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Study protocol: The Philippine COVID-19 Outcomes: a Retrospective study Of Neurological manifestations and Associated symptoms (The Philippine CORONA Study) ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-040944

Article Type: Protocol

Date Submitted by the 27-May-2020 Author:

Complete List of Authors: Espiritu, Adrian; University of the Philippines Manila College of Medicine, Neurosciences Sy, Marie Charmaine; University of the Philippines Manila College of Medicine, Neurosciences Anlacan, Veeda Michelle; University of the Philippines Manila College of Medicine, Neurosciences Jamora, Roland Dominic; University of the Philippines Manila College of Medicine, Neurosciences

Keywords: NEUROLOGY, Adult neurology < NEUROLOGY, EPIDEMIOLOGY

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45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 Study protocol: The Philippine COVID-19 Outcomes: a Retrospective study Of Neurological 7 manifestations and Associated symptoms (The Philippine CORONA Study) 8 9 10 a,b, ,† a,† a,‡ 11 Adrian I. Espiritu * , Marie Charmaine C. Sy , Veeda Michelle M. Anlacan , Roland 12 Dominic G. Jamoraa,*, ‡ 13 14 aDepartment of Neurosciences, College of Medicine and Philippine General Hospital, University 15 of the Philippines Manila, Manila, Philippines 16 b For peer review only 17 Department of Clinical Epidemiology, College of Medicine, University of the Philippines 18 Manila, Manila, Philippines 19 20 *Corresponding author; †Joint co-principal investigators; ‡Joint senior investigators 21 22 23 24 25 Contact information: 26 27 ADRIAN I. ESPIRITU, MD 28 E-mail address: [email protected] 29 Contact number: (+63) 925 852 0341 30 ORCID iD: 0000-0001-5621-1833 31 32 MARIE CHARMAINE C. SY, MD, MBA 33 http://bmjopen.bmj.com/ 34 E-mail address: [email protected] 35 Contact number: (+63) 917 843 6444 36 ORCID iD: 0000-0003-1135-6400 37 38 VEEDA MICHELLE M. ANLACAN, MD, FPNA 39 40 E-mail address: [email protected] Contact number: (+63) 917 832 7340 41 on September 26, 2021 by guest. Protected copyright. 42 ORCID iD: 0000-0002-1241-8805 43 44 ROLAND DOMINIC G. JAMORA, MD, FPNA 45 E-mail address: [email protected] 46 Contact number: (+63) 998 543 8062 47 48 ORCID iD: 0000-0001-5317-7369 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 ABSTRACT 4 5 6 Introduction: 7 The SARS-CoV-2, virus which caused the coronavirus disease (COVID-19) global pandemic, 8 may possess a neuroinvasive potential. It is hypothesized that patients with COVID-19 disease 9 may also present with neurological signs and symptoms aside from the usual respiratory 10 affectation. Moreover, it appears that COVID-19 may be associated with several neurological 11 diseases and complications, which may eventually affect clinical outcomes. 12 13 14 Objectives: 15 The Philippine CORONA study investigators will conduct a nationwide, multicenter study 16 involving 31 institutionsFor that aimspeer to determine review the neurological only manifestations and factors 17 associated with clinical outcomes in COVID-19 infection. 18 19 Methodology and analysis: 20 21 This is a retrospective cohort study (comparative between patients with and without neurological 22 manifestations) via medical chart review involving adult patients with COVID-19 infection. 23 Sample size was determined at 1,342 patients. Demographic, clinical and neurological profiles 24 will be obtained and summarized using descriptive statistics. Student’s t-test for two independent 25 samples and chi-squared test will be used to determine differences between distributions. Hazard 26 ratios (HR) and 95% confidence interval will be used as an outcome measure. Kaplan-Meier 27 curves will be constructed to plot the time to onset of mortality (survival), respiratory failure, 28 29 ICU admission, duration of ventilator dependence, length of ICU stay, and length of hospital 30 stay. The log-rank test will be employed to compare the Kaplan-Meier curves. Stratified analysis 31 will be performed to identify confounders and effects modifiers. To compute for adjusted HR 32 with 95% CI, crude HR of outcomes will be adjusted according to the prespecified possible

33 confounders. Cox-proportional regression models will be used to determine significant factors of http://bmjopen.bmj.com/ 34 outcomes. Testing for goodness-of-fit will also be done using Hosmer-Lemeshow test. Subgroup 35 analysis will be performed for proven prespecified effect modifiers. The effects of missing data 36 37 and outliers will also be evaluated in this study. 38 39 Ethical consideration: 40 This protocol was approved by the Single Joint Research Ethics Board of the Philippine

41 Department of Health (SJREB-2020-24) and the institutional review board of the different study on September 26, 2021 by guest. Protected copyright. 42 sites. 43 44 45 Registration number: NCT04386083 46 47 Keywords: COVID-19, Neurologic manifestations; Outcomes; Cohort study 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 1 BMJ Open Page 4 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 ARTICLE SUMMARY 4 5 Strengths and limitations: 6 7 8 9  CORONA is a nationwide, multicenter, retrospective, cohort study with 31 Philippine 10 11 sites. 12 13  Full spectrum of neurological manifestations of COVID-19 will be collected. 14 15 16  RetrospectiveFor gathering peer of data offers review virtually no risk only of COVID-19 infection to data 17 18 collectors. 19 20 21  Data from COVID-19 patients who did not go to the hospital are unobtainable. 22 23  Recoding bias is inherent due to the retrospective nature of the study. 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 1 Page 5 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 INTRODUCTION 4 5 6 7 The coronavirus disease (COVID-19) has been identified as the cause of an outbreak of 8 9 respiratory illness in Wuhan, Hubei Province, China in December 2019 [1]. The COVID-19 10 11 pandemic has reached the Philippines with most of its cases found in the National Capital Region 12 13 (NCR) [2]. The major clinical features of COVID-19 include fever, cough, shortness of breath, 14 15 16 myalgia, headache andFor diarrhea peer [3]. The outcomes review of this disease only lead to prolonged hospital stay, 17 18 intensive care unit (ICU) admission, dependence on invasive mechanical ventilation, respiratory 19 20 failure and mortality [4]. The specific pathogen that causes this clinical syndrome has been 21 22 23 named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is 24 25 phylogenetically similar to SARS-CoV [4]. Like the SARS-CoV strain, SARS-CoV-2 may 26 27 possess a similar neuroinvasive potential [5]. This virus utilizes angiotensin converting enzyme 2 28 29 30 (ACE2) receptor to gain entry into cells which is present in multiple organs of the body including 31 32 glial cells and neurons [5,6]. Modes of transmission by these viral pathogens may involve

33 http://bmjopen.bmj.com/ 34 transcellular, paracellular and retrograde axonal transport along sensory and olfactory nerves, 35 36 and through hematogenous spread or viremia [7]. 37 38 39 40 A study on cases with COVID‐19 found that about 36.4% of patients displayed neurologic

41 on September 26, 2021 by guest. Protected copyright. 42 manifestations of the central nervous system (CNS) and peripheral nervous system (PNS) [8]. 43 44 These estimates, however, were based on studies with small number of patients. Some reports 45 46 47 have been recently published on neurologic disorders associated with COVID-19 patients 48 49 including frequent convulsive seizures, Guillain-Barre syndrome (GBS), meningitis and acute 50 51 hemorrhagic necrotizing encephalopathy [9–12]. 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 2 BMJ Open Page 6 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 Epidemiological data on the proportions and spectrum of non-respiratory symptoms and 4 5 6 complications may be essential to increase the recognition of clinicians of the possibility of 7 8 COVID-19 infection in the presence of other symptoms, particularly neurological manifestations. 9 10 With this information, the probabilities of diagnosing COVID-19 disease may be strengthened 11 12 depending on the presence of certain neurological manifestations. Furthermore, knowledge of 13 14 15 other unrecognized symptoms and complications may allow early diagnosis which may permit 16 For peer review only 17 early institution of personal protective equipment and proper contact precautions. Lastly, the 18 19 presence of neurological manifestations may be utilized for estimating the risk of certain 20 21 22 important clinical outcomes for better and well-informed clinical decisions in patients with 23 24 COVID-19 disease. 25 26 27 To address this lack of important information in the overall management of COVID-19 patients, 28 29 30 we organized a research study entitled “The Philippine COVID-19 Outcomes: a Retrospective 31 32 study Of Neurological manifestations and Associated symptoms (The Philippine CORONA

33 http://bmjopen.bmj.com/ 34 Study)”. 35 36 37 Objectives 38 39 40 This quantitative, retrospective cohort, multicenter study aims: (1) to determine the

