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 (27074 of 193113) 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.
Emerging data suggest that the sequelae of infection with SARS-CoV-2 and the disease it causes, covid-19, could vary in presentation and extend beyond the typical postviral recovery period. Hence epidemiologic interest in morbidity after the acute infection in survivors is growing. Some survivors experience serious complications during the acute phase of the illness, affecting pulmonary, cardiovascular, hepatic, renal, cognitive, and neurologic function.1234 Survivors also report a range of persistent symptoms adversely affecting physical, mental, and social wellbeing.5678 At least some of these complications might occur independent of the severity of covid-19.9 Although individuals admitted to hospital with community acquired (non-covid-19) pneumonia or influenza are at risk of cardiovascular, cerebrovascular, and neurological complications,1011 the degree of increased risk resulting from SARS-CoV-2 infection is unclear. Longitudinal studies on survivors of other coronaviruses (Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS)) suggest long term physical and mental sequelae are not uncommon.121314
Most published studies so far have been small and mainly focused on clinical sequelae in patients admitted to hospital for covid-19.15 Hence many of these studies might not apply to the larger population of individuals infected with SARS-CoV-2. Little is known of the incidence of clinical sequelae caused by SARS-CoV-2 infection after the acute phase of the illness in adults aged 18-65 who might be considered to have a lower risk of severe covid-19. Also, few studies have been powered to evaluate whether factors such as age, sex, pre-existing conditions, and admission to hospital because of covid-19 modify the risk of clinical sequelae after the acute infection.
We estimated the excess risk and hazard ratios of new clinical sequelae attributable to SARS-CoV-2 in adults aged 18-65 after the acute phase of covid-19. Our analysis included a large generalizable sample of commercially insured adults; determined objective outcomes with the valid ICD-10 (international classification of diseases, 10th revision) codes in claims; and had the power to detect rare diagnoses and evaluate associations across subgroups.
Among 9247505 individuals meeting the study criteria in 2020, we identified 266586 (2.9%) with SARS-CoV-2 infection. After matching by propensity score, we identified 266586 matched pairs for the primary (2020) and secondary (2019) comparison groups (100% of SARS-CoV-2 individuals matched). We identified 244276 matched pairs for the viral lower respiratory tract illness comparison group (91.6% of SARS-CoV-2 individuals matched).
Individuals with SARS-CoV-2 infection were more likely than their unmatched 2020 and 2019 comparators to be younger, to be women, have a lower socioeconomic status score index, live in a zip code with a higher proportion of black or Hispanic individuals, have a pre-existing comorbidity or at risk condition, been admitted to hospital with a longer length of stay during the preceding year, visited a primary care physician or other specialists more often, and live in the northeast or southern US (areas of high incidence during the study period; all P<0.05) (table 1). Among those individuals with SARS-CoV-2, 8.2% were admitted to hospital and 1.1% were admitted to the intensive care unit. We found different patterns between individuals with SARS-CoV-2 and the viral lower respiratory tract illness comparison group who were more likely to be older, to be women, have a comorbidity, smoke, visit a primary care physician or cardiologist more often, and live in the southern or midwestern US. After matching by propensity score, most of these differences were resolved, although some small differences between the matched SARS-CoV-2 infected group and the viral lower respiratory tract illness comparator were significant (all P <0.05) (eTable 1a). Despite these minor differences, balance was achieved overall, as shown by the standardized mean differences between matched groups by key variables at less than 0.10 (eFig 1a-c).
Table 1Demographics, comorbidities, and clinical factors in unmatched adults aged 18 to 65, UnitedHealth Group Clinical Discovery Database up to 31 October 2020
Among the matched individuals infected with SARS-CoV-2 identified in our study with a follow-up time of at least 21 days from the index date (n=193113), 85.98% had no new clinical sequelae after the acute infection that required medical care during their follow-up, 10.01% had one type of new sequelae that required medical care, and 4.01% had more than one type of new sequelae (table 2). The proportion of individuals diagnosed as having any new clinical sequelae after the acute phase was higher in the SARS-CoV-2 infected group than in the three comparator groups, although the differences were smallest compared with the viral lower respiratory tract illness group.
