Post-acute sequelae of SARS-CoV-2, also known as ‘long COVID,’ involves a broad range of symptoms that may persist for months after the initial infection.

“Two years into the pandemic, we started to see a lot of patients who had had COVID-19 and still had symptoms many weeks and months later,” Michael A. Horberg, MD, MAS, FACP, FIDSA, explained. “Our group was approached by the NIH, who asked if we could provide any additional insights, given that we had a large database of patients from our integrated network of health systems.”

According to Dr. Horberg, one fact was “immediately” clear. “No one had effectively compared these patients with a documented COVID-19-negative group,” he said.

For a study published in Nature Communications, Dr. Horberg and colleagues used longitudinal data to identify post-acute sequelae of SARS-CoV-2 (PASC) within a 2020 patient cohort. “We included patients with PCR-negative and PCR-positive COVID-19 tests matched 3:1 (negative to positive) based on the month of the test, age, sex, and service area so we would have similarities in practice and testing patterns,” he explained. “We also accounted for pre-existing conditions in the 4 years before the COVID-19 test.”

PASC Risk Highest 30-120 Days After Initial Infection

The study included 28,118 patients with PCR-positive tests and 70,293 patients with PCR-negative tests. Both case and control groups were composed of more than 50% women, with a greater number of Black and Hispanic patients compared with White patients. Most patients—approximately 87%—were younger than 65.

“We observed a greater risk for PASC among patients who tested positive for COVID-19, especially after 30 days,” Dr. Horberg noted.

The researchers identified 17 PASC-related conditions (Table). The risk for any PASC-related condition was 12% greater for PCR-positive patients in the late period, or days 30-120 following the PCR-positive test date, with a significantly higher risk for anosmia, cardiac dysrhythmia, diabetes, genitourinary disorders, malaise, and non-specific chest pain.

“It’s a broad spectrum of symptoms,” Dr. Horberg explained. “Patients who had respiratory symptoms during the acute phase of COVID-19 infection did seem to have a greater number of persistent symptoms.”

The overall cumulative incidence of PASC, as defined by patients positive for COVID-19 with a PASC-related diagnosis in the acute and persistent or late periods, was 16.5%. “That’s a little lower than the percentage listed in other studies,” Dr. Horberg noted. “Importantly, however, a lot of these symptoms, especially in the acute period, were common among patients who tested positive for COVID-19, which means that the impact of COVID-19 extends far beyond the initial infection.”

‘Patients Are Not Making These Symptoms Up’

The study results indicate that the persistent symptoms patients are experiencing after COVID-19 “are real, and they need to be paid attention to,” Dr. Horberg said. “Clinicians really need to follow these patients closely.”

He suggests that clinicians “be proactive and ask about it” with patients who had COVID-19.

“Patients are not making these symptoms up,” Dr. Horberg continued. “These results made me think, ‘Wait a second. We need to believe these patients and see their symptoms as real.’ Of course, you want to be efficient with your time, and you think to yourself, ‘This patient had COVID-19; I don’t have to worry about.’ These results should expand the differential diagnosis.”

Clinicians should pay particularly close attention to mental health among patients who have had COVID-19, in regard to both exacerbations of prior mental health diagnoses and new-onset mental health diagnoses, according to Dr. Horberg. “During the stay-at-home orders in the early phases of the pandemic, patients were isolated and may have experienced fear as well as different phobias,” he said. “There may also be some biologic reasons for mental health conditions following COVID-19, including fatigue, but we don’t yet fully understand that biology. Until we learn more, we shouldn’t discount any new symptoms.”