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Interferon and the Coronavirus

Here’s a potentially important paper that’s out in Science and is getting a lot of attention. The wide variation in severity of coronavirus infection has been noted throughout the pandemic, and we already know about a few of the risk factors: age, of course, but also being male, and having pre-existing conditions such as obesity and heart disease (which are, of course, often found in the same patients).

This new work, with a huge team behind it from more than 70 institutions, suggests another one: auto-antibodies to endogenous interferons. Everyone will have heard of interferon in a general sense, but getting a real understanding of that system is another thing entirely, which we can stipulate is true about immunology in general. There are three broad classes of interferon in humans (Types I, II, and III) and a bewildering network of functions and crosstalk between them. Suffice it to say for now that they are proteins whose synthesis is generally induced by some sort of viral or bacterial infection, and they go on to modulate a wide range of immune functions and affect the transcriptional activity of hundreds of different genes downstream. They’re of great interest not only in infectious disease, but in cancer and autoimmune disease as well, and we’re still working out all the pathways involved.

It’s been known for many years that some people have inborn mutations in one or another of these interferons, with bad consequences for their response to infectious pathogens. How the human genetic background changes the course of infection and inflammation is a vast and complicated field, but here’s a recent review from experts Jean-Laurent Casanova of Rockefellar and Laurent Abel from Paris (who are part of the current paper as well). Past such inborn protein errors, that are also people who have developed an inappropriate immune response to their own interferon proteins – they have autoantibodies circulating in their blood that neutralize certain interferons when they’re produced. For reasons that are still being worked out, at some point the immune systems of such patients have been activated against these interferon types as if they were foreign proteins, and unfortunately we don’t have many techniques for resetting that sort of thing. Disease of immune tolerance such as lupus and APS-1 generally show this as one of the underlying factors.

Interferon signaling has also been found to be important in the human response to coronavirus infection, of course, both in the direct antiviral aspect and in the overactive-immune-response part later on as well. Several different trials are underway looking at various interferon types as therapeutic options, but these are complicated by the need for good timing during the course of the infection. The complexity of the field means that the clinic is really the only place that one can sort this out: hypotheses are thick on the ground in an area like this one, but you have to go run a controlled trial to shed any light at all.

In this latest work, the authors look for the intersection of these stories: pre-existing autoantibodies in coronavirus patients that neutralize one or more types of interferon. The results are striking: in 1,227 healthy controls, four patients were found to have such antibodies. In 663 patients with mild coronavirus infections, none were found at all. But in 987 severely ill patients, at least 101 of them had such antibodies against at least one of the Type I interferons (!) I hope that those four people identified in the first cohort are taking precautions, was my first thought, because it certainly looks like they in a newly identified risk group. Those numbers come out to p-values of less than ten to the minus sixteenth, which means that we all pretty much have to stand up take take off our hats – this one’s real. The anti-interferon antibody patients also skewed older, which suggests that the levels go up over the years (exactly what you don’t want, honestly).

37% of the 101 patients in this group ended up dying of the disease, which is also an extreme statistical red flag. In cellular assays, it’s been shown that interferons such as IFN-alpha2 can block the coronavirus from infecting human cells. But plasma from these patients with neutralizing anti-interferon antibodies reversed that and left the cells open to infection. So the mechanism checks out as well.

Interestingly, 95 of those auto-antibody patients were male, so this could also be one of the reasons why men add up to being a risk group of their own. You see many autoimmune disorders more commonly in women (which may be due to differences in the amounts of the transcription factor protein VGLL3), which is more expressed in women than men. This one breaks hard the other way. The connection here might be that VGLL3 promotes interferon responses, leading to a too-sensitive autoimmune situation, but autoimmunity to interferons themselves might be expected to run through a different mechanism entirely. (This last part is all my free bonus speculation; it’s not in the current paper).

So while not all severe COVID-19 patients have antibodies against interferon, having them seems to make a person far more likely to end up with a severe infection. We’ll doubtless find more risk factors as more research comes in, but I doubt if any of them will be more firmly established than this one just was. As the paper notes at the end, these results have direct clinical implications. First off, anyone who screens with such antibodies needs to take extreme precautions, because they are clearly at far greater risk of severe disease and death than the run of the population. Second, this means that treating such patients with alpha-interferon will be a doomed effort, but beta-interferon (currently being studied intranasally) might still work, because antibodies to that one were rare. And one could also consider treatments aimed at knocking down the immune response to the Type I interferons themselves, starting with straight plasma exchange to bring down the antibody levels. And at the same time, such patients should not be part of any convalescent plasma donation program. Should they actually recover, that is. . .

