COVID-19 and risk of subsequent life-threatening secondary infections: a matched cohort study in UK Biobank

Abstract

Background: With the increasing number of people infected with and recovered from coronavirus disease 2019 (COVID-19), the extent of major health consequences of COVID-19 is unclear, including risks of severe secondary infections.

Methods: Based on 445,845 UK Biobank participants registered in England, we conducted a matched cohort study where 5151 individuals with a positive test result or hospitalized with a diagnosis of COVID-19 were included in the exposed group. We then randomly selected up to 10 matched individuals without COVID-19 diagnosis for each exposed individual (n = 51,402). The life-threatening secondary infections were defined as diagnoses of severe secondary infections with high mortality rates (i.e., sepsis, endocarditis, and central nervous system infections) from the UK Biobank inpatient hospital data, or deaths from these infections from mortality data. The follow-up period was limited to 3 months after the initial COVID-19 diagnosis. Using a similar study design, we additionally constructed a matched cohort where exposed individuals were diagnosed with seasonal influenza from either inpatient hospital or primary care data between 2010 and 2019 (6169 exposed and 61,555 unexposed individuals). After controlling for multiple confounders, Cox models were used to estimate hazard ratios (HRs) of life-threatening secondary infections after COVID-19 or seasonal influenza.

Results: In the matched cohort for COVID-19, 50.22% of participants were male, and the median age at the index date was 66 years. During a median follow-up of 12.71 weeks, the incidence rate of life-threatening secondary infections was 2.23 (123/55.15) and 0.25 (151/600.55) per 1000 person-weeks for all patients with COVID-19 and their matched individuals, respectively, which corresponded to a fully adjusted HR of 8.19 (95% confidence interval [CI] 6.33-10.59). The corresponding HR of life-threatening secondary infections among all patients with seasonal influenza diagnosis was 4.50, 95% CI 3.34-6.08 (p for difference < 0.01). Also, elevated HRs were observed among hospitalized individuals for life-threatening secondary infections following hospital discharge, both in the COVID-19 (HR = 6.28 [95% CI 4.05-9.75]) and seasonal influenza (6.01 [95% CI 3.53-10.26], p for difference = 0.902) cohorts.

Conclusion: COVID-19 patients have increased subsequent risks of life-threatening secondary infections, to an equal extent or beyond risk elevations observed for patients with seasonal influenza.

Keywords: COVID-19; Life-threatening infections; Sepsis; Severe secondary infections.

Fig. 1

The flow chart of the matched cohorts for COVID-19 and for seasonal influenza. *January 31 is the date when the first UK COVID-19 case was confirmed; ^$up to 10 individuals free of exposure disease at the index date were randomly selected and individually matched to each exposed individual by birth year, sex, decile of Townsend deprivation index, and Charlson comorbidity index (0, 1, 2, or 3+); ^&individuals diagnosed with seasonal influenza between January 31 and October 31 from 2010 to 2019 based on primary care data and inpatient hospital data

Fig. 2

Temporal change of the associations between COVID-19/seasonal influenza and subsequent risk of life-threatening secondary infections. *The simulated curves were constructed using one-dimensional smoothing spline; ^#Cox models were stratified by matching identifier (sex, birth year, Charlson comorbidity index, and decile of Townsend deprivation index) and adjusted for education level, Townsend deprivation index (as a continuous variable), Charlson comorbidity index (as a continuous variable), BMI, smoking status, and history of life-threatening infections

Fig. 3

Comparison of the hazards of life-threatening secondary infections in COVID-19 and seasonal influenza patients. *Cox models were stratified by matching identifier (sex, birth year, Charlson comorbidity index, and decile of Townsend deprivation index) and adjusted for education level, Townsend deprivation index (as a continuous variable), Charlson comorbidity index (as a continuous variable), BMI, smoking status, and history of life-threatening infections; ^#for all life-threatening secondary infections, the exposed individuals were stratified into three subgroups: with hospital admission and operations/procedures, with only hospital admission, and with neither hospital admission nor operations/procedures, along with their matched unexposed individuals; ^$defined as having been discharged at the time of the life-threatening secondary infection diagnosis, and we also required that a diagnosis of prior virus infection was not present during the hospitalization of the subsequent severe secondary infections