Prognostic Value of Charlson Comorbidity Index in Patients with COVID-19

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript evaluates the prognostic utility of the Charlson Comorbidity Index (CCI) for predicting severity and outcomes among hospitalised COVID-19 patients with chronic comorbidities in Bulgaria. The study includes 373 eligible Bulgarian patients admitted between March 2020 and March 2021, covering the period dominated by the ancestral (wild-type) and Alpha variant waves. The manuscript provides useful retrospective evidence supporting the CCI as an effective tool for early risk stratification in COVID-19. The identification of a potential threshold of CCI > 5 is clinically relevant and may aid decision-making at hospital admission.

However, several aspects require clarification or improvement. Given the modest sample size, the study may be considered preliminary or “pilot”, and the authors may consider recommending future multicentre investigations to strengthen generalisability.

Comments.
1. Incorrect and misleading statement (line 35):
The statement “... and on March 11, 2020, the World Health Organization declared a global pandemic [2]. By its official end in May 2023,...” is inaccurate and misleading.
On 5 May 2023, the WHO declared that COVID-19 was no longer a Public Health Emergency of International Concern (PHEIC).
However, the end of PHEIC does not signify the end of the pandemic, which continues globally in the same way that influenza and HIV remain ongoing pandemics.

Please correct this statement accordingly.

Reference:
WHO Statement (5 May 2023): https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic

2. Country name (line 65):
As this is an international journal, please specify the country after the city name, such as “St. Marina University Hospital, Varna, Bulgaria.” Not all readers are indigenious Bulgarian.

3. SPSS version:
The manuscript states that SPSS Version 20 was used. This version is now quite outdated.
If this is accurate, it is acceptable, but please ensure that the version number is correct. If a more recent version was used, amend the text.

4. COVID-19 vaccination status:
Vaccination status is a critical determinant of clinical outcomes.
Please clarify whether all included patients were unvaccinated, partially vaccinated, or fully vaccinated.

If all patients were unvaccinated (likely for the study period), please explicitly state this in the Materials and Methods to avoid ambiguity.

5. Timing of CCI calculation:
Please clarify whether the CCI score was calculated at the time of hospital admission (acute phase), or after complications had already developed during hospitalisation or ICU admission.
This has implications for the prognostic interpretation of the index.

6. Discussion on variants beyond the study period:
The dataset reflects early pandemic conditions (wild-type and Alpha variants).
Consider adding a brief discussion on how the predictive performance of the CCI might differ with:
-later variants (e.g., Delta, Omicron),
-widespread vaccination or hybrid immunity,
-changes in clinical management over time.
This will help contextualise the relevance of the findings in current clinical settings.

7. Significant figures in p-values:
Please unify the number of decimal places for p-values throughout the manuscript.
The current text uses both two decimals (e.g., 0.80, 0.02) and three decimals (e.g., 0.005).
Consistency will improve readability and scientific.

8. Typographical issue (line 80):
The phrase “access patients’ premorbid status” should be corrected to “assess patients’ premorbid status.”

9. Limitations:
The study has value, but a several limitations should be explicitly acknowledged, including:
-single-centre, retrospective design,
-limited generalisability,
-potential confounders not adjusted for (age, sex, BMI, baseline severity),
-a small number of deaths (n = 10), which restricts the robustness of mortality-prediction analyses,
-an absence of vaccination-related or variant-specific data.
A more explicit limitations section would strengthen the manuscript’s transparency.

Author Response

1. Response to Reviewer 1:

We are thankful for the thorough and constructive evaluation of our manuscript and for the positive assessment of the clinical relevance of the Charlson Comorbidity Index in COVID-19. We have carefully addressed all comments and revised the manuscript accordingly. All changes are highlighted in yellow in the revised version.

Comment 1. Incorrect and misleading statement regarding the end of the pandemic

Reviewer comment:
Incorrect and misleading statement (line 35): The statement “... and on March 11, 2020, the World Health Organization declared a global pandemic [2]. By its official end in

May 2023,...” is inaccurate and misleading. On 5 May 2023, the WHO declared that COVID-19 was no longer a Public Health Emergency of International Concern (PHEIC). However, the end of PHEIC does not signify the end of the pandemic, which continues globally in the same way that influenza and HIV remain ongoing pandemics.

Response:
We fully agree with the reviewer clarification. The statement has been revised to accurately reflect that, on 5 May 2023, the World Health Organization declared the end of COVID-19 as a Public Health Emergency of International Concern (PHEIC), while acknowledging that SARS-CoV-2 continues to circulate globally and that COVID-19 remains an ongoing public health challenge. The statement in the Introduction has been corrected accordingly, and the appropriate WHO reference has been added. (rows 34-36)

Comment 2. Country name specification

Reviewer comment:
As this is an international journal, please specify the country after the city name, such as “St. Marina University Hospital, Varna, Bulgaria.” Not all readers are indigenous Bulgarian.

