Put up-COVID-19-associated morbidity in youngsters, adolescents, and adults: A matched cohort examine together with greater than 157,000 people with COVID-19 in Germany

Put up-COVID-19-associated morbidity in youngsters, adolescents, and adults: A matched cohort examine together with greater than 157,000 people with COVID-19 in Germany

Quotation: Roessler M, Tesch F, Batram M, Jacob J, Loser F, Weidinger O, et al. (2022) Put up-COVID-19-associated morbidity in youngsters, adolescents, and adults: A matched cohort examine together with greater than 157,000 people with COVID-19 in Germany. PLoS Med 19(11):

Educational Editor: Lars Åke Persson, London College of Hygiene and Tropical Drugs, UNITED KINGDOM

Acquired: February 22, 2022; Accepted: October 12, 2022; Printed: November 10, 2022

Copyright: © 2022 Roessler et al. That is an open entry article distributed underneath the phrases of the Inventive Commons Attribution License, which allows unrestricted use, distribution, and copy in any medium, offered the unique creator and supply are credited.

Knowledge Availability: The authors affirm that the mixed aggregated knowledge from our examine will be made accessible upon request. The info is saved on a safe drive within the ZEGV, to facilitate replication of the outcomes. For help in acquiring entry to the information, please contact [email protected].

Funding: AV, FE, FT, JJ, JS, JW, MR, MS, and ON report institutional funding for elements of this undertaking from the German BMBF (grant quantity: 01KX2021). The funders had no function in examine design, knowledge assortment and evaluation, choice to publish, or preparation of the manuscript.

Competing pursuits: I’ve learn the journal’s coverage and the authors of this manuscript have the next competing pursuits: AV, FE, FT, JJ, JS, JW, MR, MS, and ON report institutional funding for elements of this undertaking from the German BMBF. Unrelated to this examine, FT experiences funds for lectures from Dresden Worldwide College. JA experiences grants from the Federal State of Saxony. Unrelated to this examine, JS experiences grants for investigator-initiated analysis from the German GBA, the BMG, BMBF, EU, Federal State of Saxony, Novartis, Sanofi, ALK, and Pfizer. He additionally participated in advisory board conferences for Sanofi, Lilly, and ALK. MB experiences fee for knowledge evaluation which is offered on this paper from DAK‐Gesundheit. Unrelated to this examine, MB experiences grants from German GBA and Sanofi Pasteur and consulting charges 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 Illnesses (DGPI) and is the DGPI-mandated particular person for the pediatric knowledgeable group on long-COVID in youngsters and adolescents. SB is Head of Analytics and Knowledge Science at AOK PLUS, Dresden, Germany. Unrelated to this examine, STSCH experiences funds for a visitor lecture at TU Berlin. The opposite authors declare that they haven’t any competing curiosity.

Coronavirus Illness 2019; GPS,
good apply secondary knowledge evaluation; IR,
incidence charge; IRR,
incidence charge ratio; PCR,
polymerase chain response; RT-PCR,
reverse transcription PCR; SARS-CoV-2,
Extreme Acute Respiratory Syndrome Coronavirus 2; SD,
commonplace deviation; WHO,
World Well being Group; 95% CI,
95% confidence interval


There may be mounting proof {that a} but unknown proportion of individuals suffers from long-term issues after Extreme Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) an infection. Early within the pandemic, sufferers began to share their experiences within the social media on what they known as “Lengthy-haul COVID” or “Lengthy COVID.” They reported all kinds of somatic and psychological well being points that have been both persisting, recurring, or newly occurring past the 4-week part of acute Coronavirus Illness 2019 (COVID-19) and even gentle or asymptomatic SARS-CoV-2 an infection [1]. Well being organizations and medical societies on the nationwide and worldwide degree have taken efforts to systemize observations from an growing physique of observational analysis research, so as to present a practical case definition for this new well being phenomenon. A World Well being Group (WHO) working group together with sufferers and a multidisciplinary crew of medical consultants proposed a preliminary medical case definition utilizing the time period “post-COVID-19 situation.” Primarily based on a structured consensus course of, this definition refers to a broad spectrum of in any other case unexplained well being circumstances which might be current 3 months after the onset of signs or date of SARS-CoV-2 an infection and final for no less than 2 months [2]. Notably, it’s nonetheless unsure whether or not the definition applies to adults in addition to youngsters and adolescents because of the paucity of accessible knowledge amongst youthful age teams [2].

An growing variety of research have examined well being sequalae no less than 3 months after SARS-CoV-2 an infection. Nearly all of earlier research targeted on adults, and fewer than half of those research included a management group of individuals with out documented or clinically suspected SARS-CoV2-infection [3,4]. Signs incessantly noticed to be related to a historical past of SARS-CoV-2 an infection amongst adults embrace, however aren’t restricted to, fatigue, lack of reminiscence and focus, and respiratory signs [58]. Youngsters and adolescents appear to be much less incessantly affected by post-COVID-19 situation, however the paucity of knowledge precludes to attract ultimate conclusions. As well as, long-term sequelae of SARS-Cov-2-infection amongst youngsters and adolescents might properly differ from these amongst adults [913].

The necessity for contemplating signs in addition to medical circumstances in a number of organ programs is mirrored by the WHO working group definition of post-COVID-19 situation amongst adults [2] and ongoing work to develop standardized core final result units for future analysis on post-COVID-19 situation amongst youngsters and adults [1416]. As signs related to post-COVID-19 situation seem to say no over time, managed research primarily based on routine medical knowledge might assist to establish long-term well being circumstances following SARS-CoV-2 an infection, offered entry to healthcare is equally accessible to people with and with out SARS-CoV-2 an infection. Few such research have been carried out so far and virtually none of those research has included each adults and kids [5,6,1736].