41 on September 26, 2021 by guest. Protected copyright. 42 demographic, clinical and neurological profile of patients with COVID-19 disease in the 43 44 Philippines; (2) to determine the frequency of neurological symptoms and new-onset 45 46 47 neurological disorders/ complications in patients with COVID-19 disease; (3) to determine the 48 49 neurological manifestations that are significant factors of mortality, respiratory failure, duration 50 51 of ventilator dependence, ICU admission, length of ICU stay, and length of hospital stay among 52 53 54 patients with COVID-19 disease; (4) to determine if there is significant difference between 55 56 COVID-19 patients with neurological manifestations compared to those COVID-19 patients 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 3 Page 7 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 without neurological manifestations in terms of mortality, respiratory failure, duration of 4 5 6 ventilator dependence, ICU admission, length of ICU stay, and length of hospital stay; and (5) to 7 8 determine the likelihood of mortality, respiratory failure, and ICU admission, including the 9 10 likelihood of longer duration of ventilator dependence, length of ICU and hospital stay in 11 12 COVID-19 patients with neurological manifestations compared to those without neurological 13 14 15 manifestations. 16 For peer review only 17 18 Scope, limitations and delimitations 19 20 The study will include confirmed cases of COVID-19 from the 31 participating institutions in the 21 22 23 Philippines. Every country has its own health care system, whose level of development and 24 25 strategies ultimately affect patient outcomes. Thus, the results of this study cannot be accurately 26 27 generalized to other settings. In addition, patients with ages ≤ 18 years will be excluded in from 28 29 this study. These younger patients may have different characteristics and outcomes; therefore, 30 31 32 yielded estimates for adults in this study may not be applicable to this population subgroup.

33 http://bmjopen.bmj.com/ 34 Moreover, this study will collect data from the patient records of COVID-19 patients; thus, data 35 36 from patients with mild symptoms who did not go to the hospital and those who had spontaneous 37 38 39 resolution of symptoms despite true infection with COVID-19 are unobtainable. 40

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 4 BMJ Open Page 8 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 METHODOLOGY 4 5 6 7 To improve the quality of reporting of this study, the guidelines issued by the Strengthening the 8 9 Reporting of Observational Studies in Epidemiology (STROBE) Initiative will be followed [13]. 10 11 12 Study design 13 14 The study will be conducted using a retrospective cohort (comparative) design (see Fig 1). 15 16 For peer review only 17 18 Study sites and duration 19 20 We will conduct a nationwide, multicenter study involving 31 institutions in the Philippines (see 21 22 Fig 2). Most of these study sites can be found in the NCR, which remains to be the epicenter of 23 24 the COVID-19 pandemic [2]. We will collect data for 6 months after institutional review board 25 26 27 approval for every site. 28 29 30 Patient selection and cohort description 31 32 The cases will be identified using the designated COVID-19 censuses of all the participating

33 http://bmjopen.bmj.com/ 34 centers. A total enumeration of patients with confirmed COVID-19 disease will be done in this 35 36 37 study. 38 39 40 The cases identified should satisfy the following inclusion criteria: (a) adult patients at least 19

41 on September 26, 2021 by guest. Protected copyright. 42 years of age; (b) cases confirmed by testing approved patient samples (i.e. nasal swab, sputum, 43 44 45 bronchoalveolar lavage fluid) employing real-time reverse transcription polymerase chain 46 47 reaction (rRT-PCR) [14] from COVID-19 testing centers accredited by the Department of Health 48 49 (DOH) of the Philippines, with clinical symptoms and signs attributable to COVID-19 disease 50 51 52 (i.e. respiratory as well as non-respiratory clinical signs and symptoms) [15]; (c) cases with 53 54 disposition (i.e., discharged stable/recovered, home/discharged against medical advice, 55 56 transferred to other hospital, or died) at the end of the study period. Cases with conditions or 57 58 59 5 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 diseases caused by other organisms (i.e. bacteria, other viruses, fungi, etc.) or caused by other 4 5 6 pathologies unrelated to COVID-19 disease (i.e., trauma) will be excluded. 7 8 9 The first cohort will involve patients with confirmed COVID-19 infection who presented with 10 11 any neurological manifestation/s (i.e., symptoms or complications/ disorder). The comparator 12 13 cohort will comprise of patients with confirmed COVID-19 infection without neurological 14 15 16 manifestation/s. For peer review only 17 18 19 Sample size calculation 20 21 We looked into the mortality outcome measure for the purposes of sample size computation. 22 23 24 Following the cohort study of Khaledifar, et al. [16]. The sample size was calculated using the 25 26 following parameters: Two-sided 95% significance level (1 – ); 80% power (1 – ); 27 28 Unexposed/ exposed ratio of 1; 5% of unexposed with outcome (case fatality rate from 29 30 31 COVID19-PH [17] as of 8 April 2020); Assumed risk ratio 2 (to see a two-fold increase in risk 32

33 of mortality when neurologic symptoms are present). http://bmjopen.bmj.com/ 34 35 36 When these values were plugged-in to the formula for cohort studies [18], a minimum sample 37 38 size of 1,118 is required. To account for possible incomplete data, the sample was adjusted for 39 40

41 20% more. This means that the total sample size required is 1,342 patients which will be on September 26, 2021 by guest. Protected copyright. 42 43 gathered from the participating centers. 44 45 46 Data collection 47 48 TM 49 We formulated an electronic data collection form using Epi Info Software (Version 7.2.2.16). 50 51 The forms will be pilot-tested and a formal data collection workshop will be conducted to ensure 52 53 collection accuracy. The data will be obtained from the review of the medical records. 54 55 56 57 58 59 6 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 The following pertinent data will be obtained: (a) demographic data and other clinical profile 4 5 6 data (b) comorbidities; (c) past neurological history; (d) date of illness onset; (e) respiratory and 7 8 constitutional symptoms associated with COVID-19; (f) COVID-19 disease severity [19] at 9 10 nadir; (g) data if neurological manifestation/s were present at onset prior to respiratory symptoms 11 12 and the specific neurological manifestation/s present at onset; (h) neurological symptoms; (i) 13 14 15 date of neurological symptom onset; (j) new-onset neurological disorders or complications; (k) 16 For peer review only 17 date of new neurological disorder or complication onset; (l) imaging done; (m) cerebrospinal 18 19 (CSF) fluid analysis; (n) electrophysiologic studies; (o) treatment given; (p) antibiotics given; (q) 20 21 22 neurological interventions given; (r) date of mortality, cause/s of mortality; (s) date of respiratory 23 24 failure onset, date of mechanical ventilator cessation, cause/s of respiratory failure; (t) date of 25 26 first day of ICU admission, date of discharge from ICU, indication/s for ICU admission; (u) 27 28 29 other neurological outcomes at discharge; (v) date of hospital discharge; (w) final disposition. 30 31 See Table 1 for the summary of the data to be collected for this study. 32

33 http://bmjopen.bmj.com/ 34 Main outcomes considered 35 36 The following patient outcomes will be considered for this study: 37 38 39  Mortality (binary outcome) – defined as the patients with confirmed COVID-19 who 40

41 died. on September 26, 2021 by guest. Protected copyright. 42 43  Respiratory failure (binary outcome) – defined as the patients with confirmed COVID-19 44 45 46 who experienced clinical symptoms and signs of respiratory insufficiency. Clinically, this 47 48 condition may manifest as tachypnea, abnormal blood gases (hypoxemia or hypercapnia), 49 50 signs of increased work of breathing, and requiring oxygen supplementation [20]; 51 52 53  Duration of ventilator dependence (continuous outcome) – defined as the number of days 54 55 from initiation of assisted ventilation to cessation of mechanical ventilator use; 56 57 58 59 7 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

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Table 1. Data to be collected in this study. 1 2 Data Description 3 Demographic data and other Age, sex, nationality, and place of residence (city or province), weight, height, declared history of exposure (international travel, community or 4 clinical profile data domestic travel, hospital), smoking status, healthcare worker status, and pregnancy status 5 Comorbidities Hypertension, diabetes mellitus, heart failure, coronary artery disease, chronic obstructive pulmonary disease, bronchial asthma, chronic kidney 6 disease, chronic liver disease, obesity, malignancy, HIV, and others 7 Past neurological history Stroke/ other cerebrovascular diseases, epilepsy, dementia, movement disorder, headache syndrome, CNS infection, PNS infection, central 8 demyelinating syndrome, myelopathy, neuropathy, neuromuscular junction disorder, myopathy, and others 9 Respiratory and Any respiratory/constitutional symptoms, cough, rhinorrhea, sputum production, sore throat, hemoptysis, dyspnea, fever, fatigue, arthralgia, 10 constitutional symptoms diarrhea, and myalgia; date of illness onset 11 associated with COVID-19 12 COVID-19 disease severity Mild – definedFor as presence of peer mild pneumonia or absencereview of pneumonia; severe only disease – defined as the presence of dyspnea, respiratory rate > 30 13 at nadir breaths/ minute, hypoxia (SpO2 <93%), or > 50% lung involvement on imaging within 24 to 48 hours; and critical disease – defined as the 14 presence of respiratory failure, shock, or multiorgan dysfunction 15 Neurological symptoms Any neurological symptom, headache, nausea, vomiting, seizure, altered sensorium, confusion, anosmia/ hyposmia, blindness/ decreased vision, 16 eye pain, ophthalmoplegia/ ophthalmoparesis, hearing loss/ decreased hearing, dizziness, ageusia/ dysgeusia, facial numbness, facial weakness, 17 dysarthria, dysphonia, dysphagia, tongue weakness, neck weakness, extremity weakness, extremity numbness/ paresthesia, tremor, dystonia,

