The biology of coronavirus COVID-19 - including research and treatments

[Snow Leopard]

https://www.nrc.nl/nieuws/2020/04/1...virus-raken-bloedvaten-in-longen-lek-a3996526

Notably, https://en.wikipedia.org/wiki/Icatibant leads to vasodilation.

There seems to be two opposite hypotheses and a great deal of disagreement as to what is going on in the pulmonary capillaries.

The classical hypothesis based on typical ARDS is the following:



and this:



Classical ARDS also described here: https://www.ncbi.nlm.nih.gov/pubmed/29430449

Yet some emergency physicians have been reporting that they are seeing a different syndrome in COVID patients. This presumably includes those Nijmegen physicians, given that they are trialling Icatibant. (and similarly those physicians who report morphine helps)

The strongest risk factor for mortality of COVID patients is hypertension. There is a great deal of speculation as to whether it is the medication that is the risk factor.

I don't think it is the medication (and I don't think patients should, but rather hypertension itself that is the primary risk factor. This would contradict the hypothesis presented by Victor Tseng above, and instead suggest that the virus (including spike protein fragments) is causing blockage of the ACE2 receptor causing excessive vasoconstriction and hypoxemia similar to the pattern seen in high-altitude pulmonary edema. The fluid build up is due to lung damage, and isn't necessarily cardiogenic as in regular pulmonary edema. Relative vasoconstriction also inhibits fluid clearance. I suspect ACE2 receptor blockage is also a key contributor to anosmia in COVID patients as well.

 

[Barry]

The strongest risk factor for mortality of COVID patients is hypertension.

Do you know if this only applies where the hypertension is poorly managed? Or whether just having the condition is the issue, irrespective of management?

 

[Snow Leopard]

Do you know if this only applies where the hypertension is poorly managed? Or whether just having the condition is the issue, irrespective of management?

Hard to say at this point in time. I suspect there is still high risk irrespective of management.

 

[wigglethemouse]

There is a good article on Stat News that noninvasive breathing support devices perhaps should be used more before switching to ventilators, and then don't use ventilators on the high setting if possible.
https://www.statnews.com/2020/04/08/doctors-say-ventilators-overused-for-covid-19/

But one of the most severe consequences of Covid-19 suggests another reason the ventilators aren’t more beneficial. In acute respiratory distress syndrome, which results from immune cells ravaging the lungs and kills many Covid-19 patients, the air sacs of the lungs become filled with a gummy yellow fluid. “That limits oxygen transfer from the lungs to the blood even when a machine pumps in oxygen,” Gillick said.

As patients go downhill, protocols developed for other respiratory conditions call for increasing the force with which a ventilator delivers oxygen, the amount of oxygen, or the rate of delivery, she explained. But if oxygen can’t cross into the blood from the lungs in the first place, those measures, especially greater force, may prove harmful. High levels of oxygen impair the lung’s air sacs, while high pressure to force in more oxygen damages the lungs.

In a letter last week in the American Journal of Respiratory and Critical Care Medicine, researchers in Germany and Italy said their Covid-19 patients were unlike any others with acute respiratory distress. Their lungs are relatively elastic (“compliant”), a sign of health “in sharp contrast to expectations for severe ARDS.” Their low blood oxygen might result from things that ventilators don’t fix. Such patients need “the lowest possible [air pressure] and gentle ventilation,” they said, arguing against increasing the pressure even if blood oxygen levels remain low. “We need to be patient.”

Researchers and clinicians on the front lines are trying. In a small study last week in Annals of Intensive Care, physicians who treated Covid-19 patients at two hospitals in China found that the majority of patients needed no more than a nasal cannula. Among the 41% who needed more intense breathing support, none was put on a ventilator right away. Instead, they were given noninvasive devices such as BiPAP; their blood oxygen levels “significantly improved” after an hour or two. (Eventually two of seven needed to be intubated.) The researchers concluded that the more comfortable nasal cannula is just as good as BiPAP and that a middle ground is as safe for Covid-19 patients as quicker use of a ventilator.

 

[Mithriel]

My daughter is a nurse on covid19 wards. She says they are going to be trained to use CPAP machines as they are simpler than ventilators so don't need specialised training.

 

[Barry]

There is a good article on Stat News that noninvasive breathing support devices perhaps should be used more before switching to ventilators, and then don't use ventilators on the high setting if possible.
https://www.statnews.com/2020/04/08/doctors-say-ventilators-overused-for-covid-19/

"the air sacs of the lungs become filled with a gummy yellow fluid"

Is this the sort of thing @Jonathan Edwards that some kind of inhalant might help with? Something that might help liquefy the gummy fluid so that it might be easier removed? Obviously liquid in the lungs is problematic, but presumably the lower the viscosity of that fluid the better the chances of removing it?

