In for the long haul: Clinicians wrestle with post-acute COVID-19 syndromes
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The time warp of COVID-19 has offered yet another twist. As acute infections and the associated fatalities have finally begun to ebb in the United States, a new phase of the pandemic has emerged: the long-hauler phase.
While most patients manage to fight off the infection within weeks or months, increasing incidence of a spectrum of complications and ongoing syndromes is worrying experts.
Source: Arthritis and Rheumatic Disease Specialties.
Fatigue, body aches and shortness of breath are commonly reported, along with headaches, malaise, difficulty sleeping and gastrointestinal complaints. Perhaps most concerning are the mental health comorbidities, which can include depression, anxiety and what patients frequently describe as “brain fog.” These complications can range in severity from mild to incapacitating.
The phenomena are new enough that the nomenclature has yet to be determined. Patients may be referred to as “long haulers,” while “long COVID-19,” “post-COVID-19 syndrome” and “post-acute COVID-19 syndrome” (PASC) have also been used.
“We have no idea what is causing PASC,” Steven G. Deeks, MD, professor of medicine at the University of California, San Francisco, told Healio Rheumatology. “We believe there are several different unique phenotypes. Each presumably will have its own mechanism. Our own group is focusing on virus persistence as one possible mechanism, but we are agnostic and actively studying various inflammatory responses.”
Whatever this syndrome or these syndromes will ultimately be called, experts at the NIH were concerned enough to convince Congress to assign $1.15 billion to a multipronged initiative to register, categorize and research this patient population.
While that may seem like a big dollar sign, experts like Norman B. Gaylis, MD, president of Arthritis and Rheumatic Disease Specialties, believe that every penny will be put to good use. “Early numbers say that as many as one in seven patients who go through the acute phase will also have some sort of long-hauler syndrome,” he said.
Gaylis runs one of the foremost clinics for long haulers in the country. “Since that first patient walked through our door, we have seen more than 150 patients suffering from these various comorbidities in just a few months,” he said, noting that he has dealt with arthralgias, myalgias, autonomic dysfunction and pericarditis, among other conditions. “These patients have tremendous anxiety.”
It may be possible, then, to acknowledge that the “what” of long-hauler syndrome is coming into focus, albeit with a broad range of presentations. It is critical to next find out “who” and “why.” Answers are not expected anytime soon.
“Our position is that this disease is poorly understood,” Leonard Calabrese, DO, RJ Fasenmyer Chair of the Center for Clinical Immunology at Cleveland Clinic, said in an interview. “People are just starting to craft questions about these long haulers. We feel there is a lot of work to be done upfront to understand who this patient population is and why they are clearly suffering after COVID-19 infection.”
This task is going to take coordinated effort from health care professionals of all stripes. A silver lining in the millions of individuals impacted by COVID is that there will be no shortage of patients to study.
Critical Questions
Deeks laid out the first hurdle in gaining a handle on understanding long haulers. “As we lack a widely accepted definition of this syndrome, we really do not know its epidemiology,” he said.
Another concern is that while many groups around the world are studying these populations, there is little uniformity in the approach. “Everyone is measuring something different, and as a consequence the prevalence and natural history vary from study to study,” Deeks said.
It is for this reason that a coordinated effort from a body like the NIH may be an optimal response. The billion-dollar program will be comprehensive and include research into large cohorts of individuals who have recovered from the virus, along with core resources for clinical science, data and biological specimens. All of this effort will be put toward answering a number of fundamental questions:
- What does the spectrum of recovery from SARS-CoV-2 infection look like across the population?
- How many people continue to have symptoms of COVID-19, or even develop new symptoms, after acute SARS-CoV-2 infection?
- What is the underlying biological cause of these prolonged symptoms?
- What makes some people vulnerable to this but not others?
- Does SARS-CoV-2 infection trigger changes in the body that increase the risk of other conditions, such as chronic heart or brain disorders?
In addition to the NIH list, Calabrese has some questions of his own. The first is whether patients are simply suffering from end-stage organ damage that is commonly seen in patients who spend time in the ICU. “This should be the most straightforward to sort out with tests and imaging,” he said.
The second possibility is that these patients may have some persistent occult viral infection that has not been detected. “That is also being tested but appears unlikely at this point,” Calabrese said.