18 choreoathetosis, bradykinesia, ataxia, meningismus, myalgia, and others; date of neurological symptom onset.http://bmjopen.bmj.com/ 19 New-onset neurological Any neurological complication, meningitis, encephalopathy, encephalitis, meningoencephalitis, anoxic/hypoxic brain syndrome, acute 20 disorders or complications disseminated encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, any seizure disorder, acute symptomatic seizure, epilepsy, status 21 epilepticus, any acute cerebrovascular disease (CVD), acute CVD (infarction), acute CVD (hemorrhagic), any movement disorder, movement 22 disorders (hyperkinetic), movement disorders (hypokinetic), cerebellitis, optic neuritis, myelitis, sensory ganglionitis/ dorsal radiculitis, anterior 23 horn syndrome (polio-like syndrome)/ ventral radiculitis, peripheral neuritis (GBS-like syndrome), peripheral neuritis (other than GBS-like 24 syndrome), neuromuscular disorder, myositis, and others; date of new neurological disorder or complication onset 25 Imaging done Computed tomography (CT) scan, magnetic resonance imaging (MRI) scan, affected portion/s of the neuroaxis in the imaging

26 Cerebrospinal (CSF) fluid CSF total cell count, CSF neutrophil count, CSF lymphocyte count, CSF protein, CSF glucose, serum glucose, on September 26, 2021 by guest. Protected copyright. CSF COVID-19 test result, other 27 analysis CSF tests done 28 Electrophysiologic studies Electroencephalography (EEG), and electromyography-nerve conduction studies (EMG-NCS) tests, if done, and pertinent results 29 Treatment given Chloroquine, hydroxychloroquine, lopinavir + ritonavir, tocilizumab, remdesivir, systemic glucocorticoids, convalescent plasma, and others; 30 Antibiotics given 31 Neurological interventions E.g., Antiplatelet, anticoagulant, antiepileptic drugs, and others 32 Mortality Date of mortality, cause/s of mortality 33 Respiratory failure Date of respiratory failure onset, date of mechanical ventilator cessation, cause/s of respiratory failure 34 ICU admission Date of first day of ICU admission, date of discharge from ICU, indication/s for ICU admission 35 Other neurological Full neurological recovery – defined as patients with confirmed COVID-19 infection who had any neurological deficit during admission, who 36 outcomes at discharge then had full neurological recovery with no noted neurological deficits at discharge; stable with improvement of neurological deficits – defined as 37 patients with COVID-19 infection who had any neurological deficit during admission, who then had improvement but not complete resolution of 38 the neurological deficits at discharge; stable with no improvement of neurological deficits – defined as the patients with COVID-19 infection who 39 had any neurological deficit during admission, who then had no improvement of the neurological deficits at discharge 40 Final disposition Discharged stable/recovered, home against medical advice, transferred to other hospital, died/mortality); date of hospital discharge 41 42 43 44 8 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 12 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3  Intensive care unit (ICU) admission (binary outcome) - defined as the patients with 4 5 6 confirmed COVID-19 admitted to an ICU or ICU-comparable setting; 7 8  Length of ICU stay (continuous outcome) – defined as the number of days admitted in 9 10 the ICU or ICU-comparable setting; 11 12 13  Length of hospital stay (continuous outcome) – defined as the number of days from 14 15 admission to discharge. 16 For peer review only 17 18 Data analysis plan 19 20 Statistical analysis will be performed using Stata, Version 7.2.2.16 (College Station, TX: 21 22 23 StataCorp LP). 24 25 26 Demographic, clinical and neurological profiles will be summarized using descriptive statistics, 27 28 in which categorical variables will be expressed as frequencies with corresponding percentages, 29 30 31 and continuous variables will be pooled using means (standard deviation). 32

33 http://bmjopen.bmj.com/ 34 Student’s t-test for two independent samples and chi-squared test will be used to determine 35 36 differences between distributions. 37 38 39 40 Hazard ratios (HR) and 95% confidence interval will be used as an outcome measure. Kaplan-

41 on September 26, 2021 by guest. Protected copyright. 42 Meier curves will be constructed to plot the time to onset of mortality (survival), respiratory 43 44 failure, ICU admission, duration of ventilator dependence (recategorized binary form), length of 45 46 47 ICU stay (recategorized binary form), length of hospital stay (recategorized binary form). Log- 48 49 rank test will be employed to compare the Kaplan-Meier curves. Stratified analysis will be 50 51 performed to identify confounders and effects modifiers. To compute for adjusted HR with 95% 52 53 CI, crude HR of outcomes at discrete time points will be adjusted for prespecified possible 54 55 56 confounders such as age, history of cardiovascular or cerebrovascular disease, hypertension, 57 58 59 9 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 diabetes mellitus, and respiratory disease, COVID-19 disease severity at nadir, and other 4 5 6 significant confounding factors. 7 8 9 Cox-proportional regression models will be used to determine significant factors of outcomes. 10 11 Testing for goodness-of-fit will be done using Hosmer-Lemeshow test. Likelihood ratio tests and 12 13 other information criteria (Akaike Information Criterion or Bayesian Information Criterion) will 14 15 16 be used to refine theFor final model. peer Statistical review significance will onlybe considered if the 95% 17 18 confidence interval of HR or adjusted HR did not include the number one. A p value < 0.05 19 20 (two-tailed) is set for other analyses. 21 22 23 24 Subgroup analyses will be performed for proven prespecified effect modifiers. The following 25 26 variables will be considered for subgroup analyses: age (19 to 64 years vs ≥ 65 years), sex, 27 28 body-mass index (<18.5 vs 18.5 to 22.9 vs ≥ 23 kg/m2), with past history of cardiovascular or 29 30 31 cerebrovascular disease (presence or absence), hypertension (presence or absence), diabetes 32

33 mellitus (presence or absence), respiratory disease (presence or absence), smoking status http://bmjopen.bmj.com/ 34 35 (smoker or nonsmoker), and COVID-19 disease severity (mild, severe or critical disease). 36 37 38 39 The effects of missing data will be explored. All efforts will be exerted to minimize missing and 40

41 spurious data. Validity of the submitted electronic data collection will be monitored and on September 26, 2021 by guest. Protected copyright. 42 43 reviewed weekly to prevent missing or inaccurate input of data. Multiple imputations will be 44 45 performed for missing data, when possible. To check for robustness of results, analysis done for 46 47 48 patients with complete data will be compared to the analysis with the imputed data. 49 50 51 The effects of outliers will also be assessed. Outliers will be assessed by z-score or boxplot. A 52 53 cut-off of 3 standard deviations from the mean can also be used. To check for robustness of 54 55 56 results, analysis done with outliers will be compared to the analysis without the outliers. 57 58 59 10 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 Study organizational structure 4 5 A steering committee (AIE, MCS, VMA, and RDJ) was formed to direct and provide appropriate 6 7 8 scientific, technical, and methodological assistance to study site investigators and collaborators 9 10 (see Fig 3). Central administrative coordination, data management, administrative support, 11 12 documentation of progress reports, data analyses and interpretation, and journal publication are 13 14 15 the main responsibilities of the steering committee. Study site investigators and collaborators are 16 For peer review only 17 responsible for the proper collection and recording of data including the duty to maintain the 18 19 confidentiality of information and the privacy of all identified patients for all the phases of the 20 21 22 research processes. 23 24 25 Ethical considerations 26 27 This research will adhere to the Philippine National Ethical Guidelines for Health and Health- 28 29 related Research (NEGHHRR) 2017 [21]. This study is an observational, cohort study and will 30 31 32 not allocate any type of intervention. The medical records of the identified patients will be

33 http://bmjopen.bmj.com/ 34 reviewed retrospectively. To protect the privacy of the participant, the data collection forms will 35 36 not contain any information (i.e., names, institutional patient number) that could determine the 37 38 39 identity of the patients. A sequential code will be recorded for each patient in the following 40

