Comparative risk of post-acute sequelae among adults following SARS-CoV-2 or influenza virus infection: A retrospective cohort study among United States adults.

Background: Post-acute sequelae (PAS) of SARS-CoV-2 infection are well documented. However, it remains unclear whether such long-term health effects are unique to COVID-19, or also occur following other viral respiratory infections.

Methods and findings: We undertook a retrospective cohort study of 74,738 COVID-19 cases and 18,790 influenza cases within the Kaiser Permanente Southern California healthcare system diagnosed between 1 September, 2022 and 31 December, 2023. Cases received care for index infections across a spectrum of clinical settings, spanning virtual (n = 35,835; 38.3%), ambulatory (n = 26,579; 28.4%), emergency department (n = 23,388; 25.0%) and inpatient (n = 7,726; 8.3%) facilities. We compared 180-day risk of PAS-related healthcare utilization among COVID-19 cases and influenza via adjusted hazard ratios (aHRs) weighted to account for cases' index infection type and follow-up retention. Adjustment models addressed patients' demographic characteristics, comorbidity profiles, prior healthcare utilization patterns, and index episode severity. Risk of PAS diagnoses in any clinical setting was only modestly higher among COVID-19 cases in comparison to influenza cases within 31-90 days after cases' initial illness (aHR = 1.04 [95% confidence interval: 0.99, 1.09]; risk difference = 0.6 [-0.1, 1.2] cases per 100 person-months). This difference was attenuated by 91-180 days (aHR = 1.01 [0.97, 1.06]; risk difference = 0.4 [-0.1, 0.9] cases per 100 person-months). However, COVID-19 cases faced higher risk of severe PAS conditions requiring hospitalization (aHR = 1.31 [1.07, 1.59] and 1.24 [1.03, 1.49] within 31-90 and 91-180 days, respectively). This excess risk of severe PAS was concentrated among COVID-19 cases hospitalized during acute-phase illness, and was attenuated among cases who received antiviral treatment, who had up-to-date vaccination status prior to infection, or who did not require inpatient admission for acute-phase illness. As a limitation, analyses included only PAS resulting in healthcare utilization; patient-reported symptoms and quality-of-life measures were not captured.

Conclusions: In this large, real-world cohort, individuals with non-severe acute respiratory illness caused by SARS-CoV-2 experienced only modestly greater risk of PAS in comparison to those whose illness was caused by influenza. However, COVID-19 cases hospitalized for their initial illness experienced greater risk of severe PAS necessitating inpatient care, and this difference persisted through 180 days of follow-up. Our findings challenge assumptions about the uniqueness of post-acute COVID-19 morbidity and suggest the long-term burden of influenza may be underrecognized.