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

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Mamada" }, { "@type": "Person", "name": "Helnida Anggun Maliga" }, { "@type": "Person", "name": "Nur Samsu" }, { "@type": "Person", "name": "Muhammad Ilmawan" }, { "@type": "Person", "name": "Yeni Purnamasari" }, { "@type": "Person", "name": "Annisa Ayu Asmiragani" }, { "@type": "Person", "name": "Ichsan Ichsan" }, { "@type": "Person", "name": "Talha Bin Emran" }, { "@type": "Person", "name": "Ali A. Rabaan" }, { "@type": "Person", "name": "Sri Masyeni" }, { "@type": "Person", "name": "Firzan Nainu" }, { "@type": "Person", "name": "Harapan Harapan" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "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 2nd, 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)" } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/9-1316/v2", "name": "Global prevalence and pathogenesis of headache in COVID-19: A systematic..." } } ] } Home Browse Global prevalence and pathogenesis of headache in COVID-19: A systematic... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Mutiawati E, Syahrul S, Fahriani M et al. Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.12688/f1000research.27334.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Revised Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] Endang Mutiawati https://orcid.org/0000-0002-5116-2881 1,2 , Syahrul Syahrul https://orcid.org/0000-0002-7873-8713 1,2 , Marhami Fahriani https://orcid.org/0000-0003-0452-3485 3 , [...] Jonny Karunia Fajar https://orcid.org/0000-0002-0309-5813 3,4 , Sukamto S. Mamada https://orcid.org/0000-0002-7813-2164 5 , Helnida Anggun Maliga https://orcid.org/0000-0002-3702-6306 6 , Nur Samsu 4 , Muhammad Ilmawan https://orcid.org/0000-0002-9459-609X 6 , Yeni Purnamasari https://orcid.org/0000-0001-5830-3571 6 , Annisa Ayu Asmiragani https://orcid.org/0000-0002-5707-6060 6 , Ichsan Ichsan https://orcid.org/0000-0002-8903-9977 3,7 , Talha Bin Emran https://orcid.org/0000-0003-3188-2272 8 , Ali A. Rabaan https://orcid.org/0000-0002-6774-9847 9 , Sri Masyeni https://orcid.org/0000-0003-1170-1841 10,11 , Firzan Nainu https://orcid.org/0000-0003-0989-4023 5 , Harapan Harapan https://orcid.org/0000-0001-7630-8413 3,7,12 Endang Mutiawati https://orcid.org/0000-0002-5116-2881 1,2 , Syahrul Syahrul https://orcid.org/0000-0002-7873-8713 1,2 , [...] Marhami Fahriani https://orcid.org/0000-0003-0452-3485 3 , Jonny Karunia Fajar https://orcid.org/0000-0002-0309-5813 3,4 , Sukamto S. Mamada https://orcid.org/0000-0002-7813-2164 5 , Helnida Anggun Maliga https://orcid.org/0000-0002-3702-6306 6 , Nur Samsu 4 , Muhammad Ilmawan https://orcid.org/0000-0002-9459-609X 6 , Yeni Purnamasari https://orcid.org/0000-0001-5830-3571 6 , Annisa Ayu Asmiragani https://orcid.org/0000-0002-5707-6060 6 , Ichsan Ichsan https://orcid.org/0000-0002-8903-9977 3,7 , Talha Bin Emran https://orcid.org/0000-0003-3188-2272 8 , Ali A. Rabaan https://orcid.org/0000-0002-6774-9847 9 , Sri Masyeni https://orcid.org/0000-0003-1170-1841 10,11 , Firzan Nainu https://orcid.org/0000-0003-0989-4023 5 , Harapan Harapan https://orcid.org/0000-0001-7630-8413 3,7,12 PUBLISHED 10 Mar 2021 Author details Author details 1 Department of Neurology, Universitas Syiah Kuala, Banda Aceh, Aceh, 23111, Indonesia 2 Department of Neurology, Dr. Zainoel Abidin Hospital, Banda Aceh, Aceh, 23126, Indonesia 3 Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia 4 Brawijaya Internal Medicine Research Center, Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145, Indonesia 5 Faculty of Pharmacy, Hasanuddin University, Makassar, South Sulawesi, 90245, Indonesia 6 Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65117, Indonesia 7 Department of Microbiology, School of Medicine, Universitas Syiah Kual, Banda Aceh, Aceh, 23111, Indonesia 8 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh 9 Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, 31311, Saudi Arabia 10 Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitas Warmadewa, Denpasar, Bali, 80235, Indonesia 11 Department of Internal Medicine, Sanjiwani Hospital, Denpasar, Bali, 80235, Indonesia 12 Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, 23111, Indonesia Endang Mutiawati Roles: Conceptualization, Resources, Validation, Writing – Original Draft Preparation Syahrul Syahrul Roles: Resources, Validation, Writing – Review & Editing Marhami Fahriani Roles: Data Curation, Investigation, Methodology, Software, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Jonny Karunia Fajar Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Validation, Writing – Review & Editing Sukamto S. Mamada Roles: Validation, Writing – Original Draft Preparation, Writing – Review & Editing Helnida Anggun Maliga Roles: Investigation, Methodology, Validation Nur Samsu Roles: Data Curation, Formal Analysis, Investigation, Validation Muhammad Ilmawan Roles: Data Curation, Formal Analysis, Investigation, Validation Yeni Purnamasari Roles: Data Curation, Formal Analysis, Investigation, Validation Annisa Ayu Asmiragani Roles: Data Curation, Formal Analysis, Investigation, Validation Ichsan Ichsan Roles: Writing – Review & Editing Talha Bin Emran Roles: Writing – Original Draft Preparation, Writing – Review & Editing Ali A. Rabaan Roles: Writing – Review & Editing Sri Masyeni Roles: Writing – Review & Editing Firzan Nainu Roles: Writing – Original Draft Preparation, Writing – Review & Editing Harapan Harapan Roles: Conceptualization, Data Curation, Investigation, Methodology, Resources, Software, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Emerging Diseases and Outbreaks gateway. This article is included in the Coronavirus (COVID-19) collection. Abstract 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) READ ALL READ LESS Keywords COVID-19, SARS-CoV-2, headache, severity, predictor Corresponding Author(s) Endang Mutiawati ( [email protected] ) Close Corresponding author: Endang Mutiawati Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2021 Mutiawati E et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Mutiawati E, Syahrul S, Fahriani M et al. Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.12688/f1000research.27334.2 ) First published: 12 Nov 2020, 9 :1316 ( https://doi.org/10.12688/f1000research.27334.1 ) Latest published: 10 Mar 2021, 9 :1316 ( https://doi.org/10.12688/f1000research.27334.2 ) Revised 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." 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." See the authors' detailed response to the review by Morteza Arab-Zozani See the authors' detailed response to the review by Erni J. Nelwan READ REVIEWER RESPONSES 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 – 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 – 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 – 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 – 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. Methods 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. Information sources and search strategy To identify potential articles for analysis, systematic searches were conducted using three bibliographical databases ( PubMed , Scopus , and Web of Science as of September 2 nd , 2020). The search criteria were as follows. Pubmed ([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”). Scopus ([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”). 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<0.05 was 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. Results 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. Figure 1. Flowchart of the result of literature search according to the preferred reporting items of systematic reviews and meta-analyses (PRISMA). To calculate the prevalence of headache in COVID-19, full-text assessment resulted in the exclusion of 123 articles for the following reasons: case control studies (n=2), case report studies (n=69), case series (n=29), duplicated dataset (n=1), and conducted in specific population only (n=23). The targeted population studies were conducted among healthcare workers 28 – 31 , diabetic patients 32 , pediatrics 33 , pregnant women 34 , cancer patients 35 , children and young adults 36 – 40 , patient undergone surgery 41 , critical patients 42 , women undergone delivery 43 , patients with mild-moderate COVID-19 44 – 46 , patients with gastrointestinal symptoms 47 , patients with severe headache only 48 , and patients with anosmia only 49 . In total, 78 studies were included to calculate the prevalence of headache in COVID-19 and all studies were published in 2020. The studies were conducted in Brazil 50 , China 13 , 51 – 96 , Egypt 97 , France 98 – 101 , Germany 102 , India 103 , 104 , Italy 105 – 111 , Japan 112 , 113 , Jordan 114 , Somalia 115 , South Korea 116 , 117 , Spain 118 , 119 , Turkey 120 , 121 , and the US 122 – 126 . Two studies were cross-sectional 119 , 122 , five were prospective cohort studies 65 , 90 , 98 , 110 , 121 and the remaining 71 studies were retrospective studies. 