In this study we analyzed which variables were associated with the presence of headache in COVID-19 patients and whether patients with headache had a worse prognosis, assessed by the risk of all-cause, in-hospital mortality. For this, we studied a large cohort of hospitalized patients with confirmed COVID-19, and we systematically interrogated them about the presence of headache.
SARS-CoV-2 causes respiratory symptoms in most patients. However, neurological symptoms are among the most frequent extrapulmonary symptoms [8, 9]. After an incubation period of 2–14 days , most patients present general symptoms for 1–3 weeks . Patients with comorbidities are particularly vulnerable to the virus [4, 20], and there are several risk factors that have been associated with a worse prognosis [3, 21, 22]. The prompt diagnosis, isolation and treatment of patients is crucial . Every clinician should be prepared for facing the virus, as the pandemic has extended worldwide causing hundreds of thousands of deaths and millions of cases .
Headache is a frequent symptom of COVID-19. It was present in almost a quarter of our sample. This frequency was higher than in other previously reported series, which described a 6–15% prevalence [5, 6, 8, 9]. On the one hand, this finding must be interpreted with caution given that we only included hospitalized patients. On the other hand, this could be explained because we interviewed every patient or relative about the presence of headache, reaching them by telephone if necessary. We also extensively reviewed primary care records, screening for the presence of headache. Further studies will be necessary to clarify the real prevalence of headache in COVID-19 patients, including outpatient series.
The main finding of our study was that headache was associated with a lower probability of death. In our sample, headache patients had a different clinical picture, as the frequency of symptoms such as anosmia, cough, myalgia and arthralgia were higher. The higher frequency of symptoms could suggest that those patients visited the ED earlier; however, in our sample, patients with headache presented to the ED later than those without headache. This could reflect that patients without headache suffer from a more severe case of COVID-19 and therefore they seek medical attention earlier .
Many laboratory results were also different in patients with headache compared with the rest of the sample, although these results should be interpreted cautiously . Headache patients were younger, more frequently female, less disabled, and had lower frequencies of hypertension, smoking habits, cardiac disorders, and chronic neurological disorders. All of those could influence the crude results [3, 4], and therefore we did a multivariate regression analysis to assess which variables were independently associated with the presence of headache.
The baseline factors that independently increased the odds of having headache were the female sex, younger age, and lower disability level at the baseline. These variables have been associated with a lower risk of death from COVID-19 [4, 26]. However, in our study, headache was independently associated with a lower risk of death in the multivariate model.
Some symptoms were associated with higher odds of headache, such as fever, anosmia and myalgia . Fever, myalgia and headache are common in other systemic viral infections [28,29,30]. These symptoms can be related to lymphocyte and macrophage activation, interferon secretion and cytokine release [31, 32]. An efficient innate immunity response is associated with a better COVID-19 prognosis. However, in some patients, the immune response persists and causes endothelial dysfunction, thrombosis, persistent macrophage activation, fibrinoid organizing pneumonia, acute respiratory distress syndrome, multi-organ failure and death .
Laboratory biomarkers reportedly associated with COVID-19 pathophysiology include lymphocytes, CRP, D-dimer , PCT, troponins, ferritin, and IL-6, among others [22, 35]. In our sample, most of them differed between patients with and without headache. In the multivariate analysis, patients with headache had lower odds of having increased CRP, abnormal platelet values, lymphopenia and increased D-dimer at the ED visit, and these are factors that are typically associated with the cytokine storm described in COVID-19 patients [32, 36]. In our opinion, this could partially explain the lower risk of death experienced by COVID-19 patients with headache . However, it was also an unexpected finding, as we hypothesized that the presence of headache could be partially explained by those factors. We could not explain the lower levels of CRP or IL-6 due to the use of NSAIDs or steroids, as patients with headache received them less frequently than the rest of the sample. The specific causes of headache might be further studied via imaging and systematic cerebrospinal fluid evaluation.
Our findings should be interpreted with caution. In a previous prospective study that included 179 hospitalized COVID-19 patients with pneumonia, mortality was higher in patients with headache (5/21 (23.8%)) than those without headache (12/158 (7.6%)); however, it did not remain statistically significant in the multivariate regression analysis . In a meta-analysis that included 19 studies (2874 patients) published between January 1, 2020 and February 21, 2020, presence of headache was not associated with a worse prognosis . We propose that the impact of headache in COVID-19 prognosis should be studied in deeper detail. Compared with other symptoms, headache might have different phenotypes and each presentation might have a different meaning [39, 40]. We hypothesize that the impact of headache on prognosis might be linked to the causes of headache . If the presence of headache represents a more effective immune response, then it could be related to a lower mortality. In those cases in which the headache is associated with systemic complications, the prognosis might be worse. However, in our study, most of the patients reported the headache early in the course of the disease, and therefore the precise significance of later or different headache presentations should also be analyzed.
This study has notable weaknesses. It was a single-center study, so the results may not be applicable to other centers or countries. In addition, the sample included only hospitalized patients, which could limit the generalizability of the results. Further multicentric studies with larger sample sizes and inclusion of non-hospitalized patients will be necessary to evaluate our hypothesis and to clarify whether the prevalence of headache differs between admitted and non-admitted patients, particularly in patients with prior headache history. Finally, our study was retrospective and the collected data may not be complete; despite the extensive search, the frequency of headache could be underreported due to the lack of prospective and iterative evaluation, the unavailability of some patients, and the fact that in some cases we contacted the relatives instead of the patients. Some variables may be associated with the lower age and higher frequency of female sex seen in patients with headache, so direct comparisons should be interpreted cautiously. We did not assess the impact on prognosis of the different possible headache phenotypes. We encourage other researchers to pool the data and create a larger series that could better clarify the role of prior history of headache disorders in the prognosis and phenotyping of headache in COVID-19.