Soon after she got sick, Amy Siniscalchi felt as though her limbs were burning. “Then it morphed into, like, electrical buzzing,” she remembers. “At times, it would feel like my blood was gurgling, like seltzer in my veins.” Siniscalchi’s story follows a now familiar arc. In March, 2020, as a healthy forty-four-year-old, she was exposed to COVID, became ill, and never fully got better. Months later, she was still suffering from an array of strange symptoms: debilitating fatigue, memory problems, trouble walking, the seltzer sensation. She sought help from her primary-care doctor but left the encounter feeling dismissed.
“It wasn’t, like, ‘I’m so sorry for your suffering, I believe you, we just don’t know anything yet,’ ” Siniscalchi recalled. “There were a couple of doctors in the beginning that really just acted like nothing was wrong.” In search of answers, Siniscalchi went online. There, in Facebook groups and Slack channels, she found something more affirming than simple fellowship: thousands of others like her were organizing to make their suffering visible while sick and isolated at home.
Siniscalchi and I met over Zoom in May. Her face was framed with bright-red ringlets, and she had an air of eager, determined intensity. Prior to getting sick, she was a nonprofit administrator who worked fifty-to-sixty-hour weeks and exercised almost every day of the week. Since becoming ill, she has had to quit her job and, on many days, hasn’t had the energy to leave the house. In place of what she’s given up, her illness has become a kind of vocation. She spends much of her time online, connecting with others suffering from Long COVID and looking for information that might help. “When I lay down and I’m supposed to be resting, I’m scrolling studies,” she said. “And I don’t understand half of it, because I don’t have a science background, but I try to get it in context.”
Siniscalchi told me that she was hesitant to describe herself as a “citizen scientist,” but people like her—sick people who became lay experts in their own illnesses—were the first to name and characterize Long COVID. In April, 2020, a grassroots group, later called the Patient-Led Research Collaborative (P.L.R.C.), started surveying several hundred who remained sick for weeks after presumed COVID infections. Their results, published in a Google Doc, became the first systematic study of patients with Long COVID. Other groups also began to collect and disseminate data; in online forums, people with unresolved illness referred to themselves as “long haulers.” The academics Felicity Callard and Elisa Perego would later make the provocative argument that “Long COVID has a strong claim to be considered the first illness to be collectively made by patients finding one another through Twitter and other social media.”
In June of that year, the journalist Ed Yong described the P.L.R.C. survey results in an article for The Atlantic that brought “long-haulers” to mainstream attention. Conventional scientists and institutional authorities began taking notice; the Centers for Disease Control and Prevention reached out to the leaders of the P.L.R.C., asking to see their data. By the end of the pandemic’s first year, Congress had appropriated more than a billion dollars to the N.I.H. to study the condition, thanks in large part to patient-advocacy efforts.
During her first two years of illness, Siniscalchi signed up for a few institutional research efforts but found most of her experiences unsatisfying; either the studies felt like impersonal, disorganized bureaucracies, or shallow efforts to extract her data without engaging with her knowledge or perspective. Then, in September, 2022, she became a participant in an unusual clinical-research effort called the LISTEN study.
LISTEN (Listen to Immune, Symptom and Treatment Experiences Now) is an ambitious effort to understand Long COVID and similar conditions led by two renowned scientists at Yale: Harlan Krumholz, a cardiologist and clinical-outcomes researcher, and Akiko Iwasaki, an immunologist who studies virus-host interactions. Krumholz is a longtime champion of “patient-centered research”—the practice of designing and conducting a study in consultation with the people it intends to help. Iwasaki became famous beyond her field at the start of the pandemic through her active use of Twitter, on which she would explain complex scientific topics to a lay audience that had suddenly taken up virology as a hobby. Both of them appreciated that the first people to describe the symptoms of Long COVID were those afflicted with it, and recognized that the emerging patient movement would be a critical resource in studying the condition. Amid the uncertainty that characterized the early pandemic, both scientists recognized an opportunity to improve upon traditional research practices.
The project is based at Yale, but people can enroll online from anywhere in the world. The study’s extensive symptom surveys were created with patient input, and participants are invited to freewrite about their illness experience in online journals. They can also virtually consent to let the LISTEN investigators access their medical and pharmacy records. A signature feature of the study is its series of “town halls,” frequent forums in which Krumholz and Iwasaki meet virtually with any study participant who wants to attend.
Usually, investigators will identify a few patient representatives to sit on an advisory group. Krumholz and Iwasaki, in contrast, envision their study as a “safe space” designed to consider participants at every step of the discovery process. Theirs is an exercise in transparency that has few precedents in clinical science. Like local politicians showing up to regular community meetings, they open themselves to the good, bad, and out-of-left-field commentary of their entire constituency. Siniscalchi is an enthusiastic town-hall attendee. “They’re never dismissive,” she told me. “They can’t change course every time a patient says boo . . . but they at least make you feel heard, and they respond to you.”
If one legacy of the past four years has been what Iwasaki calls “the pandemic after the pandemic” of Long COVID, a related phenomenon has been an acceleration toward the type of research collaboration that LISTEN exemplifies: a democratic mode of scientific inquiry, with all the aspirational ideals and practical turmoil that a shift toward democracy implies. The LISTEN model makes explicit the politics of science: how research agendas are set, how results are interpreted, what counts as evidence. Compared with the conventional way of doing things, its path to discovery is both friendlier to its subjects, and more fraught.
One of LISTEN’s main objectives is to create a taxonomy of chronic-illness presentations that follow likely COVID infection. This involves sorting out how patients with different symptoms—respiratory illness, brain fog, neuropathies—cluster along multiple axes. In addition to looking for patterns among patients’ symptoms, demographics, and infection time lines, the study collects blood and saliva samples from a subset of participants. Iwasaki’s team analyzes these specimens for “immune signatures” that correlate with various illness presentations: Do people who have lost their sense of smell have specific T-cell responses? Or do people with “internal tremor” sensations tend to have elevated levels of certain biomarkers?
The enduring murkiness about what Long COVID actually is reflects something about its unusual ontology. Currently, it is an inclusive diagnosis organized around self-report: If you feel you have symptoms weeks or months after a likely COVID infection, you may have Long COVID. This capaciousness has made for effective coalition-building among the sick, who have consistently advocated that no sufferer be dismissed, but it poses a challenge for researchers and clinicians, who usually require clear metrics to delineate between who does and does not have a disease.
These competing priorities between patients and scientists can escalate into frank tension. Last year, investigators from the RECOVER Initiative, a government-sponsored Long COVID research effort, proposed a carefully modelled framework that identified twelve symptoms frequently associated with the disease. They published their results in the Journal of the American Medical Association, in an article filled with caveats about how this work was only the first step toward deriving a more precise Long COVID definition. But some Long COVID patient-advocacy groups swiftly denounced the study, lamenting that the framework’s scoring cutoff would leave thousands of sick people without a diagnosis. One such group called the RECOVER criteria “regressive and blunt.” More than forty-two thousand people have sent letters to the N.I.H. demanding that it retract the study and its scoring system.
Krumholz and Iwasaki’s sincere, and canny, approach to working with a highly engaged patient population is to honor everyone’s experience, no matter how controversial. They’re also investigating the link between Long COVID and other inflammatory conditions. Shortly after the study launched, the researchers began receiving messages from people who report long-term adverse effects that they attribute to COVID vaccination. Many of these patients—who variously refer to their condition as “vaccine injury,” “post-vaccine syndrome,” or “Long Vax”—describe symptoms similar to those reported by Long COVID sufferers: brain fog, dizziness, fatigue, pain. Intrigued by these similarities, Krumholz and Iwasaki decided to expand LISTEN’s scope.