84 comments on “Interferon and the Coronavirus”

  1. TallDave says:

    curious if they measured Vitamin D levels, could not tell at a glance

    obviously a lot of (again) very complicated relationships there

    1. TallDave says:

      would also be interesting to know if that same response might block mAbs

      starving for data

    2. PV=nRT says:

      I really really don’t want to hear another thing about vitamin D until there are interventional RCT data. It’s just a correlation until then, and one that has a high probability of being incidential to a third factor — especially age.

      1. sgcox says:

        The faith in vitamins is weak in you, Boyle Mariotte.

        1. David E. Young, MD says:

          But the trust in good science is strong

        1. JasonP says:

          Is this the gold standard? open label?

      2. TallDave says:

        was interested in the potential relationship between D and this interferon phenomenon

        the clinical D studies are relevant to that question but they are not the sum of all information, no reason to throw our hands in the air helplessly in the meantime – theory matters too

        anyways D levels would have been nice data to have, if they were uncorrelated that would tell us something important too

        1. Ferdinand Oeinck says:

          “was interested in the potential relationship between D and this interferon phenomenon”

          Here you have it:
          Vitamin D Is Required for IFN-γ–Mediated Antimicrobial Activity of Human Macrophages

      3. Philipp Leippe says:

        thank you!

      4. Madge Hirsch says:

        There is now an interventional RCT done at Reina Sofia Hospital in Cordoba , Spain. They used Calcidediol with impressive results. Look it up.

      5. Vincent Nestore says:

        Dr. Fauci said last week that you should be taking Vitamin D. Fauci dais that. So take the supplements peeps.

  2. Tony Smith says:

    UK based Synairgen had amazing trial results on their inhaled interferon 1b over 10 weeks ago. I don’t understand why they are still waiting for the peer reviewed paper……?
    It has been known since January the INF’s have a very good positive affect with Covid-19.
    Synairgen came in under the radar of institutional pharma due to their development being already well advanced for COPD treatment.
    Why is the treatment SNG001 being ignored when so many lives could be saved.

    1. Matt W says:

      Interesting article. Nicely explained for simpletons like me!

      I’m very keen to hear about what’s going on with Synairgen and their inhaled interferon drug too. I see it as the most promising therapeutic to get us through this winter!

    2. Bryon says:

      The Synairgen trial was expanded to 400 people and is ongoing. No one is going to approve anything based on a 100 person trial.

      There are also a bunch of other interferon beta trials going on. An injectable interferon beta was added to the NIAD large scale adaptive trial.

      1. SCINV says:

        Injectable means they have the systemic toxicity hurdle that limits the dose. Pretty much all Injectable IFN trials (there are at least 20) failed or produced lukearm results.

        1. David E. Young, MD says:

          How about we waiting until the large RCT are complete and then start discussing / debating the best Beta Interferon treatment.

          1. MattW says:

            Synairgen’s trial is for inhaled interferon.

            It also has promising data for COPD patients and data from a previous Asthma trial too. So we know the drug is well tolerated too.

            All the subsequent studies suggest that interferon treatments are likely to be effective and inhaled interferon is likely to be much more effective that injected (with fewer side effects).

        2. cosima says:

          But injectable interferon beta 1b is in use to treat multiple sclerosis since almost 20 years, so there is a longterm knowledge about

          1. SCINV says:

            Different dose and treatment regimen

    3. Philip says:

      No antiviral therapy trial is going to produce good results unless the subjects are tested almost daily. This is a pet peeve of mine. Antiviral therapy only works if given soon after infection. With SARS-CoV-2 infections, if the person progresses to COVID-19, it is days past infection. That is why trials for antiviral therapies need daily testing and if the therapies are proven to work, why we need daily testing for those at risk. With this paper, we may now know who is at risk. Great for trials and for treatment.

      1. Former Wyeth says:

        not true. HepC anti viral treatment can take place years after infection and is highly effective.

  3. Aleksei Besogonov says:

    Would it be possible to overwhelm the anti-interferon antibodies by administering a large amount of interferon?

    1. Giannis says:

      You can remove the autoantibodies with a specific process.

    2. Nesprin says:

      Yes, but the closest analogy i can think of is applying a tsunami to put out a forest fire.

  4. cynical1 says:

    “But in 987 patients, at least 101 of them had such antibodies against at least one of the Type I interferons (!)……” I went to the link but you may want to clarify that those 987 had the life threatening pneumonia. It wasn’t clear when I first read what you wrote but sort of implied that they were the severe patients.

