Burden of Disease Due to Respiratory Syncytial Virus in Adults in Five Middle-Income Countries

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I have reviewed the manuscript titled "The burden of disease due to respiratory syncytial virus in adults in five middle-income countries." by Gomez and colleagues. 

 

The study presents estimation of the burden of Respiratory Syncytial Virus (RSV) hospitalizations and deaths in adults and older adults in five middle-income countries, using hospital discharge and death statistics, focusing on the year 2019, to provide a comprehensive understanding of the RSV burden, which is critical for guiding vaccination policy and raising disease awareness.

 

This manuscript addresses an important gap in the epidemiology of RSV in older adults in middle-income countries. The use of statistical modeling to estimate RSV burden is appropriate given the limitations of direct epidemiological surveillance. However, there are areas that require further clarification and discussion.

 

A.   The manuscript should provide more detailed explanations of the statistical methods used for estimating the RSV burden and better justify the choice of using the % of hospitalizations and deaths attributed to RSV given by Fleming et al., and not use specific RSV-related ICD codes. 

 

B.    In the discussion, the manuscript notes distinct annual peaks in respiratory-related hospitalizations and deaths during winter months in Latin American countries but not in Malaysia. A more detailed analysis of how seasonality and geographic differences might affect the RSV burden across these regions would be valuable. Moreover, the impact of the COVID-19 pandemic on RSV seasonality is an important aspect that deserves deeper analysis. The reader would benefit from a discussion on how the pandemic might have influenced RSV seasonality and whether this could impact the burden of disease in different regions (1).

 

C.    The impact of certain risk conditions on the severity of RSV outcomes is mentioned but not deeply analyzed. Given the known risk factors such as chronic respiratory diseases, cardiovascular conditions, and immunosuppressive states, a more thorough examination of how these comorbidities influence RSV outcomes in the different age groups would strengthen the paper.

 

D.   Lines 250-262: This paragraph is a bit tautological. The higher RSV incidence rates in those over 65 are a direct result of applying the Fleming % attributable to RSV. Therefore, it should not be emphasized excessively as it does not provide new insight beyond the methodological application.

 

E.    I think the manuscript should better acknowledge limitations related to the use of % of hospitalizations and death attributable to RSV given by another paper only, which was also focused on another (very different) country.

 

 

1.    Del Riccio M, Caini S, Bonaccorsi G, et al. Global analysis of respiratory viral circulation and timing of epidemics in the pre-COVID-19 and COVID-19 pandemic eras, based on data from the Global Influenza Surveillance and Response System (GISRS). Int J Infect Dis. 2024;144:107052. doi:10.1016/j.ijid.2024.107052

 

Author Response

Reviewer #1:

 

Comment: The manuscript should provide more detailed explanations of the statistical methods used for estimating the RSV burden and better justify the choice of using the % of hospitalizations and deaths attributed to RSV given by Fleming et al., and not use specific RSV-related ICD codes.

 

Response:

We have carefully reviewed the content of the methods section of the manuscript and have not identified any obvious gaps in the statistical methodology used. We elected not to use specific RSV-related ICD codes because most RSV cases do not have a viral diagnosis in middle- income countries and using RSV specific reports would incur significant underreporting for the estimation of RSV burden in these countries. This information has been added to the Methods section.

 

Comment: In the discussion, the manuscript notes distinct annual peaks in respiratory-related hospitalizations and deaths during winter months in Latin American countries but not in Malaysia. A more detailed analysis of how seasonality and geographic differences might affect the RSV burden across these regions would be valuable. Moreover, the impact of the COVID-19 pandemic on RSV seasonality is an important aspect that deserves deeper analysis. The reader would benefit from a discussion on how the pandemic might have influenced RSV seasonality and whether this could impact the burden of disease in different regions (1).  1. Del Riccio M, Caini S, Bonaccorsi G, et al. Global analysis of respiratory viral circulation and timing of epidemics in the pre-COVID-19 and COVID-19 pandemic eras, based on data from the Global Influenza Surveillance and Response System (GISRS). Int J Infect Dis. 2024;144:107052. doi:10.1016/j.ijid.2024.107052

