Recent studies suggest that 5 to 10% of individuals infected with COVID-19 experience long COVID, with symptoms lasting three months or longer. Researchers have proposed various biological mechanisms to explain this phenomenon. However, a perspective article published in the latest Australian Medical Journal asserts that a significant portion, if not all, of long COVID cases may be attributed to the persistence of the virus itself in the body.
Since the onset of the pandemic, it has been recognized that in some individuals, SARS-CoV-2—or at least remnants of the virus—could remain in various tissues and organs for extended periods. This theory is known as 'viral persistence.'
While the long-term presence of residual viral fragments in some individuals is now well established, it remains uncertain whether the live virus itself, and not just old viral fragments, persists—and if so, whether this is what causes long COVID.
This distinction is crucial because living viruses can be targeted by specific antiviral approaches, unlike 'dead' viral fragments.
Viral persistence has two significant implications:
Although there is no study confirming that a persistent virus is the cause of long COVID, several recent key articles collectively present compelling arguments.
In February, a study published in Nature found that many individuals with mild COVID symptoms had prolonged periods of shedding the virus's genetic material, known as viral RNA, from their respiratory tracts. Those who exhibited persistent shedding of this viral RNA—almost certainly indicating the presence of a live virus—were at a higher risk for long COVID.
Other key articles detected viral RNA and proteins in the blood of patients years after their initial infection, suggesting that the virus likely replicates for extended periods in certain hidden reservoirs within the body, possibly including blood cells.
Another study detected viral RNA in ten different tissue sites and blood samples one to four months after acute infection. This study revealed that the risk of long COVID (measured four months after infection) was higher in individuals with persistent positive viral RNA.
The same study also provided clues about where the persistent virus resides in the body, with the gastrointestinal tract being of considerable interest as a long-term viral hideout.
Earlier this week, further evidence of persistent virus increasing the likelihood of long COVID was published as part of the RECOVER Initiative, a collaborative research project aimed at addressing the impacts of long COVID.
However, formal proof that a replicating virus can persist for years in the body remains elusive. Indeed, isolating the live virus from reservoirs inside the body where it 'hides' is technically challenging.
In the absence of such proof, we and other scientists argue that the accumulated evidence is now sufficiently compelling to galvanize action.
The obvious response to this situation is to accelerate trials of known antivirals for the prevention and treatment of long COVID.
This should include more out-of-the-box therapies such as metformin, a diabetes medication, which may offer dual benefits in the context of long COVID.
Moreover, another major goal should be the development of new drugs and the creation of clinical trial platforms for rapid testing.
Science has uncovered exciting therapeutic options. However, translating this information into usable clinical forms poses a significant hurdle that requires support and investment from governments.
The notion of 'long infection' as a contributor, or even driver, of long COVID is a powerful message. It could help demystify the illness in the eyes of the broader community and raise awareness among the general public as well as healthcare professionals.
This should contribute to increasing awareness of the importance of reducing reinfection rates. It’s not just about your first infection; every subsequent COVID infection carries a risk of long COVID.
Long COVID is common and not limited to those at high risk of severe acute illness; it affects all age groups. In one study, the highest impact was observed in individuals aged 30 to 49.
Therefore, for now, we must all reduce our exposure to the virus using available tools, a combination of:
Hopefully, one day there will be better treatments and even a cure for long COVID.
But in the meantime, increased awareness of the biomedical foundations of long COVID should encourage clinicians to take patients more seriously when they seek access to existing treatments and services.