PONE-D-22-19240COVID-19 isolation and quarantine orders in Berlin-Reinickendorf (Germany): How many, how long and to whom?PLOS ONE

Dear Dr. Jakob Schumacher,

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.

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The points need to addressed and incorporated in the revised manuscript.

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We look forward to receiving your revised manuscript.

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Academic Editor

PLOS ONE

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Additional Editor Comments:

Kindly address all the points as mentioned in the recommended revision comments.

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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: Yes

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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: The authors would benefit by including the following suggestions to strengthen the manuscript:

1. Introduction on COVID-19 with emphasis on its origin and transmission (refer and cite: doi: 10.1136/postgradmedj-2020-138234).

2. Include the role of vaccination (refer and cite: doi: 10.3390/vaccines91010640

3. Include the role of protective medications in individuals with high risk of COVID-19 (refer and cite: doi: 10.1186/s41231-021-00102-4).

4. Include a comparison of support programs in Germany with that of other regions (refer and cite: doi: 10.3389/fpubh.2022.844333)

5. Role of predictors for vaccine hesitancy in Germany. (refer and cite: doi: 10.1136/postgradmedj-2021-141365.

6. where there any inclusion and exclusion criteria among the selected populations?

7. Where there any missing records? Kindly mention in your methodology.

8. Mention if any limitations were identified in your study and also mention the follow up steps for further analysis.

Reviewer #2: Well written manuscript and I endorse it for publication. The authors have well versed the materials, methods and statistical analysis. The results are well described and illustrated in the figures and tables.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-22-19240R1COVID-19 isolation and quarantine orders in Berlin-Reinickendorf (Germany): How many, how long and to whom?PLOS ONE

Dear Dr. Jakob,

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.

==============================

Kindly incorporate all the points mentioned by the reviewers in the revised manuscript.

==============================

Please submit your revised manuscript by 15th January 2023. 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.

Please include the following items when submitting your revised manuscript:

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If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Srikanth Umakanthan

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

The authors have not incorporated the changes mentioned by the reviewers. Minor revision still stands for the submitted manuscript.

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PONE-D-22-19240R2COVID-19 isolation and quarantine orders in Berlin-Reinickendorf (Germany): How many, how long and to whom?PLOS ONE

Dear Dr. Schumacher,

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 19 2024 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.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Emanuele Crisostomi, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

This Academic Editor received the assignment of this manuscript only three weeks ago, and realized that the manuscript had a past long history with unsuccessful attempts to finding appropriate reviewers, since the original ones were not available for a second round of reviews.

The new reviews are overall positive, and a minor review is recommended. In particular, one Reviewer provides a number of punctual constructive comments for improving the manuscript.

The next round of reviews will be faster and a final decision will be taken.

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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 #3: (No Response)

Reviewer #4: All comments have been addressed

Reviewer #5: (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 #3: Partly

Reviewer #4: Yes

Reviewer #5: Yes

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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: 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 #3: (No Response)

Reviewer #4: Yes

Reviewer #5: (No Response)

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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 #3: Yes

Reviewer #4: Yes

Reviewer #5: 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 #3: Overall this is an interesting account of the work of a health department during the COVID-19 pandemic, including counts of isolation and quarantine orders as well as intervals e.g. between contact and beginning of quarantine. A few amendments might make the paper more informative. Reading the manuscript by a native speaker may be advisable.

Abstract:

-The intro could be strengthened (the harm infliction is not a great part of the paper, is it?), and please add what the aim of the paper is.

-not sure if the analysis on the “dependence on the recommendations by the Robert Koch Institute” is that informative for the readers, I suggest to de-emphasize this part throughout.

-“delay of 4 days between contact and quarantine order”: what is meant: “last contact”? what did you do with family members as there was no point contact, but usually continuous contact? (perhaps address in Methods (were they excluded for that purpose?))

-“3484 of contacts were in quarantine…”: relate to the number of cases (1/18) and to the number of quarantines, and eliminate the word “of”. If you are able to quantify the number of human resources (man-hours or something like that) you could relate to that measure, too.

