Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis

Background: This study was conducted to determine the prevalence of headache in coronavirus disease 2019 (COVID-19) and to assess its association as a predictor for COVID-19. This study also aimed to discuss the possible pathogenesis of headache in COVID-19. Methods: Available articles from PubMed, Scopus, and Web of Science were searched as of September 2 nd, 2020. Data on characteristics of the study, headache and COVID-19 were extracted following the PRISMA guidelines. Biases were assessed using the Newcastle-Ottawa scale. The cumulative prevalence of headache was calculated for the general population (i.e. adults and children). The pooled odd ratio (OR) with 95% confidence intervals (95%CI) was calculated using the Z test to assess the association between headache and the presence of COVID-19 cases. Results: We included 104,751 COVID-19 cases from 78 eligible studies to calculate the global prevalence of headache in COVID-19 and 17 studies were included to calculate the association of headache and COVID-19. The cumulative prevalence of headache in COVID-19 was 25.2% (26,464 out of 104,751 cases). Headache was found to be more prevalent, approximately by two-fold, in COVID-19 patients than in non-COVID-19 patients (other respiratory viral infections), OR: 1.73; 95% CI: 1.94, 2.5 with p=0.04. Conclusion: Headache is common among COVID-19 patients and seems to be more common in COVID-19 patients compared to those with the non-COVID-19 viral infection. No definitive mechanisms on how headache emerges in COVID-19 patients but several possible hypotheses have been proposed. However, extensive studies are warranted to elucidate the mechanisms. PROSPERO registration: CRD42020210332 (28/09/2020)


Introduction
The current coronavirus disease 2019 (COVID-19) pandemic has caused a global crisis for both the health and economic sectors.COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a member of the Coronavirinae family and Betacoronavirus subfamily together with severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle Eastern respiratory syndrome coronavirus (MERS-CoV) 1 .The virus is primarily transmitted from person-to-person through droplets from symptomatic and pre-symptomatic patients, and is likely to also be transmitted by asymptomatic individuals [2][3][4][5][6] .Currently, no effective vaccines or pharmaceutical agents against SARS-CoV-2 are available but some progressions have been made to produce vaccines and drugs against the disease [7][8][9][10] .
Although up to 20.3% of hospitalized patients require admission to the intensive care unit (ICU) 11 with complications such as hypoxemia, acute respiratory distress syndrome (ARDS), arrhythmia, shock, acute cardiac injury, and acute kidney injury [12][13][14] , most SARS-CoV-2 infections are asymptomatic or have mild symptoms 1,15,16 .The common clinical symptoms of COVID-19 include fever, dry cough, dyspnea, chest pain, fatigue and myalgia 1,12,17,18 .In some cases, other neurological manifestations such as headache, dizziness, seizure, taste and smell impairment were also reported 12,[18][19][20][21] .Headache is one of the symptoms that is also reported in various viral infections such as dengue and chikungunya that are common in the tropical regions 22,23 and therefore may not be specific for COVID-19.
In addition, the prevalence of headache in COVID-19 patients varies across studies 19,20,24 .A study found that the prevalence of headache was 17.4% (94/540) in Hubei province, the epicenter of the outbreak, and 14.1% (111/788) among patients outside the epicenter 21 .Another study in European countries found that the headache was reported in more than 40% of 417 COVID-19 patients 19 .Furthermore, the association of headache with the presence of COVID-19 is unknown.This systematic review was undertaken to provide robust evidence on the prevalence of headache in COVID-19 patients globally and its association with COVID-19 cases.Information described in this study might help clinicians to decide whether headache could be used as one of the basic symptoms to be included in diagnosing SARS-CoV-2 infection, especially those in the front line with limited resources.

Registration and protocol
This systematic review was conducted as recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines 25 .The protocol of this study was registered with PROSPERO, an international database of prospectively registered systematic reviews at the University of York, on 28 th September 2020 (CRD42020210332).

Eligibility criteria of studies
Articles reporting headache as a symptom of COVID-19 cases were included.COVID-19 cases should be diagnosed with RT-PCR test using either nasopharyngeal and oropharyngeal swab, bronchoalveolar lavage or cerebrospinal fluid (CSF).All cross-sectional and cohort studies that included COVID-19 cases randomly selected from the population were considered eligible while case reports and case series including all editorials, reviews, and commentaries were excluded.Case-control studies with pre-allocated number of patients with headache and non-headache were excluded.Studies that were conducted in specific populations only such as in pregnancy, children, cancer patients and other groups were excluded.Only articles written in English were included in this study.