 

Response:

The Reviewer makes a good point. It is possible that the epidemiologic differences between countries with seasonal peaks and without those peaks generate differences in the RSV burden. However, there are many other differences between the 5 countries analysed that could potentially affect this specific issue. We used 2019 annual, rather than seasonal data for all countries analysed, to specifically avoid the seasonal differences between countries. Our study was not designed to consider the impact of season and we are unable to speculate beyond the data available. Our analysis assumes that the annual RSV attributable risks reported for the UK are similar those in the 5 middle- income countries analysed. This is a major assumption and limitation of the analysis, as recognized in the discussion section. In this regard, we decided not to use only a point estimate of the RSV attributable risk and we considered a range of the RSV attributable risks in the analysis (Table 1) to cope with this limitation. Based on the starting point of our analysis where the burden of RSV in adults of middle-income countries is mostly unknown or underreported, we consider our study provides very useful insights for the public health authorities and policymakers of these countries

 

The spread of SARS-CoV-2 in early 2020 profoundly disrupted the circulation, timing, and duration of epidemics of respiratory viruses. After the rebound in respiratory viruses’ circulation questions arose regarding the return of their usual seasonal patterns. We decided to analyse the RSV burden in 2019 to specifically avoid the potential effects of the COVID-19 pandemic in our estimations. It was not our goal to determine if RSV will return to their typical circulation patterns or adapt to a new normality after the pandemic. Additional studies are needed to understand the epidemiology of respiratory viruses in the post-pandemic period.

 

Comment: The impact of certain risk conditions on the severity of RSV outcomes is mentioned but not deeply analyzed. Given the known risk factors such as chronic respiratory diseases, cardiovascular conditions, and immunosuppressive states, a more thorough examination of how these comorbidities influence RSV outcomes in the different age groups would strengthen the paper.

 

Response:

The goal of our study was to estimate the RSV burden in adults of the general populations of 5 middle-income countries. There was clear evidence that the burden of RSV hospitalizations and deaths increased with increasing age. We agree with the reviewer that there are well known risk factors (chronic respiratory diseases, cardiovascular conditions, and immunosuppressive states) for RSV disease. The incidence of these comorbidities also increases with age, and consequently, are certain to have influenced the RSV outcomes we observed in the countries studied. Nationwide data to explore this in more detail were not available and we are unable to examine this issue more thoroughly.

 

Comment: Lines 250-262: This paragraph is a bit tautological. The higher RSV incidence rates in those over 65 are a direct result of applying the Fleming % attributable to RSV. Therefore, it should not be emphasized excessively as it does not provide new insight beyond the methodological application.

 

Response:

We do not agree with the reviewer on this interpretation. The estimated incidence of RSV by age observed in our study is the result of 2 different pieces of data - Countrywide data on hospital discharges and deaths associated with respiratory disease, and the RSV-attributable risks reported by Fleming et al from the UK.  It is evident from the RSV- attributable risks reported in Table 1 that there was only a small increased risk in adults aged 50-64 years (5.20%) vs 65-74 years (5.80%) and ≥75 years (6.80%) in hospital discharges, and no increased risk in deaths associated with respiratory diseases in the UK (5.90%, 5.70% and 5.90%, respectively). The marked increase in rates of incident RSV and mortality with age is particularly associated with the epidemiologic features of the nationwide data obtained from each country analysed. The incidence of hospitalizations and the mortality rate associated with all respiratory diseases in the 5 countries analysed (Tables 2 & 3) increased significantly with age, and the local epidemiology is the main explanation for the observed results. The increased risk of respiratory disease with age has been long recognized, but the parallel increases in the rates of RSV hospitalizations and deaths is a new and valuable insight from our analysis.

