Copyright 2025 Hillary Johnson. All Rights Reserved.
Part 2. The Problem
For at least thirty-five years, scientists and clinicians have struggled to understand the relationship between hypovolemia and any number of vascular, cardiac and neurological abnormalities common to myalgic encephalomyelitis.
When I searched PubMed combining the terms ‘myalgic encephalomyelitis’ and ‘low blood volume,’ I stopped counting after finding 143 papers on the subject. But there are more. When I searched Google Scholar, I abandoned the task at 413 papers on page 45 of 21,700 results.
Here are links to just five of those papers at the top of the PubMed list (as I write this):
Re: Blood volume correlates with orthostatic hypotension; Cerebral blood volume reduction; Blood volume and cardiac function; Cardiovascular and haematological pathology; Blood volume and its relation to peak (O)2 consumption.
Significant findings have been made but a consensus has yet to form, or to become integrated into the otherwise subjective diagnostic criteria for the disease.
As long ago as the 1980s, in response to an outbreak of the disease in Dunedin, New Zealand—locals dubbed it ‘Poor man’s AIDS’ because research funds were unavailable— an electron microscopy expert, Les Simpson came up with a hypothesis.
Simpson’s expertise was in “hemorheology,” defined as “flow properties” of blood and its components, like plasma and red cells. He posited that the profound physical weakness imposed by myalgic encephalomyelitis might be the result of impaired blood flow through tiny capillaries that comprise the vast majority of the human circulatory system. At any given time, just five or six percent of a body’s blood is in capillaries, but they have an outsize role in carrying oxygen and nutrients to tissues.
Simpson investigated. In 1986 he reported that red blood cells in patients were misshapen. Instead of a healthy disk shape, they were “cup shaped.” The implications were dire. Red cells carry oxygen throughout the body. Impaired flow interferes with oxygen delivery to the brain and other organs, a scenario leading to cell death. Three years later, Simpson compared red blood cells in multiple sclerosis and myalgic encephalomyelitis patients. He found the cup-shaped red cells in both diseases although in ME the percentage was significantly higher. The finding, then, was nonspecific, but surely significant.
It’s always surprising when we see one of these patients who is walking around when their circulatory system looks like they’re in absolute distress.
Michael Feldschuh
Since then, several more researchers have discovered abnormalities in red cells in myalgic encephalomyelitis that suggest transport through capillaries is likely to be impaired. Ron Davis’ group at Stanford was the most recent in 2019 to identify aberrant red cells, which were characterized as “stiff”—too stiff to pass through capillaries. They lacked “deformability”—they could not adapt to changes in the microvasculature.
The Stanford paper, published in the journal Clinical Hemorheology and Microcirculation, concluded: “Our observations suggest that (red blood cell) transport through microcapillaries may explain, at least in part, the ME/CFS phenotype, and promises to be a novel first-pass diagnostic test.”
Red blood cell abnormalities that impair circulation are not necessarily specific to myalgic encephalomyelitis. As Simpson demonstrated in the 1980s, misshapen red cells are also a pathological finding in multiple sclerosis. Sickle cell disease is another, named for the sickle-shaped red cells that characterize it. The list of symptoms caused by red blood cell diseases—shortness of breath, dizziness, pale skin, muscle weakness, and so on, read like a list of myalgic encephalomyelitis symptoms. Many other serious diseases, either recognized as infectious, such as malaria, or with unknown causes, exhibit red cell abnormalities that inhibit the ability of these oxygen-carrying cells to circulate in capillaries.
Red cell abnormalities have led some myalgic encephalomyelitis researchers to speculate that blood may be leaking from capillaries into the extravascular space—the liquid-filled space between organs and cells. In that case, the blood is lost to circulation.
According to Daxor’s Feldschuh and cardiologist Jefferies, myalgic encephalomyelitis sufferers who have undergone the BVA-100 analysis do seem to have a high leak rate.
“Somebody who has an ongoing viral infection that is compromising the integrity of their endothelium—one of the hallmarks of that would be that they would have a high leak rate,” Feldschuh says. “And we have seen that in ME. Their endothelium seems to be compromised. They may feel better with saline infusions, but they find it wears out after a few days or a week or two.”
“The vascular piece is one that does make sense, potentially, if you have constriction at the capillary level,” cardiologist Jefferies adds. “If red blood cells aren’t perfusing right, that could cause local microvascular ischemia.”
The endothelium is a tissue that lines capillaries, veins, and arteries. It is just one-cell thick, yet it is able to control blood flow by several means. Damage to the endothelium caused by pathogens is amply demonstrated by septic shock, the cause of one in five deaths worldwide. The body is overwhelmed by infection, which causes an extreme inflammatory reaction that harms the endothelium and results in blood leakage from capillaries. Malaria is a prominent infectious disease that can result in inflammation leading to septic shock.