Amendments from Version 1
In the new version we have revised some parts: 1. We have provided clearer explanation what "non-COVID-19 patients" means in abstract, methods and results section.For example in Data synthesis subheading we added "non-COVID-19 cases (other respiratory viral infections such as rhinovirus, influenza, parainfluenza and respiratory syncytial virus)." 2. We have provided the approach how to solve in case there was discrepancies between two authors during evaluation of the studies.

3.
We have provided more detail information of Newcastle-Ottawa scale (NOS) -What items that were assessed and how to score as well how the studies classified.We also have added the NOS scores briefly to all studies included in the study.

4.
We have included the limitation of the data and the analysis in particular inability to do sub-analyses based on COVID-19 severity, the existence of COVID-19 co-morbidity and demographic characteristics due to scarcity of the available data.We added "In this analysis we did not analyze the prevalence of headache based on COVID-19 severity, the existence of COVID-19 co-morbidity (such as diabetes and hypertension) and based on demographic characteristics such as gender due to scarcity of the available data.Therefore, whenever enough data are available, such sub-analyses are critical to be conducted." Any further responses from the reviewers can be found at the end of the article "coronaviruses" OR "SARS 2" OR "2019-nCoV acute respiratory disease" OR "novel coronavirus pneumonia"OR "COVID") AND ([All] "Headache").Web of Science ([Title] "SARS-CoV-2" OR "COVID-19" OR "Wuhan coronavirus" OR "Wuhan virus" OR "novel coronavirus" OR "nCoV" OR "severe acute respiratory syndrome coronavirus 2" OR "coronavirus disease 2019 virus" OR "2019-nCoV" OR "2019 novel coronavirus" OR "severe acute respiratory syndrome coronavirus 2" OR "coronavirus" OR "coronaviruses" OR "SARS 2" OR "2019-nCoV acute respiratory disease" OR "novel coronavirus pneumonia"OR "COVID") AND ([All] "Headache").English as language limitation was imposed in the searches.Only peer-reviewed articles were included.Data were extracted both from the articles and the supplementary materials.Reference lists from the eligible articles were retrieved for further relevant studies.

Study selection
All titles and abstracts of identified articles were imported into the EndNote X9 (Thompson Reuters, Philadelphia, PA, USA) and duplicate records between databases were removed.Retrieved articles were initially screened based on title and abstract to identify possible eligible studies.The full texts of potentially eligible articles were then reviewed.The screening and review processes were conducted by two authors (MF and JKF).After reviewing the full texts, the eligibility of each study was decided.Any discrepancies between the two authors were solved by consulting with another investigator (HH).

Data extraction
The following data were extracted from eligible articles: study characteristics (author, title, journal, study site and study design), headache characteristics (number of patients with headache, type of headache, localization, and severity), COVID-19 characteristics (number of patients with COVID-19, severity, and outcome).

Role of the funding source
This study received no external funding.

Outcomes
The primary outcomes of this systematic review were: a) the prevalence of headache in COVID-19 cases; and b) the association between headache and COVID-19 cases compared to other viral infections.

Data synthesis
The cumulative prevalence rate of headache was calculated for COVID-19 cases in the general population.The prevalence was calculated as the number of COVID-19 cases with headache divided by the total number of COVID-19 cases with and without headache, expressed as a percentage (%).Pooled odd ratios (OR) and 95% confidence intervals (95% CI) were calculated to assess the association of headache and COVID-19 compared to non-COVID-19 cases (other respiratory viral infections such as rhinovirus, influenza, parainfluenza and respiratory syncytial virus).

Risk of bias assessment
To reduce sample selection bias, a critical assessment was specifically conducted in terms of setting of study and diagnosis of COVID-19.The quality of eligible studies was assessed using critical appraisals based on the Newcastle-Ottawa scale (NOS) 26 .This scale evaluates 9 criteria of the study including the sample selection (4 items), group comparison (1 item), and the outcome (3 items).The scores range between 0 to 9 in which classified into three groups: low (≤ 4), moderate (between 5-6), and high quality study (≥ 7).

Statistical analysis
The association between headache and the presence of COVID-19 was assessed by the calculation of a pooled OR and 95%CI using the Z test (p<0.05was considered statistically significant).Prior to analysis, gathered data from studies were evaluated for heterogeneity and potential publication bias.Heterogeneity among studies was assessed using the Q test.Initial analysis found that the data had heterogeneity (p<0.10) and therefore a random effect model was employed.Egger's test and a funnel plot were used to assess the reporting or publication bias (p<0.05 was considered having potential for publication bias).The data were analyzed using Review Manager version 5.3 27 .The cumulative pooled OR and 95%CI was presented in a forest plot.

