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Chronic coxsackievirus B (CVB) infection is associated with ME/CFS -- Is Rituximab relevant?

Discussion in 'Rituximab: News and Research' started by Hip, Oct 2, 2014.

  1. Hip

    Hip Senior Member

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    This thread was split from the following thread.

    @Jonathan Edwards

    Might this this study cited at the start of this thread have any relevance to rituximab treatment of ME/CFS?

    Chronic coxsackievirus B (CVB) infection is strongly associated with ME/CFS, and when mice with chronic CVB infection were injected with B cells taken from mice immune to CVB, this resulted in either a transient or permanent disappearance of detectable CVB in the infected mice.

    This suggests that there may be something amiss with the B cells of those susceptible to CVB, that allows the infection to become chronic, rather than being cleared by the immune system.

    Indeed, the authors found that in the mice with chronic CVB infection, approximately 1 to 10% of the B cells were infected with CVB, and the authors suggest the possibility that these CVB-infected B cells may play some role in virus dissemination, and/or that by infecting these B cells the virus may be able to modulate the host immune response.
     
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  2. Jesse2233

    Jesse2233 Senior Member

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  3. M Paine

    M Paine Senior Member

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    Honestly it just sounds like the immune mice had germline variation in their VDJ genes allowing for an effective antibody to be produced during recombination. I don't see what is suggestive of a B-cell defect. I also don't see how Rituximab is relevant here. The mice used as transplant recipients were B-cell knockouts initially. This is all a normal part of variability in genetics and antibody generation. Unless I'm missing something? The mice seem to have been selected for MHC haplotype, which makes sense for B-Cell implantation.... but I'm guessing there is variation in VDJ. Even if there's not a hereditory difference in VDJ, recombination could account for it.
     
    Last edited: Mar 1, 2017
  4. Hip

    Hip Senior Member

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    A possible B cell defect may arise from the fact that up to 10% of B cells can be infected with coxsackievirus B, which may conceivably be altering the functioning of the B cell population, and thereby modulating immune function in a way that favors the establishment of a persistent CVB infection.

    Also, the study authors suggest that the chronic coxsackievirus B infection of the B cells may be a means of spreading CVB infection throughout the body, so this is another way that CVB-infected B cells may be supporting a persistent CVB infection in the body organs and tissues. The infected B cells could perhaps act like military supply lines in the body, constantly supplying more CVB "soldiers" to all the organs and tissues, in order to maintain the persistent CVB infection of the body.

    So these are two ways in which CVB-infected B cells could promote and maintain a persistent CVB infection in the body.


    In terms of the possible relevance to rituximab: killing off these CVB-infected B cells with rituximab may then allow normal immune function to return, and destroy the military supply lines, leading to viral clearance, and thereby curing ME/CFS by eliminating this enterovirus from the body.

    So this is a potential non-autoimmune mechanism that might explain the benefits rituximab has in the treatment of ME/CFS.

    As far as I am aware, nobody conducting rituximab research on ME/CFS has yet looked at how rituximab treatments affect enterovirus titers, and whether rituximab might have a potent antiviral effects against enterovirus, by this B cell destroying mechanism.


    Interestingly enough, rituximab can be used as a treatment for chronic Epstein-Barr virus infections, and it works against EBV by precisely this mechanism: by killing off the EBV-infected B cells, rituximab allows the body to then clear the EBV infection.

    Indeed, Fluge and Mella successfully treated one patient with chronic Epstein-Barr virus infection (as distinct from ME/CFS) using rituximab to kill the EBV-infected B cells — see this post for details.
     
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  5. M Paine

    M Paine Senior Member

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    I'm not sure I follow how B-Cell depletion therapy is supposed to remove the chronic infection. If the suggestion is that the virus relies on B-cells for transport, I just don't think that idea holds weight. Perhaps in the very early stage of infection. It's extremely likely that any persistent infection would still be present after BCDT in other cell lines, and would simply then go ahead and reinfect newly produced B-cells in the case of Rituximab treatment.

    I see your point in terms of infected b-cells being candidates for acquired auto-immunity. I agree with you on that, and in other lyphotropic viruses, but I don't see Rituximab alone as a potential treatment for chronic coxsackie infection. Typically you might expect to see antivirals and NHIG used in those chronic cases of EBV where Rituximab is used.
     
    Last edited: Mar 1, 2017
  6. Hip

    Hip Senior Member

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    Whatever the mechanism, in the case of Fluge and Mella's patient, she was completely cured of chronic EBV just 3 days after the rituximab treatment. So rituximab works very fast and very effectively for chronic EBV infection, in cases like this patient's, where the B cells are infected with EBV.
     
    Last edited: Mar 1, 2017
  7. M Paine

    M Paine Senior Member

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    You're talking about a very different virus there. EBV has narrow tropism for B-cells and Epithelial cells. Infected B-cells release virions with high tropism for Epithelial cells, and vice versa. It's more understandable in that case for Rituximab to be effective, as B-cells are a lynchpin in the lifecycle of the virus. I'm less familiar with Coxsackie B, but my understanding is that there are several serotypes with a wider range of tropism.
     
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  8. Jesse2233

    Jesse2233 Senior Member

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    This would be a good question for Dr Chia and Professor Edwards
     
  9. Jesse2233

    Jesse2233 Senior Member

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    @M Paine in this case do you think it's possible that RTX's mechanism for action for CFS/ME is actually not autoimmune but for CEBV and other chronic viral cases with B-cell specificity?

    And if chronic Coxsackie B does not use B-cells as a lynchpin in its lifecycle, would there be a risk to someone with that type of infection using RTX in terms of debilitating their immune system and allowing the virus to propagate further?
     
  10. Gingergrrl

    Gingergrrl Senior Member

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    For me, it is the only treatment that really makes sense at this point for autoimmune reasons but I agree with @Hip that it could have an anti-viral function too (even if I can't explain it)! I think (for now) it is one of those things with great potential to work even if we do not know the exact mechanism in each patient.
     
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  11. Hip

    Hip Senior Member

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    @M Paine, yes they are quite different viruses, so what applies to EBV many not necessarily apply to the enteroviruses associated with ME/CFS (namely coxsackievirus B and echovirus). And the fact that this chronic EBV patient was cured so rapidly by rituximab treatment indicates how much of a lynchpin the EBV-infected B cells can be in chronic EBV infections.

    Perhaps in the case of enterovirus-associated ME/CFS, the CVB-infected B cells are not quite the lynchpin they are in EBV infections, but nevertheless these CVB-infected B cells conceivably may play an important role in maintaining a persistent CVB infection. Perhaps that is why it takes many months before rituximab starts to improve ME/CFS symptoms, because the role of CVB-infected B cells is important, but not a lynchpin. Whereas in the chronic EBV case, the patient is cured of all symptoms in a matter of days after rituximab.

    The other big difference between EBV and CVB is that CVB can exist as a chronic intracellular infection inside cells (called a non-cytolytic enterovirus infection), and this intracellular infection may be harder to clear, hence another possible reason for the longer timescale of response to rituximab (assuming that rituximab cures ME/CFS by clearing the enterovirus infection).


    I am not trying to challenge the assumed autoimmune mechanism of action of rituximab in the treatment of ME/CFS; but just suggesting another possibility. These possibilities are not mutually exclusive either: rituximab could have more than one mechanism of action in ME/CFS: partly anti-autoimmune, partly antiviral.
     
  12. M Paine

    M Paine Senior Member

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    I used to be quite attached to the idea that Rituximab might be interacting with and clearing a viral infection, in some cases temporarily, but I'm no so sure anymore. I keep an open mind to the idea, but it does seem that auto-immunity is a real possibility, and it's unclear how that relates to B-cell infection at the moment.

    Good question, I've often wondered myself how this is managed. Following treatment, a person still has an anti-body repertoire. I might have guessed that long term treatment might also involve some administered IG. Dr Edwards would have some good insights on that.
     
  13. halcyon

    halcyon Senior Member

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    The major risk here is hypogammaglobulinemia/lymphopenia contemporaneously with an acute enterovirus infection. If you don't have adequate B cell response and you become viremic with an EV infection it will disseminate everywhere and it can and has lead to deaths (see here). In ME the infection appears to be chronic and downregulated with no viremia. Even if you had a transient drop in B cells or gammaglobulins during treatment I don't think it would put you in danger. We've certainly not seen this happen to any ME patients yet.
     
  14. Jesse2233

    Jesse2233 Senior Member

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    Interesting, thanks @halcyon.

    In your opinion, is secondary virema (as in rabies) a good model for post viral ME? And would someone early into the illness (less than 6 months) be at risk for a viremic EV reaction following RTX?
     
  15. Gingergrrl

    Gingergrrl Senior Member

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    I agree that the mechanism of action is autoimmune in RTX (not just for ME/CFS but for any B-Cell dependent auto-antibodies). But I also agree that there could be other possibilities that we are not aware of yet.

    This makes sense and my dream scenario is to still be doing high-dose IVIG (which I do every 3-4 wks) and be approved for RTX at the same time. I don't mean on the same day, just in the same time period so they overlap. I'm sure this is not my insurance companies dream scenario LOL.

    I'm not sure how someone knows of their diagnosis at less than 6 months but I'd assume that the risk from RTX is the same whether someone has been sick for 6 mos or several years (but I could be totally wrong)! At 6 mos, all we thought was that I had IST (inappropriate sinus tachycardia) that would resolve on it's own and I could not have been more wrong. I actually had never even heard the term ME/CFS at the 6 month point and it took me 1.5 yrs until I learned of it from PR and found a specialist. We both thought I had it and now we both think I have something else autoimmune that is B-Cell mediated. But I guess it is possible to know at 6 mos and just did not occur in my case.
     
  16. halcyon

    halcyon Senior Member

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    No, I don't think that's quite what is occurring either. I don't think there is a good existing popular model for what's happening in ME which is part of the problem. With viral infections, the assumption is usually either seroconversion (viruses capable of being cleared are cleared entirely, and once it's gone from the blood that equates to it being gone from the body), latency/reactivation (e.g. herpesviruses), or persistent viremia (e.g. HCV, HIV). The idea of downregulated, persistently active nonviremic infection does not appear to be a popular one, but appears to be something that happens with numerous viruses. A close model I think is one described by Oldstone in the 1980s. He basically described ME without probably even knowing what it was:

    His later work on how the immune response promotes viral persistence becomes important as well as I think it applies directly to enteroviral ME.

    I think you'd want to confirm that with someone experienced with administering RTX but my guess would be, short of any issues with already low IgG levels or T cell problems, that it's probably not a danger. With that said, personally I'm > 3 years in and I probably wouldn't touch RTX until my enterovirus serology normalized (if it ever does).
     
  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I cannot see the connection to rituximab. I am also not aware of any good study relating chronic coxsackie infection to ME. Presumably the mice in the experiment were some odd form of inbred or genetically engineered mice - these sorts of experiment don't seem to tell us much about human disease to my mind.

    Edit: Sorry I see that M Paine has covered this better than me already.
     
    Last edited by a moderator: Mar 8, 2017
  18. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I have only just read the original cited paper. It just indicates that antibodies help to get rid of coxsackie virus - which is totally as expected. If anything it suggests that rituximab - making patients 'B cell knockouts' - would be a very bad idea and they would be desperate to get their B cells back, which seems to be the reverse of the evidence.
     
  19. Jesse2233

    Jesse2233 Senior Member

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    What do you make of these studies? (via @Hip)

    Epidemiological aspects of an outbreak of encephalomyelitis at the Royal Free Hospital, London, in the summer of 1955
    Nuala Crowley, Merran Nelson, and Sybille Stovin. J Hyg (Lond). 1957 March; 55(1): 102–122.

    An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955
    The Medical Staff Of The Royal Free Hospital. Br Med J. 1957 October 19; 2(5050): 895–904.

    In the Royal Free outbreak, coxsackievirus B was suspected, but at that time no serological evidence was obtained.


    ME/CFS Enterovirus Research:

    Encephalomyelitis Resembling Benign Myalgic Encephalomyelitis
    S.G.B. Innes. The Lancet. 1970 May; 1(7654): 969-971.
    ➤ This study examined 4 cases of ME. In the cerebrospinal fluid they found coxsackievirus B2 in one case and echovirus 3 in another. In the sera of the two other cases they found elevated coxsackievirus B2 and elevated coxsackievirus B5 titers via neutralization testing.

    Sporadic myalgic encephalomyelitis in a rural practice
    B. D. Keighley and E. J. Bell. J R Coll Gen Pract. 1983 June; 33(251): 339–341.
    ➤ This study found elevated coxsackievirus B titers in 16 of of 20 patients in an ME/CFS outbreak in Ayrshire, UK.

    Myalgic encephalomyelitis—report of an epidemic
    K. G. Fegan, P. O. Behan, and E. J. Bell. J R Coll Gen Pract. 1983 June; 33(251): 335–337.
    ➤ This study found elevated coxsackievirus B titers in 18 out of 20 patients in an ME/CFS outbreak in Ayrshire, UK.

    Coxsackie B infection in a Scottish general practice
    B. D. Calder and P. J. Warnock. J R Coll Gen Pract. Jan 1984; 34(258): 15-16, 18-19.
    ➤ This study found significant antibody titres to coxsackievirus B in 38 out of 81 patients who experienced a syndrome with many of the features of myalgic encephalomyelitis.

    Some long-term sequelae of Coxsackie B virus infection
    J. A. Gray. J R Coll Gen Pract. 1984 January; 34(258): 3–5.
    ➤ Discussion of coxsackievirus B and echovirus in relation to ME/CFS.

    A study of Coxsackie B virus infections, 1972-1983
    Bell EJ and McCartney RA. J Hyg (Lond). 1984 Oct;93(2):197-203
    ➤ Found that in well-documented cases of ME/CFS, 41% of patients had elevated neutralizing antibody titers, compared to 4% of healthy controls.

    Coxsackie B viruses and myalgic encephalomyelitis
    E J Bell, R A McCartney, and M H Riding. J R Soc Med. 1988 June; 81(6): 329–331.
    ➤ This study on 290 adults and 47 children with ME/CFS found 37% and 38% respectively were IgM positive for coxsackievirus B, compared to 9% in 500 healthy adult controls.

    Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA (full text here).
    Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. J Gen Virol. 1990 Jun;71 ( Pt 6):1399-402.
    ➤ This study found that normally, positive strand enterovirus RNA is 100-fold more common over negative strand enterovirus RNA; but in ME/CFS patients, equal amount of both were found. This study was the very first to demonstrate a persistent non-cytolytic enterovirus infection (aka: defective enterovirus infection) in ME/CFS patients.

    Myalgic encephalomyelitis--a persistent enteroviral infection?
    Dowsett EG, Ramsay AM, McCartney RA, Bell EJ. Postgrad Med J. 1990 Jul;66(777):526-30.
    ➤ This study found that out of 420 cases of ME/CFS, 205 had significant titers to coxsackievirus B.

    Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome
    Gow JW, Behan WM, Clements GB, Woodall C, Riding M, Behan PO. BMJ. 1991 Mar 23;302(6778):692-6.
    ➤ This study on 60 ME/CFS patients found 20% had high titers to coxsackievirus B, compared to 14% of healthy controls. Furthermore, 53% of these ME/CFS patients had enteroviral RNA sequences in their muscles, compared to 15% for healthy controls.

    Amplification and identification of enteroviral sequences in the postviral fatigue syndrome
    Gow JW1, Behan WM. Br Med Bull. 1991 Oct;47(4):872-85.
    ➤ This study found that ME/CFS patients were 6.7 times more likely to have enteroviral RNA in their muscle tissue, compared to healthy controls.

    Persistent virus infection of muscle in postviral fatigue syndrome
    Cunningham L, Bowles NE, Archard LC. Br Med Bull. 1991 Oct;47(4):852-71.
    ➤ This study found enteroviral RNA in 24% of ME/CFS patients' muscle biopsy samples, and Epstein-Barr virus DNA in a further 9% of these biopsy samples.

    Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy
    Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L, Archard LC. J Med. 1993;24(2-3):145-60.
    ➤ This study of 158 ME/CFS patients found enteroviral RNA in 26% of the patient's muscle biopsy samples, compared to only 1% in healthy controls.

    Studies on enterovirus in patients with chronic fatigue syndrome
    Gow JW, Behan WM, Simpson K, McGarry F, Keir S, Behan PO. Clin Infect Dis. 1994 Jan;18 Suppl 1:S126-9.
    ➤ This study of 121 patients with ME/CFS found enteroviral RNA in 26.4% of the patients' muscle biopsy samples, and found enteroviral RNA in 19.8% the muscle biopsies of patients other neuromuscular disorders. From these results the authors concluded that "it is unlikely that persistent enterovirus infection plays a pathogenetic role in CFS, although an effect in initiating the disease process cannot be excluded."

