RRemember when we thought Covid was a two-week illness? Michael Peluso, assistant professor of medicine at the University of California, San Francisco, also believes this.
He remembers the rush to research acute Covid infections and the flood of publications that resulted from it. But Peluso, an HIV researcher, knew what his team was good at: observing people over a longer period of time.
So they adapted their HIV research infrastructure to study Covid patients. The LIINC program, short for “Long-term Impact of Infection with Novel Coronavirus,” started in San Francisco right at the beginning of the pandemic. As early as April 2020, the team was introduced to patients with persistent symptoms and the consequences of Covid – at the time still unnamed and unpublished as Long Covid. They planned to follow the course of people’s disease for three months after infection with the virus.
By the fall, the researchers had rewritten their plans. In some people, the symptoms were so persistent that Peluso realized they needed to observe the patients longer. Research published on Wednesday in Science Translational Medicine builds on years of data. In some cases, the team followed patients for up to 900 days, making it one of the longest studies on long Covid (most studies began in 2021 or 2022, including the NIH-funded RECOVER program).
The researchers found long-lasting immune system activation months and even years after infection. And, more worryingly, they reported what looked like residual SARS-CoV-2 virus in participants’ guts. Even in those who had Covid but had no lingering symptoms, the results were different than in those who were never infected.
The team’s big idea – to hypothesize in early 2020 that Covid would persist in the body, contrary to popular belief – was “visionary,” said long-time Covid researcher Ziyad Al-Aly. “Many people don’t think that way.” Al-Aly was not involved in the study, but has other long-term studies of Covid patients. He is director of research and development at the VA Saint Louis Healthcare System.
The research uses a novel technology developed by the study’s lead authors, Henry Vanbrocklin, a professor in the department of radiology at UCSF, and Timothy Henrich, an associate professor of medicine. They discovered over the past few years that they can use an antibody that binds to HIV’s code protein as a guide to detect viral reservoirs. The HIV antibody, labeled with radioactive isotopes, can be tracked with imaging as it moves through the body and migrates into infected tissues.
At the beginning of the coronavirus pandemic, there were no antibodies to bind to. Instead, Vanbrocklin used a chemical called F-AraG, which binds to activated T cells – immune cells that flood into infected tissue. He injected patients with F-AraG and took a scan.
In the resulting image, tissues full of activated T cells glowed. The researchers found more glowing sites of immune activation in people infected with Covid than in people who were uninfected, including: brain stem, spinal cord, cardiopulmonary tissue, bone marrow, upper pharynx, chest lymph nodes and intestinal wall.
In people with long-term symptoms such as brain fog and fatigue, the study found that the intestinal wall and spinal cord were more activated than in other participants. People with persistent lung symptoms showed greater immune activation in the lungs. Intestinal biopsies in five participants appeared to show a persistent virus, said Peluso, who is part of the LongCovid Research Consortium at the PolyBio Research Foundation (which co-funded the study).
“The data are remarkable,” 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 cleanest comparison there is, before anyone on the planet could have had this virus,” Peluso said. There were 30 participants in total (24 who had Covid and six controls). Uninfected participants showed some T-cell activation, but this occurred 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 among those who report returning to their normal state of health.
The data do not explain what exactly the T cells are responding to. As Iwasaki noted, activated T cells can respond to persistent SARS-CoV-2 antigens or autoantigens found in people with autoimmune diseases. The immune response could also be to antigens from other pathogens, such as the widespread Epstein-Barr virus. That part needs further study, she said.
In the intestine, the researchers found what they believe is RNA that encodes the virus’s characteristic spike protein. Other studies have found similar pieces of virus during autopsies or within a few months of infection. Peluso’s work suggests that the virus could remain in the body for much longer – up to years after infection.
The researchers don’t know if what they’re seeing is “fossilized” virus remnants or active, productive viruses. But they did find double-stranded RNA in the guts of some patients who underwent biopsies, which should only be present if a virus is still alive and going through its life cycle, Peluso said.
Scientists and patient advocates have had suspicions about the post-Covid gut reservoir for some time. This new data could reinforce the idea that SARS-CoV-2 stays in the gut for a long time in some people and could actually cause long Covid. Or, on the other hand, it could mean that our immune response is not clearing the virus, leaving behind small pieces (that may not be harmful). There are still many questions, Peluso admitted. But the study undermines the paradigm that says a Covid infection goes away after two weeks and long Covid is just residual damage.
The results also indicate that immunomodulatory therapies and treatments targeting leftover viruses need to be more intensively evaluated.
Most researchers looking for a biomarker for long Covid have relied on blood or small pieces of tissue as a surrogate for what’s going on inside a patient. With the new imaging technique, Peluso and his team can see an entire person on their screen – the phantom figure of a patient and gossamer organs covered in spots of light. “It’s really amazing,” he said. “‘Oh, my goodness, this is happening in someone’s spinal cord, or in their gastrointestinal tract, or in their heart wall, or in their lungs.'”
For patients like Ezra Spier, a member of the LIINC cohort, the had an imaging done After the period covered in this latest study, the experience was affirming. The life-changing experience of Long Covid had finally become visible.”I can now see with my own eyes what kind of dysfunction is going on in my whole body,” said Spier, who created a website for Long Covid patients to more easily find clinical trials near them.
Most participants were infected with a preomicron variant of the virus, and one person had repeated infections throughout the study period. Two participants had been hospitalized during their first bout of Covid, but none of them received intensive care. Half a dozen patients in the study reported no long-Covid symptoms at all but still showed elevated immune activation levels.
The paper does not explain what the infection sites mean for symptoms, and immune activation in a particular organ does not correspond to symptoms (for example, a gut full of T cells may not necessarily be associated with gastrointestinal problems). More studies are needed to find out what the glowing spots mean for patients’ experience of Long Covid.
And the scans are not diagnostic. In other words, patients should not rush to San Francisco (Peluso’s group only accepts study participants from the region). The imaging technology is also not available to the general public. F-AraG is still being studied in this context.
But Peluso and Vanbrocklin said imaging could be an important tool in studying long Covid. They have expanded their research program to do imaging on about 50 more patients. They are also scanning people before and after various clinical trials on long Covid to see if immune activity changes.
