Postacute sequelae of COVID-19 at 2 years

Ella Castle

There were 138,818 and 5,985,227 participants in the COVID-19 and noninfected control groups, respectively. The COVID-19 group had a mean age of 60.91 years (s.d.: 15.96), and 11.41% of participants were female. The control group had a mean age of 62.82 years (s.d.: 16.84), and 9.93% of participants were female. […]

There were 138,818 and 5,985,227 participants in the COVID-19 and noninfected control groups, respectively. The COVID-19 group had a mean age of 60.91 years (s.d.: 15.96), and 11.41% of participants were female. The control group had a mean age of 62.82 years (s.d.: 16.84), and 9.93% of participants were female. Median follow-up time was 715 days (interquartile range (IQR): 687–720) in the COVID-19 group and 719 days (IQR: 690–720) in the control group, with a total of 255,119 and 11,181,224 person-years of follow-up, respectively, which altogether corresponded to 11,436,344 person-years of follow-up. Demographic and health characteristics of the COVID-19 and noninfected control groups before and after inverse probability weighting for baseline covariates are presented in Supplementary Tables 1 and 2.

We examined risks of death, hospitalization and a set of 80 prespecified postacute COVID-19 sequelae, as well as sequelae aggregated by organ system and aggregated as an overall outcome of PASC by care setting (nonhospitalized (n = 118,238) and hospitalized (n = 20,580) during the acute phase of SARS-CoV-2 infection) and overall (n = 138,818) during the following five time periods of the postacute phase of the disease: 30–90, 91–180, 181–360, 361–540 and 541–720 days after a SARS-CoV-2 infection.

PASC by acute phase care setting

Participant characteristics by care setting before and after weighting are presented in Supplementary Tables 3 and 4, and assessments of covariate balance are provided in Extended Data Figs. 1 and 2.

Risks among nonhospitalized group

Risks in the nonhospitalized group are presented in Fig. 1, Extended Data Fig. 3 and Supplementary Table 5. Compared to the control, people with COVID-19 who were not hospitalized during the acute phase of the disease were still at an increased risk of death during the 91–180 days after SARS-CoV-2 infection, but not the 181–720 days following SARS-CoV-2 infection, suggesting the risk horizon occurred between 91 days and 360 days (Fig. 1, Extended Data Fig. 3 and Supplementary Table 5). Compared to those without SARS-CoV-2 infection, the risk of hospitalization was increased in the 361–540 days following the infection, but not the 541–720 days after SARS-CoV-2 infection, suggesting the risk horizon occurred between 361 days and 720 days.

Fig. 1: Risk of postacute sequelae of COVID-19 up to 2 years after infection by care setting of the acute phase of the disease.
figure 1

Relative risks by days after infection plotted for time periods of 30–90, 91–180, 181–360, 361–540 and 541–720 days after infection, labeled by the last day of the corresponding time period. Heatmaps include (top row) nonhospitalized for COVID-19 during the acute phase of the disease (n = 118,238) corresponding to each sequela and (bottom row) COVID-19 hospitalization during the acute phase of the disease (n = 20,580). Relative risks were estimated in comparison to a noninfected control (n = 5,985,227). Sequelae are grouped by organ system. ACD, acute coronary disease; AIM, abnormal involuntary movements; AKI, acute kidney injury; CKD, chronic kidney disease; DVT, deep vein thrombosis; ESKD, end-stage kidney disease; GAD, general anxiety disorder; GERD, gastroesophageal reflux disease; IBS, irritable bowel syndrome; ICM, ischemic cardiomyopathy; ILD, interstitial lung disease; MI, myocardial infarction; NCD, neurocognitive decline; NICM, nonischemic cardiomyopathy; PTSD, post-traumatic stress disorder; PUD, peptic ulcer disease; TIA, transient ischemic attack; VTE, venous thromboembolism. NS, non-significant.

Over the span of 2 years of follow-up in the nonhospitalized group, risks declined and became not significant for 69% of the examined sequelae (Fig. 1, Extended Data Fig. 3 and Supplementary Table 5) and remained increased for 31% (24 of 77) of sequelae—including 7% (1 of 14) of cardiovascular sequelae, 20% (1 of 5) of coagulation and hematologic sequelae, 100% (1 of 1) endocrine sequelae, 36% (4 of 11) of gastrointestinal sequelae, 100% (1 of 1) general sequelae, 0% (0 of 4) of kidney sequelae, 15% (2 of 13) of mental health sequelae, 75% (3 of 4) of musculoskeletal sequelae, 45% (9 of 20) of neurologic sequelae and 50% (2 of 4) of pulmonary sequelae (Extended Data Fig. 3).

