SARS-CoV-2-Induced Pathology—Relevance to COVID-19 Pathophysiology

Round 1

Reviewer 1 Report

Thank you for the opportunity to review this very important paper. It is a valuable resource with 1,200 autopsies studied. I am a radiologists who has looked at COVID 19 on chest CT and like other authors noticed its predominant lower lung peripheral distribution which suggests a vascular insult as the initial point of viral entry into the lung. Please consider given your significant experience that the virus could have entered the circulation in the nose, you mention how it violates the cribiform plate. Then it would gain access to the SVC and ultimately the heart and pulmonary artery. In the smallest peripheral capillaries it could infect the endothelial cells and disrupt the basement membranes allowing leakage of fluid and virus into the interstitium and then the alveoli where it could infect the AEC2. The nasal cilia are excellent filters for particles of 5um which the virus with droplet measures and should not enter the airway. If the virus was inhaled I would expect an upper lobe central distribution instead of lower lobe peripheral. 

With the radiology in mind please consider how your findings might support this pathway given that you state the importance of the vascular infection multiple times in the manuscript. If you agree you might consider revising the paper to include this mechanism and not only inhalation.  The fact that you see the virus in other organs suggests it must travel through the blood to get to the thyroid gland for example.

I love the images you have provided but because I am not a pathologist I request that you add more description and arrows so that everyone can benefit from your observations.

 

 

 

Author Response

Dear reviewer, many thanks for your work and numerous interesting ideas concerning the pathogenesis of coronavirus infection, we included in the text. We also prepared more detailed descriptions of the figures and added appropriate arrows

Reviewer 2 Report

This article need to improve.

1. Figure legends should be details and self explanatory.
2. Results should have flow and clear. 
3. Aims of this paper not clear.
4. Figures are not clearly marked by arrows.

Author Response

Dear reviewer, thanks for your work and positive evaluation of our study We gave more detailed descriptions with arrows for the figures and making the results more clear formulated, as well added the aim of our work

Reviewer 3 Report

We congratulate the researchers for their outstanding and deep research efforts on an important topic about Covid-19

 

The authors did a comprehensive screening analysis of histopathology in l200 lethal cases of COVID 19.   They perform a wide spectrum of immune histochemical reactions ( 21 parameters including many CD, virus proteins, etc  )  in addition to electron microscopy. They could confirm the ability of SARS-COV-2 to cause myeloproliferative changes, primarily in epithelial and endothelial cells.  They demonstrated the lesions of the microcirculatory bed -  direct viral damage, and a variety of extrapulmonary lesions.  They explained the possible mechanism of COVID-19 complications leading to death including its auto-immune nature.

The article has many strengths which include : 

Originality:  The topic is authentic and deals with very important studies related to the causes of death due to the Covid-19 pandemic

 Methodology:  The methods of work are clear and lead to the achievement of the objectives of the research. In this context complete clinical autopsies were performed  &  comprehensive immunohistochemistry, and histological investigation, adopting sophisticated techniques including assessment of CD antigens, and markers of apoptosis;  in the tissues of the lungs and several internal organs.

Presenting the results in an organized and convincing manner, supported by clear images

Discussion :The explanation of the results is convincing, organized, supported by modern references, and the conclusion is derived and based on actual results and practical recommendations.

 Minor issues, ( opinion )   to consider scoring system whenever possible to evaluate the extent of histological changes in lung tissues. In discussion to address the possible impact of comorbidity, potential adverse effects of COVID-19 medication on clinical outcome

Author Response

We are grateful the reviewer for the appreciation of our work, understanding that the further investigations are necessary

Round 2

Reviewer 2 Report

It is improved.

Author Response

Dear Reviewer, thanks for your work and positive evaluation of our study. Figure legends were detalized. Aims of the sudy we added. Arrows were added in the most of the pictures ( in zip-file after revision)

Author Response File: Author Response.docx