The use of oxygen as a possible screening biomarker for the diagnosis of chronic fatigue, Pifarré et al, 2022

[Snow Leopard]

The use of oxygen as a possible screening biomarker for the diagnosis of chronic fatigue

Fernando Pifarréa, Lluís Rossellób, Raúl Hilenoc, Joan Palmic, Llúcia Bañeresc, Antoni Planasc, Joan Antoni Prat

Abstract

Background

The aim of this study was to verify whether the mean percentage of oxygen use in the aerobic-anaerobic transition phase or isocapnic buffering (IB) was lower in women with chronic fatigue syndrome (CFS) compared to healthy women, and if this variable could be used as a screening biomarker for the diagnosis of CFS

Methods

A cross-sectional study was conducted. Forty-four adult women (22 with CFS and 22 healthy) performed a cycle ergometer stress test with gas analyser (CPET). Maximum oxygen consumption (O2 max), oxygen consumption at the anaerobic threshold (O2 at Vt2), maximum ventilatory volume (E max), time of maintenance of the isocapnic buffering phase (IB duration), and mean percentage of oxygen use in isocapnic buffering phase (% O2 use in IB) were analyzed. Data were explored from a principal component analysis. Groups were matched by propensity score to be mismatched in BMI and a comparison of means and medians was performed. A logistic regression model was built to predict the probability of CFS.

Results

The mean and median values of the variables obtained in the CPET was significantly higher in the healthy group compared to the CFS. In the logistic regression model, VO2 max, IB duration, and mean % of O2 use in IB were selected as predictors. The sensitivity and specificity were greater than 90%.

Conclusion

The combination of the factors
O2 max, IB duration, and mean % of O2 use in IB can be used as a screening biomarker for the diagnosis of CFS.

https://doi.org/10.1016/j.apunsm.2022.100379 (not paywalled)

 

[Snow Leopard]

Some comments:
AUC was ~90% for sensitivity and specificity.

However, I don't think this model/"biomarker" is terribly useful as it is likely just a result of difference in fitness between the patients and poorly matched controls - I'd like to see the measures have the same results for patients who have higher VO2Max than controls for example, before I have any confidence in it's use.

I'd also have like to have seen more data, especially that which may lead to analysis that may disconfirm the finding. - workrates, ventilatory efficiency, workrate normalised data etc.

 

[alex3619]

Wasn't it David Systrom who used invasive CPET and showed at least some of us are not actually using as much oxygen as expected?

It feels like things are coming full circle for me, as I started thinking about hypoxia in CFS in the late 90s, then started talking to Martin L. Pall.

This kind of test might be used diagnostically if similar diseases do not show this, or even if they do if they can be differentially diagnosed the test is still useful diagnostically.

However this is still an early study in my view, lots more work needs to be done. They also need to figure out a non-exercise method so that very severe patients might be diagnosed.

I have not read the paper. What do they mean by a screening biomarker? Are they implying its best used as a test to rule out patients who do not have CFS?

 

[SNT Gatchaman]

From Roles of periodic breathing and isocapnic buffering period during exercise in heart failure (2020) —

In heart failure (HF), exercise-induced periodic breathing (PB) – also known as oscillatory exercise ventilation (EOV) – is defined by an oscillatory pattern of ventilation which can last for the entire exercise or for a part of it. The isocapnic buffering period is the period of exercise between the anaerobic threshold and the respiratory compensation point.

It is the part of exercise during which lactic acid is buffered by bicarbonates and pH is maintained. Its length depends on two factors: the amount of available carbon dioxide (CO2) and the threshold of arterial carbon dioxide tension (PaCO2) needed to increase ventilation by chemoreceptors. PB and the isocapnic buffering period are two features of ventilation during exercise highly dependent on chemoreflex regulation. Both carry relevant information on HF severity and prognosis.

The presence of [Periodic Breathing] and of the isocapnic buffering period are mutually exclusive, but both can be absent.

PB is related to an imbalance among circulation, muscle function and chemoreflex response, while end tidal carbon dioxide pressure (PetCO2) or, when measured, arterial partial pressure carbon dioxide (PaCO2), during the isocapnic buffering period are mirrors of the sympathetic activity, and more specifically of the chemoreflex activity. The presence of PB suggests low cardiac output, limited CO2 reserve and sympathetic overactivation; a low PetCO2 during the isocapnic buffering period also suggests sympathetic overactivation, while buffering capacity, which translates into the amount of oxygen consumption (VO2) during the isocapnic buffering period, is directly related to exercise performance.

In a maximal exercise, the absence of the isocapnic buffering period is indicative of reduced exercise performance and hyperventilation, either voluntary or related to environmental conditions, such as high altitude, or to specific disease, such as pulmonary hypertension.

 

[Simon M]

The study only has 22 patients and researchers had to combine several different factors to create a "biomarker" with reasonable results. It seems likely that they searched through many more features to get this result. Above all, there was no replication. We need researchers to raise their game - this kind of study does not help people with ME.

Added:
Given that the consensus among researchers is that ME is probably several different illnesses, we will need several different biomarkers, and much bigger samples to find them.

 

[Snow Leopard]

From Roles of periodic breathing and isocapnic buffering period during exercise in heart failure (2020) —

Yes, the isocapnia phase (though the VE/VCO2 graph) isn't perfectly flat even in healthy people) is normal (and this is why it is nonsense to blame "hyperventilation") between the gas exchange threshold (the first ventilatory threshold - this is not synonymous with a "anerobic threshold" despite what that study says) and the respiratory compensation point which is the second ventilatory threshold.

I'm guessing by your reply that many people don't actually know this.

It is hinted at in the MEpedia article: https://me-pedia.org/wiki/Two-day_cardiopulmonary_exercise_test
"while VE/VCO2 remains flat" and "neither hypocapnia nor hypercapnia occur at this threshold" ("this" being the gas exchange threshold). But maybe this should be clearer?

The periodic breathing stuff is not really relevant as it is not normally found in ME/CFS patients.
A clear example is the VE plot (figure 2) in the following paper: https://pubmed.ncbi.nlm.nih.gov/30046353/

Heart rate lags behind breathing patterns but there is feedback on the ventilatory drive if the heart is unable to respond - the latency in the feedback in both directions is what leads to the oscillation pattern.

 

[DokaGirl]

Wasn't it David Systrom who used invasive CPET and showed at least some of us are not actually using as much oxygen as expected?

It feels like things are coming full circle for me, as I started thinking about hypoxia in CFS in the late 90s, then started talking to Martin L. Pall.

This kind of test might be used diagnostically if similar diseases do not show this, or even if they do if they can be differentially diagnosed the test is still useful diagnostically.

However this is still an early study in my view, lots more work needs to be done. They also need to figure out a non-exercise method so that very severe patients might be diagnosed.

I have not read the paper. What do they mean by a screening biomarker? Are they implying its best used as a test to rule out patients who do not have CFS?

Thank you for pointing out the circular nature of research and thinking about ME.

An n=1 example, but I too, along with my husband thought about lack of oxygen in the 1990s. Many, many times we both noted my blue tinged lips and wondered if supplemental oxygen might help.

Amazing how doctors and other medical staff never seemed to notice my blueish lips. I think I did point this out to them, but to no avail.