-I suggest to add here the proportion of the population that received at least one isolation or quarantine order, for simplicity sake you could assume that all isolation and quarantine orders were different persons

-the claim that fewer days were lost due to isolation or quarantine orders is not quantified.

-I would change the conclusions. (1)the part with the Robert KochInstitute I would leave out, (2)the conclusion that the mean number of contacts is less than expected comes out of the blue as you have not said what you expected. For example: you could say that a substantial proportion of the population had been separated, that the efforts saved the children from school closures, and that a substantial number of cases occurred when in quarantine.

Methods

-perhaps start with how you did the routine work and the contact tracing, how you monitored quarantined persons if they became a case (self monitoring / health department monitoring, symptom monitoring, mandatory testing?, …)

-line 73: what was the unit of observation in that database? an order for isolation, or an order to quarantine? either?

-what you could do and would be quite cool is to quantify the cases by the day they were removed from the public, e.g. x1 number of cases on day -2 before symptom onset (because they were in quarantine), x2 number of cases from day -1 before symptom onset, x3 number of cases on the day when they had symptom onset, etc. I think that should be feasible and would be quite good information for modelers.

-paragraph on “Number of quarantine orders…”: please give examples. Line 130: “other cases”: not clear what is meant here.

-please explain here how you dealt with household contacts from the point of view “last contact”. Did you exclude household contacts because they usually had no fixed, identifiable single contact?

Results

-Line 149: there are two “??”, please complete manuscript

-Fig.1: Since this is a paper that gives detailed account of the efforts of a health department I suggest to overlay the number of persons that were involved with contact tracing (by week or month, if possible) to show the amount of work and resources that has gone into this effort.

- can you give also the number of cases reported, please?, perhaps also in Table 2 and/or Fig.1

- please describe / point out the most important things in the figure/table (don’t leave the reader alone with it)

- Table 2, footnotes: add what N means

-Line 192: the number of contacts per case is quite small. given that these include also cases in schools with likely substantially more contacts it suggests that mainly the household contacts were traced. Please add in the Limitations that this low number of contacts traced may be a reason that the percentage of contained cases of all isolation orders is not more than 14%. At any rate: could you please give a break-down of the type of contacts, e.g. household, work, school, other, or something like that? In fact, I would consider restricting the analysis of contacts to household contacts as I assume that the vast majority of contacts are household contacts. This would strengthen the paper.

- could you add in the table the ratio of contained cases per quarantined persons (ncc/nq) or ni/nq (isolations per quarantined persons)

- I think the ratio of isolations in the 1-7 days after end of quarantine : isolations during quarantine is a useful measure that should be provided.

- Lines 199/200: what do you mean by “non-contained cases”? please give raw numbers here, too.

-perhaps provide also the percentage of the population with isolation order or quarantine order?

Discussion

-Limitations are usually at the end of the paper unless the editors wish something else

-I think another limitation is that there are also cases that were never known to the health department, which is of course not the fault of the health department, however, since you do not know the true number of cases (including those never diagnosed who still contribute to transmission) you underestimate the impact of the health department

-Line 232: does that mean you could not calculate secondary attack rates, e.g. by type of contact (household, work, etc.) or age of contact, or an average number of cases by source case (e.g. to identify super-spreaders)?

-Line 240: I cannot extract that or at least not easily from Table 2, please be more precise?

-Line 283: … or a reluctance of cases to give information about contacts

-Line 295: an update has been published, however, a lot of the evidence stems from SARS and MERS; there is other publications with a focus on C-19, such as Pozo-Martin (EJE, 2023, "Comparative effectiveness..."), Craig (JMIR 2021, "Effectiveness of contact tracing...") and Fetzer (PNAS, 2021, "Measuring the scientific effectiveness...")

-Line 299: I dont understand what is meant here

-Line 327: “The rough estimate for the median delay of 4 days that we found must be considered as a flaw in the contact tracing. For COVID-19, an early detection of contact persons is key to hinder transmission of the disease” – please check English (particularly “flaw” and “hinder” ??)

-but did adherence increase and/or administrative feasibility improve?

-Line 357: for modellers that is good information. however, again, most informative would be the proportion of cases that were isolated by day in relation to symptom onset (see above).

