Post COVID-19 in children, adolescents, and adults: results of a matched cohort study including more than 150,000 individuals with COVID-19

  1. Martin Roessler
  2. Falko Tesch
  3. Manuel Batram
  4. Josephine Jacob
  5. Friedrich Loser
  6. Oliver Weidinger
  7. Danny Wende
  8. Annika Vivirito
  9. Nicole Toepfner
  10. Martin Seifert
  11. Oliver Nagel
  12. Christina König
  13. Roland Jucknewitz
  14. Jakob Peter Armann
  15. Reinhard Berner
  16. Marina Treskova-Schwarzbach
  17. Dagmar Hertle
  18. Stefan Scholz
  19. Stefan Stern
  20. Pedro Ballesteros
  21. Stefan Baßler
  22. Barbara Bertele
  23. Uwe Repschläger
  24. Nico Richter
  25. Cordula Riederer
  26. Franziska Sobik
  27. Anja Schramm
  28. Claudia Schulte
  29. Lothar Wieler
  30. Jochen Walker
  31. Christa Scheidt-Nave
  32. Jochen Schmitt

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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 more than 45 percent of the German population from January 2019 through December 2020, we investigated post COVID-19 in children/adolescents and adults.

Methods

From a total of 38 million individuals, we identified all patients with laboratory confirmed diagnosis of COVID-19 through June 30, 2020. A control cohort was assigned using 1:5 exact matching on age, sex, and propensity score matching on prevalent medical conditions. COVID-19 and control cohorts were followed for incident morbidity outcomes documented at least three months after the date of COVID-19 diagnosis, which was used as the index date for both groups. Overall, 96 pre-defined outcomes were aggregated into 13 diagnosis/symptom complexes and three domains (physical health, mental health, physical/mental overlap domain). We used Poisson regression to estimate incidence rate ratios (IRRs) with 95%-confidence intervals (95%-CI).

Results

The study population included 157,134 individuals (11,950 children/adolescents and 145,184 adults) with confirmed COVID-19. COVID-19 and control cohort were well-balanced regarding covariates. For all health outcomes combined, incidence rates (IRs) in the COVID-19 cohort were significantly higher than those in the control cohort in both children/adolescents (IRR=1.30, 95%-CI=[1.25-1.35], IR COVID-19=436.91, IR Control=335.98) and adults (IRR=1.33, 95%-CI=[1.31-1.34], 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, incidence rates were significantly higher in all 13 diagnosis/symptom complexes in adults and in ten diagnosis/symptom complexes in children/adolescents. IRR estimates were similar for the age groups 0-11 and 12-17. Incidence rates in children/adolescents were consistently lower than those in adults. Among the specific outcomes with the highest IRR and an incidence rate 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=[1.71-3.06], IR COVID-19=12.58, IR Control=5.51), cough (IRR=1.74, 95%-CI=[1.48-2.04], IR COVID-19=36.56, IR Control=21.06), and throat/chest pain (IRR=1.72, 95%-CI=[1.39-2.12], IR COVID-19=20.01, IR Control=11.66). In adults, these included dysgeusia (IRR=6.69, 95%-CI=[5.88-7.60], IR COVID-19=12.42, IR Control=1.86), fever (IRR=3.33, 95%-CI=[3.01-3.68], IR COVID-19=11.53, IR Control=3.46), and dyspnea (IRR=2.88, 95%-CI=[2.74-3.02], IR COVID-19=43.91, IR Control=15.27).

Conclusions

This large, matched cohort study indicates substantial new-onset post COVID-19 morbidity in pediatric and adult populations based on routine health care documentation. Further investigation is required to assess the persistence and long-term health impact of post COVID-19 conditions, especially in children and adolescents.

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    SciScore for 10.1101/2021.10.21.21265133: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: The competent authority of the Federal State of Saxony, Germany approved the study protocol and declared waiver of informed consent (reference number: 31-5221.40-15/68).
    IRB: The study was approved by the ethics committee of the TU Dresden (approval number: BO-EK (COVID)-482102021) and adheres to the Declaration of Helsinki and all relevant administrative and legal regulations.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisAggregation of outcomes into groups offers the advantage of higher statistical power, particularly in the case of post COVID-19, which is considered to include multiple rare symptoms and diagnoses [7,9,14].
    Cell Line AuthenticationAuthentication: Evidence synthesis: Since pooling of individual-level data was not possible due to data protection restrictions, the six health insurance datasets were analyzed separately by authorized institutes or the healthcare research department within the respective health insurance.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The POINTED consortium is coordinated by the Center for Evidence-Based Healthcare (ZEGV) at the TU Dresden and consists of large German statutory health insurances, health services research institutes (ZEGV and InGef - Institute for Applied Health Research Berlin), the Robert Koch Institute (RKI), and clinical experts.
    Evidence-Based Healthcare
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and limitations: The main strength of our analysis is its broad database including more than 150,000 individuals with available data in the post COVID-19 phase. This unselected sample from all over Germany covers both outpatient and inpatient care and, thus, constitutes a unique and comprehensive source of evidence. The 96 outcomes considered in this study were selected based on published evidence and clinical expertise and provided a sound and sensitive basis for investigation of potential long-term sequelae of COVID-19 across multiple diagnosis/symptom complexes. Our analysis is based on documented, confirmed diagnoses made by physicians and psychotherapists. Accordingly, our results are not subject to possible distortions resulting from selective, incomplete, or inadequate self-reporting of symptoms but instead rely on information provided by medical professionals. To avoid confounding of the relationships between outcomes and exposure, we applied matching on relevant covariates, i.e. age, sex, and several prevalent medical conditions. The resulting distributions of covariates in the COVID-19 and control cohorts were similar, which indicated successful balancing. Overall, our results for adults are in accordance with those of previous, international studies based on routine health data [6,7,20,22]. This similarity suggests that external validity is high and provides indirect support for the validity of our findings for children and adolescents. Data preparation a...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT05074953Active, not recruitingPost-COVID-19 Monitoring in Routine Health Insurance Data

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.10.21.21265133v1 on medRxiv