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Anti IL-6 For Coronavirus Patients: Does It Work, or Not?

It’s been looking for some time as if these coronavirus infections need a biphasic approach to therapy – an antiviral approach earlier on, and for those in serious trouble, perhaps a shift to immune modulation as the body’s reaction to the virus starts doing even more harm. That post goes into some detail on possible therapies targeting IL-6 for this purpose, and today we finally have some clinical data on the idea. Prepare yourself, if you are one of the many people who haven’t had experience with investigational therapies but are watching to see how things play out with the pandemic. Because this is another one of those cases that will make you wonder what’s going on.

There’s an antibody against the IL-6 receptor from Roche/Genentech, tocilizumab (brand name Actemra), and this morning came preliminary word from France that the CORIMUNO-TOCI trial had produced positive results. This was in patients who had “moderate to severe” disease but were not in the ICU: 65 got standard of care, and 64 got standard of care plus tocilizumab (but note: the trial, although it has a control group, was open-label). The press release says that both deaths and the need for later ventilator support were “significantly reduced” in the treatment group, with no more adverse effects than in the control group.

The French team is also studying tocilizumab in patients in intensive care, and they’re looking at another approved antibody to the IL-6 receptor as well, sarilumab (brand name Kevzara) from Sanofi and Regeneron. These two drug are both given for rheumatoid arthritis, with the same mechanism of action, but every antibody is a different beast. For example, tocilizumab is given i.v. and sarilumab is subcutaneous, so they have different pharmacokinetics right from the start.

And those results are certainly going to be interesting, because we have the results of a separate study on sarilumab this morning where it was shown to be almost completely ineffective. There had been an earlier report from China of efficacy for the drug, albeit in a small trial without a control group – and if there’s one thing that people should take away about drug discovery from this whole pandemic experience, it’s that small uncontrolled trials cannot prove anything. All they can do is to point to something that might be interesting to study for real, and you should be ready for most such signals to turn out to be noise.

In the Sanofi-Regeneron trial, patients got either standard of care, standard of care plus 200 mg of sarilumab, or standard of care plus a 400 mg dose. The patients were classified as either “severe” or “critical”, and the severe patients were not helped at all by either dose. In fact, there was some worry that they had done even worse on the drug than in the control group, but as more data came in it appears that sarilumab was merely useless. For the critical patients, though, there was a slight trend towards better outcomes in the treatment groups, especially in the higher-dose group, but the results weren’t statistically significant (and thus could be more noise).

We’re going to get more data to resolve this: Roche is running its own controlled trial of tocilizumab in coronavirus patients, and as mentioned, the French study is also looking at sarilumab. Is there such a dramatic discrepancy in the two drugs? And if so, is due to different sorts of patients being recruited in each trial or is it just that there is some weird split in activity between the two different antibodies? How good are the tocilizumab data from the open-label French study in general? And so on.

Welcome to the clinic, folks. This kind of stuff happens all the time; it’s not just with the coronavirus. What we do have is a lot more data, of widely varying quality, hitting with greater frequency with (understandably!) a lot more attention being paid to it. But this is how it goes, even when it’s just us biopharma people scratching our heads.

80 comments on “Anti IL-6 For Coronavirus Patients: Does It Work, or Not?”

  1. Joshua Roopchand says:

    Is anyone evaluating a TLR3 or TLR7 agonist for use as a therapeutic? TLR3 and TLR7 are part of the innate immune response against viruses, especially RNA viruses. See below

    “Allergic asthma and allergic rhinitis are inflammatory diseases of the respiratory tract characterized by an excessive type-2 T helper cell (Th2) immune response. Toll-like receptor 7 (TLR7) is a single-stranded viral RNA receptor expressed in the airway that initiates a Th1 immune response and has garnered interest as a novel therapeutic target for treatment of allergic airway diseases. In animal models, synthetic TLR7 agonists reduce airway hyperreactivity, eosinophilic inflammation, and airway remodeling while decreasing Th2-associated cytokines. Furthermore, activation of TLR7 rapidly relaxes airway smooth muscle via production of nitric oxide. Thus, TLR7 has dual bronchodilator and anti-inflammatory effects. Two TLR7 ligands with promising pharmacologic profiles have entered clinical trials for the treatment of allergic rhinitis. Moreover, TLR7 agonists are potential antiviral therapies against respiratory viruses. TLR7 agonists enhance influenza vaccine efficacy and also reduce viral titers when given during an active airway infection. In this review, we examine the current data supporting TLR7 as a therapeutic target in allergic airway diseases.
    Transfus Med Hemother. 2016 Mar; 43(2): 114–119.

  2. Joshua Roopchand says:

    Imiquimod (R837, S26308) is a TLR7 agonist approved for treatment of anal and genital warts, actinic keratosis, and basal cell carcinoma [29]. Resiquimod (R848, S28463) is a derivative of imiquimod that activates both TLR7 and TLR8 (another viral single-stranded RNA receptor) [30] and more potently induces TNF-α and IL-12 secretion [29] when compared with imiquimod. Gardiquimod [31], 3M-019 [32], CL097 [33], S-27609 [34], MEDI9197 (clinicaltrials.gov NCT02556463), and 852A [35] are also imidazoquinoline TLR7 agonists, while the guanosine analogues Loxoribine [36], and ANA773 [37] as well as the adenine analogues SM-324405 [38], AZ12441970 [38], GSK2245035 [39], AZD8848 [40], and GS-9620 [41] also activate TLR7. Three synthetic oligonucleotide TLR7 antagonists are currently in preclinical and clinical trials: DV1179 (dynavax.com), IMO-8400 and IMO-3100 [42].