In analyses of PASC and sequelae by organ system, risks of PASC for coagulation and hematologic disorders, pulmonary disorders, fatigue, gastrointestinal disorders, musculoskeletal disorders and diabetes remained increased 2 years after a SARS-CoV-2 infection in those not hospitalized for COVID-19 compared to those without SARS-CoV-2 infection (Fig. 2 and Supplementary Table 6). The risks of sequelae in several organ systems and disease groups became not significant during the 2 years of follow-up including risks in neurologic (not significant at 541, possible range of risk horizon: 361–720 days), cardiovascular (not significant at 541, 361–720 days), mental health (at 181, 91–360 days) and kidney (not significant at 361, 181–540 days).

Fig. 2: Risks and DALYs of postacute sequelae overall and by organ system by care setting of the acute phase of the disease.
figure 2

The first column includes risk due to COVID-19 of the outcome by time periods of 30–90, 91–180, 181–360, 361–540 and 541–720 days after infection The dot represents the relative risk, while the error bars correspond to the 95% confidence intervals. The second column includes the DALYs rate per 1,000 persons per 30 days by time period. The center of the vertical bar represents the DALYs rate, while the error bars correspond to the 95% confidence intervals. Bar widths differ by the duration of the time period. No adjustment for multiple comparisons was made for the prespecified analyses. Risks and DALYs not significantly different from the control are marked by NS. The third column presents cumulative DALYs per 1,000 persons at 2 years after infection. The center of the horizontal bar represents the cumulative DALYs rate, while the error bars correspond to 95% confidence intervals. Nonhospitalized for COVID-19 (n = 118,238), COVID-19 hospitalization (n = 20,580) and control group (n = 5,985,227). Outcomes are ordered from top to bottom by largest cumulative DALYs at 2 years after infection in the overall COVID-19 cohort. NS, non-significant.

Cumulative incident rates of sequelae by organ system in those not hospitalized with COVID-19 are presented in Fig. 3a and Supplementary Table 6, while disability-adjusted life year (DALY) rates are presented in Figs. 2 and 3b, Extended Data Fig. 4 and Supplementary Table 6. There were cumulatively 70.8 (95% confidence interval (CI): 57.8, 84.0) incident PASC per 1,000 persons at 2 years after SARS-CoV-2 infection (Fig. 3a and Supplementary Table 6)—corresponding to 80.4 (95% CI: 71.6, 89.6) DALYs per 1,000 persons at 2 years (Figs. 2 and 3b, Extended Data Fig. 4 and Supplementary Table 6). There were 23.8 (17.7, 30.4) DALYs per 1,000 persons from neurologic disorders, 14.5 (11.6, 17.6) from cardiovascular disorders, 10.7 (9.4, 12.1) from coagulation or hematologic disorders, 8.3 (5.1, 11.6) from mental health disorders, 8.2 (7.6, 8.8) from pulmonary disorders, 4.6 (4.1, 5.1) from fatigue, 3.4 (2.9, 3.9) from gastrointestinal disorders, 3.2 (2.8, 3.6) from musculoskeletal disorders, 1.6 (0.7, 2.7) from kidney disorders and 1.0 (0.7, 1.3) from diabetes (Figs. 2 and 3b, Extended Data Fig. 4 and Supplementary Table 6).

Fig. 3: Cumulative incidence and DALYs of postacute sequelae overall and by organ system at 2 years after infection.
figure 3

a, Cumulative incidence defined as at least one sequela within that organ system; b, cumulative DALYs from sequelae in an organ system. Presented for COVID-19 overall (n = 138,818) and by care setting of the acute phase of the disease (nonhospitalized (n = 118,238) and hospitalized (n = 20,580)) at 2 years after infection. The center of the horizontal bars represents the magnitude of incidence or DALY per 1,000 persons at 2 years after infection and is numerically labeled. Each plot is ordered in a descending fashion. Error bars represent 95% confidence intervals.

