Eric Wang, Senior Photographer

Long COVID patients run a gauntlet of uncertainty. Many wonder whether their lives will ever be normal again. 

Loved ones, medical staff, and the patients themselves doubt the reality of their symptoms. Doctors struggle to offer them explanations.  

At the Yale Multidisciplinary Long Covid Clinic, however, medical workers try to unravel the mystery of long COVID. The center is directed by Lisa Sanders, associate professor of general medicine, who is no stranger to medical mysteries like long COVID. She currently writes the “Diagnosis” and “Think Like a Doctor” columns for the New York Times, and she previously published two medical books,“Every Patient Tells a Story: Medical Mysteries and the Art of Diagnosis” and “Diagnosis: Solving the Most Baffling Medical Mysteries.” 

In her role as director, Sanders is essentially a detective in a white coat. When a patient is referred to the clinic, Sanders first investigates whether the culprit is long COVID. This process involves ruling out other factors that may cause similar symptoms. For example, if a patient reports feeling fatigued, she checks that the patient does not have sleep apnea. According to Sanders, by repeating this process, the researchers remove some uncertainty from a long COVID diagnosis. 

From there, Sanders told the News, she tackles the downstream effects of the disease. Because the symptoms of long COVID are known and treatable, Sanders said she can treat the effects, despite not understanding the root cause.

“If you can’t treat the actual disease, just treat the symptoms that are tormenting people and reassure them that at least some people get better,” Sanders said. “Depending on who you read, 80-plus percent of people don’t have symptoms after a year.”

The Yale Multidisciplinary Long Covid Clinic is on the third floor of Yale New Haven Hospital’s St. Raphael Campus. Patients enter a waiting room adorned with long COVID support group flyers and prints of beach paintings. A narrow hallway connects Sanders’ office, an examination room and a physical therapy room.

Sanders said that next month the Center will move to a larger space.

“Our patients say ‘oh my god, this is such a small room, this is such a small space.’ Like really?” Sanders said. “It’s gonna be so luxurious.”

Despite its small size, the Center provides each patient with help from social workers, physical therapists and Sanders. 

Early in the pandemic, this level of treatment was not available to long-haulers, a colloquial term for people with long COVID. Instead, patients in New Haven with long COVID symptoms had to seek out specialists in separate departments that best aligned with their symptoms, Sanders said. Sanders said that eventually, specialists realized that the best way to help people with long COVID was not with specialty care, rather, it was with a specialized long COVID Center. Sanders was immediately interested in leading the center.

“The thought that I could learn about this, and maybe help people with it seemed appealing,” Sanders told the News.

Part of this learning is trying to define long COVID. 

Characterized by persistent symptoms long after initial infection, long COVID remains a puzzling challenge for patients, healthcare professionals and researchers. However, common symptoms include fatigue, brain fog, cough and shortness of breath after their initial COVID-19 infection, Sanders told the News. For many patients, these symptoms can become physically and emotionally debilitating, Sanders said.

“You had COVID, and then something bad happened,” Sanders said. “But that’s all we can say now because we have no idea what the pathophysiology is.”

Parallels to polio

COVID-19 is not the first epidemic to leave a wake of people experiencing lingering symptoms, said Naomi Rogers, a history professor at Yale who studies 20th and 21st-century medicine and disability. 

In the middle of the 20th century, the United States weathered a series of polio outbreaks, a virus that primarily affects children and can, in rare cases, cause long-term paralysis. One 1955 polio epidemic infected 3,950 people in Massachusetts. Of those infected, 2,771 were paralyzed, some for a few weeks or months and some permanently.

“Polio was seen as a really scary disease because of its disabling effects,” Rogers said. “Everybody feared that if their child got it, they would never be able to work independently or live independently.” 

According to Rogers, some patients with polio also developed “post-polio” syndrome. These people had polio as children and fully recovered, but then, decades after their illness, became paralyzed.

Rogers pointed to similarities between post-polio syndrome and long COVID. Like patients with long COVID, people with post-polio syndrome continued to have symptoms of the disease long after the actual infection had passed, Rogers said. Some patients with post-polio were dismissed by their doctors because the doctors had never heard of the disease, according to Rogers. People with post-polio syndrome, like those with long COVID, Rogers said, had to advocate for themselves in medical settings and seek ways to alleviate their symptoms outside of traditional medicine. 

Rogers also highlighted similarities between long COVID and diseases such as chronic Lyme and Chronic Fatigue Syndrome. For people with these conditions, she said, it is difficult to make friends, family or doctors aware that there is an actual disease behind what she said are relatively vague symptoms. 

“You can’t see pain. You can’t see weakness. There are a lot of chronic responses that are not visible,” Rogers said.

In addition to vague symptoms, Rogers said that long COVID is complicated because nobody knows exactly what it is or how to think about it. 

Unlike other chronic diseases such as cancer or AIDS, she explained, long COVID is too recent for the public to have a clear picture of what it is like. 

“When we say long COVID, we don’t have in our minds what long COVID looks like,” Rogers said. 

