, according to recent research published in the journal Headache.
In the systematic review and meta-analysis, Víctor J. Gallardo, MSc, of the headache and neurologic pain research group, Vall d’Hebron Research Institute at the Universitat Autònoma de Barcelona, and colleagues performed a search of studies in PubMed involving headache symptoms, disease survival, and inpatient COVID-19 cases published between December 2019 and December 2020. Overall, 48 studies were identified, consisting of 43,169 inpatients with COVID-19. Using random-effects pooling models, Mr. Gallardo and colleagues estimated the prevalence of headache for inpatients who survived COVID-19, compared with those who did not survive.
Within those studies, 35,132 inpatients (81.4%) survived, while 8,037 inpatients (18.6%) died from COVID-19. The researchers found that inpatients with COVID-19 and headache symptoms had a significantly higher survival rate compared with inpatients with COVID-19 without headache symptoms (risk ratio, 1.90; 95% confidence interval, 1.46-2.47; P < .0001). There was an overall pooled prevalence of headache as a COVID-19 symptom in 10.4% of inpatients, which was reduced to an estimated pooled prevalence of 9.7% after the researchers removed outlier studies in a sensitivity analysis.
Other COVID-19 symptoms that led to improved rates of survival among inpatients were anosmia (RR, 2.94; 95% CI, 1.94-4.45) and myalgia (RR, 1.57; 95% CI, 1.34-1.83) as well as nausea or vomiting (RR, 1.41; 95% CI, 1.08-1.82), while symptoms such as dyspnea, diabetes, chronic liver diseases, chronic respiratory diseases, and chronic kidney diseases were more likely to increase the risk of dying from COVID-19.
The researchers noted several limitations in their meta-analysis that may make their findings less generalizable to future SARS-CoV-2 variants, such as including only studies that were published before COVID-19 vaccines were available and before more infectious SARS-CoV-2 variants like the B.1.617.2 (Delta) variant emerged. They also included studies where inpatients were not tested for COVID-19 because access to testing was not widely available.
“Our meta-analysis points toward a novel possibility: Headache arising secondary to an infection is not a ‘nonspecific’ symptom, but rather it may be a marker of enhanced likelihood of survival. That is, we find that patients reporting headache in the setting of COVID-19 are at reduced risk of death,” Mr. Gallardo and colleagues wrote.
More data needed on association between headache and COVID-19
While headache appeared to affect a small proportion of overall inpatients with COVID-19, the researchers noted this might be because individuals with COVID-19 and headache symptoms are less likely to require hospitalization or a visit to the ED. Another potential explanation is that “people with primary headache disorders, including migraine, may be more likely to report symptoms of COVID-19, but they also may be relatively less likely to experience a life-threatening COVID-19 disease course.”
The researchers said this potential association should be explored in future studies as well as in other viral infections or postviral syndromes such as 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.”
In a comment, Morris Levin, MD, director of the University of California San Francisco Headache Center, said the findings “of this very thought-provoking review suggest that reporting a headache during a COVID-19 infection seems to be associated with better recovery in hospitalized patients.”
Dr. Morris Levin
Dr. Levin, who was not involved with the study, acknowledged the researchers’ explanation for the overall low rate of headache in these inpatients as one possible explanation.
“Another could be that sick COVID patients were much more troubled by other symptoms like respiratory distress, which overshadowed their headache symptoms, particularly if they were very ill or if the headache pain was of only mild to moderate severity,” he said. “That could also be an alternate explanation for why less dangerously ill hospitalized patients seemed to have more headaches.”
One limitation he saw in the meta-analysis was how clearly the clinicians characterized headache symptoms in each reviewed study. Dr. Levin suggested a retrospective assessment of premorbid migraine history in hospitalized patients with COVID-19, including survivors and fatalities, might have helped clarify this issue. “The headaches themselves were not characterized so drawing conclusions regarding migraine is challenging.”
Dr. Levin noted it is still not well understood how acute and persistent headaches and other neurological symptoms like mental fog occur in patients with COVID-19. We also do not fully understand the natural history of post-COVID headaches and other neurologic sequelae and the management options for acute and persistent neurological sequelae.
Three authors reported personal and institutional relationships in the form of grants, consultancies, speaker’s bureau positions, guidelines committee member appointments, and editorial board positions for a variety of pharmaceutical companies, agencies, societies, and other organizations. Mr. Gallardo reported no relevant financial disclosures. Dr. Levin reported no relevant financial disclosures.