Over the span of 2 years of follow-up, 25.3% (18.9, 31.0) of the DALYs due to PASC were contributed from the second year (Fig. 4 and Supplementary Table 6) and 74.7% (69.0, 81.1) contributed from the first year. In total, 23.2% (9.0, 34.1) of the DALYs were due to cardiovascular sequelae, 22.2% (14.6, 28.8) due to coagulation and hematologic sequelae, 41.2% (26.2, 55.3) due to endocrine sequelae, 40.6% (32.7, 48.1) due to gastrointestinal sequelae, 30.2% (23.5, 36.2) due to general sequelae, −9.1% (−112.9, 26.3) due to kidney sequelae, 24.1% (2.4, 39.9) due to mental health sequelae, 44.4% (37.3, 51.3) due to musculoskeletal sequelae, 26.4% (8.9, 40.3) due to neurologic sequelae and 23.2% (19.2, 27.1) due to pulmonary sequelae were contributed from the second year of follow-up (Fig. 4 and Supplementary Table 6).

Fig. 4: Cumulative DALYs of postacute sequelae overall and by organ system within the first and second years after infection.
figure 4

a, Percentage of cumulative DALYs at 2 years contributed from first and second year after infection; b, cumulative DALYs per 1,000 persons in the first and second year after infection. Plots presented for nonhospitalized COVID-19 (n = 118,238), hospitalized COVID-19 (n = 20,580) and overall COVID-19 (n = 138,818) compared to control group (n = 5,985,227).

Risks among hospitalized group

Risks in the hospitalized group are presented in Fig. 1, Extended Data Fig. 3 and Supplementary Table 7. Compared to the control, those hospitalized with COVID-19 during the acute phase of the disease remained at increased risk of death and hospitalization through 2 years after SARS-CoV-2 infection (Fig. 1, Extended Data Fig. 3 and Supplementary Table 7); risks were higher in those hospitalized than those not hospitalized (Supplementary Table 8).

Over the 2 years of follow-up, the decline in risk difference between the COVID-19 group and the control group was much less pronounced in people who were hospitalized (than in those nonhospitalized) during the acute phase of SARS-CoV-2 infection (Supplementary Table 8). At 2 years after infection, compared to those without infection, risks declined and became not significant for 35% of sequelae and remained increased for 65% (50 of 77) of sequelae —including 57% (8 of 14) of cardiovascular sequelae, 80% (4 of 5) of coagulation and hematologic sequelae, 100% (1 of 1) endocrine sequelae, 82% (9 of 11) of gastrointestinal sequelae, 100% (1 of 1) general sequelae, 75% (3 of 4) of kidney sequelae, 38% (5 of 13) of mental health sequelae, 75% (3 of 4) of musculoskeletal sequelae, 60% (12 of 20) of neurologic sequelae and 100% (4 of 4) of pulmonary sequelae (Extended Data Fig. 3).

Among those hospitalized with COVID-19, risks remain increased at 2 years after SARS-CoV-2 infection for PASC and all organ systems examined (Fig. 2 and Supplementary Table 9) and were higher in the hospitalized group compared to the nonhospitalized group (Supplementary Table 10). Cumulative incident rates of sequelae by organ system in those hospitalized with COVID-19 are presented in Fig. 3a (Supplementary Table 9), while DALY rates are presented in Figs. 2 and 3b, Extended Data Fig. 4 and Supplementary Table 9. There were cumulatively 316.4 (95% CI: 302.8, 328.2) incident PASC per 1,000 persons at 2 years after SARS-CoV-2 infection (Fig. 3a and Supplementary Table 9)—corresponding to 642.8 (95% CI: 596.9, 689.3) DALYs per 1,000 persons at 2 years (Figs. 2 and 3b, Extended Data Fig. 4 and Supplementary Table 9). These included 144.0 (128.8, 161.1) DALYs per 1,000 persons from cardiovascular disorders, 130.2 (111.2, 149.5) from mental health disorders, 120.6 (96.4, 146.5) from neurological disorders, 90.8 (83.5, 98.7) from coagulation or hematologic disorders, 65.0 (58.8, 71.7) from kidney disorders, 44.9 (41.3, 48.8) from pulmonary disorders, 23.8 (21.2, 26.7) from fatigue, 19.5 (17.0, 22.1) from gastrointestinal disorders, 7.4 (5.8, 9.2) from diabetes and 6.2 (4.7, 7.7) from musculoskeletal disorders (Figs. 2 and 3b, Extended Data Fig. 4 and Supplementary Table 9).

