Virus World

"Identifying these PASC factors is a major step forward for not only understanding long COVID and potentially treating it, but also which patients are at highest risk for the development of chronic conditions," said ISB President, Dr. Jim Heath, co-corresponding author of a research paper that will be published by the journal Cell. "These findings are also helping us frame our thinking around other chronic conditions, such as post-acute Lyme syndrome, for example." Additionally, researchers found that mild cases of COVID-19, not just severe cases, are associated with long COVID. They also suggest that administering antivirals very early in the disease course may potentially prevent some PASC. "Long COVID is causing significant morbidity in survivors of COVID-19, yet the pathobiology is poorly understood," said Dr. Jason Goldman, co-corresponding author of the paper and an infectious disease expert at Swedish. "Our study pairs clinical data and patient-reported outcomes with deep multi-omic analyses to unravel important biological associations that occur in patients with PASC. Certain findings such as the low cortisol state in patients with long COVID have potential to translate rapidly to the clinic. Our results form an important foundation for the development of therapeutics to treat long COVID." Researchers collected blood and swab samples from 309 COVID-19 patients at different time points to perform comprehensive phenotyping which was integrated with clinical data and patient-reported symptoms to carry out a deep multi-omic, longitudinal investigation.

A key finding from the study deals with viral load, which can be measured near diagnosis to predict long COVID symptoms. "We found that early blood viral measurements are strongly associated with certain long COVID symptoms that patients will develop months later," said Dr. Yapeng Su, a co-first and co-corresponding author of the paper. In addition, researchers found the Epstein-Barr virus (EBV) -- a virus that infects 90 percent of the human population and is normally inactive in the body after infection -- is reactivated early on after SARS-CoV-2 infection, which is significantly associated with future long COVID symptoms. "This may be related to immune dysregulation during COVID-19 infection," Su added. The team also found that PASC is anticipated by autoantibodies (which associate with autoimmune diseases like lupus) at diagnosis, and that as autoantibodies increase, protective SARS-CoV-2 antibodies decrease. This suggests a relationship between long COVID, autoantibodies and patients at elevated risk of re-infections. "Many patients with high autoantibodies simultaneously have low (protective) antibodies that neutralize SARS-CoV-2, and that's going to make them more susceptible to breakthrough infections," said Daniel Chen, a co-first author of the paper. The research project was a collaboration between ISB, Providence, Swedish the University of Washington, Fred Hutchinson Cancer Research Center, Stanford, UCLA, UCSF, and others.

Cited Research Published in Cell (Jan. 2022):

https://doi.org/10.1016/j.cell.2022.01.014 

The new Long Covid project began in late 2020, when Yale University immunologist Akiko Iwasaki teamed up with David Putrino, a neurophysiologist at the Icahn School of Medicine at Mount Sinai who was caring for affected patients. The pair wanted to compare those patients with people who had never been infected—and those who had recovered. To Putrino’s surprise, “It was quite challenging to find people who were fully recovered from COVID.” Many post–COVID-19 volunteers described themselves as healthy but then admitted, for example, that their once-normal gym workouts were too exhausting to resume. In the end, the team signed on 39 COVID-19–recovered volunteers among a total of 116 controls. The low cortisol levels in the Long Covid patients, about half of normal levels, aren’t a total surprise: Symptoms such as fatigue and muscle weakness are associated with less of the hormone. The cause remains a mystery. ACTH, a hormone made by the pituitary gland that controls cortisol production, was at normal levels in the Long Covid group. Furthermore, note Putrino and others, some Long Covid patients outside the study have tried short courses of steroids, which can treat low cortisol, but say they haven’t helped. Next, the researchers plan to track cortisol levels throughout the day in Long Covid; the steroid rises and falls on a daily cycle, and the initial research only tested it in the morning.

The Long Covid blood samples were also awash with a category of “exhausted” T cells that can be recognized by certain markers they express. Such cells surge in the ongoing presence of pathogens—suggesting “the bodies of people with Long Covid are actively fighting something,” Putrino says. This battle would produce chronic inflammation, which matches many Long Covid symptoms. By measuring levels of antibodies against viral proteins released in the blood, the study also noted reactivation of Epstein-Barr virus and other herpesviruses whose genes can sit dormant inside infected cells for extended periods. Iwasaki was intrigued to learn that degree of T cell exhaustion appeared to track with Epstein-Barr virus reactivation, though she doesn’t consider that virus the only potential culprit. SARS-CoV-2 may linger in Long Covid patients, too, she and others say. Epstein-Barr reactivation, low cortisol, and T cell exhaustion have all turned up in some ME/CFS patients. Long Covid is far from uniform, the new study makes clear—for example, only about 20% to 30% of the study’s patients had very high levels of exhausted T cells. But, “The level of consistency is great” among recent studies probing Long Covid biology, says James Heath, president of the Institute for Systems Biology, an author of the Cell paper that found low cortisol and virus reactivation. He notes that his group’s study examined patients about 3 months after SARS-CoV-2 infection, whereas Iwasaki and Putrino’s cohort was on average more than a year out from their COVID-19. Putrino and Iwasaki say it’s time to forge ahead with new trials of potential therapies, which could also elucidate Long Covid’s causes and whether subsets of patients are more likely to respond to certain interventions. Iwasaki’s experimental therapy wish list is long and includes cortisol supplementation; Epstein-Barr virus–targeting therapy; the antiviral drug Paxlovid, now used for acute COVID-19; and even therapies that deplete B cells, which are used to treat autoimmune disease and calm the immune system. “We should be trying these right now,” Iwasaki says. “As a basic scientist, of course I’d like to have all the pieces of the puzzle” before launching trials. “But the patients, they can’t wait.”