Chemokines, soluble PD-L1, and immune cell hyporesponsiveness are distinct features of SARS-CoV-2 critical illness

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 323; no. 1; pp. L14 - L26
• Main Authors: Morrell, Eric D, Bhatraju, Pavan K, Sathe, Neha A, Lawson, Jonathan, Mabrey, Linzee, Holton, Sarah E, Presnell, Scott R, Wiedeman, Alice, Acosta-Vega, Carolina, Mitchem, Mallorie A, Liu, Ted, Chai, Xin-Ya, Sahi, Sharon, Brager, Carolyn, Orlov, Marika, Sakr, Sana S, Sader, Anthony, Lum, Dawn M, Koetje, Neall, Garay, Ashley, Barnes, Elizabeth, Cromer, Gail, Bray, Mary K, Pipavath, Sudhakar, Fink, Susan L, Evans, Laura, Long, S Alice, West, T Eoin, Wurfel, Mark M, Mikacenic, Carmen
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.07.2022
• Series: Translational Physiology
• Subjects: B7-H1 Antigen; C-reactive protein; CCL17 protein; Chemokines; Chemotactic factors; Coronaviruses; COVID-19; Critical Illness; CXCL10 protein; Cytokine storm; Cytokines; Humans; Illnesses; Immune system; Interferon; Interleukin 10; Interleukin 6; Interleukin 8; Leukocyte migration; Lymphocytes; Lymphocytes T; Monocytes; PD-L1 protein; Plasma levels; Prospective Studies; Respiratory diseases; Respiratory Insufficiency; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Tumor Necrosis Factor-alpha; Tumor necrosis factor-α; Viral diseases; γ-Interferon; COVID-19; PD-L1; pneumonia; checkpoint pathway; ARDS; sepsis
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00049.2022

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 ( = 204) or -negative ( = 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 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 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 ( 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.