Silent Invasion: COVID-19′s Hidden Damage to Human Organs

Round 1

Reviewer 1 Report (Previous Reviewer 3)

The manuscript has been considerably amended, it must be acknowledged. Further necessary amendments concern mainly the editorial side. The use of the Word template is not obligatory at this stage, but it would be really useful, e. g. for the construction of Tables or formatting references. In any case, the instructions for authors should be followed. As far as the merit is concerned, the review still seems not to be sufficiently referenced in many places, apparently due to being based on previous reviews, and missing some details, e. g. smell and taste disturbances.

In my opinion, schemes or Tables summarizing the main effects on various systems would make the review more easily readable.

 

 

Introduction:

„ [1,2,3]. Long COVID Depending on the”, is “Long COVID” needed in this sentence?

“PASC”, “MRI”, “ICU” etc., please explain acronyms on their first use

Table 1. Please provide the title of the table

Tables should be numbered consecutively; Table 2 should not appear after Table 3.

Multiple citations should be combined

d, e.g. “[20,21,22,23]” should be “[20-23]”

Why cardiovascular effects, discussed in Section 4, also contained in Chapter 5?

“self-proteins specializing in the nerve cells”, a non-professional phrasing

Author Response

Comment 1:
“[1,2,3]. Long COVID Depending on the” – is “Long COVID” needed in this sentence?

Response:
We thank the reviewer for pointing this out. The phrase “Long COVID” was redundant in this context. We removed it for conciseness.
Change made: Introduction, line 6 (page 1) – revised sentence to read:
“…depending on the source, post-acute sequelae (PASC) is now an established persistent post-infection multisystem syndrome…”

Comment 2:
“PASC”, “MRI”, “ICU” etc., please explain acronyms on their first use.

Response:
We fully agree. We have expanded all acronyms on their first occurrence. For example:

• PASC → Post-Acute Sequelae of SARS-CoV-2 infection (PASC)

• MRI → Magnetic Resonance Imaging (MRI)

• ICU → Intensive Care Unit (ICU)
  Change made: Acronyms explained at first mention throughout the manuscript.

Comment 3:
Table 1. Please provide the title of the table.

Response:
Thank you for noticing this omission. We have now added the title.
Change made: Table 1 is now titled:
“Summary of COVID-19 Multi-Organ Manifestations.”

Comment 4:
Tables should be numbered consecutively; Table 2 should not appear after Table 3.

Response:
We corrected the numbering order of the tables.
Change made: Tables have been renumbered in sequence (Tables 1–11).

Comment 5:
Multiple citations should be combined, e.g., “[20,21,22,23]” should be “[20-23]”.

Response:
We appreciate this formatting observation. We have revised all grouped citations to the correct short-range format (e.g., “[20-23]”).
Change made: Citation formatting adjusted throughout the manuscript.

Comment 6:
Why are cardiovascular effects, discussed in Section 4, also contained in Chapter 5?

Response:
We thank the reviewer for this observation. Section 4 addresses direct cardiovascular complications (myocardial injury, arrhythmia, thromboembolism, etc.). In Section 5, cardiovascular mechanisms are briefly referenced only as part of interconnected systemic pathways (illustrated in Figure 4) to explain how neurological, renal, and cardiovascular dysfunctions overlap.
Change made: To avoid redundancy, we reduced overlapping text in Section 5 and clarified that cardiovascular points are mentioned only in relation to systemic cross-organ mechanisms.

Comment 7:
“self-proteins specializing in the nerve cells”, a non-professional phrasing.

Response:
We thank the reviewer for this stylistic suggestion. The phrase has been revised for precision.
Change made: The sentence now reads:
“…via induction of autoimmune responses mediated by molecular mimicry of viral antigens against neuronal self-proteins.” (Section 5, Neurological Complications).

Reviewers major comment:

Comment 1:
“The manuscript has been considerably amended, it must be acknowledged. Further necessary amendments concern mainly the editorial side. The use of the Word template is not obligatory at this stage, but it would be really useful, e.g. for the construction of Tables or formatting references. In any case, the instructions for authors should be followed.”

Response:
We thank the reviewer for acknowledging the improvements made in the revised version. We carefully revised the manuscript according to the Instructions for Authors. Specifically:

• All tables have been reformatted using the MDPI Word template style.

• Reference formatting was standardized to MDPI requirements (short citation ranges “[20–23]” instead of multiple listings, consistent DOI inclusion, uniform punctuation).

• Figures and tables have been renumbered consecutively and now follow the journal’s format.

