-19 lung injury","volume":"10","author":"Nagashima","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.coviro.2012.04.004","article-title":"SARS coronavirus pathogenesis: Host innate immune responses and viral antagonism of interferon","volume":"2","author":"Totura","year":"2012","journal-title":"Curr. Opin. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.imlet.2017.05.001","article-title":"Effects of pidotimod soluble powder and immune enhancement of Newcastle disease vaccine in chickens","volume":"187","author":"Qu","year":"2017","journal-title":"Immunol. Lett."},{"key":"ref_32","first-page":"253","article-title":"Immunomodulating activity of Pidotimod in children with Down syndrome","volume":"27","author":"Zuccotti","year":"2013","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e13404","DOI":"10.1111\/eci.13404","article-title":"Prognostic implications of neutrophil-lymphocyte ratio in COVID-19","volume":"51","author":"Jimeno","year":"2021","journal-title":"Eur. J. Clin. Investig."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/24\/5765\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:44:09Z","timestamp":1760168649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/24\/5765"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,9]]},"references-count":33,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["jcm10245765"],"URL":"https:\/\/doi.org\/10.3390\/jcm10245765","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,9]]}}}