Persistent symptoms and association with inflammatory cytokine signatures in recovered COVID-19 patients

Ong, Sean Wei Xiang; Fong, Siew-Wai; Young, Barnaby Edward; Chan, Yi-Hao; Lee, Bernett; Amrun, Siti Naqiah; Chee, Rhonda Sin-Ling; Yeo, Nicholas Kim-Wah; Tambyah, Paul; Pada, Surinder; Tan, Seow Yen; Ding, Ying; Renia, Laurent; Leo, Yee-Sin; Ng, Lisa F P; Lye, David Chien

BACKGROUND: The complications and sequelae of coronavirus disease 2019 (COVID-19) and their effect on long-term health are unclear, and the trajectory of associated immune dysregulation poorly understood. METHODS: We conducted a prospective longitudinal multi-center cohort study at four public hospitals in Singapore. COVID-19 patients were monitored for a median of six months after recovery from acute infection. Clinical symptoms and radiologic data were collected, along with plasma samples for quantification of immune mediators. The relationship between clinical symptoms and immune cytokine profiles was investigated. RESULTS: 288 participants were recruited, and follow-up data were available for 183, 175, and 120 participants at days 30, 90 and 180 post-symptom onset respectively. Symptoms related to COVID-19 were present in 31 (16.9%), 13 (7.4%), and 14 (11.7%) at days 30, 90 and 180. In a multivariable model, age >65 years, non-Chinese ethnicity, and the severity of acute infection were associated with increased likelihood of persistent symptoms. Recovered COVID-19 patients had elevated levels of pro-inflammatory IL-17A, SCF, IL-12p70, IL-1βand pro-angiogenic MIP-1β, BDNF, VEGF at day 180 compared to healthy controls. Higher levels of MCP-1 and PDGF-BB were detected in patients with persistent symptoms, versus symptom-free patients. CONCLUSIONS: About 10% of recovered patients had persistent symptoms six months after initial infection. Immune cytokine signatures of the recovered patients reflected ongoing chronic inflammation and angiogenesis. COVID-19 patients should be monitored closely for emerging long-term health consequences.