Rremember While we thought Covid was a disease that only lasted two weeks? So does Michael Peluso, assistant professor of medicine at the University of California, San Francisco.
He remembers the rush to study acute COVID-19 infection and the resulting slew of papers. But Peluso, an HIV researcher, knew what his team excelled at: following people over the long term.
So they adapted their HIV research infrastructure to study Covid patients. The LIINC program, short for “Long-term Impact of Infection with Novel Coronavirus,” began in San Francisco at the very beginning of the pandemic. By April 2020, the team was already seeing patients arriving with lingering illness and the effects of Covid—at the time still unknown and not known as long Covid. They planned to track the course of the disease for three months after infection with the virus.
In the fall, the researchers rewrote their plans. Some people’s symptoms were so persistent that Peluso realized they needed to follow patients longer. published Wednesday in Science Translational Medicine This study draws on years of data. In some cases, the team followed patients for up to 900 days, making it one of the longest studies of long Covid (most studies launched in 2021 or 2022, including the NIH-funded RECOVER program).
The researchers found lasting immune activation months or even years after infection. And, most worryingly, they reported what looked like SARS-CoV-2 virus lingering in participants’ guts. Even those who had had Covid but had no lingering symptoms fared differently than those who had never been infected.
The team’s central idea — hypothesizing in early 2020 that, contrary to popular narrative, Covid would stay in the body — was “visionary,” said Ziyad Al-Aly, a long-Covid researcher. “A lot of people don’t think that way.” Al-Aly was not involved in the study but has published other long-term studies Covid patients. He is responsible for research and development at the VA Saint Louis Healthcare System.
The research uses a new technology developed by the study’s lead authors, Henry Vanbrocklin, a professor in the UCSF department of radiology, and Timothy Henrich, an associate professor of medicine. In recent years, they discovered they could use an antibody that binds to the HIV coding protein as a guide to see viral reservoirs. The HIV antibody, labeled with radioactive isotopes, could be tracked by imaging as it traveled through the body and migrated to infected tissues.
At the start of the coronavirus pandemic, there were no antibodies to latch onto. So Vanbrocklin used a chemical agent, called F-AraG, that binds to activated T cells—immune cells that flood infected tissues. They injected patients with F-AraG and subjected them to a CT scan.
Tissues filled with activated T cells glowed in the resulting image. The researchers found more bright sites of immune activation in people who had been infected with Covid than in those who had not, including: the brain stem, spinal cord, cardiopulmonary tissues, bone marrow, upper pharynx, thoracic lymph nodes and intestinal wall.
In people with long-Covid symptoms, such as brain fog and fatigue, the study found that the intestinal lining and spinal cord lit up more than in other participants. People with persistent lung symptoms showed greater immune activation in their lungs. Intestinal biopsies from five participants revealed what appears to be lingering virus, said Peluso, who is part of the PolyBio Research Foundation’s LongCovid Research Consortium (which helped fund the study).
“The data are striking,” said Akiko Iwasaki, a professor of immunobiology and long-COVID researcher at Yale University. Iwasaki was not involved in the study but is also part of PolyBio’s long-COVID research group.
The researchers used pre-pandemic scans as a control group, “the clearest comparison that exists, before anyone on the planet could have had this virus,” Peluso said. There were 30 participants in total (24 who had had Covid and six controls). The uninfected participants showed some T-cell activation, but it appeared in parts of the body that help clear inflammation, such as the kidneys and liver. In the post-Covid group, immune activation was widespread, even in those who reported returning to normal health.
The data don’t explain exactly what the T cells are responding to. As Iwasaki noted, activated T cells may respond to persistent SARS-CoV-2 antigens or to autoantigens present in people with autoimmune disease. The immune response could also be directed against antigens from other pathogens, such as the Epstein-Barr virus. That question requires further study, she said.
In the gut, the researchers found what they believe to be RNA that encodes the virus’s signature spike protein. Other studies have found similar fragments of the virus in autopsies or within two months of infection. Peluso’s work suggests the virus can remain in the body much longer, up to years after infection.
The researchers don’t know if what they’re seeing is “fossilized” residual virus or active, productive virus. But they have found double-stranded RNA in the intestines of some patients who have had biopsies taken. Technically, that should only be present if a virus is still alive, going through its life cycle, Peluso said.
Scientists and patient advocates have been wary of the post-Covid gut reservoir for some time. This new data could fuel the idea that SARS-CoV-2 lingers in some people’s guts for a long time and could actually be the cause of long Covid. Or, conversely, it could mean that our immune response fails to clear the virus and leaves behind small pieces (which may not be harmful). There are still many questions, Peluso admitted. But the study undermines the paradigm that Covid infection goes away after two weeks and that long Covid is just residual damage.
The results also suggest the need for more aggressive evaluation of immunomodulatory therapies and treatments targeting residual virus.
Most researchers looking for a long-term biomarker for COVID-19 have turned to blood or small pieces of tissue to represent what’s going on inside a patient. With this new imaging technique, Peluso and his team can see an entire person on their screen — a patient’s ghostly silhouette, their wispy organs covered in specks of light. “It’s really striking,” he said. “Oh, my God, this is happening in a person’s spinal cord, or their digestive tract, or their heart wall, or their lungs.”
For patients like Ezra Spier, a member of the LIINC cohort who did an imaging “After the period captured in this latest study, the experience was validated. Finally, the transformative experience of long Covid became visible.”“I can now see with my own eyes the kind of dysfunction that is happening throughout my body,” said Spier, who created a website to make it easier for patients with long Covid to find clinical trials near them.
Most participants had been infected with a pre-Omicron variant of the virus, and one person was infected multiple times throughout the study period. Two participants had been hospitalized during their first bout of Covid, but neither had received intensive care. Half a dozen patients in the study reported no symptoms of long Covid, but nevertheless showed high levels of immune activation.
The study doesn’t explain what the sites of infection mean for symptoms, and immune activation in a particular organ doesn’t correlate with symptoms (for example, a gut full of T cells doesn’t necessarily correlate with gastrointestinal problems). More studies are needed to determine what the bright spots mean for the experience of long Covid patients.
The scans are also not a diagnostic tool. In other words, patients shouldn’t rush to San Francisco (Peluso’s group is only accepting participants from the area). The imaging technique is also not available to the general public. F-AraG is still being studied in that context.
But Peluso and Vanbrocklin believe imaging could be a major tool for understanding long COVID. They have expanded their research program to do imaging on about 50 more patients. They are also looking at people before and after they receive different long COVID clinical trial interventions to see if there is a change in immune activity.