discoveries magazine

Three Big Questions About Long COVID

An illustration of a man holding a large COVID-19 molecule.

COVID-19 is distressingly unpredictable. About 10% of people recover from an initial illness only to confront a new set of chronic symptoms like fatigue, shortness of breath, "brain fog," anxiety and depression, kidney damage, gastrointestinal issues, or changes to skin, hair and sense of smell. This range of symptoms, known as "long COVID," can impact essentially every organ system, persist for months and range from mild to incapacitating. 

Investigators at Cedars-Sinai are studying long COVID to uncover ways to treat symptoms. Patients are managed by a multidisciplinary team at the COVID-19 Recovery Program, including Isabel Pedraza, MD. We asked Pedraza, as well as COVID-19 researchers Peter Chen, MD, and Susan Cheng, MD, MPH, MMSc, to outline the mysteries they seek to solve.

Why do patients experience long COVID differently?

I don’t think one disease process fits all—multiple mechanisms probably drive different types of long COVID. If we can understand what underlies long COVID, we can treat it. We need to look deeply into patients’ experiences, measuring biomarkers, genetics, diet, microbiome, demographics and health disparities to discover which ones play a role in developing long COVID. We want the entire research community to collaborate, like an extension of what we started when we were introduced to COVID-19.

I think there are still traits we’ve yet to discover and clinical manifestations we didn’t realize were long-term complications of this disease. We’re enrolling patients with long COVID in a study to see if we can identify a common pathway. That knowledge could lead us to an opportunity to treat multiple people—if we can get there. Right now, if we find inflammation in the lungs, we treat it with anti-inflammatory medications—but is that good or bad in the long term, and is it right for everyone? We need to understand what the proper therapies are in the grander scheme of things. 

Peter Chen, MD, assistant director of the Women’s Guild Lung Institute, director of the Division of Pulmonary and Critical Care Medicine, and the Medallion Chair in Molecular Medicine

Can long-term impairments from COVID-19 be treated or prevented?

At the COVID-19 Recovery Program, led by Catherine Le, MD, almost all patients I see present with fatigue and weakness. How much of that functionality will they gain back? These are things we're starting to address at the clinic: When and how can we intervene to prevent long-term disability? We know that two-thirds of patients who have pulmonary symptoms and abnormalities get better by three months, so we're currently operating on a three-month cutoff for allowing people to improve on their own. Maybe intervening early on might help them get there faster; it's not clear. I don't want to miss the opportunity to treat them to prevent long-term disability. 

I've only run across a handful of people with long COVID who don't have anxiety—almost everyone does—and we can't underestimate the importance of treating people for that. Having COVID-19 is associated with a lot of anxiety because of how the disease saturates the news—but in long COVID, it could be a direct effect of damage to the brain. There is a misconception that, among these patients, it may be a little bit in their head. Of the patients I see, everyone really wants to get back to their normal life. These include active, busy people who want to resume their activities and can't. What's most important is to take them seriously and really listen to their concerns. 

Isabel Pedraza, MD, director of the Medical Intensive Care Unit

Is long COVID driven by inflammation or autoimmunity?

What is causing long COVID—chronic inflammation, reservoirs of the virus living in the body—is hard to determine. In some people with preexisting conditions, maybe inflammation from COVID-19 triggered and lifted the roof on the issues they already had—or made them worse. Is this mostly a reawakening of preexisting conditions—or something completely new and different? It wouldn’t surprise me if a patient with heart inflammation from their initial COVID-19 infection is at higher risk for long-term cardiac issues, or if really bad lung function during COVID-19 makes someone more likely to have long-term lung issues. But it doesn’t have to be as direct: Low-lying inflammation during the acute illness could lead to chronic inflammation affecting any organ.

To home in on what is going on with the immune system, our teams are now focused on asymptomatic patients or those with mild infections who then later on paradoxically suffer these longer-term effects. One theory is that their immune systems were revved up in such a way to fight COVID-19 that they not only remained overactivated but may even have turned on themselves. A lot of the emerging data are pointing to how, in some people, COVID-19 infection triggers autoimmunity. We’re at the tip of the iceberg. Of patients who have antibodies that attack their own tissues, what makes these people different from those who recover quickly? We need to better understand why they are suffering from these chronic, amorphous, very difficult-to-pin-down conditions.

Susan Cheng, MD, MPH, MMSc, director of Public Health Research at the Smidt Heart Institute and the Erika J. Glazer Chair in Women’s Cardiovascular Health and Population Science


Long COVID raises a lot of questions, but Cedars-Sinai investigators are seeking to demystify its destructive effects. Some of the studies currently underway include: 

  • A long-term study of recovering COVID-19 patients focused on how their immune and inflammatory biomarkers change in relation to their cognitive, physical and social functions (Le).
  • An investigation into why some early COVID-19 patients required ICU care, and whether these patients suffer from long COVID at higher rates (Pedraza and Chen). 
  • A study into the role of SARS CoV2 virus “superantigens” that may cause autoimmunity in patients with MISC—post-COVID syndrome in children (Moshe Arditi, MD, executive vice chair for Research in the Department of Pediatrics, director of the Division of Pediatric Infectious Diseases and the GUESS?/Fashion Industries Guild Chair in Community Child Health).