Long Fatigue: The exhaustion that lingers after an infection

A third idea which Putrino and others have been studying, is related to impaired waste clearance. Working overtime means that mitochondria generate a lot of oxidative stress, yet the body is unable to adequately clear up after itself, because the immune system is in a state of prolonged exhaustion after battling the virus. This in itself may contribute to physical symptoms such as brain fog and muscle fatigue, impacting the ability to move and function normally. One study even showed that long Covid patients have an accumulation of toxic waste products in their muscle fibres.

Because of all this, an approach known as “pacing”, by which patients attempt to slowly work their way back to normal levels of physical activity by progressively pushing themselves to do more and more, does not always work. In some Lyme disease, ME/CFS and long Covid patients, their underlying dysfunction means that pacing can actually make them worse.

“Long Covid patients need to achieve some improvement in functional status by virtue of medication before embarking on any form of graded exercise,” says David Systrom, a pulmonologist at Brigham & Women’s Hospital.

But finding the right medication involves identifying the underlying cause of their symptoms.

A possible solution

Over several decades of studying people with ME/CFS, Betsy Keller, a professor in the department of exercise and sport sciences at Ithaca College in New York, has heard the phrase “mitochondrial dysfunction” cited repeatedly as a possible cause of their prolonged fatigue. However, she says the key question is what is causing the mitochondria to be impaired.

In some cases of post-viral fatigue stemming from Ebola, Zika and influenza viruses, research has suggested that the cause is direct viral damage to mitochondria DNA. Studies delving into possible mechanisms have found that viral invasion can inhibit the production of phosphocreatine, a crucial chemical in the energy creation process. But there are other cases where mitochondria may simply be suffering from a lack of oxygen.

Sars-CoV-2 and other viruses appear to be capable of driving the formation of micro-clots, tiny particles which move through blood vessels entrapping various proteins and impairing oxygen flow, while in other cases, viral damage can affect normal heart rate, respiratory function and blood flow.

If the mitochondria can’t get enough oxygen to function normally, Keller says that the body shifts to anaerobic energy production, a means of generating energy which is usually only required for short, intense bursts of activity such as sprinting at high speed. “When this shift towards anaerobic energy production occurs prematurely during low-level exertion, even simple activities of daily living will result in fatigue,” says Keller.

At Mount Sinai, Putrino is now leading a clinical trial looking at whether an enzyme called lumbrokinase, which breaks down fibrin, a protein which is thought to be at the core of micro-clots, can help improve mitochondrial function and energy levels in long Covid and ME/CFS patients.