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Juan Lama
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Scientists can now spot key differences in the blood of people who have long Covid symptoms— and those who don't. More than three years into the pandemic, the millions of people who have suffered from long Covid finally have scientific proof that their condition is real. Scientists have found clear differences in the blood of people with long Covid — a key first step in the development of a test to diagnose the illness. The findings, published Monday in the journal Nature, also offer clues into what could be causing the elusive condition that has perplexed doctors worldwide and left millions with ongoing fatigue, trouble with memory and other debilitating symptoms. The research is among the first to prove that "long Covid is, in fact, a biological illness," said David Putrino, principal investigator of the new study and a professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai in New York. Dr. Marc Sala, co-director of the Northwestern Medicine Comprehensive Covid-19 Center in Chicago, called the findings "important." He was not involved with the new research. "This will need to be investigated with more research, but at least it's something because, quite frankly, right now we don't have any blood tests" either to diagnose long Covid or help doctors understand why it's occurring, he said. Putrino and his colleagues compared blood samples of 268 people. Some had Covid but had fully recovered, some had never been infected, and the rest had ongoing symptoms of long Covid at least four months after their infection. Several differences in the blood of people with long Covid stood out from the other groups. The activity of immune system cells called T cells and B cells — which help fight off germs — was "irregular" in long Covid patients, Putrino said. One of the strongest findings, he said, was that long Covid patients tended to have significantly lower levels of a hormone called cortisol. A major function of the hormone is to make people feel alert and awake. Low cortisol could help explain why many people with long Covid experience profound fatigue, he said. "It was one of the findings that most definitively separated the folks with long Covid from the people without long Covid," Putrino said. The finding likely signals that the brain is having trouble regulating hormones. The research team plans to dig deeper into the role cortisol may play in long Covid in future studies. Meanwhile, doctors do not recommend simply boosting a person's cortisol levels in an attempt to "fix" the problem... Study published in Nature (Sept. 25, 2023): https://doi.org/10.1038/s41586-023-06651-y
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Juan Lama
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Study implicates lack of key hormone, battle-weary immune cells, and reawakened viruses. An ambitious study of people with Long Covid, the mysterious, disabling symptoms that can trail a SARS-CoV-2 infection, has turned up a host of abnormalities in their blood. The clues add to a body of evidence hinting at drivers of the condition and potential treatments worth testing. They also suggest that, as many scientists and patients have suspected, Long Covid shares certain features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), another condition thought to follow an infection. The new study, posted as a preprint last week, was modest in size, examining just 99 people with Long Covid. “But it went very deep, it went into granular aspects of the T cells, the antibody response,” says Eric Topol, director of the Scripps Research Translational Institute, who was not involved in the work. “This is exploratory, but it’s the foundation for much bigger studies.” The Long Covid patients, most of them struggling with intense fatigue, brain fog, and other symptoms, had low levels of cortisol, a stress hormone that helps the body control inflammation, glucose, sleep cycles, and more. Features of their T cells indicated their immune system was battling unidentified invaders, perhaps a reservoir of SARS-CoV-2 or a reactivated pathogen such as Epstein-Barr virus. Other groups studying Long Covid patients have reported similar results this year, including in a January Cell paper that documented low cortisol in those with long-lived respiratory symptoms, and reactivation of viruses in patients with neurological issues. Collectively, these data “make me think about what other drugs we can test,” such as virus-directed antibodies or targeted anti-inflammatories to tame the immune system, says Emma Wall at University College London and the Francis Crick Institute, who co-leads a large trial of potential Long Covid therapies. 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.”
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Juan Lama
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Low cortisol levels and herpes-virus reactivation are associated with prolonged COVID-19 symptoms, preliminary research suggests. Researchers looking for biological drivers and markers of long COVID have linked the syndrome to herpes viruses, as well as to reduced levels of a stress hormone1. The exploratory study drew both praise and criticism from scientists contacted by Nature. “A major weakness of this paper is the very small sample size,” says infectious-disease specialist Michael Sneller at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland. “I would take with a huge grain of salt all these findings unless they are confirmed in larger studies.” But Danny Altmann, an immunologist at Imperial College London who was not involved in the study, says such reports are exactly what the long-COVID research community needs. “We’re really desperate to work out which drugs to test” for long COVID, he says. “The more studies we have like this, the more it enables us to race off and plan appropriate randomized, controlled trials.” The study, posted on the preprint server medRxiv, has not yet been peer reviewed. The disease that lingers Long COVID consists of a constellation of sometimes debilitating symptoms that last for months or years after a SARS-CoV-2 infection. It is common — affecting anywhere from 5% to 50% of people who contract COVID-19 — but researchers have few clues to its causes. The latest study, led by immunobiologist Akiko Iwasaki at Yale School of Medicine in New Haven, Connecticut, involved performing tests that generated thousands of data points for each of 215 participants in an attempt to reveal key immunological features that distinguish people with long COVID from healthy individuals. The study included 99 people with long COVID — those who reported persistent symptoms after SARS-CoV-2 infection — and 116 healthy participants who had either never had COVID-19 or had recovered after SARS-CoV-2 infection. Most strikingly, the study found that in the long-COVID group, levels of cortisol, a stress hormone that has a role in regulating inflammation, blood sugar levels and sleep cycles, were about 50% lower than in healthy participants. The authors also found hints that in people with long COVID, Epstein–Barr virus, which can cause mononucleosis, and varicella-zoster virus, which causes chickenpox and shingles, might recently have been ‘reactivated’. Both of these viruses are in the herpes family, persist indefinitely in the body after infection and can start to multiply again after a period of quiescence. People in the long-COVID group also had unusual levels of certain types of blood and immune cell, as well as dysfunctional immune cells, suggesting that their immune systems are working overtime. Iwasaki cautions that the results do not suggest that low cortisol levels or herpes viruses cause long COVID, but that their association with the syndrome warrants further study. The findings build on previous reports associating low cortisol levels and Epstein–Barr virus with long COVID, including a Cell paper2 published in March. With only 215 participants, the Iwasaki’s study is relatively small, and only a subset of the participants were included in some parts of the work. For example, in the analysis of cortisol levels, the researchers included all 99 people with long COVID, but only 40 of the 116 healthy people. “The small number of controls compared to the long-COVID group is problematic” because it makes the study less statistically robust, says Sneller, who is leading a separate study on the drivers of long COVID. Iwasaki says that samples were collected from the remaining healthy volunteers later and are being sent for analysis this week. Another limitation of the study is that Iwasaki’s team did not analyse participants’ samples for the presence of the Epstein–Barr and varicella-zoster viruses, instead measuring levels of antibodies against the viruses. Members of the long-COVID group had higher levels of these antibodies than did the healthy people, which suggests a more recent reactivation of the virus, Iwasaki says. However, the only way to determine definitively whether there is current reactivation is to test for viral DNA in the blood. Iwasaki’s team is now running such tests. Her group also plans to test participants’ cortisol levels throughout the day, because the stress hormone’s levels tend to fluctuate, and to examine how immune features vary at different time points after infection. “This is an exploratory, hypothesis-generating study, and clearly not the conclusion to what long COVID is, but it does begin to open doors,” says Iwasaki. Published in Nature (August 25, 2022): https://doi.org/10.1038/d41586-022-02296-5
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