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 . The prevalence of headache in COVID-19 cases Our systematic review included 78 studies consisting of 104,751 COVID-19 patients and headache was reported in 26,464 patients with a cumulative prevalence of 25.26%. The list of the studies and the prevalence of headache of each study is presented in Table 1 . One study which included 51 patients described the specific location of headache: 1.96% (1/51) was a temporal headache, 35.29% (18/51) was a frontal headache, 23.52% (12/51) was a retro-orbital headache, and 39.21% (20/51) was a diffuse headache 99 . Another study which involved 46 patients reported that 40 (86%) had tension-type pain and 6 (14%) had migraine-like headache 107 . Data from 18 studies indicated that 72.17% (236/327) of headaches were reported in mild-moderate COVID-19 cases 51 , 53 , 55 – 58 , 62 , 63 , 67 , 76 , 88 , 92 – 97 , 117 . The prevalence of headache in severe COVID-19 cases from 15 studies was 27.83% (86/309) 53 , 55 , 57 , 58 , 62 , 63 , 73 , 76 , 88 , 92 , 93 , 95 – 97 , 117 . Table 1. Characteristic of eligible studies and the prevalence of headache in each study. No Country Study design Total headache Total population Headache Percentage Reference 1 Japan Retrospective 7 57 12.3 112 2 Italy Retrospective 10 213 4.7 105 3 China Retrospective 4 72 5.6 51 4 USA Cross sectional 39 59 66.1 122 5 China Retrospective 6 83 7.2 52 6 Italy Retrospective 11 70 15.7 106 7 China Retrospective 17 262 6.5 53 8 USA Retrospective 24,308 91,412 26.6 123 9 Egypt Retrospective 18 66 27.3 97 10 India Retrospective 34 522 6.5 103 11 China Retrospective 2 14 14.3 54 12 China Retrospective 5 50 10.0 55 13 India Retrospective 3 21 14.3 104 14 China Retrospective 3 36 8.3 56 15 China Retrospective 2 20 10.0 57 16 China Retrospective 19 189 10.1 58 17 China Retrospective 3 37 8.1 59 18 South Korea Retrospective 54 172 31.4 116 19 China Retrospective 12 67 17.9 60 20 China Retrospective 13 137 9.5 61 21 China Retrospective 14 204 6.9 62 22 China Retrospective 17 221 7.7 63 23 China Retrospective 4 85 4.7 64 24 France Prospective 99 197 50.2 98 25 France Retrospective 51 70 72.9 99 26 China Prospective 3 38 7.9 65 27 China Retrospective 21 62 33.9 66 28 China Retrospective 12 202 5.9 67 29 USA Retrospective 72 251 28.7 124 30 China Retrospective 9 85 10.6 68 31 China Retrospective 75 788 9.5 69 32 Jordan Retrospective 14 81 17.3 114 33 China Retrospective 3 34 8.8 70 34 Japan Retrospective 2 23 8.7 113 35 China Retrospective 8 72 11.1 71 36 China Retrospective 14 108 13.0 72 37 Italy Retrospective 46 108 42.6 107 38 China Retrospective 2 11 18.2 73 39 China Retrospective 8 51 15.7 74 40 China Retrospective 8 99 8.1 13 41 China Retrospective 12 136 8.8 75 42 South Korea Retrospective 140 694 20.2 117 43 China Retrospective 5 48 10.4 76 44 China Retrospective 4 28 14.3 77 45 China Retrospective 14 53 26.4 78 46 China Retrospective 11 125 8.8 79 47 China Retrospective 67 651 10.3 80 48 China Retrospective 98 1084 9.0 81 49 China Retrospective 6 59 10.2 82 50 Spain Retrospective 137 576 23.8 118 51 Spain Cross sectional 104 576 18.1 119 52 France Retrospective 82 139 59.0 100 53 China Retrospective 21 270 7.8 83 54 China Retrospective 80 655 12.2 84 55 China Retrospective 2 33 6.1 85 56 Brazil Retrospective 76 145 52.4 50 57 China Retrospective 9 136 6.6 86 58 China Retrospective 10 60 16.7 87 59 Somalia Retrospective 10 60 16.7 115 60 Italy Retrospective 2 10 20.0 108 61 Turkey Retrospective 43 143 30.1 120 62 Germany Retrospective 63 108 58.3 102 63 France Retrospective 10 64 15.6 101 64 China Retrospective 28 214 13.1 88 65 USA Retrospective 129 208 62.0 125 66 Italy Retrospective 30 72 41.7 109 67 Italy Prospective 14 43 32.6 110 68 China Retrospective 4 24 16.7 89 69 Turkey Prospective 64 239 26.8 121 70 China Prospective 3 8 37.5 90 71 China Retrospective 35 187 18.7 91 72 China Retrospective 5 93 5.4 92 73 China Retrospective 3 29 10.3 93 74 China Retrospective 1 108 0.9 94 75 China Retrospective 20 663 3.0 95 76 USA Retrospective 40 200 20.0 126 77 Italy Retrospective 16 72 22.2 111 78 China Retrospective 14 389 3.6 96 Total 26,464 104,751 25.2 Association of headache and COVID-19 A total of 16 studies, consisting of 5,407 COVID-19 cases in adults and 94,818 adults with non-COVID-19 infections (mostly COVID-19-like respiratory viral infections), were analyzed to determine the association between headache and COVID-19. Of these studies, an association between headache and the occurrence of COVID-19 was observed in 9 studies 28 , 29 , 31 , 105 , 122 , 127 , 129 , 130 , 132 while seven studies reported no association 50 , 70 , 99 , 120 , 131 , 133 , 134 ( Table 2 ). Our cumulative calculation revealed that headache was found to be 1.7-fold more prevalent in patients with COVID-19 compared to those with non-COVID-19 