- The authors calculated the number of contacts per case. I think it would be more instructive to stratify by those cases who were not previously in the system as contact person and those who were. The latter will likely have very few contacts, the first might have a number of contacts. In addition it would be nice to stratify by age (of the case; very broadly, say <18 and 18+ year old), because children should have quite a bit more contacts than adults.

Reviewer #4: This is a nicely conducted and well-written paper that provides detailed descriptives on the COVID-19 isolation and quarantine orders by age groups and time periods in the Berlin-Reinickendorf area in Germany. Overall, I think the manuscript is well-structured and the analyses are appropriate in answering the research questions. The authors have also responded to the previous review comments sufficiently.

I only have few minor comments for consideration before publication:

- It will help the readers understand the context better if the authors can also state in the Abstract the total number of individuals analyzed.

- In Table 2, it will be helpful to mark the percentages as “%”, and provide SD for mean values. The abbreviations are also a bit hard to understand at first glance (for example it is not intuitive to me how “ncc” refers to “quarantines that had a directly following isolation period”). As these abbreviations are used only once in Table 2, the authors can consider write them out in words or improve the labels, if possible.

- It is generally recommended to avoid using the term “elderly”. I suggest changing it to “older adults”, “older persons”, or similar throughout the manuscript.

Reviewer #5: This is an intriguing study that provides valuable insights into policies regarding isolation and quarantine for COVID-19. The methodology is robust, and the contents are well-written. The results not only capture a specific time during the COVID-19 era but also offer potential implications for future pandemics or emerging diseases. I have only a few minor comments:

1. I noticed that reference 21 was not cited in the manuscript. Additionally, please renumber the references in the order they appear in the manuscript. As an example, references 36-38 currently appear in the first paragraph of the Introduction, which requires revision for proper numbering.

2. Line 11-12: "Vaccines have been developed and proven successful in preventing severe disease and death [40], ...." → I suggest change this sentence to "Vaccines have been developed and proven successful in inducing seroconversion (cite the following reference 1), preventing severe disease and death [40], ...."

Reference:

[1] Safety and Seroconversion of Immunotherapies against SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis of Clinical Trials. Pathogens. 2021 Nov 24;10(12):1537. doi: 10.3390/pathogens10121537. PMID: 34959492; PMCID: PMC8706687.

3. Line 51-52: "Jian et al. reported on the Taiwanese digital system TRACE analysing 487 cases and 8051 contact persons [12]." → To emphasize the public health implications of these particular systems, I suggest change this sentence to: "Jian et al. reported on the Taiwanese digital system TRACE, analyzing 487 cases and 8051 contact persons [12]. Public health implications of these systems included surveillance of travel history (cite the following reference 1) and ensuring an adequate quantity of personal protective equipment (cite the following reference 2)."

References:

[1] Integrating travel history via big data analytics under universal healthcare framework for disease control and prevention in the COVID-19 pandemic. J Clin Epidemiol. 2021 Feb;130:147-148. doi: 10.1016/j.jclinepi.2020.08.016

[2] Big Data-driven personal protective equipment stockpiling framework under Universal Healthcare for Disease Control and Prevention in the COVID-19 Era. Int J Surg. 2020 Jul;79:290-291. doi: 10.1016/j.ijsu.2020.05.091

I look forward to reviewing a revised version of this work based on my feedback!

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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 #3: No

Reviewer #4: No

Reviewer #5: No

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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.

COVID-19 isolation and quarantine orders in Berlin-Reinickendorf (Germany): How many, how long and to whom?

PONE-D-22-19240R3

Dear Dr. Schumacher,

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,

Emanuele Crisostomi, PhD

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 #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

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 #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #3: N/A

Reviewer #4: 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 #3: No

Reviewer #4: Yes

**********

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 #3: Yes

Reviewer #4: 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 #3: In the point-by-point answer to the reviewers the authors have not inserted in their answer the updated text including – using the track changes mode – the indication of what has changed. If you just say for example “we incorporated the suggestion of the reviewer” the reviewer has to look for it himself or herself. Even though there is a version of the total manuscript with tracked changes this means double work for the reviewer because he/she has to search again for the position in the text and identify what has changed. Please, when you write a paper next time and get a review, always include in your point-to-point answer not only your answer but also the respective passage in the text of the manuscript.

