Millions of Americans were exposed to SARS-CoV-2 at the beginning of the pandemic. Patients who never tested positive for the virus are now presenting with post-viral syndrome (PVS) resembling long-COVID. These patients are often left in a treatment limbo and deserve the same access to care afforded to patients with a confirmed COVID-19 diagnosis, according to the results of a small study published in Neurology: Neuroimmunology and Neuroinflammation.

“Since most long COVID clinics are only accepting patients with a positive test result, these people experiencing identical symptoms are left without specialized care and excluded from research studies on long COVID,” said study author Igor J. Koralnik, MD, of Northwestern Medicine Comprehensive COVID-19 Center in Chicago. “Our data suggest that millions of Americans with PVS may have been exposed to SARS-CoV-2 at the beginning of the pandemic, and they deserve the same access to care and inclusion in research studies as people with a confirmed COVID diagnosis,” Dr Koralnik in a press release from the American Academy of Neurology.

The small study enrolled 29 people with PVS including neurologic symptoms such as problems with memory and thinking skills, headache and fatigue but who did not have a positive COVID test result between June 2020 and April 2022. They were matched with 32 people of similar age with long COVID and positive test results. Both groups were also compared to 18 people with none of those symptoms and no known exposure to COVID or positive test result. The researchers excluded patients who did not demonstrate any neurologic symptoms. 

Continue Reading

Participants with either PVS similar to Neuro-PASC or Neuro-PASC completed the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires to assess their quality of life and cognition. The research team also measured SARS CoV-2-specific humoral and cell-mediated immune responses against nucleocapsid and spike proteins among these 29 participants with PVS with suspected COVID-19, 32 participants with Neuro-PASC and confirmed COVID-19 infection, and 18 unexposed healthy controls. 

The researchers reported that 12 of the 29 patients (41%) with PVS had humoral/cellular immune responses consistent with prior SARS-CoV-2 exposure. Among these 12 patients, 75% had anti-nucleocapsid responses and 50% had anti-spike responses. Patients with PVS similar to Neuro-PASC experienced similar levels of quality-of-life impairments, including a decline in cognitive function and fatigue. However, they outperformed the Neuro-PASC cohort in terms of processing speeds, attention, working memory, and executive function. 

“Unlike our clinic, about 70% of post-COVID clinics in the US do not accept people with long COVID symptoms who do not have a positive test result for COVID,” Dr Koralnik said. “Our data suggest that at least 4 million people with post-viral syndrome similar to long COVID may indeed have detectable immune responses to support a COVID diagnosis. More research is needed to confirm our findings.”

A limitation of the study is the small number of people with PVS. Also, some of the participants may have tested positive for COVID-19 immune responses if their blood samples were collected closer to when their symptoms began.

“Patients with PVS often present with similar clinical manifestations as confirmed patients with neurologic manifestations of [long COVID], suggesting that a positive result by commercially available SARS-CoV-2 diagnostic test should not be a prerequisite for accessing care,” wrote the authors. “Patients with PVS may benefit from the same clinical care as confirmed patients with [Neuro-PASC], and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment.”


1. Orban ZS, Visvabharathy L, Perez Giraldo GS, Jimenez M, Koralnik IJ. SARS-CoV-2-specific immune responses in patients with postviral syndrome after suspected COVID-19Neurol Neuroimmunol Neuroinflamm. 2023;10(6):e200159. Published online August 23, 2023. doi:10.1212/NXI.0000000000200159

2. Conrad N, Tessman R. Small study suggests long COVID may affect more people than previously thought. American Academy of Neurology. News Release. August 23, 2023. Accessed August 28, 2023.

This article originally appeared on Clinical Advisor