The characteristics of headache in COVID-19: A literature review

Coronavirus disease 2019 (COVID-19) has become outbreak in the world since December 2020. The higher incidence and transmission of COVID-19, the higher virulence of the disease. Besides respiratory manifestations, the most common symptoms in COVID-19 are neurological manifestations. The major neurological manifestations in COVID-19 are headache and dizziness. Headache is more common as chief complaint in emergency room and hospitalized patients than dizziness. Therefore, this review aims to outline the characteristics of headache in COVID-19. The conclusion of this review is that the characteristics of headache in COVID-19 are moderate-severe intensity, frontal-temporal region, pulsatile and tight ening quality, constant duration and commonly associate with one or more COVID-19 symptoms.


InTRODuCTIOn
In the end of December 2019, there was a case of pneumonia outbreak in Wuhan which was caused by Coronavirus disease 2019 . The World Health Organization (WHO) named COVID-19 based on its genetic sequence which was found similar with severe acute respiratory syndrome corona virus (SARS-CoV). COVID-19 has been declared as pandemic by WHO on March 11, 2020 [1].
As of May 2 nd , 2021, WHO reported that there had been increment of COVID-19 cases in nine consecutive months since the pandemic occurred. It was the highest level of new weekly cases of COVID-19 (5.7 million new cases) with 6% increase of death cases from a past week. The South-East Asia was marked higher increase in new cases (19%) and death events (48%) than another region. The largest contribution to the number of new cases (188.2/100,000) and death incident (1.7/100,000) was from India. Indonesia was the second highest contribution of new cas-es (13.2/100,000) and death incident (0.4/100.000) [2].

COVID-19
The SARS-CoV-2 is club-like approximately 120nm in diameter with spike protein around envelope protein E. It is a single-stranded Ribonucleic Acid (RNA) which contains approximately 30 kilobase pair genomes and 5'methyl-guanosine cap [1,9]. It can infect easily and adapt the new host because of the recombination and variation of genome [5]. Microscopically, the shape of SARS-CoV-2 looks like a crown so that its names corona based on Latin [9]. SARS-CoV-2 is Beta-coronavirus and the third SARS which has severe symptoms and infects human following SARS-CoV epidemic in 2002-2003 and Middle East Respiratory Symptom (MERS) in 2012. Bat is the natural host of SARS-CoV, MERS and COV-ID-19 [1]. There are two types of SARS-CoV-2, such as type S and L, with type L is more aggressive then type S [9].
SARS-CoV-2 can invade the human cells via ACE2 in oral mucosa, lung, esophagus, ileum, colon, myocardium, kidney and bladder which is cleaved by serine protease TMPRSS2 and binding process with spike protein of virus. The process of translation, proteolysis, replication and translation begin after endocytosis of RNA SARS-CoV-2. Furthermore, the infected host cell can produce hundreds of new virions. Alveolar epithelial type II cells are the most frequent cells which express ACE2 and TMPRSS2. Inflammatory process is triggered by SARS-Cov-2 invasion and replication. The imbalance of type 1 and type 2 T-helper cells which is caused by cytokine storm and hypoxemia may lead to respiratory dysfunction and multiple organ failure [1,5,9].
The classification of COVID-19 had been revised into three parts (suspect, probable and confirm) on August 7 th , 2020. The criteria of suspected COVID-19, such as fever, cough (or ≥ 3 acute symptoms, such as fever, cough, fatigue, headache, myalgia, sore throat, dyspnoea, gastrointestinal symptoms, altered mental status), history of living/working/traveling within 14 days from high risk of virus transmission area and history of severe acute respiratory illness. The criteria of probable COVID-19, including suspected COVID-19 criteria, anosmia or ageusia with unknown etiology and history of contact with probable/confirmed COVID-19 or suggestive COVID-19 in chest imaging [10]. Confirmed COVID-19 was diagnosed by positive result in Reverse Transcription Polymerase Chain Reaction (rRT-PCR) method [11].
The transmission of COVID-19 can be direct/indirect contact, such as surface contact, droplet, airborne, fecal-oral, blood transfusion, vertical transmission and animal to human [2]. The term of contact is regarded as history of exposure to probable/confirmed COVID-19 in two days before and two weeks following the onset of symptoms by face-toface more than 15 minutes in a day and within one meter or direct physical contact with probable/confirmed case [10].
The size of droplet is approximately more than 5-10 µm. If the size is ≤ 5µm, it is called droplet nuclei/aerosol. Droplet can be produced by cough, sneeze, talk and sing. It can be transmitted to other person's respiratory system when the distance of each other is about one meter. Aerosol can still be infectious in the air and spread widely especially during medical procedure, such as intubation. COV-ID-19 can be detected in fomites within 48-72 hours in adequate air temperature and humidity [2].
The initial screening of COVID-19 should be performed in suspected case or in person who has history of contact to probable/confirm COVID-19 [2]. Ag-RDTs (Antigen-detecting Rapid Diagnostic Tests) can be used in the community for screening COV-ID-19 with Nucleic Acid Amplification Tests (NAATs) like rRT-PCR confirmation. If rRT-PCR is unavailable, the diagnosis of confirmed COVID-19 can be made by using Ag-RDTs which has sensitivity ≥ 80% and specificity ≥ 97%. This test should be conducted by trained operators [12].
The risk of transmission is higher when health protocols are not carried out and in poor ventilated room. Therefore, WHO promotes some ways in order to decline the transmission of COVID-19 by washing hand regularly, wearing face mask, avoiding crowded situation and poor ventilated room, and practicing social distancing [2].

Headache and COVID-19
According to the third edition of the International Classification of Headache Disorders (ICHD-III), headache is classified into primary headache, secondary headache and painful cranial neuropathies, other facial pain and other headache. Headache in COVID-19 is classified in "headache attributed to systemic viral infection" in ICHD-III. The diagnostic criteria of headache attributed to systemic viral infection are at least two of: headache associates with onset of viral infection, the severity of viral infection is comparable with the severity of headache, the improvement of headache is parallel with the improvement of systemic viral infection, and the characteristic of headache has one or both, such as diffuse pain and/or moderate to severe intensity. Moreover, other cause of headache, such as viral meningitis or encephalitis, should be rule out in order to diagnose headache attributed to systemic viral infection [8]. According to ICHD-III, the symptoms associated with headache, such as fever, light sensitivity and nausea, can suspect viral meningitis or encephalitis [13].
The pathophysiology of headache in COVID-19 relates with ACE2. The effect of ACE2 opposes the activity of ACE. Angiotensin II (Ang II) is converted from Angiotensin I (Ang I) by ACE. ACE2 is modulated to alter Ang II forming Ang I-VII whose effects are contrary with Ang II such as, vasodilatation, cardiovascular protection and decrease inflammation process, reactive oxygen species, neurodegeneration, neuronal death and nociception. The binding process between ACE2 and COVID-19 may lead to downregulation of ACE2. This process may result in the decrement of Ang I-VII production and the unbalance of ACE/Ang II activity. Ang II, substance P and Calcitonin Gene-Related Peptide (CGRP) in dorsal root ganglia of trigeminal ganglia contribute to nociception process [13]. CGRP is a neuropeptide which can provoke both migraine and headache [28]. Besides, diffuse endothelial inflammation also relates with headache as ACE2 can also be found in endothelial cell. Therefore, it can activate trigeminovascular and lead to vasculopathy [29]. The trigeminovascular activation may also be mediated by inflammatory mediators such as, interleukin-1 beta, nitric oxide, prostaglandin E2 and nuclear factor-kappa B. Furthermore, these inflammatory mediators contribute in headache process [30].

COnCluSIOnS
The prevalence of neurological manifestation is quite high in COVID-19. CNS manifestation is more common than PNS and muscle injury manifestation. Headache is the most dominant CNS manifestation of COVID-19. The characteristics of headache, observed in COVID-19, are moderate-severe intensity, frontal-temporal region, pulsatile and tightening quality, constant duration and commonly associate with other COVID-19 symptoms, such as anosmia/ hyposmia and ageusia/hypogeusia.