What Is Long COVID? Understanding the Pandemic’s Mysterious Fallout

Just weeks after the first cases of COVID-19 hit U.S. shores, an op-ed appeared in The New York Times titled “We Need to Talk About What Coronavirus Recoveries Look Like: They're a lot more complicated than most people realize.” The author, Fiona Lowenstein, is a writer and yoga teacher living in New York City, who wrote about her own illness and the symptoms she was left with once she was released from the hospital. “In the weeks since I was hospitalized for the coronavirus, the same question has flooded my email inbox, texts and direct messages: Are you better yet? I don’t yet know how to answer.”

She was better, she wrote on April 13, 2020, but she wasn’t well. And others she was in touch with were having the same issue. Unlike most diseases, Long COVID was first described not by doctors, but by the patients themselves. Even the term “Long COVID” was coined by a patient. Dr. Elisa Perego, an honorary research fellow at University College in London, came up with the hashtag #LongCOVID when tweeting about her own experience with the post-COVID syndrome. The term went viral and suddenly social media, and then the media itself, was full of these stories.

Complaints like "I can't seem to concentrate anymore" or "I'm constantly fatigued throughout the day" became increasingly common, seemingly appearing out of nowhere. With nothing abnormal turning up from their many thorough lab tests, patients and their physicians were left feeling helpless and frustrated.

The World Health Organization (WHO) has defined Long COVID as the "continuation or development of new symptoms three months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least two months with no other explanation." This deliberately broad definition reflects the complex nature of this syndrome. We now understand that these symptoms are wide-ranging, including heart palpitations, cough, nausea, fatigue, cognitive impairment (commonly referred to as "brain fog"), and more. Also, many who experience Long COVID following an acute infection face an elevated risk of such medical complications as blood clots and (type 2) diabetes.

As of March 2024, it’s estimated that about 17% of patients who get COVID-19 will go on to develop post-acute COVID-19 syndrome, the medical term for Long COVID. Data from the Centers for Disease Control and Prevention (CDC) suggest that Long COVID disproportionately affects women, and individuals between the ages of 40 and 49 have the highest reported rates of developing this post-acute infection syndrome.

Ebony Dix, MD, a Yale School of Medicine (YSM) assistant professor of psychiatry and the medical director of the geriatric psychiatry inpatient unit at Yale New Haven Hospital, said: "Unfortunately, it is not easy to say who is going to get Long COVID and who isn't." She also emphasized that "it can be overlooked and attributed to a preexisting condition. Sometimes the only thing that patients have in their history is a positive COVID test."

Dr. Dix recalled a patient she treated in the COVID psychiatry unit whose unanticipated clinical decline began with increasing fatigue during physical therapy sessions, ultimately necessitating more care over several weeks. Dr. Dix noted, "Long COVID requires time for things to settle down. It might take several months to get back to baseline." Making timely changes to a patient’s treatment plans was essential to helping her patients get back to good health, she said.

A major challenge with Long COVID is how difficult it can be to diagnose. Determining whether new-onset symptoms, such as fatigue or weakness, are related to an underlying condition or entirely attributed to a prior COVID infection is the greatest challenge for those who care for these patients. This is, in large part, due to the lack of research surrounding the topic.

Inderjit Singh, MBChB, a YSM assistant professor specializing in pulmonary, critical care, and sleep medicine, and director of the Pulmonary Vascular Program, is actively engaged in clinical trials aimed at uncovering the fundamental underpinnings of Long COVID. In one research study, patients suffering from unexplained fatigue and shortness of breath undergo exhaustive exercise testing. In order to be enrolled in this study, patients need to have already completed a substantial work-up, including an echocardiogram, pulmonary function testing, chest CT scans, and more, all which result in no alternative diagnosis.

Through this work, a significant revelation emerged. They observed that patients grappling with Long COVID and facing exercise difficulties were unable to efficiently extract oxygen from their bloodstream during physical exertion. This discovery identifies a specific cause underlying the biological underpinnings of Long COVID.

Recognizing the impracticality of conducting comprehensive exercise tests for every Long COVID patient, Dr. Singh, along with other researchers, is focused on the identification of blood-based markers to assess the severity of Long COVID. For example, a research group, led by Akiko Iwasaki, PhD, Sterling Professor of Immunobiology and Molecular, Cellular, and Developmental Biology, and director of the Center for Infection & Immunity at YSM, most recently created a new method to classify Long COVID severity with circulating immune markers.

Further investigations conducted by Dr. Singh's team identified distinctive protein signatures in the blood of Long COVID patients, which correlated with the degree of Long COVID severity. Researchers identified two major and distinct blood profiles among the patients. Some of them exhibited blood profiles indicating that excessive inflammation played a prominent role in their condition, while others displayed profiles indicative of impaired metabolism. Dr. Singh raises a pressing question: "Do we prioritize treating the inflammation or addressing the metabolic defects?"

Although his research findings and those of his peers are progressively unraveling the mysteries of Long COVID, he acknowledges that "significant challenges persist in defining this syndrome.”

The symptoms of Long COVID can vary significantly from one patient to another. Some individuals may be so fatigued that they find it difficult to get out of bed each morning. Others experience heart palpitations, lightheadedness, nausea, vomiting, diarrhea, or brain fog. This broad spectrum of symptoms—more than 200 documented—has led to various hypotheses about the underlying mechanisms at play.

Researchers currently believe that the impairment of a spectrum of key bodily functions may contribute to these diverse symptoms. These potential mechanisms include compromised immune system function, damage to blood vessels, and direct harm to the brain and nervous system. Importantly, it's likely that most patients experience symptoms arising from multiple underlying causes, which complicates both the diagnosis and treatment of Long COVID.

While the diagnosis and treatment of Long COVID remain challenging, the landscape of treatment options is evolving. At Yale’s Multidisciplinary Long COVID Care Center, a team, including respiratory therapists, physical therapists, and clinical social workers, along with an internist, work together to provide a comprehensive evaluation of each patient. Treatment approaches can vary widely and may encompass medications, supplements, physical therapy, or other interventions. Each regimen is designed to meet the specific presentation of Long COVID in each patient.

Dr. Singh’s apt summarization of the situation? "I don't think there's a magic bullet for it." Effective management of Long COVID necessitates a multidisciplinary approach that harnesses the expertise of a wide variety of specialists, working together to provide tailored care and support for these patients.

Brooks Leitner is an MD/PhD candidate at Yale School of Medicine.

I’m the internist who sees patients at Yale New Haven Health’s Multidisciplinary Long COVID Care Center. In our clinic, patients are examined by a variety of specialists to determine the best next steps for these complex patients. Sometimes that entails more testing. Often patients have had extensive testing even before they arrive, and far too often—when all the tests are normal—both doctors and patients worry that their symptoms are “all in their head.”

One of our first tasks is to reassure patients that many parts of Long COVID don’t show up on tests. We don’t know enough about the cause of many of these symptoms to create a test for them. The problem is not with the patient with the symptoms, but of the science surrounding them.

If any good can be said to come out of this pandemic, it will be a better understanding of Long COVID and many of the other post-acute infection syndromes that have existed as long as the infections themselves.

If you’d like to share your experience with Long COVID for possible use in a future post (under a pseudonym), write to us at: LongCovidDispatches@yale.edu

Information provided in Yale Medicine content is for general informational purposes only. It should never be used as a substitute for medical advice from your doctor or other qualified clinician. Always seek the individual advice of your health care provider for any questions you have regarding a medical condition.