{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T22:27:32Z","timestamp":1783117652289,"version":"3.54.6"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tyrolean Regional Government","award":["GZ 75759"],"award-info":[{"award-number":["GZ 75759"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>After COVID-19, patients have reported various complaints such as fatigue, neurological symptoms, and insomnia. Immune-mediated changes in amino acid metabolism might contribute to the development of these symptoms. Patients who had had acute, PCR-confirmed COVID-19 infection about 60 days earlier were recruited within the scope of the prospective CovILD study. We determined the inflammatory parameters and alterations in tryptophan and phenylalanine metabolism in 142 patients cross-sectionally. Symptom persistence (pain, gastrointestinal symptoms, anosmia, sleep disturbance, and neurological symptoms) and patients\u2019 physical levels of functioning were recorded. Symptoms improved in many patients after acute COVID-19 (n = 73, 51.4%). Still, a high percentage of patients had complaints, and women were affected more often. In many patients, ongoing immune activation (as indicated by high neopterin and CRP concentrations) and enhanced tryptophan catabolism were found. A higher phenylalanine to tyrosine ratio (Phe\/Tyr) was found in women with a lower level of functioning. Patients who reported improvements in pain had lower Phe\/Tyr ratios, while patients with improved gastrointestinal symptoms presented with higher tryptophan and kynurenine values. Our results suggest that women have persistent symptoms after COVID-19 more often than men. In addition, the physical level of functioning and the improvements in certain symptoms appear to be associated with immune-mediated changes in amino acid metabolism.<\/jats:p>","DOI":"10.3390\/jpm13071055","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:25:21Z","timestamp":1687911921000},"page":"1055","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Persistent Symptoms and IFN-\u03b3-Mediated Pathways after COVID-19"],"prefix":"10.3390","volume":"13","author":[{"given":"Talia","family":"Piater","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Gietl","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Hofer","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innrain 80, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1532-5177","authenticated-orcid":false,"given":"Johanna M.","family":"Gostner","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innrain 80, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Sahanic","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Tancevski","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Sonnweber","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Pizzini","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Egger","sequence":"additional","affiliation":[{"name":"Central Institute for Medical and Chemical Laboratory Diagnostics (ZIMCL), Tirol Kliniken GmbH, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Schennach","sequence":"additional","affiliation":[{"name":"Central Institute for Blood Transfusion and Immunological Department, Tirol Kliniken GmbH, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Loeffler-Ragg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0709-2158","authenticated-orcid":false,"given":"Guenter","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Kurz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1080\/22221751.2021.1898291","article-title":"Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic","volume":"10","author":"To","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"947973","DOI":"10.3389\/fpsyt.2022.947973","article-title":"Post-COVID-19 fatigue: A systematic review","volume":"13","author":"Joli","year":"2022","journal-title":"Front. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Townsend, L., Dyer, A.H., Jones, K., Dunne, J., Mooney, A., Gaffney, F., O\u2019Connor, L., Leavy, D., O\u2019Brien, K., and Dowds, J. (2020). Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS ONE, 15.","DOI":"10.1101\/2020.07.29.20164293"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1046\/j.1440-1711.2003.t01-1-01177.x","article-title":"Tryptophan and the immune response","volume":"81","author":"Moffett","year":"2003","journal-title":"Immunol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0361-9230(96)00344-9","article-title":"Changes in the Albumin Binding of Tryptophan During Postoperative Recovery: A Possible Link with Central Fatigue?","volume":"43","author":"Yamamoto","year":"1997","journal-title":"Brain Res. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1098\/rstb.2012.0109","article-title":"The 5-HT deficiency theory of depression: Perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg 439His knockin mouse","volume":"367","author":"Jacobsen","year":"2012","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.brainres.2017.09.002","article-title":"Tryptophan circuit in fatigue: From blood to brain and cognition","volume":"1675","author":"Yamashita","year":"2017","journal-title":"Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0028-3908(76)90023-X","article-title":"Inhibition of firing of raphe neurones by tryptophan and 5-hydroxytryptophan: Blockade by inhibiting serotonin synthesis with Ro-4-4602","volume":"15","author":"Gallager","year":"1976","journal-title":"Neuropharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"622","DOI":"10.2174\/138920008785821738","article-title":"Chronic Immune Stimulation Correlates with Reduced Phenylalanine Turnover","volume":"9","author":"Neurauter","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"175","DOI":"10.2174\/1389200024605082","article-title":"Neopterin as a Marker for Immune System Activation","volume":"3","author":"Murr","year":"2002","journal-title":"Curr. Drug Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1600-0625.1999.tb00367.x","article-title":"Neopterin: A review","volume":"8","author":"Hamerlinck","year":"1999","journal-title":"Exp. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1515\/pteridines.2004.15.3.107","article-title":"Neopterin: A Mediator of the Cellular Immune System","volume":"15","author":"Hoffmann","year":"2004","journal-title":"Pteridines"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11786469231154244","DOI":"10.1177\/11786469231154244","article-title":"Interferon-gamma Mediated Metabolic Pathways in Hospitalized Patients During Acute and Reconvalescent COVID-19","volume":"16","author":"Gietl","year":"2023","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1152\/physrev.00042.2006","article-title":"Catecholaminergic Systems in Stress: Structural and Molecular Genetic Approaches","volume":"89","author":"Kvetnansky","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110278","DOI":"10.1016\/j.jpsychores.2020.110278","article-title":"The effect of age, gender, income, work, and physical activity on mental health during coronavirus disease (COVID-19) lockdown in Austria","volume":"139","author":"Pieh","year":"2020","journal-title":"J. Psychosom. Res."},{"key":"ref_16","first-page":"6","article-title":"The influence of psychosocial factors on the immune system (psychoneuroimmunology) and their role for the incidence and progression of cancer","volume":"47","author":"Schubert","year":"2001","journal-title":"Z. Psychosom. Med. Psychother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/S2213-8587(20)30342-9","article-title":"Catecholamine physiology and its implications in patients with COVID-19","volume":"8","author":"Gubbi","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1365-2125.1975.tb01572.x","article-title":"The acute effects of oral (-)-tryptophan in human subjects","volume":"2","author":"Greenwood","year":"1975","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"141","DOI":"10.4137\/IJTR.S4372","article-title":"Implication of Tryptophan 2,3-Dioxygenase and its Novel Variants in the Hippocampus and Cerebellum during the Developing and Adult Brain","volume":"3","author":"Kanai","year":"2010","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.bbi.2019.10.017","article-title":"Inflammation and kynurenine pathway dysregulation in post-partum women with severe and suicidal depression","volume":"83","author":"Achtyes","year":"2020","journal-title":"Brain, Behav. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.neubiorev.2018.03.023","article-title":"Kynurenine pathway in depression: A systematic review and meta-analysis","volume":"90","author":"Ogyu","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Almulla, A.F., Supasitthumrong, T., Tunvirachaisakul, C., Algon, A.A.A., Al-Hakeim, H.K., and Maes, M. (2022). The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: A systematic review and meta-analysis. BMC Infect. Dis., 22.","DOI":"10.1186\/s12879-022-07582-1"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Robertson, J., Gostner, J., Nilsson, S., Andersson, L.-M., Fuchs, D., and Gisslen, M. (2020). Serum neopterin levels in relation to mild and severe COVID-19. BMC Infect. Dis., 20.","DOI":"10.1186\/s12879-020-05671-7"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/s41380-022-01836-9","article-title":"Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: A proof of concept and mechanism study","volume":"28","author":"Almulla","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Al-Hakeim, H.K., Al-Rubaye, H.T., Almulla, A.F., Al-Hadrawi, D.S., and Maes, M. (2023). Chronic Fatigue, Depression and Anxiety Symptoms in Long COVID Are Strongly Predicted by Neuroimmune and Neuro-Oxidative Pathways Which Are Caused by the Inflammation during Acute Infection. J. Clin. Med., 12.","DOI":"10.3390\/jcm12020511"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pizzini, A., Aichner, M., Sahanic, S., B\u00f6hm, A., Egger, A., Hoermann, G., Kurz, K., Widmann, G., Bellmann-Weiler, R., and Weiss, G. (2020). Impact of Vitamin D Deficiency on COVID-19\u2014A Prospective Analysis from the CovILD Registry. Nutrients, 12.","DOI":"10.3390\/nu12092775"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1515\/pterid-2014-0015","article-title":"Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors","volume":"26","author":"Geisler","year":"2015","journal-title":"Pteridines"},{"key":"ref_28","first-page":"873","article-title":"Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic\/psychiatric symptoms","volume":"3","author":"Fuchs","year":"1990","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1016\/j.clinbiochem.2013.10.015","article-title":"Simultaneous measurement of phenylalanine and tyrosine by high performance liquid chromatography (HPLC) with fluorescence detection","volume":"46","author":"Neurauter","year":"2013","journal-title":"Clin. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s12931-020-01546-2","article-title":"Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients\u2019 performance: A prospective observational cohort study","volume":"21","author":"Sonnweber","year":"2020","journal-title":"Respir. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"611.e9","DOI":"10.1016\/j.cmi.2021.11.002","article-title":"Female gender is associated with long COVID syndrome: A prospective cohort study","volume":"28","author":"Bai","year":"2021","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2242106","DOI":"10.1001\/jamanetworkopen.2022.42106","article-title":"Post\u2013COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs. Nonhospitalized Patients","volume":"5","year":"2022","journal-title":"JAMA Network. Open"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fneur.2015.00112","article-title":"Social and Behavioral Determinants of Perceived Insufficient Sleep","volume":"6","author":"Grandner","year":"2015","journal-title":"Front. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"792881","DOI":"10.3389\/fmed.2022.792881","article-title":"Who Is at Risk of Poor Mental Health Following Coronavirus Disease-19 Outpatient Management?","volume":"9","author":"Tymoszuk","year":"2022","journal-title":"Front. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21968","DOI":"10.1038\/s41598-021-01131-7","article-title":"Candidate genes of SARS-CoV-2 gender susceptibility","volume":"11","author":"Russo","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1053\/j.seminhematol.2021.07.001","article-title":"Iron metabolism in infections: Focus on COVID-19","volume":"58","author":"Girelli","year":"2021","journal-title":"Semin. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s10654-020-00678-5","article-title":"Anemia and iron metabolism in COVID-19: A systematic review and meta-analysis","volume":"35","author":"Taneri","year":"2020","journal-title":"Eur. J. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1021\/acs.jproteome.1c00052","article-title":"Systemic perturbations in Amine and Kynurenine Metabolism associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses","volume":"20","author":"Lawler","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"706584","DOI":"10.3389\/fpsyg.2021.706584","article-title":"Editorial: New mind-body interventions that balance human psychoneuroimmunology","volume":"12","author":"Dunne","year":"2021","journal-title":"Front. Psychol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/7\/1055\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:01:47Z","timestamp":1760126507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/7\/1055"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["jpm13071055"],"URL":"https:\/\/doi.org\/10.3390\/jpm13071055","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,27]]}}}