Long COVID incidence in adults and children between 2020 and 2023: a real-world data study from the RECOVER Initiative

Abstract

Estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) incidence, also known as Long COVID, have varied across studies and changed over time. We estimated PASC incidence among adult and pediatric populations in three nationwide research networks of electronic health records (EHR) participating in the RECOVER Initiative using different classification algorithms (computable phenotypes). Overall, 7% of children and 8.5%-26.4% of adults developed PASC, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 4% in children and ranged from 4-7% among adults, representing a lower-bound incidence estimation based on two control groups - contemporary COVID-19 negative and historical patients (2019). Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants. Our findings indicate that preventing and mitigating Long COVID remains a public health priority. Examining temporal patterns and risk factors of PASC incidence informs our understanding of etiology and can improve prevention and management.

Figure 1. Proportion of patients with PASC and associated variables over time

PASC incidence and associated variables by month. Each patient was counted as having COVID-19 once, and COVID-19 index dates were graphed on the x-axis for panels b-f. Dotted red line provides a 20% benchmark across differently sized axes. A, Count of PASC cases, with the x-axis representing the date of PASC onset. B, Count of COVID-19 index cases each month. C, Percentage of patients with PASC. Percentage was calculated using the monthly COVID-19 case count as the denominator, and number of patients with PASC within 180 days of the COVID-19 index date as the numerator. D, Percentage of COVID-19 cases hospitalized for index infection. Percentage was calculated using the monthly COVID-19 case count as the denominator, and the number of hospitalized cases with or without ICU-level care as the numerator. E, Percentage of COVID-19 cases treated with Paxlovid. Percentage was calculated using the monthly COVID-19 case count as the denominator, and the number of hospitalized cases with or without ICU-level care as the numerator. This excludes 19 N3C sites not providing any data around Paxlovid orders. F, Percentage of COVID-19 cases with prior vaccination. Percentage was calculated using the monthly COVID-19 case count as the denominator, and the number of cases with evidence of vaccination prior to the index event as the numerator.

Figure 2. PASC incidence proportion by patient subpopulation and adjusted monthly relative hazards.

A, Univariate analysis. Incidence of PASC, calculated as the proportion of COVID-19 cases who developed PASC within 180 days of index infection. 95% Confidence Intervals are provided. Patient characteristics align with categories described in Table 1. Vertical dotted lines represent overall PASC incidence proportion for each network. B, Two-Dimensional Heatmap. Heatmaps represent the proportion of COVID-19 positive patients who developed PASC. Percentages are stratified by COVID-19 severity and patient pre-existing conditions. N represents the number of patients within the group. P represents the number of PASC patients within the group. Heatmap scales are based on the percentage of PASC patients from each network, from 0% (blue) through 100% (red). The midpoint (white) of the scale represents the overall PASC rate from each network. Values three or more times greater than the overall PASC rate were colored red. C, Risk of PASC over time compared to January 2021. Multivariable hazard ratios for incident PASC per month. Hazard ratios were generated by a multivariable Cox Proportional Hazards regression model, and are presented unadjusted (black) and adjusted (orange) for age group, sex, race/ethnicity, pre-existing conditions, rurality, COVID-19 severity, vaccination status, and month of the index event. 95% Confidence Intervals are provided.

Figure 3. Control group analysis

PASC incidence proportion, by COVID-19 severity and pre-existing condition burden, among A, COVID-19 positive patients identified between 1/1/2021 – 5/30/2021; B, contemporary COVID-19 negative patientsidentified between 1/1/2021 – 5/30/2021; and C, historical control patientsidentified between 1/1/2019 – 5/30/2019. Heatmaps for each group are centered (white) on the global PASC incidence estimated in that group. Lower values are shown in shades of blue, and values up to 2.5x above the global incidence are shown in shades of red. N represents the number of patients within the group. P represents the number of PASC patients within the group.