Patients, clinicians seek answers to the mystery of ‘Long COVID’

CIDRAP

Throughout the coronavirus pandemic, public attention has mainly focused on the number of people who become severely ill and die from COVID-19. But what’s become clear in recent months is the large and growing group of people who continue to deal with prolonged symptoms long after their original illness.

In a recent study posted on the preprint server medRxiv, analysis of an international survey of more than 3,700 respondents with COVID-19 found that over two-thirds were still experiencing numerous symptoms at 6 months, with significant impacts on patients’ lives and livelihoods. Respondents with symptoms for more than 6 months said they are experiencing an average of nearly 14 symptoms across multiple organ systems.

That study has not yet been peer-reviewed, but it adds to a growing body of literature on prolonged COVID-19 symptoms. An Italian study published in JAMA in July found that 87% of 143 hospitalized COVID-19 patients had at least one symptom 2 months after illness onset. A study published this month in The Lancet found that more than three quarters of 1,655 hospitalized COVID-19 patients in Wuhan, China, had at least one symptom 6 months after discharge.

With more than 95 million confirmed COVID-19 cases since the beginning of the pandemic, these reports are likely just the tip of the “Long COVID” iceberg. And while the world is currently focused on driving down new infections, reducing deaths and hospitalizations, administering new vaccines, and getting the pandemic under control, public health experts are starting to turn their attention to these “long-haulers,” as they’ve come to be known, and the mechanisms behind their lingering symptoms

Speaking at a recent online workshop on post-acute sequelae of COVID-19 hosted by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases Director Anthony Fauci, MD, said the issue urgently needs to be studied given the number of people who’ve been infected.

“This is a phenomenon that is really quite real and quite extensive,” Fauci said. “Even a small proportion with post-acute sequelae are going to represent a significant public health issue.”          

Yesterday NIH Director Francis Collins, MD, PhD, highlighted the problem on his director’s blog and encouraged long-haulers to participate in an ongoing study.

‘I just never got well’

For Wendy Kloiber, it’s been longer than 6 months

Kloiber, of Ashland, Wisconsin, got sick on Mar 22, and describes the initial course of her illness as mild. She had fever, chills, and deep exhaustion, and, like many COVID-19 patients, lost her sense of smell. But her oxygen levels never got too low, and she was never hospitalized. Ten days of symptoms, however, turned into 2 weeks, then to 3 weeks and beyond.

“I just never got well,” Kloiber said.

More than 10 months later, she’s still dealing with fatigue and “brain fog,” a term that she says she doesn’t really like because it doesn’t accurately describe what she’s experiencing. Those are two of the most common symptoms reported by respondents in the medRxiv study. Kloiber said the combination of the two is having a significant impact on her ability to perform her job as a project manager with a health improvement philanthropy.

“I’m a person who loves my work and could really very joyfully put in 18-hour days and be very happy doing that, and I just don’t have the capacity to do that anymore,” she said. As an example, Kloiber explained that a very challenging period of work in October, one that normally would have been tiring but “exhilarating and fun,” left her wiped out and back at square one, with chills, fever, and coughing.

“There’s just no space anymore between cognitive exertion and my body,” she said. Kloiber also recently developed tachycardia on standing, an abnormal increase in heart rate that occurs after sitting up or standing.

Karen Schwartz, of Arlington, Massachusetts, has had a similar journey. She got sick on Mar 18, and experienced 2 weeks of fever, sore throat, coughing, and shortness of breath while isolating in her basement. But the ensuing months have been alternating periods of feeling better followed by stretches of extreme fatigue and chest and throat pain that come on strong after exercise.

Schwartz said she was exercising 6 days a week “hardcore” before she got sick, and now can only handle walking a mile at a slow place.

“Any time I try to get my heart rate up really high or try to push it for a real workout, I pay for it for days,” she said.

For Sue Mattison of Des Moines, Iowa, the main lingering symptom of COVID has been severe asthma-like symptoms. Originally diagnosed in April, Mattison also had a mild case of COVID-19, with no fever or loss of smell or taste but exhaustion and a severe cough. The intense coughing spells and bronchospasms have continued.

