Our study aimed to comprehensively investigate the potential causal relationship between COVID-19 traits and CM. To achieve this, we selected three COVID-19 traits, infected COVID-19, hospitalized COVID-19, and severe COVID-19 as exposures. After rigorous instrumental variable screening, we performed bidirectional univariable Mendelian randomization and found the significant causal effects of infected COVID-19 on CM (OR = 2.574613, 95% CI 1.326495-4.997100, p = 0.005189). By contrast, the causal effect of hospitalized COVID-19 on CM (OR = 1.336397, 95% CI 1.060450–1.684149, p = 0.013995), as well as the causal effect of severe COVID-19 on CM (OR = 1.145725, 95% CI 0.978811–1.341102, p = 0.090380), are insignificant. Moreover, through mediation analysis, we found that “E-selectin levels” was the mediator of the causal effects of infected COVID-19 on CM (Indirect β = 0.673348, 95% CI, 0.081898–1.264798, the mediated proportion of 70.3%, p = 0.049373).
As we mentioned above, the sporadic previous studies have reported conflicting results. Enrique et al.6 found a considerable number (54%) of mastoiditis and deep cervical infections were related to close contact with COVID-19, whilst Jesus et al. 8 found that during the social distancing measures adopted during the COVID-19 pandemic, hospitalizations for mastoiditis in children under 9 years old decreased. Our finding that the COVID-19-related trait having a causal effect on CM was infected COVID-19, but not hospitalized COVID-19 or severe COVID-19, indicating that whether the causal relationship of COVID-19 on CM exists depends on the severity of COVID-19. Our results provide a very convincing explanation for the conflict in previous research. Moreover, Choi et al.22 suggest that the measures implemented in response to COVID-19, such as emphasizing personal hygiene and social distancing, have reduced upper respiratory infections, which provides an alternative interpretation for this contradiction.
By conducting mediation analysis, we for the first time identified "E-selectin levels" as the mediator of the causal effect of infected COVID-19 on CM. E-selectin is a protein expressed on the endothelial cell surface, involved in leukocyte adhesion during inflammation. Several previous studies have reported an increase in E-selectin levels in patients infected with or recovering from COVID-19.23,24 By contrast, Palmos et al.25 found an inverse correlation between E-selectin levels and severe COVID-19 patients, while Won et al.26 reported that the autopsy of COVID-19 patients exhibited E-selectin was downregulated in pulmonary endothelial cells. All these findings suggest that E-selectin levels increase in mild cases of COVID-19, while decreasing in severe cases, which supports our results. Considering the dual role of E-selectin in the progression of disease, future research should focus on exploring the specific regulatory mechanism of E-selectin in COVID-19 infection and prognosis. Neutrophils rolling on E-selectin can induce slow rolling on intercellular adhesion molecule-1 through activation of signaling pathways such as p38 mitogen-activated protein kinase (MAPK) pathway,27 Wang et al.28 found that activating p38 MAPK pathway in chronic otitis media patients up-regulate human MUC5AC mucin transcription. MUC5AC ranks 3rd among the top 20 differentially expressed genes in RNA sequencing and using the Generalized Disequilibrium Test analysis from patients with otitis media.29 In addition, SNP rs2735733 in the region of the mucin 5, subtypes A/C gene (MUC5AC) exhibited nominal evidence for association with Chronic Otitis Media with Effusion and/or Recurrent Otitis Media by using the Generalized Disequilibrium Test analysis.30 These findings may partially explain the causal relationship between E-selectin and chronic mastoiditis, as chronic otitis media and chronic mastoiditis are closely related.
To ensure the robustness of our results, we used reasonable approaches to select instrumental variables, conduct MR analyses, and perform sensitivity analyses. However, this study still has some limitations. First, the conclusions drawn from European populations may not apply to other populations. Second, the genetic characteristics of Finnish populations differ from those of other European populations, but this difference has not been taken into account in our study. Third, as this study aimed to obtain robust results, the suggestive significant causal effect of hospitalized COVID-19 on chronic mastoiditis was not further investigated.
Overall, to the best of our knowledge, this is a study concerned with the association between COVID-19 and CM. For the first time, we conducted a study to investigate the causal effects between three COVID-19 traits and chronic mastoiditis. Our findings indicate a significant causal effect of COVID-19 infection on CM. By contrast, the causal effects of hospitalized COVID-19 and severe COVID-19 on CM are insignificant. Moreover, we initially identified “E-selectin levels” as the mediator of the causal effect of infected COVID-19 on CM. Our finding enriches the types of COVID-19 sequelae and helps to prevent mastoiditis caused by COVID-19 in the early stage, thereby eliminating the possibility of intracranial infection and other serious complications.