The impact of headache disorders on COVID-19 survival: a world population-based analysis

  1. Robert E. Shapiro
  2. Víctor J. Gallardo
  3. Edoardo Caronna
  4. Patricia Pozo-Rosich

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Abstract

Importance

COVID-19 has not impacted people or countries uniformly. This disparity has prompted investigations to identify clinical and genetic predictors of COVID-19 mortality. Headache, a COVID-19 symptom, has been associated with positive disease prognosis. It is logical to consider whether primary headache disorders, among the most prevalent and disabling diseases globally, may also be associated with reduced viral mortality and thereby may have arisen as adaptive host defences

Objective

To study the relationship between COVID-19 mortality and primary headache disorders.

Main outcome measure

Using a generalized additive model regression (GAM), we analysed data across 171 nations to identify variables which impact COVID-19 mortality rates (demographics, national wealth and government effectiveness, pandemic management indexes, latitude of the country’s capital, prevalence of headache disorders and other diseases). We performed similar analyses of seasonal influenza mortality. Separately, we meta-analysed studies of COVID-19 inpatient survival reporting headache, using PRISMA guidelines.

Results

In the global population-level analysis, we observed that a higher prevalence of headache disorders was associated with a higher COVID-19 mortality rate, and represented the main variable contributing to differences in COVID-19 mortality rates between countries (37.8%; F value=10.68). By contrast, we observed a negative trend between the prevalence of headache disorders and influenza death rates. Controversially, when considering headache as a symptom of COVID-19, in the 48 meta-analysed studies we observed a significantly higher risk ratio of survival (RR:2.178 [1.882-2.520], p<0.0001) among COVID-19 inpatients with headache.

Conclusions and Relevance

Headache as a primary disorder is more prevalent in nations with higher COVID-19 mortality, whereas headache as a COVID-19 symptom is associated with enhanced survival. Further studies should clarify whether primary headache disorders represent a risk factor for mortality for COVID-19 or, rather, whether this association reflects evolutionary adaptive processes to enhance survival that, in the case of COVID-19, are insufficiently protective.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.10.21253280: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Note, however, that a limitation of our analysis is that we could not obtain data to control for national variations in influenza vaccination rates. The hypothesis that headache, as a symptom, may confer a competitive advantage in enhancing host defences from viral infections appears to be at odds with our finding that higher population prevalence of primary headache disorders is associated with increased COVID-19 mortality. This puzzle might be reconciled by consideration of the genetics of headache disorders. That is, susceptibility alleles for highly polygenic headache disorders (e.g. migraine) may have been selected as adaptive responses to coronaviruses, rather than that headache disorders directly increase the risk of COVID-19 death.28 In the case of novel SARS-CoV-2 infection, headache disorders might be insufficiently protective to markedly reduce COVID-19 death rates at a population level. In this context, neither host responses (i.e. headache disorders), nor social responses (i.e. PHSM), might be sufficient countermeasures to the high virulence of SARS-CoV-2. Evidence is emerging that selection pressures that differ between Africa and Europe may have influenced the expression of COVID risk-altering human alleles. Zeberg and Pääbo have recently reported that the risk of developing clinically more severe COVID-19 is linked to chromosome 3 genetic variations, whereas the risk of developing clinically less severe COVID-19 is linked to chromosome 12 genetic variations.5,...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.03.10.21253280v1 on medRxiv