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What is the definition of Long COVID
Credit: Tatiana Aayzo

For much of the pandemic, long COVID has been rife with mystery. Broadly described as COVID-19 symptoms that last weeks or even months after infection, long COVID piqued the interest of researchers.  

Now, a flood of data is changing our understanding of it, related symptoms, and potential treatments, according to Leonard H. Calabrese, DO, Head of Clinical Immunology in the Department of Rheumatologic and Immunologic Disease at Cleveland Clinic, who gave a presentation on the topic at the ACR Convergence 2022.  

“The whole field of COVID-19 has been very chaotic in terms of the flow of scientific information,” says Dr. Calabrese. “From the beginning, less than three years ago, there’s been over 300,000 articles that have been published on COVID-19 — and that’s just in peer-reviewed citations.”  

Because the research is emerging so quickly, much of it comes out in pre-print studies, or those that haven’t been peer reviewed yet. There are many tens of thousands of these articles being published.  

This poses both exciting possibilities for what we’ll learn about long-haul COVID in the months and years ahead, but also challenges. Here’s what you should know about the current state of research around long COVID, plus what it means for you if you’re living with an underlying condition like axial spondyloarthritis, psoriatic arthritis, or rheumatoid arthritis.

Determining a Clear Definition for Long COVID

One hurdle that researchers have faced when studying long COVID is that there’s not one widely accepted definition for it. In fact, Dr. Calabrese notes that there are at least 50 (and maybe more than 200) definitions that have been attributed to long COVID.  

“The problem is that with long COVID, many of the symptoms in isolation like fatigue, sleep disturbances, headache, bodily pain, or neurocognitive complaints are very common in the general population,” says Dr. Calabrese. “It’s a question of when it warrants the diagnosis of long COVID. 

This is a matter of refining the definition of long COVID. As just one potential example, tiredness associated with long COVID might not just be about feeling sleepy. Instead, it may be tiredness that’s not restored by restful sleep and that’s exacerbated by daily activities that wouldn’t bother someone ordinarily.  

Similarly, the timing of symptoms are important in defining long COVID. It may feel cut-and-dry enough if someone develops new symptoms after being infected with COVID-19, but for many people, certain symptoms existed before infection and are exacerbated after infection.  

Researchers also aren’t clear on how the diagnosis of long COVID may differ based on the combinations of symptoms patients have. For example, they don’t yet understand if there’s a difference between people who have brain fog, fatigue, and headache versus those who have brain fog, musculoskeletal pain, and breathlessness after COVID-19.   

“Then there’s the question of how we capture all of this data,” says Dr. Calabrese. “There have been efforts to capture it by reviewing people’s medical records. But if you have a medical record, that means you have health care and that you went to a practitioner and they coded your complaint accurately — so it’s a very weak tool for most long COVID complications.” 

Another way to gather data is to give patients questionnaires, but if someone had COVID-19 a year or two ago, they may not accurately recall all the details of their symptoms.  

To solve this, there are several large studies underway in the United States and worldwide that are prospective, meaning they look at people before they get COVID-19 and carefully measure data before and after COVID-19 infection. Once this research emerges, experts will have more tools to measure what signs and symptoms may be consistent among those with long COVID.  

“That will be the gold standard, but as anyone would recognize, that’s going to take a long time,” says Dr. Calabrese.  

One more important note to keep in mind: Generally, long COVID is known as persistent symptoms after COVID that don’t have an adequate pathologic basis that we can clearly understand. There’s another large group of patients who have had severe COVID-19, often in the hospital. These patients may experience blood clots, strokes, lung scarring, heart failure, and other complications after this severe form of COVID-19 infection. These are two different branches of post-acute sequelae COVID-19 that are often confused.  

“It may be that there isn’t a single definition that encompasses everything,” says Jeffrey Sparks, MD, MMSc, Assistant Professor of Medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital in Boston. “There are different flavors of long COVID that may or may not be present in a given individual. Each of those might be driven by different pathologic factors, so I think it’s going to be a heterogeneous [diverse] entity that has many different manifestations and gradations of severity and duration.”  

The Data We Have Now and What’s Emerging

Researchers like Dr. Sparks are hopeful that research will continue to focus on long COVID, including its impact on rheumatic patients. Even though a flood of research is being published now, he acknowledges that some interest may wane as the pandemic enters a more manageable phase. 

“I think at the beginning of the pandemic, there were many researchers interested in how severe acute COVID was for our patients, so it was really impressive to see so much interest and we learned a lot quickly,” says Dr. Sparks. “Now, to me, it seems like a lot of people have gone back to their day jobs now, which is also important work.”  

Time and money restraints can limit the amount of research that’s possible and many researchers recognize how difficult long COVID is to study. However, researchers like those in Dr. Sparks’ group are still researching long COVID, specifically when it comes to its impact on rheumatic patients. 

There are three foundational papers from his group published this year that will help inform future research on long COVID for rheumatic patients:  

  • In a study published in Seminars in Arthritis and Rheumatism, researchers surveyed patients with systemic autoimmune rheumatic diseases (SARDs) after they had confirmed COVID-19. The median time to COVID-19 symptom resolution was 25 days and prolonged symptom duration of 28 days or more occurred in 45 percent of patients. This may indicate that participants with SARDs are particularly vulnerable to persistent worsening quality of life (including more pain and fatigue), even beyond the initial infection period. 
  • In a study published in RMD Open, researchers analyzed data from the COVID-19 Global Rheumatology Alliance Vaccine Survey (April 2, 2021 to October 15, 2021) to identify people with SARDs who reported test-confirmed COVID-19. They found that most people with SARDs had complete symptom resolution by day 15 after COVID-19 onset. However, about one in four experienced COVID-19 symptom duration of 28 days or longer — while one in 10 experienced symptoms for 90 days or longer. 
  • In a study published in the Annals of the Rheumatic Diseases, researchers surveyed patients with SARDs from a large healthcare system who had been infected with COVID-19. Vaccinated patients with SARDs were less likely to experience lingering symptoms of COVID-19 compared with those not fully vaccinated. While the researchers note that they cannot rule out the possibility that findings may be due to varying long COVID risk from different SARS-CoV-2 variants, these findings support the benefits of vaccination for patients with SARDs. 

