Around 5–10% of people with COVID infections go on to experience long COVID, with symptoms lasting three months or more.

Researchers have proposed several biological mechanisms to explain long COVID. However, in a perspective article published in the latest Medical Journal of Australia, we argue that much, if not all, long COVID appears to be driven by the virus itself persisting in the body.

Since relatively early in the pandemic, there has been a recognition that in some people, SARS-CoV-2 – or at least remnants of the virus – could stay 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 people’s bodies is now well established, what remains less certain is whether live virus itself, not just old bits of virus, is lingering – and if so, whether this is what causes long COVID. This distinction is crucial because live virus can be targeted by specific antiviral approaches in ways that “dead” viral fragments cannot.

Viral persistence has two significant implications:

1. when it occurs in some highly immunocompromised people, it is thought to be the source of new and substantially different-looking variants, such as JN.1

2. it has the potential to continue to cause symptoms in many people in the wider population long beyond the acute illness. In other words, long COVID could be caused by a long infection.

What does the research say?

While there remains no single study that confirms that persistent virus is the cause of long COVID, collectively several recent key papers make a compelling case.

In February, a study in Nature found a high number of people with mild COVID symptoms had extended periods of shedding the genetic material of the virus, so-called viral RNA, from their respiratory tract. Those with persistent shedding of this viral RNA – which almost certainly represents the presence of live virus – were at higher risk of long COVID.

Other key papers detected replicating viral RNA and proteins in blood fluid of patients years after their initial infection, a sign that the virus is likely replicating for long periods in some hidden reservoirs in the body, perhaps including blood cells.

Another study detected viral RNA in ten different tissue sites and blood samples 1–4 months after acute infection. This study found the risk of long COVID (measured four months following infection) was higher in those with persistently positive viral RNA.

The same study also gave clues about where in the body the persisting virus resides. The gastrointestinal tract is one site of considerable interest as a long-term viral hideout.

Earlier this week, further evidence of persistent virus increasing likelihood of long COVID has been published as part of the RECOVER initiative, a collaborative research project that aims to address the impacts of long COVID.

However, formal proof that virus capable of replicating can last for years in the body remains elusive. This is because isolating the live virus from reservoirs inside the body where the virus “hides” is technically challenging.

In its absence, we and other scientists argue the cumulative evidence is now sufficiently compelling to galvanise action.

What needs to happen next?

The obvious response to this is to fast-track trials of known antivirals for prevention and cure of long COVID.

This should include more left-field therapies such as the diabetes drug metformin. This has possible dual benefits in the context of long COVID:

However, another major thrust should be the development of new drugs and the establishment of clinical trial platforms for rapid testing.

Science has uncovered exciting therapeutic options. But translating these into forms usable in the clinic is a large hurdle that requires support and investment from governments.

Demystify and preventing long COVID

The notion of “long infection” as a contributor or even the driver of long COVID is a powerful message. It could help demystify the condition in the eyes of the wider community and increase awareness among the general public as well as medical professionals.

It should help raise awareness in the community of the importance of reducing rates of re-infection. It is not just your first infection, but each subsequent COVID infection carries a risk of long COVID.

Long COVID is common and isn’t restricted to those at high risk of severe acute disease but affects all age groups. In one study, the highest impact was in those aged 30 to 49 years.

So, for now, we all need to reduce our exposure to the virus with the tools available, a combination of:

• clean indoor air approaches. In its simplest form, this means being conscious of the importance of well-ventilated indoor spaces, opening the windows and improving airflow as COVID spreads through air. More sophisticated ways of ensuring indoor air is safe involve monitoring quality and filtering air in spaces that cannot be easily naturally ventilated

• using high-quality masks (that are well-fitting and don’t let air in easily, such as N95-type masks) in settings where you don’t have confidence of the quality of the indoor air and/or that are crowded

• testing, so you know when you’re positive. Then, if you’re eligible, you can get treatment. And you can be vigilant about protecting those around you with masks, staying at home where possible, and ventilating spaces

• staying up to date with COVID booster doses. Vaccines reduce long COVID and other post-COVID complications.

Hopefully one day there will be better treatments and even a cure for long COVID. But in the meantime, increased awareness of the biomedical basis of long COVID should prompt clinicians to take patients more seriously as they attempt to access the treatments and services that already exist.

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