This first careful analysis of emerging headache characteristics in the pandemic showed that COVID-19 related headaches are more closely associated with anosmia/ageusia and gastrointestinal complaints, in comparison to other usual infection findings. Moreover, bilateral headache, duration over 72 hours, male gender, and analgesic resistance are highly important variables to differentiate between COVID-19 positive patients from negative ones. Although we expected prominent worsening of primary headaches due to the pandemic-related problems, this happened only for less than 1/3 of participants, mostly related to stress.
Gender difference of COVID-19 related headaches
Despite the well-known predominance of headaches in females and the fact that more than 2/3 of participants answering our survey consisted of females, COVID-19 related headaches were reported by male patients at a high rate. This interesting finding is somewhat in line with the predominance of COVID-19 in male gender, with changing reported rates around 56-73%.12-14 It could be hypothesized that this reversed gender dominance may relate to comorbidities like atherosclerosis and hypertension which are more frequent in males. However, females with nearly three times higher rates of migraine could still have outnumbered in COVID-19 related headaches.12,15 Therefore, this finding is a striking point that needs further careful elaboration. Given the higher risk of male gender in COVID-19 cases, a protective role of female hormones or of the location of Angiotensin-converting enzyme 2 (ACE-2) on the X chromosome could be speculated.9,12 Moreover, ACE-2 expression level which is critical for the SARS- CoV-2 entry to the cells was found different between genders.14 There is some evidence that immune activity is more efficient in females in other viral infections.16 It is tempting to speculate that SARS-CoV-2 may trigger some silenced genes related to innate immunity in the X chromosome, so two X chromosomes may serve for a more effective and balanced war against COVID-19 related hyperactivation of immune pathways. Moreover, estrogens and progesterone have anti-inflammatory actions partially through inflammasome activation in some models.17 ACE also affects the display of major histocompatibility complex (MHC) class I and MHC class II peptides.18 Thus, further work with these gender-related differences may give us some clues to find out novel protective ways against COVID-19.
Possible mechanisms underlying COVID-19 related headaches in the light of our findings
The underlying mechanisms of headache related to COVID-19 are not clear at this early moment.9 A direct invasion of trigeminal nerve endings in the nasal or oral cavity by the virus seems one of the most reasonable mechanisms underlying headache according to our results showing the close relation between headache and anosmia/ageusia. Some coronaviruses were shown to be neurotropic and former SARS‐CoV has been observed in the human brain.19,20 Therefore, it is highly likely that SARS‐CoV‐2 may also enter the nervous system via the cranial nerves. Since the first observations in China, there are many worldwide reports showing heterogeneous prevalence figures around 5-85% of loss of smell.21, 22 These profound differences may relate to the viral load differences and a different individual immune response between younger milder symptomatic outpatients, who are eager to report their symptoms, and contrarily severe COVID-19 inpatients with prominent respiratory problems who probably under-report this relatively milder problem. It is well-known that methodological differences exist between questionnaire studies and objective measurements, the former being mostly with lower prevalence. Despite this fact, the rate of anosmia/ageusia was high in our study. These two distinct problems caused by different nerves were not easy to differentiate from each other in daily life, therefore anosmia and ageusia were evaluated together in our study. It was remarkable that nasal obstruction and rhinorrhea were frequently reported but not strictly correlated with anosmia and ageusia according to our results. Although the trans‐synaptic transfer of SARS-COV-2 is not proven yet, this possibility of the trans‐synaptic route was documented for other coronaviruses.23 Entrance from the nasal cavity to the olfactory bulb, then spreading to the brainstem via the piriform cortex with both passive diffusion and axonal transport has been demonstrated.24
Besides the described headache characteristics and COVID-19 related respiratory tract symptoms, abdominal pain and diarrhea should be taken into account to evaluate these patients.3-5,25 Our study found a high rate of gastrointestinal symptoms like diarrhea/stomachache in more than half of the COVID-19 cases and also high rates of nausea (71%) as an accompanying symptom of headache. A previous interesting report from China on non-classical symptoms indicated that 21.6% of patients had gastrointestinal symptoms, associated with headache, which is a higher number in comparison to patients without gastrointestinal symptoms.26 The intriguing relationship of headache with gastrointestinal symptoms also brings to mind several interesting mechanisms including increased circulating Calcium gene related peptide (CGRP) levels and “gut-brain axis” concept where several inflammatory mediators like Interleukin-1β (IL-1 β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), and Tumor necrosis factor-α (TNF-α), besides gut microbiota, and neuropeptides including CGRP are thought to play a role in this interaction. Another relevant consideration is systemic CGRP increase, possibly induced by both angiotensin II and IL-6 levels, as CGRP is clearly associated with trigemino vascular activation resulting in headache, increased gastrointestinal (GI) motility leading to diarrhea, further triggering inflammation and vascular edema.9,27 Taken together with the unusually high rate of ageusia-anosmia (60.4%), this data may lead us to the footsteps of the viral pathway in the brain. Thus, we may also suggest that neuronal invasion of this new coronavirus may cause the dysfunction of the network at brainstem sites, in addition to headache. Nausea and vomiting are associated GI symptoms of migraine headache, yet the diarrhea is a distinct GI feature associated with headache in COVID-19, which clearly shows that opposite influencers play role in SARS-CoV-2 infected gut and trigeminal nerve.
