Can the Giardia lamblia ME/CFS outbreak in Bergen explain why the phase II rituximab trials were positive, but the phase III trial negative?

Hip

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SUMMARY: Could the positive results of the early Fluge & Mella 2011 blinded phase II rituximab trial and 2015 open label phase II study be due to inadvertently including some Giardia lamblia ME/CFS patients in the study cohort, from the 2004 Bergen Giardia lamblia outbreak?

The later Fluge & Mella negative 2019 phase III multi-center rituximab study would have had much fewer Giardia lamblia patients (because it was conducted in several other cities, not just Bergen).

On the assumption that rituximab works for Giardia lamblia ME/CFS, if there were Giardia lamblia patients in the two phase II studies, this might explain why these studies were positive, whereas the later phase III study was negative.



In 2004 in Bergen Norway, there was a major outbreak of giardiasis (Giardia lamblia infection) resulting from sewage contamination of the drinking water supply, which affected an estimated 2500 people (with 1300 actual laboratory-confirmed cases of giardiasis).

Bergen of course is the city where Oystein Fluge and Olav Mella conducted their phase II rituximab studies.

From March 2009 to March 2010, five years after the giardiasis outbreak, 253 patients who had been suffering chronic fatigue symptoms ever since their giardiasis were recruited to participate in a 2013 study at Haukeland University Hospital in Bergen. The study concluded that 41.5% of the participants had ME/CFS by the CDC Fukuda criteria.

So lots of patients with Giardia lamblia-triggered ME/CFS were attending the Haukeland University Hospital at the time Fluge & Mella were conducting their phase II rituximab trials at Haukeland. The Fluge & Mella 2011 phase II trial recruited ME/CFS patients referred to the Department of Neurology, Haukeland University Hospital, from June 2008 to June 2009.

So the question is, how many of these Giardia lamblia ME/CFS patients would have been included in the rituximab phase II trials? Giardia lamblia ME/CFS is a rare form of ME/CFS, so if lots of these patients got onto the phase II trials, it would have created an unusual patient cohort.

By contrast, the phase III multi-center rituximab study was conducted in various university hospitals in different cities in Norway (Bergen, Oslo, Notodden, Trondheim and Tromsø judging by the authors' affiliations in the study). So you would thus have had far fewer Giardia lamblia ME/CFS patients in the phase III study, because the giardiasis outbreak only occurred in Bergen.

Thus if rituximab were effective for Giardia lamblia ME/CFS, it might explain why the two phase II studies showed such positive results, but the phase III study had a negative result.



Just to remind you of Fluge & Mella's rituximab trial results:

2011 blinded phase II study on 30 ME/CFS patients given rituximab or placebo.
Response rate: 67% in the rituximab group, and 13% in the placebo group.

2015 open label phase II study on 29 ME/CFS patients all given rituximab. No placebo group.
Response rate: 64%.

2019 blinded phase III study on 151 ME/CFS patients given rituximab or placebo.
Response rate: 26% in the rituximab group, and 35% in the placebo group.
 
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This is a really nice hypothesis, @Hip! And a great example of the reason for multi-centre trials.

However, if it were true, it suggests a thorough re-imagining of me/cfs is in order. The "hit-and-run" hypothesis suggests that it doesn't matter what the initial infection was, the problem is now baked into the cells (or the blood, the brain, the mitochondria, etc). And crucially, that problem is thought to be common to patients regardless of the identity of the original infection

If the type of initial infection determines your me/cfs subtype, then we have a situation that offers higher complexity, but also possibly greater opportunity - like finding another giardiasis me/cfs group and trying rituximab on them.

One question for you. How did you come up with this idea?
 

Hip

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If the type of initial infection determines your me/cfs subtype, then we have a situation that offers higher complexity, but also possibly greater opportunity - like finding another giardiasis me/cfs group and trying rituximab on them.
This idea occurred to me some years ago (I mentioned it in this post from 2015), in fact before the rituximab phase III trial.

I was wondering why Fluge and Mella had success in treating ME/CFS with rituximab in their phase II trials, whereas on the Phoenix Rising forum, very few ME/CFS patients who tried rituximab seemed to benefit. Out of around 22 PR ME/CFS patients who had rituximab treatment, only 2 responded to it. So that's a 9% response rate on PR, whereas F&M got a 67% response rate in their phase II trial.