Response:
Thank you for pointing this out. The country name has been added throughout the manuscript. The affiliation in all its mentions in the text now specify “St. Marina University Hospital, Varna, Bulgaria.” (rows 15, 67, 79, 249)

Comment 3. SPSS version

Reviewer comment:
The manuscript states that SPSS Version 20 was used. This version is now quite outdated. If this is accurate, it is acceptable, but please ensure that the version number is correct. If a more recent version was used, amend the text.

Response:
We confirm that SPSS software version 20 was used for the statistical analysis, as this was the licensed version available at our institution during the study period. The version number has been verified and retained in the revised manuscript.

Comment 4. COVID-19 vaccination status

Reviewer comment:
Vaccination status is a critical determinant of clinical outcomes. Please clarify whether all included patients were unvaccinated, partially vaccinated, or fully vaccinated. If all patients were unvaccinated (likely for the study period), please explicitly state this in the Materials and Methods to avoid ambiguity.

Response:
We agree that vaccination status is a critical determinant of COVID-19 outcomes. All patients included in this study were unvaccinated, as the study period (March 2020 – March 2021) preceded the initiation of the national COVID-19 vaccination campaign in Bulgaria. This information has now been explicitly stated in the Materials and Methods section to avoid uncertainty. (rows 73-75)

Comment 5. Timing of CCI calculation

Reviewer comment:
Please clarify whether the CCI score was calculated at the time of hospital admission (acute phase), or after complications had already developed during hospitalisation or ICU admission. This has implications for the prognostic interpretation of the index.

Response:
We thank the reviewer for this important methodological point. The Charlson Comorbidity Index was calculated at the time of hospital admission, based solely on pre-existing chronic conditions documented in the medical records, prior to the development of in-hospital complications. This clarification has been added to the Materials and Methods section to emphasize the prognostic intent of the index. (rows 85-86)

Comment 6. Discussion on variants beyond the study period

Reviewer comment:
The dataset reflects early pandemic conditions (wild-type and Alpha variants). Consider adding a brief discussion on how the predictive performance of the CCI might differ with:-later variants (e.g., Delta, Omicron), -widespread vaccination or hybrid immunity, -changes in clinical management over time. This will help contextualize the relevance of the findings in current clinical settings.

Response:
We agree and have added a new paragraph to the Discussion section addressing the potential impact of later SARS-CoV-2 variants, widespread vaccination or hybrid immunity, and advances in clinical management on the prognostic performance of the CCI. We emphasize that, although absolute risks may differ, comorbidity burden remains a fundamental determinant of adverse outcomes across pandemic phases. (rows 193-201)

Comment 7. Significant figures in p-values

Reviewer comment:
Please unify the number of decimal places for p-values throughout the manuscript. The current text uses both two decimals (e.g., 0.80, 0.02) and three decimals (e.g., 0.005). Consistency will improve readability and scientific.

Response:
We agree. All p-values in the manuscript have been standardized to three decimal places (highlighted in the text) to ensure consistency and improve readability.

Comment 8. Typographical issue

Reviewer comment:
The phrase “access patients’ premorbid status” should be corrected to “assess patients’ premorbid status.”

Response:
We thank the reviewer for noting this typographical error. The wording has been corrected accordingly.

Comment 9. Limitations

Reviewer comment:
The study has value, but a several limitations should be explicitly acknowledged, including:-single-centre, retrospective design, -limited generalisability, -potential confounders not adjusted for (age, sex, BMI, baseline severity), -a small number of deaths (n = 10), which restricts the robustness of mortality-prediction analyses,-an absence of vaccination-related or variant-specific data. A more explicit limitations section would strengthen the manuscript’s transparency.

Response:
We agree and have added a dedicated “5. Limitations” subsection in the Discussion section. This subsection explicitly addresses the reviewers’ points. We believe this addition improves the transparency and interpretability of the study. (row 216-226).

Reviewer 2 Report

Comments and Suggestions for Authors

Since your study is conducted in Varna, Bulgaria, your references in the cited literature, most of them, mostly refer to China, Turkey, India, only one from the UK. When we discuss the Eastern European population, which has its own metabolic profile (dyslipidemia, hypertriglyceridemia, insulin resistance), high smoking profile, obesity, very different from the Chinese or Indian population, I suggest you improve your study, comparing first of all the population with other populations from the Eastern EU, the Central EU, so that the results, discussions and finally the conclusions can be really useful.