    1. MD says:

      Imiquimoid (Aldara) not a good idea at all. It would me things worse. It stimulates the same bad cytokines that you want to reduce here. I had one patient that lost 15-20 kg as a side effect of Aldara with flu-like symptoms due to topical (over) use.

      Cheap and common drugs like sartans, statins, metformin and the usual “dirty dozen” can do the job and dampen TLR that puts the immunesystem to overdrive.

  3. Joshua Roopchand says:

    TLR7 and TLR3 agonists have excellent antiviral properties , part of innate immunity.

  4. Not-Immuno Specialised Scientist says:

    A non-sciency family member posed this exact question to me at the weekend:

    ‘Could we test Covid patients who are going into hospital to identify people whos immune system is most likely go into overdrive and give them something to calm the immune system down?’

    They’d read a bit about severe patients having ‘these things called cytokine storms or something’

    This seems to me what they were essentially asking about, and there may be some legs to their non-science suggestion (at least better than injecting disinfectants or inserting lightbulbs somewhere!), if i understand correctly?

    1. Nate says:

      You have to be careful with this approach, I believe Derick addressed it in a previous post if you want to dig. But the gist is that, in the midst of an active infection it is very dangerous to suppress your immune system. I.e. yes an overactive immune response giving cytokine storm is very bad, but a suppressed immune system won’t be able to fight the virus off at all. Obviously a bad outcome.

      1. Bernie says:

        I’m curious as to whether those with an already hyped-up immune system would fare better or worse, i.e. I’m currently enjoying chronic low-level hay fever due mainly to strange weather here in Oz. It’s mid-autumn, still quite warm, and various tree species are flowering – definitely out of season.

        Would that sort of information be worth noting, were I to be diagnosed with this virus?

    2. Todd says:

      Your relative is in the right direction. Doing that is difficult, of course, but that’s what these trials are intended to do. That said, it’s not the easiest thing in the world. The upshot is the weird coagulation response being observed which might cause even more chaos.

    3. PDINV says:

      They are very much so are asking a very good question. The thing is I’m not sure if anyone has an answer. Sometimes (rarely) it is trivial to estimate susceptibility to , however usually it involves a lot of work to answer that question and not necessarily very successfully. Bottom line, I don’t think it is possible to do that atm, but I’ll look around to see if anyone is actually looking and if they report anything interesting.

    4. A says:

      Testing to identify patients most likely to need significant treatment would be great… if we had any idea what to test for. Right now we just have some idea about what other risk factors seem to be worse… but even the data on those seems to change every week. Trying to determine what you should even be testing for is like looking for a needle in a haystack… if you had no idea what a needle even was and the haystack was filled with lots of other small long shiny objects.

      But then of course, we don’t even know what treatment would be effective even if we could identify people earlier.

  5. cynical1 says:

    Are there pharmacodynamic differences noted in the two different formulations between the IV drug versus the subcutaneous drug? Also, are there any clinical data in cytokine storm (CRS) associated with CAR-T therapy between the two which would be consistent with the observed efficacy observation with COVID-19? For instance, sarilumab is not used with CAR-T related CRS whereas tocilizumab is the standard of care. Perhaps it is not surprising that tocilizumab worked and sarilumab did not. Though why that would be I can not say.

    @Joshua Roopchand – If memory serves (and it might not) from reading about it decades ago, I believe that Imiquimod is extremely toxic when dosed internally. It is a topical drug.

    1. Joshua Roopchand says:

      Yes there is toxicity associated with Imiquimod given via injection (maybe as toxic as disinfectant , Ha Ha!!) but I think there maybe less toxix TLR7 and TLR3 agonists out there (mostly RNA analogs) that may be worth a try in these times of crisis.

    2. Elie Dolgin says:

      The approved formulation of sarilumab for RA is indeed subQ, but Sanofi/Regeneron seem to have reformulated the drug for COVID-19 treatment, as the listing on clinicaltrials.gov (NCT04315298) talks about a “single intravenous (IV) dose”. So, the PK shouldn’t be so different as to explain the discrepancies. Likely has more to do with the patient populations studied, methinks.

      1. johnnyboy says:

        Yes, the state of the patients is probably the best explanation for the difference. If you’re treating severe or critical patients, the tissue damage has already been done; you might decrease any more cytokine-related injury, but if the patient is already in multi-organ failure it will be hard to recover. You really need to target the more moderate/earlier disease if you want to have a preventive effect.

  6. Lane Simonian says:

    The anti-viral medication approach early combined with an IL-6 receptor antibody or antagonist late at least in theory makes considerable sense. The question is whether the virus is causing damage either independently or in concert with inflammation (or both).

    To a certain degree, oxidative stress precedes inflammation and is partially responsible for tissue and organ damage. The theory behind the following paper is probably instructive even if the prescribed treatment may not be.

    https://symbiosisonlinepublishing.com/microbiology-infectiousdiseases/microbiology-infectiousdiseases70.php

  7. Joshua Roopchand says:

    Yes there is toxicity associated with Imiquimod given via injection (maybe as toxic as disinfectant , Ha Ha!!) but I think there maybe less toxix TLR7 and TLR3 agonists out there (mostly RNA analogs) that may be worth a try in these times of crisis.

  8. steve says:

    This could just be due to differences in patient populations or clinical trial protocols. However, it’s important to keep in mind that just because two antibodies are directed to the same target does not mean they’re the same drug. For one thing, there could be antibody subtype differences. That doesn’t appear to be the case here as both are humanized IgG1. However, there could be differences in affinities, the exact epitope hit on the receptor, PK/PD or other differences that could mean that the difference between the two drugs is real.

  9. Lane Simonian says:

    Tocilizumab inhibits NF-kB activation which often plays a role in oxidation and inflammation. I am not sure if this is also true for sarilumab.

    https://www.ncbi.nlm.nih.gov/pubmed/31440860

  10. Mark says:

    Je le regret mais it has been many years since I studied French. I didn’t see any actual result numbers in the French report. I wonder what they mean by “significantly reduced.” The word “significant” has a different meaning to a statistician than the way it is used in ordinary speech. I have sat through many presentations where “significant” findings were presented in the form of two survival curves that looked pretty much the same unless I was sitting in the first three rows of the auditorium. I think we should recognize that early results are like pictures of grandchildren; often a lot less beautiful to a disinterested observer than to the presenter.

    1. loupgarous says:

      “p-value” translates very well all through Europe.

  11. MTK says:

    An open-label study where the endpoint is progression to ventilation by day 14 gives me pause. A lot of pause.

    1. eub says:

      I’d certainly want the data release to include what happened on days 15 – 28.

  12. DMF says:

    Hit two birds with one stone with the smallest possible crazy drug: dimethyl-fumarate (Tecfidera). On the one hand this drug (and its metabolite: mono-methyl ester) is a well-known thiophilic Michael acceptor which should inhibit the cysteine protease (3CLPro) meaning antiviral activity and on the other hand this drug would reduce IL-6 induced lung inflammation https://doi.org/10.1152/ajplung.90624.2008.
    In MS patients 480mg dimethyl-fumarate p.o. daily is rather safe.

  13. Rob says:

    With a binary endpoint like survival/death, do these small trials have any power? Unless the patient numbers are much larger, wouldn’t the standard error be very large?

    1. Brian R says:

      This is a press release, and I am pretty sure any reader of this blog is not a big fan of science by press release. I’m still on the edge of my seat waiting on the methodology of the serology tests that Gov Cuomi revealed that 20% of us NYCers have antibodies. But that does seem to be the trend, and I guess in some ways it is better than nothing being revealed. But yes, the power isn’t great, but it means they likely had a bit effect size. Say for deaths, if they did Chi Square, they’d see statistically significant differences with 0/65 deaths in the treatment and 4/64 in the control, or 16/65 and 32/64. Just as examples, but you’d need at least a fold difference, and I think its safe to assume deaths in the control group probably fell between 4 and 32 (they couldn’t see ssignificance with 3/64). So, yes, definitely begs replication, but also is promising to say the least. Will be interesting to see the actual numbers upon publication.

  14. JasonP says:

    What is this? The heresy, THE HORROR!!!! From a top guy drug man?

    >>>“When you try everything under the kitchen sink, most of the time it’s not going to deliver the results that you want, no matter what the small 20-patient or 30-patient studies say,” said George D. Yancopoulos, Regeneron’s co-founder and chief scientific officer.<<<<

    saracasm warning…..

  15. Barry says:

    There are many points at which one can try to modulate the inflammatory response. At least anecdotes point to histamine as a player and H2 antagonists (famotidine) as candidates. Although pneumonia is listed as a known side-effect

    https://www.sciencemag.org/news/2020/04/new-york-clinical-trial-quietly-tests-heartburn-remedy-against-coronavirus

  16. Giannis says:

    How about going back to the basics and first try things in monkeys or hamsters (that seem to be susceptible to SARS-CoV-2)?

    From the animal data it seems that Interferon response is required to stop viral on its tracks. But if this fails, then interferon seems to lead to severe damage of the lungs. Surprisingly STAT2Δ hamsters, although having higher viral titres in the lungs compared to WT mice, they have a much better clinical outcome!

    https://www.biorxiv.org/content/10.1101/2020.04.23.056838v1

    1. steve says:

      IFN increases expression of ACE2 and it’s thought to be a feed forward mechanism by which the virus propagates itself so this may not be the best idea.

  17. heteromeles says:

    I’m going to temporarily join the out-of-left-field stupid treatment theories and suggest a possible treatment that I haven’t seen so far suggested: bromelains, the enzymes found in pineapples.

    My experience is purely empirical: I have asthma, and I noticed over 20 years ago that when I had mild wheezing that wasn’t controlled by albuterol, that eating pineapple out of the can quickly cleared my lungs, and that it also worked for my family. Obviously, anecdotes aren’t data, but we’ve kept a can or two of pineapple around during cold season off an on for years.