During the follow-up, 21.3% (18.2, 24.5) of the DALYs due to PASC were contributed from the second year (Fig. 4 and Supplementary Table 9) and 78.7% (75.5, 81.8) contributed from the first year. In total, 20.0% (15.8, 24.5) of the DALYs were due to cardiovascular sequelae, 20.4% (16.7, 24.4) due to coagulation and hematologic sequelae, 17.7% (7.0, 29.1) due to endocrine sequelae, 35.4% (29.3, 41.3) due to gastrointestinal sequelae, 23.4% (18.1, 28.9) due to general sequelae, 22.0% (17.4, 26.9) due to kidney sequelae, 18.8% (12.4, 25.5) due to mental health sequelae, 28.2% (14.1, 40.6) due to musculoskeletal sequelae, 25.7% (15.0, 35.9) due to neurologic sequelae and 18.7% (15.7, 22.3) due to pulmonary sequelae were contributed from the second year of follow-up (Fig. 4 and Supplementary Table 9).

PASC in overall cohort

We then examined risks in the overall COVID-19 cohort. Assessment of standardized mean differences (SMDs) after the application of inverse probability weighting suggested that covariates were well balanced between the overall COVID-19 and the control cohort (Extended Data Figs. 5 and 6).

Risks of death, hospitalization and incident sequela during each period are provided in Fig. 5, Extended Data Fig. 3 and Supplementary Table 11. Compared to the control group, those with COVID-19 had an increased risk of death in the first 30–360 days after SARS-CoV-2 infection, but not the 361–720 days after SARS-CoV-2 infection, suggesting the risk horizon occurred between 181 days and 540 days (Fig. 5 and Supplementary Table 11). The risk of hospitalization was increased throughout the 2 years after SARS-CoV-2 infection (Fig. 5 and Supplementary Table 11).

Fig. 5: Risk of postacute sequelae of COVID-19 overall up to 2 years after infection.
figure 5

Relative risks by days after infection are plotted for time periods of 30–90, 91–180, 181–360, 361–540 and 541–720 days after infection, labeled by the last day during the corresponding time period. The relative risk is included in the text for each time period and outcome. Relative risks were estimated for overall COVID-19 (n = 138,818) in comparison to a noninfected control (n = 5,985,227). Sequelae are grouped by organ system. CICM, ischemic cardiomyopathy; KD, chronic kidney disease. NS, non-significant.

We then examined the risks of prespecified incident sequelae, provided in Fig. 5 and Supplementary Table 11. Those who had COVID-19 had a higher risk of all prespecified sequelae in the 30–90 days following SARS-CoV-2 infection. However, as time progressed, the risks of several incident sequelae were attenuated and not statistically significant. Compared to those without COVID-19, those with COVID-19 remained at increased risk of 86% (69 of 80) of sequelae 1 year after SARS-CoV-2 infection. Two years after SARS-CoV-2 infection, those with COVID-19 remained at increased risk of 60% (48 of 80) of the sequelae (Fig. 5, Extended Data Fig. 3 and Supplementary Table 11).

Risks of PASC and sequelae by organ system, provided in Fig. 6 and Supplementary Table 12, were highest in the initial postacute phase (30–90 days) and attenuated as follow-up progressed but remained increased in all organ systems 2 years after SARS-CoV-2 infection.

Fig. 6: Risk and DALYs of postacute sequelae overall and by organ system in COVID-19 overall.
figure 6

The first column includes risk of the outcome due to COVID-19 by time periods of 30–90, 91–180, 181–360, 361–540 and 541–720 days after infection. The dot represents the relative risk, while the error bars correspond to the 95% confidence intervals. The second column includes the DALYs rate per 1,000 persons per 30 days by time period. The center of the vertical bar represents the DALYs rate, while the error bars correspond to the 95% confidence intervals. Bar widths differ by the duration of the time period. The third column presents the cumulative DALYs per 1,000 persons during the postacute phase at 2 years after infection. The center of the horizontal bar represents the cumulative DALYs rate, while the error bars correspond to 95% confidence intervals. No adjustment for multiple comparisons was made for the prespecified analyses. Outcomes are ordered from top to bottom by the largest cumulative DALYs at 2 years after infection. The horizontal bar represents the cumulative DALYs rate, while the error bars correspond to the 95% confidence intervals. Overall COVID-19 (n = 138,818) and control group (n = 5,985,227).