Summary: the second sentence does not belong in the introduction, but perhaps in the conclusions.

The Materials and Methods section needs restructuring (Table 1 belongs in the Results section); Explain clearly, and not with the same notions, why and what is the reason for dropping those 185 participants? What uncomplicated premorbid status are you referring to?

Also, in the Results section, I strongly recommend that you detail exactly which comorbidities (Table 4) you selected from the study group, assuming, of course, that you have the predominant prevalence of each comorbidity.

Discussion section: other important discussions are missing, with reference to types of comorbidities, years of comorbidity, differences in lifestyle, smoking habits and/or alcohol consumption. There is one important comorbidity that, paradoxically, improved the prognosis of COVID-19. It is about allergy and asthma... you did not mention anything.

Comments on the Quality of English Language

Need another English check.

Author Response

We thank the reviewer for the critical comments, which have helped us improve the structure, clarity, and contextual relevance of the manuscript. We have revised the Introduction, Materials and Methods, Results, and Discussion sections accordingly, while maintaining the integrity of the original dataset. All subsequent changes are highlighted in green in the revised version.

Comment 1. Use of predominantly non-European literature

Reviewer comment:
Since your study is conducted in Varna, Bulgaria, your references in the cited literature, most of them, mostly refer to China, Turkey, India, only one from the UK. When we discuss the Eastern European population, which has its own metabolic profile (dyslipidemia, hypertriglyceridemia, insulin resistance), high smoking profile, obesity, very different from the Chinese or Indian population, I suggest you improve your study, comparing first of all the population with other populations from the Eastern EU, the Central EU, so that the results, discussions and finally the conclusions can be really useful.

Response:
We agree with the reviewer to a certain degree. The population-specific characteristics are important when interpreting prognostic markers in COVID-19. We have expanded the Discussion section (rows 202-215) to include comparative data from Eastern and Central European studies (with added references). The differences in metabolic profile, obesity prevalence, smoking habits, and cardiovascular risk compared with Asian populations are clearly pointed. We acknowledge the limited availability of region-specific data during the early pandemic phase and highlight the contribution of our Bulgarian cohort to the Eastern European evidence base. We also agree that a substantial number of articles have been published recently that examine the relationship between comorbidity and COVID-19. However, the purpose of a discussion is to adhere to the objectives and findings of the research. Therefore, the reference list and subsequent interpretations have been narrowed to include mainly studies that employ explicitly Charlson Comorbidity Index to evaluate the prognosis of patients with SARS-CoV-2, in a particular time of the pandemic, regardless of their country of origin.  

Comment 2. Sentence placement in the Introduction

Reviewer comment:
The second sentence does not belong in the Introduction.

Response:
We agree with the reviewer. The sentence has been removed from the Introduction.

Comment 3. Materials and Methods restructuring / Table 1 placement

Reviewer comment:
The Materials and Methods section needs restructuring (Table 1 belongs in the Results section);

Response:
We respectfully disagree. Table 1 describes the components and scoring system of the Charlson Comorbidity Index and does not present study-specific results. In accordance with standard reporting practice, it has been retained in the Materials and Methods section to support methodological transparency.

Comment 4. Exclusion of 185 patients – unclear definition

Reviewer comment:
Explain clearly, and not with the same notions, why and what is the reason for dropping those 185 participants? What uncomplicated premorbid status are you referring to?

Response:
We agree that this required clarification. The Materials and Methods and results sections have been revised to explicitly define “uncomplicated premorbid status” as the “absence of documented chronic non-infectious diseases included in the Charlson Comorbidity Index”. Patients without comorbidities relevant to CCI calculation were excluded to ensure a homogeneous study population focused on comorbidity burden. The rationale for excluding the 185 patients has now been clearly stated in Materials and Methods (rows 70-73) and Results (rows 99-101).

Comment 5. Results section – specification of comorbidities

Reviewer comment:
Also, in the Results section, I strongly recommend that you detail exactly which comorbidities (Table 4) you selected from the study group, assuming, of course, that you have the predominant prevalence of each comorbidity.

Response:
The Results include a section reporting on the predominant comorbidities and their respective prevalence in the studied population (rows 107-112). In the following analysis each of the components of column one in Table 1. is considered as a singular statistical object (marked as comorbid condition in Table 3 and Table 4) and non are “selected” or “deselected” from the study group. Then patients are grouped as having one, two or three and more of those comorbidities without any exclusions.    

Comment 6. Discussion – missing aspects (lifestyle, duration of comorbidities)

Reviewer comment:
Discussion section: other important discussions are missing, with reference to types of comorbidities, years of comorbidity, differences in lifestyle, smoking habits and/or alcohol consumption.

Response:
We agree that these factors are clinically relevant. As detailed data on smoking habits, alcohol consumption, and duration of comorbidities were not consistently available in this retrospective dataset, we have addressed these aspects in the Discussion as potential modifiers of prognosis and explicitly acknowledged their absence as a limitation. This has been incorporated into the expanded Limitations subsection. (rows 216-226)

Comment 7. Allergy and asthma paradoxically improving prognosis

Reviewer comment:
There is one important comorbidity that, paradoxically, improved the prognosis of COVID-19. It is about allergy and asthma... you did not mention anything.

Response:
We thank the reviewer for this valuable observation. A dedicated paragraph has been added to the Discussion addressing existing evidence suggesting a potentially protective role of allergic diseases and asthma in COVID-19, possibly related to altered ACE2 expression and immune response modulation. While asthma prevalence in our cohort was low, this topic is now discussed in relation to current literature. (rows 210-214)

Comment 8. Comment on the Quality of English Language

Reviewer comment:

Need another English check.

Response: We are grateful for this recommendation and have utilized our institution's Professional English Editing services. Technical and stylistic errors have been edited, while maintaining the integrity of the original content.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for thoroughly addressing the concerns I raised in your previous submission.

Author Response

We are thankful for the thorough and constructive evaluation of our manuscript and for the positive assessment of the clinical relevance of the Charlson Comorbidity Index in COVID-19.

Reviewer 2 Report

Comments and Suggestions for Authors

I have read the answers of the authors and I do not agree with 2 aspects:

1. Generally, my comments were not made for the authors to manifest their agreement or disagreement; they are made because the initial material had serious content gaps
2. I still stress the comments 4 and 5, the authors did not provide meaninfull, scientific ground. There is no consistent explanation for comment 4, nor for comment 5.
3. My decision to this second review is major  revision.

 

Comments on the Quality of English Language

Need another English check.

Author Response

Dear Reviewer,

We sincerely thank you for your constructive comments and valuable suggestions, which have helped us to improve the clarity and scientific rigor of the manuscript. We have carefully considered your recommendations and revised the manuscript accordingly. The specific changes made in response to Comments 4 and 5 are detailed below.

Comment 4. Exclusion of 185 patients – unclear definition
Reviewer comment: Explain clearly why 185 participants were excluded and what “uncomplicated premorbid status” means.

Response:
The definition of “uncomplicated premorbid status” has now been explicitly clarified in the Materials and Methods section. We specified that these patients had no documented chronic non-infectious diseases prior to SARS-CoV-2 infection and explained that this criterion constituted the rationale for their exclusion from the analysis. In addition, the exclusion of these patients has been more clearly described in the Results section to ensure consistency between methodology and reported findings.

 

Comment 5. Results section – specification of comorbidities
Reviewer comment: Detail exactly which comorbidities were selected and their prevalence.

Response:
In accordance with this recommendation, we expanded the Results section to provide a detailed description of the specific comorbidities included in the analysis, along with their respective prevalence rates. Cardiovascular, metabolic, and pulmonary conditions are now explicitly reported, and their contribution to the Charlson Comorbidity Index is clearly stated. These revisions enhance the transparency and interpretability of the comorbidity profile of the studied population.

 

All revisions have been highlighted in green and incorporated directly into the revised manuscript. We believe that these changes have substantially improved the clarity and methodological transparency of the study, and we are grateful for the reviewer’s insightful comments.

Sincerely

Author Response File: Author Response.docx

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

At this point, with all observations from your reviewers, the informations you present are more clear. 

There are two issues that cannot be adressed, still:

1. Some informations or important data you changed or first time introduced, for statistical and scientific consistency, in this 3rd round of answers points out the fact that your study design and the real implementation of certain stages did not followed the rules, from the beginning.

As for a personal conclusion, the material you submitted now, after this 3rd version, can  represent a point of vue for your study group, may be extended to a similar population from Bulgaria, but it has lots of limitations. The main problem is that you did not have a clear inclusion criteria and you wanted to discuss everything, so many variables that at the end, you question yourself: what was the title?

 

Comments on the Quality of English Language

Need another English check.

Author Response

Response to Reviewer

We sincerely thank the reviewer for the careful reading of our manuscript and for the constructive comments provided. We have carefully considered all the recommendations and suggestions, and the manuscript has been revised accordingly. All changes have been incorporated directly into the main text and are clearly highlighted in color for ease of reference. We believe that these revisions have improved the clarity, scientific rigor, and overall readability of the manuscript.

We appreciate the reviewer’s guidance and hope that the revised version meets the expectations for publication.

 

Author Response File: Author Response.docx