41 format: AAA-BBB where AAA will pertain to the three-digit code randomly assigned to each on September 26, 2021 by guest. Protected copyright. 42 43 study site; BBB will pertain to the sequential case number assigned by each study site. Each 44 45 46 participating center will designate a password-protected laptop for data collection; the password 47 48 is known only to the study site. 49 50 51 This protocol has been approved by the following institutional review boards: Single Joint 52 53 Research Ethics Board of the DOH, Philippines (SJREB-2020-24); Cardinal Santos Medical 54 55 56 57 58 59 11 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 Center, San Juan City (CSMC REC 2020-020); East Avenue Medical Center (EAMC), Quezon 4 5 6 City (EAMC IERB 2020-38); Jose B. Lingad Memorial Regional Hospital, San Fernando, 7 8 Pampanga; Manila Doctors Hospital, Manila City (MDH IRB 2020-006); Makati Medical 9 10 Center, Makati City (MMC IRB 2020-054); Philippine Heart Center, Quezon City; Research 11 12 Institute for Tropical Medicine, Muntinlupa City (RITM IRB 2020-16); Southern Philippines 13 14 15 Medical Center, Davao City; The Medical City, Pasig City; and University of Santo Tomas 16 For peer review only 17 Hospital, Manila City (UST-REC-2020-04-071-MD). 18 19 20 21 22 23 24 SUMMARY 25 26 27 The Philippine CORONA Study, a nationwide multicenter study involving 31 institutions, is 28 29 designed to address the large knowledge gap of the neurological manifestations and factors 30 31 32 leading to clinical outcomes in COVID-19 infection. The evidence that will be gleaned from this

33 http://bmjopen.bmj.com/ 34 collaborative work will serve as a benchmark information to aid physicians to better recognize 35 36 the full neurological spectrum of its clinical presentations. Furthermore, the results that will be 37 38 obtained from this study may contribute to the risk estimation of important clinical outcomes, 39 40

41 essential to the overall care of COVID-19 patients. on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 12 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 Protocol registration and technical review approval 4 5 This protocol was registered in the ClinicalTrials.gov website (Identifier: NCT04386083). It has 6 7 8 received a technical review board approval from the Department of Neurosciences, Philippine 9 10 General Hospital and College of Medicine, University of the Philippines Manila and from the 11 12 Cardinal Santos Medical Center, San Juan City, Philippines. 13 14 15 16 Funding source For peer review only 17 18 The Philippine Neurological Association (PNA), the accredited national professional society of 19 20 neurologists in the Philippines, is the major study sponsor. The study will also receive funding 21 22 from the Philippine General Hospital – Expanded Hospital Research Office, University of the 23 24 25 Philippines Manila. 26 27 28 Our funding sources had no role in the design of the protocol, and will not be involved during the 29 30 methodological execution, data analyses and interpretation, and decision to submit or to publish 31 32 the study results. 33 http://bmjopen.bmj.com/ 34 35 36 Authors’ contribution 37 38 AIE, MCS, VMA, and RDJ conceived the idea and wrote the initial drafts and revisions of the 39 40 protocol. All authors made substantial contributions in this protocol for intellectual content.

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 Conflict of interest 45 46 The authors declare no conflict of interest. 47 48 49 Acknowledgment 50 51 52 We would like to thank Almira Abigail Doreen O. Apor, MD of the Department of 53 54 Neurosciences, Philippine General Hospital, Philippines for illustrating Fig 2 for this publication. 55 56 57 58 59 13 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 Patient and public involvement 4 5 6 Patients or the public were not involved in the design, or conduct, or reporting, or dissemination 7 8 plans of our research. 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

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1 2 3 REFERENCES 4 5 6 7 1 Adhikari SP, Meng S, Wu Y-J, et al. Epidemiology, causes, clinical manifestation and 8 9 diagnosis, prevention and control of coronavirus disease (COVID-19) during the early 10 11 outbreak period: a scoping review. Infect Dis Poverty 2020;9:29. doi:10.1186/s40249-020- 12 13 14 00646-x 15 16 2 Department ofFor Health. peerCOVID-19 casereview tracker. 2020.https://www.doh.gov.ph/covid- only 17 18 19/case-tracker (accessed 10 May 2020). 19 20 21 3 Philippine Society for Microbiology and Infectious Diseases. Interim guidelines on the 22 23 clinical management of adult patients with suspected or confirmed COVID-19 infection. 24 25 2020. 26 27 4 Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. 28 29 30 N Engl J Med 2020;:NEJMoa2002032. doi:10.1056/NEJMoa2002032 31 32 5 Li Y, Bai W, Hashikawa T. The neuroinvasive potential of SARS‐CoV2 may be at least

33 http://bmjopen.bmj.com/ 34 partially responsible for the respiratory failure of COVID‐19 patients. J Med Virol 35 36 37 2020;92:552–5. doi:10.1002/jmv.25728 38 39 6 Baig AM, Khaleeq A, Ali U, et al. Evidence of the COVID-19 virus targeting the CNS: 40

41 Tissue distribution, host–virus interaction, and proposed neurotropic mechanisms. ACS on September 26, 2021 by guest. Protected copyright. 42 43 44 Chem Neurosci 2020;11:995–8. doi:10.1021/acschemneuro.0c00122 45 46 7 Robinson CP, Busl KM. Neurologic manifestations of severe respiratory viral contagions. 47 48 Crit Care Explor 2020;2:e0107. doi:10.1097/CCE.0000000000000107 49 50 8 Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with 51 52 53 coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;:e201127. 54 55 doi:10.1001/jamaneurol.2020.1127 56 57 58 59 15 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 9 Karimi N, Sharifi Razavi A, Rouhani N. Frequent convulsive seizures in an adult patient 4 5 6 with COVID-19: A case report. Iran Red Crescent Med J 2020;22. 7 8 doi:10.5812/ircmj.102828 9 10 10 Poyiadji N, Shahin G, Noujaim D, et al. COVID-19–associated acute hemorrhagic 11 12 necrotizing encephalopathy: CT and MRI features. Radiology 2020;:201187. 13 14 15 doi:10.1148/radiol.2020201187 16 For peer review only 17 11 Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 18 19 infection: Causality or coincidence? Lancet Neurol Published Online First: April 2020. 20 21 22 doi:10.1016/S1474-4422(20)30109-5 23 24 12 Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with 25 26 SARS-Coronavirus-2. Int J Infect Dis Published Online First: April 2020. 27 28 29 doi:10.1016/j.ijid.2020.03.062 30 31 13 von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational 32

33 Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational http://bmjopen.bmj.com/ 34 35 studies. J Clin Epidemiol 2008;61:344–9. doi:10.1016/j.jclinepi.2007.11.008 36 37 38 14 Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel 39 40 coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565–74.

41 on September 26, 2021 by guest. Protected copyright. 42 doi:10.1016/S0140-6736(20)30251-8 43 44 45 15 Centers for Disease Control and Prevention. Evaluating and testing persons for 46 47 coronavirus disease 2019 (COVID-19). 2020.https://www.cdc.gov/coronavirus/2019- 48 49 nCoV/hcp/clinical-criteria.html (accessed 7 Apr 2020). 50 51 52 16 Khaledifar A, Hashemzadeh M, Solati K, et al. The protocol of a population-based 53 54 prospective cohort study in southwest of Iran to analyze common non-communicable 55 56 57 58 59 16 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 22 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 diseases: Shahrekord cohort study. BMC Public Health 2018;18:660. doi:10.1186/s12889- 4 5 6 018-5364-2 7 8 17 Haw J, Uy J. COVID-19 cases and deaths in the Philippines dashboard. 9 10 2020.https://public.tableau.com/profile/jason.haw#!/vizhome/COVID- 11 12 19CasesandDeathsinthePhilippines/Dashboard?publish=yes (accessed 8 Apr 2020). 13 14 15 18 Fleiss JL. Statistical methods for rates and proportions. 1st Ed. London: : John Wiley & 16 For peer review only 17 Sons 1981. 18 19 19 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus 20 21 22 disease 2019 (COVID-19) outbreak in China. JAMA Published Online First: 24 February 23 24 2020. doi:10.1001/jama.2020.2648 25 26 20 Tulaimat A, Patel A, Wisniewski M, et al. The validity and reliability of the clinical 27 28 29 assessment of increased work of breathing in acutely ill patients. J Crit Care 30 31 2016;34:111–5. doi:10.1016/j.jcrc.2016.04.013 32

33 21 Philippine Research Ethics Board. National ethical guidelines for health and health- http://bmjopen.bmj.com/ 34 35 related research. Taguig City: : Philippine Council for Health Research and Development 36 37 38 Department of Science and Technology 2017. 39 40

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 17 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 Fig 1. Schematic diagram of the study flow. 24 25 1015x520mm (72 x 72 DPI) 26 27 28 29 30 31 32

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Fig 2. Location of study sites of the Philippine CORONA Study. 32 1411x1058mm (72 x 72 DPI)

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 Fig 3. Organizational structure of oversight of the Philippine CORONA Study. 18 19 1120x346mm (72 x 72 DPI) 20 21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

Article Type: Protocol

Date Submitted by the 12-Sep-2020 Author:

Primary Subject Neurology Heading:

Secondary Subject Heading: Epidemiology http://bmjopen.bmj.com/ NEUROLOGY, Adult neurology < NEUROLOGY, EPIDEMIOLOGY, COVID- Keywords: 19

on September 26, 2021 by guest. Protected copyright.