Table 2Proportion of adults aged 18 to 65 with new clinical sequelae of SARS-Cov-2 infection after the acute phase compared with three groups matched by propensity score, UnitedHealth Group Clinical Discovery Database up to 31 October 2020
Estimates of risk difference by type of new clinical sequelae were calculated for individuals infected with SARS-CoV-2 who were still at risk 21 days after the index date (n=193113 for 2020 comparison). Follow-up time was considered up to day 141 after the index date (120 days from the start of the post-acute period and 73.5 centile of the follow-up distribution, with a median of 87 days (interquartile range 45-124 days)). Figure 2 summarizes the most common new clinical outcomes in the SARS-CoV-2 group (incidence 0.1%) and eTable 2a the less common outcomes. Symptoms are included separately in eTable 2b and are not represented in figure 2. Overall, the excess risk attributable to SARS-CoV-2 infection was low for incident diagnoses (0.02-2.26 per 100 individuals) four months after the acute phase (fig 2 and eTable 2a-b). The increased risk, however, was consistently seen for many outcomes across all three comparison groups (2020, 2019, and viral lower respiratory tract illness groups; eTable 2a).
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
Despite the small absolute risk attributable to SARS-CoV-2 infection, the hazard ratios for individuals infected with SARS-CoV-2 and the 2020 comparator group after the acute infection were large (significant hazard ratios of 1.24-25.65 (all P<0.001 except for atopic dermatitis (P=0.033); eTable 2c-d and fig 2). When we evaluated rates over time, hazard ratios were highest in the first month of the index date but were substantially elevated up to six months for some common events, such as hypertension (hazard ratio 1.81 (95% confidence interval 1.10 to 2.96)), diabetes (2.47 (1.14 to 5.38)), sleep apnea (2.31 (1.23 to 4.32)), and fatigue (2.20 (1.48 to 3.27)), suggesting the hazard for some new clinical sequelae was sustained months after the initial SARS-CoV-2 infection (eTable 3). An increased risk 30 days before the index date was likely because of a delay in testing or documentation of a confirmed diagnosis in symptomatic individuals. Figure 3 shows select graphs of the cumulative hazards for the most common or most severe clinical sequelae.
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
Excess risk for developing many new outcomes after the acute infection increased significantly (most P<0.001) with age (fig 4 and eTable 4a). The risk for clinical sequelae was greatest in individuals aged >50 but the absolute risk in young adults aged 18-34 was significantly elevated, albeit modestly so, for some conditions including, but not limited to, hypertension, arrhythmia, hypercoagulability, amnesia, diabetes, and fatigue (all P<0.001). The risk of developing any mental health outcome was significantly increased regardless of age (Pinteraction=0.35).
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
Excess risk for new clinical sequelae after acute covid-19 rarely differed between men and women, apart from fatigue and anosmia (more commonly diagnosed in women) and myocarditis, hypercoagulability, deep vein thrombosis, kidney injury, and sleep apnea (more commonly diagnosed in men) (fig 4 and eTable 4b). With a few exceptions, individuals with pre-existing conditions (fig 4 and eTable 4c) and individuals admitted to hospital with covid-19 (fig 4 and eTable 4d) had a greater excess risk of developing new clinical sequelae because of SARS-CoV-2 infection.
We did not find a significant period effect for most outcomes (eTable 4e). In our sensitivity analysis, the risk differences increased when the post-acute phase was shortened to an index date plus 14 days (eTable 5a). Similar risk differences were seen for the index date plus 21 days and the index date plus 28 days (eTable 5b), suggesting an index date plus 21 days is a reasonable start to the post-acute phase of the illness.