The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Have the results of Dr Chia's ME/CFS interferon treatment actually proven enterovirus causes ME/CFS?

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by Hip, Apr 14, 2016.

  1. Hip

    Hip Senior Member

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    I was recently reading some of Dr John Chia's findings, and it suddenly occurred to me that his work and observations may have proved that enterovirus causes ME/CFS. The following explains my logic of why his observations provide proof.

    Executive Summary:


    Numerous studies dating back to the 1980s have demonstrated an association between enteroviruses and ME/CFS.

    However, as we know, association does not by itself imply causation, and proving that enterovirus actually causes ME/CFS requires going further.

    Research that has come tantalizing close to proving enterovirus causes ME/CFS is the data from interferon treatment studies. For ME/CFS patients with high antibody titers to enterovirus, intravenous interferon often results in major improvements in ME/CFS symptoms, and some patients experience full remission for up to a year or so (but most of these patients eventually relapse). And crucially, along with these symptomatic improvements and remissions, enteroviral load (enterovirus antibody titers and enteroviral RNA) goes down after the IV interferon treatment when symptoms improve; and enteroviral load goes back up again simultaneously with the relapse.

    This suggests (but does not yet prove) that the ME/CFS improvements and remissions after interferon therapy are the result of the reduced enteroviral load, and that a high enteroviral load can cause ME/CFS.



    There have been three published ME/CFS interferon therapy studies: one in 1993 (full paper here), one in 1996 (full paper here), and Dr John Chia's study in 2004. Some details of Dr Chia's further experiments with IV interferon are given in this 2011 article.

    All of these studies found IV interferon treatment provided significant benefit in a subset of ME/CFS patients, and there were several cases of patients completely recovering (full remission) from ME/CFS after interferon treatment, and remaining in full remission for at least a year after the treatment.

    In the 1993 study, 18 patients were treated with interferon alpha, and out of these, 5 patients improved. Of these 5 improved patients, 3 went into complete remission, and 2 of these 3 were still entirely recovered when checked 1 year later (they may have relapsed further down the line, but the study only followed them for a year).

    Significantly, 4 out of the 5 patients who recovered or improved from interferon treatment had elevated coxsackievirus B IgM antibodies. Only one of the patients who did not improve had elevated coxsackievirus B IgM antibodies. So this study gives some indication that interferon often works for ME/CFS patients with active chronic enterovirus infections, but generally does not work for ME/CFS patients who do not have enterovirus infections. We will use this fact later.

    In the 1996 study, 26 patients were treated with interferon alpha, and out of these 7 patients improved.

    In Dr Chia's 2004 study, 5 patients who had chronically high antibody titers to CVB3 or CVB5 were treated with interferon alpha and the antiviral drug ribavirin. This combined interferon + ribavirin therapy resulted a significant symptomatic improvement in 4 of 5 patients. Concomitant to their symptomatic improvements was a disappearance of enteroviral RNA in all patients, and a decrease in enterovirus antibody titers in 4 of 5 patients.

    However, relapse occurred about 4 months later in most patients, along with their antibody titers rising again to pre-treatment levels, and reappearance of enteroviral RNA.

    The 2011 article details more of Dr Chia's experiments with interferon: for example: 8 of 14 severely ill ME/CFS patients with enteroviral RNA in their blood returned to part-time or full-time work after interferon-alpha plus interferon-delta combined therapy. Most however relapsed several months later (heavy exertion was a common trigger of relapse).



    So we see in these interferon studies a general trend: patients improve or go into full remission as a result of interferon therapy, along with a concomitant reduction in enteroviral load (ie, reduced enterovirus antibody titers and disappearance of enteroviral RNA) while the patients are experiencing major improvements or full remission. Then when the patients relapse, the viral load also goes back up.

    However, suggestive though it is, this evidence does not as it stands prove that enterovirus causes ME/CFS, because again, correlation does not imply causation, and there are alternative interpretations.

    One alternative interpretation is if we assume ME/CFS is caused by an immune dysfunction or weakness, rather than a virus (let's say the viral infections in ME/CFS just arise from immune weakness, but do not cause ME/CFS): in this scenario, it is conceivable that interferon might rectify the immune dysfunction, and in that way ameliorate ME/CFS symptoms or bring on remission.

    In other words, it is a logical possibility that the beneficial effects of interferon for ME/CFS come from its modulation of the immune system, rather than from its antiviral effects in reducing enteroviral load.



