Reduced Cerebrovascular Oxygenation in Individuals with Post-Acute COVID-19 Syndrome PACS “long COVID”, 2023, Adingupu et al.

[SNT Gatchaman]

Reduced Cerebrovascular Oxygenation in Individuals with Post-Acute COVID-19 Syndrome PACS “long COVID”
Adingupu, Damilola D.; Soroush, A.; Hansen, A.; Twomey, R.; Dunn, J. F.

There is evidence that hypoxia occurs in the brain of some individuals who contracted the COVID-19 disease. Furthermore, it has been widely reported that about 13% of individuals who contracted the COVID-19 disease report persistent symptoms after the acute infection stage (>2 months post-acute infection). This is termed post-acute COVID-19 syndrome (PACS) or (“long COVID”).

In this study, we aimed to determine if hypoxia measured non-invasively with frequency domain near-infrared spectroscopy (fdNIRS) occurs in asymptomatic and symptomatic individuals with post-acute COVID-19 disease. We show that 26% of our symptomatic group, measured on average 9.6 months post-acute COVID-19 disease, were hypoxic and 12% of the asymptomatic group, measured on average 2.5 months post-acute infection, were hypoxic.

Our study indicates that fdNIRS measure of hypoxia in the brain may be a useful tool to identify individuals that are likely to respond to treatments targeted at reducing inflammation and improving oxygenation.

Link | Paywall (Conference paper: International Society on Oxygen Transport to Tissue)

 

[Hutan]

26% in the symptomatic group isn't exactly overwhelming, although I'd be quite happy believing that the hypoxia is something that comes and goes, depending on the demands placed on the body or specifically on the brain. I'd also be willing to believe that there are groups under the broad category of Long Covid for whom hypoxia is a significant symptom.

But having 12% of the asymptomatic group being similarly hypoxic seems like quite a problem to the hypothesis that brain hypoxia is a feature of (a type of) Long covid. I wonder how the authors explain this phenomenon of hypoxia but no symptoms.

Does the mean time after acute infection of only 2.5 months for the asymptomatic people mean that maybe some people were measured quite soon after the acute infection? So, maybe they still had the effects of the acute disease, but were feeling relatively good compared to having the infection? That doesn't sound like a very good explanation to me. But why else would apparently healthy people appear to have hypoxia? Are there problems in the reliability of the measurement approach?

This article gives a bit of background on the technique:
Frequency-domain vs continuous-wave near-infrared spectroscopy devices: a comparison of clinically viable monitors in controlled hypoxia 2017

 

[Hutan]

If I'm understanding correctly the 2017 paper linked above, the technique is ok for identifying changes in brain oxygenation in a person. But, it's not good for saying 'this person clearly has a problem with brain oxygenation and this person doesn't'; it's not good for comparing between people. Perhaps things have improved since 2017. But it is sounding as though the technology may not be good enough for this purpose it has been put to.

Within the specific context of acute TBI care (particularly within a pre-hospital context), decisions regarding brain health and the need for intervention are often required soon after patient contact. Should NIRS be utilised in the clinical decision making process in this tested form little could be derived from the initially extracted parameters. Certainly a trend could be established as to the direction of change in parameters after a period of observation; however without initial validation/calibration (with invasive monitoring or axial imaging) this would not be useful in immediate management. When a baseline level of function/brain health is known (as in cardiac bypass surgery/cardiopulmonary resuscitation) the uncertainty regarding baseline parameters becomes less important and the change in trends observed becomes clinically useful [20, 21]. For any NIRS device to be employed suitably within a TBI context it must be able to clearly distinguish grossly abnormal parameters (such as those related to significant hypoxia) from the expected normal observations of the majority of individuals.

