Modulation of the Host Response as a Therapeutic Strategy in Severe Lung Infections

Round 1

Reviewer 1 Report

Comments for the Authors

The authors analysed CDC data on the use of sepsis and COVID-19 on death certificates for the year 2020, the first year for COVID-19 pandemic in the US. They found that although CDC had reported sepsis in one out of six COVID-19 deaths, their analysis found it in only one out of ten COVID-19 deaths. They also found a two-fold variation (6 to 12%) of sepsis appearing on COVID-19 death certificates in ten DHHS regions. They offered no clear explanation for this difference and concluded that the correct number of sepsis-related COVID-19 deaths remained unknown, although it seemed that the association of sepsis with COVID-19 deaths was an underestimate.  

The authors concluded that COVID-19 made only a “modest” contribution to sepsis-related deaths in 2020, despite its appearing in 53% (or more) of COVID-19 deaths in reports that appeared in the second pandemic year or later. The authors correctly admit that clinicians were uncertain about the cause(s) of death for their patients in the first pandemic year, although it seemed that the association of sepsis (and its associated multi-organ dysfunction) and COVID-19 deaths was an underestimate.  

Although the authors admit that COVID-related multi-organ dysfunction represents sepsis, they avoid discussing the impact vaccination (and perhaps more effective treatment) had on COVID-related sepsis deaths. 

Author Response

Dear Reviewer 1,

Thank you very much for your comments. We would like to kindly point out that the reviews submitted do not match the contents of our review entitled “Modulation of the Host Response as a Therapeutic Strategy in Severe Lung Infections”. It appears the comments are for a different article that focuses on sepsis and COVID-19.

Reviewer 2 Report

Review:

This review by Latreille and Lee discusses the pathophysiology of ARDS caused by respiratory pathogens, the limitations of traditional anti-pathogen treatments, and the potential of host-targeting strategies as promising alternatives for mitigating damage and preparing for future pandemics.

There are a few concerns that I listed below, but overall this article is well written, timely, and provides a detailed overview that will be of interest to the ARDS research community and probably also to the general public.

Add references to lines 29-33.

Line 71: explain the “Berlin definition”.

Line 80: exchange the word “pathway” as it sounds like you’re discussing cellular pathways/signaling pathways.

The authors should consider including artesunate compounds (potent host-directed antivirals) in their review.

Typos etc…:

Include spaces before your references (“poor outcomes [1]” instead of “poor outcomes[1]”, for example).

Be consistent with British vs. American English (signalling/signaling, for example).

Check your whole manuscript for verb tense consistency again!

Remove multiple double spaces, see lines 368 or 439 for example…

Keep capitalization consistent… See “Influenza” vs “influenza” lines 13 and 31.

Throughout the manuscript, please spell out the complete terms upon their initial reference, provide the corresponding abbreviations in parentheses, and utilize the abbreviations subsequently.

PS: Quite similar reviews have been published lately… See https://doi.org/10.3389%2Ffimmu.2021.660632, https://doi.org/10.3389/fimmu.2020.00767, or https://doi.org/10.1038/s41577-022-00734-z... These should be mentioned/cited or, if not, that should be convincingly discussed in the rebuttal letter.

Author Response

Dear Reviewer 2,

Thank you very much for your feedback and the specific suggested revisions for our manuscript entitled “Modulation of the Host Response as a Therapeutic Strategy in Severe Lung Infections”. As per your suggestion, we have added a reference to lines 29-33, added spaces between the word and reference (ex word [1]), removed the word “pathway” (substituting "consequence") in line 80, double checked abbreviations and revised verb tenses throughout the manuscript. The Berlin definition is already explained in lines 71-75, but we added an additional reference. In regards to Artesunate, we believe this is beyond the scope of the review, which is focused on host modulation independent of viral replication. While Artesunate may have host modulating actions, its mechanisms of action in the context of lung injury are not as well studied. We have added the suggested references discussing reviews about host modulation as a therapeutic approach, however we would like to note that our review is unique as there is very little literature that reviews and focuses on the endothelium as we do here.