In opposition to that background, we investigated documented long-term morbidity related to COVID-19 primarily based on routine knowledge from 6 German statutory medical insurance organizations masking almost half of the inhabitants in Germany. We hypothesized that SARS-CoV-2 infections induce larger morbidity 3 months after first prognosis of COVID-19 or later in each youngsters/adolescents and adults in contrast with controls with out earlier COVID-19. We anticipated this larger morbidity to be mirrored in additional intensive utilization of healthcare providers and, therefore, medical diagnoses documented by physicians.


Examine design

As a part of the POINTED program (see Part A in S1 Appendix), we designed a retrospective matched cohort examine primarily based on routine statutory medical insurance knowledge. The examine was primarily based on complete healthcare knowledge masking the interval between January 1, 2019 and December 31, 2020. The POINTED consortium began to work on the design of this examine in Might 2021. All methodological particulars, together with cohort definitions, inclusion and exclusion standards, choice and operationalizations of outcomes and covariates, and statistical methodology, have been mentioned and documented on a web based platform (Confluence) previous to knowledge evaluation. There have been no data-driven analyses. This examine is reported as per the Reporting of research Carried out utilizing Observational Routinely-collected Knowledge (RECORD) guideline [37] (S1 RECORD Guidelines).


We used routine knowledge from 6 German statutory medical insurance organizations: AOK Bayern—Die Gesundheitskasse, AOK PLUS (analyzed by ZEGV), BARMER, BKKen (analyzed by InGef), DAK Gesundheit (analyzed by Vandage GmbH), and Techniker Krankenkasse. In complete, these knowledge cowl roughly 38 million individuals, which corresponds to 52% of all individuals within the German statutory healthcare insurance coverage system (Gesetzliche Krankenversicherung, GKV) and 46% of the whole German inhabitants. The German GKV offers equal entry to healthcare for all insured people. This contains free selection of physicians and entry to specialist outpatient and inpatient healthcare.

Along with sociodemographic traits (age and intercourse) and important standing (through the date of dying), the information utilized in our evaluation embrace complete info on healthcare utilization in ambulatory (main in addition to specialist) in addition to outpatient and inpatient hospital care. The info embrace diagnoses (in line with the Worldwide Statistical Classification of Illnesses and Associated Well being Issues—German Modification, ICD-10-GM) by physicians and psychotherapists, inpatient procedures (in line with the “Operationen- und Prozedurenschluessel,” OPS; German modification of the Worldwide Classification of Procedures in Drugs, ICPM), outpatient medical procedures (in line with “Einheitlicher Bewertungsmassstab,” EBM), and prescribed drugs (in line with the German Anatomical Therapeutic Chemical (ATC) Classification).

Put up-COVID-19 follow-up

We adopted the NICE guideline on lengthy COVID [38] and the medical case definition of post-COVID-19 situation proposed by WHO [2] and thought of a person to enter the post-COVID-19 part 3 months after prognosis of COVID-19. As a result of traits of the German healthcare billing system, outpatient diagnoses in our knowledge will be assigned reliably to a selected quarter of the yr. Accordingly, we thought-about a prognosis to have been made within the post-COVID-19 part if it was documented within the second quarter after the index date (date of COVID-19 prognosis) or later (see Part B in S1 Appendix for a graphical illustration). This operationalization ensures a time distance of no less than 3 months between date of COVID-19 prognosis and post-COVID-19 final result incidence.

COVID-19 and management cohorts

The supply inhabitants of our examine consisted of all people insured with one of many 6 thought-about medical insurance organizations for no less than 1 day in 2020 (a stream chart depicting inclusion and exclusion standards is offered within the Outcomes part; see Fig 1). The COVID-19 cohort included people with documented COVID-19 prognosis with polymerase chain response (PCR)-based laboratory virus detection (ICD-10-GM: U07.1!) till June 30, 2020. COVID-19 diagnoses could possibly be documented by physicians in each outpatient and inpatient settings. The management cohort included people with out COVID-19 prognosis in 2020. To be included within the management cohort, a person needed to be insured with one of many medical insurance organizations offering knowledge for our evaluation. Nevertheless, to keep away from bias on account of number of controls with elevated healthcare wants, people weren’t required to have utilized healthcare providers throughout the remark interval to be included within the management cohort. We usually excluded people with COVID-19 prognosis with out PCR-confirmed laboratory virus detection (ICD-10-GM: U07.2!) solely so as to keep away from distortions on account of misclassification. We additional excluded people who weren’t constantly insured with the respective medical insurance group between January 1, 2019/delivery and December 31, 2020/dying as a result of related outcomes and preexisting well being circumstances might not have been documented in our knowledge. This exclusion utilized to people who modified their medical insurance group or emigrated throughout the remark interval.


Fig 1. Circulate charts for inclusion, exclusion, and matching of youngsters/adolescents and adults with and with out COVID-19.

The variety of people insured for no less than 1 day in 2020 contains people that modified their medical insurance group in 2020. Accordingly, some people have been represented in a number of datasets of various medical insurance organizations. These people have been excluded due to discontinuous insurance coverage within the first exclusion step and, thus, weren’t included in our evaluation. Exclusion standards have been utilized stepwise within the order proven within the stream charts. COVID-19, Coronavirus Illness 2019.

