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The severity of neurologic and non-neurologic symptoms associated with long COVID appear to be linked to the severity of the initial infection, new research suggests.
Investigators at Chicago’s Northwestern Hospital compared neurologic post-acute sequelae of COVID infection in hospitalized and nonhospitalized patients about 7 months after onset of the virus and found only 60% reported they had “recovered” from the virus.
Both study groups of had an average of seven neurological symptoms, with 91% experiencing more than four symptoms. Brain fog, headache, and dizziness were the most common neurologic symptoms and fatigue was the most common non-neurologic symptom in all patients. Both groups reported impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression.
Patients who had been hospitalized were more likely to have an abnormal neurologic exam, compared with their nonhospitalized counterparts as well as a normative US population, while nonhospitalized patients had lower results only in attention tasks.
“An important take-home message of our new study is that COVID affects the nervous system and causes severe decrease in quality of life and also causes cognitive dysfunction,” senior author Igor Koralnik, MD, chief of neuroinfectious diseases and global neurology at Northwestern Medicine, Chicago, Illinois, told Medscape Medical News.
But the impairments “are not one-size-fits-all, and we observed differences in patients previously hospitalized for COVID pneumonia, compared to those who only had a mild case and were never hospitalized,” Koralnik said.
The study was published online March 26 in the Annals of Neurology.
“Apples and Oranges”
Symptoms “may persist for more than a year in previously hospitalized and nonhospitalized patients alike” but “little is known about the differences and similarities in neurologic manifestations experienced by these 2 distinct populations,” the authors write.
The definitions of “long COVID” from the Centers for Disease and Prevention, the World Health Organization, and the National Institutes of Health (NIH) are “imprecise, because they put everybody in the same basket,” Koralnik noted. “They don’t separate people based on acute symptoms severity, so they’re basically mixing apples and oranges.”
However, people who were severely ill and hospitalized might have different levels and types of symptom severity, compared with nonhospitalized people.
The researchers therefore looked at post-COVID symptoms in both populations — the first study in the US to do so, said Koralnik.
They prospectively evaluated the first consecutive 100 hospitalized and 500 nonhospitalized patients seen at the Neuro-COVID-19 clinic at Northwestern Hospital, either in person or via telemedicine, between May 2020 and August 2021.
All patients were experiencing persistent neurologic symptoms for ≥ 6 weeks from disease onset and were evaluated an average of 6.8 months after onset.
Patients completed a cognitive function evaluation with the NIH toolbox, assessing processing speed, attention, executive function, and working memory. They reported on quality of life domains using the Patient-Reported Outcomes Measurement Information System and were asked about their subjective impression of percent of recovery, compared with their baseline prior to COVID-19 onset and diagnosis.
Precision Medicine Approach
Hospitalized patients were older than their nonhospitalized counterparts (mean age, 53.9 vs 44.9 years, respectively) and less likely to be female (58% vs 64.8%, respectively).
Although hospitalized patients had more comorbidities, nonhospitalized patients were more likely to suffer from depression/anxiety prior to COVID-19.
| Comorbidity | Hospitalized | Nonhospitalized | P Value |
|---|---|---|---|
| Hypertension | 39% | 15.4% | < .0001 |
| Dyslipidemia | 22% | 12.8% | = .03 |
| Type 2 diabetes | 21% | 4.2% | < .0001 |
| Lung disease | 16% | 4.2% | < .0001 |
| Cardiovascular disease | 10% | 2.2% | = .0008 |
| Depression/anxiety | 9% | 40% | < .0001 |
Overall, 43% of the patients were vaccinated, and all, except one, were infected before vaccination.
Only 59.8% of patients regarded themselves as “recovered” (55.7% in the hospitalized and 60.6% in the nonhospitalized groups, P = .07).
The median number of COVID-related symptoms in both groups was seven, with 91% reporting more than four neurologic symptoms.
| Neurologic | |
|---|---|
| “Brain fog” | 81.2% |
| Headache | 70.3% |
| Anosmia | 55.7% |
| Dysgeusia | 54.5% |
| Dizziness | 49.5% |
| Myalgia | 47.5% |
| Pain (other than chest) | 40.5% |
| Tinnitus | 28.7% |
| Blurred vision | 26.0% |
| Non-neurologic | |
| Fatigue | 85.8% |
| Depression/anxiety | 69.3% |
| Insomnia | 57.0% |
| Shortness of breath | 48.3% |
| Dysautonomia | 34.0% |
| Chest pain | 29.7% |
| Gastrointestinal symptoms | 27.0% |
There were, however, significant differences between the groups in the most commonly reported symptoms, with nonhospitalized patients more frequently reporting anosmia, dysgeusia, and myalgia. In contrast, hospitalized patients reported shortness of breath and chest pain more frequently.
| Symptom | Nonhospitalized vs Hospitalized | P Value |
|---|---|---|
| Anosmia | 59% vs 39% | = .0003 |
| Dysgeusia | 57.6% vs 39% | = .0009 |
| Myalgia | 50.4% vs 33% | = .002 |
| Shortness of breath | 43.6% vs 72% | < .0001 |
| Chest pain | 27.4% vs 41% | = .008 |
Hospitalized patients more frequently had an abnormal neurologic exam, compared with nonhospitalized patients (62.2% vs 37.0%; P < .0001). They also showed more attention deficit, short-term memory deficit, sensory dysfunction, gait dysfunction, and motor dysfunction, compared with their nonhospitalized counterparts (all P values ≤ .0008). Nonhospitalized patients showed lower results in attention tasks only.
Patients’ subjective impressions of their cognitive ability correlated with cognitive test results only in the nonhospitalized but not in the hospitalized group.
Koralnik explained that different mechanisms may be involved between those requiring hospitalization vs those with milder disease.
“Patients who were severely ill, many intubated in the ICU, may have had complications, such as low oxygen levels, cytokine storm, or clotting or sustained brain damage during the acute illness; while patients who were never hospitalized might have autoimmune system issues potentially caused by the persistence of the virus in the body,” he suggested.
“We need to pay attention to those similarities and differences in patients with long COVID; these patients need to be treated with precision medicine based on their symptoms and needs,” he said.
Other Factors?
Commenting for Medscape Medical News, Jennifer Frontera, MD, professor of neurology, NYU Langone Grossman School of Medicine, New York City, called it an “important study because it’s the first (to my knowledge) to prospectively evaluate the impact of initial COVID severity on neurological outcomes.”
In particular, what interested her was that there is “a disconnect between subjective and objective cognitive findings,” which “suggests that other factors may be affecting the subjective impression of cognitive abnormalities in the nonhospitalized group.”
However, in terms of absolute frequencies of brain fog “the denominator is patients referred to a long COVID neurology follow-up clinic, so this does not represent the frequency of brain fog in the general population,” cautioned Frontera, who was not involved with the current study. “We can only draw conclusions comparing the hospitalized vs nonhospitalized patients referred to this clinic.”
One of the authors was supported in part by a grant from the NIH/NIA. This study was supported in part by a gift from Mr. and Mrs. Michael Ferro. The authors and Frontera have disclosed no relevant financial relationships.
Ann Neurol. Published online March 26, 2023. Full text
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as “Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom” (the memoir of two brave Afghan sisters who told her their story).
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