The Plasmapheresis Possibility for ME/CFS and Long COVID: Pt. I TPE and INUSpheresis

by Cort Johnson | Mar 8, 2025 | Apheresis, Autoimmune, Homepage, Immune, long COVID, Scheibenbogen, Treatment | 36 comments

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The GIST

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Researchers have been targeting something they don’t know the identify of. They’ve had hits and misses.

It seems soooo enticing! Multiple findings suggest that something in the blood is causing or contributing to ME/CFS, FM and/or long COVID. The easiest answer to that would seem to be to just find a way to wash it out of the blood – and that’s what several groups are trying to do.

It would help, though, if we knew what the mystery substance is. Unfortunately, Ron Davis has said that finding it is not “a trivial matter” (translation – not easy to do) and that has not been achieved yet.

Identifying it would be extremely helpful, though, as it would probably provide a biomarker, and result in a more targeted and effective treatment approach via monoclonal antibodies, inhibitors, T-cell therapy, antigen-specific immunotherapy and others.

Something in the Blood in ME/CFS, Fibromyalgia and Long COVID III: Evidence Builds that Something in the Blood is Causing These Diseases

As it is now, researchers are left with taking a broad-brush approach and are trying to cleanse the blood of all -as Dr. Kaufman put it in an Unraveled episode, “all the garbage that’s built up in it” in hopes of catching “it”.

THE GIST

Multiple findings suggest that something in the blood is causing or contributing to ME/CFS, FM and/or long COVID. The easiest answer to that would seem to be to just find a way to wash it out of the blood – and that’s what several groups are trying to do.
Knowing what the mystery substance is would help a lot, as it would probably provide a biomarker and result in a more targeted and effective treatment approach via monoclonal antibodies, inhibitors, T-cell therapy, etc.
As it is now, researchers are left with taking a broad-brush approach and are trying to cleanse the blood of all manner of possibly pathogenic substances in hopes of catching “it” which brings us to the recent therapeutic plasma exchange (TPE) trial.
The plasma in the blood is targeted because it carries the antibodies, immune complexes, cytokines, and other pathogenic substances.
In a placebo-controlled, randomized, etc., long COVID trial, about two-thirds of the participants plasma was removed and then replaced with albumin repeatedly over several weeks.
Unfortunately, the plasma removal did not produce any results; neither the participants’ symptoms nor their biological factors changed.
While the authors noted that other forms of apheresis (plasma exchange) exist, they proposed that the pathogenic portion of the long COVID patients’ illness either occurred very early or was occurring in the tissues, which the TPE could not reach.
This study does not mean the “something in the blood idea” is dead. In fact, we’re more at the beginning of the plasmapheresis story than the end. The form of apheresis used in this study is just one of the four that might be helpful.
A study assessing a different form of apheresis called INUSpheresis, which filters pathogenic factors out of the blood (instead of removing and replacing the plasma), had much better results. Many pathogenic factors were reduced and the substantial patient improvement occurred.
The knock on the study was that it was not randomized, placebo-controlled, etc., and the authors only reported the findings of those who improved. Still, the study suggested that the right kind of apheresis might work well in long COVID.
Apheresis is not the be-all and end-all. In most autoimmune diseases, apheresis is considered a last-resort treatment—to be used only when other treatments fail. For the time being, we’re kind of stuck with broad blood cleansing efforts in ME/CFS and long COVID, but knowing what the mystery factor in the blood is could give us access to all sorts of more effective, targeted treatments.
Coming up next: the immunoadsorption saga in Germany

The Therapeutic Plasma Exchange (TPE) Long-COVID Trial

The latest effort hailing out of Spain, “Plasma exchange therapy for the post COVID-19 condition: a phase II, double-blind, placebo-controlled, randomized trial“, involved a trial of 50 people who were either given six sessions of therapeutic plasma exchange (TPE) or a sham plasma exchange, and then followed for 90 days.

Plasmapheresis simply refers to the separation of the plasma from the blood. The more or less colorless plasma contains proteins, immune factors (antibodies, cytokines, complement factors, acute phase proteins (CRP)), electrolytes, nutrients (glucose, amino acids, fatty acids, and vitamins), hormones, waste products, clotting factors and enzymes.

In therapeutic plasma exchange (TPE), however, large amounts of the patients’ plasma are removed and then replaced with a substitute fluid, such as donor plasma, albumin or other solutions.

Different types of plasma exchange are possible. The therapeutic plasma exchange used in this study is most commonly used to treat autoimmune, neurological, and blood disorders.

The Big Bust

The TPE trial failed on all counts: neither symptoms or biological factors improved.

Functional status, symptomology, quality of life, and cognitive scores did not improve in individuals who received TPE compared to placebo, overall or in any subdimension evaluated.

Nor did any of a wide variety of biological factors (hematocrit, CRP, ALT, GGT, ferritin, creatinine, triglycerides, LDH, INR, bilirubin, aspartate aminotransferase, antimitochondrial antibodies, anti-smooth muscle antibodies, anti-parietal cell antibodies, anti-liver-kidney antibodies (LKM), anti-nuclear antibodies). Even though the authors dug deep to check out clotting, none of the five tests (prothrombin time, fibrinogen, D-dimer, International normalized ratio (INR) and platelet count) were impacted.