To attenuate variations between COVID-19 and management cohort when it comes to covariates that will confound relationships between outcomes and publicity, we used an identical strategy (see paragraph “Statistical analyses”). The date of the COVID-19 prognosis amongst people with COVID-19 was used because the index date for people within the COVID-19 cohort in addition to for matched controls. Assigning similar index dates to matched COVID-19 and management individuals presents the benefits that potential follow-up occasions are similar and that the timing of nonpharmaceutical interventions (e.g., lockdowns) is equally captured in each cohorts.

Given these matched knowledge, we excluded people from the COVID-19 cohort and matched management instances with an index date later than June 30, 2020, as these people couldn’t be noticed within the post-COVID-19 part. For a similar motive, we excluded people who died earlier than reaching the post-COVID-19 part (see Fig 1).

When analyzing particular well being outcomes (see paragraph “Well being outcomes”), we additional excluded people from the evaluation of post-COVID-19 incidence if the thought-about final result was documented no less than as soon as inside a 1-year look-back interval (i.e., inside the 4 quarters previous the index date). To take care of steadiness of cohorts relating to covariates, we excluded a whole matched group of COVID-19 and management individuals if the end result was preexisting for the person with COVID-19 or all of his/her matched management individuals. For estimation, we weighted knowledge from people within the management cohort with the inverse variety of individuals remaining within the respective matched group (i.e., weights between 1/5 and 1) to make sure that complete weights within the management cohort add as much as the variety of individuals within the COVID-19 cohort.

Well being outcomes

To account for the heterogeneity of potential long-term sequelae of COVID-19 highlighted within the literature [24,68,39], we chosen a big set of outcomes masking a number of organ programs and prognosis/symptom complexes. Primarily based on revealed literature, earlier work on core final result set growth [16], and medical experience within the creator crew, we chosen 96 particular person well being outcomes probably associated to post-COVID-19. These outcomes represent new-onset morbidity documented by a doctor or psychotherapist inside the statutory healthcare system. Operationalization of those outcomes was primarily based on inpatient and outpatient diagnoses in line with the ICD-10-GM coding system and the rules for good apply secondary knowledge evaluation (GPS) of the German Society for Epidemiology (DGEpi) [40]. We aggregated the 96 particular person well being outcomes into 13 prognosis/symptom complexes and three final result domains (bodily well being, psychological well being, and bodily/psychological overlap area). An outline of the outcomes and their grouping is offered within the Supporting info (Part C in S1 Appendix). Aggregation of outcomes into teams presents the benefit of upper statistical energy, significantly within the case of post-COVID-19, which is taken into account to incorporate a number of uncommon signs and diagnoses [6,7,38]. Nevertheless, aggregation may obscure related heterogeneity in outcomes. Therefore, our evaluation thought-about each particular person well being outcomes and mixture well being final result teams.


For every particular person, we used info on preexisting medical circumstances within the 4 quarters previous the index date. We chosen preexisting medical circumstances probably confounding the affiliation between publicity (COVID-19) and incident well being outcomes primarily based on revealed proof and medical experience. These included 13 preexisting medical circumstances for youngsters/adolescents and 38 preexisting medical circumstances for adults (see Part D in S1 Appendix). Consistent with earlier research [5,6], we additionally thought-about age and intercourse in addition to the severity of COVID-19 as a covariate with potential affect on post-COVID-19 by distinguishing between (1) people with outpatient diagnoses of COVID-19 solely; (2) people with no less than 1 hospital go to with COVID-19 prognosis; and (3) people with intensive care and/or air flow (ICU) with COVID-19 prognosis.

Statistical analyses

To pick the management cohort, we utilized 1:5-matching with substitute [41]. For every particular person within the COVID-19 cohort, we chosen 5 management individuals with similar age (in years) and intercourse. We selected precise matching on these traits to facilitate stratified evaluation, e.g., for various age teams. As well as, we accounted for the presence of the medical circumstances (described within the part “Covariates”) by propensity rating matching. Given totally different units of preexisting medical circumstances thought-about as covariates, we estimated separate regression fashions for youngsters/adolescents and adults. Estimation of the propensity rating was primarily based on logistic regression. No caliper was used for matching primarily based on the estimated propensity scores.

Primarily based on these matched knowledge, we estimated variations between COVID-19 and management cohort relating to incidence charges (IRs) of outcomes per 1,000 person-years utilizing Poisson regression [42]. When the conditional imply perform is appropriately specified, Poisson regression yields constant estimators of mannequin coefficients no matter the distribution of the end result [42]. Therefore, Poisson regression may be used for binary outcomes as thought-about in our evaluation [43]. Using a predominant benefit of Poisson regression, we adjusted for variations in individual-specific occasions in danger (time between index date and finish of remark interval or dying) on account of inclusion of those occasions as offset within the mannequin. As well as, Poisson regression presents the chance to regulate for added covariates that weren’t thought-about within the matching course of. Primarily based on the outcomes of Poisson regressions, we derived incidence charge ratios (IRRs) with 95% confidence intervals (95% CIs) to characterize relative incidence in COVID-19 and management cohort. We derived p-values for estimated IRRs utilizing Z-tests.

To evaluate the plausibility and robustness of our outcomes, we carried out extra sensitivity analyses. First, we estimated IRRs for all well being outcomes documented in the identical quarter because the index date or later. On this evaluation, we included all people with COVID-19 in 2020 and their matched controls. Variations in estimated IRRs between this pattern and the post-COVID-19 pattern utilized in the primary evaluation might point out attainable adjustments in well being differentials between people with and with out COVID-19 over time. Second, we outlined variables capturing hospitalizations (0 = no hospitalization, 1 = no less than 1 hospitalization) and the variety of quarters with no less than 1 doctor go to (0,1,…,4) inside the 4 quarters previous the index date. We included these variables as categorical covariates (i.e., within the type of dummy variables) in Poisson regressions to regulate for variations in healthcare utilization between the COVID-19 and the management cohort previous to the index date. If such variations weren’t totally mitigated by matching, adjustment for hospitalizations and doctor visits previous to the index date might yield qualitatively totally different IRR estimates.

