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Exploring Future Directions in the Treatment of Long COVID
Developing vaccines and therapeutics for acute COVID-19 infection within a year of the epidemic was one of the “greatest achievements of medicine in the past few decades,” said Steven Deeks, professor of medicine in residence at the University of California, San Francisco. However, it was “pretty straightforward” because the virus was easy to target for vaccines, the targets for therapeutics were well-characterized, and regulators and industry leaders were motivated to work quickly and efficiently. Unfortunately, “none of this really applies” to the treatment of Long COVID, said Deeks.
Deeks identified a number of challenges confronting the development of effective treatments for Long COVID. There are several distinct phenotypes of Long COVID, in which symptoms are focused on the cardiovascular, pulmonary, or neurocognitive systems. Long COVID involves multiple mechanisms, including direct irreversible tissue injury, inflammation, autoantibodies, and microvascular clotting. There are multiple effects on the body such as nerve damage or organ damage, and multiple types of outcomes, including postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and mast cell activation syndrome (MCAS). People are at increased susceptibility to COVID-19 and Long COVID for a huge variety of reasons, including socioeconomic factors, preexisting conditions, mental health history, sex, race, age, and access to health care. Further, said Deeks, there is not a thorough understanding of the natural history of Long COVID, and symptoms within an individual can wax and wane. Devel-
oping treatments—and developing ways to measure whether these treatments are effective—is enormously challenging because of all of this variation.
Deeks described the current approach to the management of Long COVID. The Centers for Disease Control and Prevention (CDC) says that Long COVID can be diagnosed and managed by primary care, and suggests a conservative approach for the first 4 to 12 weeks, with an aggressive workup at 12 weeks if symptoms persist (CDC, 2021a). A variety of physical tests may be employed, including orthostatic vital signs, ambulatory pulse, and exercise capacity. Laboratory testing can be conducted in order to confirm previous COVID-19 infection and to rule out common conditions with similar symptoms (e.g., arthritis, thyroid issues). Specialized testing for Long COVID may include the tilt test, a chest CT, or a brain MRI. Deeks warned that excessive testing can be harmful, as it can lead “down various rabbit holes.” Another issue with testing, he said, can be if a patient’s subjective experience does not align with the objective findings.
The goal of Long COVID treatment is to improve the patient’s quality of life, and a holistic approach is helpful for meeting this aim, observed Deeks. He listed some of the commonly used therapies, including compression stockings, physical therapy, pacing of activities, flexibility and strength exercises, and medications. There are medications for specific diagnoses (e.g., selective serotonin reuptake inhibitors for depression), and some clinicians prescribe other medications off-label (e.g., antivirals, intravenous immunoglobulin). Deeks said that a multidisciplinary, team-based approach for treatment is critical, as it can simultaneously address physical issues, mental health issues, social support, and rehabilitation. In addition, these types of clinics can validate the experiences of patients, help them cope with uncertainty, and help them access financial and other types of support.
Deeks said a search on ClinicalTrials.gov listed over 90 interventional studies related to Long COVID,1 including studies on drugs, biologics, rehabilitation interventions, medical devices, and complementary and alternative therapies. He said that, novel research designs, such as adaptive platform trials, are likely to emerge in the area of Long COVID treatment, much as they did for the management of acute COVID-19 infection.
Because multiple pathways are involved in the development of Long COVID, said Deeks, it is possible that multiple types of interventions may be necessary. For example, if the virus causes irreversible tissue damage, physical therapy and rehabilitation are more likely to benefit the patient. If the patient’s symptoms are caused by the virus persisting in the body, therapeutic
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1ClinicalTrials.gov is a resource provided by the U.S. National Library of Medicine: https://clinicaltrials.gov (accessed March 21, 2022).
vaccinations may be of use. Anti-inflammatory drugs and anticoagulants could address specific issues within the body. Antiviral therapies may not only be useful in preventing Long COVID, they may be useful in the chronic setting as well.
Many studies focus on quality of life and functional status as the outcomes of interest, he said, which poses regulatory challenges. Multiple biologic mechanisms and hard-to-define clinical outcomes that wax and wane will make drug development challenging. Further, limited industry engagement remains a major barrier, said Deeks. Despite these challenges, targetable pathways have been identified and proof-of-concept studies are underway, which can help us understand the biology behind Long COVID as well as identify potential therapies.
DISCUSSION
Following Deeks’ presentation, Andrea Lerner, physician and medical officer at the National Institute of Allergy and Infectious Diseases of the NIH, facilitated a panel discussion with Deeks, Frontera, and Nath, taking questions from the workshop participants.
Given that the majority of Long COVID cases develop in people with mild symptoms who receive no intervention, could COVID-19 treatments given at the outset of a positive COVID-19 case eliminate or significantly reduce the incidence of Long COVID?
Deeks replied that while there is no evidence in this area, it “makes sense” that the earlier therapy is started, the better the outcomes will be. For almost any infectious disease, such as HIV, early therapy is beneficial.
Are there specific symptoms of Long COVID that have shown response to physical therapy, or is the benefit of therapy limited until the cause of the symptoms has been resolved?
