Adverse Audio-Vestibular Effects of Drugs and Vaccines Used in the Treatment and Prevention of COVID-19: A Review

Round 1

Reviewer 1 Report

The Authors responded satisfactorily to all our previous comments.

Author Response

I would like to thank you for the review.

The corresponding author

Reviewer 2 Report

It is still unclear what the Authors mean by „the updated review”. I attach a manuscript that deals with various types of reviews and their goals as well as methodologies with a request to choose an appropriate review format and then apply the respective methodology.

The opening sentence in the Abstract is still problematic:

“Although the COVID-19 outbreak occurred in December 2019, when cases of the unknown disease were made public, for the next 2020, 2021 and 2022, an ongoing pandemic was the cause of one of the biggest public health crises.”

It reads: “Although the COVID-19 outbreak occurred in December 2019 (…) for the next 2020, 2021 and 2022, (…) pandemic was the cause of (..) health crises.”

First, 2022 just commenced, so one cannot be sure if the crisis persists, and one should not refer to that year in the past as it is still ongoing.

Second, there is no logical link between the “Although the COVID-19 outbreak occurred in December 2019” and “pandemic was the cause of (…) health crisis”.

“Although” means ‘in spite of something’ and is subordinating conjunction. This means that the clause it introduces is a subordinate clause, which needs a main clause to make it complete. E.g., “Although it was rainy (subordinate clause), I went for a walk (main clause).” Please revise.

The entire manuscript needs professional English revisions. Please perform these after introducing revisions regarding the methodology (type of review and respective methods).

Please specify precisely in which combination the keywords were used.

Please specify inclusion and exclusion criteria.

Please provide a table containing the information about manuscripts included in the review and the primary information extracted for this work.

Comments for author File: Comments.pdf

Author Response

Dear Reviewer,

our answers are in the separate dok in the attachment. We are truly grateful to reviewers’ critical comments and thoughtful suggestions. Based on these comments and suggestions, we have made careful modifications on the original manuscript.

Yours sincerely, corresponding author

Author Response File: Author Response.pdf

Reviewer 3 Report

Reviewing MS Manuscript ID: audiolres-1623208
 : Audio-vestibular adverse effects and ototoxicity of drugs and vaccines used in the treatment and prevention of COVID -19 in perspective of 2021 and 2022 – the scoping review.

I have read with attention the article entitled  “Audio-vestibular adverse effects and ototoxicity of drugs and vaccines used in the treatment and prevention of COVID -19 in perspective of 2021 and 2022 – the scoping review”.

This text is well documented; the introduction is interesting and well presented . However it is too long (>30 pages ), and overall the text should be simplified, is in many places difficult to understand and should need to be corrected by an English native speaking collaborator.
The Table 1 which includes 12 pages is well documented but could be simplified and the numbering of tables should be revised to be of more utility for the reader

However there are many minor and major drawbacks which must be addressed

Minor remarks

 in the abstract typing error line 29 The sentence “…is no longer recommended for patients suffer from COVID-19;…” should possibly be replaced by :“…suffering  from..” or:” …patients who suffer from…”

The sentence line 29 to 31 is not clear and should be rephrased:” oseltamivir and ivermectin, is no longer recommended for patients suffer from COVID-19; 39 publications that 15 summaries of product characteristics (as other sources of data) were enrolled to this analysis”. . Does it mean “39 Publications which summarize 15 product characteristics …” or something else…?

The word “by” line 27 could be deleted

The sentence  line 32 to 33 is not clear and should be rephrased or simplified : eg; “”..as well as be an indirect effect as a possibility of interaction..” could be:” as well as be an indirect effect for a possible interaction..”

