PONE-D-22-26429Healthcare resource utilisation and cost of pneumococcal disease from 2003 to 2019 in children ≤17 years in EnglandPLOS ONE

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Additional Editor Comments (if provided):

The manuscript describes an estimate of the healthcare resource utilisation (HCRU) and costs associated with pneumococcal disease (PD) in children aged ≤17 years in England from 2003-2019.

Episodes of invasive pneumococcal disease (IPD) were identified in hospitals in England, pneumococcal pneumonia (PP) and all-cause pneumonia (ACP) episodes were identified both in primary care as well as in hospitals, and acute otitis media (AOM) episodes were identified in primary care.

A respectable number of more than 1.5 million children were followed in the study period that was from 2003 to 2019. This period therefore includes a few years before introduction of any PCV, a few years after introduction of PCV 7 in 2006 and PCV 13 from 2010.

The authors declare conflicts of interest as some of the authors are employees of MSD and others of OXON, a company receiving funding from MSD. This is important as MSD will soon/already launch a 15 valent pneumococcal conjugate vaccine, obviously in competition with Pfizer´s 13 valent and GlaxoSmithKline 10 valent vaccines, both companies launching or preparing to launch higher valent vaccines. The authors do mention PCV 13 a few times in the paper but never PCV 10.

The paper is well written and carries interesting information. The paper needs some minor revision.

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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 study aimed to estimate healthcare resource utilisation (HCRU) and costs associated with pneumococcal disease (PD) in children aged ≤17 years in England from 2003- 2019.

The manuscript is well written, clear and precise.

Reviewer #2: Healthcare resource utilisation and cost of pneumococcal disease from 2003 to 2019 in children ≤17 years in England

PloS One

Manuscript Number: PONE-D-22-26429

Article Type: Research Article

The manuscript describes an estimate of the healthcare resource utilisation (HCRU) and costs associated with pneumococcal disease (PD) in children aged ≤17 years in England from 2003-2019. This is a comprehensive collection of data using various health-care related data banks in England. The authors evaluated the cost of pneumococcal diseases, i.e. invasive pneumococcal disease (IPD) pneumococcal pneumonia (PP), all-cause pneumonia (ACP) and acute otitis media (AOM). The last two obviously not always caused by pneumococcus.

Episodes of invasive pneumococcal disease (IPD) were identified in hospitals in England, pneumococcal pneumonia (PP) and all-cause pneumonia (ACP) episodes were identified both in primary care as well as in hospitals, and acute otitis media (AOM) episodes were identified in primary care.

A respectable number of more than 1.5 million children were followed in the study period that was from 2003 to 2019. This period therefore includes a few years before introduction of any PCV, a few years after introduction of PCV 7 in 2006 and PCV 13 from 2010.

1. The authors declare conflicts of interest as some of the authors are employees of MSD and others of OXON, a company receiving funding from MSD. This is important as MSD will soon/already launch a 15 valent pneumococcal conjugate vaccine, obviously in competition with Pfizer´s 13 valent and GlaxoSmithKline 10 valent vaccines, both companies launching or preparing to launch higher valent vaccines. The authors do mention PCV 13 a few times in the paper but never PCV 10.

The paper is well written and carries interesting information. I only have a few minor comments or suggestions.

2. The authors might want to emphasise that the structure of the study, i.e. evaluating the cost of the healthcare resource utilisation, only includes a part of the total society cost. In one of publications by Eythorsson E (PLoS One. 2021, PMID: 33831049) the indirect cost was also substantial. There are more similar publications. This indicates that a possible decrease in HCRU may underestimates the total cost reduction after initiating PCV. Having sad that, it is briefly mentioned that there are huge differences between countries in terms of “clinical practices, cultural attitudes, health insurance initiatives” and several other factors.

3. There are a few limitations to the study, most of them addressed in the discussion. The authors may want to emphasise more clearly that the study, carried out in England, reflects the situation in a high-income country. This health-economic evaluations would obviously be very much different in low-income countries.

4. I suggest the authors state more clearly that “all cause pneumonia” and “acute otitis media” are often not caused by Streptococcus pneumonia. In children, these diseases may quite often be caused by viruses or other bacteria. It does not contaminate the results in this cohort but should be expressed more clearly.

5. In contrast, however there was a significant increasing trend in AOM primary care costs overall and in both children aged 2-4 years and 5-17 years. This was driven by the increase in GP antibiotic prescription costs (results not presented) “. Maybe not a part of this study, but in my mind, this certainly needs more explanation! Are GPs in England prescribing more antibiotics for AOM after the introduction of PCV 7 and later PCV 13? This is in contrast with some other studies on the effect of PCV´s.

6. The authors claim that “To our knowledge there are no prior studies that report HCRU and cost of PD in children in England using real world data.” And later they state that “There are no recent studies reporting healthcare costs for ACP in the UK.” This may very well be true for England and/or UK, but it would surprise me if more detailed health-economic studies on PCV’s are not available. I would encourage the authors to include other health-economic studies (not necessarily only HCRU) in their discussion. I do understand that the aim of this current study was to only evaluate the HCRU. However, the picture may be bigger, and it would be of interest to include that in the discussion – not only for AOM.

7. My main comment regards the following conclusion: “In children overall a significant decreasing trend was observed in HCRU in primary care for PP, ACP and AOM. No significant trends were observed in inpatient admission yearly rates for IPD, PP or ACP. Across the study period, the primary care cost of ACP decreased while increased for AOM. Inpatient costs did not vary significantly across the study period for IPD, PP or ACP.”

To me, there are discrepancies in these conclusions, and I still don’t quite understand them. The authors may want to explain this somewhat better in the discussion section.

8. How come that HCRU in primary care was decreasing for PP, ACP and AOM whereas no trend was observed on inpatient HCRU for IPD, PP and ACP?

9. Why did the cost of ACP in primary care decrease while it increased for AOM?

10. Wouldn’t it have been logical to expect increasing cost to decrease over the study period for IPD, PP and ACP?

11. Finally, the authors obviously need to proof-read the manuscript. “Error! Reference source not found” on several places does not reflect meticulous proof-reading before submitting.

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Reviewer #1: No

Reviewer #2: No

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Healthcare resource utilisation and cost of pneumococcal disease from 2003 to 2019 in children ≤17 years in England

PONE-D-22-26429R1

Dear Dr. Salini Mohanty,

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,

Rahul Garg, 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 #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 #2: Yes

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

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 #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 #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 #2: The authors have responded to all comment in satisfactory way.

In my view, the paper can be published.

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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 #2: No

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