A Hazy Picture of Long-Haul COVID Begins to Emerge

Although COVID-19 is best known for its severe effects on respiratory function, there is mounting evidence that neurological and psychiatric problems account for a significant source of COVID-related death and disability. Early on, researchers focused on acute neurological problems such as delirium and encephalitis (brain inflammation), but as the pandemic goes on, more effort has turned to understanding the long-term neuropsychiatric impacts of this virus.

Nearly 18 months into the pandemic, much about COVID’s long-term effects remains mysterious; even the nomenclature varies, as terms including long-haul COVID, post-acute sequelae of COVID-19, and post-acute COVID-19 syndrome are used to describe symptoms patients can’t seem to shake.

Long-term symptoms can impact the lungs (shortness of breath), heart (arrythmia), immune system (arthritis), and the brain. Patients have reported chronic fatigue, headache, dizziness, cognitive problems, seizures, and loss of taste or smell. These symptoms are often accompanied by behavioral issues such as depression, anxiety, insomnia, and posttraumatic stress. The constellation of symptoms varies from patient to patient, as does when the symptoms emerge and how long they last.

Researchers in the field agree that patients who experience long-haul COVID can be divided into two broad categories: those who developed severe COVID-19 and required intensive care, and those who experienced mild symptoms of COVID-19 or remained asymptomatic only to later develop problems.

Long-haul COVID in the patients who experienced severe illness has disproportionately affected older adults with existing medical comorbidities. According to a review in the Journal of Neuropsychiatry and Clinical Neurosciences, about 70% of patients hospitalized with COVID-19 developed delirium and 30% developed encephalopathy during their hospitalization. Strokes in patients with severe COVID-19 were far less common (~1% to 3%), but studies suggest that when they occurred, they were typically severe.

Such symptoms likely arise in hospitalized patients due to a combination of factors, including isolation from family members, viral damage, and oxygen deficiency, explained Eugene Wesley Ely, M.D., a professor of medicine at Vanderbilt University Medical Center. Ely elaborated on some of these factors during a two-day NIH symposium on the neuropsychiatric effects of COVID-19 held this summer.

Some data suggest that the prevalence of long-term cognitive and behavioral symptoms among COVID-19 patients who required intensive care is no different from non-COVID patients who were hospitalized for long periods of time and required mechanical ventilation. Other patients with post-intensive care syndrome often benefit from a combination of physical, social, and cognitive rehabilitation, Ely explained, so the hope is that similar rehabilitation can help patients recovering from severe COVID-19.

About 1 in 4 patients who experience mild or asymptomatic COVID-19 infection also report long-term cognitive and behavioral symptoms, but the underlying factors in these cases are murkier than those for hospitalized patients. Blood tests, EEG scans, and other routine assessments have not identified any residual viral particles or other biological abnormalities that suggest neurological damage.

Avindra Nath, M.D., a senior investigator at the National Institute of Neurological Disorders and Stroke who helped organize the NIH symposium, noted that the commonly reported long-term symptoms in patients with mild infection—fatigue, muscle pain, difficulty concentrating, depression, and anxiety—as well as the higher prevalence of these symptoms in women versus men are reminiscent of two other mysterious conditions: Gulf War syndrome and chronic fatigue syndrome. “In both of these syndromes, persistent immune activation is believed to be involved,” he said, which may provide a clue for the origins and treatment of long-haul COVID.

Complicating the studies of long-haul COVID is that most infected individuals, along with wide swaths of the general population, have been psychologically impacted by the virus.

“The COVID-19 pandemic has had an important impact on the mental health of many individuals in the general population as a result of loss of loved ones, fear of calamity or death, financial hardships, social isolation resulting from government-mandated quarantine and social distancing requirements, and major disruptions of daily life and social connectedness,” wrote the authors of the Journal of Neuropsychiatry and Clinical Neurosciences review.

A recent analysis published in The Lancet, however, provides some data that even in the greater context of the pandemic, COVID-19 infection has a potent long-term impact. The researchers used a global network of electronic health record data to look at the incidence of psychiatric diagnosis 14 to 90 days after a COVID-19 infection. They found that people with no psychiatric history who became infected by COVID-19 were almost twice as likely to be diagnosed with a subsequent mood, anxiety, or psychotic disorder than patients who had another respiratory infection (like the flu), a skin infection, or kidney stones/gallstones during the same time. Older patients infected with COVID-19 also had higher rates of subsequent dementia compared with patients with other infections.

Patients with more severe COVID-19 symptoms were at a greater risk of developing psychosis or posttraumatic stress disorder compared with those with less severe COVID-19 symptoms. The severity of patients’ COVID-19 symptoms did not appear to affect the risk of depression and anxiety.

“More severe COVID might increase depression risk, but that might be offset by the fact the patient is getting regular medical attention at the hospital,” Emily Troyer, M.D., a child and adolescent psychiatrist and postdoctoral fellow at the University of California, San Diego, told Psychiatric News. “Meanwhile, a person with mild COVID would have to quarantine at home for two weeks, and the risks of self-isolation may increase depression risk.”

Troyer acknowledged this idea is speculative. “We are still very much in the early days of long-haul COVID research, and it will be difficult to disentangle the effects of the virus from each individual’s genetic, social, and environmental risk factors,” she said. In addition, researchers are still using older data, she noted; the impact of the numerous COVID-19 variants and vaccination status on long-term symptoms will complicate the equation even more.

“[T]he public and media are talking about neuropsychiatric illness more openly than ever before,” Troyer said. “I hope that this virus helps society understand that the brain is an organ just like the heart and lungs.” ■

“COVID-19 Infection: A Neuropsychiatric Perspective” is posted here.

“Bidirectional Associations Between COVID-19 and Psychiatric Disorder: Retrospective Cohort Studies of 62,354 COVID-19 Cases in the USA” is posted here.