Immune Biomarkers Tied to Severe COVID-19: Study

ABOVE: © ISTOCK.COM, BUSRACAVUS

A study of COVID-19 patients at two London hospitals has identified blood-based immunological changes that are linked to the disease and, in some cases, to symptom severity. The results, reported in Nature Medicine on Monday (August 17) join a growing body of data on how the human immune system responds to SARS-CoV-2 that will hopefully lead to prognostic tools and potential treatments.

“The study is a nice comprehensive characterization of the different trajectories of host response against SARS-CoV-2 [and] technically well performed,” Antonio Bertoletti an emerging infectious disease researcher at Duke-National University of Singapore who was not involved in the research, writes in an email to The Scientist. It provides “some specific findings, like the severe drop of dendritic cells and the inflammatory cytokine profile,” he adds, “[that] might predict the worsening of the disease.”

Microbiologist and immunologist Stanley Perlman of the University of Iowa who also was not a part of the research team is less optimistic about the potential for prediction. “They came up with parameters that seem to define the different [severity] groups,” he says, “but for an individual [patient] it’s very hard” to make a prediction because “there is so much overlap” between the groups.  

He nonetheless praises the efforts of the authors of the paper and similar endeavors, saying such studies provide “a sense for what seems to be happening in people who do worse, which in itself is useful, if not for prognosis . . . it can help you in management [of the disease].”

Since late 2019, the novel coronavirus SARS-CoV-2 has been relentlessly and rampantly spreading from person to person across the globe. While in many people the virus causes no ill effects, in others it ravages the lungs, leaving them hospitalized for weeks, and in some the infection is fatal. More than 780,000 people have died from the disease worldwide to date.

For a disease with such diversity of symptoms and outcomes, and in patients of different ages and sexes with different underlying conditions, finding a common immune signature for COVID-19—a set of immune proteins and cells that define the disease—may seem like an impossibility, but immunologist Adrian Hayday of King’s College London and the Francis Crick Institute was not discouraged by the odds.

Despite “extraordinary heterogeneity” within patient populations, he says, “immune responses against potentially lethal pathogens can have very dominant effects that rise above the background and therefore provide you with an immune signature.”

Discovering such a signature would be of great value, he explains. For one thing, “you might find things that are unique to COVID-19 and that might give you some very important things to target therapeutically,” he says. And, it might identify “changes that actually could give the doctors a very early indication of which way a patient was going to go.”

For Hayday and his colleagues’ study, the team collected blood samples from 63 patients with mild, moderate, and severe COVID-19 who were admitted to Guys and St. Thomas’s hospitals in London from March to May this year, and from 55 control individuals, including healthy people who had previously tested positive for coronavirus (and had had no or mild symptoms), people with other respiratory tract infections, and healthy individuals with no recent respiratory infections.

The researchers performed flow cytometry experiments and protein assays on the blood samples to analyze the presence and characteristics of various immune cell types and to measure antibodies and other immune factors.

IP-10 levels in a patient’s first blood sample could even predict the length of hospital stay

Among the results, the team found that almost all COVID-19 patients had robust production of anti–SARS-CoV-2 antibodies—which raises questions about the general usefulness of convalescent plasma treatment, which supplies antibodies from recovered donors, says clinician scientist Manu Shankar-Hari of King’s College London who coauthored the study. Indeed, the FDA’s plan to approve the treatment is now on hold due to lack of evidence of efficacy. A report in Immunity, however, suggests antibody quality, not quantity, is linked to outcome and therefore that plasma from survivors might be qualitatively better than that of very sick patients. There were also three patients in Haday and Shankar-Hari’s study in whom no antibodies were detected and all three died, suggesting select individuals may benefit.

As a whole, patient samples were also enriched for plasmablasts (antibody secreting cells), markers of T cell exhaustion, and the cytokines IL-8, IL-6, IL-10, and IP-10, while lacking in basophils and certain subpopulations of dendritic cells and monocytes compared with healthy controls.

Some of these immune features were also seen in patients with other respiratory tract infections. Others, such as low basophils and dendritic cells and high IP-10, were particular to COVID-19.

Some features correlated with the severity of disease. Through a longitudinal study of individual patients—taking blood samples on different days during the hospital stay—the team showed that those patients who had high levels of IL-6, IL-10, and especially IP-10 when their first blood sample was taken were more likely to have a poorer outcome than patients in whom these cytokine levels were lower.

The trio of cytokines was “quite an extraordinary predictor that could discern whether a patient at admission with respiratory difficulties would actually improve or worsen,” says Hayday. IP-10 levels in a patient’s first blood sample could even predict the length of hospital stay, he adds.

“It’s a great paper,” says Michael Betts of the University of Pennsylvania who was not involved in the work, and “it certainly agrees with a lot of the literature that has accumulated already.” He notes that while some differences exist between the new results and other COVID-19 signature studies, for the most part they are similar.

Hayday’s group has made the raw data available here.

It remains to be seen—in longitudinal validation studies with a larger cohort of patients—whether the trio of cytokines will be reliable predictors of severity, says Shankar-Hari, and whether they might be worthy targets for therapy.

For now, “we still know little about why different infected individuals [have] such diversity of symptoms and outcomes,” writes Bertoletti, “but at least we start to understand what is occurring in such different manifestations and this is important to clinical management.”

A.G. Laing et al., “A dynamic COVID-19 immune signature includes associations with poor prognosis,” Nat Med, doi:10.1038/s41591-020-1038-6, 2020.