Studying Long Covid

A group of interdisciplinary researchers at Yale are working to uncover what long COVID is and how it can be treated. 

During the pandemic, researchers at Yale, including Akiko Iwasaki, Sterling Professor of immunobiology at the School of Medicine, noticed that some patients who had COVID-19 developed chronic symptoms that lasted for a long time after their infection. Iwasaki and her lab also noted that some people who got the COVID-19 vaccine had an immune response.

As the pandemic progressed, Iwasaki established a network of researchers studying COVID-19 who also wanted to understand the unusual immune responses caused by COVID-19. This collaboration became the Center for Infection and Immunity, or CII, which opened in August 2023. 

The center, which Iwasaki directs, seeks to understand how chronic diseases develop and uncover links between infection and chronic disease. It also tries to connect immune responses to factors such as sex, genetics, age and environment, and develop therapies for treating chronic disease.

Iwasaki said that, because post-acute syndromes, such as long COVID, are difficult to understand and quantify, studying them requires an interdisciplinary approach.

Patient-centered approach

In studying chronic disease, the CII seeks to include patients as full participants in their research. CII partners with the Center for Outcomes Research and Evaluation, or CORE, to enhance their patient-centered research approach.

“We’re trying to create a different spirit around the research,” Harlan Krumholz, a professor at the School of Medicine and the director of CORE told the News. Krumholz is also on the CII leadership team. 

Krumholz said patients with post-acute syndromes are “desperate for answers.” 

But because chronic syndromes like long COVID are poorly understood, he said many patients feel “abandoned” by doctors, caregivers and the medical system. 

“There’s not one evidence-based therapy,” Krumholz said. “We even have trouble defining the condition, because there aren’t any diagnostics.”

To combat this feeling of neglect, CORE and CII developed a new model for doing patient research which Krumholz called “highly participant-centric.”

One way the researchers study long COVID is through the Yale LISTEN study, which stands for Listen to Immune, Symptom and Treatment Experiences Now. The LISTEN study follows a pool of participants with long COVID who share health data and specimens like blood or saliva with researchers. 

People participating in the LISTEN study can opt to participate in different research projects. For example, the CII is also conducting a trial on the effect of Paxlovid — an antiviral drug used to treat COVID-19 — on long COVID. 

The trial is being conducted virtually, to make it easy for people to participate in research. Patients involved in the study receive drugs or placebo pills by mail, then fill out surveys online and electronically transmit their data to researchers. 

The trial organizers also hold regular town hall meetings, where study participants can ask questions and suggest changes. When researchers learn new information through their research, they share it with the participants. 

New long COVID study gives hope to researchers, patients 

In September, researchers from the CII and Mount Sinai Hospital published a paper in Nature that identified biological markers associated with long COVID. By analyzing blood samples, the researchers found that hormonal dysfunction, exhaustion of certain immune cells and the reactivation of latent viruses are key factors in long COVID. 

“To us, that means that there is an immunological underpinning to this disease,” Iwasaki said. 

According to Iwasaki, the evidence that long COVID is a biological disease is an important discovery not only to understand the disease but also to validate patients’ struggles. People suffering from long COVID and other chronic diseases are often perceived as inventing or exaggerating their illness, Iwasaki said. 

The idea that patients are making up their symptoms, Iwasaki said, is one of the major misconceptions that the CII seeks to debunk. Iwasaki added that the identification of biological markers helps dispel the belief that long COVID is only a psychiatric illness. 

Sanders said she believes there should have never been a need to prove long COVID patients had an actual disease. 

“I never thought they needed any validation. I thought that people who saw it as psychiatric alone were nuts,” Sanders told the News. “Eleven million people have long COVID in the United States alone, and there’s so many more than that in the world. Over a million people don’t just come up with the same problem.” 

Long COVID is not the CII’s only focus. Researchers at the Center also study diseases such as chronic Lyme disease, which is a disease spread by ticks, and myalgic encephalomyelitis chronic fatigue syndrome, or ME/CFS.

While post-acute syndromes are complex and tricky to study, long COVID provides a unique research opportunity, Iwasaki said. People with the disease became ill around the same time and from the same virus, which allows researchers to simultaneously study a large number of people who have a similar chronic illness. 

Iwasaki said that it is difficult to find this kind of continuity with other post-acute viral syndromes because most chronic diseases occur in small numbers and at different times. 

Research developments often come up in conversation during visits to the Long COVID Clinic. Patients frequently tell Sanders about new research they have encountered, and Sanders will follow up on it. Sanders even has a Google alert that sends her every online publication that has to do with long COVID.

Like Iwasaki, Sanders views long COVID as a unique opportunity to develop our understanding of chronic illness.

“It would be terrible to waste this and not learn anything from it, like we have done with so many other infections,” Sanders said. “We have the technology and the curiosity. God only knows what other factors allowed this to be an active area of research, but I’m so glad it is.”

Adults aged between 35 and 49 exhibited the highest prevalence of experiencing long COVID.