respiratory viral infections, OR: 1.73; 95% CI: 1.94, 2.51 with p=0.04. The correlation between headache and COVID-19 is presented in Figure 2 . Table 2. Prevalence of headache in COVID-19 and non-COVID-19. Author, year Study type COVID-19 Non-COVID-19 COVID-19 severity Control criteria Reference Headache n (%) Sample size Headache n (%) Sample size Çalıca Utku et al., 2020 Case control 43 (0.30) 143 42 (0.27) 154 Mild-critical Viral symptoms, negative PCR 120 Caturegli et al., 2020 Case control 17 (0.28) 60 5 (0.09) 55 Not specified Viral symptoms, negative PCR 132 Fistera et al., 2020 Cross- sectional 5 (0.12) 43 21 (0.08) 271 Not specified Viral symptoms, negative PCR 131 He et al., 2020 Cross- sectional 3 (0.09) 34 5 (0.10) 48 Not specified Viral symptoms, negative PCR 13 Ibrahim et al., 2020 Cohort 3 (0.75) 4 22 (0.05) 429 Not specified Viral symptoms, negative PCR 127 Kosugi et al., 2020 Cross sectional 76 (0.52) 145 20 (0.53) 38 Not specified Viral symptoms, negative PCR 50 La Torre et al., 2020 Case control 18 (0.60) 30 14 (0.19) 75 Not specified Viral symptoms, negative PCR 130 Lam et al., 2020 Case control 0 (0.00) 37 7 (0.06) 111 Not specified Viral symptoms, negative PCR 128 Lan et al., 2020 Case control 34 (0.41) 83 141 (0.28) 509 Not specified Viral symptoms, negative PCR 28 Luigetti et al., 2020 Case control 10 (0.05) 213 1 (0.00) 218 Not specified Viral symptoms, negative PCR 105 Mizrahi et al., 2020 Cohort 126 (3.09) 4066 2794 (3.05) 91597 Not specified Viral symptoms, negative PCR 129 Rolan et al., 2020 Cross- sectional 93 (0.64) 145 90 (0.57) 157 Not specified Viral symptoms, negative PCR 133 Tostmann et al., 2020 Case control 64 (0.71) 90 296 (0.42) 713 Mild COVID symptoms, negative PCR 31 Van Loon et al., 2020 case control 145 (0.62) 185 116 (0.78) 186 Mild Viral symptoms, negative PCR 29 Yan et al., 2020 Cross- sectional 39 (0.66) 59 99 (0.49) 203 Not specified Viral symptoms, negative PCR 122 Zayet et al., 2020 Case control 51 (0.73) 70 31 (0.57) 54 Not specified Confirmed influenza A/B 99 Figure 2. Forest plot of the correlation between headache and the prevalence of COVID-19. Discussion 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 – 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 cyclase-activating 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 – 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 ). 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 TCC 142 , 147 . 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 – 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 – 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 – 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 – 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 . Therefore, although we found that headache is more frequent in COVID-19 patients than those of non-COVID-19 patients, diagnosis of COVID-19 should not be based on the presence of a headache. In conclusion, headache is a common symptom in COVID-19 cases. Some mechanisms have been proposed as to the mechanism for headaches in COVID-19 such as the activation of the trigeminovascular system by either direct action of the virus or indirect mechanisms induced by cytokine storm, vasculopathy, or ischemia induced by gas exchange disturbance in COVID-19 patients. Extensive efforts must be carried out to provide definitive answers about COVID-19-related headaches. Detailed investigations on the mechanisms by which SARS-CoV-2 attacks the CNS and thus generates headaches are important to improve our understanding on the pathophysiology of COVID-19, and therefore influences possible pharmacological intervention decisions. Data availability Underlying data All data underlying the results are available as part of the article and no additional source data are required. Reporting guidelines Figshare: PRISMA checklist for ‘Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis’, https://doi.org/10.6084/m9.figshare.13166783.v1 189 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgement Authors would like to thank HT Editorial Services in assisting during the study and writing processes. Faculty Opinions recommended References 1. Harapan H, Itoh N, Yufika A, et al. : Coronavirus disease 2019 (COVID-19): A literature review. J Infect Public Health. 2020; 13 (5): 667–73. PubMed Abstract | Publisher Full Text | Free Full Text 2. Zhao H, Lu X, Deng Y, et al. : COVID-19: asymptomatic carrier transmission is an underestimated problem. Epidemiol Infect. 2020; 148 : e116. 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Figure. 