 

Comment:   I think the manuscript should better acknowledge limitations related to the use of % of hospitalizations and death attributable to RSV given by another paper only, which was also focused on another (very different) country.

 

Response:

We agree with the reviewer that this is a potential limitation of the study and have expanded the limitations section of the Discussion to provide more insights on this potential issue.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

1. What is the main question addressed by the research?

In the present study, Gomez et al. aimed to determine-

·       The burden rate of RSV hospitalizations and deaths among old adults in the five middle-income countries- Argentina, Brazil, Chile, Mexico, and Malaysia

·       The burden of RSV by age group, particularly among older adults

·       Any seasonal patterns in RSV-related hospitalizations and deaths in these countries

·       The incidences of RSV-associated hospitalizations & deaths among older adults

·       The potential impact of preventive vaccines on the burden of RSV in older adults

2. What parts do you consider original or relevant for the field? What specific gap in the field does the paper address?

 Parts that are original or relevant for the field-

·       Focus on Middle-Income Countries: The study specifically examines the burden of RSV in middle-income countries (Argentina, Brazil, Chile, Mexico, and Malaysia).

·       Age-Specific Burden of Disease: This study highlights the significant burden of RSV among older adults, providing age-specific hospitalization and death rates.

·       Seasonal Variations: The identification of distinct annual peaks in respiratory-related hospitalizations and deaths during winter months in Latin American countries, contrasted with the absence of such peaks in Malaysia, provides insights into seasonal patterns and their potential implications for disease management and prevention strategies.

·       RSV-related Hospitalization and Death Rates: The study quantifies the incidence of RSV-related hospitalizations and deaths, offering data that can improve health policies

·       Potential Impact of Preventive Vaccines: The discussion on the potential impact of preventive vaccines on reducing the burden of RSV in older adults, highlights the importance of vaccine development.

Specific gap in the field does the paper address

·       Underrepresentation of Adult RSV Burden in Middle-Income Countries: The study addresses the gap in understanding the burden of RSV in adults in middle-income countries, which is often overlooked in favor of high-income countries or pediatric populations.

·       Age-Specific Data on RSV Impact: By focusing on the older adult population, the study fills a gap in age-specific data, highlighting the significant impact of RSV beyond the pediatric age group and emphasizing the need for targeted interventions for older adults.

·       Seasonal Patterns and Regional Differences: The research identifies and compares seasonal patterns of RSV-related hospitalizations and deaths in different geographical regions, addressing a gap in knowledge about how RSV behaves in varying climates and settings.

·       Implications for Vaccination Policy: The findings underscore the need for vaccines and other preventive measures in middle-income countries.

3. What does it add to the subject area compared with other published
material?

The present study adds below relevant information to the subject area-

·       While many studies on RSV focus on high-income countries, this study provides data from five middle-income countries: Argentina, Brazil, Chile, Mexico, and Malaysia.

·       This study focuses on the significant burden of RSV among older adults, a population often overlooked in RSV research, which typically focuses on children.

·       The study identifies distinct seasonal peaks in RSV-related hospitalizations and deaths in Latin American countries and contrasts these with the absence of such peaks in Malaysia. This comparative analysis helps to understand how RSV behaves in different climates and geographical regions, which can influence prevention and treatment strategies.

·       The study shows the importance of developing preventive vaccines and suggests that such vaccines could significantly reduce the burden of RSV, especially among older adults.

4. What specific improvements should the authors consider regarding the
methodology? What further controls should be considered?

·       Implementing molecular diagnostic methods like qRTPCR or ELISA to confirm RSV cases rather than relying solely on ICD-10 codes would increase the accuracy of the burden estimates.

·       Testing for other respiratory viruses (e.g., influenza, adenovirus) or bacteria to ensure that the hospitalizations and deaths attributed to RSV are not misdiagnosed.

·       Analyzing data at a more localized level within the countries like by state, could identify regional variations and hotspots for RSV.

