Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multi-centre, population-based cohort study

Abstract

Background: Post-COVID syndrome (PCS) is an important sequela of COVID-19, characterised by symptom persistence for >3 months, post-acute symptom development, and worsening of pre-existing comorbidities. The causes and public health impact of PCS are still unclear, not least for the lack of efficient means to assess the presence and severity of PCS.

Methods: COVIDOM is a population-based cohort study of polymerase chain reaction (PCR) confirmed cases of SARS-CoV-2 infection, recruited through public health authorities in three German regions (Kiel, Berlin, Würzburg) between November 15, 2020 and September 29, 2021. Main inclusion criteria were (i) a PCR confirmed SARS-CoV-2 infection and (ii) a period of at least 6 months between the infection and the visit to the COVIDOM study site. Other inclusion criteria were written informed consent and age ≥18 years. Key exclusion criterion was an acute reinfection with SARS-CoV-2. Study site visits included standardised interviews, in-depth examination, and biomaterial procurement. In sub-cohort Kiel-I, a PCS (severity) score was developed based upon 12 long-term symptom complexes. Two validation sub-cohorts (Würzburg/Berlin, Kiel-II) were used for PCS score replication and identification of clinically meaningful predictors. This study is registered at clinicaltrials.gov (NCT04679584) and at the German Registry for Clinical Studies (DRKS, DRKS00023742).

Findings: In Kiel-I (n = 667, 57% women), 90% of participants had received outpatient treatment for acute COVID-19. Neurological ailments (61·5%), fatigue (57·1%), and sleep disturbance (57·0%) were the most frequent persisting symptoms at 6-12 months after infection. Across sub-cohorts (Würzburg/Berlin, n = 316, 52% women; Kiel-II, n = 459, 56% women), higher PCS scores were associated with lower health-related quality of life (EQ-5D-5L-VAS/-index: r = -0·54/ -0·56, all p < 0·0001). Severe, moderate, and mild/no PCS according to the individual participant's PCS score occurred in 18·8%, 48·2%, and 32·9%, respectively, of the Kiel-I sub-cohort. In both validation sub-cohorts, statistically significant predictors of the PCS score included the intensity of acute phase symptoms and the level of personal resilience.

Interpretation: PCS severity can be quantified by an easy-to-use symptom-based score reflecting acute phase disease burden and general psychological predisposition. The PCS score thus holds promise to facilitate the clinical diagnosis of PCS, scientific studies of its natural course, and the development of therapeutic interventions.

Funding: The COVIDOM study is funded by the Network University Medicine (NUM) as part of the National Pandemic Cohort Network (NAPKON).

Keywords: COVID-19; Fatigue; LongCOVID, Post-acute sequelae of SARS-CoV-2 infection (PASC); Post-COVID-Syndrome (PCS); Resilience; SARS-CoV-2 infection.