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37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

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1 2 3 4 5 6 Study protocol: The Philippine COVID-19 Outcomes: a Retrospective study Of Neurological 7 manifestations and Associated symptoms (The Philippine CORONA Study) 8 9 10 a,b, ,† a,† a,‡ 11 Adrian I. Espiritu * , Marie Charmaine C. Sy , Veeda Michelle M. Anlacan , Roland 12 Dominic G. Jamoraa,*, ‡ 13 14 aDepartment of Neurosciences, College of Medicine and Philippine General Hospital, University 15 of the Philippines Manila, Manila, Philippines 16 b For peer review only 17 Department of Clinical Epidemiology, College of Medicine, University of the Philippines 18 Manila, Manila, Philippines 19 20 *Corresponding author; †Joint co-principal investigators; ‡Joint senior investigators 21 22 23 24 25 Contact information: 26 27 ADRIAN I. ESPIRITU, MD 28 E-mail address: [email protected] 29 Contact number: (+63) 925 852 0341 30 ORCID iD: 0000-0001-5621-1833 31 32 MARIE CHARMAINE C. SY, MD, MBA 33 http://bmjopen.bmj.com/ 34 E-mail address: [email protected] 35 Contact number: (+63) 917 843 6444 36 ORCID iD: 0000-0003-1135-6400 37 38 VEEDA MICHELLE M. ANLACAN, MD, FPNA 39 40 E-mail address: [email protected] Contact number: (+63) 917 832 7340 41 on September 26, 2021 by guest. Protected copyright. 42 ORCID iD: 0000-0002-1241-8805 43 44 ROLAND DOMINIC G. JAMORA, MD, FPNA 45 E-mail address: [email protected] 46 Contact number: (+63) 998 543 8062 47 48 ORCID iD: 0000-0001-5317-7369 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 ABSTRACT 4 5 6 Introduction: 7 The SARS-CoV-2, virus which caused the coronavirus disease (COVID-19) global pandemic, 8 possesses a neuroinvasive potential. Patients with COVID-19 infection presents with 9 neurological signs and symptoms aside from the usual respiratory affectation. Moreover, 10 COVID-19 associated with several neurological diseases and complications, which may 11 eventually affect clinical outcomes. 12 13 14 Objectives: 15 The Philippine CORONA study investigators will conduct a nationwide, multicenter study 16 involving 37 institutionsFor that aimspeer to determine review the neurological only manifestations and factors 17 associated with clinical outcomes in COVID-19 infection. 18 19 Methodology and analysis: 20 21 This is a retrospective cohort study (comparative between patients with and without neurological 22 manifestations) via medical chart review involving adult patients with COVID-19 infection. 23 Sample size was determined at 1,342 patients. Demographic, clinical and neurological profiles 24 will be obtained and summarized using descriptive statistics. Student’s t-test for two independent 25 samples and chi-squared test will be used to determine differences between distributions. Hazard 26 ratios (HR) and 95% confidence interval will be used as an outcome measure. Kaplan-Meier 27 curves will be constructed to plot the time to onset of mortality (survival), respiratory failure, 28 29 ICU admission, duration of ventilator dependence, length of ICU stay, and length of hospital 30 stay. The log-rank test will be employed to compare the Kaplan-Meier curves. Stratified analysis 31 will be performed to identify confounders and effects modifiers. To compute for adjusted HR 32 with 95% CI, crude HR of outcomes will be adjusted according to the prespecified possible

33 confounders. Cox-proportional regression models will be used to determine significant factors of http://bmjopen.bmj.com/ 34 outcomes. Testing for goodness-of-fit will also be done using Hosmer-Lemeshow test. Subgroup 35 analysis will be performed for proven prespecified effect modifiers. The effects of missing data 36 37 and outliers will also be evaluated in this study. 38 39 Ethics and dissemination: 40 This protocol was approved by the Single Joint Research Ethics Board of the Philippine

41 Department of Health (SJREB-2020-24) and the institutional review board of the different study on September 26, 2021 by guest. Protected copyright. 42 sites. The dissemination of results will be conducted through scientific/ medical conferences and 43 44 through journal publication. The lay versions of the results may be provided upon request. 45 46 47 Registration number: NCT04386083 48 49 Keywords: COVID-19, Neurologic manifestations; Outcomes; Cohort study 50 51 52 53 54 55 56 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 ARTICLE SUMMARY 4 5 Strengths and limitations: 6 7 8 9  CORONA is a nationwide, multicenter, retrospective, cohort study with 37 Philippine 10 11 sites. 12 13  Full spectrum of neurological manifestations of COVID-19 will be collected. 14 15 16  RetrospectiveFor gathering peer of data offers review virtually no risk only of COVID-19 infection to data 17 18 collectors. 19 20 21  Data from COVID-19 patients who did not go to the hospital are unobtainable. 22 23  Recoding bias is inherent due to the retrospective nature of the study. 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 INTRODUCTION 4 5 6 7 The coronavirus disease (COVID-19) has been identified as the cause of an outbreak of 8 9 respiratory illness in Wuhan, Hubei Province, China in December 2019 [1]. The COVID-19 10 11 pandemic has reached the Philippines with most of its cases found in the National Capital Region 12 13 (NCR) [2]. The major clinical features of COVID-19 include fever, cough, shortness of breath, 14 15 16 myalgia, headache andFor diarrhea peer [3]. The outcomes review of this disease only lead to prolonged hospital stay, 17 18 intensive care unit (ICU) admission, dependence on invasive mechanical ventilation, respiratory 19 20 failure and mortality [4]. The specific pathogen that causes this clinical syndrome has been 21 22 23 named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is 24 25 phylogenetically similar to SARS-CoV [4]. Like the SARS-CoV strain, SARS-CoV-2 may 26 27 possess a similar neuroinvasive potential [5]. 28 29 30 31 A study on cases with COVID‐19 found that about 36.4% of patients displayed neurologic 32

33 manifestations of the central nervous system (CNS) and peripheral nervous system (PNS) [6]. http://bmjopen.bmj.com/ 34 35 The associated spectrum of symptoms and signs were substantially broad such as altered mental 36 37 38 status, headache, cognitive impairment, agitation, dysexecutive syndrome, seizures, corticospinal 39 40 tract signs, dysgeusia, extraocular movement abnormalities, and myalgia [7–12]. Several reports

41 on September 26, 2021 by guest. Protected copyright. 42 were published on neurologic disorders associated with COVID-19 patients, including 43 44 cerebrovascular disorders, encephalopathy, hypoxic brain injury, frequent convulsive seizures, 45 46 47 inflammatory CNS syndromes like encephalitis, meningitis, acute disseminated 48 49 encephalomyelitis, and Guillain-Barre syndrome (GBS) [7–10,12–17]. However, the estimates of 50 51 the occurrences of these manifestations were based on studies with a relatively small sample 52 53 54 size. Furthermore, the current description of COVID-19 neurological features are hampered to 55 56 some extent by exceedingly variable reporting; thus, defining causality between this infection 57 58 59 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 and certain neurological manifestations is crucial since this may lead to considerable 4 5 6 complications [18]. An Italian observational study protocol on neurological manifestations has 7 8 also been published to further document and corroborate these findings [19]. 9 10 11 Epidemiological data on the proportions and spectrum of non-respiratory symptoms and 12 13 complications may be essential to increase the recognition of clinicians of the possibility of 14 15 16 COVID-19 infectionFor in the presence peer of other review symptoms, particularly only neurological manifestations. 17 18 With this information, the probabilities of diagnosing COVID-19 disease may be strengthened 19 20 depending on the presence of certain neurological manifestations. Furthermore, knowledge of 21 22 23 other unrecognized symptoms and complications may allow early diagnosis which may permit 24 25 early institution of personal protective equipment and proper contact precautions. Lastly, the 26 27 presence of neurological manifestations may be utilized for estimating the risk of certain 28 29 30 important clinical outcomes for better and well-informed clinical decisions in patients with 31 32 COVID-19 disease.

33 http://bmjopen.bmj.com/ 34 35 To address this lack of important information in the overall management of COVID-19 patients, 36 37 we organized a research study entitled “The Philippine COVID-19 Outcomes: a Retrospective 38 39 40 study Of Neurological manifestations and Associated symptoms (The Philippine CORONA

41 on September 26, 2021 by guest. Protected copyright. 42 Study)”. 43 44 45 Objectives 46 47 48 This quantitative, retrospective cohort, multicenter study aims: (1) to determine the 49 50 demographic, clinical and neurological profile of patients with COVID-19 disease in the 51 52 Philippines; (2) to determine the frequency of neurological symptoms and new-onset 53 54 55 neurological disorders/ complications in patients with COVID-19 disease; (3) to determine the 56 57 58 59 4 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 neurological manifestations that are significant factors of mortality, respiratory failure, duration 4 5 6 of ventilator dependence, ICU admission, length of ICU stay, and length of hospital stay among 7 8 patients with COVID-19 disease; (4) to determine if there is significant difference between 9 10 COVID-19 patients with neurological manifestations compared to those COVID-19 patients 11 12 without neurological manifestations in terms of mortality, respiratory failure, duration of 13 14 15 ventilator dependence, ICU admission, length of ICU stay, and length of hospital stay; and (5) to 16 For peer review only 17 determine the likelihood of mortality, respiratory failure, and ICU admission, including the 18 19 likelihood of longer duration of ventilator dependence, length of ICU and hospital stay in 20 21 22 COVID-19 patients with neurological manifestations compared to those without neurological 23 24 manifestations. 25 26 27 Scope, limitations and delimitations 28 29 The study will include confirmed cases of COVID-19 from the 37 participating institutions in the 30 31 32 Philippines. Every country has its own health care system, whose level of development and

33 http://bmjopen.bmj.com/ 34 strategies ultimately affect patient outcomes. Thus, the results of this study cannot be accurately 35 36 generalized to other settings. In addition, patients with ages ≤ 18 years will be excluded in from 37 38 39 this study. These younger patients may have different characteristics and outcomes; therefore, 40

41 yielded estimates for adults in this study may not be applicable to this population subgroup. on September 26, 2021 by guest. Protected copyright. 42 43 Moreover, this study will collect data from the patient records of COVID-19 patients; thus, data 44 45 46 from patients with mild symptoms who did not go to the hospital and those who had spontaneous 47 48 resolution of symptoms despite true infection with COVID-19 are unobtainable. 49 50 51 52 53 54 55 56 57 58 59 5 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 METHODOLOGY 4 5 6 7 To improve the quality of reporting of this study, the guidelines issued by the Strengthening the 8 9 Reporting of Observational Studies in Epidemiology (STROBE) Initiative will be followed [20]. 10 11 12 Study design 13 14 The study will be conducted using a retrospective cohort (comparative) design (see Fig 1). 15 16 For peer review only 17 18 Study sites and duration 19 20 We will conduct a nationwide, multicenter study involving 37 institutions in the Philippines (see 21 22 Fig 2). Most of these study sites can be found in the NCR, which remains to be the epicenter of 23 24 the COVID-19 pandemic [2]. We will collect data for 6 months after institutional review board 25 26 27 approval for every site. 28 29 30 Patient selection and cohort description 31 32 The cases will be identified using the designated COVID-19 censuses of all the participating

41 on September 26, 2021 by guest. Protected copyright. 42 years of age; (b) cases confirmed by testing approved patient samples (i.e. nasal swab, sputum, 43 44 45 bronchoalveolar lavage fluid) employing real-time reverse transcription polymerase chain 46 47 reaction (rRT-PCR) [21] from COVID-19 testing centers accredited by the Department of Health 48 49 (DOH) of the Philippines, with clinical symptoms and signs attributable to COVID-19 disease 50 51 52 (i.e. respiratory as well as non-respiratory clinical signs and symptoms) [22]; (c) cases with 53 54 disposition (i.e., discharged stable/recovered, home/discharged against medical advice, 55 56 transferred to other hospital, or died) at the end of the study period. Cases with conditions or 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 diseases caused by other organisms (i.e. bacteria, other viruses, fungi, etc.) or caused by other 4 5 6 pathologies unrelated to COVID-19 disease (i.e., trauma) will be excluded. 7 8 9 The first cohort will involve patients with confirmed COVID-19 infection who presented with 10 11 any neurological manifestation/s (i.e., symptoms or complications/ disorder). The comparator 12 13 cohort will comprise of patients with confirmed COVID-19 infection without neurological 14 15 16 manifestation/s. For peer review only 17 18 19 Sample size calculation 20 21 We looked into the mortality outcome measure for the purposes of sample size computation. 22 23 24 Following the cohort study of Khaledifar, et al. [23]. The sample size was calculated using the 25 26 following parameters: Two-sided 95% significance level (1 – ); 80% power (1 – ); 27 28 Unexposed/ exposed ratio of 1; 5% of unexposed with outcome (case fatality rate from 29 30 31 COVID19-PH [24] as of 8 April 2020); Assumed risk ratio 2 (to see a two-fold increase in risk 32

33 of mortality when neurologic symptoms are present). http://bmjopen.bmj.com/ 34 35 36 When these values were plugged-in to the formula for cohort studies [25], a minimum sample 37 38 size of 1,118 is required. To account for possible incomplete data, the sample was adjusted for 39 40

41 20% more. This means that the total sample size required is 1,342 patients which will be on September 26, 2021 by guest. Protected copyright. 42 43 gathered from the participating centers. 44 45 46 Data collection 47 48 TM 49 We formulated an electronic data collection form using Epi Info Software (Version 7.2.2.16). 50 51 The forms will be pilot-tested and a formal data collection workshop will be conducted to ensure 52 53 collection accuracy. The data will be obtained from the review of the medical records. 54 55 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 The following pertinent data will be obtained: (a) demographic data and other clinical profile 4 5 6 data (b) comorbidities; (c) past neurological history; (d) date of illness onset; (e) respiratory and 7 8 constitutional symptoms associated with COVID-19; (f) COVID-19 disease severity [26] at 9 10 nadir; (g) data if neurological manifestation/s were present at onset prior to respiratory symptoms 11 12 and the specific neurological manifestation/s present at onset; (h) neurological symptoms; (i) 13 14 15 date of neurological symptom onset; (j) new-onset neurological disorders or complications; (k) 16 For peer review only 17 date of new neurological disorder or complication onset; (l) imaging done; (m) cerebrospinal 18 19 (CSF) fluid analysis; (n) electrophysiologic studies; (o) treatment given; (p) antibiotics given; (q) 20 21 22 neurological interventions given; (r) date of mortality, cause/s of mortality; (s) date of respiratory 23 24 failure onset, date of mechanical ventilator cessation, cause/s of respiratory failure; (t) date of 25 26 first day of ICU admission, date of discharge from ICU, indication/s for ICU admission; (u) 27 28 29 other neurological outcomes at discharge; (v) date of hospital discharge; (w) final disposition. 30 31 See Table 1 for the summary of the data to be collected for this study. 32

41 died. on September 26, 2021 by guest. Protected copyright. 42 43  Respiratory failure (binary outcome) – defined as the patients with confirmed COVID-19 44 45 46 who experienced clinical symptoms and signs of respiratory insufficiency. Clinically, this 47 48 condition may manifest as tachypnea/sign of increased work of breathing (i.e., respiratory 49 50 rate of ≥ 22), abnormal blood gases (i.e., hypoxemia as evidenced by partial pressure of 51 52 53 oxygen (PaO2) < 60 or hypercapnia by partial pressure of carbon dioxide (PaCO2) of 54 55 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

