What causes Fatigue in Long Covid?

And what can we do about it?

One of the most prevalent symptoms of Long Covid is Fatigue.

Whenever you talk to anyone suffering from Long Covid, they almost always raise this symptom as one of their main issues, as well as the often accompanying symptom of post-exertional malaise (PEM).

Fatigue and PEM are really the most insidious symptoms that occur in Long Covid, because they rob people of their quality of life.

Heart rate issues and shortness of breath are also both hard, but they can be managed.

Fatigue and PEM prevent you from doing ANYTHING, and make living life hard even when you do try to manage them.

So today I want to examine what causes fatigue in Long Covid. And what some potential solutions are to help people.

But before we start talking about fatigue in Long Covid, I want to talk briefly about the fatigue we feel when we’re generally healthy, so we can talk about how Long Covid fatigue is different.

Normal Fatigue

Just about all of us experience fatigue at least once in a while when we are healthy. This kind of “normal fatigue” is usually temporary and caused by various circumstances in life or by lifestyle issues.

We can be fatigued because we are not sleeping well at night, for a variety of reasons: stress from work or home, excitement for coming events, not being able to gear down at the end of the day, taking care of a sick child (or parent), or just partying hard and enjoying life.

We can be fatigued because we are not eating properly and getting the right balance of nutrients in our diets.

We can be fatigued because of too much physical activity - like a long hike - or too little physical activity - like binge watching our favorite shows on Netflix.

But in all of these cases, the fatigue is temporary and can be overcome by getting some rest and restoring some balance to our life - mentally, emotionally, and physically.

Physiologically, normal fatigue is caused by lack of proper nutrients (or the right combination of them) or exhausting our supplies of energy (ATP) and other required cofactors and other endogenous molecules. Again, this is a temporary situation and energy can be restored by recuperating and taking better care of ourselves.

Long Covid Fatigue

The fatigue that comes with Long Covid is different from normal fatigue.

Long Covid fatigue (LC fatigue) doesn’t just go away by getting more rest. It’s not caused by circumstances or by lifestyle choices.

So what does cause fatigue in Long Covid?

Most of the current data in the literature points to LC fatigue being caused by oxygen deprivation to the tissues of the body.

When red blood cells (RBCs) circulate around the body, they diffuse into the muscle and other tissues to deliver the oxygen carried by hemoglobin.

In Long Covid, this oxygen delivery to the tissues seems to be impaired.

But at what point in the process?

Let’s review how oxygen is transported in the body. Below is a great figure from a recent publication reviewing oxygen exchange for us.

Here are the major steps:

1. The Lungs absorb oxygen and Red Blood Cells (RBCs) in blood pick up the oxygen.

2. Oxygenated blood is pumped around the body through arteries by the heart.

3. In the capillaries that run through our tissues, red blood cells deliver oxygen to muscle and other cells. The red blood cells trade oxygen for carbon dioxide.

4. Deoxygenated blood (carrying carbon dioxide) travels through veins and is pumped back to the lungs to repeat the cycle.

So in Long Covid patients, which step in the process is disrupted to cause poor oxygen delivery, which in turn causes the fatigue?

We all know that Covid has a major impact on the lungs. Are they the problem?

We all know that Long Covid patients have microclots that impair blood flow. Are they the problem?

One way to try to determine which part of the process is the problem is to look at blood oxygen levels.

Most people are familiar with fingertip pulse oximeter meters. Many people (including me) have these at home as a way to check oxygenation when someone is having health issues.

But fingertip pulse oximeter meters mainly measure arterial oxygen levels, before the blood reaches the tissues. Readings from these meters reflect how well the lungs are able to oxygenate the blood.

And in many (even most) Long Covid patients, oxygen levels measured by fingertip pulse oximeter meters are relatively normal. This means that the lungs are properly oxygenating the blood.

Since for most Long Covid patients the lungs are not the problem, that leaves us with microclots as the best explanation for what causes Long Covid fatigue.

The hypothesis is that the microclots physically blockade the capillaries, restricting blood flow and oxygen delivery to the tissues and muscles. We have also seen in past pieces that microclots are “sticky” and red blood cells become bound to the microclots, further restricting the ability of those very red blood cells to deliver oxygen to tissues.

In order to properly detect the low oxygen levels (called hypoxia) caused by a blockage of capillaries by microclots, the venous oxygen saturation has to be measured. This is a more invasive procedure that has to be done by medical professionals. I looked for but could not find any studies that measured venous oxygen saturation in Long Covid patients.

So to summarize, Long Covid fatigue is thought to be caused by microclots blocking the capillaries, which in turn impair oxygen delivery by red blood cells to tissues.

How do we know that microclots impair blood flow in capillaries?

While there are no direct, in vivo studies, there are studies of microclot formation caused by spike protein in microfluidic chambers of roughly the same size and dimensions as human capillary blood vessels. In that work, treatment of blood plasma with Covid spike protein resulted in the formation of disordered and fibrous microclots that covered the bulk of the microfluidic channel and protruded into the center, disrupting fluid flow. (Ref 2)

Link with Post-Exertional Malaise (PEM)

The hypothesis that microclots cause Long Covid fatigue also provides an explanation and mechanism for PEM in Long Covid.

During physical activity, all of the available “oxygen reservoirs” in the tissues like muscle are depleted. And due to the microclots, insufficient oxygen is delivered to that tissue to replace the consumed oxygen.

This acute tissue hypoxia leads to the “crashes” experienced in PEM as well as the need for a long recovery time while the tissues reperfuse and are re-oxygenated.

What can we do to help with Long Covid Fatigue?

We tend to treat normal fatigue with things to either help us wake up or sleep.

Most people use some form of caffeine - from coffee to energy drinks to caffeine pills - to try to stay awake and power through the fatigue until we can catch up on some sleep.

And if the normal fatigue is caused by lack of sleep, we can take everything from melatonin, Tylenol PM, or even sleeping pills like Ambien to make sure we get a proper amount of rest.

But as we have seen here, Long Covid fatigue is different and is the result of poor oxygen delivery to the muscles and other tissues.

None of those standard treatments for normal fatigue will help with Long Covid fatigue.

So what can take to help improve oxygen delivery and blood flow?

That’s the question that I’m working on next. So stay tuned!

Leave me a comment below and let me know what you think.

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Reference

1. The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications. Biochemical Journal 2022, 479, 1653–1708. https://doi.org/10.1042/BCJ20220154

2. SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Bioscience Reports 2021, 41, BSR20210611. https://doi.org/10.1042/BSR20210611