The study was a complete wipeout. Six sessions of TPE over three weeks changed nothing. It was as if the patients were replacing their plasma with their own plasma. The “something in the blood” hypothesis seemed to be shot… Or was it?

Is Apheresis (and the “Something in the Blood” Hypothesis) a Bust?

While the authors noted that other forms of apheresis exist, they suggested that the main problem was probably that their TPE was simply applied too late (2 years post-onset). They believe the “key pathogenic events” in long COVID-19 occurred very early or were occurring in the tissues—not the bloodstream. For TPE to work in long COVID-19, it has to be done early.

Of course, that doesn’t jive with the “something in the blood studies,” which have repeatedly found that something in the blood (not the tissues) is causing problems in laboratory animals or lab culture tests.

This study isn’t the end of the plasmapheresis story, either. In fact, we’re more at the beginning of the apheresis than the end. At least four kinds of apheresis could help in ME/CFS, FM, and long COVID. They include:

Therapeutic plasma exchange – removes about 2/3rds of the plasma and replaces it with a substitute
INUSpheresis – filters the plasma of autoantibodies, cytokines, etc. and then returns it to the body
HELP Apheresis – uses high doses of heparin to clean up as many clotting factors as possible – see Patrick Usher’s story
Immunoadsorption – targets and filters antibodies out of the blood.

INUSpheresis – a More Effective Kind of Plasmapheresis for ME/CFS and Long COVID?

Take the recent INUSpheresis long COVID study, which produced far better results using a different kind of apheresis.

Centrifuge vs Filtration

Centrifuge – The Spectra Optia® Apheresis System, that the TPE study used, employed a centrifuge to replace 63-78% of the substances in the plasma with albumin. (Above 78%, side effects kick in and returns diminish.) By doing 6 TPE sessions over three weeks, the researchers should have steadily lowered the amount of pathogenic substances in the long-COVID patients’ plasma. One would have thought that if something in the plasma contributed to their illness, the long-COVID patients would have seen some relief asymptotically and biologically, but neither happened.

Filtration—The INUSpheresis® group used a double-filtration approach that filters the plasma of immune complexes, autoantibodies, cytokines, viruses, and toxins and then returns it to the body. The protocol also includes a naturopathic infusion of acetyl glutathione (an antioxidant) and a vitamin preparation.

Among other things, the INUSpheresis trial reduced the number of clotting factors.

In contrast to the TPE study, the 27-person INUpheresis study found that markers of inflammation declined dramatically (sCRP, IL-1 beta and IL-6; 33%, 48%, and 64%) and so did, by one measure, oxidative stress (H202) (90%). Markers of coagulation (fibrinogen and homocysteine) dropped just as dramatically (70% and 64%) and cholesterol, triglycerides (TG), LDL, and HDL, fell below reference levels. Plus, other factors associated with coagulation (fibrin fibers, rouleaux structures (stacked red blood cells) disappeared.

The INUSpheresis study, on the other hand, was not placebo-controlled and only reported on patients who had improved (!). It was encouraging to see some patients improve (the authors said 70% did), but we need a good study to determine how many benefit.

Since both studies were designed to clear the plasma of pathogenic substances, it’s hard to know why one failed while the other did so much better.

Blood Cleanser: Apheresis in Long COVID and ME/CFS – Does it Work?

In the end, we have two conflicting results. We have a small but rigorous study using a standard TPE procedure, which failed to move the needle in long COVID, and we have a different kind of apheresis that produced much better results in a less rigorous study.

We’re not nearly at the end of the plasmapheresis story. Dr. Ruhoy has said that she’s finding plasmapheresis helpful in some patients, and we still have at least two more types of plasmapheresis to get to: immunoadsorption and H.E.L.P.

Not the Final Answer Anyway…

Time will tell how the different forms of apheresis will perform in diseases like ME/CFS, FM, and long COVID-19, but even if they don’t do well, it’s not the end of the “something in the blood” story.

While therapeutic apheresis is commonly used in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and myasthenia gravis, it is not considered the standard of care for most autoimmune illnesses. A recent review stated that, with the advent of more effective treatments, TPE is now indicated only in severe cases of lupus and rheumatoid arthritis and “catastrophic cases of antiphospholipid syndrome” where other treatments have failed.

Finding the mystery element in the blood could open the door to far more effective treatments.

Conclusion

With no hard and fast answers we turn to immunoadsoprtion – which has been getting quite a run in Germany.

Efforts to cleanse the blood of pathogenic substances are proceeding in ME/CFS and long COVID. Two recent studies indicate (surprise, surprise) that this is anything but a simple process, as several different forms of blood cleansing exist. A recent placebo-controlled, randomized, etc., therapeutic plasma exchange (TPE) study, which removed the plasma and substituted it with something else, did not affect symptoms or biology in long COVID.

The (non-placebo controlled, non-randomized, etc.) INUSphersis trial, which used a filtration process, markedly reduced inflammatory, clotting, etc., findings and improved symptoms. Some doctors have also reported success with plasmapheresis.

Coming up – a different kind of blood cleansing in “The Immunoadsorption Saga in Germany”

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