{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T13:45:19Z","timestamp":1772631919539,"version":"3.50.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsmedizin Greifswald"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Headache Pain"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>New onset or worsening of a headache disorder substantially contributes to the disease burden of post-COVID-19. Its management poses a suitable means to enhance patients\u2019 participation in professional, social, and personal activities. Unfortunately, the pathophysiology of post-COVID-19 headaches is poorly understood. This study aims to investigate the role of (neuro-) inflammatory mechanisms in order to guide the development of anti-inflammatory treatment strategies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We included patients from the interdisciplinary post-COVID-19 Rehabilitation Study (PoCoRe, <jats:italic>n<\/jats:italic>\u2009=\u2009184 patients) run at a tertiary care university hospital, comprising patients with PCR-confirmed SARS-CoV-2 infection\u2009\u2265\u20096 weeks prior to their initial consultation. Patients reporting any headache since their infection were considered for this study (<jats:italic>n<\/jats:italic>\u2009=\u200993). These were interviewed and classified according to the International Classification of Headache Disorders, Third Edition (ICHD-3) by headache specialists. Patient sera were additionally analysed for levels of VILIP-1, MCP-1 (CCL2), sTREM-2, BDNF, TGF-\u00df1, VEGF, IL-6, sTREM-1, \u00df-NGF, IL-18, TNF-alpha, sRAGE, and CX3CL1 (Fractalkine). Markers of inflammation were compared between four groups of patients (none, unchanged, worsened, or new headache disorder).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Patients reported experiencing more severe headaches (<jats:italic>n<\/jats:italic>\u2009=\u200917), new onset headaches (<jats:italic>n<\/jats:italic>\u2009=\u200946), unchanged headaches (<jats:italic>n<\/jats:italic>\u2009=\u200918), and surprisingly, some patients denied having any headaches (<jats:italic>n<\/jats:italic>\u2009=\u200912) despite self-reports. Serum levels of CX3CL1 were increased in the worsened (2145 [811\u20134866] pg\/ml) and new onset (1668 [0-7357] pg\/ml) headache group as compared to patients with no (1129 [0-5379] pg\/ml) or unchanged (1478 [346\u20134332] pg\/ml) headaches. Other markers also differed between groups, but most significantly between patients with worsened (TGF-\u00df1: 60 [0-310] pg\/ml, VEGF: 328 [86\u2013842] pg\/ml, \u00df-NGF: 6 [3\u201338] pg\/ml) as compared to unchanged headaches (TGF-\u00df1: 29 [0\u201377] pg\/ml, VEGF: 183 [72\u2013380] pg\/ml, \u00df-NGF: 3 [2\u201389] pg\/ml). The results did not differ between headache phenotypes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>This study provides evidence that worsened or new headaches following COVID-19 are associated with pro-(neuro-)inflammatory profiles. This supports the use of anti-inflammatory treatment options in this population, especially in the subacute phase.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10194-024-01810-6","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T23:02:40Z","timestamp":1718751760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Occurrence of new or more severe headaches following COVID-19 is associated with markers of microglial activation and peripheral sensitization: results from a prospective cohort study"],"prefix":"10.1186","volume":"25","author":[{"given":"Johanna","family":"Ruhnau","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max","family":"Bl\u00fccher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Bahlmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Almut","family":"Zieme","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antje","family":"Vogelgesang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anke","family":"Steinmetz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Fleischmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"1810_CR1","doi-asserted-by":"publisher","first-page":"101019","DOI":"10.1016\/j.eclinm.2021.101019","volume":"38","author":"HE Davis","year":"2021","unstructured":"Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re\u2019em Y et al (2021) Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine 38:101019","journal-title":"EClinicalMedicine"},{"issue":"3","key":"1810_CR2","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1097\/WCO.0000000000001153","volume":"36","author":"C Tana","year":"2023","unstructured":"Tana C, Giamberardino MA, Martelletti P (2023) Long COVID and especially headache syndromes. Curr Opin Neurol 36(3):168\u2013174","journal-title":"Curr Opin Neurol"},{"issue":"8","key":"1810_CR3","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1007\/s42399-021-00964-7","volume":"3","author":"P Martelletti","year":"2021","unstructured":"Martelletti P, Bentivegna E, Spuntarelli V, Luciani M (2021) Long-COVID headache. SN Compr Clin Med 3(8):1704\u20131706","journal-title":"SN Compr Clin Med"},{"issue":"1","key":"1810_CR4","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s10194-022-01450-8","volume":"23","author":"C Tana","year":"2022","unstructured":"Tana C, Bentivegna E, Cho SJ, Harriott AM, Garc\u00eda-Azor\u00edn D, Labastida-Ramirez A et al (2022) Long COVID headache. J Headache Pain 23(1):93","journal-title":"J Headache Pain"},{"issue":"10","key":"1810_CR5","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1007\/s11910-023-01296-w","volume":"23","author":"L G\u00f3mez-Dab\u00f3","year":"2023","unstructured":"G\u00f3mez-Dab\u00f3 L, Melgarejo-Mart\u00ednez L, Caronna E, Pozo-Rosich P (2023) Headache in COVID-19 and Long COVID: to know facts for clinical practice. Curr Neurol Neurosci Rep 23(10):551\u2013560","journal-title":"Curr Neurol Neurosci Rep"},{"issue":"9","key":"1810_CR6","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1093\/pm\/pnab020","volume":"22","author":"M Hussein","year":"2021","unstructured":"Hussein M, Fathy W, Eid RA, Abdel-Hamid HM, Yehia A, Sheemy MS et al (2021) Relative frequency and risk factors of COVID-19 related headache in a sample of Egyptian Population: A Hospital-based study. Pain Med 22(9):2092\u20132099","journal-title":"Pain Med"},{"key":"1810_CR7","doi-asserted-by":"publisher","first-page":"678472","DOI":"10.3389\/fnhum.2021.678472","volume":"15","author":"C Fern\u00e1ndez-de-Las-Pe\u00f1as","year":"2021","unstructured":"Fern\u00e1ndez-de-Las-Pe\u00f1as C, G\u00f3mez-Mayordomo V, Garc\u00eda-Azor\u00edn D, Palacios-Ce\u00f1a D, Florencio LL, Guerrero AL et al (2021) Previous history of migraine is Associated with fatigue, but not Headache, as long-term Post-COVID Symptom after severe Acute Respiratory SARS-CoV-2 infection: a case-control study. Front Hum Neurosci 15:678472","journal-title":"Front Hum Neurosci"},{"issue":"11","key":"1810_CR8","doi-asserted-by":"publisher","first-page":"3820","DOI":"10.1111\/ene.15040","volume":"28","author":"C Fern\u00e1ndez-de-Las-Pe\u00f1as","year":"2021","unstructured":"Fern\u00e1ndez-de-Las-Pe\u00f1as C, Navarro-Santana M, G\u00f3mez-Mayordomo V, Cuadrado ML, Garc\u00eda-Azor\u00edn D, Arendt-Nielsen L et al (2021) Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: a meta-analysis of the current literature. Eur J Neurol 28(11):3820\u20133825","journal-title":"Eur J Neurol"},{"issue":"8","key":"1810_CR9","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1177\/03331024211068074","volume":"42","author":"D Garcia-Azorin","year":"2022","unstructured":"Garcia-Azorin D, Layos-Romero A, Porta-Etessam J, Membrilla JA, Caronna E, Gonzalez-Martinez A et al (2022) Post-COVID-19 persistent headache: a multicentric 9-months follow-up study of 905 patients. Cephalalgia 42(8):804\u2013809","journal-title":"Cephalalgia"},{"issue":"1","key":"1810_CR10","doi-asserted-by":"publisher","first-page":"16144","DOI":"10.1038\/s41598-021-95565-8","volume":"11","author":"S Lopez-Leon","year":"2021","unstructured":"Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A et al (2021) More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep 11(1):16144","journal-title":"Sci Rep"},{"issue":"1","key":"1810_CR11","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s10194-022-01468-y","volume":"23","author":"R Magdy","year":"2022","unstructured":"Magdy R, Elmazny A, Soliman SH, Elsebaie EH, Ali SH, Abdel Fattah AM et al (2022) Post-COVID-19 neuropsychiatric manifestations among COVID-19 survivors suffering from migraine: a case-control study. J Headache Pain 23(1):101","journal-title":"J Headache Pain"},{"issue":"3","key":"1810_CR12","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/s41579-022-00846-2","volume":"21","author":"HE Davis","year":"2023","unstructured":"Davis HE, McCorkell L, Vogel JM, Topol EJ (2023) Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 21(3):133\u2013146","journal-title":"Nat Rev Microbiol"},{"issue":"3","key":"1810_CR13","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/s41593-024-01573-y","volume":"27","author":"J Radke","year":"2024","unstructured":"Radke J, Meinhardt J, Aschman T, Chua RL, Farztdinov V, Lukassen S et al (2024) Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19. Nat Neurosci 27(3):409\u2013420","journal-title":"Nat Neurosci"},{"issue":"3","key":"1810_CR14","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41593-024-01576-9","volume":"27","author":"C Greene","year":"2024","unstructured":"Greene C, Connolly R, Brennan D, Laffan A, O\u2019Keeffe E, Zaporojan L et al (2024) Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci 27(3):421\u2013432","journal-title":"Nat Neurosci"},{"issue":"7","key":"1810_CR15","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1111\/j.1526-4610.2006.00722.x","volume":"47","author":"T Rozen","year":"2007","unstructured":"Rozen T, Swidan SZ (2007) Elevation of CSF tumor necrosis factor alpha levels in new daily persistent headache and treatment refractory chronic migraine. Headache 47(7):1050\u20131055","journal-title":"Headache"},{"issue":"7","key":"1810_CR16","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1007\/s11916-014-0431-6","volume":"18","author":"TD Rozen","year":"2014","unstructured":"Rozen TD (2014) New daily persistent headache: an update. Curr Pain Headache Rep 18(7):431","journal-title":"Curr Pain Headache Rep"},{"key":"1810_CR17","doi-asserted-by":"crossref","unstructured":"Steinmetz A, Bahlmann S, Bergelt C, Broker BM, Ewert R, Felix SB et al (2023) The Greifswald Post COVID Rehabilitation Study and Research (PoCoRe)-Study design, characteristics and evaluation tools. J Clin Med. ;12(2)","DOI":"10.3390\/jcm12020624"},{"issue":"5","key":"1810_CR18","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/S1474-4422(18)30085-1","volume":"17","author":"J Olesen","year":"2018","unstructured":"Olesen J (2018) International classification of Headache disorders. Lancet Neurol 17(5):396\u2013397","journal-title":"Lancet Neurol"},{"key":"1810_CR19","doi-asserted-by":"crossref","unstructured":"Winter T, Friedrich N, Lamp S, Sch\u00e4fer C, Schattschneider M, Bollmann S et al (2020) The Integrated Research Biobank of the University Medicine Greifswald. Open J Bioresources","DOI":"10.5334\/ojb.64"},{"issue":"7","key":"1810_CR20","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1111\/head.13856","volume":"60","author":"H Bolay","year":"2020","unstructured":"Bolay H, G\u00fcl A, Baykan B (2020) COVID-19 is a real headache! Headache 60(7):1415\u20131421","journal-title":"Headache"},{"key":"1810_CR21","doi-asserted-by":"crossref","unstructured":"Silvestro M, Tessitore A, Orologio I, Sozio P, Napolitano G, Siciliano M et al (2021) Headache worsening after COVID-19 vaccination: an online questionnaire-based study on 841 patients with migraine. J Clin Med. ;10(24)","DOI":"10.3390\/jcm10245914"},{"issue":"19","key":"1810_CR22","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1056\/NEJMra1915327","volume":"383","author":"M Ashina","year":"2020","unstructured":"Ashina M, Migraine (2020) N Engl J Med 383(19):1866\u20131876","journal-title":"N Engl J Med"},{"key":"1810_CR23","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.neulet.2014.12.022","volume":"587","author":"LB Martins","year":"2015","unstructured":"Martins LB, Duarte H, Ferreira AVM, Rocha NP, Teixeira AL, Domingues RB (2015) Migraine is associated with altered levels of neurotrophins. Neurosci Lett 587:6\u201310","journal-title":"Neurosci Lett"},{"issue":"1","key":"1810_CR24","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s10194-024-01757-8","volume":"25","author":"M S\u00fc\u00dfe","year":"2024","unstructured":"S\u00fc\u00dfe M, Kloetzer C, Strau\u00df S, Ruhnau J, Overeem LH, Bendig M et al (2024) Increased CX3CL1 in cerebrospinal fluid and ictal serum t-tau elevations in migraine: results from a cross-sectional exploratory case-control study. J Headache Pain 25(1):46","journal-title":"J Headache Pain"},{"issue":"3","key":"1810_CR25","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1111\/j.1468-2982.2008.01727.x","volume":"29","author":"SH