By 2022, researchers were were zeroing in on severe endothelial damage in yet another infectious disease: acute Covid-19. A paper that year in Nature called Covid-19 “…a (micro)vascular and endothelial disease.” The authors wrote, “Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction.”
Cautioning that there are “a number of unknowns,” Feldschuh continues, “One of the things I will say about septic patients, and it is corroborative around this theory of ME, is that septic patients are known to have elevated leak rate due to endothelial wall damage. We see this not only in sepsis, but it’s also true of (acute) Covid—they had some of the highest leak rates we’ve ever seen. So, you may say that somebody who has an ongoing viral infection, which is compromising the integrity of their endothelium—one of the hallmarks of that would be that they would have high leak rate.”
So much of the immunology of myalgic encephalomyelitis argues for a viral etiology—is endothelial leakage yet another argument for approaching ME as an infectious disease?
All these patients have something wrong with their homeostatic mechanism.
Michael Feldschuh
Feldschuh and Jefferies have been surprised on occasion by the severity of the vascular leak problem in myalgic encephalomyelitis, which they are able to discern with blood volume analysis.
Their test monitors albumin, an abundant protein in blood that helps to maintain fluid balance and prevent leakage. According to the Daxor website, the test provides a precise measure of “capillary permeability.” Feldschuh notes that by measuring albumin over three blood draws separated by four minutes each, “We can see the rate of the leak from (blood) sample to sample. And using linear regression, we can see the slope of that line. The patient who has a normally functioning intravascular space has a slope that’s very gentle. They tend to lose about point-two percent of their albumin. We have seen ME patients who have a continuous leak rate of point four—which is only really seen in patients that are decompensated with some kind of shock.
“There are many different kinds of shock,” Feldschuh adds, “but an elevated leak rate is one of those forms of septic shock where perfusion acutely matters. So, for us, it’s always surprising when we see one of these patients who is walking around when their circulatory system looks like they’re in absolute distress.”
Feldschuh’s observation reminds me of a woman in a clinical trial organized by David Bell, the New York doctor who identified an outbreak of myalgic encephalomyelitis in his upstate town in 1984. Collaborating with orthostatic hypotension expert William Streeten in the early 1990s, Bell selected nineteen patients and tested them for low blood volume. Twelve of the nineteen, all but two of the women, were hypovolemic.
“Women’s blood loss was twice as severe as men’s,” Bell told me during a conversation several years ago.
One woman met the classification for grade four shock—she was missing forty percent of her blood mass. She wasn’t “walking around.” She reported she was able to stand upright for a few minutes at a time if she wore MAST trousers (“military anti-shock trousers”) that shunted the blood from her lower extremities to her heart and brain. The inflatable trousers, little used today, were designed to keep badly wounded soldiers alive during transport to field hospitals in the Vietnam war.
Surviving myalgic encephalomyelitis involves significant compensatory mechanisms. Surviving as some portion of myalgic encephalomyelitis-injured patients must do, demands extraordinary compensatory responses including, for some, near-total inactivity.
In his 2016 paper, Metabolic features of chronic fatigue syndrome,” (sic) Robert Naviaux, a professor who founded and co-directs the Mitochondrial and Metabolic Disease Center at UC San Diego, described the disease as a hypometabolic state akin to hibernation. Naviaux even compared patients to nematode worms that lay in a dormant state, barely alive, under the ground during harsh environmental conditions. (British psychiatrist Simon Wessely has called myalgic encephalomyelitis patients terrorists. I wonder—is nematodes a bridge too far?) Naviaux referenced a German word, “dauer,” which means long-lived, or persisting. Patients seemed to have the “latent ability” to enter the dauer state, Naviaux wrote, but he also noted that the advantage came “at the cost of significant long-term disability, pain, and suffering.”
There has been substantial misattribution to the causes and drivers of the underlying symptoms.
Michael Feldschuh
“All these patients have something wrong with their homeostatic mechanism,” Feldschuh says. “You have to actually do the [blood volume] test to understand better which direction to pursue, in order to correct the homeostatic position. The question is, What is wrong? And blood volume can answer ‘What.’ But, that doesn’t tell you why. Is it some virus? Some environmental toxin? We don’t know the answer.”
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Very informative. Thank you Hillary. There's no doubt in my mind that this is viral in nature and absolutely unbelievable that nothing has been done about getting to the actual cause for such a serious disease.
One day when this gets solved there is going to be a big come to Jesus on how we were treated... basically while experiencing something akin to sepsis.