 

[Andy]

I couldn't find this webpage posted but apologies if I'm duplicating anything.

Researchers from Cambridge, UK, and Germany have reconstructed the early “evolutionary paths” of COVID-19 in humans – as infection spread from Wuhan out to Europe and North America – using genetic network techniques.

By analysing the first 160 complete virus genomes to be sequenced from human patients, the scientists have mapped some of the original spread of the new coronavirus through its mutations, which creates different viral lineages.

“There are too many rapid mutations to neatly trace a COVID-19 family tree. We used a mathematical network algorithm to visualise all the plausible trees simultaneously,” said geneticist Dr Peter Forster, lead author from the University of Cambridge.

“These techniques are mostly known for mapping the movements of prehistoric human populations through DNA. We think this is one of the first times they have been used to trace the infection routes of a coronavirus like COVID-19.”

The team used data from virus genomes sampled from across the world between 24 December 2019 and 4 March 2020. The research revealed three distinct “variants” of COVID-19, consisting of clusters of closely related lineages, which they label ‘A’, ‘B’ and ‘C’.

https://www.cam.ac.uk/research/news...nalysis-provides-snapshot-of-pandemic-origins

 

[TrixieStix]

This possible aspect of Covid-19 seems to be gaining traction....

Neurological Implications of COVID-19 Raise Concerns
Brain infection may contribute to respiratory failure in COVID-19.

https://www.psychologytoday.com/us/...ological-implications-covid-19-raise-concerns

 

[Sly Saint]

This possible aspect of Covid-19 seems to be gaining traction....

Neurological Implications of COVID-19 Raise Concerns
Brain infection may contribute to respiratory failure in COVID-19.

https://www.psychologytoday.com/us/...ological-implications-covid-19-raise-concerns

Another consequence of neuronal infection raises future concerns for patients who recover from acute illnesses. The pandemic has hit so suddenly, possible long-term consequences of the infection are unknown. It is unclear whether the loss of sense of smell is permanent, for example, but recent studies report that the virus remains detectable in some cases for weeks after patients recover and in one patient for as long as 37 days post-recovery. Other viruses that infect neurons can persist for life, such as the herpes virus (HSV-1) that causes cold sores and the chickenpox virus (varicella) that causes shingles. This is because most neurons, unlike most other cells, are not replaced throughout life. So too may SARS-CoV2 reside inside neurons long after the initial lung infection and the pandemic are over.

preprint paper referred to
Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study

Abstract
OBJECTIVE: To study the neurological manifestations of patients with coronavirus disease 2019 (COVID-19). DESIGN: Retrospective case series SETTING: Three designated COVID-19 care hospitals of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. PARTICIPANTS: Two hundred fourteen hospitalized patients with laboratory confirmed diagnosis of severe acute respiratory syndrome from coronavirus 2 (SARS-CoV-2) infection. Data were collected from 16 January 2020 to 19 February 2020. MAIN OUTCOME MEASURES: Clinical data were extracted from electronic medical records and reviewed by a trained team of physicians. Neurological symptoms fall into three categories: central nervous system (CNS) symptoms or diseases (headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, and epilepsy), peripheral nervous system (PNS) symptoms (hypogeusia, hyposmia, hypopsia, and neuralgia), and skeletal muscular symptoms. Data of all neurological symptoms were checked by two trained neurologists. RESULTS: Of 214 patients studied, 88 (41.1%) were severe and 126 (58.9%) were non-severe patients. Compared with non-severe patients, severe patients were older (58.7 ± 15.0 years vs 48.9 ± 14.7 years), had more underlying disorders (42 [47.7%] vs 41 [32.5%]), especially hypertension (32 [36.4%] vs 19 [15.1%]), and showed less typical symptoms such as fever (40 [45.5%] vs 92 [73%]) and cough (30 [34.1%] vs 77 [61.1%]). Seventy-eight (36.4%) patients had neurologic manifestations. More severe patients were likely to have neurologic symptoms (40 [45.5%] vs 38 [30.2%]), such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]) and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). CONCLUSION: Compared with non-severe patients with COVID-19, severe patients commonly had neurologic symptoms manifested as acute cerebrovascular diseases, consciousness impairment and skeletal muscle symptoms.

https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1

 

[TrixieStix]

Coronavirus could attack immune system like HIV by targeting protective cells, warn scientists

"Further investigations to the coronavirus infection on primary T cells would evoke “new ideas about pathogenic mechanisms and therapeutic interventions,” the researchers said in a paper published in the peer-reviewed journal Cellular & Molecular Immunology this week."

https://www.scmp.com/news/china/soc...uld-target-immune-system-targeting-protective

 

[Jonathan Edwards]

"the air sacs of the lungs become filled with a gummy yellow fluid"

Is this the sort of thing @Jonathan Edwards that some kind of inhalant might help with? Something that might help liquefy the gummy fluid so that it might be easier removed? Obviously liquid in the lungs is problematic, but presumably the lower the viscosity of that fluid the better the chances of removing it?

Inhalants are useful for clearing bronchial secretions - which are composed of thick fluid coating the larger air tubes that can be coughed up. Fluid in the alveoli is a different matter. There is no air behind the fluid to push it out during a cough. I also think the idea of a yellow gummy fluid may be a bit poetic. The alveoli are so small that fluid flow is not really relevant.

 

[Perrier]

Interesting video of cat scan of a 59 yr old patient in the usa. Commentary by the Thoracic surgeon saying this is nothing like the flu or bacterial pneumonia.
https://www.washingtonpost.com/science/2020/04/12/storm-inside/?arc404=true

 

[Barry]

Interesting video of cat scan of a 59 yr old patient in the usa. Commentary by the Thoracic surgeon saying this is nothing like the flu or bacterial pneumonia.
https://www.washingtonpost.com/science/2020/04/12/storm-inside/?arc404=true

Any way to access this without a subscription?

 

[Arnie Pye]

Any way to access this without a subscription?

Clear cookies and site data for that particular site. On Firefox I can do this by clicking on the padlock in the web address box and then clicking on "Clear cookies and site data" at the bottom of the box that comes up. If there is more than one page in an article you may have to repeat this for every page.

 

[Barry]

Clear cookies and site data for that particular site. On Firefox I can do this by clicking on the padlock in the web address box and then clicking on "Clear cookies and site data" at the bottom of the box that comes up. If there is more than one page in an article you may have to repeat this for every page.

You learn something new every day . Thanks.

 

[rvallee]

Clear cookies and site data for that particular site. On Firefox I can do this by clicking on the padlock in the web address box and then clicking on "Clear cookies and site data" at the bottom of the box that comes up. If there is more than one page in an article you may have to repeat this for every page.

Even easier option: use incognito mode. You can right-click on a link and choose open insafe/incognito/private browsing.

 

[Perrier]

Any way to access this without a subscription?

Dear Barry, so very sorry; I am a subscriber of a number of newspapers, and I completely forgot that one might need to be subscribed. Very sorry. I just don't know how to get the video to you. But the doctor basically shows the Cat scan and points out that the virus lodges in many places, not just in one area, and he wants to stress that this Covid infection does not resemble the flu or pneumonia.

 

[Barry]

Dear Barry, so very sorry; I am a subscriber of a number of newspapers, and I completely forgot that one might need to be subscribed. Very sorry. I just don't know how to get the video to you. But the doctor basically shows the Cat scan and points out that the virus lodges in many places, not just in one area, and he wants to stress that this Covid infection does not resemble the flu or pneumonia.

Many thanks. No worries, @Arnie Pye and @rvallee have fixes - see above .

 

[Adrian]

This paper came out yesterday talking about ACE-2 receptors and the relationship with SARS.

https://www.biorxiv.org/content/10.1101/2020.04.10.036418v1

The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates entry of SARS-CoV-2 into cells expressing the angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of the 1273-amino acid S-protein protomer. Antibodies to the RBD domain of SARS-CoV (SARS-CoV-1), a closely related coronavirus which emerged in 2002-2003, have been shown to potently neutralize SARS-CoV-1 S-protein-mediated entry, and the presence of anti-RBD antibodies correlates with neutralization in SARS-CoV-2 convalescent sera. Here we show that immunization with the SARS-CoV-2 RBD elicits a robust neutralizing antibody response in rodents, comparable to 100 μg/ml of ACE2-Ig, a potent SARS-CoV-2 entry inhibitor. Importantly, anti-sera from immunized animals did not mediate antibody-dependent enhancement (ADE) of S-protein-mediated entry under conditions in which Zika virus ADE was readily observed. These data suggest that an RBD-based vaccine for SARS-CoV-2 could be safe and effective.

Also another story talking of ACE2 receptors

https://www.radboudumc.nl/en/nieuws/2020/radboudumc-researchers-publish-new-insights-into-covid-19

which refers to this paper
https://www.preprints.org/manuscript/202004.0023/v1

Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that anti-inflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.

None of it makes much sense to me as someone who doesn't know much biology.

 

[Arnie Pye]

Even easier option: use incognito mode. You can right-click on a link and choose open insafe/incognito/private browsing.

I have found that some sites recognise when private browsing is being used and they then cover part of the page with a sign saying "Get a subscription" which doesn't have a close option and they disable scrolling. This wasn't always true, and I used to use incognito mode. But getting rid of cookies and site data is, for now, the most reliable method I've found.