Yet another question is whether these patients have a condition similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). “It is still a work in progress to determine this but, for many of the patients we have seen thus far, the similarities are striking,” Calabrese said. “It requires further investigation and reflection.”
The good news is that, with studies on long haulers emerging daily in the peer-reviewed literature, the work is, in fact, in progress.
Epidemiology and Symptoms
In a study published in the Annals of Internal Medicine, Chopra and colleagues observed 1,648 patients hospitalized with COVID-19 at 38 hospitals in Michigan between March 2020 and July 2020. Among 488 patients who completed a phone survey 60 days after discharge, 159 reported cardiopulmonary symptoms. Of that group, 92 patients had new or worsening symptoms and 65 had a persistent loss of taste or smell.
“Most of the studies suggest that perhaps 10% to 20% of people who recover from the acute stage will have significant symptoms persisting for at least 3 to 4 months,” Deeks said.
A study from Carfi and colleagues published in JAMA included 143 COVID-19 patients who were surveyed approximately 60 days after symptom onset. Results at that timepoint showed that just 12.6% were completely free of any symptoms associated with the virus, while 87.4% were not. The researchers noted that 32% reported one or two symptoms and 55% had three or more symptoms. Dyspnea, joint pain and chest pain all impacted a substantial proportion of patients.
“Smaller numbers have pulmonary symptoms like dyspnea or cardiovascular symptoms like palpitations,” Jinoos Yazdany, MD, MPH, chief of the division of rheumatology at Zuckerberg San Francisco General Hospital, told Healio Rheumatology.
As more such studies are published — and even a cursory search of the peer-reviewed literature will turn up dozens of results — the clinical community will get a clearer picture of the various groups of long haulers. Equally important, though, will be centers like the Cleveland Clinic’s reCOVer Clinic, which is geared specifically toward this patient population.
“Patients with a physician referral who have documented persistent COVID-19 see a reCOVer Clinic provider and go through a standardized workup to address their symptoms,” Cassandra Calabrese, DO, an associate staff member in the department of rheumatic and immunologic disease in the department of infectious disease at the Cleveland Clinic Foundation, said in an interview.
The test checks for joint or chest pain and shortness of breath. If cardiopulmonary symptoms are present, patients undergo a series of tests including a 6-minute walk and an echocardiogram, along with a neurological examination, according to Cassandra Calabrese. “If they have joint pain, they see me,” she said. “If they have brain fog, they may see a neurologist, and if they have trouble breathing, they see pulmonology.”
This type of methodology will be hugely beneficial not only in sorting out the impact of COVID-19 on the general population, but also in understanding how inflammation and autoimmunity fit into the equation.
Impact on Rheumatic Diseases
In addition to the aforementioned list of general questions about long haulers, Leonard Calabrese also discussed where patients with rheumatic and autoimmune diseases may fit into the equation. “There is a small population who probably had some type of autoimmune disease that was clinically silent when they got the virus,” he said. “Then COVID-19 set it on fire.”
Gaylis does not believe patients with rheumatic or autoimmune diseases, silent or not, are at greater risk for long hauler syndromes, but he did offer a comment on patients with these conditions being treated with biologic therapies. “There has been some speculation that biologics were increasing potential defense mechanisms against COVID-19,” he said. “But this is just speculating.”
A companion possibility, according to Leonard Calabrese, is that COVID-19 is generating an entirely new inflammatory or autoimmune pathway. “That also seems testable to us and is being done by several groups utilizing deep immune profiling,” he said.
Cassandra Calabrese noted that, thus far, their clinic has “rarely found objective evidence of new inflammatory conditions.”
As for whether COVID-19 itself is generating an autoimmune or inflammatory condition, Leonard Calabrese suggested that some underlying genetic predisposition may be present in some patients. “They may have also been predisposed due to their behaviors or exposures,” he said.
Drawing comparison between long-hauler outcomes in individuals with and without rheumatic diseases may be illuminating, according to Cassandra Calabrese. “We will also be looking at the nature of their COVID-19 course and whether or not they were hospitalized,” she said.
But, as one would expect, there are no clear answers to any of these questions as yet. If there is one certainty about long haulers, however, it is that their lives are often vastly different than they were before COVID-19 infection.
