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Long COVID is no stranger to either patients or those immersed in studies of its effects. In the U.S., one in 7 adults–about 14% of the adult population–has experienced symptoms that lasted three months or longer after first contracting the virus. The worldwide estimate for long COVID is 65 million people.

What is less clear–because it’s still so early in the process–is the impact of some of SARS-CoV-2’s most dangerous characteristics on those hit by long COVID. But some researchers are warily watching for the worst: a potential connection to cancer.

No such connection has been established, and the process of learning whether there is one–and to what extent–will rightfully take years. The experts who spoke with me cautioned that most of what they are considering is hypothetical, and the National Cancer Institute did not respond to multiple interview requests.

But in part because of what appears to be SARS-CoV-2’sability to sometimes incite chronic inflammation, among other things, some scientists are wondering whether the same processes through which other viruses contribute to the creation of cancer cells might be in play with COVID-19.

Concerns over chronic inflammation

Viral infections are thought to be responsible for about 15% to 20% of cancer cases globally. And on sheer scale alone–more than 770 million cases worldwide, nearly 7 million deaths, and the ability of some strains to transmit efficiently and evade vaccine- or infection-acquired immunity–SARS-CoV-2 has proven to be a formidable, if yet mysterious, pathogen.

“We don’t really understand the virus quite well, so I can only speculate whether SARS-CoV-2 can lead to cancers,” says Akiko Iwasaki, a professor at Yale School of Medicine and co-lead investigator of Yale’s COVID-19 Recovery Study, which aims to understand changes in the immune response in people with Long COVID after vaccination. “We just don’t know yet what this virus is capable of doing.”

Chronic inflammation, Iwasaki says, “sort of creates a situation for more mutations to accumulate in different cells…and those that proliferate can become cancerous.” Cancer also seldom results from a single event; it typically requires multiple mutagenic events that occur over an extended period.

Cancerous viruses usually establish persistent long-term infections in their host, and they’re good at hiding from the immune system. Further, emerging evidence supports the idea that some people harbor “viral reservoirs,” places in the body where perhaps SARS-CoV-2 or some fragment of the virus might persist. The viral reservoir could be replicating the virus (we don’t have evidence of that in humans, but it was detected in infected macaques), or pieces of viral RNA could be producing proteins or be lying dormant, says Iwasaki.

Even if the remaining pieces of the virus are not infectious, researchers hypothesize that their presence may still be able to alter people’s immune responses in damaging ways. But while we know SARS-CoV-2 RNA persists in many tissues, Iwasaki says, it’s completely uncertain whether that drives the kinds of chronic inflammation that could lead to cancer.

Acutely, COVID-19 can prompt a significant inflammatory response as the body rushes to fight off infection, which can result in immune dysregulation and in severe cases can even lead to a cytokine storm–an uncontrolled release of pro-inflammatory molecules. “The immune system is really stimulated–it’s in hyperdrive,” says Rudolf Jaenisch, a professor of biology at MIT and a pioneer of transgenic science.

Much less is known about the long-term effects, but one theory is that some long COVID patients experience a sort of continuous low-grade inflammation that can contribute to tissue and organ damage. An estimated three out of five people worldwide die from chronic inflammatory diseases such as diabetes, heart issues, cancer, and others, and some researchers now refer to an inflammatory tumor microenvironment, in which cancer cells and surrounding stromal and inflammatory cells engage in reciprocal interactions.

Immunologist Troy Torgerson and his team found evidence of persistent inflammation in the blood of more than half of the 55 unvaccinated adults they studied, each of whom had COVID symptoms lasting at least 60 days. A non-peer-reviewed preprint funded by the NIH found that individuals with Long COVID exhibited systemic inflammation and immune dysregulation eight months following infection (and prior to receiving any COVID-19 vaccine). And others, too, have documented findings of a prolonged inflammatory response among long COVID patients.

Extensive tissue damage, which has been observed both in people with COVID and long COVID (even those without risk factors); chronic inflammation, low levels of oxygen in the tissues, oxidative stress, impaired T-Cell responses, and elevated levels of cytokines are all mechanisms through which, it is postulated, SARS-CoV-2 may increase the risk of cancer development.

“I estimate that chronic inflammation is involved in one way or another in 30% to 50% of cancer-related deaths,” says Michael Karin, a professor at the UC San Diego School of Medicine and expert in mechanisms of inflammation. Adds Julie Overbaugh, professor of biology at the Fred Hutchinson Cancer Center in Seattle, “I think many people probably have very low levels of potential tumor cells in the body that are kept at bay by the immune system. Viruses target this and go after it, like an antagonist to that process of the cell.”

Proinflammatory cytokines are part of the immune response in COVID-19 and scientists believe that some cytokines can augment tumor growth and proliferation. Both interferon and certain cytokines have been found to be elevated in some long COVID patients.

A growing body of evidence suggests that both viral infection and chronic inflammation can be risk factors for cancer and other diseases. None of this is the same thing as saying a patient with Long COVID will head down such a path, but without question, ongoing inflammation is the subject of close scrutiny by those examining the long tail of SARS-CoV-2.

Ziyad Al-Aly, director of the clinical epidemiology center at Veterans Affairs St. Louis Health Care System and a professor at Washington University, said although it’s already known that SARS-CoV-2 causes inflammation and persists in many patients, “I have not seen empiric evidence that (the virus) can lead to cancer yet.” But he added that the possibility can’t be ruled out: “We know cancer formation takes years to manifest.”

Clearly, uncertainty is not in short supply on this topic. Jae Jung, chair of Cleveland Clinic’s Department of Cancer Biology, says, “Most cancer-causing viruses carry a viral oncoprotein that changes cell proliferation and ultimately causes cancer. (With) SARS-CoV-2, I don’t think that the viral proteins carry oncogene activity. Inflammation is not sufficient to cause cancer because it requires a viral oncoprotein.”

Other risks to watch out for

Broadly speaking, viruses can provoke cancer in several ways. Viruses may contain a protein that interferes with oncosuppressors, or cancer fighters. As Aureliano Stingi, a cancer biology expert, explains it, “We have two pedals—the accelerator and the brake. An oncosuppressor is the brake. An oncogene is the accelerator. When you imbalance the two, you end up with cancer.”

Hepatitis B can integrate directly into the genome and impact signaling pathways in the liver, promoting cancerous activity. Hepatitis C does not integrate, but over 20 to 40 years, it can activate pathways that led to inflammation, fibrosis, and cancer. Others, like HIV, don’t cause cancer directly, but can weaken the immune system, potentially allowing tumor cell growth.

MIT’s Jaenisch is among those who believe that SARS-CoV-2 can integrate into the human genome, rarely, affecting perhaps one in 1,000 cells. This work was done in mostly laboratory-infected cultured cells. (Traditional cancer-causing viruses often exert their effects by integrating into one’s genome.)

“The question is, can integration make cancer? I think it’s very unlikely, because you activate only bits and pieces of DNA, small pieces, and they don’t activate anything,” he says. SARS’ ability to integrate into the genome is a subject of significant controversy, and many don’t think that it occurs. 

A few published studies suggest that SARs-CoV-2 may be able to activate cancer-causing pathways, potentially increasing the risk of cancer formation. Studies on the closely related SARS-CoV have implicated viral proteins in the possible degradation of p53 and pRB, which are critical oncosuppressors.

“P53 is definitely one of the prime targets of many viruses in terms of inactivating it, and then that predisposes (a person) for cancer,” says Melanie Ott, a director and senior investigator at the Gladstone Institute of Virology and a professor at UC San Francisco’s department of medicine. But what’s known about SARS-CoV-2 in this area is extremely limited, she says.

Iwasaki is equally cautious. “Most infected cells are bound to die, as opposed to being transformed, proliferating and causing cancer,” she says. “But some infected cells, because of the sort of ways in which our immune systems are set up, kind of go under the radar for elimination. It is possible that in those cells, those oncogenic processes can be triggered. But again, we don’t really know.”

Iwasaki added that SARS-CoV-2 can reduce some of the PacMan-type T cells that usually patrol our body, looking to destroy infected and diseased/cancer cells. The virus has been shown to hide infected cells from detection by these killer T cells, she says. One hypothesis is that with the cops off duty, some cancerous cells might thrive.

The search for usable data

Several studies have documented the reactivation (or awakening) of a dormant Epstein-Barr virus (EBV) in some COVID-19 patients. As EBV is believed to be associated with various cancers, especially lymphoma, this bears watching. Interestingly though, some authors have described unexpected cancer remission in some lymphoma patients who had acute COVID infection.

“I wouldn’t use other coronaviruses as a benchmark,” cautions Overbaugh.” Coronaviruses are usually cleared from the body quickly, are primarily respiratory, and are fairly benign for infection. (But) just because one virus in the family doesn’t do something, it doesn’t always predict that another virus in the family will behave the same.”

At his community oncology clinic in Rock Hill, S.C., Kashyap Patel said that in the post-COVID era he and his partners began to notice a sharp uptick in some rare cancers, and in patients at earlier ages than usual. Further, some patients were presenting with multiple cancers within a short time span, and Patel told me that one commonality was their experience with SARS-CoV-2, either long COVID or multiple exposures.

“We are seeing close to 20% more patients than we did in pre-Covid days,” Patel says, “and the population has not gone up 20% in the area.” Though it’s purely anecdotal at this point, the oncologist is building a database of about 250 likely long-COVID patients, to look through their labs for biomarkers of inflammation and of atypical cancers. Patel’s colleague in India, Shailesh Talati, told me he’s also seen an increase in advanced “unusual cancers” post-pandemic.

At MIT, Jaenisch and others are developing a reporter system that could isolate the cells that carry an integration. The hope is that this will yield further insight into whether SARS-CoV-2 plays a direct role in cancer initiation. “There’s no reason to think so at this point,” he says. “We just don’t know enough about it, but I believe all the evidence is not consistent.”

The search for usable data will continue. Cancer is generally a slow-developing disease and SARS-CoV-2 is, relatively speaking, a new virus. “There’s not great evidence to support SARS-CoV-2 being an oncogenic virus,” says Iwasaki. “But this virus has surprised us over and over.”

Researchers and experts are watching closely for that next surprise. “Even if you imagine that 1% of the people with persistent infection would develop a cancer, the number is huge,” says Stingi. “Hopefully it’s not even 1%. It’s like 0%. That’s why I think we should run some experiments–just to be sure that nothing’s going to happen. Just to be on the safe side.”

This article originally appeared on https://fortune.com/2023/11/23/inside-long-covids-war-body-researchers-trying-find-out-virus-potential-cancer-carolyn-barber/