We carried out all statistical analyses utilizing R (model 3.6.1) [44].

Since pooling of individual-level knowledge was not attainable on account of knowledge safety restrictions, the 6 medical insurance datasets have been analyzed individually by licensed institutes or the healthcare analysis division inside the respective medical insurance group. To synthesize proof throughout datasets, we used the truth that Poisson regression fashions will be estimated primarily based on individual-level or mixture knowledge with similar level estimates [45]. Every licensed institute calculated the required mixture statistics and offered them to ZEGV, the place regressions primarily based on mixed mixture knowledge have been carried out.


Descriptive statistics

After excluding people with out steady insurance coverage and U07.2! prognosis solely, 5,421,270 youngsters/adolescents and 29,600,265 adults have been eligible for inclusion in our examine (Fig 1). In 2020, 57,763 of those youngsters/adolescents and 621,205 of those adults, respectively, had a U07.1! prognosis. In our ultimate pattern, 157,134 people (11,950 youngsters/adolescents and 145,184 adults) who acquired their first COVID-19 prognosis earlier than July 2020 have been included. For correspondence with estimation outcomes, knowledge from people within the management cohort have been weighted in line with the inverse measurement of the respective matched group for descriptive evaluation (Desk 1; the total descriptive statistics are offered in Part E in S1 Appendix). The distributions of covariates within the COVID-19 and the matched management cohort have been related for each youngsters/adolescents and adults, which indicated profitable balancing. Profitable balancing was additionally mirrored in virtually similar distributions of the propensity scores in each cohorts (see Part E in S1 Appendix). The prevalence of medical circumstances chosen as covariates was usually decrease in youngsters/adolescents than in adults. Whereas our pattern included 8,407 (5.8%) hospitalized adults and three,075 (2.1%) adults with intensive care and/or air flow, smaller proportions of included youngsters/adolescents have been hospitalized with COVID-19 (n = 117; 1.0%) and acquired intensive care and/or air flow (n = 51; 0.4%). The typical follow-up time since index date was 236 days (commonplace deviation (SD) = 44 days, vary = 121 to 339 days) in youngsters/adolescents and 254 days (SD = 36 days, vary = 93 to 340 days) in adults. Descriptive statistics for all people with COVID-19 prognosis in 2020 (together with these with prognosis in July 2020 or later), who have been included in a sensitivity evaluation, are proven within the Supporting info (Part F in S1 Appendix).

Incidence of documented well being outcomes

To establish probably the most incessantly documented long-term well being issues amongst individuals with COVID-19, we thought-about outcomes with an incidence of no less than 1/100 person-years within the COVID-19 cohort. We then sorted these outcomes by IRR for youngsters/adolescents (Desk 2) and adults (Desk 3). The ensuing lists had 5 similar outcomes (cough, fever, headache, malaise/fatigue/exhaustion, and throat/chest ache) throughout age teams. The outcomes with the very best IRRs in youngsters and adolescents have been malaise/fatigue/exhaustion (IRR: 2.28, 95% CI: 1.71 to three.06, p < 0.01, IR COVID-19: 12.58, IR Management: 5.51), cough (IRR: 1.74, 95% CI: 1.48 to 2.04, p < 0.01, IR COVID-19: 36.56, IR Management: 21.06), and throat/chest ache (IRR: 1.72, 95% CI: 1.39 to 2.12, p < 0.01, IR COVID-19: 20.01, IR Management: 11.66). The outcomes with the biggest IRRs in adults have been disturbances of odor and style (IRR: 6.69, 95% CI: 5.88 to 7.60, p < 0.01, IR COVID-19: 12.42, IR Management: 1.86), fever (IRR: 3.33, 95% CI: 3.01 to three.68, p < 0.01, IR COVID-19: 11.53, IR Management: 3.46), and dyspnea (IRR: 2.88, 95% CI: 2.74 to three.02, p < 0.01, IR COVID-19: 43.91, IR Management: 15.27). IRRs in adults have been larger than in youngsters/adolescents for many outcomes assessed. For all listed outcomes, estimated IRRs have been statistically important. Whereas the unspecific prognosis malaise/fatigue/exhaustion (ICD-10-GM: R53) was represented within the lists for each youngsters/adolescents and adults, the continual fatigue syndrome (ICD-10-GM: G93.3) was not. Nevertheless, continual fatigue syndrome was additionally coded extra incessantly within the COVID-19 than within the management cohort in adults (IRR: 3.04, 95% CI: 2.66 to three.48, p < 0.01, IR COVID-19: 5.94, IR Management: 1.95). In youngsters, the estimated IRR was higher than 1 however not statistically important (IRR: 1.25, 95% CI: 0.24 to six.65, p = 0.79, IR COVID-19: 0.26, IR Management: 0.21). Estimation outcomes for all well being outcomes are proven within the Supporting info (Part G in S1 Appendix).