In the abstract conclusion the sentence line 38-39 :” The ototoxicity of the drugs presented in the manuscript does not represent such severe symptoms as the drugs used in the treatment of COVID-19 in 2020 (e.g. hydroxychloroquine)” is not clear and should be rephrased

The last sentence  line 42 -43 should be modified and the end of the sentence:“..can be used in the diagnosis of patients.”  should be deleted since the diagnosis of covid 19 patients does not depend on audiological tests but on PCR tests etc..If you want to keep the end of this sentence ( which is not necessary) you must precise “… diagnosis of patients with side effects”

Chapter 1.1.  line 79 title “ pharmacological treatment of CVOID-19” should be :”…COVID -19”

line80 “ approved( UE)” should be “approved (EU)”

Chapter material and methods line1 72; “there were not limit the time -frame of our work” should possibly be:” there was no limit to the time -frame of our work” or : there were no limits to the time -frame of our work”

Line 187:”The inclusion criteria for searching was (1) …”should possibly be : ”The inclusion criteria for searching were (1) …” or: ”The inclusion criterion for searching was (1) …”

There is a problem of numbering into tables: there are 2 tables 1 : the first one with 39 ref.  is mentioned p 19 ( It concerns the 39 peer reviewed papers selected in literature and retained by the authors( Products double blinded studies vs placebo)( a possible classification in 3 categories (for example)of these 39 data papers by topics could be appreciated)

The second table 1 which is a mingle of different vaccines and anti viral treatment is mentioned p 29

And there is a third table p 25 – 26 which has no numbering (and is separated in the present presentation from the table p 25-26) and could be a table 2? And possibly be part  of the table p 29 which could be more precisely and clearly entitled : “ the 15 products characteristics..): in this table there is a mingle of side effects of corticosteroids  and antiviral therapies (which could be classified by topics of interest and triggers of treatment)

Chapter discussion: line526: “..for patients suffered from COVID..” should be ““..for patients suffering from COVID”

Line568: “..hearing threshold sat such high..” should be ““..hearing threshold at such high..”

Line 573-574:”..DPOAEs cand effect ototoxic..” do you want to tell:” :”..DPOAEs can detect ototoxic…”

Line 599”..possible to for perform baseline..” should be “possible to perform baseline” (delete”for”)

Chapter conclusion line 630: possible  typing errors  “…occur only in hypersensitive people as apart of anaphylactic shock and as adverse re action..) should possibly  be:” occur only in hypersensitive people as apart of anaphylactic shock and as adverse reaction” (suppress the gap in “re action” and possibly to  avoid any confusion replace  “apart” by “different from”)

There is in some places a problem of line intervals ( e.g. lines 491 to 510 the interval is different from the following and previous other parts : please homogenize)

Other remarks

In the introduction one could regret the absence of presentation of possible cochleo vestibular effects by the Covid 19  itself as it has been described possible vestibular neuritis and it is already known that cranial nerves (such as for olfaction) could be implemented. This could be more commented also in the discussion

Chapter  1.1  too long: in this chapter entitled pharmacological treatment of COVID 19 it is question  line 123  to 137 of aminoglucosides, platinum derivates, loop diuretics, valproate, carbamazepine etc.. . there is no place for such considerations in this chapter. It could be suppressed or displaced to the chapter discussion.

In the chapter results the Tables should be adequately numbered

For example inside each  table first part could deal with ant inflammatory or corticosteroids treatment

And a part 2 could deal with anti-viral medication and antibodies therapy

And a part 3 with Vaccines treatment

In the current state these very interesting tables can be poorly used because their contents are too numerous or mingled

Discussion: The natural evolution of CoVID 19 toward otoneurological or vestibular complications should be more precisely discussed in front of drugs side effects

The possible mechanisms of drugs side effects particularly vestibular side effects are not much detailed or discussed (cytotoxic effect, metabolic mechanisms, neuronal mechanism etc..)

Conclusion: the sentence line 631-634 is not understandable in its current form and should be rephrased

Line 636-638: the sentence : “The presented methods of audiological tests allow for very quick determination of drug ototoxicity and can be used in the diagnosis of patients.” Should be for more accuracy: “The presented methods of audiological tests allow for very quick determination of drug ototoxicity and can be used in the diagnosis of patients presenting  side effects.”

Overall this paper is well documented and presents a lot of interesting  information and  data which are unfortunately not well presented or ordered and classified to be better used by the reader. It needs to be clarified and simplified. The tables must be ordered and numbered correctly and classified by topics. There are numerous typing errors  and English language errors in some places which should need a revision by an English speaking native collaborator to improve its understanding

This paper  needs to be modified and major revisions are required mainly in the presentation to improve its usefulness and understanding

Reviewing MS Manuscript ID: audiolres-1623208
 : Audio-vestibular adverse effects and ototoxicity of drugs and vaccines used in the treatment and prevention of COVID -19 in perspective of 2021 and 2022 – the scoping review.