 

Further control to consider-

Including an analysis of RSV burden in children would give a better picture.

·       Subdividing the elderly population to different age brackets (e.g., 65-74, 75-84, 85+) to understand how RSV affects differently in various age groups among adults.

 

5. Please describe how the conclusions are or are not consistent with the
evidence and arguments presented. Please also indicate if all main questions
posed were addressed and by which specific experiments.

The conclusions described here are consistent with the evidence provided. For example-

·       This study claims to estimate the burden of RSV hospitalizations and deaths in adults across five middle-income countries. The evidence presented includes hospital discharge and death statistics due to respiratory diseases from 2010–2022. This supports the conclusion that RSV is a significant cause of severe respiratory disease in older adults in these countries.

·       This study suggests that most of the RSV-related hospitalizations and deaths occur in adults aged ≥65 years. The statistics data provided support this conclusion.

·       The evidence showing distinct annual peaks in respiratory-related hospitalizations and deaths during winter months in Latin American countries but not in Malaysia is consistent with the conclusion that the season impact RSV infection in different regions.

 

Yes, all the main questions have been addressed through a specific methodology. For example-

 

·       Burden of RSV hospitalization and death in 5 middle-income countries- Addressed by obtaining and analyzing hospital discharge and death statistics.

·       Age The burden of RSV by age groups was determined by hospitalization and death rate.

·       Seasonal variation-Annual peaks in RSV-related hospitalization and deaths were determined statically.

 6. Are the references appropriate?

The references used in this manuscript are appropriate and effectively support the study objectives.

7. Please include any additional comments on the tables and figures and
quality of the data.

·       Figure is not clear. I am not able to read anything in the figure. Please fix this issue. The figure legends are difficult to read and must be improved for better readability.

·       I have not found supplementary figures and tables anywhere in the manuscript.

·       Page 3, line 124-It should be “Fleming et al.2015. Table 1.

 

 

Author Response

Reviewer #2:

 

Comment: Figure is not clear. I am not able to read anything in the figure. Please fix this issue. The figure legends are difficult to read and must be improved for better readability.

 

Response:  

We have updated the quality and readability of figures included in the manuscript

 

Comment:

I have not found supplementary figures and tables anywhere in the manuscript.

 

 

Response:  

We originally uploaded the supplemental data to the web page MDPI and we are repeating this action again in this resubmission.

 

Comment:  Page 3, line 124-It should be “Fleming et al.2015. Table 1.

 

Response: 

Thank you.  We have corrected this error.

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The article entitled “The burden of disease due to respiratory syncytial virus in adults in five middle-income countries” by Gómez et al., describes the burden of RSV hospitalizations and mortality in some middle-income countries. This paper can be of broad interest to those investigating the impact of respiratory diseases on different age groups. I have some recommendations that can addressed below:

1.      Line 24: consider including the respective countries in the statement: “There were 3,518, 9,115, 801, 704, and 3,806 RSV-attributable deaths…”

2.      Figures 1 and 3 resolution require improvement.

3.      The supplementary tables were unavailable to the reviewers.

4.      Consider including in the discussion section a reason for the highest number of deaths in Argentine, although it does not present the highest number of hospitalizations in the population over 65 years of age

5.      Lines 266-273: It is difficult for the authors to include these statements since the time ranges used for comparative purposes between countries are different. For instance, Mexico: 2018-2021, while in other countries the interval was much longer: Brazil/Malaysia, 2010-2022.

6.      Consider including a brief description of the conditions of the public health system in these countries and their impact on deaths in the different age groups, especially in older adults.

Comments on the Quality of English Language

No comments

Author Response

Reviewer #3:

 

Comment: Line 24: consider including the respective countries in the statement: “There were 3,518, 9,115, 801, 704, and 3,806 RSV-attributable deaths…”

 

Response:

Thank you for this comment. We have added the country names in this sentence.

