Stupid question in case anyone here has a medical background.
I was under the impression that covid19 was a two step process. First the virus infects and attacks the protective layer of the lungs (causing cough and fever). Then, the damage done to the protective layer of the lungs results in an infection / pneumonia, and that's where people have respiratory problems and may be in critical condition. But at this stage the viral load is low and the virus isn't the problem anymore, the pneumonia is [1].
This is why I thought Pr Raoult was advocating for the use of chloroquine in the early days of the disease, combined with prompt testing.
But it seems that anti-virals (like the study mentioned in this post and other studies in the US and Europe) are tested on patients in critical phase, i.e. with serious cases of pneumonia. Am I missing something or should we not expect anti-virals to be of much use in those cases, as it is too late, we are not dealing with a virus but with a pneumonia?
We don't have data to really address this, but it's likely a flawed picture in that it's an uncommon progression even for severe cases. The reasoning is that antibiotics don't seem to be very effective for the most severe cases, and at least anecdotally among physicians, the evidence for secondary infection is usually weak. There seems to be a lot of primary damage caused by the virus itself to the point of diminished lung function.
Without getting overly technical, there's also some atypical results in some of the labs that seems to indicate that the virus is just overwhelming parts of their immune system, which are in collapse. This can drive up other parts that are inflammatory in nature leading to the cytokine storm and ARDS which comes on very rapidly. However, the fact that things like steroids are leading to WORSE outcomes suggests that the immune suppression is very unhelpful which suggests the problem is more that tissues are just getting overwhelmed with virus.
Sorry for the ignorant question but you mentioned steroids and immune suppression. Does that imply that steroids suppress the immune system in some way?
I’ve tried googling but came up empty besides a paper on “ glucocorticoids” which seems to be something to do with cortisol shots for reduced inflammation, which has immune suppression tendencies.
Is that what you mean? And if yes, is this for all levels of steroids or just some particular types? (IE steroids in an asthma inhaler vs cortisol shot vs anabolic steroids).
> Does that imply that steroids suppress the immune system in some way?
Yes. This is the reason why they're used in the first place.
> steroids in an asthma inhaler
Yes, but an entire year's worth of asthma inhaler is like one dose of oral prednisone, so the impact is quite low and you should not stop using your inhaler.
Steroids are an entire class of chemicals that have a specific pattern in their structure.
Hormones are signalling molecules that get transported throughout your body.
Steroid hormones are chemicals that are both a steroid and a hormone. Not all steroids are hormones (ex cholesterol) and not all hormones are steroids.
A subgroup of steroid hormones is corticosteroids. A subgroup of corticosteroids is glucocorticoids, (most of?) which exhibit strong effects on the immune system (roughly speaking, they suppress the immune system and reduce inflammation).
Corticosteroids suppress the immune system, as do anabolic steroids, but it's not a property inherent to steroids. For instance estrogen is also a steroid and doesn't suppress the immune system.
There's a trial[1] whose objective is to determine if chloroquine is actually useful early on in the infection.
With a target sample size of 3000 individuals it would have at least sufficient numbers to show if it's actually viable, helps a little, or does not help at all.
I'm also looking forward to this study. Kudos to U of M to get this kicked off quickly. I find it interesting to see how fast they were able to marshal a response. Basically, we go from nothing to something started in 10 days. I've been reflecting on how western culture does not seem as effective as China in suppression of the disease, but the west's ability to do "start up" type activity is amazing, and a place for hope.
https://www.twincities.com/2020/03/18/preventing-coronavirus...
Tho they've focused mostly on care instead of the science (they don't believe in randomized trials), and it's going to be hard to know if the treatment is efficient from those (the EU and Michigan studies should help figuring that out).
In the absence of other viable treatments, the efficiency isn't really important.
Frankly, if it is only modestly effective, it should still be given to everyone without contraindications.
Efficiency only becomes important in a year or two when there are competing therapies.
When the choices are Chloroquine or Hopes and Prayers, Chloroquine is the obvious choice (for those that don't have the contraindications, of course -- for those patients, you'd need more evidence to know that the benefits outweighed the risks)
There's a very interesting hypothesis that lung inflammation is a secondary effect caused by the virus damaging red blood cells, making them unable to transport oxygen. See this thread:
What would be the mechanism for damaging the red blood cells, considering that they don't have a nucleus, and therefore the virus cannot replicate in them?
The title of the article for those curious is: "COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism"
It is not a stupid question at all but nobody has a legit answer yet, with so many tentative protocols under way all over the world. Some people recover because of non-standard drugs reducing the most critical effects, some other recover because they get non-standard cocktails at early stage, some other die because prolonged fever leads to multiorgan failure or infections. Gilead is making its part, which is laudable.
> I was under the impression that covid19 was a two step process. First the virus infects and attacks the protective layer of the lungs (causing cough and fever). Then, the damage done to the protective layer of the lungs results in an infection / pneumonia, and that's where people have respiratory problems and may be in critical condition. But at this stage the viral load is low and the virus isn't the problem anymore, the pneumonia is [1].
There are apparently a large number of cases that work differently, with hypoxemia prior to any evidence of severe lung dysfunction:
Yeah, in the last two days there is increasing evidence that there's something else going on in at least some patients beyond "pneumonia resulting in ARDS"
That tweet is interesting. Some folks are starting the theorize that many of the pneumonia (especially, bilateral) diagnoses based on CXR might be mistaken.