    Fortunately for science, it looks like researchers have found that bromelains are active anti- inflammatory agents that interact with IL-6 and other molecules in ways that do control asthma. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998156/). They are also active against platelet aggregration and thrombus formation. I wonder if they might be useful treatments for Covid19?

    The nice thing about this, aside from the potential for a run on the shelves at the supermarkets if pineapple turns out to be a useful adjunct, is that bromelains can apparently be tolerated in large doses, administered orally (sometimes deliciously) and have a half-life of 6-9 hours. Purified forms of the enzymes are already available, with the usual caveat that many of the preps look destined for the creepy part of the nutritional supplements aisle, rather than the clinical pharmacy.

    Sorry for relegating myself to the loony bin, but I figured I’d share, in case anyone wants an excuse to eat more pineapples, or try it and see if it helps.

    1. N says:

      Wouldn’t canned pineapple be pasteurized, therefore destroying the activity of the bromelain?

      1. heteromeles says:

        Good point. Not sure. I do know that the initial effect wasn’t a placebo, since I had no expectation of any medical effect and was just eating dessert when I suddenly noticed I was breathing easier. The fruit in the can isn’t cooked, so I’m not sure what they do to sterilize it.

        1. eub says:

          Canning processes do use high heat — ~250 degrees F for commercial canning — to sterilize the food (notably to achieve 10^12 reduction of botulism spores). I don’t see stability data on bromelain at that high a temperature, but from lower-temperature inactivation times I am pretty confident it’s completely denatured. So I dunno. You ever use frozen pineapple?

    2. PV=nRT says:

      How the heck do we think bromelain would get to the lung surface?

      1. mayfin says:

        Nebulized pineapple extract wouldn’t be the daftest proposed for this pandemic … though admittedly that’s a very, VERY low bar to trumple.

  18. Anonymous says:

    Derek,

    Several years back you commented on the MIT broad spectrum anti-viral DRACO proof of concept paper.
    https://blogs.sciencemag.org/pipeline/archives/2011/08/22/dracos_new_antivirals_against_pretty_much_everything

    Any new thoughts about it given current circumstances? I have no background in any of this so please forgive my ignorance. Despite that I am really grateful for your posts.

    1. sort_of_knowledgeable says:

      Funding seems to have run out in 2016. Speculation for reason for lack funding is concern that a large amount of protein is needed that might induce an immune reaction and too many cells with benign virus might also be killed.

      https://www.openphilanthropy.org/informal-writeup-dracos-potential-antiviral-treatment

  19. Stephen says:

    Slightly off topic – anyone know what is causing the marked weekly cycle in swedish corona deaths here https://www.worldometers.info/coronavirus/country/sweden/ . The UK also shows a weaker weekly cycle. Is is reporting or changes in care?

    1. Ian Malone says:

      Can’t speak for Sweden, but in the UK it is apparently largely about the time for reports to get through the system. The Sunday and Monday figures are for deaths recorded Saturday and Sunday, some get delayed to later days. This is related to our daily figures being deaths by date reported, not actual date of death. See https://www.england.nhs.uk/statistics/statistical-work-areas/covid-19-daily-deaths/ (but n.b. that the numbers there are just England, not all of the UK, and none of the headline figures we report include deaths outside hospital like care homes).

    2. Philip says:

      We see it in the US in confirmed infections. Speculation, testing over the weekend is lower, with Monday and Tuesday being make up days. Here is an explanation from a University of North Carolina modeling guy:

      https://www.danreichart.com/covid19-reports

  20. NITRIC OXIDE
    There is little information on the role of nitric oxide (NO) in innate immunity to respiratory coronavirus (CoV) infections. We examined NO levels by Greiss assay in bronchoalveolar lavage (BAL) of pigs infected with either porcine respiratory coronavirus (PRCV) or porcine reproductive and respiratory syndrome virus (PRRSV), a member of Nidovirales, like CoV. The antiviral effects of NO on these two viruses were tested in an in vitro system using a NO donor, S-nitroso-N-acetylpenicillamine (SNAP). We detected a large increase in NO levels in BAL fluids of PRCV-infected pigs, but not in PRRSV-infected pigs. Pulmonary epithelial cell necrosis induced by PRCV coincided with increased NO. Moreover, NO levels in cell culture medium of PRRSV-infected alveolar macrophages (AMs) did not differ from that of mock-infected AMs. Antiviral assays showed that NO significantly inhibited PRCV replication in swine testicular (ST) cells, whereas PRRSV was not susceptible to NO based on the conditions tested. Our study suggests that unlike PRRSV which induces apoptosis in AMs, respiratory CoVs such as PRCV that infect pulmonary epithelial cells and cause cytolysis, induce NO production in the respiratory tract. Thus, NO may play a role in innate immunity to respiratory CoV infections by inhibiting viral replication.

    https://pesquisa.bvsalud.org/portal/resource/pt/mdl-20409593

    1. Alan Goldhammer says:

      Nitric Oxide is already in clinical trials.

  21. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing

    https://academic.oup.com/cid/article/39/10/1531/460542&prev=search

  22. BCG against tuberculosis. In Eastern Europe the universal vaccine against the disease is still used, while in the West this practice has been abandoned.