I

Comments for author File: Comments.docx

Author Response

On behalf of other authors, I would like to thank the reviewer for all very important and crucial comments that result in the better quality of this manuscript. To sum up we decided to leave only one table. This table has the most crucial, useful and most important information in the area of ENT and audiology. We hope that this is acceptable for the reviewer. Additionally, the manuscript was cut shot were it was possible. We are still open for further discussion about this manuscript. The team (authors of this manuscript) are specialist in different medical field (ENT, audiology, pharmacy and pharmacology), as a result we have possibility to discussed the problem of audio-vestibular side effects of covid -19 drugs form different angles.

                                                                                            Corresponding author.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Thank you for addressing my comments. However, despite the detailed answer, not much has been changed in the manuscript.

1. It is still unclear what kind of review it is. I asked the Authors to get acquainted with the publication about the TYPES OF REVIEWS that I attached to my previous comments. Unfortunately, the type of review still remains unclear, and so is the methodology used. The type of review should be named in the title, and the methodology specific for a given type of review should be specified and visibly applied throughout the manuscript.
2. The table with manuscripts included has been used only in the reply but not in the revised manuscript. Apart from that, the table does not contain information about the data extracted from each publication.
3. It still remains unclear which information was extracted from the manuscripts included and used in the review. It is unclear what is the source information about the drugs included. For instance, the source of reference [87] “uvaxovid-Epar-Product-Information_en” is unknown. Please provide precise information (address of web page, date accessed).
4. In the next revision, please substitute the “Diagram 1” with the flow diagram from PRISMA http://prisma-statement.org/ and cite it accordingly.
5. Please specify the information extracted from the publications before getting to the drug characteristics. At present, there is no visible link between the literature search and the description of adverse effects of drugs selected for the review. The reader should know what information from the manuscripts was used in this review and why (justification).
6. Please get acquainted with PRISMA checklist. Although applying PRISMA is necessary for systematic reviews, which this review is not, using PRISMA concepts will be helpful to make this work a whole and not a scrapbook of pharmacological information about the drugs used to treat COVID-19 and their adverse effects on hearing and balance.

Author Response

Dear reviewer, the answers are in the attachment. We hope that our answers will be sufficient.

Yours sincerely, corresponding author

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments on the revised version of the MS 1623208

Adverse audio-vestibular effects and the ototoxicity of drugs

and vaccines used in the treatment and prevention of COVID-19: a scoping review for 2021 and 2022

The previous title was:

Audio-vestibular adverse effects and ototoxicity of drugs and

vaccines used in the treatment and prevention of COVID -19 in perspective of 2021 and 2022 – the scoping review.

In this revised version of the MS there is an effort of shortening and simplification from the authors

However the  title includes redundancies or pleonasm and “audio vestibular adverse effect” is including “ototoxicity”. We suggest to shorten the title  to only mention

“Adverse audio-vestibular effects  of drugs and vaccines used in the treatment and prevention of COVID-19: a review.”

And to delete “scoping” since a review is “de-facto” a scoping work or “updated”

Abstract Line 46 -47: “.. and can be used to help diagnose patients” could be for more clarity: ““.. and can be used to help for the treatment in diagnosed patients” or ““.. and can be used to help to detect side effects in patients ” or more simply to delete it

The last sentence line 45 should be” The audiological tests outlined here allow very quick determination of a drug’s ototoxicity”. This could help to shorten the Abstract which is a bit too long and since” …and can be used to help diagnose patients” does not bring or add real further information.

Line 73” ….ototoxicity and of inducing audiological disorders arising from…” could be for more accuracy :”… ototoxicity and of inducing audiological or vestibular disorders arising from…”

The reader has some difficulties to understand the numbering of chapters

The introduction is numbered: 1.

At the end of the introduction there is a chapter 1.1. entitled: “Ototoxicity as an adverse reaction of drugs in COVID-19”

But there is no Chapter 1.2

Instead the reader finds a chapter 2. Material and methods

Could this be homogenized?

