The New England Journal of MedicinePostacute Sequelae of SARS-CoV-2 Infection in the Pre-Delta, Delta, and Omicron Eras

PASC Risk Declines Over Pandemic Eras, Vaccination Plays Key Role

A comprehensive study of 441,583 veterans with SARS-CoV-2 infection and 4,748,504 noninfected controls reveals a significant decrease in the risk of postacute sequelae of SARS-CoV-2 infection (PASC) over the course of the COVID-19 pandemic. The research provides crucial insights into the changing landscape of PASC across the pre-delta, delta, and omicron eras, while highlighting the substantial impact of vaccination on reducing PASC incidence.

Key Points:

• The cumulative incidence of PASC at 1 year after infection decreased from 10.42 cases per 100 persons among unvaccinated individuals in the pre-delta era to 3.50 cases per 100 persons among vaccinated individuals in the omicron era.
• Unvaccinated persons showed a consistent decrease in PASC incidence across eras: 10.42 events per 100 persons (pre-delta), 9.51 (delta), and 7.76 (omicron).
• Vaccination significantly reduced PASC risk: during the delta era, vaccinated individuals had 5.34 events per 100 persons compared to 9.51 for unvaccinated; in the omicron era, 3.50 for vaccinated versus 7.76 for unvaccinated.
• Decomposition analysis revealed that 28.11% of the decrease in PASC incidence was attributable to era-related effects (changes in virus pathogenicity and other temporal factors), while 71.89% was due to vaccines.
• Most disease categories showed lower risk of sequelae in later eras, but gastrointestinal, metabolic, and musculoskeletal disorders showed higher risk during the omicron era compared to earlier eras among unvaccinated individuals.
• Among vaccinated persons, nearly all disease categories showed lower PASC incidence during the omicron era compared to the delta era.
• The study population consisted predominantly of older White men, which may limit generalizability to other demographics.
• Despite the overall decrease, the cumulative incidence of PASC at 1 year among vaccinated persons during the omicron era remained substantial at 3.50 cases per 100 persons.
• The large number of infections during the omicron era, ongoing new infections and reinfections, and poor vaccination uptake may contribute to a high absolute number of persons with PASC.
• Sensitivity analyses, including assessment of unmeasured confounding and exposure misclassification, supported the robustness of the primary findings.

HCN Medical Memo
Although the risk of PASC has decreased significantly over the course of the pandemic, particularly among vaccinated individuals, it remains a substantial concern. Clinicians should continue to monitor patients for long-term sequelae of COVID-19, especially considering the potential for high absolute numbers of PASC cases due to widespread omicron infections and suboptimal vaccination rates.

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