    See Spain and Portugal. The latter included tuberculosis vaccine in its national mandatory vaccination plan, while Spain did not. Portugal has five times fewer inhabitants than its neighbor, but the number of infected people is ten times lower and the number of deaths in Spain is 39 times higher.

    1. Alan Goldhammer says:

      There are an equal number of preprints disproving the BCG hypothesis

      1. Jean-Baptiste Thiébaut says:

        HRV could be an interesting marker.
        Do you know if VNT (vagous nerve stimulation) was tested against inflammation ?

  23. Toni says:

    If you follow the reports of doctors on the front line more closely, you may find that Covid is probably not just a pure lung disease. In particular, the topic of vascular changes with microemboli at the level of small and very small vessels seems very likely.
    From this, damage to the lungs, brain, kidneys and ultimately all organs can be explained in a comprehensible way. This could also explain very well why elderly people, patients with high blood pressure, diabetes, i.e. people with latent damage to the endothelium, are much more susceptible.
    Since there are reports that SARS also affects the complement system (I think C5), there might even be a connection with the coagulation system, because both systems can influence each other.

    1. Barry says:

      preliminary reports suggest that underlying heart disease is a more dire co-morbidity than underlying lung disease

    2. JasonP says:

      Seems like the ACE2 receptor is on the endothelial cells (lining of blood vessels), infection/inflammation appears to lead to release of VWF, a pro-coagulant. Perhaps that coagulant is causing the damage in the brain (stroke), kidneys, etc.?

      Medical “explanation”/theory here:
      https://youtu.be/22Bn8jsGI54
      starts @ 4:30

      The “cure” for this VWF excess is UFH, unfractionated Heprin a widely used anti-coagulant.

      https://www.thrombosisresearch.com/article/S0049-3848(20)30130-4/pdf

      So yeah, perhaps the cure for this isn’t going to be a mono-therapy, but something(s) that slows the virus and other ‘standard of care’ drugs to deal with the rest: cytokine storm, thrombosis, secondary/opportunistic infection and oxidative stress?

    3. Toni says:

      there are more and more reports about thrombotic/embolic complications. One paper reports on 184 patients treated in intensive care units, 31% of whom were diagnosed with thrombotic complications.
      This is a really high number in view of the fact that all patients received all anticoagulant drugs.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146714/pdf/main.pdf
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151364/pdf/main.pdf

  24. Philip says:

    I have questions, lots of questions. I am a computer programmer, so this is outside of my area of expertise. I am looking for answers from those that know more than I do.

    The following is my understanding of how COVID-19 progresses and what makes sense for treatment in patients that end up with severe or worse disease. Please let me know what I have wrong, or what we just don’t have an idea about at this time.

    Day 0: The patient is infected, most likely by breathing in a droplet from an infected person. At this time the patient does not know they are infected and they are not contagious.

    Days 1-2: The virus is replicating. The patient does not know they are infected. The patient is still not contagious. If we had a great combination of testing and contact tracing, we would be able to find the patient before they feel sick, before they are contagious and while antivirals may help. I also think this is when the innate immune system kicks in and way before the adaptive immune system gets going. It is way too early to try to calm down the adaptive immune with drugs like tocilizumab, sarilumab, siltuximab or steroids such as prednisone. Calming the adaptive immune system at this time would be detrimental to the patient.

    Days 3-4: The virus is replicating. The patient does not know they are infected. The patient is now contagious. The innate immune system is still going it alone. It is not too late for an antiviral to help and still too early to try to calm the adaptive immune system.

    Days 5-7: The virus is replicating. The patient is feeling sick. The patient is still contagious. It maybe too late for antivirals and too early to calm the adaptive immune system.

    Days 8-14: Virus replication is down or has stopped. The patient is sick and starting to have problems with O2 saturation. Defiantly too late for antivirals. Time to try to calm the adaptive immune system.

    Days 15+: The patient’s adaptive immune system is killing the patient. The treatment is to try to calm the adaptive immune system and raise O2 saturation as much as possible, while trying to keep the patient off of a ventilator. Not an easy task. At this point in time the patient’s fate maybe set.

    COVID-19 appears to cause other problems, such as clotting. I am not addressing clotting or other problems in this post.

    I really want to see good controlled studies of antivirals and immune system moderators. I don’t care to see antivirals tested on very sick patients. I don’t want immune system moderators tested on people early in the course of the disease.

    Please tell me what I have wrong.

    Thanks.

