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Clinical evolution, management and outcomes of patients with COVID-19 admitted at Tygerberg Hospital, Cape Town, South Africa: a research protocol

Introduction The outbreak of the SARS-CoV-2 virus causing COVID-19, declared a global pandemic by the WHO, is a novel infection with a high rate of morbidity and mortality. In South Africa, 55 421 cases have been confirmed as of 10 June 2020, with most cases in the Western Cape Province. Coronavirus leaves us in a position of uncertainty regarding the best clinical approach to successfully manage the expected high number of severely ill patients with COVID-19. This presents a unique opportunity to gather data to inform best practices in clinical approach and public health interventions to control COVID-19 locally. Furthermore, this pandemic challenges our resolve due to the high burden of HIV and tuberculosis (TB) in our country as data are scarce. This study endeavours to determine the clinical presentation, severity and prognosis of patients with COVID-19 admitted to our hospital. Methods and analysis The study will use multiple approaches taking into account the evolving nature of the COVID-19 pandemic. Prospective observational design to describe specific patterns of risk predictors of poor outcomes among patients with severe COVID-19 admitted to Tygerberg Hospital. Data will be collected from medical records of patients with severe COVID-19 admitted at Tygerberg Hospital. Using the Cox proportional hazards model, we will investigate the association between the survival time of patients with COVID-19 in relation to one or more of the predictor variables including HIV and TB. Ethics and dissemination The research team obtained ethical approval from the Health Research Ethics Committee of the Faculty of Medicine and Health Sciences, Stellenbosch University and Research Committee of the Tygerberg Hospital. All procedures for the ethical conduct of scientific investigation will be adhered to by the research team. The findings will be disseminated in clinical seminars, scientific forums and conferences targeting clinical care providers and policy-makers.

expressed widely in the previous point. Background 1) Lines 40-43. It could be interesting for the readers to know the current incidence of cases in the country and some information about the adopted public health strategies for their identification. Data collection and management 1) The investigators should define a period of study, indicating the date of the beginning of data collection and the expected date of its end. Radiological examinations 1) It is not clear if the mentioned examinations will be part of the standard care or diagnostic interventions of the study. The investigators should state clearly if they will collect data from radiological reports, as seem appropriate for an observational study, or if examinations will be requested because of patients' inclusion in the study. Conclusions 1) Investigators should mention the potential role of their result as hypothesis-generating for further studies and more cautiously mention the potential effects on public health intervention, considering the design of the study.

REVIEWER
Professor Nirmal Kumar WWL NHS FT REVIEW RETURNED 26-Apr-2020

GENERAL COMMENTS
The research protocol is well founded and the variables assessed including age, associated conditions such as HIV and TB as also other socio-economic factors will be a valuable adjunct to the knowledge base on this pandemic. It is particularly relevant in developing countries where the risks posed compared to health care resources available will be very important to mitigate against. A statistical review will be advised as the analysis used must be the most appropriate due to multiple variables and confounding factors

GENERAL COMMENTS
This protocol describe a prospective study which aim is to determine factors that could influence the outcome of patients admitted with a diagnosis of COVID-19 to an hospital based in the Eastern Metropole in South Africa. I think this study could contribute to the emerging evidence on clinical outcome of COVID-19. In particular could contribute to build evidence in South Africa characterised by a specific demographic and socio-economic context, but it is important that the evidence will be based on a well-planned, well-conducted study. My review is mainly focused on the epidemiologic designs and statistical analysis sections. I have some major concern on this study protocol 1. I can see this study as a prospective study which main aim is to determine factors that could influence the outcome of patients admitted with a diagnosis of COVID-19. This is clearly stated in the last sentence in the abstract introduction. I think the authors should make an attempt to simplify the protocol in order to reach their aim.
In particular the long list of specific outcomes in table 1 poses questions on the rational and feasibility of this study. In particular, my suggestion is to define 4 main objectives: 3. Variable measurement section a. Some of these measures will be measured at (or just after) admission and can be used for objectives 1 and 2 listed above. Other measurements will be taken during the hospitalisation (e.g. treatments, laboratory) and can be used for objectives 3 and 4. It would be good to have a description that identify baseline and repeated measurements. There is no mention of exams (and their frequency) to evaluate effect on individual organ systems (e.g. cardiovascular, renal, and neurological). 4. Statistical analysis: a. The definition of the primary and secondary outcomes (page 15 lines 23-32) is not very clear. My understanding is that the primary outcome will be in-hospital mortality (I would remove the classification good/poor). The time to event classification is event (death) or censored (alive at discharge). It is not clear how the disease progression outcome is defined; is it (severe/critical/death)? Will be measured during the hospitalisation? The sentence on lines 30-32 is not clear. b. I think that factors to be included in the multivariate regression model should be chosen based on a causal pathway instead of a statistical automatic process. c. As the outcome is binary the regression model should be the logistic regression model. d. There is no mention on how the disease progression outcome will be used in this analysis. e. The methods described in the statistical sections apply for Objectives 1 and 2 which study design can be viewed as prospective cohort designs. There is no mention in the statistical analysis section on how the longitudinal measures and outcomes describing the impact individual organ systems will be described and analysed.

