Persisting Shadows: Unraveling the Impact of Long COVID-19 on Respiratory, Cardiovascular, and Nervous Systems

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors, This is a very timely article about COVID and its consequences. I am two minds about your article. Either this could go with minor revision, but this would end up being another review on long covid or with some revisions you can make it a very insightful article which will contribute substantially to the understanding of COVID.  I will raise this to the editor in chief.  So, if I suggest a major revision, it is by no mean a deficiency in your article. It is simply to add some missing links to make sense of this condition. I am sure that you will agree with me.

First, some editing. I would move the pulmonary effects to the top, followed by cardiovascular then CNS. This is because COVID is primarily a pulmonary inflammatory viral infection.

In the lung, COVID causes serious lung inflammation. However, we need to distinguish between upper airway inflammation and 'deep lung' alveolar inflammation. The majority of the cases suffers from the former and recover sufficiently. it is those who have alveolar inflammation which are of concerns. This is because it is followed by fibrosis. Unlike the fibrosis observed in occupational settings which cause 'hot spots' of fibrotic lesions. This fibrosis is extensive across the alveolar region. it is difficult to spot by x-ray, however, a tracer study clearly demonstrates an impairment of oxygen transfer to the blood. Hence hypoxia.

During lung inflammation, the cortisol level increases which causes an increase in blood pressure. This is common in any organ inflammation and can lead to vessel injury. The vessel repair generates 'microclots' or microparticles in the blood. They are part of the repair process and can be seen as markers of vessel injury.  This is an important clue on how the infection can affect secondary organs. 

People with upper airways inflammation tend to recover fully. The restoration of oxygen transfer to the blood resumes and the vessel injury heals (injury needs oxygen to heal). However, those with alveolar inflammation, there is a persistence of fibrosis which continue to impair oxygen transfer. This means that the vessel injury fails to heal (the microclots persist long after lung inflammation).

It is the impairment of oxygen transfer and the persistence of vessel injury which influence the cardiovascular and CNS effects observed. Furthermore, after the massive inflammation, there is the exhaustion of CD4+ T cells. It is well known  that this is the cells which oversees the transition from inflammation to repair in wound healing. This too can help in the persistence of inflammation. These conditions, rather than the virus presence in the cardiovascular of CNS, can explain the observations. To date, some studies shown viral RNA in these areas but a viral spread is not oberved.

Finally, lots is being said about the low level of serotonin in covid.  Serotonin is produced by the gut and can be suppressed by Interferon, e.g. gut inflammation. There are paper that covid can be stored in the gut and gut inflammation can be used to explain the depression suffered by long covid sufferers.

This explain why hyperbaric oxygen treatment helps to reduce the symptoms of long covid. And vitamin C will be helpful. it is Vitamin C is antioxidant and it seems that some long coid patients are vitamin C deficient.

I hope the inclusions of some of points is taken on board, I am sure this will make the paper more up to date as these are the major topics in long covid research. See latest New Scientist article.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Authors review very well about “long COVID-19” which is the global issue after COVID-19 pandemic. I reviewed this manuscript mainly in focus on “Nervous system”. This manuscript has some value to be published in IDR, but there are some specific comments. 

 

Comments to the authors. 

Major comments:

The authors review mainly Central nervous system (CNS), but almost no review about Peripheral Nervous System (PNS) symptoms and Vaccination effects in Long COVID-19. It would be better to review PNS symptoms and vaccination effects in Long COVID-19.

 

Minor comments:  

P1, L33; ACE2 receptor is found in nervous system (See . Journal of Molecular Neuroscience (2021) 71:2192–2209, https://doi.org/10.1007/s12031-020-01767-6). It is better to add “nervous system” in the sentence.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors. Thank you for the extensive editing in such a short time.  This is now a very interesting article. As the field progresses very quickly. I strongly suggest you to consider a follow up paper on a hypothesis regarding long covid which goes beyond what is written here.

Here are a few comments for the next paper (to be anticipated) :)

1. ACE2 is vital for vasoregulation. The desactivation of ACE2 means increase in blood pressure.

2. the microclot is made of fibrin and other materials generated by vessel injury. In long covid these microclots persist in the bloods months after lung inflammation has subsided. This means that the vessels injury persists. This could be due to the lack of oxygen due to fibrosis.  It is worth mentioning that that the covid fibrosis is very different from the fibrosis encountered in occupational settings where it is unevenly distributed in the alveolar regions with some hotspots. In covid it is much more uniformed and not easily seen by x-ray.

Anyway, this is for the next paper. Well done! I enjoyed reading your article. Look forward to the publication,

Author Response

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Author Response File: Author Response.pdf