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PONE-D-20-32255

Characterizing COVID-19 Clinical Phenotypes and Associated Comorbidities and Complication Profiles

PLOS ONE

Dear Dr. Ingraham,

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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?

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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

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Reviewer #1: Yes

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: Follow the tips in the attachment.

Complete the description of the tables.

Follow the journal format.

Mention the study interval.

You need to explain the practical purpose further.

Identify the importance of the studied phenotypes and intermediate phenotypes.

Reviewer #2: The Authors report on a retrospective study aimed at assessing whether distinct phenotypes can be identified within the COVID-19 spectrum of clinical presentation. A large series of patients admitted to 14 hospital was ascertained.

As the Authors sensibly state, a multidimensional approach is needed to better understand COVID-19 and interpret the variation in clinical outcomes. The article may provide novel pieces of evidence in order to establish a reliable stratification of patients.

The Authors reported that the data set includes all consecutive patients – this strategy limits the ascertainment bias and is an element of strength of the study.

A few issues could be addressed to improve the overall quality of the manuscript.

The study cohort comprised patients admitted to inpatient clinics (n=1022, out of 7538 patients). Therefore, the wide spectrum of phenotypes caused by SARS-CoV-2 infection which was exhibited by the majority of individuals could not be accounted for. I understand that the recruitment setting is constrained by the study design. However, the generalisability of results should be discussed accounting for this limitation.

To put data into the health care context, a brief description of the hospital setting could be helpful – e.g. geographical distribution, dimension of the hospital, type of unit [if not ICU], etc., including the population served.

It is noteworthy that phenotype I was found associated with being non-white and non-English speaking. Though the socioeconomic status was not differently distributed, this finding should be discussed.

To this regard, it should be reported how race/ethnicity was ascertained.

Dissecting the role for constitutional risk factors, and particularly genetic risk factors, is of paramount importance to design effective health care strategies for COVID-19. To this purpose, a clear-cut, evidence-based characterisation of phenotypes is a fundamental step. With this perspective, the implications of the present study deserve to be properly addressed.

Conversely, the Authors outlined the impact of the study in a very simplistic way.

As far as concerns genetic predisposition, accelerated aging is far from being a pivotal reference [page 10 first paragraph, ref. 30]; the term ‘exome data’ [page 11, last paragraph of Discussion] is inappropriate. The Authors should be aware that there is a line of research focussing on the role for host genetic factors in determining variable susceptibility to develop the phenotypes associated to SARS-CoV-2 infection. A large body of literature has been published – see for instance ‘Genetic variants of the human host influencing the coronavirus-associated phenotypes (SARS, MERS and COVID-19): rapid systematic review and field synopsis’, Human Genomics 2020, which also addresses the quality of methodological approaches; Beck and Aksentijevich, Science 2020, and citations therein; and the recently published genome-wide association studies.

Minor issues:

- Some references are incomplete.

- A few acronyms should be defined [e.g. SOFA, RDW].

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Reviewer #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: PONE.docx

Characterizing COVID-19 Clinical Phenotypes and Associated Comorbidities and Complication Profiles

PONE-D-20-32255R1

Dear Dr. Ingraham,

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.

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Kind regards,

Chiara Lazzeri

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: