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Upper Airway Resistance Syndrome (UARS): a common underlying cause for all "chronic complex illnesses"? (ME/CFS, fibro, GWI, etc.)
- Thread starter nataliezzz
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Hi @nataliezzz and welcome. One thing that has become very clear with the SARS2 pandemic is the large (~40%) number of acutely asymptomatic infections. A proportion of these patients have gone on to ME/CFS. Without looking in depth at someone's viral history, eg via T cell immune profiling, people simply do not know with certainty that their trigger was non-infectious.
A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection (2023)
Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 (2021)
Global Percentage of Asymptomatic SARS-CoV-2 Infections Among the Tested Population and Individuals With Confirmed COVID-19 Diagnosis: A Systematic Review and Meta-analysis (2021)
SARS-CoV-2-specific CD8+ T cells from people with long COVID establish and maintain effector phenotype and key TCR signatures over 2 years (2024)
nataliezzz
Established Member (Voting Rights)
Thank you. It's fine to suggest that some/many people may have had asymptomatic infections being the trigger for their illness. What I find ridiculous is people suggesting that someone who had their illness clearly triggered by something else like surgery, childbirth, physical trauma, chemical/mold exposure, etc. simultaneously acquired an asymptomatic infection that is actually the trigger.
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wigglethemouse
Senior Member (Voting Rights)
It looks like inspiratory flow limitation is very common in the normal population. Evidence without comparison to proper controls are meaningless.
Inspiratory Flow Limitation in a Normal Population of Adults in São Paulo, Brazil
This limitation almost always happens in POTS studies for example, so we don't know how to interpret many of those studies. ME/CFS researchers who have studied POTS in ME/CFS and Healthy Control volunteers find a very high prevalence of the POTS diagnostic >30bpm from horizontal to vertical in healthy controls. For example Bateman et al for ~33% of healthy controls had >30bpm change in their study.
Inspiratory Flow Limitation in a Normal Population of Adults in São Paulo, Brazil
This limitation almost always happens in POTS studies for example, so we don't know how to interpret many of those studies. ME/CFS researchers who have studied POTS in ME/CFS and Healthy Control volunteers find a very high prevalence of the POTS diagnostic >30bpm from horizontal to vertical in healthy controls. For example Bateman et al for ~33% of healthy controls had >30bpm change in their study.
nataliezzz
Established Member (Voting Rights)
Yes, inspiratory flow limitation (just like OSA) is very common in asymptomatic people (& thank you for citing that study!)
Here is the GWI study data (recall that the controls were age/BMI-matched asymptomatic Gulf War vets). Flow limitation (well, flow limitation + the brain's response to it) appears to be the primary relevant factor here (& the p-value is <.0001)
I think this is the study:
Inspiratory airflow dynamics during sleep in veterans with Gulf War illness: a controlled study (2011, Sleep and Breathing)
So is the point that you think CPAP is the treatment for all these conditions? I saw this other study in the Twitter thread:
The effect of nasal continuous positive airway pressure on the symptoms of Gulf War illness (2011, Sleep and Breathing)
It says there was sham CPAP, but I don't see how it could be blinded. I've used APAP and the pressure is very noticeable. And I'll note that there is more potential for bias in that all the outcomes were self-report questionnaires.
Edit: I missed that the study is on people with diagnosed sleep disordered breathing (which Wikipedia seems to say is basically a catch all for many different sleep disorders like sleep apnea and snoring). So they gave people with clear issues with sleep a treatment for sleep apnea and it helped, which doesn't sound surprising. I don't think it can be linked with Gulf War Illness until it's tested in just random people with GWI, not those chosen based on having sleep issues.
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nataliezzz
Established Member (Voting Rights)
Yes, PAP (CPAP/BiPAP) - many people with milder sleep-disordered breathing seem to do better on BiPAP (bilevel) than CPAP though. There's also mandibular advancement device & surgeries (which may be more curative). And I do think some people can recover from UARS/OSAS spontaneously, & I also do believe some people have recovered with nervous system regulation techniques (waiting to get demolished for this) though like I have said, if the sensitization/stress response is occurring in people's sleep, how much control they can be said to have over it with what they are doing during the day? In Dr. Gold's fibro & GWI studies (& in his broader clinical experience with ME/CFS & fibromyalgia patients - I asked him) people feel ~35-50% better on CPAP (I don't think he uses much BiPAP) but not cures, and he believes it is because CPAP is also acting as a stressor. He has seen many fibromyalgia patients because the rheumatology department at his university has caught on to the sleep-disordered breathing connection & refers them for evaluation/treatment.
