RECOVER charts progress toward better understanding of different autonomic symptoms
Researchers say it’s important to study specific symptom clusters to better understand how Long COVID causes autonomic dysfunction, which occurs when essential, automatic processes in the body do not work as expected and leads to many different symptoms.
As RECOVER enters the next phase of its adult observational study, researchers continue to study how Long COVID impacts specific systems in the body. One area of study focuses on problems with the autonomic nervous system—otherwise known as autonomic dysfunction. Autonomic dysfunction affects the body’s automatic processes, such as regulating heart rate and body temperature, breathing, and digestion.
“Looking through the data collected [during the first phase of the adult study], we see that autonomic dysfunction is one of the most debilitating areas within Long COVID,” said Rachel Hess, MD, MS, a RECOVER researcher who is leading studies in this focus area. “Because people experience so many different symptoms, symptom characterization [defining and differentiating among symptoms] is difficult. To date, we’ve seen similar areas get grouped together, but in reality, the origin story of why these symptoms are occurring may be very different.”
As an example, Dr. Hess pointed to the differences between Type 1 and Type 2 diabetes. “When they went in with a hammer and gave everyone insulin, it wasn’t addressing the right mechanism to improve Type 2 diabetes,” she explained. “They first needed to understand the different biological mechanisms and create different treatments that addressed them.”
Similarly, she said, researchers can’t take a one-size-fits-all approach with Long COVID symptoms related to autonomic dysfunction.
Autonomic dysfunction contains many symptoms
“After my second bout of COVID, I would lose my bearings when standing. I used to do aqua therapy, but I passed out many times in the water and had to give it up. My heart races and my blood pressure rises for no reason just sitting down. My cholesterol went over 300 mg/dL, and my liver enzymes also shot up. Both my autonomic and metabolic functions were significantly affected.”
— Julie Lam, MFA, RECOVER Patient Representative
People who have autonomic dysfunction related to Long COVID may experience symptoms such as dizziness, rapid heart rate, and extreme fatigue. These symptoms may present as a condition called postural orthostatic tachycardia syndrome (POTS), which occurs when not enough blood flows to a person’s heart when they stand from a seated or lying position and can cause dizziness or fainting.
However, POTS and POTS-like presentations are only one aspect of autonomic dysfunction. The broad category of potential autonomic symptoms may include certain problems related to the stomach and digestion, trouble regulating one’s temperature, neuropathy (which may present as numbness, tingling, pain, or sensitivity), and problems with how the brain functions, among others.
Researchers are also interested in exploring the relationships between COVID and other chronic conditions that, like Long COVID, develop after an infection. Conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and similar illnesses have been recognized for longer than Long COVID, but advocates say that additional research is needed to better understand them.
RECOVER studies have revealed a link between COVID and some of these conditions. A publication from the RECOVER adult study’s first phase revealed that people who had COVID-19 were about 5 times more likely to develop ME/CFS than those who did not have COVID-19. The symptom most frequently reported by people in the study was post-exertional malaise (PEM), or exhaustion triggered by even small amounts of physical, mental, or emotional activity.
“These symptoms [and conditions] are one of the most under-studied areas in health,” Dr. Hess said. She added that steps forward have been made; in her lifetime alone, she said, “These symptoms [and conditions] have gone from being relegated to mental health to conditions that are now understood as biology.”
However, she said, much more progress is needed—and RECOVER enables researchers to apply a Long COVID perspective to study many of these symptoms and conditions that are not yet fully understood.
Mady Hornig, MD, MA is a RECOVER Patient Representative who is also a translational physician-scientist (a doctor who bridges the gap between research findings and patient care) and professor. She agreed that understanding the biological mechanisms behind the many symptoms associated with autonomic dysfunction is key. “We need to account for the huge amount of differences among Long COVID patients and parse the symptoms out into clusters when we study them,” she said.
At the same time, she noted, researchers must be cautious about separating people into too many different study groups, which could lead to research findings that miss commonalities among those experiencing autonomic dysfunction, or study groups that include too few people to make a meaningful conclusion.
Challenges in studying autonomic dysfunction
“Autonomic dysfunction creates havoc throughout the body. It is a completely debilitating condition for which there is no cure yet and it led to my disabled status. It is relentless, but then again, so am I.”
— Cynthia Horvath Garbutt, RECOVER Patient Representative
During the second phase of the adult study, the study team will take steps toward understanding the differences among the many Long COVID symptoms and related conditions that are commonly referred to as autonomic dysfunction.
