Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study

Abstract

Objective: To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65.

Design: Retrospective cohort study.

Setting: Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database.

Participants: Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness.

Main outcome measures: More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated.

Results: 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group.

Conclusions: The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

Fig 1

Flowchart with details of population sampling of the 2020 cohort sample

Fig 2

Risk difference (per 100 individuals) and hazard ratios for the most common clinical sequelae in the SARS-CoV-2 versus the 2020 comparator group, UnitedHealth Group Clinical Discovery Database up to 31 October 2020. Clinical sequelae are diagnoses with an incidence ≥0.1 in the SARS-CoV-2 group during the first four months after the acute infection (index date plus 21 days) and highest in hierarchy if an aggregate diagnosis. We adopted this rule to avoid confidence intervals that were too wide to display. Symptoms are not displayed. All associations for each of the 51 outcomes are listed in eTable 2a-2d. Filled symbols indicate significant risk difference or hazard ratio (Bonferroni corrected P value ≤0.05). Atopic dermatitis is present in all plots as a negative control. *Aggregate diagnosis includes all subdiagnoses listed in eTable 1. DVT=deep vein thrombosis; PE=pulmonary embolism

Fig 3

Cumulative incidence rate for new clinical sequelae and symptoms after SARS-CoV-2 infection with three groups matched by propensity score, UnitedHealth Group Clinical Discovery Database up to 31 October 2020. vLRTI=viral lower respiratory tract illness. *P<0.05

Fig 4

Risk difference (per 100 individuals) for the most common clinical sequelae by subpopulation, UnitedHealth Group Clinical Discovery Database up to 31 October 2020. Clinical sequelae are diagnoses with an incidence ≥0.1 in the SARS-CoV-2 group for any subgroups during the first four months after the acute infection (index date plus 21 days) and highest in hierarchy if an aggregate diagnosis. We adopted this rule to avoid confidence intervals that were too wide to display. Symptoms are not displayed. All associations for each of the 51 outcomes are listed in eTable 4a-4d. Filled symbols indicate significant interaction term (Bonferroni corrected P value ≤0.05). Atopic dermatitis is present in all plots as a negative control. *Aggregate diagnosis includes all subdiagnoses listed in eTable 1. DVT=deep vein thrombosis; PE=pulmonary embolism