Pulmonary Involvement in Recurrent Respiratory Papillomatosis: A Systematic Review

Round 1

Reviewer 1 Report

This is a very good data analysis and literature search that the authors have worked on. As they mention, this entity can indeed be a debilitating condition often requiring multiple surgeries. 

The authors are also self critical and acknowledge the limitations of their study due to the nature of some of the studies and missing variables which is commendable. 

I believe this is a very good presentation and can be accepted. 

Author Response

We really appreciated the Reviewer's efforts and your valuable comments.

On behalf of all the Authors, we really thank you for your approval.

Author Response File: Author Response.pdf

Reviewer 2 Report

This is a comprehensive, largely well-structured manuscript, valuable to pertinent clinical and research readership. 

The reviewer recommends minor edits and feedback prior to acceptance for publication. 

1. Line 85-87: Is the decreased incidence of RRP as a result of vaccines being administered pre-infection (preventive strategy), or vaccination received after infection as prophylaxis? Please highlight this. 

Line 87: ‘potentially therapeutic preventing recurrences.’ This statement is misleading, please update this. 

2. Line 97-98: ‘scanty evidence on the mechanisms implicated in lung/pulmonary involvement and dysplasia in RRP is currently available’ - this seems to be the key hypothesis for this scientific study?!

However, the study design defined in Line 99-102 seems to be – 1. prevalence of lung involvement and lung tumor, 2. Association of HPV subtypes with disease development and progression. Neither of these imply the exploration of mechanisms implicated with RRP. They represent incidence and association- etiology. 

Additionally, the abstract states the evaluation of only one of these hypotheses – ‘The present systematic review was aimed to evaluate the prevalence of severe complications, as lung involvement and lung tumor in JORRP and AORRP patients.’

This creates some confusion to the reader. Please consistently word the aims of this study across the manuscript.

3. Line 161 & Figure 1: 48 Studies were screened; 25 full texts were evaluated. Explain why remaining 23 were removed? In figure 1, are these 23 part of the reports not retrieved n=0? 

4. Lines 324-327: This is an important highlight and outcome for the study; however, the wording is confusing and tedious. Please reframe to simplify. 

E.g., Our study highlights the value of standardizing HPV testing and genotyping clinically for RRP lesions. This would help pave the way for further studies that evaluate the mechanisms toward lung involvement and tumor development and their potential for malignant transformation, considering the known association of HPV and cancer development.

5. Conclusion – Please include a conclusion of the study aims mentioned at the end of introduction section lines 97-102, and consistent with the changes suggested in review point 2 above. 

6. 1 supplementary file was provided, labelled S1. Table 3. Reference to this supplementary file in the main text is missing. Additionally, supplementary tables 1 and 2 were missing alongside the supplementary file.

Minor editing of the English language is required.

Author Response

Please, see the attached file.

Author Response File: Author Response.pdf

Reviewer 3 Report

This is a potentially important contribution to the literature regarding pulmonary involvement in RRP among children and adults. 

Please address the following concerns:

1. With the uptake of the HPV4/HPV9 vaccine in the developed world, the incidence of JORRP has decreased dramatically.  The references 2-6 are insufficient and misleading regarding previously reported incidence of 4/100,000.  A discussion of this phenomena would be important along with updated references in the US and Australia would be appropriate.

2.  References 11,12 and 5 do not adequately cover the role of adjuvant therapies.  Line 304 stating that the two most common adjuvants are interferon and cidofovir is inaccurate.  Systemic bevacizumab, HPV vaccine and cidofovir are currently the most commonly used adjuvants with systemic bevacizumab, immune checkpoint inhibitors and the investigational DNA vaccines in clinical studies by Inovio and Precigen are the most commonly used for pulmonary disease.  Please update references and discuss the current state of the art.

There are minor grammatical errors that are correctable by having a native English speaker review the manuscript.

Author Response

Please, see the attached file.

Author Response File: Author Response.pdf