Strengths and limitations of this study
Comments: 1) Lines 7-10. This first sentence is not completely clear. I suggest rephrasing it. I suppose the authors' aim was to highlight that the study could provide data about a population with different characteristics from those already described in literature, e.g. age. If no previous similar studies have been published, this could be stated here.
Response: Line 80-84, this statement has been corrected to make it clearer to the reader. "Our study will provide data about a population with different characteristics from those already described in literature for example age as no previous similar studies have been published" Comment: 2) Lines 10-15. It could be interesting to report here data on the prevalence of HIV and TB in the country.
Response: Line 85-89, we have provided data for prevalence of HIV and incidence rate of TB in South Africa

Comment: 3)
Lines 17-24. I suggest the authors to explicitly describe every condition they refer to, without giving it for already known by the readers. A solution can be providing some data about the socio-economical and demographic condition of the population.
Response: Line 89-94, we have addresses this to make it clearer we are interested in looking at the effect social economic and demographic factors have on COVID-19. In Cape Town, higher proportion of cases come from areas that are historically disadvantaged such as Khayelitsha.

Comment: 4)
Lines 35-37. The phrase 'and much of the population serviced by the hospital is from low-income areas' could result repetitive here if expressed widely in the previous point.
Response: Line 97-101, the statement has been modified to remove the element of repetition.

Comment: 1)
Lines 40-43. It could be interesting for the readers to know the current incidence of cases in the country and some information about the adopted public health strategies for their identification.

Data collection and management Comment: 1)
The investigators should define a period of study, indicating the date of the beginning of data collection and the expected date of its end.

Radiological examinations Comment: 1)
It is not clear if the mentioned examinations will be part of the standard care or diagnostic interventions of the study. The investigators should state clearly if they will collect data from radiological reports, as seem appropriate for an observational study, or if examinations will be requested because of patients' inclusion in the study.
Response: This has been clarified. We added a statement on line 290-292, to clarify that data will be collected from Radiographic/ultrasound reports of examination requested as part of standard clinical care.

Comment: 1)
Investigators should mention the potential role of their result as hypothesisgenerating for further studies and more cautiously mention the potential effects on public health intervention, considering the design of the study.
Response: According to advice given above, information for authors' protocol does not need to contain conclusion section. Therefore, the conclusion has been deleted off the manuscript. We have however added this statement under 'Rationale of the Study' line 190-193.

Reviewer: 2
Reviewer Name: Professor Nirmal Kumar Institution and Country: WWL NHS FT Please state any competing interests or state 'None declared': None declared Please leave your comments for the authors below General Comment: The research protocol is well founded and the variables assessed including age, associated conditions such as HIV and TB as also other socio-economic factors will be a valuable adjunct to the knowledge base on this pandemic. It is particularly relevant in developing countries where the risks posed compared to health care resources available will be very important to mitigate against. A statistical review will be advised as the analysis used must be the most appropriate due to multiple variables and confounding factors Response: Thanks for the positive comments. Looking at the number of variables and potential founding challenges we might encounter, we will assess for all variables that could lead to strenuous relationship including assessing for effect modification so that we arrive at factors that independently predicts outcome or diseases severity.

Reviewer: 3
Reviewer Name: Francesco Sera Institution and Country: London School of Hygiene and Tropical Medicine Please state any competing interests or state 'None declared': None declared. Please leave your comments for the authors below General Comment: This protocol describe a prospective study which aim is to determine factors that could influence the outcome of patients admitted with a diagnosis of COVID-19 to an hospital based in the Eastern Metropole in South Africa. I think this study could contribute to the emerging evidence on clinical outcome of COVID-19. In particular could contribute to build evidence in South Africa characterised by a specific demographic and socio-economic context, but it is important that the evidence will be based on a well-planned, well-conducted study. My review is mainly focused on the epidemiologic designs and statistical analysis sections. I have some major concern on this study protocol Specific Comments Comment: 1.
I can see this study as a prospective study which main aim is to determine factors that could influence the outcome of patients admitted with a diagnosis of COVID-19. This is clearly stated in the last sentence in the abstract introduction. I think the authors should make an attempt to simplify the protocol in order to reach their aim. In particular the long list of specific outcomes in table 1 poses questions on the rational and feasibility of this study. In particular, my suggestion is to define 4 main objectives: a.
Objective 1. Identify baseline factors associated with the outcome of the diseases (e.g HIV loads and immunological markers, Chronic Kidney Disease (CKD), TB, rheumatic conditions, comorbidities). b.
Objective 2. Develop a risk score to predict the outcome based on baseline factors. c.
Objective 3. Assess supportive and directed therapeutic interventions d.
Objective 4. Assess the effect of COVID-19 on individual organ systems These 4 specific objectives have a specific study design, measurement setting and statistical methods.

