Long COVID Risk Has Fallen, Largely Attributable to Vaccine Rollout

The risk of developing long COVID, or post-acute sequelae of COVID-19 (PASC), has decreased substantially over the course of the pandemic, according to an analysis of Veterans Affairs data.

During the pre-Delta era, there were 10.42 cases of long COVID per 100 unvaccinated people at 1 year after COVID-19 infection, decreasing to 9.51 cases during the Delta variant era, and dropping to 7.76 cases per 100 unvaccinated people during the Omicron era, Ziyad Al-Aly, MD, of the VA St. Louis Health Care System in Missouri, and colleagues reported in the New England Journal of Medicine.

Rates of long COVID among people who had received a vaccine were lower, and also decreased over time. During the Delta era, there were 5.34 cases of long COVID per 100 vaccinated people 1 year after infection, dropping to 3.5 cases per 100 people during the Omicron era.

“The good news is that PASC declined,” Al-Aly told MedPage Today. “But literally millions of people get infected in the U.S., and many more around the world, so 3.5% is sizeable when multiplied by the number of COVID infections.”

Of note, another recent study found that about 7% of adults living in the community report ever having long COVID as of early 2023.

In a decomposition analysis, Al-Aly and colleagues found that about 72% (95% CI 69.50-74.43) of the decrease in the cumulative risk of long COVID between the Omicron era and earlier eras could be attributed to vaccines and about 28% (95% CI 25.57-30.50) could be attributed to era-related effects, such as changes in virus pathogenicity. “These findings suggest that vaccine uptake will be key to maintaining the lower cumulative incidence of PASC relative to earlier phases of the pandemic,” Al-Aly and colleagues wrote.

Despite the overall decrease, the residual risk of long COVID, even among vaccinated persons infected during the Omicron era, suggests that new cases of long COVID will probably continue to occur, Clifford Rosen, MD, of the MaineHealth Institute for Research in Scarborough, wrote in an accompanying editorial.

“What are the messages from this study?” Rosen queried. “First, vaccinations can prevent many but not all cases of long COVID. Second, viral variants influence the risk of PASC.”

Researchers also looked to see if individual health outcomes associated with long COVID had changed over time. They analyzed rates of cardiovascular, coagulation and hematologic, pulmonary, neurologic, metabolic, gastrointestinal, mental health, kidney, musculoskeletal, and fatigue disease categories. Although there was an overall decline in many sequelae associated with long COVID, the incidence for gastrointestinal, metabolic, and musculoskeletal disorders increased during the Omicron era among unvaccinated individuals.

“Long COVID in the pre-Delta and Delta era was actually different than long COVID that’s happening in the Omicron era,” Al-Aly said. “That tells us that not only is the risk quantitatively changing over time, but also that the disease itself has its own fingerprint — it’s not the same disease.”

“The study suggests that new cases of PASC may continue unabated, owing to a potentially greater prevalence of metabolic dysfunction and its associated coexisting conditions among persons infected during the Omicron era,” Rosen wrote. “Taken together, changes in the clinical presentation of long COVID are a function of ‘points in time’ and must be considered in any future trial or study design, as well as in clinical assessments.”

Researchers analyzed health records of 441,583 veterans who were diagnosed with COVID-19 infection between March 2020 and the end of January 2022 and also included over 4.7 million non-infected controls. The study included five cohorts that included unvaccinated people with COVID-19 infected with the original strain in 2020 (n=206,011), the Delta variant in 2021 (n=54,002), and the Omicron variant in 2022 (n=40,367), and vaccinated people infected with the Delta variant (n=56,260) or the Omicron variant (n=84,943).

The study had several limitations. The population consisted primarily of older white male U.S. veterans and the study did not evaluate data on long COVID beyond January 2022. Moreover, the study may have missed confounding variables that could have led to misclassification of COVID-19 infection status.

Despite these limitations, the study provides “insight into the epidemiology of a complex disorder and may help guide clinicians in understanding the perplexing clinical course of PASC,” Rosen concluded in his editorial.

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