Abstract
Critically ill patients manifest many of the same immune features seen in coronavirus disease 2019 (COVID-19), including both “cytokine storm” and “immune suppression.” However, direct comparisons of molecular and cellular profiles between contemporaneously enrolled critically ill patients with and without severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited. We sought to identify immune signatures specifically enriched in critically ill patients with COVID-19 compared with patients without COVID-19. We enrolled a multisite prospective cohort of patients admitted under suspicion for COVID-19, who were then determined to be SARS-CoV-2-positive ( n = 204) or -negative ( n = 122). SARS-CoV-2-positive patients had higher plasma levels of CXCL10, sPD-L1, IFN-γ, CCL26, C-reactive protein (CRP), and TNF-α relative to SARS-CoV-2-negative patients adjusting for demographics and severity of illness (Bonferroni P value < 0.05). In contrast, the levels of IL-6, IL-8, IL-10, and IL-17A were not significantly different between the two groups. In SARS-CoV-2-positive patients, higher plasma levels of sPD-L1 and TNF-α were associated with fewer ventilator-free days (VFDs) and higher mortality rates (Bonferroni P value < 0.05). Lymphocyte chemoattractants such as CCL17 were associated with more severe respiratory failure in SARS-CoV-2-positive patients, but less severe respiratory failure in SARS-CoV-2-negative patients ( P value for interaction < 0.01). Circulating T cells and monocytes from SARS-CoV-2-positive subjects were hyporesponsive to in vitro stimulation compared with SARS-CoV-2-negative subjects. Critically ill SARS-CoV-2-positive patients exhibit an immune signature of high interferon-induced lymphocyte chemoattractants (e.g., CXCL10 and CCL17) and immune cell hyporesponsiveness when directly compared with SARS-CoV-2-negative patients. This suggests a specific role for T-cell migration coupled with an immune-checkpoint regulatory response in COVID-19-related critical illness.
Keywords: ARDS; COVID-19; PD-L1; checkpoint pathway; pneumonia; sepsis.
【저자키워드】 COVID-19, ARDS, Pneumonia, Sepsis, PD-L1, checkpoint pathway, 【초록키워드】 coronavirus disease, SARS-CoV-2, IL-17A, IL-6, CXCL10, severity, severe respiratory failure, C-reactive protein, CRP, Sepsis, in vitro, immune, monocyte, Regulatory, lymphocyte, T cell, Migration, comparison, Patient, IL-8, plasma, mortality rate, molecular, T-cell, IL-10, prospective cohort, Critical, patients, IFN-γ, TNF-α, Coronavirus-2, cellular, Interaction, Immune cell, demographics, p value, Critically ill patient, acute respiratory syndrome, two groups, profile, subject, SARS-CoV-2-positive patients, CCL17, feature, hyporesponsiveness, immune signature, enrolled, identify, less, subjects, CCL26, chemoattractant, multisite, not significantly different, patients without COVID-19, SARS-CoV-2-positive patient, ventilator-free day, with COVID-19, 【제목키워드】 SARS-CoV-2, Critical, Immune cell, feature, hyporesponsiveness,