There were cumulatively 96.0 (95% CI: 82.5,110.9) incident PASC per 1,000 persons at 2 years after SARS-CoV-2 infection (Fig. 3a and Supplementary Table 12). Cumulative incident rates of sequelae by organ system are presented in Fig. 3a and Supplementary Table 12. DALY rates of sequelae by organ system are presented in Figs. 3b and 5, Extended Data Fig. 7 and Supplementary Table 12. Cumulatively at 2 years after SARS-CoV-2 infection, PASC contributed 151.0 (95% CI: 141.6, 161.0) DALYs per 1,000 persons, including 37.5 (31.8, 44.0) DALYs per 1,000 persons from neurologic disorders, 30.7 (27.5, 34.2) from cardiovascular disorders, 24.0 (20.5, 27.6) from mental health disorders, 20.7 (19.2, 22.3) from coagulation or hematologic disorders, 12.8 (12.1, 13.5) from pulmonary disorders, 8.9 (7.8, 10.0) from kidney disorders, 6.7 (6.2, 7.2) from fatigue, 5.4 (4.9, 5.9) from gastrointestinal disorders, 3.5 (3.1, 3.9) from musculoskeletal disorders and 1.6 (1.4, 2.0) from diabetes (Figs. 3b and Fig. 5, Extended Data Fig. 7 and Supplementary Table 12).

Over the span of 2 years of follow-up, 24.8% (21.6, 27.8) of the DALYs due to PASC were contributed from the second year (Fig. 4 and Supplementary Table 12) and 75.2% (72.2, 78.4) contributed from the first year. In total, 24.1% (18.6, 29.4) of the DALYs were due to cardiovascular sequelae, 21.4% (17.5, 25.2) due to coagulation and hematologic sequelae, 31.4% (21.8, 40.8) due to endocrine sequelae, 40.2% (35.0, 45.3) due to gastrointestinal sequelae, 27.1% (22.7, 31.4) due to general sequelae, 16.7% (9.6, 23.4) due to kidney sequelae, 20.3% (12.9, 27.2) due to mental health sequelae, 43.8% (37.8, 49.7) due to musculoskeletal sequelae, 29.4% (19.5, 38.5) due to neurologic sequelae and 21.2% (18.5, 23.8) due to pulmonary sequelae were contributed from the second year of follow-up (Fig. 4 and Supplementary Table 12).

Sensitivity analyses

We performed several sensitivity analyses of the risk of postacute sequelae in those with COVID-19 compared to the no-infection control group (Supplementary Table 13). As an alternative to the primary analytic approach that used inverse weighting at baseline to adjust for potential confounding, we used a conditional modeling approach that adjusted for baseline covariates in analyses of each time period to account for potential changes in the composition of the cohort as follow-up progressed (n = 6,124,045). In addition to adjusting for baseline covariates through inverse probability weighting, as evidence has suggested that vaccination after infection may be associated with reduced risks of postacute sequelae, we adjusted for vaccination status as a time-varying covariate (n = 6,124,045). As an alternative approach to the assessment of the occurrence of outcomes where reinfection contributes additional risks (in addition to those incurred after the primary infection), we additionally censored follow-up of those with COVID-19 at the time of reinfection (n = 6,124,045). In addition to the baseline covariates, in consideration of potential differences in healthcare resource utilization between groups, we adjusted for the probability of healthcare resource utilization during follow-up (n = 6,124,045). As an additional cohort inclusion criterion, to enhance comparability in receipt of care during follow-up between the COVID-19 group and the control group, we conducted analyses in a subcohort of those that had at least one healthcare encounter per period of analysis during follow-up (n = 4,961,017). To examine the influence of iteration of bootstrapping, we conducted 500 iterations of bootstrapping instead of 1,000 iterations used in the primary approach (n = 6,124,045). All sensitivity analyses yielded results that were consistent with those produced using the primary approach (Supplementary Table 13).

To further examine the influence of those who were censored during each period on risk estimates, we conducted analyses to estimate the relative risk in those with COVID-19 overall compared to the noninfected control during each time period by including those who were censored in that time period (n = 6,124,045). We also used survival models within each time period to estimate the hazard ratios (n = 6,124,045). These two additional sensitivity analyses presented in Supplementary Table 14 yielded results consistent with the primary approach presented in Fig. 6.

Negative outcome control

We examined the association between COVID-19 and incident neoplasms during the 2 years of follow-up as negative outcome control. The analyses suggested no association between COVID-19 infection and the negative outcome control (relative risk of 1.04 (0.95, 1.14), 1.01 (0.92, 1.11), 0.96 (0.90, 1.03) and 1.01 (0.94, 1.10) in the period between 30–90, 91–180, 181–360, 361–540 and 541–720 days, respectively).

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