    Also, with regards to the predominance of autoimmunity in women, ALS is a notable exception.

    WRT to VGLL3, if it promotes interferon responses would you not expect a correlation then with multiple sclerosis as both Interferon alpha and beta are efficacious in treating that disease. It’s just that beta is better tolerated and therefore used exclusively for treatment.

    1. B says:

      MS is also more common (but less severe) in women than men.

  5. mayfin says:

    You mention endogenous interferon autoantibodies as a possible factor behind autoimmune diseases such as lupus – any idea if there is a similar link with MS ?

    More generally, anyone seem any papers analysing patient records for COVID-19 vs MS, either with respect to MS in general, or possible interaction with the immune modulating MS DMDs ?
    I seem to vaguely remember some mention of Tecfidera as possibly having benefits, but not much else either way ..

  6. Thomas says:

    I wonder what this means for a vaccine. Would a vaccine help these interferon-challenged individuals at all?

  7. Rheophile says:

    Very naively, it seems like if auto-antibodies increase with age and maleness, two factors that are correlated with risk, there’s a huge risk of confounding. Fig. S4 shows that they have very few healthy controls or asymptomatic COVID with age over 70, but this accounts for 30% of their life-threatening COVID. These populations aren’t comparable, and I don’t know how they control for this in their p-value. I didn’t see this discussed in a quick skim, but honestly I don’t know how they could possibly deal with this without computing the enrichment of the auto-antibody population, stratified over age. I’d believe this if they saw the same signature in only the 20-40 year olds.

    Related issue: Fig. 4 shows that the life-threatening COVID group with auto-antibodies is 50-50 over 65 – but the life-threatening COVID group without auto-antibodies is younger. Wouldn’t you expect, if you identified something that increased risk for young people, that the high-risk population with disease would be younger on average?

    I’d really like this to be true (clear screening for high-risk population!!) but a little worried here.

    1. Todd says:

      One thing that makes this look real is that one of the few women with this same issue had a mutation that effectively knocked out one of her X chromosomes in all of her cells, as opposed to the mosaicity XX people display. That just screams sex-linked to me. It’s real, and it’s dangerous.

  8. SCINV says:

    Nebulised interferon type I might alleviate systemic toxicity issues while delivering the drug exactly where is needed. Take a look if you have time at the trial below (multi-center, quadruple blinded, placebo controlled) which showed some pretty impressive results (though not very high number of patients) in the interim.

    1. SCINV says:

      Correction, it is double blinded

  9. Kent Matlack says:

    Hello Derek,

    In the third paragraph, I assume you mean “987 patients with severe disease” or “987 hospitalized patients”. The context strongly suggests it, but I’d like to be sure.

  10. Marko says:

    “such patients should not be part of any convalescent plasma donation program. Should they actually recover, that is. . .”

    We may have been unwittingly selecting convalescent plasma enriched for these autoantibodies by aiming for those with the highest antibody titers , who are more likely to be those who’ve recovered from severe disease.

    Hopefully CP will prove to be more efficacious as a therapeutic once we start weeding out the donors who are autoantibody-positive.

  11. Peter Ellis says:

    Elephant in the room – what causes the autoantibodies? They were apparently very rare indeed in the non-infected controls and not present at all in the “mild” group.

    So is it that some fraction of the population have these antibodies and are susceptible to severe disease, or is it that in some fraction of patients SARS-CoV-2 triggers the formation of autoantibodies as part of the disease process?

    1. MrRogers says:

      The authors asked this by looking for previous plasma samples. They found samples for two of the patients and those already had autoantibodies before COVID.

      1. Larry76 says:

        …aka, an antibody-dependent enhancement by some pre-existing, non-neutralizing antibodies. So, where did they (the AB) originate from?–that is the “elephant in the room” question.

        1. Marko says:

          The anti-interferon antibodies are analogous to antibodies against other normal human proteins seen in various autoimmune disorders. Some of those are suspected to arise after viral or bacterial infections via some sort of “molecular mimicry”.

          In this case , given the background prevalence of autoantibodies seen in the healthy population ( which could easily account for the results seen in the COVID-19 groups ) , it doesn’t appear that SARS-CoV-2 is the causative agent. It could be due any number of previous infections , or some other cause. I suspect it will be a hard thing to sort out , based on the track record with other autoimmune diseases.

          1. Larry76 says:

            Sure, but mentioned autoimmune response (downregulation of IFN) is also a hallmark of antibody-dependent enhancement after specific viral infections (e.g., dengue).