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26 Cerebrospinal (CSF) fluid CSF total cell count, CSF neutrophil count, CSF lymphocyte count, CSF protein, CSF glucose, serum glucose, on September 26, 2021 by guest. Protected copyright. CSF COVID-19 test result, other 27 analysis CSF tests done 28 Electrophysiologic studies Electroencephalography (EEG), and electromyography-nerve conduction studies (EMG-NCS) tests, if done, and pertinent results 29 Treatment given Chloroquine, hydroxychloroquine, lopinavir + ritonavir, tocilizumab, remdesivir, systemic glucocorticoids, convalescent plasma, and others; 30 Antibiotics given 31 Neurological interventions E.g., Antiplatelet, anticoagulant, antiepileptic drugs, and others 32 Mortality Date of mortality, cause/s of mortality 33 Respiratory failure Date of respiratory failure onset, date of mechanical ventilator cessation, cause/s of respiratory failure 34 ICU admission Date of first day of ICU admission, date of discharge from ICU, indication/s for ICU admission 35 Other neurological Full neurological recovery – defined as patients with confirmed COVID-19 infection who had any neurological deficit during admission, who 36 outcomes at discharge then had full neurological recovery with no noted neurological deficits at discharge; stable with improvement of neurological deficits – defined as 37 patients with COVID-19 infection who had any neurological deficit during admission, who then had improvement but not complete resolution of 38 the neurological deficits at discharge; stable with no improvement of neurological deficits – defined as the patients with COVID-19 infection who 39 had any neurological deficit during admission, who then had no improvement of the neurological deficits at discharge 40 Final disposition Discharged stable/recovered, home against medical advice, transferred to other hospital, died/mortality); date of hospital discharge 41 42 43 9 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 12 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 > 45), or requiring oxygen supplementation (i.e., PaO2 < 60 or ratio of PaO2/fraction of 4 5 6 inspired oxygen (FiO2) [P/F ratio]) < 300); 7 8  Duration of ventilator dependence (continuous outcome) – defined as the number of days 9 10 from initiation of assisted ventilation to cessation of mechanical ventilator use; 11 12 13  Intensive care unit (ICU) admission (binary outcome) - defined as the patients with 14 15 confirmed COVID-19 admitted to an ICU or ICU-comparable setting; 16 For peer review only 17  Length of ICU stay (continuous outcome) – defined as the number of days admitted in 18 19 20 the ICU or ICU-comparable setting; 21 22  Length of hospital stay (continuous outcome) – defined as the number of days from 23 24 admission to discharge. 25 26 27 28 Data analysis plan 29  30 Statistical analysis will be performed using Stata , Version 7.2.2.16 (College Station, TX: 31 32 StataCorp LP).

33 http://bmjopen.bmj.com/ 34 35 Demographic, clinical and neurological profiles will be summarized using descriptive statistics, 36 37 38 in which categorical variables will be expressed as frequencies with corresponding percentages, 39 40 and continuous variables will be pooled using means (standard deviation).

41 on September 26, 2021 by guest. Protected copyright. 42 43 Student’s t-test for two independent samples and chi-squared test will be used to determine 44 45 46 differences between distributions. 47 48 49 Hazard ratios (HR) and 95% confidence interval will be used as an outcome measure. Kaplan- 50 51 Meier curves will be constructed to plot the time to onset of mortality (survival), respiratory 52 53 54 failure, ICU admission, duration of ventilator dependence (recategorized binary form), length of 55 56 ICU stay (recategorized binary form), length of hospital stay (recategorized binary form). Log- 57 58 59 10 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 rank test will be employed to compare the Kaplan-Meier curves. Stratified analysis will be 4 5 6 performed to identify confounders and effects modifiers. To compute for adjusted HR with 95% 7 8 CI, crude HR of outcomes at discrete time points will be adjusted for prespecified possible 9 10 confounders such as age, history of cardiovascular or cerebrovascular disease, hypertension, 11 12 diabetes mellitus, and respiratory disease, COVID-19 disease severity at nadir, and other 13 14 15 significant confounding factors. 16 For peer review only 17 18 Cox-proportional regression models will be used to determine significant factors of outcomes. 19 20 Testing for goodness-of-fit will be done using Hosmer-Lemeshow test. Likelihood ratio tests and 21 22 23 other information criteria (Akaike Information Criterion or Bayesian Information Criterion) will 24 25 be used to refine the final model. Statistical significance will be considered if the 95% 26 27 confidence interval of HR or adjusted HR did not include the number one. A p value < 0.05 28 29 30 (two-tailed) is set for other analyses. 31 32

33 Subgroup analyses will be performed for proven prespecified effect modifiers. The following http://bmjopen.bmj.com/ 34 35 variables will be considered for subgroup analyses: age (19 to 64 years vs ≥ 65 years), sex, 36 37 2 38 body-mass index (<18.5 vs 18.5 to 22.9 vs ≥ 23 kg/m ), with past history of cardiovascular or 39 40 cerebrovascular disease (presence or absence), hypertension (presence or absence), diabetes

41 on September 26, 2021 by guest. Protected copyright. 42 mellitus (presence or absence), respiratory disease (presence or absence), smoking status 43 44 (smoker or nonsmoker), and COVID-19 disease severity (mild, severe or critical disease). 45 46 47 48 The effects of missing data will be explored. All efforts will be exerted to minimize missing and 49 50 spurious data. Validity of the submitted electronic data collection will be monitored and 51 52 reviewed weekly to prevent missing or inaccurate input of data. Multiple imputations will be 53 54 55 56 57 58 59 11 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 performed for missing data, when possible. To check for robustness of results, analysis done for 4 5 6 patients with complete data will be compared to the analysis with the imputed data. 7 8 9 The effects of outliers will also be assessed. Outliers will be assessed by z-score or boxplot. A 10 11 cut-off of 3 standard deviations from the mean can also be used. To check for robustness of 12 13 results, analysis done with outliers will be compared to the analysis without the outliers. 14 15 16 For peer review only 17 Study organizational structure 18 19 A steering committee (AIE, MCS, VMA, and RDJ) was formed to direct and provide appropriate 20 21 scientific, technical, and methodological assistance to study site investigators and collaborators 22 23 24 (see Fig 3). Central administrative coordination, data management, administrative support, 25 26 documentation of progress reports, data analyses and interpretation, and journal publication are 27 28 the main responsibilities of the steering committee. Study site investigators and collaborators are 29 30 responsible for the proper collection and recording of data including the duty to maintain the 31 32 confidentiality of information and the privacy of all identified patients for all the phases of the 33 http://bmjopen.bmj.com/ 34 35 research processes. 36 37 38 This section is highlighted as part of the required formatting amendments by the Journal. 39 40

41 on September 26, 2021 by guest. Protected copyright. 42 Ethics and dissemination 43 44 This research will adhere to the Philippine National Ethical Guidelines for Health and Health- 45 46 related Research (NEGHHRR) 2017 [27]. This study is an observational, cohort study and will 47 48 49 not allocate any type of intervention. The medical records of the identified patients will be 50 51 reviewed retrospectively. To protect the privacy of the participant, the data collection forms will 52 53 not contain any information (i.e., names, institutional patient number) that could determine the 54 55 identity of the patients. A sequential code will be recorded for each patient in the following 56 57 58 59 12 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 format: AAA-BBB where AAA will pertain to the three-digit code randomly assigned to each 4 5 6 study site; BBB will pertain to the sequential case number assigned by each study site. Each 7 8 participating center will designate a password-protected laptop for data collection; the password 9 10 is known only to the study site. 11 12 13 This protocol was approved by the following institutional review boards: Single Joint Research 14 15 16 Ethics Board of the ForDOH, Philippines peer (SJREB-2020-24); review Asian only Hospital and Medical Center 17 18 (AHMC), Muntinlupa City (2020-010-A); Baguio General Hospital and Medical Center 19 20 (BGHMC), Baguio City (BGHMC-ERC-2020-13); Capitol Medical Center (CMC), Quezon 21 22 23 City; Cardinal Santos Medical Center (CSMC), San Juan City (CSMC REC 2020-020); Chong 24 25 Hua Hospital (CHH), Cebu City (IRB 2420-04); East Avenue Medical Center (EAMC), Quezon 26 27 City (EAMC IERB 2020-38); Jose R. Reyes Memorial Medical Center (JRRMMC), Manila; 28 29 30 Jose B. Lingad Memorial Regional Hospital, San Fernando, Pampanga; Dr. Jose N. Rodriguez 31 32 Memorial Hospital (Tala Leprosarium), Caloocan City; Lung Center of the Philippines (LCP),

33 http://bmjopen.bmj.com/ 34 Quezon City (LCP-CT-010-2020); Manila Doctors Hospital, Manila City (MDH IRB 2020-006); 35 36 Makati Medical Center, Makati City (MMC IRB 2020-054); Manila Medical Center 37 38 39 (ManilaMed), Manila (MMERC 2020-09); Northern Mindanao Medical Center, Cagayan de Oro 40