    However, this conclusion may not be a logical, firstly because persistent enterovirus is associated with a wide range of diseases, including chronic inflammatory myopathy, and thus might also be playing a role in these other neuromuscular disorders; and secondly because persistent enterovirus infection are found in other organs in ME/CFS patients, such as the brain and stomach (although this fact was not known at the time of publication).

    Enterovirus in the chronic fatigue syndrome (full text here)
    McGarry F, Gow J, Behan PO. Ann Intern Med. 1994 Jun 1;120(11):972-3.
    ➤ This study details an autopsy of a deceased ME/CFS patient. Enteroviral RNA was found in the heart, muscles, hypothalamus and brainstem of this patient, and this RNA showed an 83% similarity to coxsackievirus B3. Control tissue samples taken from four patients who died of cerebrovascular diseases, and another four who had depression and committed suicide, showed no evidence of enteroviral RNA.

    Detection of enterovirus-specific RNA in serum: the relationship to chronic fatigue
    Clements GB, McGarry F, Nairn C, Galbraith DN. J Med Virol. 1995 Feb;45(2):156-61.
    ➤ This study of 88 ME/CFS patients found enteroviral RNA in the serum of 41% of patients, compared to 2% of healthy controls.

    Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome
    Galbraith DN, Nairn C, Clements GB. J Gen Virol. 1995 Jul;76 ( Pt 7):1701-7.
    ➤ This study found that ME/CFS patients with persistent enteroviral infections nearly always have viruses with a different genetic makeup compared to enteroviruses found in acute, self-limiting infections in healthy controls. This is strong evidence for enteroviruses playing a causal role in ME/CFS, and indicates that the enteroviruses which may cause ME/CFS are different in nature to the enteroviruses in general circulation.

    Viral Isolation from Brain in Myalgic Encephalomyelitis (A Case Report)
    Richardson, J. Journal of Chronic Fatigue Syndrome, Vol. 9(3/4) 2001, pp. 15-19.
    ➤ This study examined the brain of an ME patient who died through suicide, and found enteroviral VP1 protein in the fibroblasts of small blood vessels in the cerebral cortex, plus some patchy distribution of enteroviral VP1 protein in a small fraction of glial cells.

    Enterovirus related metabolic myopathy: a postviral fatigue syndrome
    Lane RJ, Soteriou BA, Zhang H, Archard LC. J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1382-6.
    ➤ This study of 48 patients with ME/CFS found enteroviral sequences by RT-NPCR in 20.8% of patients' muscle biopsy samples, while all the 29 control samples were negative for such sequences.
    Just for completeness, Dr John Chia's ME/CFS enterovirus studies are these:
    The role of enterovirus in chronic fatigue syndrome.
    Chia JK. J Clin Pathol. 2005 Nov;58(11):1126-32.

    Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach.
    Chia JK, Chia AY. J Clin Pathol. 2008 Jan;61(1):43-8. Epub 2007 Sep 13. Full paper here.
    ➤ This study of 165 ME/CFS patients found enterovirus VP1 protein in 82% of stomach tissue samples from patients, compared to 20% in healthy controls. 37% of the ME/CFS patient stomach tissue samples tested positive for enterovirus RNA, compared to less than 1% for healthy controls.

    Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence.
    Chia J, Chia A, Voeller M, Lee T, Chang R. J Clin Pathol. 2010 Feb;63(2):165-8. doi: 10.1136/jcp.2009.070466.
    ➤ This study followed patients who were hospitalized for acute enterovirus infections, and found that in the next few years subsequent to the acute infections, symptoms consistent with ME/CFS emerged in some patients.


    In addition to the above, three separate brain autopsies on deceased ME/CFS patients found enterovirus / coxsackievirus B infection in the brain tissues. See here.
     
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  20. Gingergrrl

    Gingergrrl Senior Member

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    Now I am confused! So in your opinion, there is no connection between Coxsackie virus and ME? I do not know the answer but had assumed this was an established fact (that at least one subgroup of ME has an EV). Versus my illness turned out to be autoimmune subgroup etc.
     

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