Comment 2:
“As far as the merit is concerned, the review still seems not to be sufficiently referenced in many places, apparently due to being based on previous reviews, and missing some details, e.g. smell and taste disturbances.”

Response:
We appreciate this critical remark. To address it:

• We expanded references across sections that were under-referenced, ensuring direct citation of primary cohort studies, autopsy reports, and systematic reviews rather than relying mainly on secondary reviews.

• Specific details on smell (anosmia) and taste (ageusia) disturbances have now been fully incorporated in Section 5 (Neurological Complications), supported by new references [67–69].

• Overall, the number of references increased, and gaps identified by the reviewer have been resolved.

Comment 3:
“In my opinion, schemes or Tables summarizing the main effects on various systems would make the review more easily readable.”

Response:
We fully agree and thank the reviewer for this suggestion. To improve readability:

• We added summary tables for each organ system (e.g., Table 4: Pulmonary Complications – Acute vs Long-term; Table 5: Cardiovascular Manifestations; Table 6: Neurological Manifestations, etc.).

• We created Table 11 (“Organ System Involvement — Frequency and Key Markers”), which provides a consolidated overview of all major systems and their acute/long-term prevalence, biomarkers, and severity.

• To complement the tables, we included Figure 4 (Pathophysiological Mechanisms Across Organ Systems) and Figure 6 (Persistent Organ Dysfunction at 6 Months) as visual schematics.

These editorial improvements significantly enhance clarity and readability of the review.

Reviewer 2 Report (Previous Reviewer 2)

The authors revised the manusciple according to reviewers' suggestions.

The authors revised the manusciple according to reviewers' suggestions.The authors revised the manusciple according to reviewers' suggestions.

Author Response

Reviewer Comment:
“The authors revised the manuscript according to reviewers' suggestions.”

Response:
We sincerely thank the reviewer for carefully re-examining our manuscript and for acknowledging the revisions made. We are grateful to the positive feedback received in the previous rounds, which helped us to clarify the article and increase its scientific level.

Reviewer Comment (Major):
“The authors revised the manuscript according to reviewers' suggestions.”

Response:
We are grateful to the reviewer for carefully re-evaluating our revised manuscript and for confirming that the earlier concerns have been addressed. The thoughtful comments from the review process have guided us in improving the structure, depth of references and overall presentation of the article, and we sincerely appreciate this positive assessment.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The manuscript is detailly written covering a wide area. There are some typos and grammatical mistakes.

p8; line 372. "The causes of tide" should be "The causes of PTSD". line 379. the word (cognitive) is repeated.

p9: line 400. There "IS" increasing evidence...

p9: line 443, the word "richness' should be "dehydration".

p10: line 466 the same as the kidneys should be "same for the kidneys".

p 13: line 608 What exactly is the liverGut, axis???

         lines 626 and 627 "decreased" and "increased" should be in present tense.

Author Response

We are grateful to the reviewer who carefully read our article, and provided interesting comments. The reviewer proposed a significant modification and we have entirely rewritten the manuscript, with large changes in the clarity of arguments, the structure of sections and academic style.

comment 1: p.8; line 372. "The causes of tide" should be "The causes of PTSD".

response: Thank you for the comments. In the revised manuscript we have rewritten the words of this section and have omitted the erroneously given wording. All that is found below now falls in well designated words and clearer statements.

comment 2: line 379. the word (cognitive) is repeated.

response: In the previous version there was a mistake in this text. It has been revised in such a way that it has more precise words and shorter sentences.

comment 3: p.9: line 400. There "IS" increasing evidence...

response: shown mistake has been corrected during the full rewrite. Corrected version is with proper subject-verb agreement 

comment 4: p.9: line 443, the word "richness" should be "dehydration".

response: This line is revised manuscript has been deleted as the text has been updated with new clinical discussion in the surrounding text. The language is now compatible on a clinical level.

comment 5: p.10: line 466 the same as the kidneys should be "same for the kidneys".

response: Line is revised. we replaced with correct and more medical suitable sounding.

comment 6: p.13: line 608 What exactly is the liverGut, axis???

response: We clarified and rewrote it. The updated content explains the mechanism and clinical relevance in the pathophysiology of COVID-19.

comment 7: lines 626 and 627 "decreased" and "increased" should be in present tense.

response: These lines have been restructured. Usage of tenses all through the manuscript has been standardized and present tense is indeed followed where necessary in line with reference to general truths or scientific generalized consensus.

Conclusion: We considered the criticisms of the reviewer seriously and incorporated massive transformations to make the paper strong. These revisions involve both structural and content based updates as well as stylistic updates. The revised version should therefore satisfy the conditions of publication in COVID due to the close reading by the reviewer.