Study eligibility results
The literature searches yielded 732 articles, of which 229 were excluded as duplicates between databases.Following a screening process of the titles and abstracts of the remaining 503 articles, an additional 253 articles were excluded due to irrelevant studies leaving 250 articles (Figure 1).The full texts of the remaining 250 articles were retrieved and screened for eligibility.This process excluded additional 49 articles that were not eligible as they did not fulfill the inclusion criteria.A full assessment was conducted on 201 articles.All included studies had high quality with NOS score ≥ 7.
To calculate the association between headache and COVID-19, the full-text assessment yielded 16 eligible studies.The rest of the references had been excluded for these reasons: (a) the studies were case reports or case-series (n=98); (b) the full-text did not include data of outcome of interest (n=84); and (c) low quality of study (n=3) (Figure 1).The included studies were conducted in a wide ranges of regions: Australia 127 , Belgium 29 , Brazil 50 , China 70 , France 99 , Hongkong 128 , Israel 129 , Italy 130 , Germany 131 , Netherlands 31 , Turkey 120 , and the US 28,105,122,132,133 .Out of the studies, ten were case-control 28,29,31,99,105,120,128,130,132 , four were cross-sectional 50,70,122,131,133 , and two were prospective cohort studies 127,129 .

Headache and COVID-19
As a non-specific symptom, headache might present not only in COVID-19 cases but also in other viral diseases, therefore, headache might not raise suspicion of SARS-CoV-2 infection 22,23 .However, a study described that headache is one of the main neurological symptoms of coronavirus infection including SARS-CoV-2 135 .The global prevalence of headache in our systematic review is more than 25% out of 104,751 COVID-19 cases.This result was almost double that of the previously reported prevalence from studies in China early in the pandemic that ranged from 6.5-13.1% 53, 88 .This suggests that headache is prevalent in SARS-CoV-2 infection and therefore could potentially be used as one of the indicators to diagnose COVID-19 cases.In this analysis we did not analyze the prevalence of headache based on COVID-19 severity, the existence of COVID-19 co-morbidity (such as diabetes and hypertension) and based on demographic characteristics such as gender due to scarcity of the available data.Therefore, whenever enough data are available, such sub-analyses are critical to be conducted.
Our study also highlights that headache was significantly more prevalent in COVID-19 patients, 2.2-fold, than suspected non-COVID-19 viral infection (other respiratory viral infections).A study found that only around 11% of MERS patients reported they suffered from headaches 136 .
A study in COVID-19 patients with pre-existing primary headache disorders revealed that the headache during COVID-19 had an unusual presentation with 42% (44/104) reporting a recent onset of headaches, 49% (51/104) had a change in headache pattern, and 39% (39/104) reported the worst headache they had ever had 119 .These results suggest that new onset headache and changes of headache pattern should be carefully explored as this might be able to differentiate patients with COVID-19 from those without.