Line 77 and 78 the Acronyms EMA and FDA  (used here for the first time) must be now and there explained since they have been  suppressed in the former initial part of the introduction” Medical Agency (EMA) and the U.S. Food and Drug Administration (FDA).” (line 56)

In the new table 1 at the beginning of the table, column 1 it is mentioned

“NAME OF MEDICATION

AND SOURCINFORMATION

TREATMENT ANTICOVID:

MONOCLONAL

ANTIBIDIES,

ANTI »

What is the last word « anti” addressed to ? :”anti-inflammatory”?  or what else ?; please complete it or delete it. Respect the gaps between each word:” SOURCINFORMATION”

Discussion line 437-438 probable typing error:

It is mentioned” (1) very common (≥ 1/10), common (≥ 1/100 to < 1/100), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (<1/10000), and the last, not known..”

should possibly be:” (1) very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (<1/10000), and the last, not known…”

Line 442 “but this relationship is described as indirect”. Could you briefly explain for the common reader: what does “indirect” mean

Line 449 “..risk death” could be “risk of death” or “death risk”

Line 453 and line 456. Interesting chapter:  vestibular neuritis has been described by Italian authors in some Covid 19 diseases but the ref 88 does not correspond to this situation.

Lines 507 to 516 currently suppressed could have been kept to explain  the criteria retained to consider hearing impairment

In the conclusion . Line 549-550 delete the end of the sentence ”..and can be used in the diagnosis of patients.”

In some sentences the English could be improved by a native English speaking collaborator.

This paper has been improved ; however there are still  improvements to bring and the MS  cannot be accepted in its current form. Care must be brought in its final presentation: chapters numbering coherence, more precise notifications and accurate references are needed in the discussion

Author Response

Dear reviewer,

please see the attachment.

Corresponding author

Author Response File: Author Response.docx

Round 3

Reviewer 2 Report

Thank you for addressing some of my concerns.

I am asking you to read the comments below very carefully and introduce the appropriate changes in the manuscript. 

The proper PRISMA diagram is still not there(can be downloaded free of charge from the PRISMA page). Please use it.

Search technique:
Start a new paragraph for that section. Specify if the keywords were used as separate words or if boolean operators were used? If the latter is the case, please specify the type of boolean operators used and in which combinations with which of the keywords were used.
What was searched? Full text? Abstract and titles? Titles only? Please specify. 
What do you mean by "the clinical trial database"? There are several clinical trial databases, please provide the source.

What were the languages used to write the manuscripts included in the review? It is presently stated that "the majority of publications were written in English." "The majority is not 100%. What were the other languages? Please specify in the manuscripts. 

The inclusion criteria are challenging to understand. "(inclusion criteria based mainly on the e.g. type of clinical trial (randomised, placebo – controlled clinical trials), the number of patients included for trial)". Please list the inclusion criteria following the example below:
The list of inclusion criteria:
-randomized clinical trials
-other clinical trials (here list what other kinds of trials were included)
More than (here number) of subjects)
-another criterion
-another criterion

The list of exclusion criteria:
-publication in Chinese 
-another criterion

If there were no exclusion criteria, please indicate them in the text.

Please make a Table in which the following information will be included:
1. The reference included in the review (with DOI or other sources)
2. Type of reference (peer-reviewed publication, clinical trial)
3. Variables extracted from the publications, for instance, the name of the medication, the dosage, and duration of therapy, the number of patients, the endpoint of the study, results of the study, adverse effects, etc. etc.
This table should be inserted into the text as Table 1.

Table 1 will then feed Table 2, which also needs to be revised, as each medication listed there needs a reference for the source of information provided.  Please revise that Table accordingly. 

Please reorganize the structure of your abstract and discussion. The findings of the scoping review should be addressed first (e.g., the number of publications, types and quality of trials, number of medications identified in total). After that, one can start discussing the adverse effects and mechanisms.

The title indicates that the review will be dealing with "Audio-vestibular adverse effects and ototoxicity". However, the distinction between the "audio-vestibular adverse effects" and "ototoxicity" is not clear. Please define what is meant by each term or use one term only (and the other as a synonym). 