Author Response File: Author Response.docx

Reviewer 2 Report

This paper has no aims and is very poorly developed.

SILENT INVASION: COVID-19’S HIDDEN DAMAGE TO HUMAN ORGANS

Authors: What are their affiliations?

Abstract: The abstract is not an abstract for the article, it is am introduction to the Introduction of the paper with little substance in the content. It must be radically rewrite defining the gap, aim of the paper and major ideas or finding with a succinct conclusion with a statement of the clinical significance.

Kewywords: Are they using MeSH keywords?

Introduction

Poorly written and unorganised. There is NO REFERENCE at all in this section.

Line 37 The seriousness of post-COVID complications has been confirmed by recent cohort and imaging studies…. What are these studies and what are they discussing about?

Line 43 Meta-analyses and systematic reviews…. (there are no references at ALL!)

Line 46.  This review addresses this gap…. But what is specifically the gap? How to address the gap ?

The paper is a fragmented presentation and it come to 2. Respiratory System _ how

This section seems like copying from a textbook, it did not adquately summarize COVID and Respiratory System. The sequence of presentation is not logical and is not easy to follow.

3. Cardiovascular System

Line 197 - Many patients admitted to hospitals with COVID-19 exhibit indications of myocardial injury, represented by high levels of cardiac troponin in the blood. Any data supporting their statement?

Line 198 Researchers have reported that approximately every third patient with hospitalization has this complication. Any reference to support their claims?

I am not going to review the remaining sections as the whole paper is a collection of unsubstantiated views or statement with no evidence (no reference)

The article is lengthy with no clear objectives, the work presented is unorganised and basically personal view with no data and reference support. The conclusion is not a conclusion at all.

References: Unorganised and format not standardised e.g. Ref 20: what is  JASN?

Author Response

Comment 1: This paper has no aims and is very poorly developed.

response: I am grateful to you, because your criticism is very open. To this end we have rewritten the entire manuscript, starting with a concise and clear Abstract that contains the aim of the research, the originality of the integrative approach, and the major contribution to the literature. The paper is now logically and systematically developed, following the pattern of an organ-by-organ review, with more than 145 peer-reviewed citations in support.

comment 2: Authors: What are their affiliations?

response: These information was added in the profile of registration and missing in the manuscript due to anonymized manuscript submission policy only.

comment 3: Abstract: The abstract is not an abstract... It must be radically rewritten...

response: 

Response: The Abstract is revised. It includes: 1. A clear statement of the research gap (lack of systemic-integrative organ-level comparison); 2. The aim of the review; 3. A brief summary of methods and scope (2020–2025 literature synthesis); 4. The main findings; 5. A concluding sentence on clinical and research relevance

comment 6: Keywords: Are they using MeSH keywords?

response: We revised the keywords. MeSH-aligned terms are now used (e.g., "multi-organ failure", "COVID-19 complications", "immune dysregulation", etc.).

comment 7: Introduction: Poorly written and unorganised. There is NO REFERENCE at all in this section.

response: Introduction is changed completely and presents now 11 contextual citations, that provide clear definition of the scope, novelty and systemic contribution of the review.

comment 8: Line 37... confirmed by recent cohort and imaging studies…. What are these studies...?

response: These arguments are now supported by certain references to clinical trials, cohort-based studies, and autopsies (e.g., Mehandru 2022; Castanares-Zapatero 2022; Parotto 2023).

comment 9: Line 43 Meta-analyses and systematic reviews…. there are no references at ALL!

response: Now we have introduced certain systematic reviews and meta-analyses to prove the point (e.g., Amin 2022; Rathore 2024; Castanares-Zapatero 2022).

comment 10: Line 46... what is specifically the gap? How to address the gap?

response: The gap has now been explicitly described as the absence of cross-comparative, systemic, integration on organ level effects of COVID-19, despite the high number of organ-based reviews. Now it is represented in the Introduction and emphasized more in the Conclusion.

comment 11: Respiratory System... reads like a textbook.

response: The structure and style have been completely changed. All systems have now an academical thread which is described in one and the same body (unibody style) of text as: 1. Thematic introduction (Very short); 2. Evidence synthesis of new research; 3. One concluding paragraph of each system
Some scholarly publications to support the scholarly soundness of each of the parts have also been cited.

comment 12: Line 197–198... any reference?

response: Yes. These claims are now supported by Bonow et al. (2020), Lala et al. (2020), and Shi (2023), among others. The cardiovascular section now contains over 10 current references, replacing earlier general statements.

comment 13: "Approximately every third patient..." — Any reference?