What’s more, other studies looking at treatments for COVID-19 and long COVID specifically may provide answers around how to ease long-term symptoms.  

“I’m very interested right now in therapeutic trials, which have grown from less than a handful a year ago to scores of trials launching right now,” says Dr. Calabrese.  

For instance, researchers are planning to measure the impact of Pfizer’s Paxlovid (nirmatrelvir and ritonavir) on long COVID next year in a clinical trial enrolling 1,700 adults, as part of the National Institutes of Health’s $1.15 billion RECOVER program, per The Washington Post. However, results are not expected until 2024. 

“That will be very exciting, because one of the leading hypotheses in long COVID is that there is some form of persistent viral infection that has been under the radar,” says Dr. Calabrese.  

A November 2022 pre-print study found that people treated with Paxlovid were less likely to experience several key symptoms associated with long COVID.  

There are also a number of other trials looking at alternative approaches to long COVID, such as nutraceuticals. “I’m very excited to look at the well-done controlled trials of integrative medicine that try to attack this with mind-body therapy, exercise, dietary or nutritional modifications, and beyond,” says Dr. Calabrese. “If the trials are done well, we’ll learn from them.”  

The Lessons We Can Take From Other Infections

Many people have suffered from post-acute sequelae caused by other infectious diseases such as the flu or Lyme disease for years. However, the long-term effects of diseases like these still are poorly understood.  

“This is a very difficult area to study, there was no interest in it, researchers who worked in this were marginalized, and patients who had it were often ignored or looked at as though they had some sort of ‘psychosomatic’ illness,” says Dr. Calabrese. “Those who ignore history are doomed to repeat its failures. Any lessons that have been learned in that area need to be well-appreciated and we don’t want to repeat mistakes.” 

For instance, similar to long COVID, “long flu” can cause lingering symptoms like anxiety, fatigue, pain, and abnormal breathing three to six months after infection, per a September 2021 PLOS Medicine study of nearly 115,000 influenza patients.  

Experts like Dr. Calabrese are hopeful that the scientific community will glean lessons from the lack of data on long-term effects of other infectious diseases and recognize that these conditions need to continue to be addressed in medical literature.  

What Emerging Research Means for the Immunocompromised

If you’re high-risk for COVID-19, there’s no denying the daily impact the pandemic has had on your life. To add on to this, long COVID may be more likely to occur in those who have experienced severe infection. Read about our new poll that shines light on immunocompromised experience with long COVID.

“It seems from previous research that the severity of the acute illness could be a risk factor for long COVID, and it seems like some of our patients may be at risk for having a more severe course — not just related to hospitalization, but also related to the severity of the acute symptoms and the number of organ systems involved,” says Dr. Sparks.  

What’s more, long COVID can sometimes confusingly mimic symptoms of your underlying condition. COVID-19 seems to encourage inflammation, antibody production, blood clotting issues, and fibrosis, all disease processes intertwined in patients with immune-mediated inflammatory diseases. “We know from that many other viruses and infections can trigger the immune response that could cause a flare of the underlying rheumatic disease, so it’s possible that it can be really hard to distinguish between a flare of, say, rheumatoid arthritis and long COVID,” says Dr. Sparks. “They have a lot of features that are overlapping.”  

As the current research emerges, health care providers will have a better sense of how to treat and prevent long COVID in high-risk patients. Although many of the questions around long COVID are still unanswered, Dr. Sparks notes that there are two main reasons to remain hopeful. “First, it’s really good news that we’re not talking as much about the really severe COVID, where people are incubated and dying — there are certainly still patients that this happens to, but in a way, it’s a positive that it’s not as prominent now,” says Dr. Sparks. “Secondly, by and large, most people with rheumatic diseases do really well with COVID. More people do not get long COVID than do and many patients return to normalcy.”  

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Interview with Leonard H. Calabrese, DO, Head of Clinical Immunology in the Department of Rheumatologic and Immunologic Disease at Cleveland Clinic 

Interview with Jeffrey Sparks, MD, MMSc, Assistant Professor of Medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital in Boston 

Di Iorio M, et al. DMARD disruption, rheumatic disease flare, and prolonged COVID-19 symptom duration after acute COVID-19 among patients with rheumatic disease: A prospective study. Seminars in Arthritis and Rheumatism. May 18, 2022. doi: https://doi.org/10.1016/j.semarthrit.2022.152025.   

Di Iorio M, et al. Prolonged COVID-19 symptom duration in people with systemic autoimmune rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey. RMD Open. August 26, 2022. doi: http://doi.org/10.1136/rmdopen-2022-002587 

Patel NJ, et al. Impact of vaccination on postacute sequelae of SARS CoV-2 infection in patients with rheumatic diseases. Epidemiology. November 15, 2022. doi: http://doi.org/10.1136/ard-2022-223439.   

Paxlovid may reduce long covid risk for some patients, VA study finds. The Washington Post. November 7, 2022. https://www.washingtonpost.com/health/2022/11/07/paxlovid-reduces-long-covid/.   

Xie Y, et al. Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19 [pre-print abstract]. medRxiv. November 5, 2022. https://doi.org/10.1101/2022.11.03.22281783.   

Taquet M, et al. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLOS Medicine. September 28, 2021. https://doi.org/10.1371/journal.pmed.1003773