Yes, those are the studies being referenced. Yes, good point about the sham CPAP (I have honestly been waiting to have these types of discussions for months on Twitter but everyone continually ignores me lol); sham CPAP does incorporate a large air leak so it has noise/some sensation of airflow, but if you are not naive to CPAP you would be able to tell whether you were on sham CPAP vs. therapeutic CPAP (when Dr. Gold did the CPAP titration on the GWI patients while they were asleep the pressure was lowered to normal before they woke up to facilitate masking). Notably, the GWI patients on sham CPAP got slightly worse while those on therapeutic CPAP got better, & there was an objective finding (decreases in sleep stage shifts) associated with symptom improvement.
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Interesting idea. I wonder if the CPAP being turned on at night might wake some people up and alert them to it. Or if any people just wake up naturally a few times and would know. Doesn't look like they mention using this method in this study anyway though.
Looking at the study, it says at baseline they had an AHI (for the benefit of others: apnea-hypopnea index) of 22. Cleveland Clinic says 15-30 is moderate sleep apnea. So people with sleep apnea improved with CPAP. It just seems like the connection to CPAP improving Gulf War illness is very weak here.
Edit: Maybe you're saying they did do this titration and lowering pressure while asleep for placebo in this study? They link to this other study for the placebo method, but I don't see where it says they did that:
In any case, even if it's very well blinded and shows a definite improvement, I don't think it tells us much about GWI.
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jnmaciuch
Senior Member (Voting Rights)
For what it’s worth I know two pwME who use CPAP machines, one since before getting sick. The CPAP helps because they feel much worse on top of baseline symptoms when they’re not sleeping well, but it definitely didn’t treat their ME/CFS at all. They are both still rarely able to leave the house
My doctor also had me trial a CPAP (well APAP, which adjusts the pressure automatically) for a few months after a sleep study showed very mild sleep apnea. It made no difference in any way to ME/CFS or anything else.
shak8
Senior Member (Voting Rights)
Upper airway resistance as the cause of damn near everything is a "homeopathic hypothesis" in that the effects of miniscule airway resistance measurements do not, and cannot account for clinically relevant underpinnings for FM, ME, etc.
That being said, I posted the emboldened phrase to the Pompous Parsnip thread where lovely @Wyva may, with the assistance of supernatural AI helpers, create an image that will elucidate the previously undiscovered force underlying all aspects of upper airway resistance and invalidate all previous scientific knowledge.
That being said, I posted the emboldened phrase to the Pompous Parsnip thread where lovely @Wyva may, with the assistance of supernatural AI helpers, create an image that will elucidate the previously undiscovered force underlying all aspects of upper airway resistance and invalidate all previous scientific knowledge.
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nataliezzz
Established Member (Voting Rights)
I meant that when they came into the sleep lab for the titration study (where Dr. Gold determined what pressure to put them on to resolve inspiratory flow limitation) that the pressure was lowered to atmospheric pressure before they woke up (therefore none of them had experienced the sensation of therapeutic CPAP - unless they woke up in their sleep during the titration study - before they were sent home with the CPAP machines)
Did you look at the individual GWI patient data? Not all of them met criteria for OSA (& some of the asymptomatic controls met criteria for OSA). How do you explain the p <.0001 difference between % inspiratory flow limitation in the GWI patients (96%±5) vs. the asymptomatic age/BMI-matched Gulf War vets (36±25%)? Why do you think this finding "doesn't tell us much about GWI"? Is it just because the sample size is small? Or is there some other explanation for why GWI patients would have high % IFL during sleep compared to controls? And when treated with CPAP, experience decreased sleep stage shifts correlated with improvement in the symptoms of GWI [fatigue, pain, cognitive dysfunction, etc.] w/ p-values in the <.00x - <.000x range (while GWI pts on sham CPAP did not experience decreased sleep stage shifts & got slightly worse)?
I see that all but one in the active group had an AHI of at least 5, so at least mild sleep apnea, and two had severe sleep apnea. Out of all the objective measures, it looks like change in AHI was the most significant change compared to sham, which matches with the idea that the CPAP is mainly reducing sleep apnea.
Is this about the other study? I haven't really looked at that one. I'm just trying to figure out if this one tells us anything useful. But I'm not sure what you mean by how do I explain it? Maybe they do have worse air flow, but that doesn't mean worse air flow causes GWI. Maybe it's the other way around or something else causes both.
No, it's because it looks like they treated people with sleep apnea using a treatment known to treat sleep apnea. If they recruited people with brain cancer + sleep apnea or foot fungus + sleep apnea and gave them CPAP, I think they'd get similar results, but I wouldn't say CPAP treats cancer or fungus.
nataliezzz
Established Member (Voting Rights)
Apneas, hypopneas, & the arousals associated with them are not the primary cause of sleepiness & fatigue in OSA patients! (again, how could they possibly be if >50% of OSA patients are asymptomatic?) Forget GWI for a second, if >50% of people with OSA are asymptomatic, what do you propose is causing the sleepiness, fatigue & cognitive dysfunction (that is well-recognized to be reduced/alleviated by CPAP/surgery/etc.) in OSA syndrome patients? I recommend actually reading the below thread, it would be impossible for me to write out all the relevant information from it here.
They were not specifically recruiting GWI patients with suspected sleep-disordered breathing. Unrefreshing sleep & sleep disturbances like sleep-onset & sleep maintenance insomnia (which are also well recognized to be associated with OSA) are core symptoms of GWI, fibromyalgia & ME/CFS (in fact, unrefreshing sleep is a required symptom in IOM ME/CFS criteria). It would be impossible to recruit a sample of patients with these illnesses without sleep disturbances.
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nataliezzz
Established Member (Voting Rights)
Yes, from the first study: (Inspiratory airflow dynamics during sleep in veterans with Gulf War illness: A controlled study), not the CPAP treatment one. Let's discuss it again after you look at the individual patient data from that one (who again were not recruited specifically for suspected sleep-disordered breathing). Thank you for discussing it with me!
The question of whether high % inspiratory flow limitation is a downstream effect is a good one; I think all of the data together suggests not, but especially the Pcrit (pharyngeal critical closing pressure) data from Dr. Gold's fibromyalgia study; Pcrit is a measure of how collapsible the airway is, not how much it's collapsing during sleep, so it negates that sleep-disordered breathing is just a downstream effect of some brain pathology causing increased airway collapse during sleep (16 of the fibro patients in this study were specifically referred for complaints of fatigue/sleepiness/disturbed sleep, 12 others were recruited elsewhere - all were previously diagnosed by a rheumatologist & met ACR fibromyalgia criteria. 11/28 (39%) had alpha-delta sleep, an objective finding associated with both fibromyalgia & UARS).
And here is a study (not by Dr. Gold!) where consecutive female fibromyalgia patients from a rheumatology clinic (not specifically complaining of sleep disturbances) were offered to undergo polysomnography - all 23 who did had OSA (that does not happen by chance).
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I read the Bluesky thread just now. Isn't the idea that the symptoms in both OSA and snoring would be caused by lack of oxygen while sleeping? I'm not sure I'm seeing what's important about whether it's distinct full apneas or constant narrowness that causes the symptoms.
Unrefreshing sleep is a subjective symptom. This review from 2021 says there's very little objective difference in sleep (edit: maybe microarousals are consistent):
Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2021, Healthcare)
Anyway, if people with ME/CFS or GWI or whatever have issues with sleep, even if just subjective sleep symptoms, I don't see an issue with trying CPAP. It was the first thing my new doctor suggested trying, so it doesn't seem like its a hard to get treatment. It's such a common treatment that it seems like it'd be common knowledge if most people with these chronic conditions were getting much better from it, though.
I'm not sure I have the energy to dig too much into papers about this and try to learn about all this stuff like Pcrit. I have no objections to patients trying CPAP or doing more trials (as well blinded as possible and with objective outcomes like actimetry) of CPAP in any of these conditions.
nataliezzz
Established Member (Voting Rights)
No, otherwise there should be no UARS; by definition, UARS patients do not have oxygen desaturation (hypoxemia) during sleep, & yet they are fatigued/sleepy (& their fatigue/sleepiness has been shown to be improved with CPAP). The data from the Sleep Heart Health Study showed that in people with an AHI <5, the presence of snoring was associated with a large increase in sleepiness, and people with an AHI <5 have no significant oxygen desaturation. There was also no correlation between % sleep time below 90% oxygen saturation (SpO2) & fatigue/sleepiness in the OSA patients in Dr. Gold's study.
