Researchers at the Brigham are collaborating on clinical trials to address the effects of long COVID, including its often-debilitating neurological impacts.This story is a part of a series about the efforts happening across Mass General Brigham to understand, treat and prevent long COVID.

According to the Centers for Disease Control and Prevention, 1 in 13 adults in the United States infected with COVID-19 report lingering symptoms long after clearing the virus, a condition known as long COVID. Some of the neurological symptoms of long COVID include brain fog, chronic pain, weakness, and POTS, or postural orthostatic tachycardia syndrome. POTS is an autonomic disorder most commonly affecting women of child-bearing age. It can lead to lightheadedness, blurred vision, headaches, fainting, an increased heart rate upon standing and chronic fatigue.

Researchers at the Brigham are leading multiple clinical trials that could give answers to patients dealing with long COVID and clinicians and researchers who are working to treat the condition.

Peter Novak, MD, a neurologist at the Brigham and the director of the autonomic laboratory at Brigham and Women’s Faulkner Hospital, has seen the neurological effects of COVID-19 on his patients firsthand. He is committed to finding answers to help relieve lingering symptoms.

“The neurological complications of long COVID can have a significant impact on a patient’s day-to-day life,” Novak said. “They can be very disabling for the patient.”

Understanding Symptoms

Peter Novak

POTS is diagnosed through autonomic testing, a series of tests including the tilt test to determine how well the body is regulating the internal organs. Dysautonomia is the dysfunction of that regulation.

“We’re doing a lot of autonomic testing on patients with regards to long COVID. We’re checking dysautonomia and which type it is, because not everyone who has long COVID symptoms has POTS,” Novak said.

Novak is also conducting skin biopsies on patients who may have nerve damage because of long COVID.

“We’re also checking cerebral blood flow. Dysregulation of the cerebral blood flow leading to cerebral hypoperfusion is a typical issue that comes with long COVID and could be one of the reasons why people have brain fog and chronic fatigue,” Novak said.

Searching for Treatment and Causes        

Novak is the principal investigator on a phase 2 trial funded by the company Argenx. The trial, which started to enroll patients, is using the antibody, Efgartigimod, against immunoglobulins on patients with long COVID and POTS. It’s a double-blinded study in which patients will receive infusions weekly. Through the trial, Novak hopes to learn more about how to treat long COVID, what causes it and if it’s autoimmune or inflammatory.

“Is it due to autoimmunity, reactivation of a previous virus, vascular insufficiency or is it a persistence of the virus that causes COVID-19?” Novak wondered.

On a larger scale, Novak’s work is part of the National Institutes of Health (NIH) RECOVER study which seeks to better understand the constellation of long-term complications that can occur after infection and lay the groundwork for preventing and treating symptoms. The Brigham is part of the greater Boston COVID Recovery Cohort, which is helping recruit participants as part of the nationwide study. Participants will be followed for three years.

The POTS trial that Novak is leading is placebo-controlled, meaning some patients will get Intravenous Immunoglobulin Therapy, or IVIG, and others will get a placebo. That study is expected to start this summer. Another part of this study involves looking at the history of long COVID.

“This means we look at how severe it is, how many patients recovered spontaneously, how many patients will have persistent effects. These are all questions we don’t know the answers to yet,” Novak said.

Studies Surrounding Chronic Fatigue

David Systrom

POTS and long COVID often have chronic fatigue or similar symptoms. David Systrom, MD, director of the Advanced Cardiopulmonary Exercise Testing Program and the Dyspnea Clinic at the Brigham, said his patients with chronic fatigue, also known as Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), often have extreme tiredness for more than six months, post-exertional malaise or “crashing” hours to days after over-exerting themselves and non-refreshing sleep. Systrom is a co-chair on the NIH RECOVER study’s Commonalities task force. The goal is to find suspected similarities between ME/CFS and long COVID through autonomic testing and exercise tests. He’s also working on smaller trials surrounding chronic fatigue in long COVID.

“We are about to launch a two-day, non-invasive cardiopulmonary exercise study that is designed to investigate post-exertional malaise,” Systrom said.

Thirty patients divided into three groups will be studied. The patients either have long COVID, ME/CFS with no history of COVID or fatigue without post-exertional malaise. The three groups will exercise to exhaustion and be monitored for ventilation, oxygen and carbon dioxide exchange. Systrom plans to take a deeper dive by also conducting muscle biopsies on patients on both days. From this, he hopes to identify skeletal muscle mitochondrial dysfunction, something he suspects happens in both patients with ME/CFS and long COVID. This dysfunction of the mitochondria may contribute to fatigue and post exertional malaise. Systrom is also doing blood and muscle transcriptomics, metabolomics and proteomics to study RNA molecules, metabolites and proteins that may change in patients with long COVID.

“We’ll sample whole blood and spin it down to send plasma for testing,” he said. “We’re hoping to find any signatures in the plasma and muscle that are different in ME/CFS and in long COVID.”

Systrom said those results could be used to diagnose patients in the future, identifying cases not only of chronic fatigue but also potentially subsets of the disease. Systrom said patients have suffered because diagnosing chronic fatigue, POTS and long COVID requires sophisticated clinical testing, such as exercise tests and autonomic tests, instead of a simple blood test.

“ME/CFS and long COVID cannot be diagnosed and understood currently with a simple blood test,” he said. “But we’ve found organic abnormalities with our studies which help understand what’s underlying the symptoms, which we hope will pave the way toward effective treatment.”


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