Conflict of interest statement

TB reports support for the present manuscript by Network University Medicine (NUM)/ German Federal Ministry of Education and Research (BMBF); grants or contracts from the German Center for Lung Research (DZL); consulting fees from AstraZeneca, GlaxoSmithKline; honoraria from AstraZeneca, GlaxoSmithKline, Novartis, Roche, Chiesi, Boeringer-Ingelheim, Merck; Support for attending meetings and/or travel from Chiesi, AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for CoVit-2 (NCT04751604); CB has nothing to disclose; WL has nothing to disclose; AHo has nothing to disclose; LK has nothing to disclose; JF has nothing to disclose; CS reports consulting fees from Celtrend; honoraria from MSD, Novartis, Astra Zeneca, Boeringer Ingelheim, Bayer, Fresenius, Octapharma, and Oberberg; payment for expert testimony from IQWIG, support for attending meetings from Octapharma and Fresenius; patents for ß2 rececptor antibodies for diagnosis of ME/CFS (Charité); participation on a data safety monitoring board for Curevac, HDIT, and Vaccibody; being a board member of EUROMEDE, and DGMECFS; KFR reports honoraria from AstraZeneca, BoeringerIngelheim, Chiesi Pharmaceuticals, Novartis, Sanofi & Regeneron, GlaxoSmithKline, BerlinChemie, Roche; participation on a Data Safety Monitoring Board or Advisory Boards for AstraZeneca, BoeringerIngelheim, Sanofi & Regeneron; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for German Center for Lung Research (DZL), German Chest Society (DGP), American Thoracic Society (ATS); WM has nothing to disclose; CM has nothing to disclose; ML reports support for the present manuscript by the German Federal Ministry for Education and Research (BMBF) and by a state fund of Schleswig-Holstein; honoraria by Olympus, Novartis and Sanofi; participation on a Data Safety Monitoring Board or Advisory Board for GSK; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for board of the working group Rhinology/ Rhino-Surgery DGHNO and advisory board John Grube Foundation; DF reports grants or contracts from DFG Sachbeihilfe, DZHK Standortprojekt, Edwards Lifesciences grant; honoraria from AstraZeneca, Bayer, Edwards LifeSciences, Medtronic, Pfizer, Daiichi Sankyo, BoehringerIngelheim, Novartis, Janssen; SB reports BioNTech stocks from 11/20 to 5/21; AHe has nothing to disclose; OM has nothing to disclose; KGH reports grants or contracts from Bayer Healthcare; honoraria from Abbott, Bayer, Biotronik, BoeringerIngelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer, Sanofi-Aventis, SUN Pharma, W.L. Gore & Associates; participation on a Data Safety Monitoring Board or Advisory Boards for AMARIN, Alexion, AstraZeneca, Bayer, BoeringerIngelheim, Daiichi Sankyo, EIP Pharma, Edwards Lifesciences, Medtronic, Pfizer, Portola, Premier Research; NEEM has nothing to disclose; MW reports grants or contracts from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Stiftung, Capnetz Stiftung, International Max Planck Research School, Vaxxilon, Actelion, Bayer Health Care, Biotest, Boehringer Ingelheim; consulting fees from Noxxon, Pantherna, Vaxxilon, Aptarion, Glaxo Smith Kline, Sinoxa, Biotest, Thieme; honoraria from Astra Zeneca, Berlin Chemie, Chiesi, Novartis, Actelion, Boehringer Ingelheim, Glaxo Smith Kline, Biotest, Bayer Health Care; patents, issued or pending for EPO 12181535.1 : IL-27 for modulation of immune response in acute lung injury, WO/2010/094491: Means for inhibiting the expression of Ang-2; JJV reports grants from Merck/MSD, Gilead, Pfizer, Astellas Pharma, Basilea, German Center for Infection Research (DZIF), German Federal Ministry of Education and Research (BMBF), DLR (Deutsches Zentrum für Luft- und Raumfahrt), University of Bristol, Righospital Copenhagen; consulting fees from Pfizer, Gilead and Shiongi, honoraria from MSD/ Merck, Gilead, Pfizer, Astellas Pharma, Basilea, German Center for Infection Research (DZIF), University Hopsital of Freiburg/ Congress and Communication, Academy for Infectious Medicine, University Manchester, German Society for Infectious Diseases (DGI), Ärztekammer Nordrhein, University Hospital Aachen, BackRay Strategies, German Society for Internal Medicine (DGIM), Shionogi, Molecular Health, Netzwerk Univerisity Medicine (NUM), Janssen, NordForsk; DK has nothing to disclose; DP reports support for attending meetings from Advanz Pharma Germany; FAM reports grants from the German Research Council (Deutsche Forschungsgemeinschaft, DFG); MKo has nothing to disclose; CMo has nothing to disclose; SStö reports research support in form of case payments covering for study staff and consumables by a grant of the German Federal Ministry of Education and Research; JPR reports grants from the German Ministry of Research and Education during the conduct of the study; grants from the German Ministry of Research and Education, grants from Bavarian State (ministry for science and the arts), grants from Federal Joint Committee (G-BA) within the Innovationfond, grants from the German Center for Lung Research, personal fees from the Landesaerztekammer Hessen, outside the submitted work; TK reports support for the present manuscript by the Federal Ministry of Education and Research, Germany; PH reports grants from the German Ministry of Research and Education during the conduct of the study; research grants from the German Ministry of Research and Education, European Union, Charité – Universitätsmedizin Berlin, Berlin Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert Koch Institute, German Heart Foundation, Federal Joint Committee (G-BA) within the Innovationfond, German Research Foundation, Bavarian State (ministry for science and the arts), German Cancer Aid, Charité – Universitätsmedizin Berlin (within Mondafis; supported by an unrestricted research grant to the Charité from Bayer), University Göttingen (within FIND-AF randomized; supported by an unrestricted research grant to the University Göttingen from Boehringer-Ingelheim), University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo), outside the submitted work; MKr has nothing to disclose; SSch reports consulting fees from Abbvie, Allergosan Amgen, Arena, BMS, Biogen, Celltrion, Celgene, Ferring, Fresenius, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal Takeda, Theravance, UCB; honoraria from Abbvie, Allergosan Amgen, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal Takeda, Theravance, UCB; payment for expert testimony from Allergosan; support for attending meetings and/ or travel from Abbvie, Allergosan Amgen, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal Takeda, Theravance, UCB; participation on a Data Safety Monitoring Board or Advisory Boards for Abbvie, Allergosan Amgen, Arena, BMS, Biogen, Celltrion, Celgene, Ferring, Fresenius, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal Takeda, Theravance, UCB.

© 2022 The Author(s).

Figures

Figure 1

Frequency of symptom complexes in COVIDOM sub-cohorts. Bar lengths correspond to the percentage prevalence, in the respective COVIDOM sub-cohort, of one of the 12 long-term symptom complexes of COVID-19 upon which the Post-COVID syndrome (PCS) score definition is based (Kiel-I, black; Würzburg/Berlin, blue; Kiel-II, red). Symptom complexes are ordered according to their prevalence in the Kiel-I sub-cohort.

Figure 2

Distribution of the Post-COVID syndrome (PCS) score in COVIDOM sub-cohorts. (a) Frequency of PCS score-defined severity classes. A PCS score of 0 (light blue, hatched) means complete absence of long-term symptoms, which was observed in 91 (15·7%, Kiel-I), 77 (27·5%, Würzburg/Berlin), and 66 (16·2%, Kiel-II) of the participants in COVIDOM, respectively. Severe PCS, defined as a PCS score ≥26·25 (dark blue), was present in 109 (18·8%, Kiel-I), 36 (12·9%, Würzburg/Berlin), and 82 (20·1%, Kiel-II) participants, respectively. (b) Cumulative distribution function of PCS score. The PCS score distribution in Würzburg/Berlin was notably different from those in the two Kiel sub-cohorts owing to a larger proportion in the former sub-cohort of participants with a PCS score equal to zero. Consequently, the mean PCS score equalled 13·0 (SD: 12·6) in Würzburg/Berlin, which was significantly lower than in both Kiel-I I (17·0, SD: 12·4) and Kiel-II (17·0, SD: 12·1; both p < 0·0001).