  12. Giannis says:

    The link in ” but here’s a recent review from ” is broken

  13. Marko says:

    “…in 1,227 healthy controls, four patients were found to have such antibodies”

    Using that figure as a proxy for the population as a whole , that means that .33% of people have what should come to be be viewed as a severe immunodeficiency in the context of a disease like COVID-19. Given that the overall IFR for COVID-19 is ~.5% or less , this cohort could be having a major impact on the current mortality figures , and argues strongly for a screening program to identify this subpopulation and provide a means of protecting them until an effective vaccine is available to them.

  14. Todd says:

    The age leading to increased Anti-IFN antibodies thing seems plausible. You’d think lifelong exposure to infections over the course of a lifetime would lead to increased Anti-IFN antibody generation risk. Still, the P-value is striking. There are Holy books with lower P values.

    The next obvious thing to do is screen the bejesus out of anyone who was hospitalized with COVID-19 and their first degree blood relatives. This has potential to be a Stop The Presses development.

    1. Agda says:

      Regarding life-long exposure to infections/pathogens increasing risk of anti-IFN Abs: this could work in the opposite direction, with those most exposed during their lifetime having a more tolerant immune response as has been speculated about Covid19 outcomes in Africa. Immunosenescence has reasons other than repeated infections.

      1. Todd says:

        There’s no good answer here, and working that out will go on long past the pandemic. My point is to not reject it out of hand.

  15. sgcox says:

    There is another paper in Science about basically the same topic but from a different direction.

  16. Mysterious Sarcoid says:

    Any opinions about whether this result puts those with sarcoidosis at extreme risk? Its underlying etiology is poorly understood, but I believe related to interferon.

    This isn’t a theoretical concern for me: I had/have (mild, I think) sarcoidosis, detected in early 2014 because it caused a rash. (And also some simultaneous unilateral hearing loss in the same month the rash appeared, though we don’t know for sure that that was it, but boy was the timing suspicious.) I was on HCQ for it, and started tapering off it very slowly in early 2017, finally stopping around January 2020 (yes, just before it became entirely unavailable for reasons we all know). I’m in my mid-50’s, so the COVID-19 risk is getting up there regardless, though I’m without other apparent comorbidities.

    I’ve been paranoid about exposure since day one and have been able to almost never leave the house, and I’ve also been paranoid about fomites because “not the primary mode of transmission” doesn’t strike me as “never happens.” (And I would love to see some believable
    research about that one way or the other, and is there anything useful about that case in NZ six weeks ago which they believe was from surface contamination in a refrigerated warehouse? Last I see in any source is “surface testing is underway” and then nothing.)

    But this paper makes me wonder if I need to be even more paranoid.

    P.S. Long-time (15 years?) reader, first-time commenter.

    1. David E. Young, MD says:

      Probably not extreme risk. Probably no different than anyone else your age. But you are right to be very cautious and even very cautious to a bit of extreme is okay with me. The more people are cautious, the better the outcomes will be.

    2. NotaKiwi says:

      “… is there anything useful about that case in NZ six weeks ago which they believe was from surface contamination in a refrigerated warehouse? Last I see in any source is “surface testing is underway” and then nothing.)”

      None of the surface swabs from the cold-pack facility came back positive so take that with the usual caveats about absence of evidence from a test that was likely somewhat improvised on the fly.

      I went through NZ’s managed isolation process back in May and can confirm that it is not air tight – although I hear it’s gotten tighter. Since then, several patients have tested positive in isolation, but didn’t have sufficient viral titers for the lab techs to get a full genomic sequence (necessary for tracking purposes). It’s certainly possible that Auckland’s August cluster originated from such a patient in one of these facilities, but further studies are needed…

      Sorry, that probably won’t do much to allay your worries, but covid is not the only fomite-transmitted pathogen that you could be worrying about. Flu season seems to be the latest victim of cancel culture and that’s probably a good thing.

  17. Bob Smith says:

    Couple thoughts:

    Based on this I hope that soon there will be blood tests that can quickly identify high risk individuals. This might be almost as valuable as vaccines. Especially if vaccines end up being non sterilizing.

    Second, coming out of this we may know a lot more about autoimmune diseases, including lupus, MS, even arthritis. Could be an amazing silver lining.

  18. Prefer not to say says:

    Take the autoantibodies story with a grain of salt. Casanova/Abel have done iffy work at times. But most of their stuff is good.

  19. Robert Michaels says:

    The Russians have been using interferons in their covid19 protocols since day one.

    American researchers just now discovering it’s importance have a lot of people suspicious that the American medical establishment actually preplanned to make sure people admitted to hospitals got sicker and stayed longer so they could maximize billings$$$.

    1. SCINV says:

      Keep your pants up comrade. Checking again yesterday, over 50 interferon trials (including with all the combinations) that mostly failed around the world. So the exact interferon, method of delivery and target population was not clear at all and systemic administration can cause issues. With the latest publications, we are starting to get some answers on these questions and of your Russians had done that work, make no mistake they would have published it themselves and then shouting it left and right.

  20. anti dat establishment says:

    Auto-antibodies is just dropped in there as if we should all know what they are. Inferring from the rest of the article, it seems that auto-antibodies are, or include, antibodies to interferon. More generally does this refer to antibodies to the hosts own cells, making these (potentially) a component of autoimmune diseases?

    1. mzchem says:

      Yep. Antibodies to self. The term is general in that it refers to any antibodies that trigger to cells of the body. There are several checkpoints the reduce the production of B cells that generate them, but they may be produced nonetheless. A more knowledgeable person could probably explain in better detail the possible sources.

    2. Phil says:

      If only there were some way to quickly search a vast collection of human knowledge for the word autoantibodies and get, say, “About 4,360,000 results” in about “(0.54 seconds)”

  21. anon says:

    I am not a clinician so I am just shooting from the hip here…

    If I were to use plasma for convalescent plasma therapy, I would go after previously severely ill patients and collect their plasma. Then, I would pool it to remove variance and to cover a broader range of potentially neutralizing antibodies. Is this how it is done? If yes, would pooling not dramatically increase the chances that the plasma used for therapy will include a fraction with IFN autoantibodies? Will this not send the recipient into a steep decline? Is this a potential reason why data from plasma therapy was underwhelming – because the benefit of neutralizing ABs was outweighed from the harm of auto ABs?

  22. theasdgamer says:

    Grossman study has been published. “Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients”

    “Results. Patients taking zinc sulphate in addition to hydroxychloroquine and azithromycin (n=411) and patients taking hydroxychloroquine and azithromycin alone (n=521) did not differ in age, race, sex, tobacco use or relevant comorbidities. The addition of zinc sulphate did not impact the length of hospitalization, duration of ventilation or intensive care unit (ICU) duration. In univariate analyses, zinc sulphate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulphate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95 % CI 1.12–2.09) and reduction in mortality or transfer to hospice among patients who did not require ICU level of care remained significant (OR 0.449, 95 % CI 0.271–0.744).”

    1. Let’s go ahead and skip to the conclusion of this observational study, shall we?


      Zinc sulphate added to hydroxychloroquine and azithromycin associates with a decrease in mortality or transfer to hospice among patients who do not require ICU level of care and an increased likelihood to be discharged directly home from the hospital. In light of study limitations, this study alone is not sufficient to guide clinical practice. Rather, these findings suggest a potential role for zinc sulphate in COVID-19 patients and support the initiation of future randomized clinical trials investigating zinc sulphate against COVID-19.”

      So: plausibility established for a clinical trial. Great! Now we just need RCT results to see if the reported results were an artifact of confounding by indication or lack of randomization.

      1. theasdgamer says:

        “Understanding and misunderstanding randomized controlled trials”


        Randomization does not balance confounders in any single trial.

        Unbiasedness is of limited practical value compared with precision.

        Asymmetric distributions of treatment effects pose threats to significance testing.

        The best method depends on hypothesis tested, what’s known, and cost of mistakes.

        RCT results can serve science but are weak ground for inferring ‘what works’.”

      2. theasdgamer says:

        In my county, those over 80 have a covid IFR of 30%. In Utah, the same age cohort has a covid IFR of 10%. What is the difference?

        1. Some idiot says:

          Good grief.. the S/N had been increasing nicely… then IT came back to bomb the conversation…

          1. theasdgamer says:

            Mr. Idiot, you are well named, since you confuse signal with noise. Have a nice day.

          2. Some idiot says:

            Mr T, you have not contributed any further knowledge than was already available, ie that observational studies suggest an effect. Therefore you have not contributed any Signal. But you seem to be ignoring the conclusions from the authors that further clinical studies are required in order to see whether or not this has clinical relevance. There you are significantly increasing noise.

            If you are so interested in pushing a particular agenda, then I suggest you start your own blog, instead of bombing a well-functioning one. Having said that, if you have new, relevant data (for example RCTs), I, for one, would be very interested in seeing it. That would increase S/N.