“I take a steroid inhaler twice a day, which I’ve never done in my life, and also a rescue inhaler, when I need it,” Mattison said.

While these symptoms are among the most common being experienced by COVID long-haulers, they are just a few of many manifestations. Other symptoms include heart palpitations, changes in pulse, chronic headaches, gastrointestinal (GI) issues, sleep disturbance, and depression and anxiety, said Alejandro Comellas, MD, a pulmonologist and medical director of the Respiratory Illness Follow-Up Clinic at the University of Iowa Hospitals & Clinics.

“At this point, I would say 20% of our population are still having a lot of these symptoms a couple of months after having had COVID,” Comellas said, including some who are experiencing symptoms 8 to 9 months after falling ill. “We are not sure whether this is unique to COVID, but what is unique is the volume of patients because so many people have been affected.”

A poor understanding of Long COVID

For many clinicians who are treating COVID long-haulers and researchers who are starting to look in the phenomenon, there are a lot of questions and not many answers. There isn’t even a working definition at the moment.

“This is an area that we really have a very poor understanding of right now,” John Brooks, MD, the chief medical officer for the Centers for Disease Control and Prevention’s COVID-19 response, said during the NIH workshop. “This is an area we’re really working on, epidemiologically, to understand.”

Comellas’ clinic is just one of many that are popping up around the country to treat patients who have prolonged post-COVID symptoms. Another is the Post-COVID-19 Clinic at UC Davis Health, where Christian Sandrock, MD, MPH, sees patients. Sandrock said the staff at the clinic first started seeing the signs of prolonged post-COVID issues in some of their colleagues who had gotten ill in the spring.

“Then we started also seeing this in patients, and we realized, as the literature and data was coming out, that there were just a number of patients with varying needs, whether it was brain fog, or shortness of breath, or chest pain, or fatigue,” Sandrock said. “We realized we needed to get on top of it.”

Sandrock noted that the most common prolonged symptoms he and his colleagues see are chest pain, shortness of breath, and decreased exercise tolerance. “I have some patients who are really short of breath just walking down a block,” he said. “I have another group that does fine for the most part but can’t maximally exercise like they used to.”

Both clinics are treating long-haul symptoms in patients who had severe illness, some of whom were in intensive care units (ICUs), and patients who had mild COVID-19 cases. Comellas said the primary impetus for starting the Iowa clinic was the anticipation that they would likely be dealing with patients who’d been in the ICU and were experiencing post–intensive care syndrome, which is common in patients who survive severe illness and ICU treatment.

But he said it’s the number of patients with mild cases who have lingering symptoms, and the severity of some of those symptoms, that’s been so surprising.

“I’ve seen patients who were actually in the ICU and they ended up on ECMO [extracorporeal membrane oxygenation], and they are not feeling as sick and debilitated as people that had COVID as an outpatient,” he says. “The severity of your disease doesn’t seem to predict how you’re going to respond down the road in regards to the chronicity of the symptoms.”

That observation is reflected in the medRxiv study, which analyzed a survey created by patients who are members of the Body Politic online COVID-19 support group. Of the 3,762 respondents, only 8.4% were hospitalized during their original illness.

The ‘brain fog’ mystery

Among the most confounding symptoms experienced by COVID long-haulers is the brain fog, which is marked, in varying degrees, by problems with memory, attention, and multitasking. Mattison, a provost at Drake University, said she first noticed signs of it shortly before her diagnosis, when she went to pick up a prescription from her pharmacy and couldn’t remember her phone number.

“My mind just kind of went blank,” she said. “I’d not had that kind of experience before.”

Though she’s not experiencing these symptoms any more, Mattison said the difficulties with forgetting things and recalling the right word lasted throughout the summer. Schwartz is still dealing with issues like word retrieval.

“It’s just like a slower process going on for me right now,” she said.

