The risks of autoimmune- and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the US, and Korea

Objectives We aimed to assess the risk of autoimmune- and inflammatory post-acute COVID-19 conditions. Design Descriptive network cohort study. Setting Electronic health records from UK and Dutch primary care, Norwegian linked health registry, hospital records of specialist centres in Spain, France, and Korea, and healthcare claims from Estonia and the US. Participants We followed individuals between September 2020 and the latest available data from the day they fulfilled at least 365 days of prior observation (general population), additionally from day 91 after a SARS-Cov-2 negative test (comparator) or a COVID-19 record (exposed patients). Main outcome measures We assessed postural orthostatic tachycardia syndrome (POTS) diagnoses/symptoms, myalgic encephalomyelitis / chronic fatigues syndrome (ME/CFS) diagnoses/symptoms, multi-inflammatory syndrome (MIS), and several autoimmune diseases. For contextualisation, we assessed any diabetes mellitus (DM). Meta-analysed crude incidence rate ratios (IRR) of outcomes measures after COVID-19 versus negative testing yield the ratios of absolute risks. Furthermore, incidence rates (IR) of the outcomes in the general population describe the total disease burden. Results We included 34’549’575 individuals of whom 2’521’812 had COVID-19, and 4’233’145 a first negative test. After COVID-19 compared to test negative patients, we observed IRRs of 1.24 (1.23-1.25), 1.22 (1.21-1.23), and 1.12 (1.04-1.21) for POTS symptoms, ME/CFS symptoms and diagnoses, respectively. In contrast, autoimmune diseases and DM did not yield higher rates after COVID-19. In individual general database populations, IRs of POTS and ME/CFS diagnoses were 17-1’477/100’000 person-years (pys) and 2-473/100’000 pys, respectively. IRs of MIS were lowest with IRs 0.4-16/100’000 pys, those of DM as a benchmark 8-86/100’000 pys. IRs largely depended on the care setting. Conclusion In our unmatched comparison, we observed that, following COVID-19, POTS and ME/CFS yielded higher rates than after negative testing. In absolute terms, we observed POTS and ME/CFS diagnoses to have a similar disease burden as DM. WHAT IS ALREADY KNOWN ON THIS TOPIC WHAT THIS STUDY ADDS ### Competing Interest Statement All authors have completed the ICMJE disclosure form at and declare the following interests: DPAs research group has received research grants from the European Medicines Agency; the Innovative Medicines Initiative; Amgen, Chiesi, and UCB Biopharma; and consultancy or speaker fees from Astellas, Amgen, and UCB Biopharma. DDed and JOO are employees of the Medicines and Healthcare Products Regulatory Agency which provides the CPRD research service. KK is a consortia author in the US National Institutes of Health National COVID Cohort Collaborative (funding expired in 2022 with no renewal or active impact on any current work). RP has received receiving research grants paid to his institution from MSD, ViiV Healthcare, Gilead Sciences, and PharmaMar, and has participated in advisory boards for Gilead Sciences, Inc, Pfizer, Inc, Roche Therapeutics, MSD, GSK, ViiV Healthcare, Eli Lilly and Company, PharmaMar, and Atea Pharmaceuticals Inc.LM has received research grants from Grifols, consulting fees from Gilead Sciences and Merck, and honoraria from AstraZeneca, Gilead Sciences, GSK, and Pfizer. ### Funding Statement This research was partially funded by the European Health Data and Evidence Network (EHDEN) [grant number 806968], and the Oxford NIHR Biomedical Research Centre. The study funders had no role in the conceptualisation, design, data collection, analysis, decision to publish, or preparation of the manuscript. DPA receives funding from the UK National Institute for Health Research (NIHR) in the form of a senior research fellowship and the Oxford NIHR Biomedical Research Centre. KLG was supported by the Medical Research Council (grant number MR/W006731/1) and Bayer AG. LPC is funded by a Sara Borrell fellowship (CD23/00223) awarded by the Spanish Institute of Health Carlos III. CK and the institution he works for was supported by a government-wide R&D Fund project for infectious disease research (GFID), Republic of Korea (grant number: HG22C0024). RK was supported by the European Regional Development Fund (RITA 1/02-120) and the Estonian Research Council grant (PRG1844). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol for this research was approved by the independent scientific advisory committee for Medicine and Healthcare products Regulatory Agency database research (protocol number 23_002603). Informed consent of individual patients was not required as anonymised information was obtained from medical records. Ethical approval for the Norwegian data in this study was obtained from The Regional Committee for Research Ethics (approval number 155294) and the Data Protection Officer at the University of Oslo (approval number 523275). Ethical approval for CORIVA data was obtained from the Research Ethics Committee of the University of Tartu (No. 351/M-8). Ethical approval for IMASIS was obtained by the Parc de Salut Mar Research Ethics Committee CEIm-Parc de Salut Mar (number 2021/9975). Ethical approval for IPCI was obtained by the Integrated Primary Care Information review board (registration number 9/2023). For CHUM, no ethical approval was required according to French law for this study. All patients admitted to the hospital are provided with general information about the collection and secondary use of their data, and an opt-out option is offered. PharMetrics Plus for Academics needed no approval for use of pseudoanonymised secondary data. Ethical approval for AUSOM was obtained by the Ajou University Medical Center Institutional Review Board (No. AJOUIRB-MDB-2021-694). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Patient level data cannot be shared without approval from data custodians owing to local information governance and data protection regulations. The analytical code is available at . The code for postprocessing and aggregated results are available at [https://github.com/tiozab/immune\_inflammatory\_PACS/][1] [1]: https://github.com/tiozab/immune_inflammatory_PACS/