Acute and postacute sequelae associated with SARS-CoV-2 reinfection

Abstract

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93-2.45), hospitalization (HR = 3.32, 95% CI 3.13-3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

Fig. 1. Risk and burden of sequelae in people with SARS-CoV-2 reinfection versus no reinfection.

Risk and 6-month excess burden of all-cause mortality, hospitalization, at least one sequela and sequelae by organ system are plotted. Incident outcomes were assessed from reinfection to the end of the follow-up. Results from SARS-CoV-2 reinfection (n = 40,947) and no SARS-CoV-2 reinfection (n = 443,588) are compared. Adjusted HRs (dots) and 95% CIs (error bars) are presented, as are the estimated excess burden (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at 6 months of follow-up from the time of reinfection.

Fig. 2. Risk and burden of sequelae in people with SARS-CoV-2 reinfection versus no reinfection by vaccination status before reinfection.

Risk of all-cause mortality, hospitalization, at least one sequela and sequelae by organ system are plotted. Incident outcomes were assessed from reinfection to the end of the follow-up. Results from SARS-CoV-2 reinfection (n = 40,947) versus no SARS-CoV-2 reinfection (n = 443,588) are compared. At the time of comparison, there were 51.3%, 12.6% and 36.2% with no, one and two or more vaccinations, respectively, among those who had reinfection. At the time of comparison, there were 41.1%, 11.7% and 47.2% with no, one and two or more vaccinations, respectively, among the no reinfection group. Adjusted HRs (dots) and 95% CIs (error bars) are presented.

Fig. 3. Risk and burden of all-cause mortality, hospitalization and at least one sequela in the acute and postacute phases of SARS-CoV-2 reinfection versus no reinfection.

Risk and 6-month burden of all-cause mortality, hospitalization and at least one sequela of SARS-CoV-2 reinfection versus no reinfection in 30-d intervals covering the acute and postacute phases of reinfection. Incident outcomes were assessed from reinfection to the end of the follow-up. Results from SARS-CoV-2 reinfection (n = 40,947) versus first SARS-CoV-2 infection (n = 443,588) by time since reinfection were compared. Adjusted HRs (dots) and 95% CIs (error bars) are presented for each 30-d period since the time of reinfection, as are the estimated excess burden (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at every 30-d period of the follow-up from the time of reinfection.

Fig. 4. Risk and burden of sequelae by organ system in the acute and postacute phases of SARS-CoV-2 reinfection versus no reinfection.

Risk and 6-month excess burden of sequelae by organ system of SARS-CoV-2 reinfection versus no reinfection in 30-d intervals covering the acute and postacute phases of reinfection. Incident outcomes were assessed from reinfection to the end of the follow-up. Results from SARS-CoV-2 reinfection (n = 40,947) versus first SARS-CoV-2 infection (n = 443,588) by time since reinfection are compared. Adjusted HRs (dots) and 95% CIs (error bars) are presented for each 30-d period since the time of reinfection, as are the estimated excess burden (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at every 30-d period of the follow-up from the time of reinfection.

Fig. 5. Cumulative risk and burden of sequelae in people with one, two and three or more SARS-CoV-2 infections compared to noninfected controls.

Risk and 1-year excess burden of hospitalization, at least one sequela and sequelae by organ system are plotted. Incident outcomes were assessed from 30 d after the first positive SARS-CoV-2 test to the end of the follow-up. Results from one SARS-CoV-2 infection (n = 234,990), two SARS-CoV-2 infections (n = 28,509) and three or more SARS-CoV-2 infections (n = 1,023) versus noninfected controls (n = 5,334,729), in those with a first infection before the Omicron wave, are compared. Adjusted HRs (dots) and 95% CIs (error bars) are presented, as are the estimated excess burden (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at 1 year of follow-up.

Extended Data Fig. 1

Cohort flowchart.