Response: Thanks for the clear suggestion. Line 200-209, the objectives have been rephrased and now only focus at the four as suggested. This greatly simplifies the proposal.
Comment: In my opinion I would consider healthcare workers as a stratum of the patient enrolled in this study. It is not clear how the efficacy and measurement of preventive or post-exposure measures will be assessed in this study, as there is no mention in the method and measurement sections. Moreover, it's not clear how long-term effects of COVID-19 will be measured and assessed. I suggest to remove these objective.
Response: Thanks for the guidance. We fully understand and agree with the opinion. This objective has been removed.

Study design section:
Comment: 2 a.
it's not clear what the mathematical modelling would add to this project. In any case is not a study design and I would put this activity in the statistical methods sections.
Response: Thanks for the observation, the mathematical modelling approach has been removed.

Comment 2 b.
it's not clear how case-control design could be used in this study. What are exposures mentioned on page 14 line 31?
Response: Thanks for this observation. The case control design has been removed from this proposal. Line 288, page 16 these are samples that will be collected from suspected individuals for diagnostic purposes.

Comment 3.
Variable measurement section a.
Some of these measures will be measured at (or just after) admission and can be used for objectives 1 and 2 listed above. Other measurements will be taken during the hospitalisation (e.g. treatments, laboratory) and can be used for objectives 3 and 4. It would be good to have a description that identify baseline and repeated measurements. There is no mention of examinations (and their frequency) to evaluate effect on individual organ systems (e.g. cardiovascular, renal, and neurological).
Response: Thanks for the suggestion. This is very useful, and we have addressed this in Line 270-275 after table 1. We have described baseline assessment and what it entails as well as repeated assessment to monitor organ function during admission.

Comment: 4.
Statistical analysis: a. The definition of the primary and secondary outcomes (page 15 lines 23-32) is not very clear. My understanding is that the primary outcome will be in-hospital mortality (I would remove the classification good/poor). The time to event classification is event (death) or censored (alive at discharge). It is not clear how the disease progression outcome is defined; is it (severe/critical/death)? Will be measured during the hospitalisation? The sentence on lines 30-32 is not clear.
Response: Thanks for these observations. We agree with your observation, the 'primary outcome is in-hospital mortality; and time to event classification (death) or censored (alive at discharge) has been modified. Progression of disease while hospitalised will be defined as severe to critical/death. This has been clarified, lines 319 to 323. The sentence on line323-324.
I think that factors to be included in the multivariate regression model should be chosen based on a causal pathway instead of a statistical automatic process.
Response: Thanks. This has been modified and stepwise regression approach has been deleted. Line 338-341 we have added this statement "Causal diagrams will be used to select variables to be included in the multivariable logistic regression models. Factors showing a significant association with the outcome defined at a conservative 10% significance level will be selected for inclusion in the multivariable logistic regression model" Comment: c.
As the outcome is binary the regression model should be the logistic regression model. Response: Thanks, this has been clarified in lines 335 and 336.

Comment: d.
There is no mention on how the disease progression outcome will be used in this analysis. Response: Thanks for this observation. We have described in Lines 330-332 how diseases outcome will be used in this analysis.
The methods described in the statistical sections apply for Objectives 1 and 2 which study design can be viewed as prospective cohort designs. There is no mention in the statistical analysis section on how the longitudinal measures and outcomes describing the impact individual organ systems will be described and analysed.
Response: Thanks for the comments and suggestions. We have described on line 344-347 on how the longitudinal measures and outcomes describing the impact individual organ systems will be described and analysed.

REVIEWER
Andrea Cortegiani University of Palermo, Italy REVIEW RETURNED 13-Jul-2020

GENERAL COMMENTS
No further comments.

Francesco Sera
London School of hygiene & Tropical Medicine, London, UK REVIEW RETURNED 28-Jul-2020

GENERAL COMMENTS
I think the authors made a good effort on reply to mycomments. The manuscript has improved with cleared objectives and more appropriate description of the study design and analytical methods. I have no further comments or suggestions.