Infectious Disease

Rheumatologists brace for long COVID’s impact

November 22, 2022

16 min read

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Disclosures:
Ballering and Sparks report no relevant financial disclosures. Calabrese reports professional relationships with AbbVie, AstraZeneca, Bristol Myers Squibb, Galvani, Genentech, GlaxoSmithKline, Janssen, Novartis, Regeneron, Sanofi and UCB. Laster reports consulting and/or speaking fees from Amgen, Chemocentryx, Exagen, Eli Lilly, Novartis, Pfizer, Roche/Genentech and Sanofi.

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In an interview with “60 Minutes” that aired on Sept. 18, President Joe Biden declared, “The pandemic is over.” And in some ways, he was correct.

According to an Ipsos poll released 5 days prior to the interview airing, just 37% of Americans reported wearing a mask when they left the house at least sometimes, while 46% said they had returned to their pre-pandemic lives.

Source: Aranka Ballering, MSc.

Long COVID has the potential to wreak havoc throughout multiple medical specialties, including rheumatology. However, nearly everything from its prevalence to how it is even defined — let alone possible treatments — remains largely unknown. Researchers have begun to draw together data to answer these key questions, but exceptions and confounders seem to abound. “One problem is that when we are dealing with long COVID, we are always at least 3 months behind,” Aranka Ballering, MSc, told Healio Rheumatology. Still, this is not the first time rheumatologists have been involved in a fight against a mysterious disease. Their experience and expertise in managing complex conditions may even make then uniquely suited for the job.
Source: Aranka Ballering, MSc.

However, this sentiment is far from universal. For patients who are immunocompromised, for example, COVID-19 remains a danger very much in the here and now.

And then there are those experiencing post-acute COVID syndromes. For these patients, the pain and the fear associated with their symptoms never ended.

And for physicians managing long COVID, it may only be the beginning.

“We have not even begun to address the impact of long COVID,” Leonard H. Calabrese, DO, director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic, told Healio Rheumatology. “We are in the early stages of understanding it.”

For Calabrese, the list of still unanswered, yet absolutely critical, questions about the nature of long COVID demands serious consideration from physicians, including rheumatologists.

“How do we define this?” he said. “Is long COVID unique or is it similar to other post-infectious disorders?”

Other questions that require answers include those about the pathobiology of post-acute COVID syndromes, and what treatments, if any, may be useful. Yet another: Who, if any specific group, is most likely to develop long COVID? Still another: Are patients with rheumatic and autoimmune disorders, or those on immunosuppressive medications, at greater risk?

At times, it can feel as though the number of pressing questions far outstrips the available answers.

“Although our vision of it is sharpening, we still do not have universal classification or diagnostic criteria,” Calabrese added, noting that as many as 50 symptoms and syndromes have been implicated in long COVID. “However, there may be several times more than that.”

Jeffrey A. Sparks, MD, MMSc
Jeffrey A. Sparks

According to Jeffrey A. Sparks, MD, MMSc, a rheumatologist at the division of rheumatology, inflammation and immunity, and director of immuno-oncology and autoimmunity, at Brigham and Women’s Hospital, and assistant professor of medicine at Harvard Medical School, it may be useful to narrow it down to the most common of those symptoms.

“Although long COVID is a broad term that encapsulates many domains, lingering fatigue and cognitive dysfunction — brain fog — as well as altered taste and smell are particularly common symptoms,” he said. “Some people also have persistent cough, chest pain and shortness of breath, presumably from lung damage from the acute infection that may take time to heal or could result in fibrosis in some.”

Clinicians and researchers of all stripes are working to catalog and categorize the features of long COVID. However, as professionals who commonly deal with persistent, unexplained disorders, rheumatologists may be uniquely positioned to be at the forefront of this fight, according to Calabrese.

In other words, although the foe may still be largely unknown, fighting against the unknown should be familiar ground for rheumatologists.

“We need to define our role in care and research,” Calabrese said. “COVID has disrupted the practice of rheumatology, and we need to figure out how to tackle the challenges presented by this virus.”

Aranka V. Ballering, MSc, of the department of psychiatry at the University of Groningen and the University Medical Center Groningen, in the Netherlands, laid out a pathway for research.

“There should be two branches of research: one epidemiological and one biomedical,” she said.

According to Ballering, the epidemiology side should focus on questions of who develops long COVID and what symptoms they experience.

“Meanwhile, the biomedical side should dig into all possible underlying pathophysiological mechanisms, from inflammation in the blood vessels to loss of gray matter in the brain,” she said.

This research is under way, with a paper authored by Ballering and colleagues serving as a potential springboard for a significant amount of future study.

As Data Trickle in, ‘Exceptions Abound’

In a paper published in August in TheLancet, Ballering and colleagues gathered data from more than 76,000 participants who completed 888,793 questionnaires regarding COVID-19.

The analysis included 4,231 participants with COVID-19 and 8,462 controls, and investigated 23 symptoms, including headaches, dizziness, chest pain, back pain, nausea, painful muscles, breathing difficulty, feeling hot and cold alternately, tingling extremities, lump in the throat, general tiredness, heavy arms or legs, painful breathing, runny nose, sore throat, dry cough, wet cough, fever, diarrhea, stomach pain, ageusia or anosmia, sneezing and itchy eyes.

According to the findings, persistent symptoms at 90 to 150 days after COVID-19 among those who were positive, compared with before COVID-19 with matched controls, included chest pain, breathing difficulties, painful breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness.

The researchers added that these symptoms could be attributed to COVID-19 in 12.7% of patients.

“We found that about one in every eight patients are affected by persistent symptoms after COVID-19,” Ballering and colleagues wrote. “This finding shows that post-COVID-19 condition is an urgent problem with a mounting human toll.”

Also among the findings: Multiple somatic symptoms, including alternating feelings of hot and cold, lump in throat and general tiredness, were more severe after COVID-19 in women than in men, compared with controls.

“We know that female sex predicts more somatic symptoms,” Ballering told Healio Rheumatology.

“However, feminine gender is also associated with more health care-seeking behavior.”

In another paper, published in Clinical Rheumatology, Karaarslan and colleagues aimed to document severity, type and locations of rheumatic and musculoskeletal symptoms, along with persistent COVID-19 symptoms, at 3 and 6 months after hospitalization for COVID-19. Patients were surveyed via telephone. Their findings demonstrated that women were more likely to report fatigue, myalgia and joint pain, compared with men.

“The increased incidence of long COVID among women compared with men has been reproducibly identified,” Calabrese said.

Further findings from Karaarslan and colleagues suggest that nearly 60% of survivors demonstrated at least one persistent symptom, while 43.2% reported at least one rheumatic or musculoskeletal symptom. Regarding those rheumatology-associated symptoms, 31.6% reported fatigue, while 18.6% had joint pain and 15.1% experienced myalgia.

Leonard H. Calabrese, DO
Leonard H. Calabrese

As experts begin to get a sense of the raw numbers surrounding long COVID — with a rate of one in eight patients experiencing at least one ongoing symptom emerging as the current consensus — Calabrese stated he is also interested in who, demographically, may be at risk.

“Starting with age, it seems to start at around 40 years and older,” he said. “Young children appear to be spared this, by and large.”

In addition, although severe acute COVID-19 infection may increase the likelihood of acquiring post-acute syndromes, there are not yet hard data to confirm this hypothesis. Moreover, individuals with mild or moderate acute COVID-19 symptoms also may develop various types of post-acute symptoms.

“It may be based on the symptoms, or the number of symptoms, of the initial infection,” Calabrese said. “But some patients who have had all or most of the possible symptoms do not end up getting long COVID.”

As researchers continue to wrestle with the factors that predict long COVID, it may also help to look at potentially protective factors.

“We know that in some cases, having mild acute disease can be protective,” Calabrese said. “Also younger age, as I mentioned, and being vaccinated. This is important information for us.”

Meanwhile, there is some indication that long COVID may be less likely to follow infection from omicron variants, but the data on this point remains similarly unclear, according to Calabrese.

Sparks also counseled caution about drawing any hasty conclusions based on the data that have become available so far.

“Since long COVID is not a single entity, it will be hard to make sweeping statements on who is and is not affected,” he said. “However, our research suggests that those with higher number of symptoms at COVID-19 onset were at higher risk of long COVID. Therefore, severity of acute COVID-19 seems to be associated with risk of long COVID. That said, many exceptions abound.”

As experts research and debate the epidemiology, a closer look at the symptomatology may hold some answers to the frequency and nature of the phenomenon.