Yes, it's a good point. However, most people are not actually manually titrated in a sleep lab to eliminate inspiratory flow limitation. They are just told that if their AHI is <5 on CPAP that they are all good (you can have AHI down on CPAP & still have a ton of flow limitation). It requires being manually titrated in a lab or doing it yourself by putting an SD card in your machine & analyzing your breathing curves in OSCAR (free computer program). Even when people are titrated to eliminate flow limitation, they often only feel 35-50% better (again in Dr. Gold's clinical experience with many fibromyalgia patients over the years), likely because CPAP is also acting as a stressor. We did see the case report of the woman whose fibromyalgia symptoms were "totally improved" on CPAP though so it is possibly for some people to completely recover on CPAP, apparently.
nataliezzz
Established Member (Voting Rights)
Understand, I appreciate you engaging with me on it and actually looking into some of the data/evidence.
Jonathan Edwards
Senior Member (Voting Rights)
@nataliezzz,
Sorry to sound dismissive, but there are reasons for everyone being sceptical here.
Most of us do not use social media - I don't even know what Blue Sky is - and many specifically prefer not to have anything to do with X. It is hard to find what the theory really is from your first post but it seems to be, in plain English, something like "all chronic unexplained illnesses like FM and MECFS are due to narrowing of the trachea, glottis or pharynx".
To make a start on testing that we would need some evidence that there was a striking difference between all people with these illnesses and everyone else, using a blinded study of a cohort that was not selected by attendance at clinics that might have biased samples. Is there any such evidence?
Beyond that the theory seems to slip into the pseudoscientific language of psychology - things like 'dysfunctional stress response' - of the sort popular with the therapy professions who have been instrumental in pretending to treat ME/CFS while in reality making peoples' lives a misery. Language of this sort is too vague to be of any scientific use and anyway nobody should be suggesting treating people on the basis of a theory without adequate trials. In this respect Dr Gold appears to be exactly like Wessely and Chalder on the CBT side and equally the hypermobility physicians who have built up the story that somehow chronic fatigue is linked to 'hEDS', which then got linked to ME/CFS by the psychologists who think ME/CFS is chronic fatigue.
At one level we can be certain that all ME/CFS symptoms are generated in the brain. But we need to understand the specific causal pathways that lead to that - which are likely to be both inside and outside the brain (airway obstruction isn't in the brain). I (and many researchers) think it is very likely that ME/CFS symptoms have nothing much to do with mitochondria or metabolism, but building a theory requires proposing specific alternative pathways. And you are never going to know the theory is right until you have tested it therapeutically with an adequately controlled study.
All the stuff I have seen from sleep medicine physicians since the 'specialty' became fashionable about twenty years ago has been deeply unimpressive. There is no excuse for tinkering about with treatments as 'a clinician' without doing proper trials. There is nothing worthy about that sort of behaviour.
Sorry to sound dismissive, but there are reasons for everyone being sceptical here.
Most of us do not use social media - I don't even know what Blue Sky is - and many specifically prefer not to have anything to do with X. It is hard to find what the theory really is from your first post but it seems to be, in plain English, something like "all chronic unexplained illnesses like FM and MECFS are due to narrowing of the trachea, glottis or pharynx".
To make a start on testing that we would need some evidence that there was a striking difference between all people with these illnesses and everyone else, using a blinded study of a cohort that was not selected by attendance at clinics that might have biased samples. Is there any such evidence?
Beyond that the theory seems to slip into the pseudoscientific language of psychology - things like 'dysfunctional stress response' - of the sort popular with the therapy professions who have been instrumental in pretending to treat ME/CFS while in reality making peoples' lives a misery. Language of this sort is too vague to be of any scientific use and anyway nobody should be suggesting treating people on the basis of a theory without adequate trials. In this respect Dr Gold appears to be exactly like Wessely and Chalder on the CBT side and equally the hypermobility physicians who have built up the story that somehow chronic fatigue is linked to 'hEDS', which then got linked to ME/CFS by the psychologists who think ME/CFS is chronic fatigue.
At one level we can be certain that all ME/CFS symptoms are generated in the brain. But we need to understand the specific causal pathways that lead to that - which are likely to be both inside and outside the brain (airway obstruction isn't in the brain). I (and many researchers) think it is very likely that ME/CFS symptoms have nothing much to do with mitochondria or metabolism, but building a theory requires proposing specific alternative pathways. And you are never going to know the theory is right until you have tested it therapeutically with an adequately controlled study.
All the stuff I have seen from sleep medicine physicians since the 'specialty' became fashionable about twenty years ago has been deeply unimpressive. There is no excuse for tinkering about with treatments as 'a clinician' without doing proper trials. There is nothing worthy about that sort of behaviour.