    1. johnnyboy says:

      Overall I think you give a fair description of what may be happening. A few caveats: the stage by day that you provide is a reasonable approximation, but in real life it probably varies more from patient to patient. One big variable would be the infective dose: a small dose might take a while before enough replication has occurred for the patient to feel sick (or the replication might take so long that the patient has time to mount an immune response and get rid of the virus without feeling that sick); a large dose might progress more quickly.
      Also the dichotomy between innate immune system and adaptive, while a good concept overall, is probably a bit too simple for the processes going on in this disease. It’s not merely an activation of the adaptive immune system that causes cases to progress to the severe stage, but an excessive reaction, which likely involves cells like macrophages, which are traditionally considered part of the innate system). And as you know, only about 20% of patients progress to the severe stage, even though in the 80% of mild cases the adaptive immune system has surely been activated. The lung injury in severe cases is an ARDS type injury, which most likely is due to cytokines released by overactive immune cells, rather than a direct viral injury to the lung tissue. Patients in ICU also commonly develop cardiac and renal damage, which are probably due in part to that cytokine release.
      Overall I think you’re right with what the general therapeutic approach should be: antivirals logically would only have an effect in the very early stage of disease, if they can decrease viral replication. But in reality, by the time a patient feels quite sick, most of the viral injury has probably been done. Which is why I think it is pointless to think about antivirals for this disease, unless you were able to administer them to hundreds of thousands of people extremely quickly and efficiently based on early testing results. But logistically I don’t think any country is in that place. Right now only sick people are getting tested, and then the results come out a day or two later, so by the time this is communicated to the physician, who would then prescribe the drug, which the patient would have to procure, then take, then wait to have a decent systemic drug concentration… The damage will be done. By contrast the approach of tamping down the cytokine release with immunosuppressive drug like tocilizumab is more realistic, as this will involve fewer patients, who will likely already be hospitalised, and can be treated quickly as soon as there are signs that they might benefit. This would have to be based on biomarkers predictive for this cytokine release, which at the moment are probably not well understood, but I’m sure there’s research going on to identify them.

      1. Squirrilla says:

        I think you have a very good point about antiviral therapy needing to be started early.
        Resveratrol may be active against the virus spike protein as well as an immune modulator. Its also active against MERS and SARS.

        See Stilbene-based Natural Compounds as Promising Drug Candidates against COVID-19.
        https://www.ncbi.nlm.nih.gov/pubmed/32345140
        Also lots like https://www.ncbi.nlm.nih.gov/pubmed/32104238

  25. Ryan says:

    IL-6 and TNF-alpha are mentioned in passing as one of the targets of this approach (a very, very old drug and the ancestor of chloroquine). The bulk of the video discusses the difference between ARDS and COVID-19 and similarities with methemoglobinemia: https://www.youtube.com/watch?v=ZlzDtaOMYPo

  26. Rebekah says:

    So if you’re already on Actemra how would that work..?

  27. Rebekah says:

    So if you’re already on Actemra how would that work. No cytokines storm? Less chance of ..?

    1. DMF says:

      Or Tecfidera!??

    2. loupgarous says:

      If I’m reading Derek right, the studies he’s writing about used higher dosages of Actemra than usually are given to treat what Actremra’s usually prescribed for (or was prescribed for before the pandemic). And studies with actual Covid-19 patients are the only way to tell if it’ll work in the disease.

  28. If IL-6 inhibitor is the hammer... says:

    What about Celebrex? Also an IL-6 inhibitor, no?

    1. loupgarous says:

      “Effects of nimesulide and sodium diclofenac on interleukin-6, interleukin-8, proteoglycans and prostaglandin E2 production by human articular chondrocytes in vitro,” Henrotin YE et al says

      “From the results of this study we conclude that nimesulide and diclofenac at therapeutic concentrations are potent inhibitors of PGE2 and IL-6 production while they do not modify proteoglycan or IL-8 production.

      IDK about Celebrex, but Voltaren’s another known IL-6 inhibitor. So far, by sheer luck of the draw I seem to have been prescribed an ACE1 inhibitor (lisinopril), an antidiabetic agent now being studied to prevent/minimize late-stage Covid-19 lung damage (dapaglifozin), and now an NSAID which helps with IL-6 (diclofenac). Which is great, because I’m also in the high-risk group for Covid-19 organ damage.

      1. eub says:

        Nice little mix, now just avoid going out eaten by vultures, perchance.

        (Backstory: see “Indian vulture crisis” caused by veterinary diclofenac poisoning.)

        1. loupgarous says:

          You have to wonder how loaded, say, a water buffalo has to be with diclofenac that its meat kills vultures.

          Something about having the district vet come out and slip a bolus of Voltaren down faithful old Abdul’s throat every week so the rice gets harvested on time, then he drops dead of exertion (or a massive diclofenac-mediated coronary) that’s a little sad.

          1. eub says:

            Internet suggests you dose your cattles 2.5 mg/kg /day i.m., while in vultures “an LD50 of 0.1–0.2 mg  kg−1”. So I guess, depending on kinetics, a vulture gets poisoned on something like a tenth of its own body weight?

            Theory aside,
            https://www.sciencedirect.com/science/article/pii/B9781437719864000469
            “Similar experiments reproduced visceral gout and diclofenac residues in vultures that were fed meat from a buffalo treated with standard label doses of veterinary diclofenac.”

      2. BO. K says:

        HI, how did that treatment turn out for you?

        Personally I would tell the world to study Lisinopril or any LYSINE based ACEi and AVOID ACEi that have arginine as an active or inactive ingredient.

        Arginine is an essential requirement for the replication of viruses and progression of viral infections. Arginine bioavailability is absolutely necessary for the replication of herpes simplex virus, which causes cold sores/genital herpes.Apr 13, 2017
        https://www.bioceuticals.com.au › all
        Arginine and its effects on viral replication – BioCeuticals

        Lysine based Acei have inhibitory effect on arginine, arginase NO production, will have a calming effect on the cytokine storm on two fronts. The IL-6 and NO.

