Patterns of Past COVID-19 and EBV Infection in Primary Headache Disorders: A Population Study

INTRODUCTION: Viral illnesses are known to trigger chronic headaches. Following the COVID-19 (coronavirus disease 2019) pandemic, many patients reported prolonged headaches. However, the impact on the incidence of primary headache disorders remains unclear. The aim of our study was to evaluate whether patients with newly diagnosed primary headache disorders had higher rates of prior COVID-19 and Epstein-Barr virus (EBV) infections, to further explore the impact of viral infections on primary headache disorders. METHODS: A case-control study using data from the Clalit Health Services database comparing patients with newly diagnosed primary headache disorders, between June 2020 and June 2023, to non-headache controls, with regard to rates of prior COVID-19 and EBV infection. RESULTS: Our cohort comprised 39,693 patients with primary headaches: 30,956 with migraine, 7984 with tension-type headache (TTH), and 753 with cluster headache (CH). The control group included 69,272 individuals. EBV infection was associated with both migraine (OR 1.13, 95% CI 1.09-1.17) and TTH (OR 1.11, 95% CI 1.03-1.20). However, in a multivariable analysis, only the association with migraine remained significant. COVID-19 infection was associated with migraine (OR 1.04, 95% CI 1.01-1.07), but lost significance when adjusted for comorbidities. The association between COVID-19 and TTH was nonsignificant in a univariable analysis (OR 1.05, 95% CI 1.00-1.12). However, in a stratified analysis, COVID-19 was significantly associated with TTH among patients with anxiety or depression. The CH group showed no significant differences compared to controls. CONCLUSION: Different viral infections have varying effects on primary headache disorders: EBV infection is primarily associated with migraine, while COVID-19 is primarily associated with TTH. These findings underscore the distinct pathophysiological mechanisms underlying these disorders and suggest a differential involvement of the immune system in their development.