To the Editor,
Coronavirus disease 2019 (COVID-19), the new pandemic infectious disease sustained by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already affected millions of people worldwide, causing over 150,000 deaths . The clinical course of this new pathology can be mild in up to 75–80% of subjects, characterized only by onset of bland and common respiratory symptoms. Nevertheless, the epidemiological importance of diagnosing COVID-19 in mildly symptomatic patients should not be underestimated, as these subjects have theoretically the same risk of transmitting the disease as overtly symptomatic patients . Moreover, a consistent number of COVID-19 patients initially presenting with mild symptoms are at risk of progressing to severe disease, with development of respiratory distress, severe inflammatory response syndrome (SIRS), even progressing to death, when not timely and appropriately treated . In a French cohort of 64 COVID-19 patients consecutively admitted for ARDS, features of neurologic illness were observed in up 91% of patients . While it is established that headache is a common symptom in patients with coronavirus diseases , we aimed to explore here whether the incidence of this symptom may predict the risk of having COVID-19.
We carried out an electronic search in Scopus, Web of Science and Medline (PubMed interface), using the keywords “headache” AND “coronavirus 2019” OR “COVID-19” in all fields, between 2019 and the present date (i. e., April 17, 2020), limiting our search to articles containing not less than 10 COVID-19 patients and published in the English language. The title, abstract and full text (when available) of all items that could be initially detected with these search criteria were read, and those articles describing the incidence of headache in patients diagnosed with COVID-19 were then included in a pooled analysis. The reference list of all documents was also carefully scrutinized for retrieving further potentially eligible studies. A pooled analysis of individual data was finally conducted, by estimation of odds ratio (OR) and the 95% confidence interval (95% CI) for the incidence of headache in COVID-19 patients compared to the incidence of headache in the same geographical area, as retrievable from the Global Health Data Exchange (GHDx) registry, the largest worldwide database of health-related data and human pathologies . The statistical analysis was carried out using MetaXL, software Version 5.3 (EpiGear International Pty Ltd., Sunrise Beach, Australia). The study was carried out in accordance with the declaration of Helsinki and with the term of local legislation.
A total number of 76 documents were originally identified based on our search criteria, 64 of which were immediately excluded because they were review articles (n=10), editorial materials (n=9), case reports (n=5), contained no incidence data of headache in COVID-19 patients (n=7), or dealt with pathologies other than COVID-19 (n=33). Two additional studies were identified by reading the reference list of these articles, so that a final number of 14 studies, totaling 2863 COVID-19 patients, could be finally included in our analysis , , , , , , , , , , , , ,  (Table 1). Twelve of these studies were located in China, where the incidence of headache according to the GDHx registry is 2.69% (95% CI, 2.40–30.4%) , , , , , , , , , , , , one in Korea (headache incidence, 2.98%; 95% CI 2.67–3.30%) , and one in India (headache incidence, 2.81%; 95% CI, 2.51–3.13%) . In all except one of these epidemiologic investigations, the incidence of headache was higher in COVID-19 patients than in the general population of the corresponding geographical area (Figure 1). Overall, headache was hence cumulatively reported by 11.8% (95% CI, 11.5–12.1%) of COVID-19 patients, compared to the 2.8% cumulative incidence in the general population of the same geographical areas. Therefore, incident headache was associated with a nearly 5-fold higher risk (11.8 vs. 2.8%; OR, 4.95; 95% CI, 3.50–6.92; I2, 55%) of being diagnosed as having COVID-19 (Figure 1).
Summary of studies reporting the incidence of headache in coronavirus disease 2019 (COVID-19) patients.
