One of the most mysterious and disturbing aspects of SARS-CoV-2 infection is so-called “long COVID,” which presents as a panoply of symptoms that can linger for months after even mild acute cases.

The Centers for Disease Control and Prevention (CDC) held a clinical outreach call on this phenomenon recently, which included an overview by Alfonso Hernandez-Romieu, MD, a member of the CDC’s COVID-19 Late Sequelae Unit.

“Based on information available so far, persons with long COVID often present reporting persistent severe fatigue, headaches, and brain fog, which is defined as mild subjective cognitive impairment, approximately four weeks after acute illness,” he said. “Reports from clinicians have highlighted that long COVID may be independent of acute illness severity.”

A study in China found that 76% of 1,733 patients reported at least one symptom of long COVID six months after their acute illness.1 Overall, 63% reported fatigue or muscle weakness and 26% had labored breathing. Sleep problems occurred in 26%, and 22% reported anxiety or depression.

“One in five patients not requiring supplemental oxygen during hospitalization had decreased lung function after six months,” Hernandez-Romieu said.

Indeed, long COVID can follow mild infections not requiring hospitalization. A study of patients in a post-COVID-19 clinic in France found that 35% to 54% of patients with initial mild cases had persistent symptoms after two to four months.2

“Half to three-fourths of patients attending the post-acute COVID clinic in France [reported] new symptoms not initially present or symptoms that reappeared after initial resolution,” he said. “In addition, 9% of patients in a Faroe Islands study reported persistent severe symptoms at four months.”3

In the post-acute COVID clinic in France, more than 25% of patients developed new neurological signs and symptoms after their acute COVID-19 illness.

These included cognitive dysfunction, balance disorders, and swallowing and speech disorders, Hernandez-Romieu said.

Empathy

“It is important for providers evaluating patients to perform baseline and serial comprehensive reviews of systems and physical exams to detect new or recurrent manifestations in patients with possible long COVID and improve its medical management,” Hernandez-Romieu said. “There is still a lot we do not understand, and empathy toward patients experiencing long COVID is fundamental.”

This point was raised by another speaker who emphasized that long COVID patients should be reassured during treatment, even in the absence of medical explanations for some of the aspects of their suffering.

“While we don’t know what’s causing these symptoms, they are very real for patients, and we are seeing patients get better. I think it’s important to reassure them of that, while still supporting them in their journey,” said Allison Navis, MD, lead clinical neurologist at Post-COVID Center at Mount Sinai Hospital.

Navis described a 42-year-old female patient woman who was experiencing cognitive issues, although she continued to work on reduced hours.

“She also noted physical fatigue that worsened with exercise,” she said. “She had a tingling sensation throughout her body, but it was worse in her hands, and she also had heart rate elevations, palpitations, and shortness of breath.”

One of the initially clinical suspicions was that long COVID was a widespread neurological process that could include the brain.

“There’s been some evidence that COVID can affect the brain, but that seems to be very rare and less common than the inflammatory changes,” she said.

Distinct from brain impairment, brain fog is one of the most common neurological symptoms seen in these patients.

“Brain fog is a symptom. It is not a diagnosis, and it means many different things to different people,” Navis said. “Oftentimes, it’s a combination of short-term memory issues, concentration, or a sort of word-finding speech difficulty.”

It is important to highlight that brain fog does not equal dementia, she emphasized.

“Dementia is a neurological diagnosis, but we are seeing a lot of reassuring cognitive test results,” Navis said. “That doesn’t mean that these changes are not present and affecting these patients, but we’re not seeing patients who were previously high functioning coming in with dementia”

Thus, it is unlikely that long COVID involves widespread infection in the brain, she said.

“There could be some inflammation. There could be a role of the vasculature playing into this, but we really don’t know,” Navis said. “Could the peripheral nervous system be affected? It absolutely could. It’s much more vulnerable to systemic insult. It’s not protected by the blood/brain barrier.”

Young Patients with Long COVID

As the studies cited previously noted, Navis finds no “clear correlation with the severity of COVID infection, age, or risk factors meaning that we’re seeing a lot of patients who had mild COVID and were not hospitalized. We’re seeing a lot of younger patients and those who were previously healthy.”

The symptoms often fluctuate, as patients report feeling like their normal selves and then will have bad day with fatigue and other symptoms.

“The impact on life varies,” she says. “Some patients are able to continue working. It might be a little bit more challenging, but they haven’t had to stop working. Whereas, others are on disability.”

Sleep disorders of some variety are common, with some long COVID patients having difficulty falling asleep, or waking up frequently.

“We’re also seeing a lot of mood symptoms so many patients expressing depression, anxiety, or post-traumatic stress disorder [PTSD]-like symptoms,” Navis said. “In addition to the brain fog, we’re also seeing these other symptoms as well. Headaches are probably the second most common symptoms that we’re seeing.”

These can vary from tension headaches to something that would be closer to a migraine.

“Many [of these] patients don’t have a history of headaches, and now they complain of frequent headaches,” she said. “A lot of patients complaining of tingling or numbness sometimes a burning sensation. It can be focal. It can be throughout the entire body, and sometimes alternating in locations, and more often, patients will say that it’s a little bit worse distally in their extremities.”

Clinicians also are seeing fluctuating heart rates and blood pressure, with patients complaining of lightheadedness, palpitations, and gastrointestinal disturbances.

“In terms of neuroimaging, we’re really not seeing large, inflammatory, or infectious lesions,” Navis said. “We’re not seeing signs of what looks like encephalitis. We’re not even really seeing many strokes.”

There could be damage to the central nervous system, but again there is not substantive evidence to support or refute it on a large scale.

“Any inflammatory or metabolic changes can cause neuropathies, and we are seeing the presence of a small fiber neuropathy on some of our patients,” Navis said. “So that could explain some of the symptoms as well as dysautonomia and tingling.”

Broaching a delicate subject, Navis raised the question of whether and to what degree the mental health of patients could be contributing to long COVID symptoms.

“I want to highlight the importance of mental health aspects,” she said. “I think it’s extremely important to address those, to not be dismissive of them, but also not to [link] everything to it. A lot of patients do have depression and anxiety that’s secondary to these ongoing symptoms, and I think that’s extremely understandable. However, we do know that depression, anxiety, and PTSD can affect cognition and other symptoms, and that is something we can act on, and, hopefully, improve those symptoms.”

With few available cures for neurological damage, a lot of the treatment is going to be symptomatic and supportive, and a multidisciplinary approach is really critical, she said.

REFERENCES

  1. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021;397:220-232.
  2. Salmon-Ceron D, Slama D, De Broucker, T, et al. Clinical, virological and imaging profile in patients with prolonged forms of COVID-19: A cross-sectional study. J Infect 2020; Dec 4. doi: 10.1016/j.jinf.2020.12.002. [Online ahead of print].
  3. Petersen MS, Kristiansen MF, Hanusson KD, et al. Long COVID in the Faroe Islands - a longitudinal study among non-hospitalized patients. Clin Infect Dis 2020; Nov 30. doi: 10.1093/cid/ciaa1792. [Online ahead of print].