A multidisciplinary team of clinicians and researchers at Brigham and Women’s Hospital is leading clinical initiatives and research to better understand why some patients who recover from COVID-19 experience long-term health complications.
While it’s still unclear how many patients experience long-term symptoms, such as persistent flu-like symptoms, chronic fatigue and brain fog, following COVID-19 illness, some studies estimate that 10 percent of patients in the U.S. have ongoing symptoms.
“The Brigham is leading a number of clinical trials and research efforts to try and understand exactly what’s causing these long-term effects in some COVID-19 patients,” said Jean Marie Connors, MD, a hematologist at the Brigham. “The Brigham has the depth of clinical expertise, the scientific knowledge and expert, multidisciplinary teams to help solve this difficult problem.”
A variety of neurological health complications have been shown to persist in some patients who recover from COVID-19. Some patients who recover from their illness may continue to experience neuropsychiatric issues, including fatigue, ‘fuzzy brain,’ or confusion.
“In the current absence of direct therapies to treat long-term effects of COVID-19, we can offer the most up-to-date, evidenced-based care to manage patients’ symptoms,” said Shamik Bhattacharyya, MD, MS, a Brigham neurologist. “For neurological symptoms, this may include prescribing a medication for mental fog, physical therapy for mobility problems, or psychotherapy for individuals with psychiatric issues, such as anxiety or depression.”
To understand the long-term neurological complications of COVID-19, Dr. Bhattacharyya is launching a study that will use advanced imaging to examine the brains of patients who’ve recovered from COVID-19. The study will use the Brigham’s 7 Tesla (7T) magnetic resonance imaging (MRI) scanner—one of only a few in the country to be approved for clinical use—and functional MRI (fMRI) to examine functioning and connectivity in the brain. The research could pinpoint differences in the brains of patients who develop long-term symptoms.
“We might discover a ‘danger signal’ that is being sent to the brain in these patients who haven’t fully recovered from COVID-19,” said Dr. Bhattacharyya. “If we can find regions in the brain that are making these patients feel unwell, we might uncover ways to modulate these brain areas that could help these individuals feel better again.”
Additionally, Brigham neurologists Tanuja Chitnis, MD, and Maria Houtchens, MD, have launched a trial to examine how COVID-19 influences the immune system in patients with multiple sclerosis (MS). The trial assesses the short and long-term outcomes of COVID-19 infection in MS patients and how certain immunotherapeutic treatments used to treat MS impact COVID-19 outcomes.
At the Brigham’s Division of Cardiovascular Medicine, several teams are leading trials that could answer pressing questions about the long-term effects of COVID-19 on the heart.
“About a third of patients who are hospitalized for COVID-19 have evidence in their blood tests of injury to their hearts,” said Peter Libby, MD, a cardiologist at the Brigham. “We understand from research at the Brigham that this damage isn’t the result of the coronavirus directly infecting the heart. Rather, the heart damage is caused by the inflammation the virus triggers. This can then cause long-term heart problems, such as abnormal heart rhythms or heart attacks.”
Currently, Dr. Libby is collaborating on a study investigating how COVID-19 affects the endothelial cells in the large and small blood vessels. He recently published a paper in the European Heart Journal proposing that the major complications associated with COVID-19 likely involve altered endothelium functioning.
Some patients who recover from COVID-19 experience various long-term complications of the lungs. These individuals may have ongoing pulmonary dysfunction, like difficulty breathing and shortness of breath. Others never regain normal lung function.
“Studies have shown that many patients with COVID-19 have increased clotting activity that is driven by inflammation,” said Dr. Connors. “In COVID-19 patients, these blood clots can appear in the small vessels inside the lungs and heart as well as in the bigger pulmonary arteries and large veins in the legs. The clots can lead to scarring in the lungs, which can impair blood flow and reduce the capacity of the lungs.”
Daniela J. Lamas, MD, a pulmonologist and critical care physician at the Brigham, notes that most blood clotting can be resolved through the rapid use of anticoagulants. However, some major clotting events may lead to long-term pulmonary complications, like chronic shortness of breath, or even a pulmonary embolism, which can be fatal in some cases.
“There are some long-term effects that might result in patients who experienced low oxygen levels due to a severe case of COVID-19,” said Dr. Lamas. “Some long-term effects may also result from advanced treatment options, like being on a ventilator for weeks or months.”