Headache in relation with a systemic viral infection, (without signs of meningo-encephalitis) is described in the International Classification of Headache Disorders-3. The underlying mechanisms of this entity are not illuminated so far. Regarding its characteristics, diffuse pain of moderate/severe intensity, commonly with fever was noted.11 However, in our analyses, the association of headache with fever seems not to be decisive (in all COVID-19 patients with headache, only 40% reported high fever). Also, rhinosinusitis and other respiratory tract symptoms did not seem to explain the headaches in many of these cases, as seen in Table 1. Therefore, for this emerging COVID-19 related headache, the simplistic view of a "causal" relationship with fever or upper respiratory symptoms is not explanatory.
The course of headaches during the pandemic and reported triggers for headache
Most of the patients with pre-existing headaches easily noticed that this was a different problem if they had COVID-19 related headache according to our survey. In a recent case report, the authors highlighted the need to consider secondary headaches, related to central nervous system infections in the setting of COVID-19 in patients experiencing refractory headache, even if the patient had chronic migraine.28 On the other hand, it was also intriguing that 22.5% of the COVID-19 positive cases with previous headaches did not suffer from headache during the pandemic and during the infection. There is no clear explanation for the lack of headache in these cases; causes related to viral load, transmission route, or individual differences may play a role. Other interesting data were the stabile course (53%) or even decrease of the attack frequencies (12%) and reduced severity of the pre-existing headaches in the pandemic period despite the apparent stressful conditions. Social isolation may have helped to avoid stressful social interactions; a healthy diet, and mild sports activities are possible with spending more time at home, also reducing the stress of daily-work life during the pandemic; all these points were possible reasons for the better headache outcome than expected.
The triggers for headaches showed significant differences between participants with and without COVID-19 infection. Headache was triggered more frequently by stress and social isolation in patients without COVID-19 whereas patients diagnosed with COVID-19 reported also infection itself and the drugs as triggers of headache. Furthermore, wearing masks as well as stress both were the main triggers of headache and were more frequently reported by healthcare workers than by the others. Standard hygiene precautions seemed to reduce the risk for the healthcare workers who did not show an increased risk for COVID-19 compared to other participants in our study. It was reported from Germany that an overall seroprevalence of SARS-CoV-2 in a tertiary hospital was low, given the standard hygiene measures taken.29
Other differentiating features and associations of COVID-19 related headache
The clinical features of COVID-19 infection in non-hospitalized adults were reported to be different from hospitalized patients warranting greater awareness of this wider spectrum of clinical symptoms.30 Headache as the leader of the COVID-19 related neurological symptoms is the most frequent complaint in outpatient clinics.31 Thus, it is essential to recognize those patients with COVID-19 at the beginning of the visit or even in telemedicine visits. In this study, we provided evidence that long-lasting bilateral headaches over 48-72 hours and headaches resistant to analgesics suggested the likelihood of being infected by COVID-19 similar to other secondary headaches. The interesting distributions of pulsating and pressing characters in COVID-19 patients, as seen in Table 1, showed that pulsating type was more pronounced in patients with previous headaches; this may indicate that individual backgrounds are important in the final phenotypic presentation of COVID-related headache. COVID-19 infection may play a synergistic role in nociception using similar pathways of the trigeminovascular complex as the underlying primary headache such as migraine. However, different characteristics like pulsating, pressing, and even stabbing quality may indicate that more than one mechanism is involved in COVID-19 related headache emergence. A case report by a headache expert diagnosed with COVID-19 also indicated that several types of headaches can be seen during COVID-19 infection based on a single case (himself).32 Our data had a cross-sectional design; and many participants have chosen only one type despite the availability of multiple choices. Another intriguing finding was that photophobia was more frequently experienced by infected participants than those without COVID-19, reaching statistical significance between the subgroups without prior headache. Moreover, osmophobia was more frequently seen in the group with COVID-19, which may also be related to the olfactory dysfunction. Further basic studies are needed to clarify the mechanism of COVID-19-related headache and to unravel the mysteries of the environmental factors including viruses for the headache mechanisms, to make the pandemic disaster an opportunity.
Limitations and strengths of the study
There are some limitations to this study. First of all, we investigated headache characteristics via questionnaire; the results were based on the answers of the patients, with the potential of a reporting bias well known in all survey studies. Secondly, the patients with COVID-19 were not examined by a physician or headache specialist. Furthermore, our questionnaire was a web-based survey, therefore, only individuals who were able to use new technological devices, thus probably younger and educated people could participate in the study. Among the participants, there may also be some patients who were not tested for COVID-19 due to the lack of other accompanying symptoms. Moreover, patients with severe COVID-19, at the time of the survey, could not be included.
The main strength of our study was the participation of a large number of people in a very short time in the increasing phase of the pandemic. We used a detailed dedicated questionnaire investigating various characteristics of previous and current headaches, including also cross-questions to avoid misunderstandings. The answers given by participants were also examined meticulously to minimize discrepancies. Furthermore, the presence of healthcare workers, reaching nearly half of the participants has increased the reliability of the study.