Author Response

Dear Reviewer,

the answers are attached in the attachment. Thank you for all the comments, we hope that now the manuscript will meet the criteria.

Yours sincerely, authors.

Author Response File: Author Response.pdf

Reviewer 3 Report

The present MS can be accepted in its current form

Round 4

Reviewer 2 Report

The manuscript improves continuously – we are getting there but not quite ready yet.

Figure 1 – this new figure indicates a sequential search. Was it so? Please describe the strategy in the figure description.

Figure 2 – Please adopt the default description to your study.

Please split the results into two main sections: publication-based and drug information-based results. I suggest the following structuring of the opening paragraph in the Results section:

1. Please indicate which drugs have been identified during the literature search and during the product search.
2. Please indicate possible overlaps.
3. Please create the classes of drugs (e.g., biologics, anti-inflammatory, etc. etc.) and then present the results from the literature search AND from the product information for each drug identified.

Discussion still needs work. I asked for this in my previous Reviews, but not much has changed. It would help if the Authors opened the Discussion with their own FINDINGS from the literature and product search. How many drugs were identified by your search (literature and product)? To which classes belong the identified drugs?, How many overlaps were there between the two searches? Were there any drugs reported in the literature search but not in the product description or vice versa? What were the symptoms of the adverse effects? Were there any differences in adverse reactions reported in the literature and the product description?

The methods used to detect ototoxicity. Was this information extracted during the literature/product information review? If yes, it should be added to Table 1, or you could create another Table. That could be a piece of very valuable information fitting perfectly into the profile of this journal. By the way, pure tone audiometry (PTA) or speech audiometry are not even mentioned once, and these would be the primary tests performed in clinical settings.

The Conclusions

I will use the present Conclusions to demonstrate the still vague and incoherent statements, which need not only English but also scientific writer revisions. Apart from the grammar and syntax problems, there is no flow, it is just a bunch of sentences unrelated to each other.

Is: The most frequently adverse reactions of audio-vestibular disorders reported in clinical trials and publications in the area of audiology and otorhinolaryngology following the treatment of COVID-19 were dizziness, blurry vision with dizziness, nasopharyngitis, dysgeusia, tinnitus.

Should be: The most frequent adverse reactions of COVID-19 therapies affecting the audio-vestibular system reported in the literature were dizziness, blurry vision with dizziness, nasopharyngitis, dysgeusia, tinnitus.

Is: As far as vaccines are considered, dizziness as an ototoxic effect may occur only in hypersensitive people as apart of anaphylactic shock and as adverse re action with uncommon frequency.

Should be: Dizziness may be infrequently caused by anaphylactic shock induced by vaccination of hypersensitive persons.

Is: The ototoxicity of the drugs presented in the manuscript does not represent such severe symptoms as the drugs used in the treatment of COVID-19 in 2020 (e.g. hydroxychloroquine) and relates mainly to disorders of the vestibulocochlear system.

Should be: The ototoxicity grade of the drugs identified in this work is not as severe as the drugs used in the treatment of COVID-19 in 2020 (e.g. hydroxychloroquine).

Comment: ototoxicity relates to the vestibulo-cochlear system per definition.

Is: However, there is still a need to monitor possible ototoxic side effects as a result of interactions with other ototoxic drugs.

Should be: However, there is still a need to monitor possible ototoxic side effects possibly resulting from the interactions with other drugs.

Comment: which “other ototoxic drugs” do you mean?

Is: Many of drugs approved by EMA and FDA are new substances, and as a result not every side effect is known.

Should be: New drugs approved by EMA and FDA for the treatment of prevention of COVID-19 should be continuously monitored for ototoxicity, as it may occur at a later time.

Is: The presented methods of audiological tests allow for very quick determination of drug ototoxicity and can be used in the diagnosis of patients.

Should be: The presented methods of audiological tests allow for rapid determination of drug ototoxicity and can be used to diagnose patients.

Comment: The audiological tests were not the focus of this review, and this is an inappropriate closing statement for this paper.

Author Response

Answers were attached.

Author Response File: Author Response.docx