41 City (025-2020); Quirino Memorial Medical Center (QMMC), Quezon City (QMMC REB GCS on September 26, 2021 by guest. Protected copyright. 42 43 2020-28); Ospital ng Makati (OsMak), Makati City; Philippine General Hospital, Manila; 44 45 46 Philippine Heart Center (PHC), Quezon City; Research Institute for Tropical Medicine, 47 48 Muntinlupa City (RITM IRB 2020-16); San Lazaro Hospital, Manila; San Juan De Dios 49 50 Educational Foundation Inc. (SJDEFI) – Hospital, Pasay City (SJRIB 2020-0006); Southern 51 52 53 Isabela Medical Center (SIMC), Santiago City (2020-03); St. Luke’s Medical Center, Quezon 54 55 City (SL-20116); St. Luke’s Medical Center, Bonifacio Global City (SLMC-GC), Taguig City 56 57 58 59 13 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 (SL-20116); Southern Philippines Medical Center (SPMC), Davao City; The Medical City 4 5 6 (TMC), Pasig City; University of Santo Tomas Hospital, Manila City (UST-REC-2020-04-071- 7 8 MD); University of the East Ramon Magsaysay Memorial Medical Center (UERMMMC), Inc., 9 10 Quezon City (0835/E/2020/063) and Vicente Sotto Memorial Medical Center, Cebu City 11 12 (VSMMC-REC-O-2020-048). 13 14 15 16 The dissemination ofFor results willpeer be conducted review through scientific/ only medical conferences and 17 18 through journal publication. Only the aggregate results of the study shall be disseminated. The 19 20 lay versions of the results may be provided upon request. 21 22 23 24 Protocol registration and technical review approval 25 26 This protocol was registered in the ClinicalTrials.gov website (Identifier: NCT04386083). It has 27 28 received technical review board approvals from the Department of Neurosciences, Philippine 29 30 General Hospital and College of Medicine, University of the Philippines Manila, from the 31 32 Cardinal Santos Medical Center (San Juan City) and from the Research Center for Clinical 33 http://bmjopen.bmj.com/ 34 35 Epidemiology and Biostatistics, De La Salle Medical and Health Sciences Institute (Dasmariñas, 36 37 Cavite). 38 39 40 Funding sources 41 on September 26, 2021 by guest. Protected copyright. 42 43  Philippine Neurological Association (PNA) (Grant/Award Number: N/A). 44 45  Expanded Hospital Research Office (EHRO), Philippine General Hospital (PGH) 46 47 48 (Grant/Award Number: N/A). 49 50 51 52 53 54 55 56 57 58 59 14 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 Role of funding sources 4 5 6 Our funding sources had no role in the design of the protocol, and will not be involved during the 7 8 methodological execution, data analyses and interpretation, and decision to submit or to publish 9 10 the study results. 11 12 13 Authors’ contribution 14 15 16 AIE, MCS, VMA, andFor RDJ conceivedpeer the review idea and wrote theonly initial drafts and revisions of the 17 18 protocol. All authors made substantial contributions in this protocol for intellectual content. 19 20 21 Conflict of interest 22 23 24 The authors declare no conflict of interest. 25 26 27 Acknowledgment 28 29 We would like to thank Almira Abigail Doreen O. Apor, MD of the Department of 30 31 Neurosciences, Philippine General Hospital, Philippines for illustrating Fig 2 for this publication. 32

33 http://bmjopen.bmj.com/ 34 35 Patient and public involvement 36 37 Patients or the public were not involved in the design, or conduct, or reporting, or dissemination 38 39 plans of our research. 40

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 15 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

33 http://bmjopen.bmj.com/ 34 partially responsible for the respiratory failure of COVID‐19 patients. J Med Virol 35 36 37 2020;92:552–5. doi:10.1002/jmv.25728 38 39 6 Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with 40

41 coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;:e201127. on September 26, 2021 by guest. Protected copyright. 42 43 44 doi:10.1001/jamaneurol.2020.1127 45 46 7 Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 47 48 neurology: Clinical, radiological and laboratory findings. Brain Published Online First: 8 49 50 51 July 2020. doi:10.1093/brain/awaa240 52 53 8 Pinna P, Grewal P, Hall JP, et al. Neurological manifestations and COVID-19: 54 55 Experiences from a tertiary care center at the frontline. J Neurol Sci 2020;415:116969. 56 57 58 59 16 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 doi:10.1016/j.jns.2020.116969 4 5 6 9 Varatharaj A, Thomas N, Ellul MA, et al. Neurological and neuropsychiatric 7 8 complications of COVID-19 in 153 patients: A UK-wide surveillance study. The Lancet 9 10 Psychiatry Published Online First: June 2020. doi:10.1016/S2215-0366(20)30287-X 11 12 10 Mahammedi A, Saba L, Vagal A, et al. Imaging in neurological disease of hospitalized 13 14 15 COVID-19 patients: An Italian multicenter retrospective observational study. Radiology 16 For peer review only 17 2020;:201933. doi:10.1148/radiol.2020201933 18 19 11 Collantes ME, Espiritu A, Sy MC, et al. Neurological manifestations in COVID-19 20 21 22 infection: A systematic review and meta-analysis. Can J Neurol Sci / J Can des Sci Neurol 23 24 2020;:1–26. doi:10.1017/cjn.2020.146 25 26 12 Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. 27 28 29 N Engl J Med 2020;:NEJMc2008597. doi:10.1056/NEJMc2008597 30 31 13 Karimi N, Sharifi Razavi A, Rouhani N. Frequent convulsive seizures in an adult patient 32

33 with COVID-19: A case report. Iran Red Crescent Med J 2020;22. http://bmjopen.bmj.com/ 34 35 doi:10.5812/ircmj.102828 36 37 38 14 Poyiadji N, Shahin G, Noujaim D, et al. COVID-19–associated acute hemorrhagic 39 40 necrotizing encephalopathy: CT and MRI features. Radiology 2020;:201187.

41 on September 26, 2021 by guest. Protected copyright. 42 doi:10.1148/radiol.2020201187 43 44 45 15 Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 46 47 infection: Causality or coincidence? Lancet Neurol Published Online First: April 2020. 48 49 doi:10.1016/S1474-4422(20)30109-5 50 51 52 16 Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with 53 54 SARS-Coronavirus-2. Int J Infect Dis Published Online First: April 2020. 55 56 57 58 59 17 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 24 BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 doi:10.1016/j.ijid.2020.03.062 4 5 6 17 Collantes ME V., Espiritu AI, Sy MCC, et al. Neurological manifestations in COVID-19 7 8 infection: A systematic review and meta-analysis. Can J Neurol Sci / J Can des Sci Neurol 9 10 2020;:1–26. doi:10.1017/cjn.2020.146 11 12 18 Ellul M, Varatharaj A, Nicholson TR, et al. Defining causality in COVID-19 and 13 14 15 neurological disorders. J Neurol Neurosurg Psychiatry 2020;91:811–2. doi:10.1136/jnnp- 16 For peer review only 17 2020-323667 18 19 19 Ferrarese C, Silani V, Priori A, et al. An Italian multicenter retrospective-prospective 20 21 22 observational study on neurological manifestations of COVID-19 (NEUROCOVID). 23 24 Neurol Sci 2020;41:1355–9. doi:10.1007/s10072-020-04450-1 25 26 20 von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational 27 28 29 Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational 30 31 studies. J Clin Epidemiol 2008;61:344–9. doi:10.1016/j.jclinepi.2007.11.008 32

33 21 Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel http://bmjopen.bmj.com/ 34 35 coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565–74. 36 37 38 doi:10.1016/S0140-6736(20)30251-8 39 40 22 Centers for Disease Control and Prevention. Evaluating and testing persons for

41 on September 26, 2021 by guest. Protected copyright. 42 coronavirus disease 2019 (COVID-19). 2020.https://www.cdc.gov/coronavirus/2019- 43 44 45 nCoV/hcp/clinical-criteria.html (accessed 7 Apr 2020). 46 47 23 Khaledifar A, Hashemzadeh M, Solati K, et al. The protocol of a population-based 48 49 prospective cohort study in southwest of Iran to analyze common non-communicable 50 51 52 diseases: Shahrekord cohort study. BMC Public Health 2018;18:660. doi:10.1186/s12889- 53 54 018-5364-2 55 56 57 58 59 18 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 24 Haw J, Uy J. COVID-19 cases and deaths in the Philippines dashboard. 4 5 6 2020.https://public.tableau.com/profile/jason.haw#!/vizhome/COVID- 7 8 19CasesandDeathsinthePhilippines/Dashboard?publish=yes (accessed 8 Apr 2020). 9 10 25 Fleiss JL. Statistical methods for rates and proportions. 1st Ed. London: : John Wiley & 11 12 Sons 1981. 13 14 15 26 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus 16 For peer review only 17 disease 2019 (COVID-19) outbreak in China. JAMA Published Online First: 24 February 18 19 2020. doi:10.1001/jama.2020.2648 20 21 22 27 Philippine Research Ethics Board. National ethical guidelines for health and health- 23 24 related research. Taguig City: : Philippine Council for Health Research and Development 25 26 Department of Science and Technology 2017. 27 28 29 30 31 32

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1 2 3 FIGURE CAPTIONS 4 5 6 7 8 Fig 1. Schematic diagram of the study flow. 9 10 Fig 2. Location of 37 study sites of the Philippine CORONA Study. 11 12 Fig 3. Organizational structure of oversight of the Philippine CORONA Study 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 20 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 Fig 1. Schematic diagram of the study flow. 24 25 1015x520mm (72 x 72 DPI) 26 27 28 29 30 31 32

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Fig 2. Location of 37 study sites of the Philippine CORONA Study 32 1411x1058mm (72 x 72 DPI)

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-040944 on 30 November 2020. Downloaded from

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41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml