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

Barry · Apr 8, 2020

Jonathan Edwards said: ↑

You could think of the lung as a bit like a heat exchanger in a heating system. Oxygen is sucked into tiny cavities (about the size of a salt grain) at the ends of the branching bronchial tubes in the lung. The cavities are lined with unbelievably thin walls about three cells thick (maybe ten times thinner than cellophane) on the other side of which blood carrying red cells is flowing past through meshes of capillaries surrounding the cavity. Instead of heat, oxygen diffuses from air cavity through the wall to the blood and into the red cell and binds to haemoglobin. The red cells are whisked off to the heart and around the body.

Pneumonia and respiratory distress syndromes bloc the process largely by the oozing of fluid out of the capillaries (as in a blister or burn). The fluid may ooze into the cavity wall making it thicker or, if there is more, ooze into the air cavity and fill it up. In the first case oxygen diffusion across the wall is impaired and in the second it does not even get into the cavity.

In acute respiratory distress syndrome (ARDS) ventilation is thought to help by providing a positive pressure of air passing to the air cavities. When we breathe normally we suck air in by lifting the chest wall and pulling down the diaphragm, lie the sucking of opening a bellows. Unfortunately, that will tend to suck more fluid from the leaky oozing capillaries into the air cavities. On the other hand opening up the lung by blowing into it with positive pressure does the opposite. It pushes fluid out of the cavities. So ventilation and CPAP (continuous positive pressure ventilation, in which you breathe on your own but with the help of a blower to open the lungs) were thought to be helpful for Covid19 too.

The other reason why ventilation may help is simply that it gets oxygen into the air spaces without any effort required by the patient and crucially does so during sleep when oxygen levels are likely to fall. The current scientific discussion suggests that this is actually what matters for Covid19 and that the positive pressure factor may not help and may be harmful. The problem with the positive pressure is that it interferes with the way pressure is used by the heart to keep blood flow through the capillaries.

The simplest way to increase oxygen intake is just to increase the oxygen concentration in the air breathed in. That is usually the first step. However, increasing oxygen can interfere with regulation of carbon dioxide excretion and has other problems. The worst problem is in newborn infants who go blind with high oxygen levels (as in the case of Stevie Wonder). For short periods high oxygen concentrations are tolerated but may not be enough if there is obstruction by fluid.

The ultimate method is to forget the lungs and pass the blood through an extracorporeal oxygen exchanger. But this has problems with control of clotting and other things and is unlikely to be feasible for large numbers of patients.
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Many thanks for that Jonathan, an excellent explanation. Your last paragraph is what I notionally had in the back of my mind, though I presumed it would be far too difficult to scale up as would be needed. But as you point out, it is far from ideal clinically anyway.

DokaGirl · Apr 9, 2020

Apologies if this Canadian research has already been posted.

Several universities and hospitals across Canada are participating in this 1,000 subject trial with plasma from recovered COVID-19 patients:

https://brighterworld.mcmaster.ca/a...-trial-tests-old-plasma-therapy-for-covid-19/

ETA: This is from @wigglethemouse from a previous post. It is alarming the findings show low antibodies. Perhaps this research and therapy won't work:

"Here is the news article she refers to about a preliminary pre-peer review paper that antibodies in 1/3 of people are low or undetectable after mild COVID-19 infection."
https://www.scmp.com/news/china/sci...rus-low-antibody-levels-raise-questions-about

Roy S · Apr 9, 2020

*Preliminary study; thread

https://twitter.com/user/status/1248064961408045059

Barry · Apr 9, 2020

A thought re Covid 19, in the light of pwME's experiences, especially those whose ME may have started with a virus infection.

Is it possible that people's chances of a good recovery might be affected by whether they rest up (really rest) even when (maybe especially when?) they have only mild symptoms? Could it be that trying to "push through" Covid 19 is the very last thing you should do?

Trish · Apr 9, 2020

Barry said: ↑

A thought re Covid 19, in the light of pwME's experiences, especially those whose ME may have started with a virus infection.

Is it possible that people's chances of a good recovery might be affected by whether they rest up (really rest) even when (maybe especially when?) they have only mild symptoms? Could it be that trying to "push through" Covid 19 is the very last thing you should do?
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You are thinking what a lot of us are thinking Barry. We even have a thread to discuss it:
Possibility of ME or PVFS after COVID-19

Ron · Apr 10, 2020

Posting in case anyone is interested:

How does COVID-19 kill? Uncertainty is hampering doctors’ ability to choose treatments
https://www.nature.com/articles/d41586-020-01056-

How does COVID-19 kill? Uncertainty over whether it is the virus itself — or the response by a person’s immune system — that ultimately overwhelms a patient’s organs, is making it difficult for doctors to determine the best way to treat patients who are critically ill with the coronavirus.

Clinical data suggest that the immune system plays a part in the decline and death of people infected with the new coronavirus, and this has spurred a push for treatments such as steroids that rein in that immune response. But some of these treatments act broadly to suppress the immune system, stoking fears that they could actually hamper the body’s ability to keep the viral infection in check.

“My greatest fear is that this gets taken to an extreme, where people are using whatever they can get their hands on to turn off the immune response,” says Daniel Chen, an immunologist and chief medical officer at IGM Biosciences in Mountain View, California. “You can’t knock down the immune system at a time when it’s battling an infection.”
[...]
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Edited to a short quote for copyright reasons.

Sly Saint · Apr 10, 2020

On c4 news last night they were saying that it was looking like the reason that some badly affected patients were going into kidney failure was because they were treating them as tho they were ARDS patients and restricting fluids, causing dehydration.

lansbergen · Apr 10, 2020

Ron said: ↑

How does COVID-19 kill? Uncertainty over whether it is the virus itself — or the response by a person’s immune system — that ultimately overwhelms a patient’s organs, is making it difficult for doctors to determine the best way to treat patients who are critically ill with the coronavirus.
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Question is why it is not stopped in the upper airways by the immune system.

spinoza577 · Apr 10, 2020

re: IL-6

the dose-response association between nitrogen dioxide exposure and serum interleukin-6 concentration
Perret et al 2017

abstract

Systemic inflammation is an integral part of chronic obstructive pulmonary disease (COPD), and air pollution is associated with cardiorespiratory mortality, yet the interrelationships are not fully defined. We examined associations between nitrogen dioxide (NO2) exposure (as a marker of traffic-related air pollution) and pro-inflammatory cytokines, and investigated effect modification and mediation by post-bronchodilator airflow obstruction (post-BD-AO) and cardiovascular risk. Data from middle-aged participants in the Tasmanian Longitudinal Health Study (TAHS, n = 1389) were analyzed by multivariable logistic regression, using serum interleukin (IL)-6, IL-8 and tumor necrosis factor-α (TNF-α) as the outcome. Mean annual NO2 exposure was estimated at residential addresses using a validated satellite-based land-use regression model. Post-BD-AO was defined by post-BD forced expiratory ratio (FEV1/FVC) < lower limit of normal, and cardiovascular risk by a history of either cerebrovascular or ischaemic heart disease. We found a positive association with increasing serum IL-6 concentration (geometric mean 1.20 (95% CI: 1.1 to 1.3, p = 0.001) per quartile increase in NO2). This was predominantly a direct relationship, with little evidence for either effect modification or mediation via post-BD-AO, or for the small subgroup who reported cardiovascular events. However, there was some evidence consistent with serum IL-6 being on the causal pathway between NO2 and cardiovascular risk. These findings raise the possibility that the interplay between air pollution and systemic inflammation may differ between post-BD airflow obstruction and cardiovascular diseases.
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conclusion

In a cross-sectional analysis of middle-aged adults, we have described an incremental pattern of pollution-related responses for serum IL-6 with regard to NO2 exposure, which was not observed for other pro-inflammatory cytokines, namely, IL-8 and TNF-α. Although case numbers were limited, we have shown that this NO2-IL-6 relationship was neither modified nor mediated by the presence of post-BD-AO. In contrast to this lack of influence from post-BD-AO, serum IL-6 was found to act on cardiovascular risk, which is consistent with IL-6 being on the causal pathway between NO2 and cardiovascular disease. While it is important to examine the cardiorespiratory effects of pollutant co-exposures including PM2.5, overall, these findings reinforce public health recommendations to reduce exposure to outdoor air pollutants. This includes the avoidance of combustion-derived pollution from gasoline and diesel, industry and sources of biomass burning, which is relevant even in low-pollution settings.
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In so far the corona deaths might rather be not of respsiratory origin
maybe this could be an explanation for a pattern to be possibly seen in the future
as corona deaths are highest in Sao Paulo so far, in Brazil (if NO 2 is very high there, too)

effects of NO 2 exposure on daily mortality in sao paulo, brazil
Costa et al 2017

Background: Recent reports have suggested that air pollution mixtures represented by nitrogen dioxide (NO2) may have effects on human health, which are independent from those of particulate matter mass. We evaluate the association between NO2 and daily mortality among elderly using one- and multipollutant models.

Methods: This study was a daily time series of non-accidental and cause-specific mortality among the elderly living in São Paulo, Brazil, between 2000 and 2011. Effects of NO2, particulate matter smaller than 10µm (PM10), carbon monoxide (CO) and ozone (O3) were estimated in Poisson generalized additive models. The single lag effect at lags 0 and 1 days and the cumulative effect from 0 to lag 10 days were evaluated in one-, two-, three- and four-pollutant models. The cumulative risk index (CRI) recently proposed to analyze associations with health of multiple correlated pollutants was additionally estimated for each multipollutant model.

Results: An association between NO2, PM10, CO and O3 exposures and non-accidental and cause-specific deaths was found in one-pollutant models. NO2 effects remained significant in multipollutant models for non-accidental and circulatory deaths. The estimated CRIs suggested that circulatory deaths were mainly associated with NO2, and respiratory deaths mainly with CO and O3, regardless the lag. For non-accidental deaths, multipollutant models were associated with the highest CRI, with the main pollutants depending on the chosen lag.

Conclusions: The results suggest that air pollution mixtures represented by NO2 have an effect on non-accidental and circulatory mortality, which is independent from PM10, CO and O3. The CRI was always larger than the risks associated with single pollutants.
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spinoza577 · Apr 10, 2020

NO 2 in Feb in Europe.

In this picture the numbers from France may not fit in.
In Spain Madrid was affected first.

from facts about covid-19https://swprs.org/a-swiss-doctor-on-covid-19/

spinoza577 · Apr 16, 2020

NO 2 is, if I remember rightly, physiologically produced to get rid of physiological NO, cf second article here.
This might be an avenue, I think.

Interaction of Nitrogen Monoxide With Hemoglobin and the Artefactual Production of S-nitroso-hemoglobin
Herold 2003, a review

Hemoglobin (Hb) is probably the most thoroughly studied protein in the human body. However, it has recently been proposed that in addition to the well known function of dioxygen and carbon dioxide transporter, one of the main roles of hemoglobin is to store and transport nitrogen monoxide. This hypothesis is highly disputed and is in contrast to the proposal that hemoglobin serves as an NO. scavenger in the blood. In this short review, I have presented the current status of research on the much-debated mechanism of the reaction between circulating hemoglobin and NO.. Despite the fact that oxyHb is extremely rapidly oxidized by NO., under basal physiological conditions the biological activity of NO. in the blood vessels is not completely lost. It has been shown that three factors reduce the efficiency of hemoglobin to scavenge NO.: a so-called red blood cell-free zone created close to the vessel wall by intravascular flow, an undisturbed layer around the red blood cells--where the NO. concentration is much smaller than the bulk concentration--and/or the red blood cell membrane. Alternatively, it has been proposed that NO. binds to Cys beta 93 of oxyHb, is liberated after deoxygenation of Hb, and consequently allows for a more effective delivery of O2 to peripheral tissues. However, because of the extremely fast rate of the reaction between NO. and oxyHb, experiments in vitro lead to artefactual production of large amounts of S-nitroso-hemoglobin. These results, together with other data, which challenge most steps of the NO.-transporter hypothesis, are discussed.
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Reaction of Hemoglobin With Nitric Oxide and Nitrogen Dioxide in Mice
Oda et al 1980

The reaction of hemoglobin with NO and NO2 was compared in mice exposed to these cases. Nitrosyl hemoglobin (NOHb) and methemoglobin (MetHb) were determined simultaneously by electron spin resonance spectrometry at -140 degrees C. In mice exposed to 40 ppm NO, NOHb became constant (0.7%) in 30 min and declined rapidly with a half-life of several minutes when the mice were removed to room air. An increase of MetHb (5%) was also caused by exposure to NO and the time course was almost the same as that of NOHb. Exposure to 40 ppm NO2 produced only NOHb (0.2%); MetHb did not increase. The time course of NOHb was identical to that observed with NO exposure. Dose-effect relationships were determined with both gases at concentrations ranging from 20 to 80 ppm. A linear relationship could be observed between the concentrations of the gases and NOHb, but NO produced more NOHb than did NO2. There was an exponential increase of MetHb, particularly at high concentrations of NO.
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spinoza577 · Apr 10, 2020

Doing a last try with this speculation.

Jonathan Edwards said: ↑

Yes very interesting. It seems that Covid19 patients have no hypoxic respiratory drive.

One faint possibility is that the problem is that CO2 is being excreted adequately but that oxygen transfer is preferentially blocked. That would mean there is no CO2 retention respiratory drive. But I find it hard to believe that oxygen levels at 70 are not going to drive extreme breathlessness. I get very breathless at altitude purely due to low oxygen. Everest climbers do not go in to renal failure because of no CO2 drive.

That suggests a primary defect in oxygen depletion respiratory drive. I wonder if this could possibly have some relation to the loss of smell and taste? It seems like a chemosensory failure. I think that is far fetched but it is hard to see what other explanation there is.
...
The idea of the virus interfering with haem is not totally crazy but I have not yet heard of any clinically based evidence to support that.

The other thing that might be relevant is the frequent complaint of very severe atypical headache, which of course occurs with primary hypoxia in altitude sickness.
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Transport and Peripheral Bioactivities of Nitrogen Oxides Carried by Red Blood Cell Hemoglobin: Role in Oxygen Delivery
Sonveaux et al 2007

The biology of NO (nitric oxide) is poorly explained by the activity of the free radical NO (·NO) itself. Although ·NO acts in an autocrine and paracrine manner, it is also in chemical equilibrium with other NO species that constitute stable stores of NO bioactivity. Among these species, S-nitrosylated hemoglobin (S-nitrosohemoglobin; SNO-Hb) is an evolved transducer of NO bioactivity that acts in a responsive and exquisitely regulated manner to control cardiopulmonary and vascular homeostasis.

In SNO-Hb, O2 sensing is dynamically coupled to formation and release of vasodilating SNOs, endowing the red blood cell (RBC) with the capacity to regulate its own principal function, O2 delivery, via regulation of blood flow. Analogous, physiological actions of RBC SNO-Hb also contribute to central nervous responses to blood hypoxia, the uptake of O2 from the lung to blood, and baroreceptor-mediated control of the systemic flow of blood.

Dysregulation of the formation, export, or actions of RBC-derived SNOs has been implicated in human diseases including sepsis, sickle cell anemia, pulmonary arterial hypertension, and diabetes mellitus. Delivery of SNOs by the RBC can be harnessed for therapeutic gain, and early results support the logic of this approach in the treatment of diseases as varied as cancer and neonatal pulmonary hypertension.
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Kalliope · Apr 10, 2020

Here's a list over COVID-19 research projects currently applying for funds from the Research Council of Norway.

Nothing about ME or post viral infection fatigue.