So I was trying to work out why F&M were seemingly getting good results, but Phoenix Rising patients were not.

Then I started thinking in terms of the possibility that Norway or Bergen might have an epidemic of ME/CFS due to a specific type of pathogen which rituximab might be good at treating.

I was already aware of the Giardia lamblia ME/CFS outbreak in Bergen. And on further investigation of this outbreak, I found that Bergen Giardia lamblia ME/CFS patients were actually being enrolled in studies at Fluge and Mella's university in Haukeland at around the same time that F&M were recruiting ME/CFS patients for their rituximab study. So it seemed plausible that there might be a lot of Giardia lamblia-affected ME/CFS patients in F&M's rituximab phase II study cohort.
 
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This idea occurred to me some years ago (I mentioned it in this post from 2015), in fact before the rituximab phase III trial.

I was wondering why Fluge and Mella had success in treating ME/CFS with rituximab in their phase II trials, whereas on the Phoenix Rising forum, very few ME/CFS patients who tried rituximab seemed to benefit. Out of around 22 PR ME/CFS patients who had rituximab treatment, only 2 responded to it. So that's a 9% response rate on PR, whereas F&M got a 67% response rate in their phase II trial.

So I was trying to work out why F&M were seemingly getting good results, but Phoenix Rising patients were not.

Then I started thinking in terms of the possibility that Norway or Bergen might have an epidemic of ME/CFS due to a specific type of pathogen which rituximab might be good at treating.

I was already aware of the Giardia lamblia ME/CFS outbreak in Bergen. And on further investigation of this outbreak, I found that Bergen Giardia lamblia ME/CFS patients were actually being enrolled in studies at Fluge and Mella's university in Haukeland at around the same time that F&M were recruiting ME/CFS patients for their rituximab study. So it seemed plausible that there might be a lot of Giardia lamblia-affected ME/CFS patients in F&M's rituximab phase II study cohort.
Great example of experience, domain knowledge and logical thinking coming together!

If you can come up with a plausible pathological mechansim whereby giardia uniquely creates b-antibodies or has some other feature that rituximab could affect, I'm interested. (Noting of course that with a bit of motivated reasoning, a hypothetical pathway is likely to be imaginable, and the ability to imagine it says little about its chance of being true IRL.)
 

Hip

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If you can come up with a plausible pathological mechansim whereby giardia uniquely creates b-antibodies or has some other feature that rituximab could affect, I'm interested.
Now that's where my theory falls short! I checked whether Giardia lamblia might be associated with autoimmune diseases; if Giardia can trigger autoimmunity, it might explain rituximab's success at treating Giardia lamblia ME/CFS. But I could not find much in terms of an autoimmune association.

There was one study which found Giardia lamblia infection led to allergies, and of course allergy and autoimmunity are closely linked.


One way to help confirm or refute this Giardia lamblia theory is to test the Fluge and Mella's phase II rituximab responders for Giardia lamblia antibodies. The phase II 2011 study only had 15 ME/CFS patients on rituximab, so not too difficult to test those, if they can be contacted. If there were a high number positive for Giardia lamblia among that 15, then that adds weight to the theory.
 

Gingergrrl

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If the type of initial infection determines your me/cfs subtype, then we have a situation that offers higher complexity, but also possibly greater opportunity -
This is my feeling (totally separate from Rituximab) that the initial type of infection or trigger does matter. If someone had a purely viral trigger their treatment would be different than if Lyme was the trigger and same for toxic mold/mycotoxins or EDS/CCI, etc. Although in most cases, there are multiple triggers, not just one.

Now that's where my theory falls short! I checked whether Giardia lamblia might be associated with autoimmune diseases; if Giardia can trigger autoimmunity, it might explain rituximab's success at treating Giardia lamblia ME/CFS. But I could not find much in terms of an autoimmune association.
I had asked you this in the other thread @Hip before reading this so you don't need to answer in both places! I had wondered if you found some connection between Giardia and autoimmunity/ B-cells prior to developing your theory but it sounds like you didn't find one?

My two main treating doctors said that EBV often shifts into autoimmunity and Rituximab also targets EBV in the B cells (and this is me paraphrasing and not the exact words of my doctors in case I have screwed up the explanation :xeyes: !) My illness started as a post-viral fatigue syndrome but later morphed into autoimmunity.