    Thus the crux of the issue here is trying to determine whether interferon's highly beneficial effects for ME/CFS are the direct result of its antiviral action on enteroviruses, or the result of its immunomodulatory effects (or the result of some other disease-modifying effects interferon may have, that are unrelated to viruses).

    If we can prove that the beneficial effects arise from interferon's antiviral action on enteroviruses, then we have more-or-less proven that enteroviruses can cause ME/CFS. So I am now going to attempt to prove this.

    The proof starts with a statement made by Dr Chia in his presentation at the Invest in ME 2009 London Conference. At timecode 42:31 of this video, Dr Chia talks about his interferon-alpha + ribavirin combination therapy for enterovirus-associated ME/CFS. Dr Chia says:
    Dr Chia is saying that he has found interferon-alpha is ineffective for coxsackievirus B4, ie, that interferon-alpha does not reduce CVB4 viral loads, although interferon is effective for other coxsackieviruses, such as CVB3.

    Now Dr Chia has noted that CVB3 and CVB4 are the two most common enteroviruses he finds in ME/CFS patients as active infections (then less frequently, he finds CVB2, EV6, EV7 and EV9 as active infections).

    So Dr Chia finds both CVB3 and CVB4 are strongly associated with ME/CFS; yet interferon is effective for fighting CVB3, but not CVB4.



    Now comes the logical climax to my proposition that Chia's observations prove enterovirus causes ME/CFS:

    If it were the case that interferon ameliorates ME/CFS not by any antiviral mechanism, but through modulating immune function (or via some other disease-modifying mechanism), then you would expect interferon treatment to have the same success rate for all classes of ME/CFS patient, irrespective of what active viral infections the patient has.

    In particular, if interferon ameliorates ME/CFS via a non-antiviral mechanism, then you would expect interferon to work equally well for patients with active CVB3 and for patients with active CVB4. And indeed, equally well whether the patient has an enterovirus infection, or an infection with some other virus (or no viral infection at all).

    However, Dr Chia found that interferon-alpha works for patients with CVB3, but not for patients with CVB4.

    And furthermore, the 1993 study found that by and large, interferon-alpha only worked for patients with enterovirus infections. They found interferon-alpha rarely worked for ME/CFS patients without enterovirus infections.

    So these findings clearly contradict the idea that interferon ameliorates ME/CFS by a mechanism unrelated to its antiviral effect. Because where interferon is ineffectual against a particular virus, it does not help ME/CFS patients with that virus.

    Therefore we have to accept the explanation that interferon ameliorates ME/CFS via its antiviral action, an action which has been shown to significantly reduce enteroviral loads.

    Thus this leads us to the conclusion that chronic active enteroviral infections are a cause of ME/CFS.



    Note that in the above, I am not arguing that enterovirus is the only cause of ME/CFS. Other pathogens may well also cause this disease; and there may be non-pathogenic causes as well.

    I am just suggesting that the status of enterovirus as merely an association of ME/CFS might be re-examined: I am questioning whether enterovirus can now be upgraded to a probable cause of ME/CFS.

    Of course, there could be flaw in my argument. Please point it out if you find one.


    Note also that Dr Chia does not use interferon much these days, due I believe to the cost (around $15,000 for a course of treatment), and the fact that relapse is the norm.
     
    Last edited: Jun 3, 2017
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  2. Richard7

    Richard7 Senior Member

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    I do not understand any of the underlying science, and am just putting this stuff together as best I can.

    What your saying makes sense to me, just applying logic, but can it explain all the symptoms.

    I'm not sure I understand Jared Younger's arguments about leptin and trigger happy microglia.

    But as I understand it he found that changes in symptoms mapped changes in leptin levels.

    He explains this connection by noting that most people have active infections of bacteria that are at too low a level for the microglia to be activated but that leptin lowers the trigger threshold and that fluctuations in leptin levels for people around that trigger threshold could causing the symptoms of chronic fatigue.

    Could Chia's viral infections operate in the same way, as a bacterial infection.

    I also wonder about how Jared Younger's work fits into Julia Newton's work on muscles, but she compared the muscles of those with ME/CFS to those of healthy controls. I don't know if those with normal functional fatigue from an infection or lack of sleep would have found their muscles behaved like the controls or those with ME/CFS.

    (If they behaved like the controls Younger's solution would seem to be insufficient.)

