Impact of cytokine storm on severity of COVID-19 disease in a private hospital in West Jakarta prior to vaccination

Diana Laila Ramatillah; Siew Hua Gan; Ika Pratiwy; Syed Azhar Syed Sulaiman; Ammar Ali Saleh Jaber; Nina Jusnita; Stefanus Lukas; Usman Abu Bakar

doi:10.1371/journal.pone.0262438

Peer Review History

Original SubmissionOctober 9, 2021
9 Dec 2021 Decision Letter - Sanjay Kumar Singh Patel, Editor PONE-D-21-31980Impact of Cytokine Storm on severity of COVID-19 infection in a private Hospital in West Jakarta Prior to VaccinationPLOS ONE Dear Dr. Ramatillah, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jan 21 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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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 research article entitled, "Impact of Cytokine Storm on severity of COVID-19 infection in a private Hospital in West Jakarta Prior to Vaccination" by Ramatillah et al., assessed the role of cytokine storms in patients’ high mortality rate during COVID-19 pandemic using retrospective cohort study included only COVID-19 positive patients hospitalized in a Private Hospital in West Jakarta between March and September 2020. Authors found the clinical outcome of COVID-19 patients following medical therapy was either cured (85.7%) or died (14.3%), with 14.3% patients reported to have cytokine storm, from which 23.1% led to fatalities. Finally, authors have concluded that based on the treatment duration and survival rate, the most effective therapy was a combination of oseltamivir+favipiravir+hydroxychloroquine+antibiotics+vitamins/mineral. Altogether this is an important and timely research article, this reviewer has certain suggestions that would help produce a more comprehensive overview of the topic: Comments: 1. Did authors find any global data on female COVID-19 patients with cytokine storms? This will be noteworthy to know and authors can include this data to their study. 2. Did authors/or any other find cytokine storms in relatively younger COVID-19 patients and how was the response to the cytokine storms? 3. At least one supplementary Figure as illustration may be afforded as to highlight the summary or prospect of this study. 4. Author may explain how to adjust the limitation in their study? 5. The abbreviations should be cross validated in the manuscript (First define them fully followed by abbreviation) and one paragraph can be added for abbreviations. Reviewer #2: This retrospective study investigated the impact of cytokine storm on severity of COVID-19 disease in a private Hospital in West Jakarta Prior to Vaccination. The authors should distinguish infection from disease, because in COVID-19 disease, SARS-CoV-2 infection severity (high viral load) is not corelated to COVID-19 disease severity [1] In Title, “COVID-19 infection” should be “COVID-19 disease” Page 5, line 5, “severity of COVID-19 infection” should be “severity of COVID-19 disease” Page 6, line 12 from bottom, “more severe infection” should be “more severe disease” Page 9, line 6, “the severity of COVID-19 infection” should be “the severity of COVID-19 disease” Page 9, Table 1, row 24, “Severity of COVID-19 infection” should be “Severity of COVID-19 disease” Page 11, line 3 from bottom, “COVID-19 infection” should be “COVID-19 disease” Page 12, line 6, “following COVID-19 infection” should be “following SARA-CoV-2 viral infection” Page 14, last line, “patients with COVID-19 infection” should be “patients with COVID-19 disease” Page 15, line 9, “COVID-19 infection” should be “COVID-19 disease” Page 16, Conclusion, line 2, “severity of infection” should be “severity of disease” Reference 1. Shah S, Singhal T, Davar N, Thakkar P. No correlation between Ct values and severity of disease or mortality in patients with COVID 19 disease. Indian J Med Microbiol. 2021; 39(1): 116- 117.DOI: 10.1016/j.ijmmb.2020.10.021 Reviewer #3: In this paper entitled "Impact of cytokine storm on the severity of COVID-19 infection in a private hospital in West Jakarta prior vaccination", the authors used the convenience sampling method and included subjects who are not vaccinated. The clinal outcomes of the study are fascinating. The manuscript showed that cytokine storm was more in males (mean age 60) than women and interestingly, all hypertension/diabetes subjects experienced cytokine storm. It has many exciting findings which make this manuscript engaging and lucid. However, It has minor concerns. Minor comments: 1) Please add limitations of the study. 2) The cytokine storm is a fatal reaction of human immune system. Cytokine storm is present in influenza, SARS, and MERS. In few lines, please compare it. (doi:10.1016/j.clim.2020.108652). ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0262438.r001
Revision 1
20 Dec 2021 Author Response Reviewer 1 1. Did authors find any global data on female COVID-19 patients with cytokine storms? This will be noteworthy to know and authors can include this data to their study. Answer : Unfortunately, to date, there is no reported global data on female COVID-19 patients with cytokine storm, to date, since our data is the first reported one on male. 2. Did authors/or any other find cytokine storms in relatively younger COVID-19 patients and how was the response to the cytokine storms? Answer : Similar to point 1 above, since our sample population was mostly among the older age group (mean age of 60 years), we could not report on the incidence of cytokine storms in relatively younger COVID-19 patients as well as their responses. It would be interesting to see the differences in a future study, using our data as a basis for the comparison. 3. At least one supplementary Figure as illustration may be afforded as to highlight the summary or prospect of this study. Answer : We have included a supplementary Figure accordingly. Refer to Figure 2. 