Post-COVID-19-associated morbidity in children, adolescents, and adults: A matched cohort study including more than 157,000 individuals with COVID-19 in Germany

Abstract

Background: Long-term health sequelae of the Coronavirus Disease 2019 (COVID-19) are a major public health concern. However, evidence on post-acute COVID-19 syndrome (post-COVID-19) is still limited, particularly for children and adolescents. Utilizing comprehensive healthcare data on approximately 46% of the German population, we investigated post-COVID-19-associated morbidity in children/adolescents and adults.

Methods and findings: We used routine data from German statutory health insurance organizations covering the period between January 1, 2019 and December 31, 2020. The base population included all individuals insured for at least 1 day in 2020. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through June 30, 2020. A control cohort was assigned using 1:5 exact matching on age and sex, and propensity score matching on preexisting medical conditions. The date of COVID-19 diagnosis was used as index date for both cohorts, which were followed for incident morbidity outcomes documented in the second quarter after index date or later.Overall, 96 prespecified outcomes were aggregated into 13 diagnosis/symptom complexes and 3 domains (physical health, mental health, and physical/mental overlap domain). We used Poisson regression to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). The study population included 11,950 children/adolescents (48.1% female, 67.2% aged between 0 and 11 years) and 145,184 adults (60.2% female, 51.1% aged between 18 and 49 years). The mean follow-up time was 236 days (standard deviation (SD) = 44 days, range = 121 to 339 days) in children/adolescents and 254 days (SD = 36 days, range = 93 to 340 days) in adults. COVID-19 and control cohort were well balanced regarding covariates. The specific outcomes with the highest IRR and an incidence rate (IR) of at least 1/100 person-years in the COVID-19 cohort in children and adolescents were malaise/fatigue/exhaustion (IRR: 2.28, 95% CI: 1.71 to 3.06, p < 0.01, IR COVID-19: 12.58, IR Control: 5.51), cough (IRR: 1.74, 95% CI: 1.48 to 2.04, p < 0.01, IR COVID-19: 36.56, IR Control: 21.06), and throat/chest pain (IRR: 1.72, 95% CI: 1.39 to 2.12, p < 0.01, IR COVID-19: 20.01, IR Control: 11.66). In adults, these included disturbances of smell and taste (IRR: 6.69, 95% CI: 5.88 to 7.60, p < 0.01, IR COVID-19: 12.42, IR Control: 1.86), fever (IRR: 3.33, 95% CI: 3.01 to 3.68, p < 0.01, IR COVID-19: 11.53, IR Control: 3.46), and dyspnea (IRR: 2.88, 95% CI: 2.74 to 3.02, p < 0.01, IR COVID-19: 43.91, IR Control: 15.27). For all health outcomes combined, IRs per 1,000 person-years in the COVID-19 cohort were significantly higher than those in the control cohort in both children/adolescents (IRR: 1.30, 95% CI: 1.25 to 1.35, p < 0.01, IR COVID-19: 436.91, IR Control: 335.98) and adults (IRR: 1.33, 95% CI: 1.31 to 1.34, p < 0.01, IR COVID-19: 615.82, IR Control: 464.15). The relative magnitude of increased documented morbidity was similar for the physical, mental, and physical/mental overlap domain. In the COVID-19 cohort, IRs were significantly higher in all 13 diagnosis/symptom complexes in adults and in 10 diagnosis/symptom complexes in children/adolescents. IRR estimates were similar for age groups 0 to 11 and 12 to 17. IRs in children/adolescents were consistently lower than those in adults. Limitations of our study include potentially unmeasured confounding and detection bias.

Conclusions: In this retrospective matched cohort study, we observed significant new onset morbidity in children, adolescents, and adults across 13 prespecified diagnosis/symptom complexes, following COVID-19 infection. These findings expand the existing available evidence on post-COVID-19 conditions in younger age groups and confirm previous findings in adults.

Trial registration: ClinicalTrials.gov https://ichgcp.net/clinical-trials-registry/NCT05074953.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: AV, FE, FT, JJ, JS, JW, MR, MS, and ON report institutional funding for parts of this project from the German BMBF. Unrelated to this study, FT reports payments for lectures from Dresden International University. JA reports grants from the Federal State of Saxony. Unrelated to this study, JS reports grants for investigator-initiated research from the German GBA, the BMG, BMBF, EU, Federal State of Saxony, Novartis, Sanofi, ALK, and Pfizer. He also participated in advisory board meetings for Sanofi, Lilly, and ALK. MB reports payment for data analysis which is presented in this paper from DAK‐Gesundheit. Unrelated to this study, MB reports grants from German GBA and Sanofi Pasteur and consulting fees from Janssen‐Cilag. He participated in an advisory board for GSK. NT is member of the Steering Committee of the German Society for Pediatric Infectious Diseases (DGPI) and is the DGPI-mandated person for the pediatric expert group on long-COVID in children and adolescents. SB is Head of Analytics and Data Science at AOK PLUS, Dresden, Germany. Unrelated to this study, STSCH reports payments for a guest lecture at TU Berlin. The other authors declare that they have no competing interest.

Copyright: © 2022 Roessler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Figures

Fig 1. Flow charts for inclusion, exclusion, and matching of children/adolescents and adults with and without COVID-19.

The number of individuals insured for at least 1 day in 2020 includes individuals that changed their health insurance organization in 2020. Accordingly, some individuals were represented in multiple datasets of different health insurance organizations. These individuals were excluded because of discontinuous insurance in the first exclusion step and, thus, were not included in our analysis. Exclusion criteria were applied stepwise in the order shown in the flow charts. COVID-19, Coronavirus Disease 2019.

Fig 2. Estimated IRRs with 95% CIs and IRs per 1,000 person-years in COVID-19 cohort for children/adolescents and adults by outcome domain and diagnosis/symptom complex.

IRs in the control cohort are shown in pale color. COVID-19, Coronavirus Disease 2019; ENT, ear, nose and throat; IR, incidence rate; IRR, incidence rate ratio; 95% CI, 95% confidence interval.

Fig 3. Estimated IRRs with 95% CIs in children/adolescents and adults by severity of COVID-19 and domain.

COVID-19, Coronavirus Disease 2019; ICU, intensive care unit; IRR, incidence rate ratio; 95% CI, 95% confidence interval. Estimation results are shown on the log-scale.