Overall the paper has improved since the modification.

I still have a few comments:

I think you need to rethink the structure of the paper somewhat. It is unclear what the objective was, “quantification and analysis” cannot be a goal, it is a method, that is used for a purpose. You say in your response that you think it is important to know “if local agencies follow or dont follow national recommendations”. Why don’t you use that as a goal? something like “During the pandemic the burden of work for local health departments was enormous and the federal public health agency (the Robert Koch Institute) adapted its recommendation several times. We aim to investigate if a local health department was capable to follow the recommendations of the Robert Koch Institute.” With that goal in mind you need to add something in that regard in the abstract and come to a conclusion. To do that you can use a lot of the results that are already in the main part of the paper. A second goal is the estimation of the impact of the efforts of the health department.

I say something to both goals:

If you want to compare the number of RKI-recommended days of isolation or days of quarantine with the number of isolation / quarantine days per person I suggest to put both together in one graph, e.g. as a modification of figure 2 (for example the number of recommended days in a different colour or as a horizontal line), otherwise the reader has to pull it together from several locations (Table 1 and Figure 2) in the paper which is bothersome for the reader.

Regarding the impact I suggest to add to measures/indicators:

(1) the ratio of ncc : nncc which is roughly 4:1 in children and 10:1 in adults, or, the proportion of cases arising from known contacts that were contained (ncc/(ncc+nncc), which is about 80% in children and about 90% for adults.

(2) Another indicator for impact would be ncc/ni, which is the proportion of all cases (with isolation order) who were contained. This is roughly 28% in young children and goes down to 11% in adults.

(3) And a third indicator would be the estimation of the proportion of all infectious days in the population that you had prevented. That indicator combines data of quarantine and isolation. How can you do it:

Step 1: you estimate the number of infectious days (inf-days) in the population which is: ni*inf-days. You have to make an assumption about the infectious period, say day of illness onset -2 until day of illness onset + 5 or so (see e.g. Ke, Nature Microbiology, 2022, or: National Institute for Infectious Disease in Japan (“Active epidemiological investigation on SARS-CoV-2 infection…”). (Nota bene: there is very scarce literature on the shedding kinetic of virus that can be isolated, whereas shedding of virus that can be detected via PCR is abundant, but much different. What you need is the shedding of virus that can be isolated in cell culture)). But you could say you assume illness onset + 5 days (or something else). At any rate this is your denominator.

Step 2: You estimate the number of inf-days prevented. Because ni=ncc + rest, you have to calculate the number of prevented days first for the ncc and then for the “rest” (=ni-ncc). For the ncc the number of prevented inf-days is simply = ncc*inf-days.

For the rest (ni-ncc) the number of prevented inf-days you can calculate as follows:

you calculate the average day after symptom onset when you placed the isolation order. For example it is day 2 after symptom onset. Then the average number of prevented inf-days per person would be 3 days. Then the number of prevented inf-days is: (ni-ncc)*3 days.

Now you have to add the two numbers of prevented inf-days: ncc*inf-days + (ni-ncc)*3 days. This is the numerator.

Step 3: put both in relation: number of prevented inf-days = numerator / denominator.

(This calculation assumes that non-isolated cases would continue to meet their contacts as before their infection; that is a limitation)

I think you said that the day of symptom onset is not part of the database, but you should be able to link it with the cases-database where you have the names and the date of symptom onset. If you cannot link the isolation/quarantine database with the cases database for some reason you can still either take a best guess from your co-workers (“Delphi method”), and/or pull the files of say 100 cases, and look it up. Then you calculate what you need based on these 100 cases.

- I suggest you rephrase your title, for example: “Adherence and impact estimation of COVID-19 isolation and quarantine orders in Berlin-Rheinickendorf, Germany, 2020-2022”

- another small point: Although 2 contacts per case is probably too low Reference 22 (Mossong) is in my eyes not a good comparator for the number of contacts because for sure the population changed their behavior for an extended period of time during 2020-2021.

- Table 2 is doubled.

Reviewer #4: I would like to thank the authors for their thoughtful response to my previous comments. The paper is much improved, and I have no further questions.

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