The main finding of this study is that alpha-CGRP levels are significantly increased in COVID-19 inpatients with acute headache as compared to healthy controls. These data indicate that trigemino-vascular activation is involved in the pathophysiology of acute headache in COVID-19 patients and, as happens in chronic migraine [10,11], invite to suggest a role of a rather permanent activation of the trigeminal system in the pathophysiology of persistent post-COVID-19 headache.
To our knowledge, serum CGRP levels have been measured in COVID-19 patients in two previous works [14,15]. In the study by Ochoa-Callejero et al., CGRP levels were decreased in COVID-19 patients versus healthy controls, but the samples of healthy volunteers were obtained “before the initiation of the pandemia” and were not matched for age. Just as an example, the mean age of controls in that study was 41 years and that of symptomatic inpatients (those who would be theoretically comparable to our patients) was 81 years. Additionally, they do not report whether their COVID-19 subjects had headache and their serum CGRP levels of control subjects was unusually high (an average of 220.7 pg/mL, when most published studies show CGRP levels in healthy controls below 50 pg/mL) [7,10,11]. In a second study, Bolay et al. determined serum CGRP in COVID-19 inpatients with and without headache. The levels of CGRP were similar in both groups, but they did not analyze, for instance, the influence on CGRP levels of acute analgesics or steroids and, what is most important, there was no control group of healthy subjects [15].
Even considering that we obtained data from a limited number of subjects, the increase in alpha-CGRP found here was clear even in the presence of drugs such as corticosteroids or analgesics, which could theoretically diminish CGRP release, supports a role for this neuropeptide in the headache manifestations of COVID-19 and, together with the recently described specific increase in CGRPβ serum levels in COVID-19 patients with diarrhea (16), suggests that CGRP could be one of the molecules released in the cytokine storm induced by the COVID-19 infection. CGRP is known to enhance interleukin-6 production, the main biomarker of COVID-19 severity, which has even brought the proposal that CGRP antagonists could be of help in COVID-19 infection (17,18).