    But the point is that I would think that any solution would have to link all the pieces of evidence together.
     
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  3. halcyon

    halcyon Senior Member

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    It's truly sad that we're having to question this in 2016. The link between ME and enterovirus goes back even further than the 1980s. S.G.B. Innes found coxsackie B and echovirus in the CSF of several ME patients in 1970. W. H. Lyle found echovirus 9 in 1959. All of the evidence from the 80s and Ramsay's final ME paper in 1990 just strengthened the link. It seems that only time has erased the link, not evidence to the contrary.
     
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  4. halcyon

    halcyon Senior Member

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    A CNS infection with enterovirus (which has already been found in 3 different cases postmortem, plus the CSF evidence mentioned above) could explain activated microglia in the CNS.

    Enterovirus infects muscle and has already been found in the muscle of ME patients. From Behan 1985:
     
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  5. Deltrus

    Deltrus Senior Member

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    I got CFS after dealing with pericarditus off and on for 2 years, which is a common symptom of enterovirus.

    I personally think it is possible that the virus may be interfering with some sort of nutrient metabolism, such as electrolytes or b vitamins.

    Man wouldn't it be nice if I could just go to the doctor, get a test, and get diagnosed. I'd be so eternally grateful even if I had to wait for a cure.
     
    Last edited: Apr 15, 2016
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  6. msf

    msf Senior Member

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    I don´t think there is anything wrong with the logic of your argument, I think the problem is that it hinges on Chia´s report of lack of response to Interferon in those with CVB4. Of course, this is the problem with any theory of ME - there aren´t enough studies to go on, so we have to rely on physician´s reports and so on. Do you know if Chia is working on any studies at the moment?
     
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  7. duncan

    duncan Senior Member

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    This is a strikingly similar pattern to Lyme. X percent get sick. X get IV treatment and do well while on it, but get sick again when finished. X get IV treatment and get well. X get IV treatment and get better for a while, then relapse.

    A question might be do enteroviruses cause ME/CFS by themselves, or do they need a combination of pathogens or stressors or contributors?

    I think there has to be an accounting for the numbers and demographics underlying ME cases, and one way I can see the math working is combinations - unless we just shrug it off to genetics, which I think borders dangerously on being intellectually lazy (even though it might be correct).
     
    Last edited: Apr 15, 2016
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  8. Hip

    Hip Senior Member

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    I see you followed the logic of the argument well!

    What you are saying is indeed the case: my argument it does (in part) hinge on Dr Chia's observation that interferon works for ME/CFS with high CVB3 titers, but not for ME/CFS with high CVB4 titers.

    However, I would think that knowledge of the antiviral efficacy of interferon for various Coxsackie B viruses probably exists in other medical areas, so we should be able to corroborate this observation. I did search online for more info about interferon's antiviral effects against various enteroviruses, but could not find much.

    However, if your search Google Scholar for studies of interferon's effects on coxsackievirus B, you find plenty of papers showing efficacy against CVB3 myocarditis, but none showing efficacy against CVB4 myocarditis or any other CVB4-induced disease.

    So this goes some way to corroborating Chia's observation that interferon does not work for CVB4. I am sure if one were to contact some researchers or clinicians who use interferon on coxsackievirus B infections, they could probably tell your about its efficacy or lack thereof against the various CVBs.



    Note however that Chia's CVB4 / CVB4 observation is just one part of my argument. The other observation that also supports my conclusion comes from the 1993 interferon study I detailed above, which found that out of 18 ME/CFS patients given interferon-alpha, 5 patients improved or fully recovered, but the other 13 patients did not improve.

    Now the study found that 4 out of those 5 who improved or recovered had high CVB antibodies, whereas only 1 out of the 13 who did not improve had high CVB antibodies (I presume the most of the 13 who did not improve either had another active viral infections like EBV, or had no active viral infections).

    So we find from this 1993 study that again interferon seems to work for ME/CFS patients with active CVB, but usually does not work for patients with other active viruses or no viruses.

    So again this tends to support the conclusion that it is the antiviral effects of interferon that ameliorate ME/CFS, rather than any other disease-modifying effects that interferon may have.

    Which in turn means that chronic active enterovirus infection must be a cause of ME/CFS, not an innocent bystander infection.
     
  9. Hip

    Hip Senior Member

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    Very interesting, I did not know about Innes, nor Lyle. The 1970 Innes paper is here. I could not find the 1959 Lyle paper though.

