The young man pulled something from behind both ears. “I can’t hear anything without my new hearing aids,” said the 32-year-old husband and father. “My body is broken, Doc.” Once a fireman and emergency medical technician, he’d had covid more than 18 months before and was nearly deaf. He was also newly suffering from incapacitating anxiety, cognitive impairment and depression. Likewise, a 51-year-old woman told me through tears: “It’s almost two years. My old self is gone. I can’t even think clearly enough to keep my finances straight.” These are real people immersed in the global public health catastrophe of long covid, which the medical world is struggling to grasp and society is failing to confront.
As such stories clearly indicate, covid is biologically dangerous long after the initial viral infection. One of the leading hypotheses behind long covid is that the coronavirus is somehow able to establish a reservoir in tissues such as the gastrointestinal tract. I believe the explanation for long covid is more sinister.
The science makes it increasingly clear that covid-19 turns on inflammation and alters the nervous system even when the virus itself seems to be long gone. The virus starts by infecting nasal and respiratory lining cells, and the resulting inflammation sends molecules through the blood that trigger the release of cytokines in the brain. This can happen even in mild covid cases. Through these cell-to-cell conversations, cells in the nervous system called microglia and astrocytes are revved up in ways that continue for months — maybe years. It’s like a rock weighing down on the accelerator of a car, spinning its engine out of control. All of this causes injury to many cells, including neurons. It is past time we recognized this fact and began incorporating it into the ways we care for those who have survived covid.
For too long, the mysteries of long covid led many health-care professionals to dismiss it as an untreatable malady or a psychosomatic illness without a scientific basis. Some of this confusion comes down to the stuttering cadence of scientific progress. Early in the pandemic, autopsy findings from patients who died of covid “did not show encephalitis or other specific brain changes referable to the virus” as one report noted. Patients with profound neurological illnesses resulting from covid-19 had no trace of the virus in the cerebrospinal fluid encasing their brains.
These studies left most medical professionals mistakenly convinced that the virus was not damaging the brain. Accordingly, we narrowed our focus to the lungs and heart and then scratched our heads in wonder at the coma and delirium found in more than 80 percent of covid ICU patients. A robust study from the Netherlands showed that at least 12.5 percent of covid patients end up with long covid three months afterward, yet because “brain fog” wasn’t identified until later in the pandemic, these investigators didn’t include cognitive problems or mental health disorders in the data they collected. Thus, this otherwise beautifully executed study almost certainly underestimated the rate of long covid.
Since the early days of the pandemic, we’ve learned a great deal about the neurological effects of SARS-CoV-2. Earlier this year, the UK Biobank neuroimaging study showed that even mild covid can lead to an overall reduction in the size of the brain, with notable effects in the frontal cortex and limbic system. These findings help explain the profound anxiety, depression, memory loss and cognitive impairment experienced by so many long-covid patients.
A new study published in the Lancet of more than 2.5 million people matched covid-19 patients with non-covid patients to determine the rate of recovery from mental health complaints and neurological deficits like the depression and brain fog in my own patients. What it revealed is partly encouraging and partly devastating: The anxiety and mood disorders in long covid tend to resolve over months, while serious dementia-like problems, psychosis and seizures persist at two years.
Now, researchers are assembling the science to piece together what happens on a cellular level with long covid, using animal models. As in the lungs, the blood vessels of mammalian brains are lined with endothelial cells, which have angiotensin-converting enzyme 2 (ACE2) receptors, a protein that the coronavirus “hooks” onto. Once infected, these cells become inflamed, leading to problems with blood flow and a loss of integrity in the brain’s protective fortress, the blood-brain-barrier. When this barrier is damaged, inflammatory cells and fluid leak, beginning a process of swelling and brain injury that can be hard to turn off. The hamsters and mice in these studies don’t dream up symptoms and tissue changes, and our patients don’t either.
Medical researchers have recently learned that the coronavirus can also infect cells called astrocytes, the glue that holds the brain together. Instead of using the ACE2 receptor, it appears SARS-CoV-2 attacks astrocytes through completely different types of glycoprotein receptors. When the virus directly damages astrocytes and other cells in the nervous system, the supportive and nourishing environment for our 100 billion neurons breaks down. Even though neurons are not directly infected, the brain’s cell-to-cell relationships are so intimate that infection of other types of cells creates a cascade of brain injury.
Corroborating evidence of brain dysfunction in long-covid patients comes from abnormal PET scans that show “cold” spots in the olfactory and limbic systems as well as the brainstem and cerebellum — as if these areas went from being vibrant to wilted. The way the machinery of the brain slows down aligns with patients’ problems involving smell, memory, cognitive abilities, chronic pain and sleep disorders.
Long-covid patients face hardships as they attempt the tasks associated with their jobs. When we test them at Vanderbilt University’s Critical Illness, Brain Dysfunction, and Survivorship Center many months after their initial infection, they demonstrate profound memory deficits and executive dysfunction — problems finishing daily chores and task lists, meeting schedules, controlling emotions, analyzing data, and processing information. In other words, they have a hard time living life. In fact, their symptoms are similar to mild to moderate Alzheimer’s disease, or the type of brain injury seen in cancer patients after chemotherapy and in ICU survivors with post-intensive care syndrome. Clinically, there is also a lot of overlap between long-covid-related brain fog and the cognitive dysfunction found in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
The bad news is that this neurological injury is occurring most frequently in younger long-covid patients (20 to 50 years old) who were never hospitalized for covid. The good news is that, at least in some patients, it may not be permanent or progressive. Both our clinical experience and clinical trials have shown that cancer patients and ICU survivors with newly acquired dementia-like brain injury can get mentally sharper after several months of exercising their brains with computer programs as well as word and number games. We recently completed, in a a paper currently in submission, the analysis of a 10-year neuropsychological follow-up of our large cohort study of ICU survivors and found that about a third stay the same, a third get better, and a third suffer inexorable decline.
So, what do we do now?
First, we physicians must validate our patients’ stories and complaints. They are not making this up. I often feel the need to apologize to my patients for not having enough answers and treatment options. Then I assure them that I will not leave them while we gain more knowledge and options to improve their health in the coming months and years.
Second, there is a need for well-designed, randomized, placebo-controlled clinical trials of medications and other treatment approaches for patients with long covid. Too many people are losing hope. A study of 150,000 covid survivors showed a 10-to-15-fold higher risk of considering suicide compared with 11 million control patients. Many medications are being proposed, and trials should target specific symptoms like brain, heart or lung problems to make progress faster in specific areas of need.
In addition, patients should know that the brain has an immensely powerful ability to remodel itself. Its 1,000 trillion synapses are constantly being modified every second of every day. It is too early to know if this neuroplasticity can be harnessed for long-covid patients. But our lab at Vanderbilt and other investigators are studying whether computerized cognitive rehabilitation programs will help patients recover brain function.
Lastly, a heaping dose of compassion and empathy will help begin the healing process for those who feel alone in the haunted house of their own body, lighting a candle toward recovery.