Long Covid, New Research

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By Mary Carpenter

PREDICTING WHO might be likely to develop “long-haul” symptoms of Covid—disabling fatigue, cognitive problems, pain and shortness of breath—might relieve the biggest worry many people have about the coronavirus. Last week, Seattle researchers described four biological factors linked to higher risk for Long Covid—which could help determine early on which patients should receive Covid treatment, although existing antiviral drugs are currently difficult to procure.

In addition, in tandem with one of the biological factors —high levels of autoantibodies that mistakenly attack the bodies’ own tissues—the researchers found another indicator, low levels of protective antibodies against Covid. Having fewer protective antibodies, even in the fully vaccinated, can mean a poor immune response to Covid in those patients who suffer the virus’s long-term as well as its most virulent effects.

Besides the autoantibodies, another of the four factors linked to Long Covid was high levels of coronavirus RNA, or “viral load,” in the blood early on, which can lead to more severe infection.  Reactivation of Epstein-Barr virus (EBV) was a third factor: Like chickenpox and other herpesviruses, EBV can remain dormant in the body following infection and is present in some 90% of the world’s population. In rare cases, EBV can lead to Guillain Barré— an autoimmune syndrome with symptoms, such as severe fatigue, similar to those of Long Covid.

Type 2 diabetes was the fourth factor, although the researchers cautioned that could turn out to be only one of several medical conditions associated with Long Covid. In addition, sufferers with long-haul respiratory problems had low levels of the stress hormone cortisol either caused by the steroids given to treat infection-related lung damage or because adrenal glands are among the organs targeted by the coronavirus. According to ZRT Laboratory, diminished cortisol can lead to chronic health problems like fatigue.

Looking at 20 possible symptoms of Long Covid in more than 200 patients two to three months after infection, the Seattle researchers found one to two Long Covid symptoms in 24%—and three or more symptoms in 37%, among whom almost all had one or more of the four biological factors. The most influential of these factors, the autoantibodies, occurred in two-thirds of the Long Covid cases.

Outside commentators noted possible weaknesses in the Seattle research, which was conducted at several universities and centers, including the Institute for Systems Biology, Swedish Medical Center and the University of Washington—such as the relatively short two-to-three-month follow-up. Another was the high number of patients who had been hospitalized, which made untangling the effects of different variables more complicated. In the Seattle patient group—ranging in age from 18 to 89—more than 70% had been hospitalized with the initial infection.

But a different study at the University of Washington found similar biological factors in a group of 100 patients that included many with mild infections—and used data from 457 healthy people as comparison. “The [four-factors Seattle] study is large and comprehensive and is a great resource for the community studying Long Covid,” said Yale immunologist Akiko Iwasaki.

Autoantibodies or “rogue” antibodies—responsible for autoimmune diseases like lupus—can disable immune system proteins and attack other organs affected by Covid, explained David Lee at New York University Langone Health. Although women with Covid infections have less severe symptoms and fewer deaths, they experience long-haul difficulties at more than four times the rate of men. (Women are also more likely to have autoimmune diseases, such as lupus, MS and rheumatoid arthritis.)

Along with the high autoantibody levels, the high viral load and low levels of protective Covid antibody levels together contribute to long-haul symptoms. Iwasaki told the New York Times: “The quicker one can eliminate the virus, the less likelihood of developing persistent virus or autoimmunity, which may drive Long Covid.”

A similar, so-called “immunoglobulin, signature,” proposed by Zurich researchers, includes having asthma along with low pre-infection blood levels of protective antibodies — which together indicate greater risk of Long Covid as well as of reinfection with the virus. University Hospital Zurich immunologist Carlo Cervia told The Guardian: “People with asthma and low [protective antibody] levels can assume they are at an increased risk for Long Covid.”

To what degree vaccination might protect against Long Covid is unclear —with mixed results from the few studies that investigated the question, especially for the omicron variant, Iwasaki told Nature. In an Israeli study of more than 3,000 participants, those fully vaccinated with the Pfizer-BioNTech vaccine were 54% less likely to report headaches, 64% less likely to report fatigue and 68% less likely to report muscle pain than their unvaccinated counterparts.

But if recovering quickly from Covid infection means less risk of long-haul symptoms, the two antiviral medications “supposed to be an important weapon against the pandemic in the U.S.” are in short supply, according to TIME magazine. And of the two, the “pill considered to be far superior, Pfizer’s, takes six to eight months to manufacture…[now] being carefully rationed, reserved for the highest-risk patients.”

But a positive benefit of the new Long Covid findings may affect investigators of long-haul Lyme disease. Symptoms common to both include disabling fatigue; cognitive problems that include difficulty focusing; and pain. Respiratory problems that occur with Long Covid, on the other hand, are not typical of those with long-haul Lyme. Posted last May on the Johns Hopkins Lyme Disease Research Center site: “We are hopeful that the tremendous resources for long-haul Covid research could help accelerate Lyme disease knowledge and treatments as well.”

—Mary Carpenter keeps track of news on the Covid-19 front.