One of the challenging parts of studying these specific symptoms is that they can be very difficult to measure. Although there are clinical definitions for each symptom or related condition, actual measurement depends on a limited number of patient-reported items on surveys—and these reports may vary based on how people interpret the surveys.
“There’s so much variability in how people experience even the same symptom,” said Dr. Hornig. For example, she explained, POTS flare-ups depend on a variety of factors, including time of day.
In addition, the trigger that causes a symptom and the symptom itself may not be explicitly linked—which also makes measurement difficult. For example, people who experience PEM may not feel the debilitating exhaustion that they often refer to as a “crash” until up to 2 days after they exert even a small amount of energy.
“The changes or symptoms that people experience don’t always happen at exactly the same time point,” Dr. Hornig said. She added that structured studies often have a set time period for follow-up, which is a constraint because studies may miss symptoms that occur outside that time range.
When designing future studies, Dr. Hornig noted, researchers may need to adjust time intervals to better capture all symptoms and more fully understand the triggers that lead to these symptoms. Taking multiple measures of potential biomarkers and symptoms over time can help researchers begin to unravel the mechanisms leading to PEM and other autonomic disturbances. She added that some studies have included carefully controlled stimuli that require cognitive or physical exertion, which can provide clues about what causes these symptoms and how they may be avoided.
These challenges were also evident during the RECOVER-AUTONOMIC (Ivabradine) clinical trial, which tested whether the medication ivabradine could help manage POTS. The trial also tested how people did when they received coordinated non-drug care versus usual care. Although ivabradine did work to lower people’s heart rate, this change did not result in a meaningful improvement in their POTS symptoms. However, participants who received coordinated care in addition to ivabradine did report an improvement in their symptoms compared to those who received ivabradine and usual care. These results may suggest that, because POTS is a condition with variable symptoms, the same treatment will not work for everyone. As researchers improve their understanding of the mechanisms behind symptoms like POTS, these findings can support the development of targeted treatments.
Plans for the second phase
“What has been hardest is how much this has changed my everyday life. Things I used to genuinely enjoy—running, being outside, being active, and spending time with people—can now take much more energy and planning. I feel like I went from being someone who could pretty much do whatever I wanted physically to having to constantly think about what my body will allow me to do that day.”
— Karima Floyd, LCSW, RECOVER Patient Representative
Dr. Hess sees the second phase of the adult observational study as both an extension of the first phase and as a launchpad to begin to answer important questions about the broader spectrum of autonomic dysfunction. During the first phase, she explained, researchers began to understand the Long COVID symptoms related to the autonomic nervous system while also learning where Long COVID is associated with or is similar to other infection-associated chronic conditions. During the next phase, researchers will continue exploring and hope to learn more about the causes of these symptoms.
“What we know now [about Long COVID] is much different than what we knew [at the beginning of RECOVER],” she explained. “We know much more about variations within symptoms and subtypes of the condition, and we know that Long COVID is not monolithic [or presenting in the same way across all people].”
Although the exact study design to continue investigation into autonomic dysfunction is still being finalized in the overall adult observational study plan, Dr. Hess said, “The question we asked going into the next phase of the adult observational study was two-fold. As we start to look at the different symptom phenotypes [types of symptoms people experience], how can we (1) provoke them [so that we can measure them] and (2) understand what’s going on behind the scenes?”
She emphasized that it will be important to capture input from study participants on both “good days” (when their symptoms were not as pronounced) and “bad days” (during symptom flare-ups). For example, researchers plan to pair survey results with saliva samples to see if stress hormones such as cortisol differ on “good days” versus “bad days.” Because the next phase extends the adult observational study for an additional 2 years, this type of comparison will be possible over a longer time.
“This is a uniquely complicated condition,” she said. “We’re looking at characteristics that lessen and return over time, and we haven’t found a biomarker that can explain it. There will likely never be one single biomarker that unifies all of these symptom phenotypes.”
RECOVER’s next phase will allow researchers 2 additional years to study a large group of people from all walks of life across the United States. This study group will continue their contributions to study data and biosamples, in addition to the data and biosamples they have already contributed, which will enable researchers to ask and address many new questions related to autonomic dysfunction. Researchers hope the additional data and sample collection will contribute to answers they are urgently seeking on behalf of people living with Long COVID.
“As someone who’s lived with Long COVID for over 6 years and studied infection-associated conditions for far longer than that, I know firsthand how dire these questions are,” said Dr. Hornig. “RECOVER, including its search for biomarkers through its ongoing systems biology studies, provides an opportunity to learn more about potential causes of these symptoms and come closer to answers.”