B\u00f8","year":"2009","unstructured":"B\u00f8 SH, Davidsen EM, Gulbrandsen P, Dietrichs E, Bovim G, Stovner LJ et al (2009) Cerebrospinal fluid cytokine levels in migraine, tension-type headache and cervicogenic headache. Cephalalgia 29(3):365\u2013372","journal-title":"Cephalalgia"},{"issue":"4","key":"1810_CR26","doi-asserted-by":"publisher","first-page":"357","DOI":"10.5114\/ninp.2013.36760","volume":"47","author":"I G\u00fczel","year":"2013","unstructured":"G\u00fczel I, Ta\u015fdemir N, \u00c7elik Y (2013) Evaluation of serum transforming growth factor \u03b21 and C-reactive protein levels in migraine patients. Neurol Neurochir Pol 47(4):357\u2013362","journal-title":"Neurol Neurochir Pol"},{"issue":"1","key":"1810_CR27","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s10194-021-01306-7","volume":"22","author":"H Bolay","year":"2021","unstructured":"Bolay H, Karadas \u00d6, Ozt\u00fcrk B, Sonkaya R, Tasdelen B, Bulut TDS et al (2021) HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: a window to the infection-related headache mechanism. J Headache Pain 22(1):94","journal-title":"J Headache Pain"},{"issue":"1","key":"1810_CR28","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1212\/WNL.57.1.132","volume":"57","author":"P Sarchielli","year":"2001","unstructured":"Sarchielli P, Alberti A, Floridi A, Gallai V (2001) Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients. Neurology 57(1):132\u2013134","journal-title":"Neurology"},{"key":"1810_CR29","doi-asserted-by":"crossref","unstructured":"Steinmetz A, Gross S, Lehnert K, L\u00fccker P, Friedrich N, Nauck M et al (2023) Longitudinal clinical features of Post-COVID-19 Patients-Symptoms, fatigue and physical function at 3- and 6-Month Follow-Up. J Clin Med. ;12(12)","DOI":"10.3390\/jcm12123966"},{"issue":"1","key":"1810_CR30","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1186\/s12879-023-08898-2","volume":"23","author":"FS Carri\u00f3n-Nessi","year":"2023","unstructured":"Carri\u00f3n-Nessi FS, Ascanio LC, Pineda-Arap\u00e9 AG, Oma\u00f1a-\u00c1vila \u00d3D, Mendoza-Mill\u00e1n DL, Romero SR et al (2023) New daily persistent headache after SARS-CoV-2 infection in Latin America: a cross-sectional study. BMC Infect Dis 23(1):877","journal-title":"BMC Infect Dis"},{"key":"1810_CR31","doi-asserted-by":"publisher","first-page":"102456","DOI":"10.1016\/j.eclinm.2024.102456","volume":"69","author":"TJ Hartung","year":"2024","unstructured":"Hartung TJ, Bahmer T, Chaplinskaya-Sobol I, Deckert J, Endres M, Franzpotter K et al (2024) Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study. EClinicalMedicine 69:102456","journal-title":"EClinicalMedicine"},{"key":"1810_CR32","doi-asserted-by":"publisher","first-page":"102456","DOI":"10.1016\/j.eclinm.2024.102456","volume":"69","author":"TJ Hartung","year":"2024","unstructured":"Hartung TJ, Bahmer T, Chaplinskaya-Sobol I, Deckert J, Endres M, Franzp\u00f6tter K et al (2024) Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study. eClinicalMedicine 69:102456","journal-title":"eClinicalMedicine"},{"issue":"1\u20132","key":"1810_CR33","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.pain.2006.01.040","volume":"123","author":"L Buchgreitz","year":"2006","unstructured":"Buchgreitz L, Lyngberg AC, Bendtsen L, Jensen R (2006) Frequency of headache is related to sensitization: a population study. Pain 123(1\u20132):19\u201327","journal-title":"Pain"}],"container-title":["The Journal of Headache and Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10194-024-01810-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10194-024-01810-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10194-024-01810-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T23:02:49Z","timestamp":1718751769000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejournalofheadacheandpain.biomedcentral.com\/articles\/10.1186\/s10194-024-01810-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,19]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1810"],"URL":"https:\/\/doi.org\/10.1186\/s10194-024-01810-6","relation":{},"ISSN":["1129-2377"],"issn-type":[{"value":"1129-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,19]]},"assertion":[{"value":"31 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"101"}}