In the acute phase of COVID-19, early rehabilitation has been shown to have beneficial effects, including shortening length of stay and enhancing pulmonary recovery, said Frontera. In Long COVID, evidence is limited, but there are good indications that symptoms such as shortness of breath and fatigue respond well to exercise interventions. The results are consistent among the small number of studies (Foged et al., 2021; Wasilewski et al., 2022) that have been conducted in this area, he said, but we will need to follow patients for a longer period of time to determine if therapy has been curative.
Given that specialty clinics and centers of excellence may disproportionately treat primarily White, more financially secure patients, how can we prevent these centers from exacerbating disparities?
There was great progress made in securing access to HIV care for lower-income and marginalized populations, said Deeks. This was accomplished through massive investment from the federal government; this investment means that patients, regardless of financial means or insurance, can go to clinics and receive primary care, specialty care, social services, psychiatric care, and so on. Deeks said there is some discussion in California to fund this type of approach for Long COVID. He added that while it will be an expensive endeavor to provide this holistic approach, right now, “people have no options.” Frontera said that the issue of access and disparities is common in the field of rehabilitation because most centers that treat complex conditions are located in academic medical centers. One option, he said, is to develop a specialized clinic and then make it available to smaller hospitals via telehealth. The effectiveness of this approach is under investigation, he said, but it could be one that works for improving access to care for Long COVID.
How do we strike the balance between the need to start trials to find effective therapeutics for Long COVID and the need to understand different phenotypes and subtypes of post-COVID conditions so trial populations are not so heterogenous that any effect is masked?
It is not easy, said Nath. Studies need carefully characterized inclusion criteria, which generally results in small sample sizes. However, if a study uses a larger, heterogeneous population, “you will never find anything.” Nath shared an example of a study he and his colleagues conducted for chronic fatigue syndrome. Out of an initial group of 250 patients, 21 were enrolled, all of whom had an infection before they developed symptoms, and all of whom had the same pattern of symptoms. A study like this will by its nature examine a narrow population that may not be at all generalizable for the general population. Deeks added that these types of studies can also help further our understanding of biology, mechanisms, and clinical phenotypes. Nath agreed and said that in the study that narrowed to 21 patients, data were collected on all 250 initial patients, which helped further the understanding of the condition. Nath said that another illustrative example of this tension can be seen in studies on postinfectious syndromes. For example, herpes encephalitis is an antibody-mediated phenomenon, so therapies include intravenous immunoglobulin or anti-B cell therapies. Other kinds of postinfectious syndromes, such as acute disseminated encephalomyelitis, are a T-cell-mediated phenomenon, so the treatment would be very different. With Long COVID, said Nath, we may find that even the immunotypic profile of post-COVID-19 patients is heterogeneous.
Is there any evidence that specific variants of COVID-19 affect the development of Long COVID differently?
Anecdotally, said Deeks, the worst cases of Long COVID are from the first couple of waves. However, it is a complicated question because variants occurred in different eras of the pandemic. For example, Delta happened in an era when there were vaccines and treatments emerging. Deeks said he is not aware of any good data on this question. Probably the most important question, he said, is whether and to what extent the Omicron variant causes Long COVID. The numbers of people who have been infected with Omicron is so massive, both in the United States and globally, that if the frequency of Long COVID is the same as with previous variants, “we are going to be in big trouble.” There will be a massive wave of people with really serious issues, he said, that will overwhelm primary care physicians, primary care clinics, and Long COVID clinics.
What are meaningful clinical trial outcomes for Long COVID therapeutics?
The endpoints in our studies are subjective, said Nath, and “that is the biggest problem.” There are well-accepted scales, such as the Health Utility Index, that are validated, but they are still subjective. Taking this type of evidence to the U.S. Food and Drug Administration (FDA) for drug approval could be challenging, he said, although FDA does have experience with treating pain and depression and other conditions that include subjective measures. Frontera added that there are several outcomes that are important for Long COVID, including fatigue and intolerance to exercise. For the purposes of determining if a person could perform work, it could be useful to look separately at cardiovascular tolerance and neuromuscular tolerance. The specific testing that is useful depends on the nature of the job activity, he said.
How can patients educate doctors who do not understand the experience of Long COVID?
One approach that has been useful in the world of rehabilitation, said Frontera, is to invite patients to talk to residents in training about their personal experience with different conditions. This has been helpful for doctors to understand conditions such as amputations and traumatic brain injury, and may be useful in Long COVID as well.
When will a therapeutic for Long COVID become available?
This will likely take time, said Deeks, but much progress is being made. We are making progress on identifying the mechanisms of Long COVID, particularly how inflammation can result in a number of outcomes. Once the mechanisms are clearly identified, there will be advances that can be made and clinical trials can be started.
Is it possible that what is now known as PASC will eventually be categorized as several different conditions, based on the mechanism or end effect?
Deeks responded that this is already the case in some ways. Some conditions that are associated with Long COVID have been identified and have different mechanisms and therapies, for example, post-ICU syndrome and POTS.
CLOSE OF WORKSHOP
At the close of the workshop, Frontera thanked SSA for its support; thanked the speakers for sharing their knowledge, expertise, experience, and ideas; and thanked the workshop participants for their many thought-provoking comments and questions. Frontera adjourned the workshop.