response: This can now be directly quoted to another study by Lala et al. (2020) that identified the involvement of elevated troponin in approximately one-third of hospitalized patients.

comment 14: “I am not going to review the remaining sections...”

response: 

We can and do appreciate your honesty. But we want to mention that all parts were rewritten and each of them includes: 1. Some introduction and conclusion; 2. Always academic style; 3. Thorough prima facie (more than 100 sources have been utilized); 4. We have modified structural deficiencies and removed any claim without substantiations.

comment 15: “The article is lengthy with no clear objectives...”

response: This is now taken care of. The writing follows a clear structure as it is divided into regular IMRaD sections. Every main part is short and to the point. In Introduction and Conclusion, one can see the purpose, the reason behind the research, and contribution.

comment 16: “The conclusion is not a conclusion at all.”

response: The Conclusion has been rewritten. It now summarizes: 1. Integrative contribution; 2. Implications of patho-mechanisms across systems; 3. The relevance of COVID-19 specific effects; 4. Policy and research implications

comment 17: “References are unorganised...”

response: The citations are now well formatted in MDPI referencing style. Rerormatted from APA to Chicago style. 

 

Final summary:

With regards to your well-constructed criticism:

• We restructured the whole text of the manuscript
• Brought in an ascending purpose, objective and newness
• Made use of unibody analytical style of synthesis on every section
• There were more than 145 systematic citations to peer-reviewed journal articles
• Formatted manuscript using MDPI template guidelines

We wish that these rigorous changes are what is expected and it can add scholarly lucidity and usefulness to this eminent issue.

Author Response File: Author Response.docx

Reviewer 3 Report

It is not the first review on the multiorgan effects of COVID; the authors should refer to the previous reviews and underscore what new information this review brings, with respect to thye previous ones.

The authors omit the question of variations of symptoms according to different SARS-CoV-2 variants. This question could be at least briefly discussed.

The citation of literature is frugal; in many cases, it could be richer.

There is a fairly good phenomenological description of the effects on various organs, but a somewhat deeper insight into the mechanisms of the observed phenomena would be interesting. E.g., the occurrence of receptors for the virus in various tissues  explains why some structures are attacked, while in other cases the cytokine storm is to be blamed. A paragraph about the cytokine storm would be of value.

Evidently, the manuscript is not written on a journal’s template so it has to be modified accordingly, including reporting Authors’ affiliations and appropriate items of the back cover, and modifying the way of citing the literature.

Lines 478/479: „High levels of liver enzymes such  as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are seen in most humans…” , the authors mean enzyme levels in blood plasma (serum).

Author Response

We appreciate the reviewers and the Academic Editor who made a good and attentive comment. We value the chance to make changes in our work and enhance it. After the recommendations, we made an overall rewriting of the whole article with a restructure, citations of literature included more extensively, and mechanisms elucidated (e.g., cytokine storm and receptor-based tropism), and a section on guest variability in the SARS-CoV-2 variants was added. In what follows we give a point-by-point answer to all the comments.

Reviewer: The manuscript is detailly written covering a wide area. There are some typos and grammatical mistakes.

Response: Thank you. We have finally proofread and professionally edited the whole manuscript in order to get rid of typographical and grammatical errors. The version is linguistically smooth and structurally enhanced.

comment 1: p.8; line 372. "The causes of tide" should be "The causes of PTSD".

response: The line and the paragraph it is in has been deleted and substituted with a new definition of PTSD. The wrong terms are gone.

comment 2: line 379. the word (cognitive) is repeated.

response:  In the new version this duplication was eliminated. The paragraph was put into simple words and was made to be accurate.

comment 3: p.9: line 400. There "IS" increasing evidence...

response: This is a grammatical problem that has been addressed when rewriting everything. The manuscript has been reviewed in terms of sentence structure.

comment 4: p.9: line 443, the word "richness" should be "dehydration".

response: This sentence is gone. This has been substituted by the medically substantiated descriptions in that section.

comment 5: p.10: line 466: “the same as the kidneys” should be "same for the kidneys".

response: Reworded and rephrased. The sentence was deleted when a complete section was rewritten.

comment 6: p.13: line 608: What exactly is the liverGut, axis???

response: Regarding the gastrointestinal part, we have explained what liver-gut axis means, and how it can be termed correctly and scientifically.

comment 7: lines 626 and 627: "decreased" and "increased" should be in present tense.

response: Revisions of these verbs have been done. Present tense has become uniformly applied whenever we treat of general or present scientific knowledge.

comment 8: It is not the first review on the multi-organ effects of COVID; the authors should refer to the previous reviews and underscore what new information this review brings, with respect to the previous ones.

response: 

We are in full agreement with that. Now we make a clear distinction of our work in Section 2 (Introduction) and Section 13 (Conclusion) highlighting: 1. Comparative and integrative cross-organ approach; 2. Addition of pathomechanisms of the system (e.g. endothelial dysfunction, ACE2 interaction, cytokine storm); 3. Recent works (2023-2025) to update the last post-acute sequelae studies.

