A study by Vall d’Hebron shows that headache could indicate a better clinical course of COVID-19

Local neuroinflammation near the nasal passages where the virus enters could be a defense system that would prevent the systemic cytokine storm associated with severe COVID-19.


A team from Vall d’Hebron has described that the presence of headache in patients with COVID-19 would be associated with a better evolution of the disease. The Neurology and Immunology Services of the Vall d’Hebron University Hospital and the Headache and Neurological Pain and Diagnostic Immunology research groups at Vall d’Hebron Research Institute (VHIR) participated in the study.

Headache, along with anosmia (loss of smell) and ageusia (loss of taste), are common neurological symptoms that have been associated with COVID-19. Faced with the lack of knowledge of its ability to predict the course of the disease, Vall d’Hebron researchers decided to define and describe the characteristics of headache and look for an association between its appearance and the prognosis of COVID-19. The results have been published in the journal Cephalalgia.

The study analyzed the symptoms and evolution of 130 patients with COVID-19 who were admitted at the emergency room of Vall d’Hebron for three weeks between March and April 2020. All of them were visited by a neurologist due to the need for reorganization of the professionals to adapt to the high number of patients during the COVID-19 crisis. “The fact that some patients were visited by doctors with different specialties allowed to carry out studies from different points of view, which provided information related to symptoms that are not only respiratory”, explains Dr. Patricia Pozo Rosich, head of the Headache and Neurological Pain group at VHIR, specialist from the Neurology Service at Vall d’Hebron University Hospital and head of the Migraine Adaptive Brain Center in Vall d’Hebron. Of these patients, 97 (74,6%) had headaches, although only 19,6% had a history of episodic migraines prior to the disease. Most of them had mild or moderate headache, but in one in every four patients, it was similar to a migraine. It mostly happened in women and young people.

In 21.4% of patients with persistent headaches, this was a prodromal symptom of COVID-19, that is, it appeared before any other symptom of the disease. Regarding its evolution, patients who presented headaches when they arrived at the emergency room had a clinical duration of COVID-19 approximately one week shorter: about 24 days when they had headache, while, in the cases without headache, the average duration of the disease was about 31 days. “It seems clear that the presence of headache is a good prognostic factor for COVID-19 and could be used to predict its evolution”, highlights Dr. Pozo Rosich.

The researchers also found an association between headache and anosmia and ageusia, since loss of these senses was much more common in people with headaches.


Headache persists in 40% of patients

Six weeks after their arrival to the emergency room, the evolution of 100 patients who had participated in the first phase of the study was monitored. Among them, there were 74 people who had a headache at the time of hospital admission. At the time of follow-up, 28 of these (37.8%) still had headache with little response to treatment and it was often the only remaining symptom of COVID-19. These results show that headache may persist after COVID-19 is resolved, even in people without a previous history of migraines or recurrent headaches.

The study has some limitations, as it is a hospital series that does not include very serious cases of the disease (as they could not be interviewed) nor very mild (they did not go to the hospital). However, Dr. Pozo Rosich emphasizes that, based on the results, “it is important to change the concept that headache is an irrelevant symptom in patients with COVID-19 and, therefore, it is necessary to study in depth their association in order to understand the evolution of the disease and improve its treatment”.


Local neuroinflammation, possible defense system against the virus

In order to understand the association between COVID-19 and headache, the researchers in the study propose some hypotheses about how SARS-CoV-2 infection could cause headaches.

One hypothesis explains that the virus could mimic the onset of migraine, which causes severe inflammation of the trigeminovascular system, which causes pain. “This local inflammation near the nostrils would serve as an initial defense system against the virus, which would be stronger in people with headaches”, says Dr. Pozo Rosich. “If patients have a greater local response, the virus will be prevented from producing severe systemic inflammation with the release of a cytokine storm”.

In this regard, they studied levels of IL-6, a molecule that, if appears systemically, is very involved in the cytokine storm that often causes the death of patients with COVID-19. In the case of patients with headache, IL-6 levels were lower and remained stable throughout the disease. “This fact points out that, in patients with headaches, IL-6 is released in the local neuroinflammation and, therefore, people do not develop as much systemic inflammation and have a better evolution of the disease”, Dr. Pozo Rosich adds.

This hypothesis is consistent with the relationship with anosmia, as the virus would act not only in the olfactory epithelium causing loss of smell, but also in the branches of the trigeminal nerve, very close to the nostrils through which the virus enters. In this regard, it would be necessary to study whether sensitization of the trigeminovascular system persists when SARS-CoV-2 infection disappears.

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