Dynamic Changes in the Immune Response Correlate with Disease Severity and Outcomes During Infection with SARS-CoV-2.

INTRODUCTION: The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout China and worldwide. Little is known about the dynamic changes in the patient immune responses to SARS-CoV-2 and how different responses are correlated with disease severity and outcomes. METHODS: Seventy-four patients with confirmed COVID-19 were enrolled in this prospective research. The demographic information, medical history, symptoms, signs and laboratory results were analyzed and compared between severe and non-severe patients. The leukocytes, lymphocyte subsets and inflammatory cytokines were longitudinally collected. RESULTS: Of the 74 patients included, 17 suffered from severe disease. The severe patients tended be older (65.29 ± 12.33 years vs. 45.37 ± 18.66 years) and had a greater degree of underlying disease (41.18% vs. 24.56%), lower baseline lymphocyte counts [0.64 (0.46-0.95) × 109 vs. 1.27 (0.95-1.70) × 109], higher neutrophil-lymphocyte ratios [NLRs; 3.76 (3.15-5.51) vs. 2.07 (1.48-2.93)] and lower baseline eosinophil counts [0 (0-0.01) × 109 vs. 0.03 (0.01-0.06) × 109] than those in non-severe patients. The baseline helper T (Th) cells (335.47 vs. 666.46/µl), suppressor T(Ts) cells (158 vs. 334/µl), B cells (95 vs. 210/µl) and natural killer (NK) cells (52 vs. 122/µl) were significantly decreased in severe cases compared to that in non-severe cases. In addition, the baseline neutrophils were positively correlated with the severity of COVID-19, and the baseline lymphocytes were negatively correlated with the severity of COVID-19. The dynamic change of T cells, Th cells and IFN-γ in the severe cases were parallel to the amelioration of the disease. CONCLUSIONS: Collectively, our study provides novel information on the kinetics of the immune responses in a cohort of COVID-19 patients with different disease severities. Furthermore, our study indicates that both innate and adaptive immune responses correlate with better clinical outcomes.

HMGB1 as a potential biomarker and therapeutic target for severe COVID-19.

COVID-19 has attracted global attention due to its rapid spread around the world with substantial morbidity and associated mortality. Severe COVID-19 can be complicated by the acute respiratory distress syndrome, sepsis and septic shock leading to death. These complications are thought to result from an overactivation of the immune system, leading to a cytokine storm syndrome associated with multiple organ failure. Here, we report that high mobility group box 1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP) and a central mediator of lethal inflammation, could be a potential target for innovative therapeutic strategies for COVID-19. Serum HMGB1 in severe COVID-19 patients is elevated (189.40 ± 140.88 ng/ml). Exogenous HMGB1 induces the expression of SARS-CoV-2 entry receptor ACE2 in alveolar epithelial cells in an AGER-dependent manner. Importantly, genetic (using AGER siRNA) or pharmacological (using glycyrrhizin, chloroquine, hydroxychloroquine, and FPS-ZM1) inhibition of the HMGB1-AGER pathway blocks ACE2 expression. Thus, HMGB1 inhibitors are likewise promising drug candidates for the treatment of patients suffering from COVID-19.