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Searching for Clues in Long COVID – A Mystery to Be Solved

Someone pulling a giant germ representing the symptoms of long COVID

Millions of people around the world have now been infected with the COVID-19 virus. The vast majority have weathered various symptoms for a period of time and returned to normal function. Of course, that has not been the case for many who became severely ill and succumbed to their infection, and it’s also not the case for millions of others who have persistent symptoms lasting months to years. Known as long COVID, these individuals suffer a lasting effect of COVID-19 that resists conventional treatments. Certainly, some clues exist that suggest why these symptoms of long COVID persist. But researchers are far from knowing precisely why some people get it and others don’t.

Someone with the symptoms of long COVID
The symptoms of long COVID persist, and represent a grave health concern for many.

When it comes to the lasting effect of COVID-19 in these patients, there appears to be some additional insult that occurs. Routine examinations and tests reveal nothing in particular such as persistent viral infection, pneumonia or even examination abnormalities. Despite this, several symptoms of long COVID remain, preventing people from leading a normal life. Recent evidence now suggests that these specific patients suffer from additional effects from the virus involving different physiological systems. But defining exactly what these effects of COVID-19 has remained a challenge. And defining treatments in these cases are even more difficult as a result. Revolutionary healthcare improvements are needed.

(Thankfully, 2022 did produce some revolutionary improvements in healthcare–read about it in this Bold story.)

“Clearly, there’s something going on that’s interfering with that normal [physiological] response [in long COVID].” – Dr. Stephen J. Carter, Exercise Physiologist, Indiana University, Bloomington School of Public Health

A Typical Profile of Long COVID

Unlike most who contract the coronavirus, those with symptoms are long COVID are notably different. Common symptoms include a persistent shortness of breath that worsens with activity. Fatigue, headache, depression, and joint pains are also usually present. But according to researchers, the most telltale symptom is that of exercise intolerance and feeling worse after exercise. In fact, providers have a name for the condition called post-exertional malaise. Instead of physical activity building stamina and endurance, this lasting effect of COVID-19 manifests as just the opposite. Some providers believe exercise may actually be detrimental to individuals who have long COVID.

Other symptoms of long COVID may also exist and last many months, years, or even indefinitely. Some patients describe chest pain, persistent nausea, and brain fog. Others will also complain of disrupted sleep that makes their existing fatigue even worse. Understanding this, it seems like some type of multi-organ or systemic process accounting for the effect of COVID-19 in these patients. But routine blood work, x-rays, and physical examination fail to reveal any abnormalities at all. Naturally, this leaves many individuals frustrated and searching for answers for which few thus far are available.

“The research that I’ve done has shown that inability to exercise is one of the most common long-term symptoms.” – Dr. Natalie Lambert, Biostatistician and Health Data Scientist, Indiana University School of Medicine

Key Clues in the Long COVID Investigation

Given the lack of findings by routine investigations, scientists and researchers are trying to dig a little deeper. One of the first clues about the cause of long COVID involves some of the similarities it shares with other conditions. Specifically, it mimics chronic fatigue syndrome in many ways, which is why some believe there may be a common mechanism. Though a precise etiology of chronic fatigue syndrome is not known, many have poor vascular responses to exercise. As it turns out, those with symptoms of long COVID have similar phenomena. Because of this, some suspect a lasting effect of COVID-19 on vascular endothelial cell function.

A cartoon of someone fighting the effect of COVID-19
What has COVID taught us? That winning the initial battle doesn’t necessarily mean we’ve won the war.

Another seemingly important clue to the cause of long COVID involves blood pressure regulation. Known as postural orthostatic tachycardia syndrome, or POTS, many patients with long COVID present with this. The condition involves an inability for the body to adjust blood pressure when going from sitting to standing. As a result, individuals get dizzy and may even pass out briefly. Here again, this effect of COVID-19 might be due to vascular dysfunction. Or some suspect it may be problems with nervous system regulation of heart rate and blood pressure responses. Either way, these findings support that the effect of COVID-19 in these people are more extensive than most.

“There are both patients and doctors who are vehemently against any exercise…If you can get the patient in a better place with medications, then you can embark on a graded exercise program without precipitating crashes.” – Dr. David Systrom, Pulmonary and Critical Care Physician, Brigham and Women’s Hospital, Boston

Living with Long COVID

Someone dodging the effect of COVID-19
One lasting effect of COVID-19 will likely be the caution we all need to observe.

The trouble with having symptoms of long COVID is not just the vast array of problems experienced. It’s also finding consistent recommendations on how to cope with these complaints. Because the cause of the lasting effect of COVID-19 in these individuals is not fully known, different opinions about management exist, many providers have encouraged exercise training and activity, but this often leads to worsening problems. Others have prescribed diets, immune stimulants, probiotics and even antidepressants in hopes of improving symptoms of long COVID. But these have proven to be inconsistent as well, helping some while making others feel worse. And of course, there’s always the frustration of not knowing why one feels so poor in the first place.

At the current time, experts in long COVID research call for individualizing care. Based on limited experience, it seems different patients respond to different interventions. One of the most common ones used for symptoms of long COVID is termed pacing. Pacing refers to gradually advancing activity as tolerated while avoiding post-exertional malaise. Not only can this be used to improve physical stamina and fatigue but also to help with brain fog and memory loss. Other treatments are more symptomatic in nature based on specific patient complaints. In this regard, current management appears to be mostly trial and error. Until further research can delineate whether specific approaches are effective, this is the best science currently has to offer.

Directions of Future Research 

It is currently estimated that 65 million people have symptoms of long COVID in the world today. Likewise, estimates suggest about 10% of those with COVID actually feel the effect of COVID-19 long-term. Certainly, there are clues that suggest damage to vascular and nervous systems may occur with these conditions. But at the same time, others suspect immune system insults and injury to the microbiome as also being important. Without question, these are the areas that will need more extensive research. But based on the number of individuals affect, such investigations should be prioritized in the coming years.


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