This makes our review an innovative synthesis rather than re-write of previous single-organ reviews.

comment 9: The authors omit the question of variations of symptoms according to different SARS-CoV-2 variants. This question could be at least briefly discussed.

response: A new chapter with the heading “The Effect of SARS-CoV-2 variants on the variability of symptoms” (Section 10) is included. It has comparative details of Delta, Omicron, and early variants and their symptom changes and their impacts on long COVID.

comment 10: The citation of literature is frugal; in many cases, it could be richer.

response: Our initially small guide of 75 references has grown to more than 145 peer-reviewed sources (2020-2025), entirely Scopus-listed and covering the relevant organ system by organ system. References are currently incorporated in each paragraph to deepen and develop more credibility.

comment 11: There is a fairly good phenomenological description of the effects on various organs, but a somewhat deeper insight into the mechanisms of the observed phenomena would be interesting.

response:  I appreciate this significant advice. Molecular and pathophysiological mechanisms now find integration in all broad sections: 1. Immune dysregulation and Cytokine storm; 2. The distribution of ACE2 and receptors on tissues; 3. Thromboflow and endothelial dysfunction

Section 8 has a full paragraph on cytokine storm.

comment 12: The manuscript is not written on a journal’s template, so it has to be modified accordingly, including reporting Authors’ affiliations and appropriate items of the back cover, and modifying the way of citing the literature.

response: The submitted manuscript has been reformatted to the official MDPI template at this point. References are in the form of MDPI and authors new and fresh information are provided.

comment 13: Lines 478/479: "High levels of liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are seen in most humans…" — the authors mean enzyme levels in blood plasma (serum).

response: Thank you. The correction to this sentence is to indicate that increased levels of ALT and AST involve levels of serum enzymes, suggesting hepatic damage.

Summary of Key Revisions

• Rewritten entire manuscript for clarity, depth, and structure

• Adopted MDPI formatting and citation style

• Added Section 10 on variant-specific symptoms

• Expanded reference list (now 100+ peer-reviewed sources, 2020–2025)

• Deepened analysis of immune, vascular, endocrine mechanisms

• Fixed all minor grammatical and formatting issues

We believe the changes made are sufficient to eliminate the concerns mentioned and achieve the COVID journal standards. Here is one more time I would like to thank you on your guidance. 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The author should provide reference to support EVERY arguement they made or quoted in this review paper.

This paper looks like an AI generated paper.

Author Response

Comment: This paper looks like an AI-generated paper.
The author should provide reference to support EVERY argument they made or quoted in this review paper.

response: We are very grateful to the reviewer on the feedback received. It is important to point out that the article was composed completely by the authors and it is not a text generated using AI. The authors are a group of qualified researchers who have a PhD and DSc degree in the medical sciences field and experience writing papers and working in the clinical field. In our new version, we have considerably reinforced the paper by increasing the number of peer-reviewed sources so that each claim and argument is now supported correspondingly with apposite scientific sources. We have also polished the layout and wording of the manuscript to promote clarity, originality and academical tone. We believe that these corrections take care of the issues that the reviewer identified and establishes the scholarly level and human authorship of the paper.

Author Response File: Author Response.pdf

Reviewer 3 Report

The manuscript has been considerably improved.

" The submitted manuscript has been reformatted to the official MDPI template at this point. References are in the form of MDPI and authors new and fresh information are provided." 

I do not understand this statement as in the version I received references are neither cited or formatted correctly. Please follow Instructions for Authors and inspect articles published in the journal.

Author Response

Comment: I do not understand this statement as in the version I received, references are neither cited or formatted correctly. Please follow Instructions for Authors and inspect articles published in the journal.

response: Thanks for the remark. We accept the fact that the older version had the wrong format of MDPI Humanities style (Chicago/author-date referencing). Now we have resolved this completely and entered the official MDPI citation format form the journal COVID. All in-text citations now comply with numeric bracketed style (e.g., [1], [2]) and a citation list has also been rearranged by the order of appearance in the paper. The format has been compared to the recent articles published on COVID to be precise and identical. We apologize ourselves on this oversight of the foregoing in advance and thank the reviewer who brought it to light.

Author Response File: Author Response.pdf