Prolonged Inflammation in COVID-19 Survivors Resolves 2 Years After Coronavirus Disease 2019 (COVID-19)

Background: Long-term complications from coronavirus disease 2019 (COVID-19) are concerning, as survivors can develop subclinical multi-organ dysfunction. It is unknown if such complications are due to prolonged inflammation, and SARS-CoV-2 vaccination may reduce sequele.Methods: We conducted a prospective longitudinal study on COVID-19 survivors over 24 months. Clinical symptoms were collected by self-reporting during follow-up, along with blood samples for quantification of inflammatory markers and immune cell frequencies. All survivors were given one dose of mRNA vaccine at 12 to 16 months. Their immune profiles before and after vaccination were compared.Results: Approximately 37% and 39% of our survivors reported post-COVID-19 symptoms at 12 and 24 months, respectively. The proportion of symptomatic survivors with more than one symptom decreased from 69% at 12 months to 56% at 24 months. Longitudinal cytokine profiling revealed a cluster of individuals with persistently high inflammatory cytokine levels 12 months after infection. Survivors with prolonged inflammation showed elevated terminally differentiated memory T cells in their blood; 54% had symptoms at 12 months. The majority of inflammatory markers and dysregulated immune cells in vaccinated survivors recovered to a healthy baseline at 24 months, even though symptoms persisted.Interpretation: Post-COVID-19 symptoms can linger for two years after initial infection and are associated with prolonged inflammation. We define a set of analytes associated with persistent inflammation and presence of symptoms, which could be useful biomarkers for identifying and monitoring high-risk survivors. Prolonged inflammation in survivors resolves after receiving SARS-CoV-2 vaccines, suggesting that vaccines may alleviate prolonged COVID syndrome.Funding: This work was supported by A*STAR Infectious Diseases Labs core research grants and COVID-19 (project number H20/04/g1/006) research grant provided to Singapore Immunology Network by the Biomedical Research Council (BMRC). Subject recruitment and sample collection were funded by the National Medical Research Council (NMRC) COVID-19 Research fund (COVID19RF-001, COVID19RF-007, COVID19RF-008, COVID19RF-060 and OF-LCG19May-0034). The SIgN Multiplex Analysis of Proteins (MAP) platform was supported by a grant from the National Research Foundation, Immunomonitoring Service Platform (ISP) (NRF2017_SISFP09) from the National Research Foundation Singapore (NRF). The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, or approval of the 495 manuscript; and decision to submit the manuscript for publication.Declaration of Interest: No interest declared.Ethical Approval: The study design and protocol for the COVID-19 PROTECT study group were approved by the National Healthcare Group (NHG) Domain Specific Review Board (DSRB) (study number 2012/00917). SingHealth Centralized Institutional Review Board (CIRB) approved the collection of healthy donor samples under study number 2017/2806 and NUS IRB 04-140. Written informed consent was obtained from participants in accordance with the Declaration of Helsinki for Human Research.