Currently, true quantitatively accurate NIRS parameters have only been obtained within breast tissue [22], utilising a diffuse optical tomographic (DOT) array. These techniques involve large (clinically impractical) arrays of sources and detectors and parameters are not able to be effectively reconstructed in real time, and still fail to provide absolute quantification in the context of cerebral tissue monitoring [23]. A significant limiting factor in all currently available (clinically viable) NIRS devices is knowledge of spatial priors [24] (specific dimensions of tissue layers), and incorporation of patient specific atlas (MRI) based data may aid in the development of future clinically viable devices that can provide a better quantitative measurement of chromophore concentration within cerebral tissue [25].

I wonder if a measurement of the change in oxygenation when oxygen intake is restricted might be more useful? As in, the healthy oxygenated brain will show a big decrease, but a brain that is already rather de-oxygenated might not show much of a change.

I really want to know if there are differences in brain oxygenation. It feels as though there should be and it would help us know what is going on. I think ME/CFS is a lot like operating at high altitude.

I assume the measurements were done with the participants supine. I wonder what would happen with the participant upright.

 

[SNT Gatchaman]

I assume the measurements were done with the participants supine. I wonder what would happen with the participant upright.

I can't access this paper, so can only go on the above summary. I would like to read it though. I had the same question: how the measurements were taken: lying, sitting, standing? When I did this test, looking at frontal lobe saturations I had a 10% drop from lying to standing within a minute.

But having 12% of the asymptomatic group being similarly hypoxic seems like quite a problem to the hypothesis that brain hypoxia is a feature of (a type of) Long covid. I wonder how the authors explain this phenomenon of hypoxia but no symptoms.

We know that many people report full recovery from acute covid, only to develop LC 2 or 3 months down the line. Perhaps the 12% in the "asymptomatic" group are "not yet symptomatic".

Alternatively, the Perth (/Imperial/Addenbrooke's) pheno-metabolomics team have been indicating that post Covid, there are major metabolic changes, which may be affecting cardiovascular performance even at a subclinical/asymptomatic level. Eg even back in 2020: Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection (2020, Journal of Proteome Research) —

Key discriminant metabolites included markers of inflammation including elevated α-1-acid glycoprotein and an increased kynurenine/ tryptophan ratio. There was also an abnormal lipoprotein, glucose, and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides), plus multiple highly significant amino acid markers of liver dysfunction (including the elevated reduced glutamine/glutamate and Fischer’s ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern.

A multivariate training-test set model was validated using independent samples from additional SARS-CoV-2 positive patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems.

It is of note that in a 12-year follow-up study on patients who had recovered from the original SARS-CoV-1 infection that 68% had hyperlipidemia and 44% had cardiovascular abnormalities and 60% had disorders of glucose metabolism disorders.

In this relatively small study on COVID-19 patients, we have used an array of technologies to probe the profound metabolic alterations that accompany the disease [...] the metabolic models and markers detected in this study are unusually strong and highly distinctive of a multisystem involvement, consistent with the reported extensive microvascular effects that would be expected to compromise multiple organ functions.

Taken collectively, our data present a complex pattern of disturbance of systemic metabolism caused by SARS-CoV-2 viral infection associated with multiple organ specific changes that are not simply related to the primary respiratory symptoms. These studies indicate the potential importance of [...] identify those who might have newly acquired metabolic diseases of the type described here. Such problems would inevitably complicate the patients’ recovery and should be addressed and managed as early as possible to help avoid long-term complications of the type that are have been recently described as “long COVID disease”.

 

[Hutan]

When I did this test, looking at frontal lobe saturations I had a 10% drop from lying to standing within a minute.

That sounds like quite a lot. In that 2017 paper, oxygen saturations dropped 15% from baseline when the participants had oxygen restriction similar to being 5000 m above sea level. That's just a bit less than the altitude where supplementary oxygen is typically used (and that's after a careful acclimatisation process to the lower oxygen levels, conducted over days).

For sure there is something weird going on with blood supply. Yesterday my son was doing a trick where he held his arm up and it would immediately blanch white, and then turn grey, as if it was dead. It was as if there was a tap and the blood was gushing out of the arm into the body. Then he would lower the arm and it would rapidly turn bright red. If that is happening in an arm, it would not be at all surprising that oxygen supply is not right in the brain either.