The neurologic impacts of the coronavirus first caught the attention of Igor Koralnik, MD, chief of neuroinfectious diseases and global neurology at Northwestern Medicine, in March 2020. That’s when he read a paper by Chinese scientists that found that more than a third of hospitalized COVID-19 patients experienced neurologic manifestations. That led Koralnik and colleagues to review data on the first 509 patients hospitalized at Northwestern Memorial Hospital for COVID-19 during the spring surge in Chicago.

Their research showed neurologic manifestations were present in 82.3% of patients at any time during the course of the disease. The most frequent neurologic manifestations were myalgias (muscle pain), headaches, and encephalopathy, or diminished brain function. Patients with severe COVID-19 were more likely to develop neurologic symptoms.

The findings led Koralnik and his colleagues to open the Neuro COVID-19 Clinic at Northwestern Memorial Hospital to treat patients experiencing some of these neurologic side effects. They soon started seeing COVID-19 patients who had never been hospitalized who were also experiencing neurologic issues.

“These ‘long-haulers’ had many different neurologic manifestations that were persisting despite the fact that they didn’t have pneumonia,” Koralnik said.

In a paper published in June in the Annals of Neurology, Koralnik and Kenneth Tyler, MD, of the University of Colorado School of Medicine, reviewed some of the potential mechanisms that may be linked to neurologic manifestations in COVID-19 patients. These include systemic disease marked by multiorgan failure and global inflammation, direct viral infection of the central nervous system, and postinfectious autoimmune-mediated processes.

While neurologic problems in patients with severe COVID-19 may be linked to the first two mechanisms, Koralnik thinks the third mechanism is a potential explanation for the neurologic symptoms that non-hospitalized long haulers are experiencing, and he is currently studying that in his lab.

“It’s more likely a post-infectious auto-immune problem,” he said. “The immune system has been confused by the virus in some ways, and now the immune system is attacking normal components of the nervous system.”

Kloiber says the research into the neurologic issues is what she’s keeping an eye on. “What I’m really watching for closely is can folks figure out…what is actually the mechanism of what’s happening to people’s minds,” she said.

Investigating potential mechanisms

While treating long-haul patients is his focus at the moment, Comellas, like Koralnik, Sandrock, and other clinicians treating COVID long-haulers, is also interested in figuring out what’s behind these lingering symptoms. He’s trying to put together a pilot study to further explore the potential mechanisms.

“One hypothesis that we have is that autonomic dysfunction could be part of this mechanism,” he said, referring to the autonomic nervous system, which controls functions such as breathing, blood pressure regulation, digestion, and temperature regulation.

“A lot of these patients are having temperature changes. They feel febrile or very cold, they have these palpitations with pulses going up and down, they have some gastrointestinal complaints…so one speculation is that the virus is affecting the autonomic system,” Comellas said.

Sandrock suggests the lingering symptoms could be another manifestation of the varying inflammatory response that people have had to the virus.

“The inflammatory response we have to the virus has been so variable in people,” he said, with some people having no symptoms whatsoever and others dying very quickly. “We have some patients that just have chronic signs of inflammation, and some that don’t.”

Sandrock added that he would like to see some large cohort studies that can help define what it means to have persistent symptoms.

That could soon be on the agenda. At the NIH workshop, Janet Diaz, MD, head of clinical care for the World Health Organization’s COVID-19 response, said the agency hopes to convene a meeting early this year to further discuss research into the pathophysiology of prolonged COVID symptoms. Other aims include agreeing on a working definition, estimating the actual burden of disease, and updating clinical guidance for physicians treating Long COVID patients.

Diaz said the prolonged illness in non-hospitalized COVID patients in particular “urgently needs to be better understood and investigated for us to make decisions on policy or interventions.”

Schwartz, who has been through a battery of physical and cognitive tests that have all come back normal, would just like to start getting some answers for the constant fatigue, post-exertional malaise, and persistent chest and throat pain that have dogged her since March.

“Honestly, the longer journey has been worse than the first 2 weeks,” Schwartz said. “My life is not what it was.”


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