2020. http://www.doi.org/10.6084/m9.figshare.13166783.v1 Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 12 Nov 2020 ADD YOUR COMMENT Comment Author details Author details 1 Department of Neurology, Universitas Syiah Kuala, Banda Aceh, Aceh, 23111, Indonesia 2 Department of Neurology, Dr. Zainoel Abidin Hospital, Banda Aceh, Aceh, 23126, Indonesia 3 Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia 4 Brawijaya Internal Medicine Research Center, Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145, Indonesia 5 Faculty of Pharmacy, Hasanuddin University, Makassar, South Sulawesi, 90245, Indonesia 6 Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65117, Indonesia 7 Department of Microbiology, School of Medicine, Universitas Syiah Kual, Banda Aceh, Aceh, 23111, Indonesia 8 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh 9 Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, 31311, Saudi Arabia 10 Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitas Warmadewa, Denpasar, Bali, 80235, Indonesia 11 Department of Internal Medicine, Sanjiwani Hospital, Denpasar, Bali, 80235, Indonesia 12 Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, 23111, Indonesia Endang Mutiawati Roles: Conceptualization, Resources, Validation, Writing – Original Draft Preparation Syahrul Syahrul Roles: Resources, Validation, Writing – Review & Editing Marhami Fahriani Roles: Data Curation, Investigation, Methodology, Software, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Jonny Karunia Fajar Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Validation, Writing – Review & Editing Sukamto S. Mamada Roles: Validation, Writing – Original Draft Preparation, Writing – Review & Editing Helnida Anggun Maliga Roles: Investigation, Methodology, Validation Nur Samsu Roles: Data Curation, Formal Analysis, Investigation, Validation Muhammad Ilmawan Roles: Data Curation, Formal Analysis, Investigation, Validation Yeni Purnamasari Roles: Data Curation, Formal Analysis, Investigation, Validation Annisa Ayu Asmiragani Roles: Data Curation, Formal Analysis, Investigation, Validation Ichsan Ichsan Roles: Writing – Review & Editing Talha Bin Emran Roles: Writing – Original Draft Preparation, Writing – Review & Editing Ali A. Rabaan Roles: Writing – Review & Editing Sri Masyeni Roles: Writing – Review & Editing Firzan Nainu Roles: Writing – Original Draft Preparation, Writing – Review & Editing Harapan Harapan Roles: Conceptualization, Data Curation, Investigation, Methodology, Resources, Software, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 10 Mar 2021, 9:1316 https://doi.org/10.12688/f1000research.27334.2 version 1 Published: 12 Nov 2020, 9:1316 https://doi.org/10.12688/f1000research.27334.1 Copyright © 2021 Mutiawati E et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Mutiawati E, Syahrul S, Fahriani M et al. Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.12688/f1000research.27334.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 10 Mar 2021 Revised Views 0 Cite How to cite this report: Nelwan EJ. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.55021.r81184 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v2#referee-response-81184 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 14 Apr 2021 Erni J. Nelwan , Division of Tropical Medicine and Infectious Disease, Department of Internal Medicine, Medical Faculty, Cipto Mangunkusumo General Hospital, University of Indonesia, Jakarta, Indonesia; Infectious Diseases and Immunology Research Cluster, Faculty of Medicine, Universitas Indonesia, Depok City, Indonesia Approved VIEWS 0 https://doi.org/10.5256/f1000research.55021.r81184 I confirm that I have read this submission and believe that I have an appropriate level of expertise ... Continue reading READ ALL I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however, I have significant reservations, as outlined above. Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Nelwan EJ. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.55021.r81184 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v2#referee-response-81184 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Arab-Zozani M. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.55021.r81183 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v2#referee-response-81183 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 11 Mar 2021 Morteza Arab-Zozani , Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran Approved VIEWS 0 https://doi.org/10.5256/f1000research.55021.r81183 Thank you for modifying your paper and clearly addressing ... Continue reading READ ALL Thank you for modifying your paper and clearly addressing my comments. In my opinion, the manuscript is acceptable. Cheers Competing Interests: No competing interests were disclosed. Reviewer Expertise: Health Policy and Management, an expert in systematic review and meta-analysis methodology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Arab-Zozani M. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.55021.r81183 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v2#referee-response-81183 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 12 Nov 2020 Views 0 Cite How to cite this report: Arab-Zozani M. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.30205.r79512 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v1#referee-response-79512 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 15 Feb 2021 Morteza Arab-Zozani , Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.30205.r79512 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 ... Continue reading READ ALL 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. Was it not possible to analyze the subgroups? For example, based on age groups or gender. Please add some details about the NOS checklist and also add the result of the quality appraisal to the manuscript. 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? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Health Policy and Management, an expert in systematic review and meta-analysis methodology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Arab-Zozani M. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.30205.r79512 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v1#referee-response-79512 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Mar 2021 Endang Mutiawati , Department of Neurology, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia 10 Mar 2021 Author Response Dear Dr Morteza Arab-Zozani, Thank you for your comments. 1. We have provide the approach how to solve in case there was discrepancies between two authors during evaluation of ... Continue reading Dear Dr Morteza Arab-Zozani, Thank you for your comments. 1. We have provide the approach how to solve in case there was discrepancies between two authors during evaluation of the studies. 2. We were unable to do sub-group analysis based on age and gender due to available of data. We have added this as one of our limitation: 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 sub-analyses are critical to be conducted." 3. We have provide 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. Thank you Dear Dr Morteza Arab-Zozani, Thank you for your comments. 1. We have provide the approach how to solve in case there was discrepancies between two authors during evaluation of the studies. 2. We were unable to do sub-group analysis based on age and gender due to available of data. We have added this as one of our limitation: 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 sub-analyses are critical to be conducted." 3. We have provide 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. Thank you Competing Interests: I do not have conflict of interest. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Mar 2021 Endang Mutiawati , Department of Neurology, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia 10 Mar 2021 Author Response Dear Dr Morteza Arab-Zozani, Thank you for your comments. 1. We have provide the approach how to solve in case there was discrepancies between two authors during evaluation of ... Continue reading Dear Dr Morteza Arab-Zozani, Thank you for your comments. 1. We have provide the approach how to solve in case there was discrepancies between two authors during evaluation of the studies. 2. We were unable to do sub-group analysis based on age and gender due to available of data. We have added this as one of our limitation: 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 sub-analyses are critical to be conducted." 3. We have provide 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. Thank you Dear Dr Morteza Arab-Zozani, Thank you for your comments. 1. We have provide the approach how to solve in case there was discrepancies between two authors during evaluation of the studies. 2. We were unable to do sub-group analysis based on age and gender due to available of data. We have added this as one of our limitation: 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 sub-analyses are critical to be conducted." 3. We have provide 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. Thank you Competing Interests: I do not have conflict of interest. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Nelwan EJ. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.30205.r74699 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v1#referee-response-74699 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 04 Dec 2020 Erni J. Nelwan , Division of Tropical Medicine and Infectious Disease, Department of Internal Medicine, Medical Faculty, Cipto Mangunkusumo General Hospital, University of Indonesia, Jakarta, Indonesia; Infectious Diseases and Immunology Research Cluster, Faculty of Medicine, Universitas Indonesia, Depok City, Indonesia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.30205.r74699 Authors seem not considered potential important bias while choosing headaches to be analysed. While among patients with fever (mainly), headache is in the same pathophysiology response due to prostaglandin release. Not to include other symptoms, so it is not merely ... Continue reading READ ALL Authors seem not considered potential important bias while choosing headaches to be analysed. While among patients with fever (mainly), headache is in the same pathophysiology response due to prostaglandin release. Not to include other symptoms, so it is not merely a headache as a symptom. How about the existence of co-morbidity such as Hypertension (uncontrolled hypertension)? It is not clear how to justify data with such condition concomitantly. In the results section, what does this statement mean? "Headache was found to be more prevalent, approximately by two-fold, in COVID-19 patients than in non-COVID-19 patients with symptoms of other respiratory viral infections, OR: 1.73; 95% CI: 1.94, 2.5 with p=0.04." What kind of non-covid-19 patients with symptoms of other respiratory viral infections? This is a confusing statement. As a clinician taking care of Covid-19 patients, the importance of this article is low. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? No Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: infectious disease I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Nelwan EJ. Reviewer Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.30205.r74699 ) The direct URL for this report is: https://f1000research.com/articles/9-1316/v1#referee-response-74699 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Mar 2021 Endang Mutiawati , Department of Neurology, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia 10 Mar 2021 Author Response 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 ... Continue reading 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 sub-analyses 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. 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 sub-analyses 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. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Mar 2021 Endang Mutiawati , Department of Neurology, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia 10 Mar 2021 Author Response 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 ... Continue reading 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 sub-analyses 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. 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 sub-analyses 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. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 12 Nov 2020 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 10 Mar 21 read read Version 1 12 Nov 20 read read Erni J. Nelwan , University of Indonesia, Jakarta, Indonesia; Universitas Indonesia, Depok City, Indonesia Morteza Arab-Zozani , Birjand University of Medical Sciences, Birjand, Iran Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2021 Nelwan E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 14 Apr 2021 | for Version 2 Erni J. Nelwan , Division of Tropical Medicine and Infectious Disease, Department of Internal Medicine, Medical Faculty, Cipto Mangunkusumo General Hospital, University of Indonesia, Jakarta, Indonesia; Infectious Diseases and Immunology Research Cluster, Faculty of Medicine, Universitas Indonesia, Depok City, Indonesia 0 Views copyright © 2021 Nelwan E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however, I have significant reservations, as outlined above. Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Nelwan EJ. Peer Review Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.55021.r81184) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/9-1316/v2#referee-response-81184 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2021 Arab-Zozani M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 11 Mar 2021 | for Version 2 Morteza Arab-Zozani , Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran 0 Views copyright © 2021 Arab-Zozani M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Thank you for modifying your paper and clearly addressing my comments. In my opinion, the manuscript is acceptable. Cheers Competing Interests No competing interests were disclosed. Reviewer Expertise Health Policy and Management, an expert in systematic review and meta-analysis methodology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Arab-Zozani M. Peer Review Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.55021.r81183) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/9-1316/v2#referee-response-81183 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2021 Arab-Zozani M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 15 Feb 2021 | for Version 1 Morteza Arab-Zozani , Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran 0 Views copyright © 2021 Arab-Zozani M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 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. Was it not possible to analyze the subgroups? For example, based on age groups or gender. Please add some details about the NOS checklist and also add the result of the quality appraisal to the manuscript. 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? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Health Policy and Management, an expert in systematic review and meta-analysis methodology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 10 Mar 2021 Endang Mutiawati, Department of Neurology, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia Dear Dr Morteza Arab-Zozani, Thank you for your comments. 1. We have provide the approach how to solve in case there was discrepancies between two authors during evaluation of the studies. 2. We were unable to do sub-group analysis based on age and gender due to available of data. We have added this as one of our limitation: 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 sub-analyses are critical to be conducted." 3. We have provide 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. Thank you View more View less Competing Interests I do not have conflict of interest. reply Respond Report a concern Arab-Zozani M. Peer Review Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.30205.r79512) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/9-1316/v1#referee-response-79512 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2020 Nelwan E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 04 Dec 2020 | for Version 1 Erni J. Nelwan , Division of Tropical Medicine and Infectious Disease, Department of Internal Medicine, Medical Faculty, Cipto Mangunkusumo General Hospital, University of Indonesia, Jakarta, Indonesia; Infectious Diseases and Immunology Research Cluster, Faculty of Medicine, Universitas Indonesia, Depok City, Indonesia 0 Views copyright © 2020 Nelwan E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Authors seem not considered potential important bias while choosing headaches to be analysed. While among patients with fever (mainly), headache is in the same pathophysiology response due to prostaglandin release. Not to include other symptoms, so it is not merely a headache as a symptom. How about the existence of co-morbidity such as Hypertension (uncontrolled hypertension)? It is not clear how to justify data with such condition concomitantly. In the results section, what does this statement mean? "Headache was found to be more prevalent, approximately by two-fold, in COVID-19 patients than in non-COVID-19 patients with symptoms of other respiratory viral infections, OR: 1.73; 95% CI: 1.94, 2.5 with p=0.04." What kind of non-covid-19 patients with symptoms of other respiratory viral infections? This is a confusing statement. As a clinician taking care of Covid-19 patients, the importance of this article is low. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? No Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise infectious disease I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 10 Mar 2021 Endang Mutiawati, Department of Neurology, Universitas Syiah Kuala, Banda Aceh, 23111, 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 sub-analyses 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. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Nelwan EJ. Peer Review Report For: Global prevalence and pathogenesis of headache in COVID-19: A systematic review and meta-analysis [version 2; peer review: 2 approved] . F1000Research 2021, 9 :1316 ( https://doi.org/10.5256/f1000research.30205.r74699) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/9-1316/v1#referee-response-74699 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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