Headache pathogenesis in COVID-19
We explored the available literature to broaden our knowledge of the pathogenesis of headache in COVID-19.In general, three main primary headaches are observed in COVID-19 patients i.e. migraine, cluster headache and tension-type headache [137][138][139][140] .No fixed mechanisms have been reported on how these headaches emerge in COVID-19 patients.However, it has been proposed that the activation of trigeminal nerve ending in the periphery followed by the sensitization of various sites in the brain is one of the main pathomechanism of headache in these patients 137,138 .
A headache attack is initiated by the release of several vasoactive neuropeptides such as glutamate, calcitonin gene-related peptide (CGRP), substance P and pituitary adenylate cyclaseactivating polypeptide (PACAP), from nociceptive sensory fibers (especially nociceptive C-fibers and Aδ-fibers) innervating blood vessels located in the meninges and other cranial structures leading to vasodilation, degranulation of mast cells and plasma protein extravasation in those vascular structures [141][142][143] .The release of those peptides from the fibers could be due to either electrical, chemical or mechanical induction emerged from three branches of the trigeminal nerve i.e. ophthalmic, maxillary and mandibular branches 143 .However, because of its wider area of innervation in the meninges and cranial blood vessels, ophthalmic branch seems to play more of a role in stimulating nociceptive processes in meningeal structures than the other two branches 143,144 .
Next, any physiological events, such as vasodilation, that have occurred in the meningeal and large cerebral blood vessels will become a stimulus which is sent to the trigeminal ganglion (TG) where other nociceptive information from other afferent trigeminal branches are also converging 141 .Although cerebral and meningeal vasodilation is not the sole cause of headache 145 , most studies have agreed on the critical role of blood vessel dilation in the emergence of headaches.
From the TG, the stimulus is projected to an area in the brainstem called the trigeminocervical complex (TCC) via first-order neurons 143 .These transmissions are then projected to the diencephalon structures, including the thalamus and hypothalamus, via the second-order neurons 143,146 .The third-order neurons are subsequently responsible for transmitting the information from diencephalic systems to various cortical areas associated with motoric, somatosensory, auditory, retrosplenial and visual functions 141,143 , leading to the manifestation of headache pain and other related symptoms (Figure 3).
During these transmission processes, the release of neuropeptides, especially CGRP, is limited only in the meninges and in the central terminals of trigeminal afferents 147 .When the transmission reaches TCC structures, CGRP and substance P may act to induce the release of glutamate and reduce gamma aminobutyric acid (GABA) production 147,148 .It has been proposed that during a headache attack, the level of glutamate in the TCC increases, while GABA release is decreased 148 .This condition could result in the increase of nociceptive neurons excitability 149 .Moreover, low level of serotonin in trigeminal nerve might also be involved in migraine pathophysiology as the release of this neurotransmitter has been linked to the inhibition of CGRP in trigeminal nerves 150,151 .Several mechanisms have been postulated to explain how trigeminovascular system is activated in COVID-19.Firstly, direct invasion of the virus may activate the peripheral trigeminal system 137 .This theory is hypothesized according to a study, confirming that trigeminal ganglia possess an angiotensinergic activity 152 .Thus, the viral attack would hypothetically disturb the activity of the renin-angiotensin-aldosterone system (RAAS), which may increase the level of CGRP 153 .Although the invasion of SARS-CoV-2 into the olfactory nerve ending seems to be the main route [154][155][156] , the action of the virus on the trigeminal nerve must not be overlooked, as suggested by Perlman et al. (1989).They demonstrated that the trigeminal nerve, in addition to the olfactory nerve, was a route used by neurotropic murine coronavirus to invade the central nervous system (CNS) 157 .
The hypothesis of trigeminal nerve attack by SARS-CoV-2 is also supported by the fact that olfactory mucosa is innervated by the trigeminal nerve 158,159 suggesting the invasion of the olfactory mucosa by SARS-CoV-2 may also induce trigeminal nerve injury.
Following entry into the trigeminal nerve, SARS-CoV-2 may hijack the transneuronal transport system to direct the virus to enter the nucleus via a retrograde axonal transport mechanism.This transport occurs by the involvement of cytoskeletal motor proteins called dynein supported by cofactor dynactin that function to move substances, such as endosomes and vesicles, including hijacking viruses, on microtubule towards the cell body 160 .Once the virus gains access to the nucleus in the cell body through the microtubule-organizing center (MTOC), viral replication is initiated 161 .Finally, viral progenies may spread to other areas of the body, including the CNS, via anterograde axonal transport assisted by the kinesin motor protein family 160 .
A study suggested a transneuronal transport system used by coronavirus after investigating the neuroinvasiveness of HCoV-OC43 in mice 162 .Furthermore, the movement of SARS-CoV-2 via retrograde axonal transport is also hypothesized as it has been reported that the envelope protein of SARS-CoV could subvert dynein function either directly or indirectly 163 .The role of dynein in the retrograde axonal movement of several viruses, such as herpesviruses, West Nile virus, rabies, and influenza virus, upon their penetration in the neuronal plasma membrane has also been reported [164][165][166][167][168][169] .
Secondly, SARS-CoV-2 may also invade the trigeminal nerve by indirect mechanisms.Cytokine storm and vasculopathy mechanisms are also proposed to explain the activation of trigeminal nerve upon SARS-CoV-2 infection 137 .Cytokine storm has attracted substantial interest from researchers and clinicians as this unwanted condition is strongly suggested to be related to the increased mortality in SARS-CoV-2-infected patients 170,171 .
It is hypothesized that the headache suffered by COVID-19 patients at the later stage of this infection is induced by the cytokine storm 139,172,173 .This notion has been supported by the fact that proinflammatory cytokines, such as IL-1, IL-6 and TNF-α, have been linked to the activation of the trigeminovascular system, which is responsible for the emergence and development of headache through the modulation of CGRP [174][175][176][177] .
Moreover, the presence of angiotensin-converting enzyme 2 (ACE2) receptor on the endothelial cells makes the blood vessels vulnerable to invasion by SARS-CoV-2 178,179 .It is known that ACE2 is associated with several protective mechanisms within the body, such as vasodilation 180 and antinociception 181 .ACE2 also diminishes excessive free radical production which prevents oxidative stress 182 .The utilization of this receptor by the virus may decrease its activities, leading to the disturbance of vascular function.The perivascular trigeminal nerve may in turn be affected resulting in the COVID-19-related headache 137 .
More studies are required to improve our understanding on the role of the ACE2 receptor in headache pathophysiology.
Another hypothesis by which SARS-CoV-2 could induce headache is offered by Abboud et al. (2020).They proposed that gas exchange disturbance in alveolar tissues triggered by the viruses would induce hypoxia, which in turn leads to ischemia 170,183 .Ischemia itself has been known to have a strong relation with headache incidents 184 that could be induced by exaggerating the production of free radicals.
In regards to the headache characteristics presented by COVID-19 patients compared to the headache induced by other viral infections, no apparent differences could be observed.Headache in COVID-19 could be worsened by physical or head movement, felt in either the entire head (holocranial) or unilaterally (hemicranial) and the pain is typically pressing or tightening 139 .It is hypothesized that headaches occurring in COVID-19 patients might be the result of the same mechanisms as observed in influenza A and influenza B infections, which could be related to the activity of cytokines 173,[185][186][187] .
A recent report on dengue-related headache suggested that the headache could be pulsating and either affect the entire brain, only frontal, or orbital area, which may resemble primary headaches reported in COVID-19 patients 139,172,188

