PONE-D-20-22384

Ocular surface manifestations of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis

PLOS ONE

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Deepak Shukla

Academic Editor

PLOS ONE

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2. We note that you assessed risk of bias with a checklist with domains including representativeness of the target population, random selection, likelihood of non-response bias, data collection, use of case definitions, reliability and validity of measuring tools, and appropriate use of numerator and denominator for the ocular symptoms. Please ensure that you have provided a table in your manuscript with the scores for all individual risk of bias domains for all studies included your systematic review.

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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: Yes

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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: 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: This is an excellent meta-analysis by the authors discussing considerable amount of data available out there. While the data that they have used is not perfect (due to heterogeneity of testing methods in the original studies), the authors have tried to extract as much meaningful data as possible. The authors were able to remove as many non-compliant studies as possible from their manuscript as possible while providing good meaningful data.

Minor revisions

1. May be the authors could talk about some potential drugs that were used in these studies to control the ocular manifestation. Some info can be found in PMID: 32714563, PMID: 32560227

2. Page 14 first line, "white" needs to be "while"

3. The authors say that 3.5% of the patients had RT-PCR based viral RNA detection in ocular samples. It wasnt very clear in the manuscript whether this percentage is out of 3000 patients or 2300 patients or only the studies that did conjuctival swabs. It would be good to know the total number.

4. Figure 2 and 3, quality of the image is not very good. May be provide a better version for publication.

Reviewer #2: Ocular surface manifestations of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis

Reviewer’s comments

In this study, the authors have described the meta-analysis of cases having ocular manifestation of COVID-19 around the world. The manuscript highlights the meta-analysis of clinical symptoms during ocular manifestation of COVID-19 such as ocular pain, discharge, redness and follicular conjunctivitis. The meta-analysis has been performed in which 222 citations were identified by online database search. After screening process described by the authors, 16 papers were found relevant. The data from 16 research articles was used which were published from China, Netherlands, Iran, Singapore, Italy and Brazil. The data includes a sum total of 2347 positive cases out of 3064 patients. Out of these, 196 patients (8.35%) were reported with ocular manifestation.

The meta-analysis does not include any studies published from India.

Also, the meta-analysis of pooled data revealed that 6.91% of the patients with ocular manifestations suffered from severe pneumonia the association of ocular manifestation with the severity of the respiratory complications or the prognosis is not discussed in details.

Incidence refers to the occurrence of new cases of disease or injury in a population over a specified period of time.

Abstract: Prevalence: Prevalence in epidemiology is the proportion of a particular population found to be affected by a medical condition at a specific time.

Incidence refers to the occurrence of new cases of disease or injury in a population over a specified period of time.

But the population included in this study is not uniform. So instead of prevalence, incidence/occurrence can be a better word.

● The study states that 11.6% patients had ocular manifestation of COVID-19. Out of these Ocular pain (31.2%), discharge (19.2%), redness (10.8%), and follicular conjunctivitis (7.7%) were the main features. But 31.2 + 19.2 + 10.8 + 7.7 = 68.9 %.

● Does remaining 31.1% patients signify some other uncommon symptoms? Please specify in details.

Introduction

● The studies published thus far suffer from significant publication bias and heterogeneity, and robust data collection and reporting of ocular manifestations is needed in the future. (Please re-phrase this sentence)

● It was declared a public health emergency of international concern on 30th January 2020 and in March 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic (Please rephrase this sentence: Outbreak and Pandemic are two different epidemiological terms).

● The causative pathogen of this potentially fatal disease is a novel enveloped RNA beta coronavirus 2, a member of the Coronaviridae family, also known as severe acute respiratory syndrome coronavirus2 (Please rephrase this sentence. Enveloped positive sense ss-RNA virus. Betacoronavirus and Coronaviridae is written in Italics)

● During the current pandemic, there have been various reports of ocular involvement including features of follicular conjunctivitis in patients infected with SARS-CoV 2 with some of them even demonstrating the presence of viral RNA in conjunctival or tear specimens collected from these patients.

● Rate of reverse transcriptase polymerase chain reaction (RT-PCR) positivity for viral RNA in ocular fluids (The rate of positivity can be calculated in a Cohort study. Because rate is with respect to time in which the study is been performed. In a cross-sectional study, only number of positive cases can be stated)

Materials and methods

● Confirmed COVID-19 cases indicate patients who were diagnosed COVID-19 positive either on the basis of clinical criteria or positive RT-PCR for viral RNA from nasopharyngeal swabs (Please check about this line). (The diagnosis should be done on the basis of clinical signs and confirmation by RT-PCR. Only clinical criteria might not be sufficient)

● The heterogeneity on the basis of I2:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

Please provide a reference it might be needed.

Study outcome:

● Clinical features, demographic profile and ocular complications of COVID-19 patients with ophthalmic manifestation (Ocular and ophthalmic is repetition: might need to rephrase the sentence)

Risk of bias: The risk of bias is demonstrated to be moderate in this study. But it needs more elaboration. Also, in the discussion part questions have been raised by the authors regarding risk of bias. This might contradict the study.

Table 1:

● The reference Zhang et al (Ref no 24) is actually Xu et al., 2020 (Please check author names)

● (Reference number should be checked properly: The reference numbers given in the table are interchanged)

● Tostmann et al: (Ref no 21): 20 number

● Zhou et al: (Ref no 22): 21 number

● Qianqian et al., (Ref no 23) is actually Lan et al., 2020

● Table 1: row number 7 reference not cited properly

Discussion

Several questions have been raised in the discussion part of the review. Possibilities of various bias that can be encountered during the data collections have been discussed such as recall bias, study design bias and bias due to pre-existing ocular features. Apart from this, few more constraints such as in severe cases ocular features may go unnoticed or non-specific conditions such as dry eyes, pain chemosis and redness. These conditions might subject the judgement of healthcare workers to be biased. Therefore, in many cases the conjunctival swabs or tear samples did not test positive for SARS-CoV-2 RNA by qRT-PCR.

But the data presented in this study shows, only 2.2% of the patients show ocular manifestation as the first clinical sign. Apart from this 6.9% patients with ocular symptoms suffered from severe pneumonia. This data is not sufficient to have a concrete conclusion. More data analysis might be considered for the analysis. Also, the analysis should be supported by significant statistical analysis.

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Reviewer #1: No

Reviewer #2: Yes: Dr Shyam Sundar Nandi

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Attachments

Attachment

Submitted filename: Dr. Nandi_Plos Occular manifestation of COVID-19 review_comments.docx

Ocular surface manifestations of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis

PONE-D-20-22384R1

Dear Dr. Gupta,

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,

Deepak Shukla

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: All comments have been addressed

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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: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

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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

**********

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 have adequately addressed the comments previously made. All the queries are answered satisfactorily. The article should be accepted for publication.

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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: Yes: Dr Shyam Sundar Nandi

Attachments

Attachment

Submitted filename: Dr. Nandis comments PlosOne.docx