        How do I know, because I have seen plain 1,500mg of plain LYSINE calm a cytokine storm in a few short hours, with vitals stabilizing like it was a dam miracle. Of course if intubated, won’t help unless you can IV it in. Compassionate care, you should keep either lisinopril handy or two lysine tablets in your pocket and give it to them before intubation. When you try this and find it to be true, I have a few more valuable discoveries.

  29. Mary says:

    With ref to the comment about pineapple. I also find Bromaline helpful for my asthma and in relation to Covid 19 Bromaline lowers Brandykinin, increases of B are suggested to cause micro clotting in the lungs of Covid patients .
    https://www.ncbi.nlm.nih.gov/pubmed/2203073

    1. loupgarous says:

      Googled “brandykinin” because any therapy involving brandy appeals, but just boring old bradykinin came up.

      Seriously, the work on bromelain as a counteragent to bradykinin seems to be mostly inspired by its roots in folk medicine such as ayurveda. Most of the recent papers I’ve seen have either been reviews of the literature or reports of bromelain’s activity in vitro.

      I made bromalin tea for my wife last night while she was suffering a weird kind of cluster headache that her prescribed gabapentin and anti-inflammatory drugs weren’t helping with. It seemed to help, but by the time I did that, her prescription medications were already onboard, so confounding causes both for the headache and its apparent cessation with time abound. I’d hesitate to say this was a “win” for bromelain as a tea, but it couldn’t hurt.

      1. Bolognesus says:

        I’m with eub on the chances of bromealin doing, well, anything really, after having been heated that much. Tea is generally brewed at a fair bit more than 80 deg C; check out the graph on page 3 of the following paper:
        https://web.archive.org/web/20141129015814/http://kasetsartjournal.ku.ac.th/kuj_files/2010/A1010081847262467.pdf

        Even if you brew your tea at just 80 C (AFAIK about as low as one should? Honestly, I’m just not a tea drinker at all…), by the time you actually drink the tea, there would be ~0% residual activity left.

        Score one win for the prescription meds in this case, I’m afraid.

        1. Mary says:

          Yes prescription meds likely better – if they are available! In the Uk that may not be likely, so one considers other things in their absence.
          I already take bromaline mixed with quercitin for vein and circulation issues, as well as asthma and find it helpful for all of these. I was thinking about supplements though, not heated tea. Though raw fresh pineapple would probably be a good source.
          …Often enjoy a brandy when reading these posts 🙂

        2. loupgarous says:

          We don’t boil our water for tea, we heat it in the microwave, then steep the bag in the water until strong enough, but I take your point on heat inactivation – you’re right.

          Our next step would be to try bromelain, which the local dietary supplement stores stock. I stipulate the chances of getting useful purity of it through supplement houses is dicey at best, but my wife has digestive issues with raw pineapple. But she’s suggested Co Q10 and quercetin as acceptable things to try as well. I’m just fine with raw pineapple, pineapple juice, just about any form of pineapple.

  30. fonda says:

    COVID-19 cytokine storm: the interplay between inflammation and coagulation https://doi.org/10.1016/S2213-2600(20)30216-2 interesting Lancet paper yesterday: looks wise to give patients anti-coagulation factor Xa drugs such as fondaparinux or rivaroxaban

    1. Christopher Schindler says:

      Protocol from a French Doctor with advanced training in General Immunololgy:

      https://blogs.mediapart.fr/pierre-jacques-raybaud/blog/020420/covid-19-proposal-new-treatment-and-protocol-using-triple-therapy

      No one considers Doxycycline? IL-6 Inhibitor, remarkably safe antibiotic. It has many other pleiotropic effects. I believe the Doctor is conservatively recommending 200mg daily, around double the standard dose but still within the therapeutic range.

    2. Bannem says:

      Reports of cases of a CoVid-19 linked ‘Kawasaki-like’ disease in children in the UK . . .
      https://www.mylondon.news/news/uk-world-news/least-12-children-taken-intensive-18161078

  31. Walter Sobchak says:

    “He ran marathons and was fit. So why did Covid-19 almost kill him?” By Gabrielle Glaser | April 21, 2020

    https://www.statnews.com/2020/04/21/he-ran-marathons-why-did-coronavirus-almost-kill-him/?mod=article_inline

    “Sultana was running out of options, and she had to act quickly. She researched the anecdotal reports on treatments with potential against the coronavirus. One was a powerful anti-inflammatory drug often used to treat rheumatoid arthritis, an autoimmune disease in which the immune system also goes into overdrive, attacking the body. She reasoned that Fiske might respond to this drug, called Actemra, which inhibits a particular cytokine called IL-6. …

    “On the morning of March 26, with Fiske’s fever still near 104, Welch gave him the infusion of Actemra. Within two hours, his fever dropped to 99 degrees and his oxygen levels returned to near normal.”