    I know in the 1955 Royal Free Hospital ME outbreak coxsackievirus B was suspected, but I don't think they were able to prove this by lab testing.
     
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  10. Chrisb

    Chrisb Senior Member

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    I seem to remember that David G Smith's book Understanding Myalgic Encephalomyelitis had discussion of the state of play with regard to interferon in 1989. I don't know where my copy got to. It probably would not help anyway. I mention it to emphasise the 25 year hiatus due to the conduct of our good friends.
     
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  11. msf

    msf Senior Member

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    Hmm, I think it´s still some way off proof. Enterovirus, for instance, might be a co-infection of some other bug, and that is why those with Enterovirus antibodies improve.

    I have another question - if the Interferon results were so good, why isn´t it being used for these patients? I seem to remember Chia saying that the side effects were too bad - is that right?
     
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  12. u&iraok

    u&iraok Senior Member

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    Thanks for studying this, Hip. Very provocative information. I can tell you're very excited about it, with cause!

    I want to understand this, so here are my questions. Forgive me if some of them are stupid!

    It's too bad the studies only followed the people for a year after treatment. We have no way to know if the fully recovered stayed recovered. (Write in, people and let us know!)

    But of the ones that did relapse (in 2004 and 2011 it appears to be that most of the subjects relapsed), is it that the damage has been done and that's why the remission isn't permanent? If the damage has been done is it possibly that the damage is the proximate cause and enterovirus the ultimate cause? In other words, genetic errors/damage, weak immune system, toxins or other causes prime the PWC for ME/CFS and while enterovirus was the event that caused it technically, it may have happened by some other cause/trigger? Or may not?

    Even though the patient goes into remission when the enterovirus is removed from the PWC, what happens if another trigger comes along?

    So, of the patients who didn't improve, do we conclude that enterovirus wasn't the cause of their ME/CFS? It looks like roughly 25% of the subjects in the 1993 and 1996 studies improved.Do you posit that there are viral causes for most or all of the others and that an appropriate therapy for them just needs to be found?
     
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  13. Gemini

    Gemini Senior Member

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    Interestingly recent findings re: enterovirus/host interactions at the microRNA level suggest new treatments & targets.

    A January 2016 paper -- These "viruses utilize cellular factors to hi-jack host bio-energy, evade immune attacks and enforce viral replication." They can cause encephalomyelitis, and host factors such as age, sex, immune response, and nutritional status play a role.[my bold]

    www.ncbi.nlm.nih.gov/pmc/articles/PMC4728571
     
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  14. Hip

    Hip Senior Member

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    Logically that is a possibility, but once you also consider Dr Chia's CVB3 / CVB4 observations, it looks very unlikely.



    As it stands, interferon is generally not really a viable treatment for ME/CFS, because patients relapse, usually a few months later, though some patients may go a year or so in complete remission before they relapse. When they do relapse, Chia found that often a second course of interferon does not work (although it does work for some).

    A course of intravenous interferon (which itself takes several months) can also have significant side effects in terms of inducing nasty levels of depression in some people. And as mentioned, the cost is around $15,000 for a course of treatment.

    However, I don't know the full details about interferon treatment, because like most of us, I only learn about Dr Chia's results from papers and blog articles. Some years ago Dr Chia did much experimentation with various interferon protocols, but he says he does not use it much these days, so there must be good reason.

    Though I am curious to know whether there may exist a small set of ME/CFS patients who respond well to interferon and get a year's full remission, and then after relapse, also respond well on subsequent interferon treatments, such that they are able to remain in permanently remission by getting a fresh course of interferon once each year. I am just wondering if there are any patients like that.



    Dr Chia's has found that relapse is the norm with interferon treatments; if these relapses did not occur, interferon would be a very viable cure for enterovirus-associated ME/CFS.

    The likely reason that relapse occurs is that interferon does not clear out all the enterovirus infection from the body, and in particular, does not clear out the non-cytolytic enteroviruses that exist within cells in the form of dsRNA. This dsRNA is very resistant to immune attack. Dr Chia calls the dsRNA form of the enterovirus infection the "seeds", because unless you wipe out the seeds as well, the infection will always grow back from these seeds.

    So if someone developed a new drug that could wipe out the non-cytolytic dsRNA form of the enterovirus infection, then this drug, along with interferon therapy, would likely wipe out the entire enterovirus infection and all its dsRNA seeds for good, and thereby likely permanently cure enterovirus-associated ME/CFS in one go.