 

Comment: Figures 1 and 3 resolution require improvement.

 

Response:

Thank you for this comment. We have updated the quality and resolution of figures 1 and 3 included in the manuscript.

 

Comment: The supplementary tables were unavailable to the reviewers.

 

Response:

We originally uploaded the supplemental data to the web page and we are repeating this action again in this resubmission.

 

Comment: Consider including in the discussion section a reason for the highest number of deaths in Argentine, although it does not present the highest number of hospitalizations in the population over 65 years of age.

 

Response:

We briefly reviewed the observed differences between countries in the discussion and this statement is already included: “Results from the individual countries in our study are difficult to compare because of differences in health care systems, clinical practice and thresholds for hospitalization, and potential differences in ICD coding conventions and guidelines for coding from death certificates, or completeness of reporting”. Regarding the specific comment form Reviewer 3, our opinion is that there are differences in ICD coding conventions in the death certificates for Argentina, that might be responsible in the higher mortality rates. We have added this to the Discussion.

 

Comment: Lines 266-273: It is difficult for the authors to include these statements since the time ranges used for comparative purposes between countries are different. For instance, Mexico: 2018-2021, while in other countries the interval was much longer: Brazil/Malaysia, 2010-2022.

 

Response:

We agree with this point. Time ranges between countries were different but we observed that the incidence of hospital discharges associated with any respiratory disease in the different countries was quite stable over time. We consistently observed much lower levels for Mexico than any other country analysed (see Figure 1, Figure 3, and Supplemental data tables). After review of the data by the investigators and local experts, we concluded that the lower disease burden in Mexico is an issue generated by systemic underreporting. We have modified the results and discussion section text in the manuscript to indicate this.

 

Comment: Consider including a brief description of the conditions of the public health system in these countries and their impact on deaths in the different age groups, especially in older adults

 

Response:

Our estimation of RSV burden covers the complete health system of each country analysed. The structure of the health system in each country is complex and it is out of the specific goal of the study. We do not think these updates will make the analysis more complete or easier to comprehend to the reader. We hope that our study will generate additional research in this area within the specific countries that would include an analysis on how the health systems can address the disease burden. .

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The article is very interesting, and RSV infection is a very important and sometimes neglected topic.

I think the authors could make some minor revisions.

Table 1: This sentence is duplicated (RSV-attributable risk in adult populations reported by outcome, age group, and ICD-10 codes for the United Kingdom. Data from Fleming et al., 2015 [11]). It is also written in the notes.

Quality of the Figures: The quality (resolution) of the figures could be improved. The current quality is poor, making them difficult to understand.

 

References: 

17. - The indicated site is not working

27: - The presented link is from Google Tradutor, not from CONAPO

Author Response

Reviewer #4:

 

Comment: Table 1: This sentence is duplicated (RSV-attributable risk in adult populations reported by outcome, age group, and ICD-10 codes for the United Kingdom. Data from Fleming et al., 2015 [11]). It is also written in the notes.

 

Response:

Thank you for this comment. We have corrected the error.

 

Comment: Quality of the Figures: The quality (resolution) of the figures could be improved. The current quality is poor, making them difficult to understand.

 

Response:

Thank you for this comment. We have updated the quality and resolution of figures 1 and 3 included in the manuscript.

 

Comment: References: 17. - The indicated site is not working

 

Response:

We have checked the link:

www.Argentina.gob.ar/sites/default/files/indicadores-basicos-2018.pdf

and it is working properly.

 

Comment: References: 27. - The presented link is from Google Translator, not from CONAPO

 

Response:

Thanks for the comment. The correct link has been updated in the reference list: 

https://datos.gob.mx/busca/dataset/proyecciones-de-la-poblacion-de-mexico-y-de-las-entidades-federativas-2020-2070

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for addressing my comments, either integrating them in the manuscript or giving a thorough explanation.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors covered the majority of the points in this version.