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Headache may predict clinical evolution of COVID-19



Headache may be a key symptom of COVID-19 that predicts the disease’s clinical evolution in individual patients, new research suggests. An observational study of more than 100 patients showed that headache onset could occur during the presymptomatic or symptomatic phase of COVID-19 and could resemble tension-type or migraine headache.

Headache itself was associated with a shorter symptomatic period, while headache and anosmia were associated with a shorter hospitalization period. In a subgroup of participants, headache persisted even after the symptoms of COVID-19 had been resolved.

Investigators noted that understanding the pathophysiology of headache in COVID-19 could improve understanding of migraine and other headache disorders. “It seems that those patients who start early on, during the asymptomatic or early symptomatic period of COVID-19, with headache have a more localized inflammatory response that may reflect the ability of the body to better control and respond to the infection by SARS-CoV-2,” lead investigator Patricia Pozo-Rosich, MD, PhD, head of the headache and craniofacial pain unit at Vall d’Hebron University Hospital, Barcelona, said in an interview.

She presented the findings at the virtual annual meeting of the American Headache Society.

Systemic inflammation

Headache is one of the main symptoms of COVID-19. A recent study of 214 patients with COVID-19 showed that approximately 13% of the participants had headache and 5% had anosmia.

SARS-CoV-2 penetrates the cells through the ACE2 receptor, which is present throughout the body. “SARS-CoV-2 enters the body through the nasal cavity and it probably penetrates the nervous system in the periphery through afferent branches of the olfactory and trigeminal nerve,” Dr. Pozo-Rosich said. It travels to the lungs and, later, the bloodstream. This generates systemic inflammation that may turn into a cytokine storm. Evidence has identified cortical hyperintensities and olfactory bulb hyperintensities in patients with COVID-19, suggesting that the virus directly infects the CNS.

Interleukin-6, one of the main inflammatory molecules, has been proven to be related to COVID-19 and has become a therapeutic target. Levels of IL-6 may be lower and tend to be more stable in patients with both COVID-19 and headache than in patients with COVID-19 only.

The researchers observed 130 patients (51% women; mean age, 54 years) with COVID-19 who were attended by neurologists at Vall d’Hebron. In this group, 74.4% had headache. Patients with headache tended to be younger than those without headache (mean age, 50 years vs. 63 years, respectively) and tended to be women (58.6% vs. 29.4%).

Approximately one-third of patients with headache had a history of migraine. Most reported mild to moderate pain that resembled tension-type headache. In participants with severe pain and migraine-like features, headache more often began during the asymptomatic phase of COVID-19.

Disease evolution predictor?

The investigators followed up on 100 of the 130 patients with COVID-19, of whom 74 had headache. About 38% of these patients had ongoing headache after 6 weeks, which suggests that some patients may develop a new daily persistent headache once a 3-month period has elapsed. Half of this group had no previous headache history. Headache had been the prodromal symptom of COVID-19 for 21.4% of these patients.

Results showed that headache predicted the clinical evolution of COVID-19. The symptomatic phase of COVID-19 was 7 days shorter for patients with headache than for those without headache. In addition, the period of hospitalization was 7 days shorter for patients with headache and anosmia, compared with patients who had neither headache nor anosmia.

Most therapies, including ibuprofen, candesartan, and anti–calcitonin gene–related peptide (CGRP) monoclonal antibodies, are safe for treating headache in COVID-19, the investigators noted. “We should just try to initially avoid steroids to avoid interference with the body’s reaction to SARS-CoV-2,” Dr. Pozo-Rosich said.

Researchers at Sidney Kimmel Medical College, Philadelphia, are currently studying intranasal vazegepant, an anti-CGRP therapy, as a way to potentially blunt the severe inflammatory response in the lungs of patients with COVID-19, she noted, adding that this peptide may have a future role not only in headache, but also in COVID-19.

Historical link to viral infections

Commenting on the study, Matthew S. Robbins, MD, associate professor of neurology at Weill Cornell Medicine, New York, said the findings associating headache with a shorter symptomatic phase of COVID-19 were “interesting.”

“Headache is common with mild viral infections. More severe viral infections may simply feature more overwhelming respiratory symptoms and fever that lead to underreporting or underascertainment of headache,” said Dr. Robbins, who was not involved with the research.

He noted that the finding showing an association of headache and COVID-19 with a younger age and in women “may be related to a higher prevalence of migraine biology in such patients, and being triggered by the virus or the psychological stress associated with it.”

Dr. Robbins added that viral illnesses have long been associated with new daily persistent headache, “dating back to the early 1980s,” when it was first described in association with Epstein-Barr virus. These infections have also been implicated in the progression of migraine to chronic migraine in adolescents.

“In my view, treatment should be aimed at the symptomatic headache type for which new daily persistent headache resembles, regardless of the potential inciting factor,” Dr. Robbins said.

Dr. Pozo-Rosich has received consulting fees from Allergan, Amgen, Almirall, Biohaven, Chiesi, Eli Lilly, Medscape, Novartis, and Teva Pharmaceuticals. Dr. Robbins has disclosed no relevant financial relationships.

A version of this article originally appeared on

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