Researchers Seek Answers for Millions With Long COVID-19

Researchers Seek Answers for Millions With Long COVID-19 2121 1414 IEEE Pulse

“I am now eight-and-a-half months into my journey with long COVID … My symptoms include diagnosed post-COVID tachycardia and acute fatigue. I also have chest tightness and breathlessness from time to time; anxiety; muscle aches and pains, especially in the evening; memory loss; and insomnia.”—38-year-old female from the U.K.

“I have been experiencing for the last seven months the same ongoing symptoms of dry cough, shortness of breath, chest pains on the left side, and low-grade fever … I have been unable to return to working face-to-face and I have had to suspend my post-graduate studies. I have also had to move back in with my parents as I was unable to cope by myself.”—28-year-old female from Greece

“I have had symptoms the last nine months … I didn’t know that it would last 256 days and still counting.”—34-year-old male from Finland

Figure 1. Post-acute COVID syndrome, colloquially known as long-haul COVID or long COVID, is a much larger problem than most people realize. Estimates suggest that it affects 10% of people who have COVID symptoms that do not require hospitalization, and the average age of patients is 40. Patients experience a wide range of symptoms, including debilitating fatigue, cognitive fog, dizziness, sleeping difficulties, and joint and muscle pain, all of which often leave them unable to work or do daily chores. [Illustration by: Leslie Mertz. Coronavirus image: Alissa Eckert, MSMI, Dan Higgins, MAMS (].

These alarming statements were made as part of an international forum on post-acute COVID syndrome (Figure 1), colloquially known as long-haul COVID or long COVID [1], and recently referred to as post-acute sequelae of SARS-CoV-2 infection (PASC) by Dr. Anthony Fauci, director of NIAID and chief medical advisor to President Biden. Dozens of researchers participated in the December 2020 forum, including long-COVID expert Danny Altmann, Ph.D., professor of immunology at Imperial College London, who remarked, “When I look at what’s going on at the moment with long COVID, my guess is that we probably have way more than 5 million people on the planet now with long COVID.” This is no small matter, he added. “The legacy that the virus leaves behind can actually be a far more desperate burden for the sufferers and for the health care system than the acute infection that triggered it. I think that’s some real food for  thought.”

Figure 2. David Putrino, is affiliated with Mount Sinai’s Center for Post-COVID Care, and has been both tracking symptoms of and treating patients with post-acute COVID syndrome since late last spring. He and his group are using sophisticated, qualitative-data-analysis techniques, and statistical methods, such as multilevel modeling, to understand the syndrome and the course of symptoms. With that information, they hope to generate diagnostic criteria, and both refine and bolster treatment protocols. (Photo courtesy of Mount Sinai Health System.)

Making a diagnosis

The United States has been especially hard-hit, according to David Putrino, Ph.D., director of rehabilitation innovation for the Mount Sinai Health System and assistant professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai (Figure 2). He is affiliated with Mount Sinai’s Center for Post-COVID Care, which launched in May 2020 as the first major multidisciplinary long-COVID treatment and research center in the United States [2], and has been both tracking symptoms of and treating patients with long COVID since late last spring.

“From our data so far, of those individuals who have COVID infection that does not require hospitalization, around 10% will go on to develop signs and symptoms of post-acute COVID syndrome, and the majority of these people are incredibly debilitated, can’t leave their homes, can’t work, have intense symptoms on a daily basis, and they’re having a lot of trouble shaking it several months after their initial COVID infection,” Putrino said. Using the 10% estimate, which he considers conservative, he added, “that would mean that around 3 million Americans suddenly can’t work and can’t get on with their daily lives.”

Based on the information gathered from the Mount Sinai patient cohort, he provided this snapshot of long COVID:

  • Fatigue and post-exercise malaise affect more than 90% of patients. “People feel extremely fatigued and if they do anything to bring their heart rate up, it will hit them even harder,” he said. “And I’m not talking about getting-on-a-treadmill type of exercise. I’m talking about walking their groceries up the stairs to get into their apartment—that can knock them out for one or two days.”
  • More than 50% of patients on a daily basis experience cognitive fog, short-term memory issues, difficulty concentrating, shortness of breath, dizziness, irregular heartbeat, rapid heartbeat, body-temperature disturbances, sleeping difficulties, chest pain, joint and muscle pain, and tingling down the arms.
  • While COVID-19 deaths typically hit elderly patients or those who have underlying medical conditions, long COVID tends toward a younger, healthier demographic. The median age of a person with long COVID is 40, and the majority were previously fit and healthy, exercised frequently, and had no prior health conditions.

Putting together a working picture of long COVID [3] has been a challenge, Putrino said. “It’s similar to many post-viral syndromes in that the symptoms are hard things to catch on traditional labs and objective measures, so much of what we’re doing is based on subjective symptom reporting.” For that, he and his group are using sophisticated, validated, qualitative-data-analysis techniques, and statistical methods, such as multilevel modeling, to cluster individuals into different groups as a way to understand the syndrome and the course of symptoms. With that information, they hope to develop concrete criteria that can be used for diagnosis, even if the patient never received a COVID-19 test to verify the initial infection.

Finding a cause

The Putrino group is also collaborating on another project on long COVID, this time to determine the syndrome’s underlying cause. The project leader is Akiko Iwasaki, Ph.D., immunologist and virologist at Yale University and Howard Hughes Medical Institute investigator (Figure 3). When she turned her attention to long COVID in Fall 2020, she had already spent several months investigating the immune response to coronavirus among hospitalized patients. “We have gained a lot of insights into moderate and severe cases [4], but we still don’t know if long COVID is driven by the virus or the immune system,” she said. To do that work, she and her research group needed to analyze blood cells and plasma from patients as a way to understand the basic mechanism of this disease, and found the perfect source in Putrino’s clinically annotated cohort of long COVID patients. “We are very excited about this collaboration,” she commented.

Figure 3. Through a collaboration with Putrino’s group, Akiko Iwasaki, immunologist and virologist at Yale University and Howard Hughes Medical Institute investigator, and her research team are investigating whether long COVID is driven by the virus or the immune system. This work involves the new REAP technology (developed by Yale colleague and immunologist Aaron Ring), which is a genetically barcoded library of yeast cells that express thousands of human proteins on the surface and can be used to screen for the autoantibodies patients are making. (Photo courtesy of Dan Renzetti.)

Iwasaki hypothesizes that long COVID can result in one of three ways. In one, a lingering viral infection is not detectable via a nasal-swab test, but is nonetheless present somewhere in the body, and causes inflammation and damage leading to symptoms. A second possibility is that viral components, whether they be protein or ribonucleic acid (RNA), are “hiding somewhere in the body” and causing immune response and inflammation in affected tissues.

A third prospect is autoimmune disease, in which patients develop autoantibodies that target different organs and manifest in the symptoms they experience. “By studying patient blood cells and plasma, we can rule in or rule out these possibilities,” she explained.

Current work in Iwasaki’s group involves a new technology called rapid exoproteome antibody profiling (REAP), which was developed by Yale colleague and immunologist Aaron Ring, Ph.D. REAP is basically a genetically barcoded library of yeast cells that express about 3000 human proteins on the surface, Iwasaki described [5]. “If you add human serum on top of this library, you can select for those expressing the antigens that the antibodies bind to, so we can comprehensively and in an unbiased manner, look at what kinds of autoantibodies people are making.” In addition to antibodies, Iwasaki’s group will work toward an even broader view by examining all blood cell types, T cells, and serum cytokines in long COVID disease.