Symptoms ‘Cluster Together’

Taking a closer look at the Ballering paper, a comparison was made between persistent symptoms in the COVID-19 group at 90 to 150 days post-infection with symptoms these individuals experienced prior to acquiring the virus.

“We should take into account that symptoms like sneezing, coughing or headache are common, and that some of our patients experienced these symptoms before COVID diagnosis,” Ballering said.

“Some of the post-acute COVID symptoms may not necessarily be related to COVID,” she added.

That said, the investigators defined a series of “core symptoms,” including chest pain, difficulty or pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness.

“The most common symptom we see is fatigue, followed by neurocognitive dysfunction,” Calabrese said. “Breathlessness and other respiratory symptoms are common, along with headache and musculoskeletal pain.”

Regarding the frequency of the outcomes Ballering observed, 21.4% of patients in the COVID group experienced at least one of the core symptoms, compared with 8.7% of COVID-negative controls who also experienced one of these symptoms.

“As a result, in 12.7% of our patients, these symptoms could be attributed to COVID-19,” Ballering said.

Another potentially important point for future research is that certain symptom groups may “cluster together,” according to Ballering.

“Pulmonary symptoms may tend to cluster together, more cough symptoms may cluster together,” she said.“Pulmonary symptoms tended to cluster together, more cough symptoms clustered together,” she said.

The possible clinical implications of this are significant. Ballering suggested that if such patterns emerge in future research, experts may gain further understanding of the underlying pathophysiological mechanism at play in long COVID.

“To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic,” Ballering and colleagues concluded.

Experts acknowledge that separating common colds and other pre-COVID symptoms from actual long COVID can be daunting. For Calabrese, it is not just a matter of the clustering of symptoms, but also of compounding symptoms.

“One individual may have a sore throat and sniffles a few months after infection, and it may just be a cold,” he said. “But if we see sore throat and sniffles accompanied by a fever and body aches, those might be statistical risk factors that amount to long COVID.”

Calabrese added that the brain fog described by many patients with long COVID has some distinguishing features from other types of brain fog.

“We see it as a post-exertional malaise,” he said. “Patients who have this can range from mild to severe, and the fatigue can come from physical, intellectual or emotional exertion.”

In their pre-COVID life, the fatigue an individual might describe after such exertion would either not occur at all or go away easily, according to Calabrese.

“But we have seen patients worn out after going to the store, doing a light workout or having to multitask,” he added.

Ballering and colleagues also attempted to determine whether, and how, symptoms change before and after COVID-19. For example, they found that the aforementioned core symptoms were increased at 3 to 5 months after COVID-19, and are likely to decrease functioning, lead patients to seek help, and demonstrate “plausible underlying pathophysiological mechanisms,” they wrote.

However, Ballering warned that there are pitfalls in drawing a conclusion from these examples.

“One problem is that when we are dealing with long COVID, we are always at least 3 months behind,” she said. “When you want to research — clinical or epidemiological — there is always a risk of recall bias. However, in our study we minimized this risk by distributing weekly and biweekly questionnaires during our study period.”

This type of recall bias is just one of many potential confounders when trying to define the parameters of long COVID. Another complicating factor is that patients with rheumatic and autoimmune conditions commonly experience many of the symptoms now being attributed to long COVID.

‘We Just Don’t Have an Answer Yet’

In a paper published in Clinical Rheumatology, Sapkota and Nune wrote that there are “shared clinical features, laboratory and imaging findings” between long COVID and other rheumatic diseases. It follows that this could pose huge diagnostic challenges for all clinicians, including rheumatologists.

Andrew J. Laster, MD
Andrew J. Laster

“We just don’t have an answer yet as to the prevalence of long COVID in our patients with rheumatic diseases,” Andrew J. Laster, MD, president of Arthritis & Osteoporosis Consultants of the Carolinas, said in an interview. “A friend of mine who is an internist in town bemoaned the large number of patients with long COVID who are flooding his practice. It’s something that I just have not seen in large numbers in my patients on immunosuppressive therapy.”

Laster spoke to the extensive list of symptoms and clusters discussed by Ballering and Calabrese.

“Part of the challenge is defining what is meant by long COVID,” he said. “I think the WHO case definition is helpful regarding having symptoms at 3 months from onset of COVID-19 infection that last for at least 2 months and can’t be explained by an alternative diagnosis. Being aware of the 3 most common symptoms of fatigue, shortness of breath and cognitive dysfunction can also help.”

According to Laster, a survey of rheumatology patients could be effective in truly determining the impact on that population.

“What we really need is a study where we go back to our practice, identify patients who have had COVID, query them as to whether or not they have had symptoms that would be consistent with long COVID, while comparing whether or not they are on immunosuppressive therapy, and see if it really is one in eight patients who are experiencing these post-acute syndromes,” he said. “If the numbers are lower, it could be an intriguing consideration for the discussion.”

Laster added that it is also worth considering that some patients, particularly those with pre-existing rheumatic conditions that resemble post-acute COVID-19 syndromes, may simply be taking longer to get over the initial infection.

“They may have just had severe disease,” he said.

Because of the overlap between rheumatology and long COVID syndromes, Sparks said he expects many studies will yield “inconclusive” results.

“However, it seems very possible that those with rheumatic or autoimmune conditions could have higher risk for long COVID,” he said, calling for a detailed investigation into the pathophysiology related to the inflammation, autoimmunity, fibrosis and hypercoagulability that mark both rheumatology and post-acute COVID-19 patients.

However, this is just one part of how rheumatology and long COVID may potentially interact.

Changes in Cytokines

In a paper published in the Annals of the Rheumatic Diseases, Sparks and colleagues aimed to assess how the use of biologic or targeted synthetic disease-modifying antirheumatic drugs impact COVID-19 outcomes in a cohort of 2,869 patients with rheumatoid arthritis, pulled from the COVID-19 Global Rheumatology Alliance physician registry.

The analysis included patients treated with abatacept (Orencia, Bristol Myers Squibb), rituximab (Rituxan, Genentech), an interleukin-6 inhibitor, a Janus kinase inhibitor or a TNF inhibitor. Results demonstrated that, compared with TNF inhibition, both rituximab (OR = 4.15; 95% CI, 3.16-5.44) and JAK inhibition (OR = 2.06; 95% CI, 1.60-2.65) were associated with worse COVID-19 severity. No such associations were observed for abatacept or IL-6 inhibitors.

According to Laster, biologics could potentially lead to changes in cytokines in the brain that could be preventing long COVID, especially since an autoimmune reaction is postulated as one of the mechanisms of long COVID.

“Pre-COVID, I have had several patients report that when they went off their TNF inhibitors, they were not as mentally sharp,” he said. “And we know from several clinical trials that IL-6 receptor blockers can impact the perception of pain without necessarily decreasing joint swelling. Our drugs could potentially have a protective effect in patients who have had COVID-19 infection that might lower the likelihood of developing long COVID.”

According to Sparks, it is possible that the immunosuppression and altered immunity might veer these patients away from long COVID symptoms.

“This will be another important area of research,” he said.

“Since both long COVID and rheumatic diseases are quite heterogeneous, there may be subgroups that may be susceptible or relatively resistant to long COVID,” he added.

DiIorio and colleagues also explored the impact of DMARDs in the long COVID setting in a paper published in Seminars in Arthritis and Rheumatism. Specifically, they examined DMARD disruption, rheumatic disease flare and activity, and long COVID duration among 174 COVID-19 survivors with systemic autoimmune rheumatic diseases (SARDs).

The cohort was more than 80% women and 80% white, with half of the study population being patients with RA. Results showed that, among the 127 respondents who were taking any DMARD, 51% reported a disruption to this drug regimen after COVID-19 onset. In all, the proportion of DMARDs that were disrupted at COVID-19 onset ranged between 56% and 77%. The researchers concluded that DMARD disruption, SARD flare and prolonged COVID-19 symptom duration were common in this population, “suggesting substantial impact on SARDs after acute COVID-19.”

Findings like these may be the foundation for the next level of research not just in rheumatology patients, but in the general population, according to Ballering.

Meanwhile, for Laster, timing of symptom onset may be an important factor to consider.

“The WHO definition is that it occurs at 3 months out from acute infection,” he said.

However, data from the paper by Sparks and colleagues included some patients who had post-acute symptoms as early as 45 days out.

“This paper is helpful in looking at patients with rheumatic and autoimmune disorders, but all of the patients may not land squarely in where we are thinking about long COVID,” Laster said.

