PONE-D-21-00016

Predictors of severity and development of critical illness in Egyptian COVID-19 patients: A multicenter study

PLOS ONE

Dear Dr. Omran,

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Andreas Zirlik, MD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The retrospective and multicenter analysis by Omran et al. summs up the total number of hospitalized patients in the GOTHI affiliated hospitals with positive COVID-19 PCR from March to July 2020.

Out of 2724 patients 423 were rated critically ill.

Several factors could be identified which predicted worse outcome (to be rated critically ill).

This is a large study with little selection bias as all COVID-19 patients of the hospitals analysed were included. PCR as the gold standard to detect SARS-CoV2 was used. The study was approved by the respective ethics committee. The data confirms many aspects already described in other populations within an egypt population. Some factors seem to diverge (such as lacking increased risk in male patients) and are discussed accordingly.

There are some aspects to be clarified or discussed in more detail:

1.) Please state how many COVID-19 tests were performed in the population analyzed and what the positive-rate of these tests was.

2.) Have there been specific algorithms to trigger testing and was PCR the only test? Or did PCR confirm antigen tests for example? Did all positively tested patients show COVID-related symptoms or does the study also include "chance findings" in asymptomatic patients tested for other reasons (potential contact person...) How many patients were rated ill or critically ill due to COVID-19 and how many due to other diseases?

3.) What was the rationale for selecting the analysed time frame from March to July?

4.) The authors state a fatality rate of 5.8 for egypt (citation). How was the rate in these hospitalized patients?

5.) With respect to comorbidities some numbers seem to be unusual. There are only 9 COPD Patients in the whole cohort despite more than 10% smokers. And only 1 out of 2301 patients in the non-critical group was diagnosed with arrhythmias. Which arrhythmias were analysed as atrial fibrillation is obviously not included. I suggest to only display clinical characteristics for comorbidities with reliable data (which of course cannot always be available in retrospective analysis)

6.) FiO2 is stated to be 20.71+-28.08 in the non critical group. Assuming 21% oxygen within natural air, this seems to be to low as some patients obviously received oxygen. How was oxygen calculated into FiO2 if most patients were not on respirators?

7.) Regarding the unchanged risk between the two genders; is it possible that other risk factors might be differing, too. Are, for instance, female patients older in this cohort?

Reviewer #2: The manuscript entitled "Predictors of severity and development of critical illness in Egyptian COVID-19 patients: A multicenter study" by Omran et al. gives an overview on the factors leading to a severe illness during the "first wave" of the COVID19 pandemic. The conclusion of the authors is that higher age (> 60 years), preexisting comorbidities, more symptoms presenting at baseline (I assume the data are baseline data), and unfavorable vital signs (high heart rate, low oxygen saturation) are associated with a more severe COVID19 illness.

The manuscript is well written and most data used in their statistical analysis are given. Although the results are not surprising, regional analysis of the COVID19 disease is of interest.

However, there are some points that need to be discussed and further described.

Major points:

1) Additional information regarding the Ethics approval is missing (registration number or something comparable).

2) Timing of the data collection (I assume these are baseline data)

3) Have all data been collected? How did the authors manage missing data (“unknown” counted as “no”; insert the number of laboratory samples that could be analyzed). This needs to be addressed and data must be given in a this transparent way

4) No gender-specific differentiation in laboratory findings has been made, this is of particular importance for the liver enzymes that are associated with a more severe illness.

5) Lack of medical history at baseline (at least substance classes like ACE-inhibitors, statins, oral antidiabetic drugs etc.) -> this should also be statistically analyzed. Although hypertension predicted a more severe illness, the blood pressure was comparable in the "critical" and "non-critical" group. Of note, ACE-inhibitors are currently discussed to influence the severity of COVID19.

6) BMI (or height & weight) are missing as demographic variables (see as reference Simonnet et al., Obesity 2020 PMID 32271993)

7) The duration of symptoms is not given (symptom onset untill positive RT-PCR)

8) No information is given on fatal outcomes. It would be reasonable to calculate the prediction value of different biomarkers and variables for a more severe illness for fatal outcome too. This would help to classify the clinical impact of the results described in the manuscript

Minor points:

- Just some minor spelling mistakes

- Consider the definition of potentially unclear preexisting comorbidities (for example in a supplementary file). How was hypertension defined? How was heart failure defined? Cut-off for chronic renal insufficiency? What was the definition for dyslipidemia? What was the cut-off value for fever (maybe split this in fever > 38.5°C and "subfebrile temperature 37 - 38.5°C"?

My summary:

It is an interesting data set. However, given its retrospective nature, a more detailled analysis must be performed before any conclusion can be drawn.

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Reviewer #1: No

Reviewer #2: No

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Predictors of severity and development of critical illness in Egyptian COVID-19 patients: A multicenter study

PONE-D-21-00016R1

Dear Dr. Omran,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Andreas Zirlik, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors improved the manuscript by adding information regarding transparency and data availability. Unfortunately, most major points of my previous review could not be addressed in an adequate way (mostly due to lack of data, see comments 5 – 7 of the previous review). These facts are now being discussed in the manuscript. Despite noting in their response that comorbidities have been defined in the “Methods” section, none such definitions can be found (see minor comment of the previous review).

A serious issue is the accuracy of the database of this retrospective analysis. Many mistakes have already been identified in the database after the first revision. Some statistical calculations use the number of symptoms / comorbidities given in table 1, that do not differentiate between “unknown” and “no” (see comment 3 of the previous review). The low number of sampled biomarkers (e.g., only 75 % of all patients have a documented systolic blood pressure and only 90 % of all patients have a documented oxygen saturation � table 2) implies that the number of documented diagnoses / symptoms / comorbidities (table 1) is severely underestimated. Therefore, a serious conclusion cannot be drawn. This limitation is also not addressed adequately in the discussion but reported as the conclusion.

Another serious point is to hold back information on fatal outcomes (and including these into statistical analysis) to publish these data in a different manuscript. This issue weakens the current manuscript and the proposed predictors in a significant way.

Despite the need to understand the COVID-19 disease to overcome the pandemic (and here, regional aspects must be included), the scientific impact of the current manuscript stays low. This is mostly due to the retrospective nature of the analysis and the incomplete dataset. Therefore, the manuscript should not be published in its current way. Probably the best accuracy of the data can be found in the critical ill patients and an extensive workup of these data combined with outcomes may serve this purpose.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No