The most interesting hypothesis I have encountered (way too little evidence yet to do anything but study it) is that the virus is directly interfering with haemoglobin saturation, and that the abnormal CXR is actually looking at tissue damage caused by haemoglobin degradation somewhat akin to that found in Malaria patients.
That hypothesis intends to explain the apparent efficacy of chloroquine, magnified when taken by patients early in the disease, by hypothesizing a similar mechanism of action in COVID as in Malaria -- not by being antiviral, but by inhibiting heme polymerase.
The apparent antiviral properties of the treatment are then merely keeping the patient healthy and lung-damage-free while the immune system does its thing.
If that were true, then treating COVID patients for pneumonia could be highly counterproductive.
Of course, even if the hypothesis is correct, there might be some COVID patients who do develop a bacterial secondary pneumonia -- that is an uncommon-but-not-rare complication of all respiratory illnesses. That might also explain why Azithromycin seems to make Chloroquine more effective -- each drug helping a different subset of patients, rather than actually as a combined effect.
As I say, though, there is nowhere near enough evidence yet for this hypothesis -- but it is pretty interesting. It is probably worth a study or two to evaluate.
It is a neat hypothesis in that it takes a wide variety of disparate and otherwise apparently contradictory datapoints from clinical experience and weaves them together into a coherent narrative.
Of course, that it makes a good narrative is in no way evidence for it's truth, no matter how much we humans love good narratives.
If that hypothesis is correct then hyperbaric oxygen therapy (HBOT) should be effective. However there are very few hyperbaric chambers available and little prospect of building more quickly.
I don't know the answer to the best time to give antivirals, but the lung inflammation happens for some, but not all patients. A non-trivial amount have relatively normal lungs, low oxygen saturation, and an extremely high heartrate.
The reasons for this are unknown, but it is an active area of research. Some doctors are beginning to call for treating covid patients like they altitude sickness.[1]
It's not super clear yet what the mechanism of Chloroquine (and derivatives like HCQ) is in combating COVID-19 / Coronavirus, and I imagine people are not sure about Remdesivir either, except that it was previously developed as an Ebola treatment (ineffective), but also shown to be effective in some in vitro studies on SARS-COV-1.
Disclaimer: I'm not a doctor or an expert.
Chloroquine is suspected to have general prophylactic abilities (like Remdesivir), but also hypothesized that if taken with Zinc, [1] acts as an ionophore with which Zn2+ ions can inactivate the first part of the viral replication step. But at this time, clinical trials for HCQ have been somewhat mixed, with small N-size studies reporting weak benefits or lack of benefits. I don't know of any RCTs that include Zn2+ in the treatment group along with HCQ. It's still as yet unclear.
With untested drugs, the risk-benefit is considered such that only people who are certainly going to die without intervention can be treated without incurring further liability. So only "terminal" cases get remdesivir in the first place.
To use HIV as an example, every infected T cell releases ~50,000 virions when it bursts. So that's ~10^4 times the number of infected cells. So during an infection only 10^9 of your 10^13 cells would need to be infected to get up into the 10^13 range. That's obviously a TINY fraction at 10^9/10^13 = 10^-4. So saying there's trillions of viruses in your body during a major infection like COVID is hardly an exaggeration. 10^15 may or may not be though, in fairness.
Compare that to the amount of virus you'd be exposed to in the air though in a COVID ward and its just totally negligible. Unless you're getting injected with virions, it's just not relevant to the progression of your infection when you're already a week into it. I'd be shocked if you could daily environmental viral loads above 10^6.
So fine I'll revise it to 6-9 orders of magnitude. The point stands though, it's just not relevant to your immune system compared to the virus it has to deal with from your own cells.
Right, with this and chloroquine, assuming it works to prevent the virus from binding to ACE2, you'd want it to be in the early stages, before massive damage to the lungs, liver, intestines and brains are done (all of these are targeted by this virus). All other countries that are testing these are giving the drugs to patients in both the early and late stage of the infection. In the US alone, trials are only being done in the very late stage, after permanent damage has been done, and it's less likely to be of much use.
There is a large-scale clinical trial with 3000 participants (https://clinicaltrials.gov/ct2/show/NCT04308668) to see if chloroquine prevents progression to severe disease when given shortly after exposure, because when patients are symptomatic it was proved to be completely useless.
There isn't a shortage of participants, and at that scale we'll know soon enough if Trump's wonder drug does something. Probably it won't.
I was under the impression that covid19 was a two step process. First the virus infects and attacks the protective layer of the lungs (causing cough and fever). Then, the damage done to the protective layer of the lungs results in an infection / pneumonia, and that's where people have respiratory problems and may be in critical condition. But at this stage the viral load is low and the virus isn't the problem anymore, the pneumonia is [1].
This is why I thought Pr Raoult was advocating for the use of chloroquine in the early days of the disease, combined with prompt testing.
But it seems that anti-virals (like the study mentioned in this post and other studies in the US and Europe) are tested on patients in critical phase, i.e. with serious cases of pneumonia. Am I missing something or should we not expect anti-virals to be of much use in those cases, as it is too late, we are not dealing with a virus but with a pneumonia?
[1] see this useful video: https://www.youtube.com/watch?v=BtN-goy9VOY