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COVID-19 Headache Positively Associated With Mortality, Meta-Analysis Suggests

In addition to headache, other COVID-19 symptoms such as anosmia, myalgia, and nausea or vomiting were associated with higher survival rates.

Findings from a large-scale, systematic search showed a significantly higher survival rate among inpatients with COVID-19 who reported headache as a symptom vs those without headache. Investigators concluded that these data point toward the idea that headache arising secondary to infection is not a “nonspecific” symptom, but rather potentially a marker of enhanced likelihood of survival.1

The meta-analysis comprised of 48 full-text, peer-reviewed publications of COVID-19 inpatient mortality studies that also reported headache as a COVID-19 symptom. All told, the presence of headache symptoms was statistically significantly association with infected inpatients who survived, compared with those who did not (unadjusted risk ratio [RR], 1.90 [95% CI, 1.46-2.47]; I2 = 80.0%; P <.0001; age-adjusted RR, 2.28 [95% CI, 1.78-2.92]; I2 = 52.8%; P <.0001).

Senior investigator Patricia Pozo-Rosich, MD, PhD, neurologist, Vall d’Hebron University Hospital, Barcelona, Spain, and colleagues wrote that, "Further studies are needed to clarify the roles of headaches and headache disorders in the context of viral infections or post-viral syndromes (eg, long COVID). Defining specific headache mechanisms that could enhance survival from viral infections represents an opportunity for the potential discovery of improved viral therapeutics, as well as for understanding whether, and how, primary headache disorders may be adaptive."

Three investigators examined all titles and abstracts and obtained full texts of potentially relevant papers, including supplementary materials. Information on study country, study size, COVID-19 confirmation, patients’ characteristics including demographics, presence of headache among COVID-19 accompanying symptoms, and comorbidities, were all extracted for the analysis. In total, 43,169 inpatients with COVID-19 were included in the analysis, and 81.4% (n = 35,132) survived.

Although there was statistically significant heterogeneity between studies, the overall pooled prevalence of headache as a symptom among inpatients with COVID-19 was 10.4%. In addition to headache, investigators found that other COVID-19 symptoms such as anosmia (RR, 2.94; 95% CI, 1.94-4.45; I2 = 84.5%), myalgia (RR, 1.57; 95% CI, 1.34-1.83; I2 = 48.8%), and nausea or vomiting (RR, 1.41; 95% CI, 1.08-1.82; I2 = 57.2%) were associated with higher survival rates.

In contrast, dyspnea and all comorbid diseases studies were associated with COVID-19 nonsurvival. Additionally, consistently higher RRs of headache among inpatients with COVID-19 who survived were observed on sensitivity analyses. After excluding studies with lower quality, headache RR increased without a statistically significant heterogeneity between studies (RR, 2.60; 95% CI, 2.03-3.32; I2 = 23.6%; P <.0001).

In a separate analysis stratifying first COVID-19 symptom to hospital admission, statistically significant associations were observed between early admission of less than 1 week and higher survival odds (RR, 2.98; 95% CI, 2.35-3.78; I2 = 0.0%; P = .010). Even after collecting data on the timing of the medical evaluation, the setting of the medical evaluation, and the data missingness to control for potential bias, the presence of headache symptoms remained statistically significantly associated with patients’ survival rate.

There were several strengths and limitations to the study, ranging from the large sample size that spanned across 14 nations, to the exclusion of studies following COVID-19 vaccination or the appearance of the more virulent SARS-CoV-2 variant strains. For the latter reason, the results may not generalize to all variants, the study investigators noted. Additionally, by analyzing studies of infected patients who reported either the presence or absence of headache symptoms, there was a possibility of bias against inclusion of those who would be unable to report these symptoms, such as individuals who were intubated at the time of presentation to the hospital.

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1. Gallardo VJm Shapiro RE, Caronna E, Pozo-Rosich P. The relationship of headache as a symptom to COVID-19 survival: a systematic review and meta-analysis of survival of 43,169 inpatients with COVID-19. Headache. Published online September 3, 2022. doi:10.1111/head.14376