          3. theasdgamer says:

            Mr. Idiot,

            Repeated signal is still signal. Confirmed signal adds to signal strength and confidence.

            There have been plenty of RCTs where people were treated with hydroxychloroquine and zinc early. Just go look at to verify that. But results in a RCT don’t necessarily mean that the treatment is practically effective. Retrospectives can help with that because they are more real-world situations. Patients can double dose and forget dosing.

            RCTs in a hospital are meaningless if the HCQ is given late.

            RCTs where one arm is given anticoagulants, steroids, and HCQ but the control is given nothing says nothing about HCQ’s role.

          4. Some idiot says:

            Mr T, repetition of already known observations does not equate with more signal. It has been known for a while that observational studies suggest an effect, so you are not adding anything new there. Thank you for the link to the studies, but I also observe that none of the positive studies were RCTs; most inconclusive, with some negative.

            And to your next points: History is littered with examples of people thinking they were doing good things with (eg) medical procedures etc until they were actually tested using RCTs and shown wanting. Therefore, observational studies can be suggestive, but only by doing the RCTs in a properly controlled manner can you see for sure whether or not the effect is real.

            One thing we can agree on is that if an RCT is set up inappropriately, with confounding effects and insufficient statistical backup, then it will not be much use (and this may be one of the reasons for so many inconclusive RCTs on the link you provided). But the same applies to observational studies, but more so, because unconscious bias will also be a factor.

            You also say that HCQ is useless if given late. What I would suggest is that it would be more correct to say that your hypothesis is that HCQ is useless if given late, since there are no RCTs to support (or disprove, for that matter) that statement. And this is the point. There is so much conjecture in this debate, but far too little solid evidence (RCT). We need to be sure about what we know, and honest about what we don’t know. On both sides of the discussion. Only in that way will science progress towards helping the people who need it.

            And although I have been (in exasperation) harsh on occasions, I am pretty sure that both of us have that goal in mind: helping the people who need it.

          5. theasdgamer says:

            Mr. I,

            I appreciate your attempt to find agreement.

            I have gone to some pains to attempt to understand the covid disease process and progression and have learned a great deal.

            Would you expect an antiviral to work after a patient has progressed to ARDS? And are you aware that covid has a stage that is pre-ARDS (with hypoxia but not dyspnea) and may be mistaken for ARDS (with both hypoxia and dyspnea)? Are you aware that the Berlin definition of ARDS may lead to premature mechanical ventilation if followed strictly in the case of covid, perhaps resulting in ventilation-induced lung injury?

            Once we agree about the covid disease process, maybe then we can agree that studies testing late treatment of covid with HC are meaningless.

          6. Some idiot says:

            Mr T: I am glad we are both trying to achieve some sort of consensus (and I really mean that! 🙂 ).

            I agree that the place for antivirals is early, before the immune system goes berserk. However, the evidence strongly suggest that HCQ is not an antiviral against COVID-19. Yes, the earliest data using cells were encouraging, but later studies showed conclusively that it did not work, and also showed that the false positives from the earlier experiments were due to the use of an inappropriate cell line (and, importantly, why that cell line was inappropriate).

            I accept that I read this material some months ago, and I accept that I cannot remember whether or not the addition of Zn supplements was examined in these experiments. However, at best, it would be unlikely… But I will check again.

            More generally though, if I have understood your argument correctly, (and I accept that I am simplifying matters somewhat), you are more or less saying “you can’t do a RCT with HCQ because it is an antiviral, as opposed to an immune system modulator.” However, Remdesivir (no miracle drug, but…!) has been found to be useful in a clinical trial, so I would therefore expect that if HCQ was effective as an antiviral, then this should also be able to tip a RCT in the right direction as well…

          7. theasdgamer says:

            Mr. I,

            Please reference those in vitro studies that you mentioned.

            My view of RCTs is that they are best put to use on chronic problems like diabetes. Maybe they will someday be useful for novel infectious viral diseases, but I don’t hold out much hope based on history.

            RCTs are heavily controlled and will have their best application in heavily controlled contexts like a hospital.

            “How the laws of physics lie” examined this question about science and the usefulness of strictly controlled science.

            For studies of outpatient settings, we probably need some statistical framework that accounts for occasional improper dosing and occasional failure to follow medical instructions.

            It struck me as very strange that the early retrospective studies of HC were in hospital settings where treatment was given very late. I was forced to conclude that these studies were an attempt to poison the well. I was surprised that other people missed this.