4. Author may explain how to adjust the limitation in their study? Answer : This is something that is challenging since they are indeed the limitations of the study. Nevertheless, we have attempted to explain it more clearly in the text now and have added another statement: “Additionally, since our data reported mainly on males and also the elderly, it would be interesting to see the incidence in females as well as in the younger age group and their responses against cytokine storms”. Thank you for the suggestion. 5. The abbreviations should be cross validated in the manuscript (First define them fully followed by abbreviation) and one paragraph can be added for abbreviations. Answer: We have added it in the newly-revised manuscript. Thank you for the suggestion. Reviewer 2 Reviewer #2: This retrospective study investigated the impact of cytokine storm on severity of COVID-19 disease in a private Hospital in West Jakarta Prior to Vaccination. The authors should distinguish infection from disease, because in COVID-19 disease, SARS-CoV-2 infection severity (high viral load) is not correlated to COVID-19 disease severity [1] In Title, “COVID-19 infection” should be “COVID-19 disease”: This has been changed accordingly, thank you. Page 5, line 5, “severity of COVID-19 infection” should be “severity of COVID-19 disease”. This has been changed accordingly, thank you. Page 6, line 12 from bottom, “more severe infection” should be “more severe disease”. This has been changed accordingly, thank you. Page 9, line 6, “the severity of COVID-19 infection” should be “the severity of COVID-19 disease”. This has been changed accordingly, thank you. Page 9, Table 1, row 24, “Severity of COVID-19 infection” should be “Severity of COVID-19 . This has been changed accordingly, thank you. disease” Page 11, line 3 from bottom, “COVID-19 infection” should be “COVID-19 disease”. This has been changed accordingly, thank you. Page 12, line 6, “following COVID-19 infection” should be “following SARA-CoV-2 viral infection”. This has been changed accordingly, thank you. Page 14, last line, “patients with COVID-19 infection” should be “patients with COVID-19 disease”. This has been changed accordingly, thank you. Page 15, line 9, “COVID-19 infection” should be “COVID-19 disease”. This has been changed accordingly, thank you. Page 16, Conclusion, line 2, “severity of infection” should be “severity of disease”. This has been changed accordingly, thank you. Answer: We have added all in the newly-revised manuscript. Thank you for the suggestion. Reviewer 3 Reviewer #3: In this paper entitled "Impact of cytokine storm on the severity of COVID-19 infection in a private hospital in West Jakarta prior vaccination", the authors used the convenience sampling method and included subjects who are not vaccinated. The clinal outcomes of the study are fascinating. The manuscript showed that cytokine storm was more in males (mean age 60) than women and interestingly, all hypertension/diabetes subjects experienced cytokine storm. It has many exciting findings which make this manuscript engaging and lucid. However, It has minor concerns. Thank you for the overall positive comments on our paper. We highly appreciate it. Minor comments: 1) Please add limitations of the study. Answer : We have added the limitation of the study in the manuscript accordingly The study has some limitations since the duration is rather short and the fact that the published care data to date came from a small observational data (no more than 250 patients). Additionally, the types of treatment administered are not based on the WHO guideline but rather, on the local context, besides being conducted during the time when vaccines have not been introduced in the country. We have elaborated further to include the fact that future study should focus on females and the younger age group since our sample includes mostly males and the elderly. 2) The cytokine storm is a fatal reaction of human immune system. Cytokine storm is present in influenza, SARS, and MERS. In few lines, please compare it. (doi:10.1016/j.clim.2020.108652). Thank you very much for the excellent suggestion. We have added a paragraph “Besides COVID-19, cytokine storms are also present in influenza, SARS, and MERS. Based on the immunopathology in COVID-19, SARS, and influenza infections, all the diseases show some hyperinflammation, hypercytokinemia, increased CRP levels, hyperferritinemia associated with poor prognosis, immunosuppression, lymphopenia associated with the severe disease, reduction of NK cell counts in the blood and/or NK cell dysfunction and reduction in both CD4 and CD8 T-cell counts in the blood associated with more severe disease. However, MERS tends to reveal hyperinflammation and hypercytokinemia associated with a poorer prognosis [56].” and have also quoted the said paper accordingly. Thank you. Attachments Attachment Submitted filename: Response to reviewers comments PLOS ONE.docx https://doi.org/10.1371/journal.pone.0262438.r002
24 Dec 2021 Decision Letter - Sanjay Kumar Singh Patel, Editor Impact of Cytokine Storm on severity of COVID-19 disease in a private Hospital in West Jakarta Prior to Vaccination PONE-D-21-31980R1 Dear Dr. Ramatillah, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Sanjay Kumar Singh Patel, Ph.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0262438.r003
Formally Accepted
31 Dec 2021 Acceptance Letter - Sanjay Kumar Singh Patel, Editor PONE-D-21-31980R1 Impact of Cytokine Storm on severity of COVID-19 disease in a private Hospital in West Jakarta Prior to Vaccination Dear Dr. Ramatillah: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Sanjay Kumar Singh Patel Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0262438.r004

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