Johanna Ruhnau, Max Blücher, Susanne Bahlmann, Almut Zieme, Antje Vogelgesang, Anke Steinmetz, Robert Fleischmann

• Background 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’ 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. Methods We included patients from the interdisciplinary post-COVID-19 Rehabilitation Study (PoCoRe, n  = 184 patients) run at a tertiary care university hospital, comprising patients with PCR-confirmed SARS-CoV-2 infection ≥ 6 weeks prior to their initial consultation. Patients reporting any headache since their infection were considered for this study ( n  = 93). 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-ß1, VEGF, IL-6, sTREM-1, ß-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). Results Patients reported experiencing more severe headaches ( n  = 17), new onset headaches ( n  = 46), unchanged headaches ( n  = 18), and surprisingly, some patients denied having any headaches ( n  = 12) despite self-reports. Serum levels of CX3CL1 were increased in the worsened (2145 [811–4866] 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 [346–4332] pg/ml) headaches. Other markers also differed between groups, but most significantly between patients with worsened (TGF-ß1: 60 [0-310] pg/ml, VEGF: 328 [86–842] pg/ml, ß-NGF: 6 [3–38] pg/ml) as compared to unchanged headaches (TGF-ß1: 29 [0–77] pg/ml, VEGF: 183 [72–380] pg/ml, ß-NGF: 3 [2–89] pg/ml). The results did not differ between headache phenotypes. Discussion 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.