            I don’t know that zinc supplementation is necessary for everybody. I suspect that women aren’t deficient in zinc and neither are young men and children. Old men have a problem with zinc deficiency and this is why you see some zinc supplementation in prostate supplements and 50+ vitamins. In any case, zinc levels ought to be tested by doctors and tracked in covid studies.

            Now vitamin D deficiency should also be examined. According to what I have read in “science” news, 40% of American adults are deficient in vitamin D.

            Old black men are most at risk from covid and they are also most likely to be deficient in both zinc and vitamin D, which affects immune health.

            I’m not 100% convinced that HC is as effective as some claim, but I think that there is clear evidence from retrospective studies that it reduces hospitalization by 80%–I’ve seen this in several studies, including one of a very high risk group (Heras). Not surprisingly, reducing hospitalization means that severity of covid and mortality will also follow.

          8. Some idiot says:

            Here is a link to the results I mentioned. I have been very busy recently (and will be) so have not been able to identify the the individual papers, but but you should be able to find them.

            I’m stopping here, mainly because I do not have the time, and partially because I can see we do not agree about the critical importance of RCTs. Yes, there can be logistical obstacles to setting them up appropriately , but the alternative is much worse.

          9. theasdgamer says:

            Mr. I,

            I looked at the thread you referenced. The author appears not to know that the primary damage to lungs is caused by microemboli, not by alveolar infection. We would have to look at ACE2 activation in endothelial capillaries for SARS-2.

            Also, there is the argument that HC not only inhibits entry of SARS-2 into cells, but its alkalinic effect in endosomes inhibits viral replication by trapping the virus in the endosome where it is eliminated by a lysozome.

            Finally, I know that we disagree about this, but I still think that there’s merit to the zinc ionophore argument.

            I wouldn’t use Boulware for anything. I could make an argument that it supports prophylactic effect, but there are just too many problems with that study.

            I don’t know anything about using animals for drug testing. I suspect that they are primarily used in lieu of humans because of the uncertainty of new drugs–especially risks.

            Strictly controlled experiments work great in chemistry and physics. I know that from limited experience. I haven’t tried any experiments outside of those disciplines and certainly nothing pharmaceutical.

            I suspect that RCTs work best in the context of chronic treatment. They are one tool in the tool box, but hardly the only one.

            With novel acute viral infectious diseases, you can have a rapidly changing standard of care like we saw with covid. There will be problems with trying to use old and new data and adjusting for improved understanding of disease processes as time passes. And those diseases tend to follow a gompertz curve, so RCTs so far have been late to the party.


        2. confused says:

          Do you mean CFR or IFR? Is this definitely not a testing issue?

          Utah does seem to do pretty well in terms of CFR, but there may be many confounders. Utah is a fairly atypical state.

          I don’t know where your county is, but places like Utah hit relatively recently should be expected to have lower IFRs than those like NYC and Boston hit early (when this was less well understood and we didn’t know about dexamethasone & maybe remdesivir) should be expected to have higher IFR than places hit late. Also, nearly all infections in those places are resolved; that’s not the case in Utah.

          1. theasdgamer says:

            Mr. confused, for over the 80+ cohort, cfr and ifr are practically the same.

            Your answer indicates that you haven’t looked at the historical data for Utah. The cfr for Utah has been fairly flat.

            The BIG confounder in my speculation is that my county has 3x the number of blacks as Utah, and blacks have 2x the covid fatality rate of whites. Still, we might expect Africa to show high covid fatality rates, but that hasn’t been the case, so it’s not purely a racial thing. I suspect vitamin D deficiency in blacks in my county making them more susceptible to covid.

            Someone could put the hydroxychloroquine question to rest one way or another by looking at hospitalization and mortality from covid for 80+ y.o. black men who were treated within 5 days of symptom onset with HCQ. A 200 case retrospective study should be perfectly adequate for this purpose.

          2. confused says:

            >>Your answer indicates that you haven’t looked at the historical data for Utah. The cfr for Utah has been fairly flat.

            Maybe I’m missing something, but my point is that Utah had very few deaths in the earliest part of the pandemic when treatment was most poorly understood. Given extreme limitations on testing back then, CFRs probably don’t mean much.

          3. theasdgamer says:

            Mr. Confused,

            If the doctors in Utah had learned from the doctors in New York, we’d expect to see a cfr that drops with time progression in Utah–high in the beginning and lower later. However, the cfr is flat and has always been low in Utah. Low cfr in the spring and winter and low cfr when they got more cases this summer.