Morteza Arab-Zozani
Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran Thank you for considering a great area of interest related to COVID-19.This study aimed to investigate the prevalence and pathogenesis of headache in COVID-19 patients, globally.The methodology is completely rigorous and the results are interesting.I have a few minor comments to the authors as follow: In the study selection and/or quality appraisal stages are the authors faced with discrepancies?Please state how resolved these potential discrepancies.

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Was it not possible to analyze the subgroups?For example, based on age groups or gender.

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Please add some details about the NOS checklist and also add the result of the quality appraisal to the manuscript.

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Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?Yes Are the conclusions drawn adequately supported by the results presented in the review?
Endang Mutiawati, Universitas Syiah Kuala, Banda Aceh, Indonesia Dear Dr Erni J. Nelwan We agreed that our study have limitation since we did not able to analysed the data based on existence of COVID-19 co-morbidity.This is mainly because the available of data.The data was scarce.
We have added this in our manuscript: "In this analysis we did not analyze the prevalence of headache based on COVID-19 severity, the existence of COVID-19 co-morbidity (such as diabetes and hypertension) and based on demographic characteristics such as gender due to scarcity of the available data.Therefore, whenever enough data are available, such subanalyses are critical to be conducted." We have provided a clear explanation about the non-COVID-19 in Method section as requestioned.Not-COVID-19 in our study refers to other respiratory viral infections such as rhinovirus, influenza, parainfluenza and respiratory syncytial virus.We added: "non-COVID-19 cases (other respiratory viral infections such as rhinovirus, influenza, parainfluenza and respiratory syncytial virus)" in text.
We also also agreed that the pathogenesis of headache is complex including the production of prostaglandin while fever.Therefore in our study we compared the occurrence of headache in COVID-19 and other non-COVID-19 respiratory infection as control.This to reduce the effect of fever since in both COVID-19 and non-COVID-19 cases the fever are present.Due to this complexity we did not claim any diagnostic for direct clinical practice.
Competing Interests: No competing interests were disclosed.
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Figure 1 .
Figure 1.Flowchart of the result of literature search according to the preferred reporting items of systematic reviews and meta-analyses (PRISMA).

Figure 3 .
Figure 3. Proposed pathway of headache pathophysiology.Nociceptive information coming from peripheral networks is transmitted to trigeminal ganglion acting as central hub between peripheral and central nervous systems.Next, this information is sent to TCC located in the brainstem, transmitted to diencephalon structures and terminated in various areas in cortex.The transmission in this pathway is linked to the pivotal involvement of neurotransmitters (e.g.glutamate, GABA and serotonin) and nociceptive neuropeptides (e.g.CGRP, substance P and PACAP) released from nerve fibers synapses, particularly nociceptive C-fibers and Aδ-fibers.The receptors of these signaling molecules are identified in both peripheral blood vessel, trigeminal ganglion and central structures, such as in cerebrospinal fluid and TCC142,147 .

Figure 2 .
Figure 2. Forest plot of the correlation between headache and the prevalence of COVID-19.