If there is a silver lining for rheumatology patients, it is that they are generally “well-educated” when it comes to their conditions, symptoms and medications, Laster added.

“They understand what happens when they flare, and, if pressed, they will likely know whether they are experiencing disease-related symptoms or something new that could be long COVID,” he said.

Implications of Stress and Fear

Given that almost any symptom and predictive factor could be in play, Calabrese discussed the impact of the pandemic itself — the lockdowns, the stress and the fear, among other issues — as a potential contributor or confounder in the long COVID discussion.

“This could potentially be a huge factor,” Calabrese said. “If you had anxiety and depression before the pandemic, it may contribute to this.”

He additionally asserted that the old notion of “psychosomatic illness” does not serve well the current understanding that the brain and immune system are highly integrated.

“I routinely tell my patients that the brain and immune system are one,” Calabrese said.

This, he added, can empower patients to examine parts of their lifestyle, such as sleep, stress modification and wellness behaviors like mindfulness meditation, qigong and tai chi.

“Naysayers may describe this as a ‘psychosomatic phenomenon,’ but it may be worth looking to see if the neurological pathways that were present beforehand were activated with the stress of the pandemic,” Calabrese said.

In a perfect world, research into the psychosomatic effect of the pandemic as a function of long COVD would be underway.

However, there are still many more pressing questions to answer, according to Laster.

“We still do not know if long COVID is more common with different variants,” he said. “We do not know if the vaccine is protective.”

Calabrese, for his part, noted that there are recent data suggesting that vaccination may reduce the likelihood of long COVID by one-third.

That said, the impact of antiviral therapy during the acute phase on the development of long COVID has also not been adequately explored. Laster added that ongoing investigations should keep track of the natural history, longevity and severity of long COVID.

“Will it peter out after a year?” he said. “Could we be dealing with it for 3 or 5 years, or longer?”

Meanwhile, a broader concern pertains to the looming shortage of health care professionals — and not just in rheumatology.

“If this is truly going to impact one in eight patients, we do not have enough health care providers to deal with this,” Laster said, noting that there have been approximately 97 million COVID-19 cases reported in the United States. “We just do not have the manpower. Take for example the subset of patients with long COVID who have postural orthostatic tachycardia syndrome (POTS). That frequently requires a detailed evaluation in a clinic specifically designed to perform autonomic studies.”

Even if not all patients with long COVID have severe symptoms, it will still be a “significant challenge” to manage, according to Laster.

Combine this physician shortage with the fact that many of the symptoms of long COVID manifest as unexplained physical complaints, and it becomes clear that many — if not most — rheumatologists will likely to be called in to deal with long COVID at some point sooner than later.

According to Calabrese, this, plus the emerging body of data demonstrating the crossover between rheumatology and long COVID, underscores the significant role rheumatologists may play in combating this post-acute pandemic.

“Rheumatologists know about unexplained pain and fatigue,” he said. “We have seen everything from musculoskeletal pain to brain fog.”

‘We Have Been Here Before’

With that in mind, Calabrese spoke directly to the rheumatology community.

“At the moment, many of us in our field lack confidence in this,” he said. “But we have been here before with these unexplained conditions, from Kawasaki disease to COVID itself. We are well positioned and experienced to manage this condition and do the research. As we have done before, I urge everyone in our field to keep an open mind right now.”

Given that there are no clearly defined treatment protocols, Laster offered a bit of advice for daily practice.

“I urge compassion,” Laster said. “I urge a focus on wellness. I urge empathy. Above all, I urge you not to dismiss these patients out of hand. Let them know that you may not necessarily know what is happening, but you will do everything you can to help.”

Calabrese agreed, added that listening, validation and empathy are key.

“We do not have interventions that are curative as yet, but let your patients know that you recognize their pain and fatigue, and that you will do everything you can to help,” he said.

However, experience with empathy and unexplained symptoms are not the only qualities a rheumatologist can offer to a patient with potential long COVID, according to Laster.

“We are used to collaborating with other specialists in a coordinated way, which is what many of these patients need,” he said.

That said, empathy and collaboration still may not be enough to help many of these patients, at least not right away. Above all, Calabrese was clear that both COVID-19 and long COVID are going to be ongoing challenges for every rheumatologist.

“This will be with us for the rest of our professional careers,” he said.

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