Authors: William A. Haseltine January 2922 Posted July 2022 Forbes

For many Covid-19 patients, the end of the acute stage of infection is only the beginning of another difficult experience: Long Covid. Defined by the persistence of physical and neuropsychiatric symptoms over a period of 12 weeks or longer, the exact causes of long Covid remain largely elusive. A recent analysis by researchers at the University of New South Wales’ Kirby institute and St Vincent’s Hospital Sydney sheds some light on the topic. In long Covid patients they have uncovered evidence of sustained inflammation and activation of the immune response for at least 8 months after initial infection. These findings provide a framework through which to define more accurately and diagnose long Covid.

Phetsouphanh et al. were given a chance to look for “biomarkers” underlying long Covid with help from data gathered as part of St Vincent’s Hospital’s ADAPT study. The study collected blood samples from unvaccinated Australians during the height of the country’s first pandemic wave.

Immune biomarkers are measurable indicators that act as a kind of map key, letting researchers know what processes and responses characterize a certain disease. This study represents the first laboratory analysis of long Covid’s impact on the immune system.

To pin down exactly what’s happening to Covid “long-haulers,” as they’ve come to be known, Phetsouphanh et al. compared the blood samples from the ADAPT study with those derived from healthy donors unexposed to SARS-CoV-2. The ADAPT cohort was made up of individuals with PCR-confirmed Covid-19 infections, tracked over a period of eight months. Blood samples were drawn two months, four months, and eight months after the initial infection. After four months, 31 of a total 147 participants were classified as having long Covid based on the persistence of one of three major symptoms: fatigue, labored breathing, or chest pain. Those exhibiting long Covid symptoms were matched with 31 symptom-free participants of the same trial, used as an additional control cohort.

The team of researchers also compared the blood samples with those of individuals infected with other, non-SARS-CoV-2 human coronaviruses.

“As immunologists we’re almost like detectives at a crime scene. We have thousands of potential biomarkers – or leads – to investigate, but only a handful of them will reveal something useful. We can use some of our knowledge of what’s been measured in acute COVID and other post-viral fatigue syndromes to narrow the investigation down a little bit, but because long COVID is still a new syndrome, we have to take a broad examination of the evidence and look almost everywhere,” says Dr. Phetsouphanh.

Of the 28 potential markers the researchers analyzed, six were noticeably elevated in both the long Covid cohort and the asymptomatic control cohort four months after initial infection. All six were proinflammatory cytokines, signaling proteins that help boost inflammation as part of the innate immune response. Two proinflammatory cytokines stood out as particularly elevated in the Covid cohorts vis-à-vis the other two cohorts: interferon β (IFN-β), and interferon λ1 (IFN-λ1).

The remaining 22 analytes were the same across all four cohorts.

Inflammation is a critical part of recovery, helping the body get rid of the source of damage and helping it repair injured tissue, but too much of it can have unwanted effects. Especially when the inflammation persists beyond any actual outside threat.

Professor Gail Matthews, the study’s senior researcher, mentioned: “But what we’re seeing with long COVID is that even when the virus has completely left the body, the immune system remains switched on. If you measure the same thing after a standard cough or cold, which we did in this study through one of our control groups, this signal is not there. It’s unique to sufferers of long COVID.”

The long Covid cohort and the asymptomatic matched control cohort may have had the same readings four months in, but at eight months the two began to come apart. The levels of proinflammatory cytokines in the asymptomatic cohort dropped off, whereas those in the long Covid cohort remained more or less steady, with only a statistically insignificant decrease.

Four of the markers, analyzed via a data model, proved to be especially accurate in predicting long Covid: IFN-β, PTX3, IFN-λ2/3 and IL-6. Of these, IFN-β was the single most important indicator of long Covid, present 94% of the time when modeled in a set of four markers.

As exciting as this data is, the researchers are already looking ahead: how does the rate of long Covid incidence and distribution of biomarkers change depending on vaccination status, the variant with which one was infected, and the severity of one’s infection?

The plight of long haulers was dismissed early on in the pandemic, often leaving sufferers to deal with life-altering symptoms on their own, without clinical or institutional support. This analysis by Phetsouphanh et al. helps firmly ground their experiences in biology. Long Covid is a medical condition, often debilitating, and has to be treated as such.