On page 3 is a project from Oslo University Hospital called: Treatments versus Management: The Mind-Body App for Pain and Mental Healthcare Delivery.
Can't find any more info per now but hope it doesn't imply a BPS approach.

https://kommunikasjon.ntb.no/data/attachments/00176/cf663f8c-b92e-4f8a-a4f1-aa611a7ae18f.pdf

mango · Apr 10, 2020

Google Translate said:

The Swedish Research Council has decided on a time-limited opportunity to use research funding for research related to SARS-CoV-2 and covid-19, regardless of which project idea the funding was initially granted for.
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"Researchers do not have to spend time writing new applications and reviewing other researchers' applications. Instead, we use the quality review of researchers that has been done on previous occasions" says Sven Stafström, Director General of the Swedish Research Council.
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https://www.vr.se/aktuellt/nyheter/...v-ditt-bidrag-till-forskning-om-covid-19.html

Google Translate, English

Mij · Apr 10, 2020

To date, more than 380 trials for COVID-19 have been posted on Clinical Trials ranging from repurposed antiviral drugs to diagnostic imaging techniques.

Kalliope · Apr 10, 2020

https://twitter.com/user/status/1248707983112048644

Snow Leopard · Apr 11, 2020

Nicholas Christakis on Twitter said:

Here is a classic 1990 study of 15 volunteers who were *deliberately* infected with a *different* coronavirus squirted into their nose, with immunity monitored for a year. Immunity reached a maximum at 2 weeks. It had lapsed by a year later.
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Very little about longevity of immunity to future infections can be deduced simply from from absolute levels of circulating antibodies from an initial infection (so long as seroconversion did in fact happen). The only way to determine whether immunity is maintained is through subsequent immune challenge (either exposure to the virus or vaccine)

That tweet (25) is contradicted by his next tweet which noted that 9 participants were re-exposed to the virus and none developed symptoms - which suggests that they all maintained sufficient immunity, despite waning quantities of circulating antibodies.

Nicholas Christakis the sociologist said:

Alas, as an aside, the decline in titers also means that developing a vaccine for COVID19 may be very challenging, similar to the reasons we do not yet have a vaccine for the common cold (but that is the topic for another thread).
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Nope. The reason we don't have a vaccine for the common cold is due to constant genetic drift and a lack of societal demand.

Also, note that it took him 5 days before he realised he overlooked the most important point in his thread, namely not mentioning the limitations of serological tests (poor sensitivity and specificity leading to high error rates when applied to large population groups).

Adrian · Apr 11, 2020

Snow Leopard said: ↑

That tweet (25) is contradicted by his next tweet which noted that 9 participants were re-exposed to the virus and none developed symptoms - which suggests that they all maintained sufficient immunity, despite waning quantities of circulating antibodies.
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I wonder if it suggest something about levels of antibodies or the effectiveness of the testing rather than real immunity levels. Also some of the 9 did get the disease but without symptoms.

Snow Leopard · Apr 11, 2020

Adrian said: ↑

I wonder if it suggest something about levels of antibodies or the effectiveness of the testing rather than real immunity levels. Also some of the 9 did get the disease but without symptoms.
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The disease and reinfection are two different things. No symptoms = no disease.

Reinfection was defined as

virus shedding on at least one day and/or a significant rise in serum specific IgG
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Note that a rise in serum specific IgG is not evidence of reinfection, but simply an immune response. So it is hard to generalise these results!

Solstice · Apr 11, 2020

"The first symptoms of patients entering the hospital with Covid-19 indicate pulmonary edema, caused by fluid escaping into the alveoli," says internist-infectiologist Frank van de Veerdonk of Radboudumc in Nijmegen. Together with six Nijmegen colleagues, he wrote down his insights in a scientific article that is already online before it is published in a magazine. Van de Veerdonk: “The clinical picture is very similar to that of a rare hereditary disease: hereditary angioedema. We have also tried the drug that exists against it, Icatibant, in a few Covid-19 patients, with cautiously positive results. ”

Cautious success
Careful, emphasizes Van de Veerdonk, because only five patients have been treated with it. “In three out of five, we saw that the oxygen requirement decreased significantly within a day to a day and a half. In the other two patients it is still too early to say anything about it. ”
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https://www.nrc.nl/nieuws/2020/04/1...virus-raken-bloedvaten-in-longen-lek-a3996526

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