Virus World

Increases in the levels of three cytokines are among the features linked to poor outcomes. 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..

Research published in Nature Medicine (August 17, 2020):

https://doi.org/10.1038/s41591-020-1038-6

Many Covid-19 patients may be dying from their immune response to the virus, not from the virus itself. Can science figure out how to save them? Back in April, as the pandemic was cresting over New York, Iris Navarro-Millán, a physician at Weill Cornell Medicine in Manhattan, treated a Covid-19 patient, a Hispanic woman in her 60s, who would prove to be a turning point in how she approached the disease. The woman was just a little short of breath when Navarro-Millán first saw her; a day later, she deteriorated so rapidly that she was rushed to intensive care, put on a ventilator and hooked up to a dialysis machine for her failing kidneys. Navarro-Millán feared that she would die. (She survived after spending two months sedated on the breathing machine.) When Navarro-Millán saw another Covid-19 patient soon after — a white man in his 60s already struggling to breathe — her first thought was, Not again. Believing that the prevailing standard of care — which, lacking drugs to directly fight the virus, consisted primarily of supportive measures like supplemental oxygen — was insufficient, she resolved to try something different, a treatment that was heretical in some circles but that she thought could save his life.

Navarro-Millán had unusual expertise for a hospitalist. Weill Cornell had asked her to move into that role when the pandemic hit, but she was a rheumatologist by training, a doctor whose specialty is autoimmune ailments in which the immune system, tasked with defending the self from invading pathogens, inexplicably turns on the body’s own tissues. Now she drew on her experience to try to help this Covid-19 patient. She suspected that the greatest danger here wasn’t the coronavirus itself but an immune overreaction so severe that it could cause lungs to fill up with fluid and prompt organs to shut down, possibly killing the patient. Rheumatologists often describe this type of immune reaction as a “cytokine storm” or “cytokine release syndrome.” Cytokines are proteins released by cells in order to send messages to other cells — signaling, for instance, that a viral invasion is underway. The number of different cytokines is large, perhaps exceeding 100, and each one calls for a specific response. To save her patient, Navarro-Millán decided that she would have to calm his immune system and prevent that storm from getting started. Early in her career, Navarro-Millán worked at the University of Alabama at Birmingham, where most of her patients had lupus, an autoimmune disease that can affect various parts of the body, including the kidneys, blood and even the brain. Its sufferers are especially prone to cytokine storms, which are often triggered by viral infections. What Navarro-Millán saw now in her Covid-19 patients wasn’t, she thought, all that different from what she encountered in Alabama.

A major lesson learned from her years there was that saving patients from cytokine storms often required doctors to intervene early, preferably long before the patients landed in the I.C.U., when it was frequently too late to bring the immune system to heel. So, the sooner she treated her Covid patient by tamping down his inflammatory response, she figured, the better. At the same time, she was leery of subduing his immune system for too long or too profoundly, because that might hobble his body’s ability to fight the virus that was making him sick in the first place. An array of drugs was available to her, ranging from antibodies that target specific pathways in the immune system to molecules that have a more widespread effect on the body. One, called tocilizumab, blocked the cytokine interleukin-6, but it remained in the body for up to a month — too long, in her view. Steroids, which dampen the entire immune system, might open the door to other infections. (Hydroxychloroquine, an antimalarial drug that has been promoted by President Trump for its supposed coronavirus-fighting potential, also happens to suppress the immune system. But because this effect, which is mild, comes only after months of daily use, it is unlikely to be suitable as a way to quell an immune firestorm started by an infection. The evidence so far suggests that it doesn’t work as an antiviral remedy, either, and that it can cause severe side effects.)..