|Xu YH et al., 2020 ||China||50||42%||5||45||10.0%|
|Tian S et al., 2020 ||China||262||52%||17||245||6.5%|
|Chen N et al., 2020 ||China||99||32%||8||91||8.1%|
|Huang C et al., 2020 ||China||38||27%||3||35||7.9%|
|Xu XW et al., 2020 ||China||62||44%||21||41||33.9%|
|Mao L et al., 2020 ||China||214||59%||28||186||13.1%|
|Song F et al., 2020 ||China||51||51%||8||43||15.7%|
|Jin X et al., 2020 ||China||651||49%||67||584||10.3%|
|Liu K et al., 2020 ||China||137||55%||13||124||9.5%|
|Guan W et al., 2020 ||China||1099||42%||150||949||13.6%|
|Chang D et al., 2020 ||China||13||23%||3||10||23.1%|
|Wang DW et al., 2020 ||China||138||46%||9||129||6.5%|
|Korea CDC, 2020 ||Korea||28||46%||3||25||10.7%|
|Gupta N et al., 2020 ||India||21||33%||3||18||14.3%|
In conclusion, the results of this pooled analysis of the recent scientific literature suggest that headache, especially that of new onset in subjects who do not regularly suffer from this condition, should raise early concern to the possibility of being infected by COVID-19.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
World Health Organization. Coronavirus disease 2019 (COVID-19) situation report – 87; 2019. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/ [Accessed 17 April 2020].
Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177–9. https://doi.org/10.1056/NEJMc2001737.
Goh KJ, Choong MC, Cheong EH, Kalimuddin S, Duu Wen S, Phua GC, et al. Rapid progression to acute respiratory distress syndrome: review of current understanding of critical illness from COVID-19 infection. Ann Acad Med Singapore 2020;49:1–9.
Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med 2020. https://doi.org/10.1056/NEJMc2008597. 32294339.
Jackson GG, Dowling HF, Spiesman IG, Boand AV. Transmission of the common cold to volunteers under controlled conditions. I. The common cold as a clinical entity. AMA Arch Intern Med 1958;101:267–78. https://doi.org/10.1001/archinte.1958.00260140099015.
Xu YH, Dong JH, An WM, Lv XY, Yin XP, Zhang JZ, et al. Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2. J Infect 2020;80:394–400. https://doi.org/10.1016/j.jinf.2020.02.017.
Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, et al. Characteristics of COVID-19 infection in Beijing. J Infect 2020;80:401–6. https://doi.org/10.1016/j.jinf.2020.02.018.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507–13. https://doi.org/10.1016/S0140-6736(20)30211-7.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506. https://doi.org/10.1016/S0140-6736(20)30183-5.
Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020;368:m606. https://doi.org/10.1136/bmj.m606.
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020 Apr 10. https://doi.org/10.1001/jamaneurol.2020.1127 [Epub ahead of print].
Song F, Shi N, Shan F, Zhang Z, Shen J, Lu H, et al. Emerging 2019 novel coronavirus (2019-nCoV) pneumonia. Radiology 2020;295:210–7. https://doi.org/10.1148/radiol.2020200274.
Jin X, Lian JS, Hu JH, Gao J, Zheng L, Zhang YM, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut 2020 Mar 24. https://doi.org/10.1136/gutjnl-2020-320926 [Epub ahead of print]. pii: gutjnl-2020-320926.
Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl) 2020 Feb 7. https://doi.org/10.1097/CM9.0000000000000744 [Epub ahead of print].
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Feb 28. https://doi.org/10.1056/NEJMoa2002032 [Epub ahead of print].
Chang, Lin M, Wei L, Xie L, Zhu G, Dela Cruz CS, et al. Epidemiologic and clinical characteristics of novel coronavirus infections involving 13 patients outside Wuhan, China. J Am Med Assoc. 2020 Feb 7. https://doi.org/10.1001/jama.2020.1623 [Epub ahead of print].
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. J Am Med Assoc. 2020 Feb 7. https://doi.org/10.1001/jama.2020.1585 [Epub ahead of print].
COVID-19 National Emergency Response Center, Epidemiology and case management team, Korea centers for disease control and prevention. Early epidemiological and clinical characteristics of 28 cases of coronavirus disease in South Korea. Osong Public Health Res Perspect 2020;11:8–14. https://doi.org/10.24171/j.phrp.2020.11.1.03.
Gupta N, Agrawal S, Ish P, Mishra S, Gaind R, Usha G, et al. Clinical and epidemiologic profile of the initial COVID-19 patients at a tertiary care centre in India. Monaldi Arch Chest Dis 2020 Apr 10;90. https://doi.org/10.4081/monaldi.2020.1294.