Incidence of documented well being final result teams

Contemplating all outcomes mixed, the IR per 1,000 person-years of documented well being issues within the COVID-19 cohort was considerably larger than that within the management cohort (higher left panel of Fig 2). This discovering holds for each youngsters/adolescents (IRR: 1.30, 95% CI: 1.25 to 1.35, p < 0.01, IR COVID-19: 436.91, IR Management: 335.98) and adults (IRR: 1.33, 95% CI: 1.31 to 1.34, p < 0.01, IR COVID-19: 615.82, IR Management: 464.15). Moreover, we discovered considerably larger IRs within the COVID-19 cohort in contrast with the management cohort throughout all thought-about final result domains, i.e., bodily well being (youngsters/adolescents: IRR: 1.31, 95% CI: 1.24 to 1.38, p < 0.01, IR COVID-19: 254.58, IR Management: 194.45; adults: IRR: 1.39, 95% CI: 1.37 to 1.41, p < 0.01, IR COVID-19: 422.87, IR Management: 304.42), psychological well being (youngsters/adolescents: IRR: 1.39, 95% CI: 1.28 to 1.52, p < 0.01, IR COVID-19: 102.17, IR Management: 73.24; adults: IRR: 1.27, 95% CI: 1.25 to 1.29, p < 0.01, IR COVID-19: 215.62, IR Management: 169.50), and the bodily/psychological overlap area (youngsters/adolescents: IRR: 1.32, 95% CI: 1.24 to 1.40, p < 0.01, IR COVID-19: 209.26, IR Management: 158.71; adults: IRR: 1.45, 95% CI: 1.42 to 1.47, p < 0.01, IR COVID-19: 278.58, IR Management: 192.59). For all 13 prognosis/symptom complexes, IRs within the grownup COVID-19 cohort have been considerably larger than these within the grownup management cohort (decrease left panel of Fig 2). In youngsters/adolescents, considerably larger IRs within the COVID-19 cohort in contrast with the management cohort have been noticed for 10 out of the 13 outlined prognosis/symptom complexes. Estimated IRRs ranged from 1.00 (95% CI: 0.80 to 1.25, p = 1.00; dermatological prognosis/symptom complicated) to 1.98 (95% CI: 1.43 to 2.75, p < 0.01; vascular/coagulation prognosis/symptom complicated) in youngsters/adolescents and from 1.11 (95% CI: 1.07 to 1.14, p < 0.01; gynecological/urogenital prognosis/symptom complicated) to 2.62 (95% CI: 2.53 to 2.71, p < 0.01; pulmonary prognosis/symptom complicated) in adults. Given a 162% larger post-COVID-19 IR within the grownup COVID-19 cohort in contrast with the grownup management cohort, pulmonary prognosis/symptom complicated confirmed probably the most pronounced general distinction. Stratified estimations for the age teams 0 to 11 and 12 to 17 yielded related IRRs (see Part H in S1 Appendix).


Fig 2. Estimated IRRs with 95% CIs and IRs per 1,000 person-years in COVID-19 cohort for youngsters/adolescents and adults by final result area and prognosis/symptom complicated.

IRs within the management cohort are proven in pale colour. COVID-19, Coronavirus Illness 2019; ENT, ear, nostril and throat; IR, incidence charge; IRR, incidence charge ratio; 95% CI, 95% confidence interval.

Throughout all final result domains and prognosis/symptom complexes, IRs within the COVID-19 cohort have been decrease in youngsters/adolescents than in adults (proper panels of Fig 2). Relating to all outcomes mixed, the IR in adults with COVID-19 (IR = 615.82) was 41% larger than the IR in youngsters and adolescents with COVID-19 (IR = 436.91).

The total outcomes are offered within the Supporting info (Part I in S1 Appendix).

Incidence of documented well being final result teams by severity of COVID-19

Estimations stratified by severity indicated that IRRs for people with hospital visits or intensive care have been larger than IRRs for people with outpatient diagnoses of COVID-19 solely (Fig 3). This consequence holds for each youngsters/adolescents and adults. Nevertheless, because of the small variety of youngsters/adolescents with COVID-19-related hospital visits and intensive care and/or air flow, precision of the corresponding IRR estimates was low as mirrored in massive confidence intervals.


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

COVID-19, Coronavirus Illness 2019; ICU, intensive care unit; IRR, incidence charge ratio; 95% CI, 95% confidence interval. Estimation outcomes are proven on the log-scale.


This massive matched cohort examine used routine healthcare knowledge to look at the incidence of 96 prespecified diagnoses probably related to post-COVID-19 situation amongst 157,134 people (11,950 youngsters/adolescents and 145,184 adults) with PCR-confirmed SARS-CoV-2 an infection as in contrast with matched controls. Primarily based on a minimal follow-up time of three months, we noticed larger IRs of newly documented diagnoses within the COVID-19 cohort in contrast with the management cohort amongst youngsters/adolescents and adults. The relative magnitude of considerably elevated newly documented morbidity in affiliation with COVID-19 was related amongst adults and kids/adolescents. IRs within the COVID-19 and management cohorts have been usually decrease in youngsters/adolescents than in adults. There have been additionally some variations within the COVID-19-associated morbidity between adults and kids/adolescents. Amongst adults, IRRs have been highest for disturbances of odor and style (IRR: 6.69), fever (IRR: 3.33), and respiratory signs corresponding to dyspnea (IRR: 2.88), cough (IRR: 2.80), and respiratory insufficiency (IRR: 2.47), adopted by throat and chest ache, hair loss, malaise/fatigue/exhaustion, dysphagia, and headache. Amongst youngsters, IRRs have been highest for malaise, fatigue/exhaustion (IRR: 2.28), cough (IRR: 1.74), throat/chest ache (IRR: 1.72), adjustment dysfunction (IRR: 1.71), adopted by somatization dysfunction, headache, fever, nervousness dysfunction, stomach ache, and despair. With regard to the 13 aggregated symptom/prognosis complexes, IRs amongst adults have been all considerably larger within the COVID-19 than within the management cohort with IRRs starting from 1.11 for gynecological/urogenital diagnoses to 2.62 for pulmonary diagnoses. Amongst youngsters, IRs within the COVID-19 cohort have been considerably larger than within the management cohort in 10 out of 13 symptom/prognosis complexes with IRRs starting from 1.00 for dermatological diagnoses to 1.98 within the vascular/coagulation symptom/prognosis complicated. Constant amongst adults and kids/adolescents, there was a transparent gradient in IRRs in affiliation with the severity of COVID-19, with the very best IRRs amongst these people that had acquired intensive care.