    More info about the very stubborn non-cytolytic dsRNA form of the enterovirus in this post.
     
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  15. Hip

    Hip Senior Member

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    If you did completely wipe out the enterovirus infection and go into permanent remission, I guess that would not give you any immunity from developing ME/CFS again from a different trigger.



    I don't think we have enough data to conclude that, but certainly from what we have seen so far, it seems that if you have the right sort of enteroviruses that respond to interferon (ie, not CVB4), then there is a good chance you will improve on interferon, although it's generally only a temporary improvement before you relapse again (I am not aware of any cases of interferon treatment leading to permanent remission, but there may be some; Dr Chia would know about this).



    The most common pathogenic associations to ME/CFS are probably enterovirus, Epstein-Barr virus and HHV-6 (though there are many other pathogens also linked to ME/CFS).

    Some ME/CFS patients with active EBV and HHV-6 infections experience major improvements from the potent antiviral Valcyte (though it takes 6 months or so for the benefits to manifest, and it seems the improvements slowly disappear if you stop Valcyte). There are cases of patients being able to return to full-time work as a result of Valcyte. Though this is a drug with potentially serious side effects. It's also expensive: around $800 a month even if you use the cheapest Indian pharmacies, and around £2,000 a month if you buy from Western pharmacies.
     
    Last edited: Apr 15, 2016
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  16. Deltrus

    Deltrus Senior Member

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    I've brainstormed quite a lot, wrote a few posts and deleted them in the process of refining my ideas. I can only think of one problem, but it would be a long shot.

    What if CVB3 and CVB4 are linked to two distinct vulnerabilities, both of which cause CFS symptoms? In this option, the vulnerabilities are the root cause of CFS symptoms, not the enterovirus. And at the same time interferon could correct the vulnerability for CBV3 but not CVB4.

    For example, lets say EBV causes CVB3 vulnerability, and immune response to lectins/gluten/gut bacteria causes CVB4 vulnerability. Or autoimmune ion channel problems cause CVB4 vulnerability. Or poor microcirculation causes CVB4 vulnerability. Or disruption of a metabolic pathway etc.

    In this case, it would be possible that interferon fixes a problem higher up in the chain, and CVB3/4 are barely relevant to the symptoms. Targetting CVB3/4 with anti-virals would do very little in this case.

    This is dependent on CVB3 and CVB4 behaving quite differently, despite being closely related viruses.

    For this reason I find this flaw unlikely. The simplest answer is usually the correct one.

    But it was the best I could come up with.
     
    Last edited: Apr 15, 2016
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  17. Hip

    Hip Senior Member

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    @Deltrus
    I did think along similar lines to your example, but like you, to me it also seemed this possibility is contrived and unlikely, so I discounted it.
     
    Last edited: Apr 15, 2016
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  18. halcyon

    halcyon Senior Member

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    Interferon is barely tolerable for people with Hep C and they often have little to no other symptoms. People with ME are already so sick that it's very difficult to tolerate on top of everything else. The course needed to really put a dent in enterovirus titers is long. Also it's off label for use with enterovirus and with the risk of relapse so high it's just not worth risking throwing away $15k on, though people are throwing away $40k on rituximab these days with similar risk.

    Chia has found that he can get acceptable efficacy out of oxymatrine with little risk and low cost, so that is the route he seems to be taking these days.
     
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  19. Skippa

    Skippa Senior Member

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    No, I think @Deltrus is onto something.

    Think of AIDS. AIDS doesn't kill you, it opens the door so that other stuff can kill you. No defences.

    Think of ME/CFS as being caused by a low level pathogen that affects multiple bodily systems, in different combinations, thus giving rise to some of the more idiopathic symptoms found.

    Then it is just a waiting game... Which virus/bacteria/other takes hold first?

    For some this is EBV3, for some EBV4 (and for others, plenty more pathogens out there).

    That firstly agrees with your observations that the EBV4 is being wiped out by interferon, and leading to symptom remission. It also explains why post-treatment, relapse is encountered.

    The underlying "open door" isn't being closed.
     
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  20. Hip

    Hip Senior Member

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    I am not sure you have understood the point that @Deltrus made, and why he made it. It's more of point of logic than a point of biology, and I agree with his point, because I thought of the same alternative interpretation myself. And both @Deltrus and I think that this alternative interpretation is unlikely.
     

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