    “Kirkland doctor who nearly died from COVID-19 recovers after experimental treatment”

    https://www.kiro7.com/news/local/experimental-drug-may-have-saved-life-er-doctor-ill-with-coronavirus/UHVGZK5FFNAAJJR5L3DPLJGJQQ/

    “SEATTLE — An EvergreenHealth ER doctor got sick with coronavirus and almost died. But he got an experimental treatment at Swedish Hospital that’s been used on about 40 patients there so far — and it might have saved his life.

    “The drug he got is called tocilizumab (brand name Actemra) – currently FDA-approved to treat rheumatoid arthritis. Doctors were trying several treatments at the same time so can’t say for certain that it’s tocilizumab that saved his life but believe the drug may have played a role.

    * * *

    “In matter of 24 hours he went from breathing on oxygen to requiring a ventilator and some advanced therapies. From there he continued to get worse,” …

    “They had to take over his lungs and pump his blood into a ECMO machine to give it oxygen, then pump it back into his bloodstream.

    “His kidneys weren’t working, we had to take that function over as well,” Hartman said.

    * * *

    “With no other options, doctors decided to try an experimental treatment, including tocilizumab.

    * * *

    “They started seeing results in four to five days. And then Padgett came off of the machines that were keeping him alive.

    * * *

    “And shortly after, Padgett was able to go home.

    * * *

    “Swedish will be joining a global randomized clinical trial to study the effectiveness of tocilizumab that could start here as early as next week.”

  32. Walter Sobchak says:

    “Southwest Ohio woman whose family said goodbye to her survives after first COVID-19 trial” By Kaitlin Schroeder, Staff Writer | April 24, 2020
    https://www.daytondailynews.com/news/local/woman-whose-family-called-say-goodbye-survives-following-first-covid-trial/LULFUY1hx9Xs99CyRVrfrJ/

    Her husband Thomas De Vos said he was feeling hopeless then got a phone call from Dr. Thomas Pitts, director of neurology at Hudson Medical in New York, also with Premier Health’s tele-neurology program, seeking consent to enroll De Vos into the clinical trial. …

    On March 23, De Vos became the first patient enrolled nationwide in a clinical trial of Soliris. Her grave condition rapidly improved just a few hours after her first dose of the drug. …

    Soliris, made by Boston-based Alexion Pharmaceuticals, has been FDA-approved since 2007 for treatment of immune response problems associated with several rare conditions.

    ============================================================

    Eculizumab, sold under the trade name Soliris among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica. … It is a humanized monoclonal antibody functioning as a terminal complement inhibitor.
    https://en.wikipedia.org/wiki/Eculizumab

  33. Walter Sobchak says:

    The hits just keep coming. This is news report of a paper published in Nature Communications, to which I do not have access:

    “Scientists Create Antibody That Defeats Coronavirus in Lab” by Tim Loh | May 4, 2020 |
    https://www.bloomberg.com/news/articles/2020-05-04/scientists-create-antibody-that-defeats-coronavirus-in-lab

    Scientists created a monoclonal antibody that can defeat the new coronavirus in the lab, an early but promising step in efforts to find treatments and curb the pandemic’s spread.

    The experimental antibody has neutralized the virus in cell cultures. While that’s early in the drug development process — before animal research and human trials — the antibody may help prevent or treat Covid-19 and related diseases in the future, either alone or in a drug combination, according to a study published Monday in the journal Nature Communications.

    More research is needed to see whether the findings are confirmed in a clinical setting and how precisely the antibody defeats the virus, Berend-Jan Bosch of Utrecht University in the Netherlands and colleagues wrote in the paper.

    The antibody known as 47D11 targets the spike protein that gives the new coronavirus a crown-like shape and lets it enter human cells. In the Utrecht experiments, it didn’t just defeat the virus responsible for Covid-19 but also a cousin equipped with similar spike proteins, which causes Severe Acute Respiratory Syndrome, or SARS.

  34. Walter Sobchak says:

    We seem to be getting a new MAB story every day. Here is todays:

    “Israel’s IIBR finds antibody that neutralizes coronavirus”
    By Maayan Jaffe-Hoffman, Anna Ahronheim, Idan Zonshine | May 5, 2020
    https://www.jpost.com/health-science/iibr-completes-development-phase-of-covid-19-vaccine-626913

    The Israel Institute for Biological Research (IIBR) has completed a groundbreaking scientific development, identifying an antibody that neutralizes the coronavirus, SARS-CoV-2 …

    This scientific breakthrough has three key parameters: The antibody is monoclonal, new and refined, and contains an exceptionally low proportion of harmful proteins; the institute has demonstrated the ability of the antibody to neutralize the novel coronavirus; and the antibody was specifically tested on the aggressive coronavirus. …

  35. M says:

    If you have chronic (non-diabetic, non-obese, no high bp) systemic inflammation to start with, are you at greater risk of a cytokine storm?

    Nitric oxide sounds great, but I read that it promotes inflammation in people who are already chronically inflamed. https://pubmed.ncbi.nlm.nih.gov/18236016/

    I’ve been looking at beet root supplements to increase nitric oxide. Should I avoid them if I am already inflamed?

  36. Adrian Jones says:

    Does anyone know if the Abatacept will have the same benefits to IL-6 and the other parts of the beneficial effects from the ‘mab drugs.

  37. Doxy watcher says:

    Could some of the existing antibiotics actually be immune modulating? This might be a promising angle.

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