The outcomes of our examine add to the proof from plenty of earlier managed research on post-COVID-19-related signs, new diagnoses, and healthcare providers utilization. Of their fast overview final up to date on October 29, 2021, Flatby and colleagues recognized 9 managed research utilizing totally different knowledge sources, well being outcomes, and follow-up occasions [4]. All of those research have been restricted to adults. About half of those research targeted on psychological well being or neuropsychiatric outcomes. At 6 months of follow-up, these research noticed important associations between a historical past of SARS-COV-2 an infection and the prevalence of post-traumatic stress dysfunction, decrease cognitive perform scores [24], danger of new-onset dementia [25], the prevalence of a wide range of psychological well being circumstances [26], and new-onset neurological and psychiatric ailments, together with dementia, cerebrovascular occasions, parkinsonian syndromes, nervousness, temper problems, illicit drug use problems, and insomnia [5]. The rest of earlier research investigated a wider vary of well being outcomes thought-about to be attainable long-term sequelae of SARS-CoV-2 an infection. Primarily based on digital healthcare knowledge primarily from america, Taquet and colleagues reported hazard ratios between 1.44 and a couple of.04 for 9 chosen well being outcomes (e.g., fatigue/malaise, chest/throat ache headache, different ache) amongst adults beforehand recognized with COVID-19 in contrast with matched controls beforehand recognized with influenza 3 to six months after an infection [39]. Utilizing Danish well being registry knowledge, Lund and colleagues reported considerably elevated charges of general normal practitioner and outpatient hospital visits in addition to newly initiated drug prescriptions in affiliation with a historical past of SARS-CoV-2 an infection [27]. Notably, the follow-up interval on this earlier examine coated 2 weeks to six months after a constructive or, amongst controls, unfavorable SARS-CoV-2 take a look at consequence. A big population-based cohort examine evaluating SARS-CoV-2 contaminated and noninfected adults in Norway noticed that 13 out of twenty-two preselected signs have been considerably related to SARS-CoV-2 an infection at 12 months after an infection [28]. Consistent with outcomes from our examine, the strongest associations on this earlier report have been seen for altered odor or style, shortness of breath, poor reminiscence, fatigue, and chest ache.

Extra just lately, a nationwide examine in Norway used a singular database of all adults examined for SARS-CoV-2 between March 1, 2020 to February 1, 2021 and located elevated main healthcare utilization on account of respiratory and normal/unspecified circumstances in affiliation with SARS-CoV-2 an infection 2 to three months after an infection, however not later at 4 to six months after an infection [19]. Notably, this earlier examine included solely nonhospitalized adults with constructive take a look at outcomes, which can clarify why elevated main healthcare use in affiliation with prior SARS-CoV-2 an infection was restricted in time and specialist care use was not elevated in relation to SARS-CoV-2 an infection at any time throughout follow-up [19]. Two just lately revealed managed research of post-COVID-19 situation amongst adults help our strategy to analyze a variety of attainable well being sequelae of SARS-Cov-2 an infection as advised by earlier work primarily based on structured knowledgeable consensus [16]. Utilizing a retrospective matched cohort design and United Kingdom main care knowledge, Subramanian and colleagues noticed a big affiliation of SARS-CoV-2 an infection with post-COVID-19 situation as outlined by WHO standards, but additionally 62 particular person signs, solely partly coated by WHO standards [22]. In an ongoing potential, population-based matched cohort examine carried out within the north of the Netherlands, Ballering and colleagues recognized signs considerably associated to SARS-CoV-2 an infection 90 to 150 days after an infection primarily based on comparability of symptom profiles between contaminated individuals and matched controls in addition to earlier than and after an infection inside the group of individuals with constructive take a look at outcomes or clinically recognized COVID-19 [29]. These authors discovered 1 in 8 adults with a historical past of SARS-CoV-2 an infection to expertise long-term signs together with chest ache, difficulties with respiration, muscle pains, lack of style or odor, tingling extremities, lump in throat, feeling cold and warm alternately, heavy arms or legs, and normal tiredness [29].

Our examine extends current proof on post-COVID-19 syndrome amongst youngsters and adolescents. We noticed related post-COVID-19 healthcare utilization and new-onset morbidity patterns documented by physicians in youngsters and adolescents following SARS-CoV-2 an infection in a big pattern of sufferers with confirmed COVID-19 in contrast with a matched management group. Our outcomes distinction with findings from a number of earlier epidemiological research amongst youngsters and adolescents, which didn’t observe important group variations between youngsters and adolescents with COVID-19 and controls [17,3033]. These variations might presumably be on account of excessive dropout charges and/or excessive danger of choice bias [30], self-reported final result evaluation [30,31], insufficiently lengthy follow-up time to evaluate post-COVID-19 outcomes [30,32], and low pattern measurement leading to low statistical energy [17,32,33]. Utilizing nationwide SARS-CoV-2 testing knowledge collected in early January 2021 within the UK, Zavala and colleagues reported a barely larger frequency of any persisting signs in affiliation with a constructive PCR take a look at consequence amongst youngsters aged 2 to 16 years after 1 month of follow-up [34]. Out of a complete of 64 particular person well being signs assessed by questionnaire through mum or dad proxy report, 9 signs have been considerably extra prevalent amongst youngsters with constructive PCR take a look at outcomes in contrast with matched controls. Nevertheless, noticed variations have been restricted to youngsters with symptomatic SARS-CoV-2 an infection [34].