            Hydroxychloroquine MAY be the reason or it may be because the percent of black people in Utah is very low. Covid may be a disease that is exacerbated by nutritional deficiencies–low vitamin D (40% of US adults are deficient) and zinc (typically elderly men have zinc deficiencies. Both vitamin D and zinc deficiencies handicap the immune system. Black people who work indoors tend to have vitamin D deficiencies. I was surprised to learn that it can take a fair-complected person 15 minutes of exposure to sunshine to generate an adequate amount of vitamin D, but that some people require THREE HOURS of exposure to generate the same amount of vitamin D. Mostly the people we see dying of covid are elderly black men in nursing homes.

            Maybe a lot of the deaths can be avoided by getting enough sunshine and taking some zinc supplements.

          4. theasdgamer says:

            Mr. confused,

            I’m not sure if PCR tests mean very much either early or late if it takes 50 PCR cycles to generate a positive result. Diagnosing covid can be problematic. Maybe the “covid” patient had covid or maybe the flu or maybe covid AND flu. Maybe the covid was merely incidental. It’s a mess to sort this out and data from early on will always be problematic for a novel disease. So there’s lots of noise in data from Utah and New York from early on. But we can assume that there’s the same level of noise in all the early data.

            The most accurate piece in covid diagnosis is the trained clinician who has experienced a LOT of covid patients. New York had a lot of them early on and likely Salt Lake City had a fair number as well early on. Flu testing has the same problems as covid testing and ruling out flu is as problematic as ruling out covid.

            Back to comparing New York and Utah. New York is ranked 15th in per capita covid cases and Utah is ranked 21st. So there’s not a lot of difference between them in experience with covid. (25,000 per mil covid cases for New York versus 23,000 per mil covid cases for Utah.)

            And the infections graph for covid for Utah looks very similar to that of the US generally. Same starting point in April and pretty much the same slope.

            So I don’t think that the data supports your “Utah didn’t know what it was doing early on” hypothesis.

  23. Lev says:

    To quote from Derek’s post: “..Past such inborn protein errors, that are also people who ” you probably meant to say : “. Apart from such inborn protein errors, there are also people who “

  24. confused says:

    While not directly related to interferon, this is the most recent COVID-related post… this blog has been extremely helpful for me in terms of cutting through all the hype about COVID treatments. Could you please say something about the recent Vitamin D study (studies?)

    1. Jacky says:

      Hi , may I ask for your opinion? Some experts (including some well-known ones) insisted that first batch of vaccines will only reduce the severity of getting covid-19, so we need to wear masks afterwards. Is this too cruel to people? Do we really need to ‘end’ the pandemic by eliminating covid-19 from all over the world? Why can’t we treat covid-19 as normal seasonal flu after vaccines are launched? Really feel desperate after reading what such experts like Eric Topol had suggested or agreed…(and who will be willing to get covid vaccine if they have to keep social distance afterwards?!)

      1. confused says:

        I am sure some people will continue to wear masks… but I really can’t see people or local governments in my state (TX) keeping any sort of measures up once an even moderately effective vaccine is widely distributed.

        But then, here masks are mandated, but plenty of people just wear them on their chins and don’t take it at all seriously…

  25. Barry says:

    “Despite early reports to the contrary, there is increasing evidence that patients with severe COVID-19 have a robust type I interferon response, which contrasts with the delayed, possibly suppressed, interferon response seen early in infection…recombinant IFN-I proteins, including both IFNα and IFNβ, are being clinically investigated for the treatment of patients with COVID-19 either as a single agent or in combination with other antiviral agents. As of 6 August 2020, four studies have been completed and report a favourable response to early IFNβ use (for example, NCT04276688), and 18 studies are underway testing the clinical efficacies of IFNα or IFNβ. However, as IFN-I seems to exacerbate inflammation in the progression to severe COVID-19, the timing of administration and targeted subgroups for IFN-I treatment need to be considered with caution. A recent retrospective study of 446 patients with COVID-19 reported that early use of IFNα decreased mortality, whereas late use of IFNα increased mortality and delayed recovery”

  26. theasdgamer says:

    Here’s a retrospective study of 100 patients given hydroxychloroquine where median age is 85+:

    Not large, not RCT, but includes only high risk nursing home patients, which is somewhat different from other studies.

    Bottom line: 80% decrease in mortality if given the treatment.

  27. Jim Green says:

    Interestingly enough, (IFN)-β 1a was looked at back in 2004 as a potential treatment for the original SARS virus.

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