It’s interesting to follow the scientific exploration of a new clinical entity in real time. It reveals a lot about how medical science works, and how scientists nibble away at complex problems. This is partly why I have been closely following the story of long COVID as it has unfolded over the last few years. I also see patients with long COVID so it’s important to my clinical practice as well.
Long COVID, technically known as postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), is a host of symptoms that persist after active infection with SARS-CoV-2 has completely resolved. It is estimated that between 5 and 30% of people who had a COVID infection have some symptoms of Long COVID, which can persist for weeks, or even months or years after the infection. The high range of estimates is due to the heterogeneous nature of the syndrome – what counts as Long COVID? Also, there is great variability is how the syndrome is reported and diagnosed.
There are many potential symptoms, but the most common are fatigue, brain fog, weakness, dizziness, tremor, and GI symptoms. We know that COVID is a multi-system disease (not just respiratory), so it makes sense that many different organ systems can be involved in long COVID. But this does make diagnosis and investigating potential causes difficult. It also lead many early patients to be dismissed as psychogenic, but recognition of long COVID is now standard.
There is still a long list of potential causes of long COVID, including: direct or indirect invasion of the virus into the brain, immune dysregulation, hormonal disturbances, elevated cytokine levels due to immune reaction leading to chronic inflammation, direct tissue damage to other organs, and persistent low-grade infection. Persistent, latent, or reactivation of viral activity has also been proposed. Over the last few years research has been trending toward immune dysregulation, but that is not fully established. It’s likely that there are different causes in different people.
A recent study, for example, has shows that antigens left behind by COVID infection changes the response to cortisol, especially in the brain. This may cause an exaggerated inflammatory stress response.
Diagnosis remains tricky because so far no clinically useful biomarker has been identified. Biomarkers are changes in a measurable parameter (like a blood test of physiological measure) that correlates with existence of an identifiable clinical syndrome. For example, high blood sugar is a marker for diabetes mellitus, and can be used to establish the diagnosis. Long COVID has no such biomarker.
This does not call Long COVID into question, as many recognized clinical entities lack biomarkers (such as migraines). Biomarkers are also especially difficult to establish when the clinical entity is multifactorial or includes many related phenomena. Long COVID, in other words, is likely to be more than one thing – different organ systems being affected by the COVID infection in different ways.
There is also a bidirectional relationship between biomarkers and understanding the pathophysiology of a clinical syndrome. If we identify a biomarker, that is a clue as to what is causes the symptoms. And if we understood what is causing one or more symptoms that would suggest a potential biomarker to look at. So far we have established neither definitively, so we are still in the exploration phase.
Regardless of our early stage of understanding of long COVID, can it be treated? Yes and no. A recent systematic review of treatments for long COVID found six published trials showing significant improvement of long COVID symptoms with specific treatments. However, these treatments were all symptom-based, not targeting any potential etiology. In other words, if you treat fatigue with stimulants or headaches with analgesics, they may work, but that tells us nothing about the causes of the fatigue or headaches.
The review also found that we are in the early stages of this research, with very heterogeneous results. They conclude: “Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.”
Over the last four years we have seen long COVID go from a clinical observation, often dismissed as psychogenic, to a recognized syndrome that has a huge impact of patient quality of life and ability to function. COVID is a systemic serious infectious disease, and it is no surprise that it potentially leads to post-infectious symptoms (something that is very common with serious systemic infections). We are starting to zero in on potential causes, at least part of which seems to be immune dysregulation following infection. Treatments so far are symptomatic, but can be very helpful and improve quality of life.
But there is a lot of research to be done, and a lot of reporting as this interesting scientific story continues to unfold.