A number of massive nationwide research from the UK, Norway, Denmark, and the US have just lately contributed additional proof on the well being and social impression of lengthy COVID amongst youngsters and adolescents with conflicting outcomes [20,21,23,35,36,46]. At 3 months of follow-up, the British nationwide matched cohort examine of post-COVID-19 situation amongst youngsters and adolescents 11 to 17 years of age noticed small variations between people with constructive PCR take a look at outcomes in contrast with controls with regard to particular person well being signs [46]. Nevertheless, a number of signs have been considerably extra prevalent in in affiliation with SARS-CoV-2 an infection. A nationwide register-based examine of youngsters and adolescents 0 to five and 6 to 17 years of age in Denmark retrospectively assessed (mum or dad proxy report) group variations within the sort and period of signs lasting 4 weeks or longer amongst youngsters and adolescents with and with out constructive reverse transcription PCR (RT-PCR) take a look at outcomes for SARS-CoV-2 as much as March 2021 [35]. These authors discovered a big distinction in affiliation with a historical past of SARS-CoV-2 an infection solely amongst youngsters 6 to 17 years of age and most signs resolved inside 5 months [35]. Conducting a earlier than and after register-based examine in Norway, Magnusson and colleagues discovered a relative improve in main however not specialist healthcare providers utilization amongst youngsters and adolescents with PCR-confirmed SARS-CoV-2 an infection between August 2020 and February 2021 in contrast with management teams with unfavorable take a look at outcomes or not examined [21]. Noticed will increase in main healthcare use in affiliation with SARS-CoV-2 an infection have been brief termed as much as 3 months following the receipt of take a look at outcomes amongst youngsters 6 years of age and older, however nonetheless current at 3 to six months amongst youngsters 1 to five years of age [21].

Much like our findings, cross-sectional nationwide research primarily based on Danish nationwide register knowledge demonstrated that a lot of predefined well being signs lasting greater than 2 or 3 months have been considerably extra frequent amongst youngsters and adolescents with a historical past of a constructive SARS-CoV-2 take a look at till July 2021 in contrast with age- and sex-matched controls [20,36]. Signs most incessantly related to prior SARS-CoV-2 an infection in these earlier analyses included all kinds of well being circumstances, e.g., temper swings, cough, and abdomen aches amongst younger youngsters 0 to three years of age, fatigue, and temper swings amongst older youngsters [36], and sore throat, chest ache, and palpitations amongst adolescents [20]. That is according to our observations, though the restricted variety of youngsters and adolescents in our examine precluded additional stratification in line with age teams and therefore age-specific comparisons. Authors from the US Facilities of Illness Management and Prevention just lately reported considerably elevated IRs of doubtless extreme signs and circumstances amongst youngsters and adolescents aged 0 to 17 years in affiliation with confirmed SARS-CoV-2 an infection at follow-up occasions between 60 and one year after testing [23]. Signs and circumstances related to COVID-19 included odor and style disturbances, malaise and fatigue, and musculoskeletal ache, but additionally extreme issues, corresponding to acute pulmonary embolism, myocarditis and cardiomyopathy, sort 1 diabetes, and kind 2 diabetes. As identified by the authors, this matched cohort examine was topic to plenty of potential sources of bias and desires additional affirmation.

Consistent with earlier research, we noticed that IRs in youngsters/adolescents with COVID-19 have been usually decrease than these in adults. Given related relative magnitudes of post-COVID-19 final result incidence, the estimated long-term sequelae of COVID-19 due to this fact seem like much less pronounced in youngsters and adolescents in absolute phrases, however excessive an infection charges emphasize that post-COVID-19 can’t be dismissed amongst youngsters and adolescents.

The principle power of our evaluation is its broad database together with greater than 150,000 people with accessible knowledge within the post-COVID-19 part. This unselected pattern from throughout Germany covers each outpatient and inpatient care and, thus, constitutes a singular and complete supply of proof. The 96 outcomes thought-about on this examine have been chosen primarily based on revealed proof and medical experience and offered a sound foundation for investigation of potential long-term sequelae of COVID-19 throughout a number of prognosis/symptom complexes. Our evaluation relies on documented, confirmed diagnoses made by physicians and psychotherapists. Accordingly, our outcomes aren’t topic to attainable distortions ensuing from selective, incomplete, or insufficient self-reporting of signs however as an alternative depend on info offered by medical professionals. To keep away from confounding of the relationships between outcomes and publicity, we utilized matching on related covariates, i.e., age, intercourse, and several other preexisting medical circumstances. The ensuing distributions of covariates within the COVID-19 and management cohorts have been related, which indicated profitable balancing. Our predominant findings remained secure after we moreover adjusted IRR estimates for healthcare utilization within the 4 quarters previous the index date. Due to this fact, the outcomes of this sensitivity evaluation additional underline the robustness of our findings. Total, our outcomes for adults are in accordance with these of earlier, worldwide research primarily based on routine well being knowledge [5,6,18,39]. This similarity means that exterior validity is excessive and offers oblique help for the validity of our findings for youngsters and adolescents. Knowledge preparation and evaluation in accordance with the GPS of the DGEpi moreover helps the validity and reliability of our outcomes.

As a result of observational nature of our examine, a predominant limitation is that its design doesn’t induce a causal interpretation of outcomes. This limitation is inherent to all observational research and, thus, just about all research on post-COVID-19. We can not exclude that our outcomes could also be affected by unmeasured confounding, though we minimized variations between COVID-19 and management cohort through matching. Our outcomes may be topic to detection bias that will come up if the well being standing of people after onset of COVID-19 was extra carefully monitored and higher documented by physicians. Though media protection of lengthy COVID was much less intensive throughout the remark interval than at this time, some people with COVID-19 might have visited physicians as a result of they have been involved of attainable long-term sequelae. Physicians, in flip, might have scheduled extra follow-up appointments with these sufferers, which can have resulted in higher documentation of morbidity within the COVID-19 cohort in contrast with the management cohort. Usually, psychological and societal elements like media protection might have influenced the conduct of people included in our examine cohorts otherwise and, thus, brought about bias in our IRR estimators. Such psychological and societal elements may have influenced the sorts of signs and ailments documented by physicians, presumably with a bias towards psychiatric circumstances. People with gentle or asymptomatic course of COVID-19 are more likely to be underrepresented in our examine as a result of SARS-CoV-2 infections might not have been documented [47], particularly within the first months of the pandemic. The ensuing number of extra extreme COVID-19 instances might result in larger incidence estimates on this cohort. By the identical token, people with undocumented SARS-CoV-2 an infection might have been included within the management cohort. To the extent that post-COVID-19 additionally occurred in individuals with undocumented infections, this misclassification induces an overestimation of IRs within the management group and, thus, a bias towards the null in estimators of IRRs. This may occasionally significantly be a priority within the analyses of youngsters/adolescents, as acute COVID-19 signs are extra incessantly gentle and/or absent on this group in order that they could not have resulted in a medical session and thus not have been documented within the knowledge used for this examine.

To synthesize proof throughout the datasets offered by 6 medical insurance organizations, we used the truth that Poisson regression fashions will be estimated primarily based on mixture knowledge. Whereas level estimates are similar, variance estimates primarily based on mixture knowledge are usually bigger than these primarily based on individual-level knowledge. Statistical effectivity positive factors on account of 1:5-matching couldn’t be exploited due to knowledge aggregation. These facets suggest that our outcomes are conservative when it comes to statistical significance. A possible underestimation of variance arises from the lacking chance to regulate commonplace error estimators primarily based on mixture knowledge to account for a number of representations of the identical people on account of matching with substitute. Consequently, the web impact of utilizing mixture knowledge on variance estimators of IRRs is ambiguous. In opposition to that background, estimates of confidence intervals and p-values reported in our examine must be interpreted with some warning.

Usually, we assume that diagnoses made by physicians and psychotherapists have larger validity than self-reported outcomes. Nevertheless, this will not be true for all coded diagnoses, since using sure diagnoses is likely to be related for billing functions. In our examine, the validity of U07.1! diagnoses is essential for proper identification of people with PCR-confirmed SARS-CoV-2 an infection. We can not totally exclude that a few of these diagnoses have been documented with out PCR affirmation of SARS-CoV-2 an infection. Observe-up occasions after COVID-19 prognosis in our pattern have been restricted as a result of knowledge have been accessible as much as the top of 2020 solely. Accordingly, follow-up past 3 to six months inside the post-COVID-19 part was not attainable. Whereas we used an identical strategy to steadiness the COVID-19 and management cohorts relating to age, intercourse, and preexisting medical circumstances, our knowledge didn’t present info on ethnicity. Due to this fact, we can not exclude that the distribution of ethnicity differed between the examine cohorts. We additionally can not exclude that outcomes or medical circumstances used for propensity rating matching weren’t recognized and documented by physicians for some people. This might have induced bias in our IRR estimators if COVID-19 and management cohorts differed within the frequency of such unobserved diagnoses. Lastly, the dynamic of the COVID-19 pandemic throughout the examine interval in 2020 was totally different than it’s presently. Accordingly, utilization of well being providers has modified over time and isn’t essentially the identical in 2021 to 2022 because it was early within the pandemic. As well as, current variants of SARS-CoV-2, together with Omicron, weren’t coated by our pattern and a probably mitigating function of vaccination towards SARS-CoV-2 relating to long-term sequelae of COVID-19 couldn’t be assessed. Therefore, long-term and ongoing remark is required to evaluate the generalizability of our outcomes to later phases of the pandemic.

In conclusion, the outcomes of the current examine point out that post-COVID-19 can’t be dismissed amongst youngsters and adolescents. We discovered that COVID-19 prognosis was related to larger long-term demand for healthcare providers as mirrored in outpatient and inpatient diagnoses of a broad set of outcomes greater than 3 months after confirmed SARS-CoV-2 an infection. Whereas youngsters and adolescents seem like much less affected than adults, these findings are statistically important for all age teams. In youngsters and adolescents, the IRR of documented new-onset psychological well being issues throughout follow-up was larger in contrast with adults, whereas the other was true for documented well being outcomes of the pulmonary prognosis/symptom complicated. Managed population-based research with prolonged follow-up and additional in-depth analyses are required to substantiate outcomes amongst youngsters and adolescents and their impression for people and well being care programs.

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