While this work is just beginning, Iwasaki and Ring hope it will yield autoantibodies common to long COVID patients, which can then be used to develop diagnostic tests and potential treatments. Their findings could also shed light on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diseases that similarly tend to occur following a viral infection. “If autoantibodies are the culprit, we would eventually like to have at least a panel of autoantibodies for long COVID, so doctors can look at it, diagnose it, and see what they should do about it, as opposed to what often happens now with doctors thinking a patient has gastrointestinal issues or some sort of psychiatric issue as opposed to an autoimmune disease,” she remarked. “Whether long COVID is occurring from a lingering viral infection or autoantibodies, or perhaps both, this process of examination will help get to the bottom of it.”

Treating long COVID

Back at Mount Sinai, Putrino’s group is also using patient-reported data to track progress and determine the best intervention protocols. Many of those protocols are versions of treatment approaches used for patients with dysautonomia, a group of medical conditions related to an improperly functioning autonomic nervous system. “We have banded together with a team of health professionals who have a lot of experience in the field of autonomic reconditioning, and have developed a less-intense protocol that patients with post-acute COVID syndrome can tolerate,” he said.

The protocol includes optimizing nutrition and hydration; wearing certain types of clothing, such as compression socks to regulate blood pressure, and loose-fitting clothing around the chest and torso; working on breathwork to improve carbon dioxide tolerance and retention; and gradual introduction to gentle, fixed, low-intensity exercise designed to recondition the autonomic nervous system.

“Under the protocol, we’re seeing dramatic improvements in our earliest patients, but it is a very long and arduous process that requires a lot of rehabilitation and a lot of patience,” Putrino reported. “After four to six months of rehabilitation, we’re getting people to a point where they can possibly exercise again, they can leave the house without worrying that they’re going to have an attack, and so on.”

Still, he would like to do more. “We want to develop a better pathophysiological understanding, which is why we’re working with Dr. Iwasaki and other leading immunologists around the country to try to understand the serological profile of individuals with post-acute COVID syndrome,” Putrino said. “That is how we can start to understand if this is an old or a new problem—if it is dysautonomia or something completely different that we haven’t seen before—because we are basing a lot of our interventional approaches on assumptions. Right now, we’re saying, ‘Clinical judgment says it looks like this, so we’re going to treat it like this,’ and while people are slowly improving, it would be much, much better if we understood what was actually happening on a pathophysiological level so we could start to bring in targeted therapeutics and be a little bit surer about our approach to reconditioning.”

Moving forward

Long COVID remains a medical mystery, but slowly researchers are taking steps to understand what it is, why some patients are susceptible, how to diagnose it, and how to treat it. It is important work. Patients and clinicians are very frustrated with the lack of knowledge at this point “and I totally get it,” Iwasaki said, “so we are working around the clock to try to get everything done and get answers as to what’s going on. It does take a lot to get there, but we’re doing it.”

In a more general sense, Putrino remarked, “The message we need to get out there is that death is not the only negative consequence of COVID-19. There are long-term post-viral effects that we’re struggling to understand, manage, and treat. And with cases surging all over the country, we need to come up with concrete strategies to deal with them.” He added, “Post-acute COVID syndrome—long COVID—is really a condition that can affect anybody who contracts COVID-19. Everyone should be concerned about this.”


  1. Long COVID Forum, International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), Dec. 9–10, 2020. Accessed: Jan. 15, 2021. [Online]. Available:
  2. Mount Sinai, “Mount Sinai announces first-of-its-kind Center for Post-COVID Care,” press release, May 13, 2020. Accessed: Jan. 15, 2021. [Online]. Available:
  3. L. Tabacof et al., “Post-acute COVID-19 syndrome negatively impacts health and wellbeing despite less severe acute infection,” medRxiv, Nov. 5, 2020. [Online]. Available:
  4. C. Lucas et al., “Longitudinal analyses reveal immunological misfiring in severe COVID-19,” Nature, vol. 584, no. 7821, pp. 463–469, Aug. 2020.
  5. E. Y. Wang et al., “Diverse functional autoantibodies in patients with COVID-19,” medRxiv, Feb. 1, 2021. Accessed: Feb. 11, 2021. [Online]. Available: