Determinants of the Onset and Prognosis of the Post-COVID-19 Condition: A 2-Year Prospective Cohort Study

Abstract

Background: At least 5-10% of subjects surviving COVID-19 develop the post-COVID-19 condition (PCC) or “Long COVID”. The clinical presentation of PCC is heterogeneous, its pathogenesis is being deciphered, and objective, validated biomarkers are lacking. It is unknown if PCC is a single entity or a heterogeneous syndrome with overlapping pathophysiological basis. In a large crossectional evaluation, the RECOVER study in the US identified four clusters of subjects with PCC according to their presenting symptoms. The long-term clinical implications of PCC remain unknown.

Methods: We conducted a 2-year prospective cohort study of subjects surviving COVID-19, including individuals fulfilling the WHO PCC definition and subjects with full clinical recovery. We systematically collected post-COVID-19 symptoms using prespecified questionnaires and performed additional diagnostic imaging tests when needed. Factors associated with PCC were identified and modeled using logistic regression. Unsupervised clustering analysis was used to group subjects with PCC according to their presenting symptoms. Factors associated with PCC recovery were modelled using a direct acyclic graph approach.

Findings: The study included 548 individuals, 341 with PCC, followed for a median of 23 months (IQR 16·5 – 23·5), and 207 subjects fully recovered. In the model with the best fit, subjects who were male and had tertiary studies were less likely to develop PCC, whereas a history of headache, or presence of tachycardia, fatigue, neurocognitive and neurosensitive complaints and dyspnea at COVID-19 diagnosis predicted the development of PCC. The cluster analysis revealed the presence of three symptom clusters with an additive number of symptoms. Only 26 subjects (7·6%) recovered from PCC during follow-up; almost all of them (n=24) belonged to the less symptomatic cluster A, dominated mainly by fatigue. Recovery from PCC was more likely in subjects who were male, required ICU admission, or had cardiovascular comorbidities, hyporexia and/or smell/taste alterations during acute COVID-19. Subjects presenting with muscle pain, impaired attention, dyspnea, or tachycardia, conversely, were less likely to recover from PCC.

Interpretation: Preexisting medical and socioeconomic factors, as well as acute COVID-19 symptoms, predict the development of and recovery from the PCC. Recovery is extremely rare during the first 2 years, posing a major challenge to healthcare systems.

Funding: This work was funded by the crowdfunding initiatives “yomecorono.com“, BonPreu/Esclat and Correos, and with the collaboration of “Programa de Becas Gilead a la Investigación Biomédica, GLD21_00070”. MM was granted with RYC2020-028934-I/AEI/10.13039/501100011033 from Spanish Ministry of Science and Innovation and State Research Agency and the European Social Fund “investing in your future”. FM was supported by Sorigué Foundation.

Declaration of Interest: RP has participated in advisory boards for Pfizer, Gilead, MSD, GSK, Atea, Lilly, Roche, Astra-Zeneca, ViiV Healthcare and Theratechnologies, has participated in lectures and seminars funded by Gilead, Pfizer, GSK and AstraZeneca, and has received research funds awarded to his institution from Gilead, Pfizer, and MSD. MM participated in lectures and seminars funded by Gilead. The other authors declare no competing interests.

Ethical Approval: The independent ethics committee of the Germans Trias i Pujol Hospital approved the study protocol (PI- 20-217). All procedures were conducted according to good clinical practices and the General Data Protection Regulation 2016/679 on data protection and privacy for all individuals within the European Union. All study participants provided signed informed consent to participate in the study.

Keywords: COVID-19, post-COVID-19 condition, long COVID-19