For patients with long-term smell disturbances, Brigham otolaryngologists Regan W. Bergmark, MD, and Alice Z. Maxfield, MD, have recommended “olfactory training” to some patients. This technique has been used in other types of virus-associated smell loss. For several months, patients smell different odors (e.g., cinnamon, lemon) for five minutes in the morning and evening. The therapy aims to stimulate olfactory nerves and get them to regenerate.
“In previous research on smell loss from other cold viruses, patients are more likely to improve with olfactory training,” said Dr. Bergmark. “We need to study these patients further to understand whether olfactory training is an effective treatment for long-term smell loss. We’re currently doing that by collecting data on these patients and tracking them over time.”
It’s not clear why long-term complications persist in some patients who recover from COVID-19. However, most experts agree that the long-term effects of COVID-19 are associated with the coronavirus’ ability to trigger a massive inflammatory response in some individuals.
“This inflammation, which results in blood clotting in blood vessels in the lungs, heart, brain, kidneys, and even legs,” said Dr. Connors. “This clotting can injure blood vessels, leading to scarring of these vessels and a wide range of long-term health complications.”
Some research shows that people who have long-term effects had a moderate or severe case of COVID-19, whereas those who were asymptomatic or had a mild case didn’t develop long-term symptoms. That said, the opposite has also been observed.
“I’ve taken care of COVID-19 patients who were catastrophically sick in the ICU and have had remarkable recoveries, versus other patients who had a mild case, were never hospitalized, and are now dealing with ongoing, debilitating health problems,” said Dr. Lamas. “We don’t yet have an explanation for these observations.”
At present, Dr. Lamas is caring for a patient who recovered from a mild case of COVID-19 in March. The patient hadn’t been hospitalized or received advanced care for the illness. And yet, this patient often feels “profoundly fatigued,” has heart palpitations and trouble concentrating.
“At this time, there’s nothing measurable on diagnostic tests that physicians can see to explain these patients’ lingering symptoms,” said Dr. Lamas. “It’s why some of these long-term patients have questioned whether their symptoms are ‘all in their head.’ That’s why we’re doing everything possible to better understand why these long-term symptoms are happening.”
Some COVID-19 patients who stay in the Brigham’s ICU receive follow-up care in the post-ICU clinic. There, pulmonologists like Dr. Lamas and Gerald Weinhouse, MD, along with mental health experts like Nomi Levy-Carrick, MD, and Stacey Salomon, LICSW, care for patients with long-term complications. Some experience mental health conditions as a result of a long stay in the ICU. These include post-traumatic stress disorder (PTSD), anxiety or depression.
“Some patients in our post-ICU clinic had been very ill, were on a ventilator for weeks and had a high risk for death,” said Dr. Lamas. “That said, we’re also seeing patients coming to the post-ICU clinic who weren’t hospitalized or admitted to the ICU. Some of these people are young, otherwise healthy and only had a mild case of COVID-19. And yet, now they have a constellation of long-term symptoms, such as fatigue, brain fog and an inability to concentrate.”
While the U.S. Food and Drug Administration (FDA) has approved the antiviral drug remdesivir for the treatment of COVID-19, there still is no direct therapy that can treat the long-term symptoms of COVID-19. What if these long-term effects could be prevented?
In October, the Brigham launched a national clinical trial that aims to prevent the development of blood clots in patients with enduring symptoms of COVID-19. Dr. Connors is the study’s national principal investigator; Paul M. Ridker, MD, MPH is the trial’s chairman.
“We’re using an anticoagulant to prevent thrombosis and hopefully pulmonary microvascular thrombosis that—along with inflammation which can damage the lungs, heart and kidneys—is causing these long-term symptoms,” said Dr. Connors. “We believe this could be a promising way to prevent some patients’ long-term problems after recovery.”
The Brigham team is enrolling participants from around the country. These patients have been newly diagnosed with COVID-19 and don’t require hospitalization. During the study, patients will either receive an antiplatelet agent, an anti-coagulant or a placebo. Results are expected in 2021.
“We still have so much to learn about the long-term health complications of COVID-19,” said Dr. Lamas. “But I’m encouraged by the fact that these patients overcame their illness. Whenever I care for a critically ill patient, who was intubated, paralyzed and deeply sedated for weeks, it’s extraordinarily powerful to see them get better and go back to their lives.”