Disruption of Life
The analysis from Chopra and colleagues also included 195 patients who were employed before hospitalization. While 117 of those patients were able to return to work, 78 had ongoing health issues that prevented employment. Thirty of the 117 patients who returned to work reported reduced hours or modified duties due to health concerns.
“It is not just people who were in poor physical condition to start with who are experiencing these outcomes,” Cassandra Calabrese said. “We have seen these effects in high-functioning, physically active people who now are unable to get off their couch.”
Emotional outcomes were reported in 238 of the 488 patients in the full Chopra cohort, while 28 sought mental health services. Fifty-eight percent of the full study population had new or worsening difficulty in completing daily activities.
“Recent studies suggest a significant number of patients have neurological or neuropsychiatric sequelae, like anosmia, ageusia and cognitive fogging,” Yazdany said.
There may be a logical explanation for these outcomes, according to Gaylis. “While we do not know for sure why this happens, we do know that the virus goes through the blood-brain barrier,” he said. “Loss of taste and smell is an indication that the virus has reached the brain.”
The thought is that if the virus is in the brain, it can wreak a great deal of havoc. “If I had to look for one particular signal that can lead to the anxiety and brain fog that we are seeing, it might be loss of taste and smell,” Gaylis said.
The effects do not stop there. Further findings from the Chopra study showed that 179 patients reported a financial impact of COVID-19 infection, with 47 patients reporting that they had to use all or most of their savings to meet basic needs.
This is not the only study showing this type of impact. In the study by Carfi and colleagues, more than 40% of patients reported a poorer quality of life post-infection, while fatigue was reported in more than half.
Cassandra Calabrese said that brain fog is “probably the No. 1” complaint from patients at her clinic, but that it does not exist in isolation. “This issue is tied to poor sleep and a reduction in daily physical activity,” she said. “Chronic mood disorders may be involved, as well as chronic pain.”
The group is actively trying to determine who is likely to experience this type of fog, fatigue and malaise, but no clear answers have emerged.
Severe Disease as Predictive Factor
In a paper published in the Lancet, Huang and colleagues presented 6-month follow-up data for 1,733 patients with COVID-19. They found the expected rundown of complications: 76% of patients had at least one ongoing symptom at this timepoint, with fatigue or muscle weakness occurring in 63%, difficulty sleeping in 26%, hair loss in 22% and trouble with mobility in 7%. Around 10% reported difficulty with smell and taste. But perhaps the most telling finding was that patients who had more severe infection in the acute phase were more likely to experience these ongoing symptoms.
“Although we do not really know the prevalence, we are getting a consensus on who is at risk,” Deeks said. “People who were more symptomatic during the acute phase are more likely to have PASC, which is not particularly surprising. One assumes that viral load during the acute phase and/or the inflammatory response to that virus are driving disease in the acute and chronic phases.”
Older age may also predispose an individual to ongoing symptoms, according to Yazdany. “Female sex and a greater number of symptoms in the first week of infection have predicted prolonged symptoms, but more work needs to be done in this area,” she said.
Deeks also has seen evidence that women may be more likely than men to experience these complications. “Given our experience with many of the rheumatologic diseases that share similar presentations, this may not be surprising,” he said. “It does raise the hypothesis that the immune response is a key driver of disease. I assume that the study of PASC will prove highly informative in helping us understand the pathogenesis of a number of rheumatologic diseases.”
If individuals with severe acute infection were the only population experiencing long hauler symptoms, the epidemiology might be easier. But that is not the case, according to Leonard Calabrese. “The group that is daunting and challenging is people who had milder forms of COVID-19 who 2 or 4 or 8 months later are displaying symptoms that are limiting their quality of life,” he said. “This is something that is a public health catastrophe that could potentially involve a large segment of the population.”
With so much at stake, coming up with treatment strategies for the various types of long haulers is of utmost importance.
Treatment Paradigms
“Without a mechanism, most treatments are going to be supportive,” Deeks said. “Of course, using potential treatments as a tool to disrupt various pathways may prove to be the best way to figure out the mechanism.”
Deeks called for more “experimental medicine” in this area. “I am optimistic we will have substantial support from the NIH,” he said. “What we really need is more engagement by our partners in the biotechnology and pharmaceutical industries.”
Until that engagement materializes, groups around the world are beginning to piece together the puzzle of treating long haulers.
Mendelson and colleagues wrote about treatment paradigms in a paper published in the South African Medical Journal. “Symptoms are as markedly heterogeneous as seen in acute COVID-19 and may be constant, fluctuate, or appear and be replaced by symptoms relating to other systems with varying frequency,” they wrote. “Such multisystem involvement requires a holistic approach to management of long-COVID-19.”
Gaylis believes that rheumatologists may be uniquely positioned to treat these patients, given their experience managing cytokine disruptions in lupus and vasculitis. “We have been getting about a 60% response rate measuring what cytokines were out of line and then treating appropriately,” he said. “Sometimes we do better, sometimes we do worse.”
For patients with disruptions in autonomic dysfunction, Gaylis and his colleagues have been measuring the sympathetic and parasympathetic nervous system. Selective serotonin reuptake inhibitors and H1 antagonists may be beneficial these patients. “These are drugs that have played a role in rebalancing the autonomic nervous system,” he said.
Other patients who have visited Gaylis’s clinic have benefited from a combination of biologics and mood stabilizers. “We have used physical therapy and psychological counseling,” he added.
Given the limited evidence available, treatment paradigms are “evolving,” according to Yazdany. “For patients who have symptoms persisting after 12 weeks, there are currently no primary research studies that test management strategies,” she said. “A variety of strategies are being used in clinical practice, such as involvement of an interdisciplinary team, including rehabilitation professionals, self-management programs and medical management of specific symptoms.”
Like Gaylis, Yazdany stressed the necessity of managing each unique patient and the particular complications impacting them. “Importantly, listening and empathy are important to validate the patient’s lived experience and reduce anxiety,” she said.
In the absence of actual treatments, Cassandra Calabrese offered a therapeutic option for clinicians to consider. “We are starting to see that in some patients, vaccination led to partial or complete resolution of post-acute COVID syndromes,” she said. “We are not clear if this is a placebo effect or some other mechanism, but we are certainly encouraging our patients to get vaccinated.”
Call to Action
As for the role of rheumatologists, Yazdany urged her colleagues to help direct their patients to the right specialist to manage their particular symptoms, from pulmonary complaints to what she described as the “post-traumatic stress” of COVID-19 infection. “Addressing these aspects, on top of ensuring adequate control of their rheumatic disease, is going to be key to helping patients heal and regain their quality of life,” she said.
Leonard Calabrese echoed this sentiment. “Clinicians need to truly listen to these patients, which requires presence and empathy,” he said. “Whatever the cause, these patients need validation. Just because we don’t understand it right now does not mean it’s not real.”
Managing long haulers is essential because this ongoing phase of the pandemic may ultimately prove most costly, according to Gaylis. “What we are seeing is not unique,” he said. “Every day, our phone is ringing off the hook with more and more patients and more and more clinicians who have questions about these patients.”
While Gaylis and his group are only starting to formulate answers, he has embraced the learning curve that this conundrum has presented. “Not a day goes by that we are not learning something new about this patient population,” he said.
Learning, then, should give way to action, according to Deeks. “Once we know what we are dealing with, we can leverage those existing longitudinal cohorts in which biologic specimens were collected and stored to figure out the possible mechanisms,” he said. “Once we have viable mechanisms, we and others can start doing the hard work, which will be developing treatments.”
- References:
- Carfi A, et al. JAMA. 2020;doi:10.1001/jama.2020.12603.
- Chopra V, et al. Ann Intern Med. 2020;doi: 10.7326/M20-5661.
- Huang C, et al. Lancet. 2021;doi: 10.1016/S0140-6736(20)32656-8.
- Mendelson M, et al. S Afr Med J. 2020; doi:10.7196/SAMJ.2020.v111i11.15433.
- For more information:
- Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: calabrc@ccf.org.
- Leonard Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: calabrl@ccf.org.
- Steven G. Deeks, MD, can be reached at steven.deeks@ucsf.edu.
- Norman Gaylis, MD, can be reached at 2801 NE 213th St., Suite 801, Aventura, FL 33180; email: jsagliani@aol.com.
- Jinoos Yazdany, MD, MPH, can be reached at 1001 Potrero Ave., Suite 3300, San Francisco, CA 94110; email: jinoos.yazdany@ucsf.edu.
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