High mobility group box 1, ATP, lipid mediators, and tissue factor are elevated in COVID-19 patients: HMGB1 as a biomarker of worst prognosis

The severe acute respiratory syndrome coronavirus 2, the agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, has spread worldwide since it was first identified in November 2019 in Wuhan, China. Since then, progress in pathogenesis linked severity of this systemic disease to the hyperactivation of network of cytokine-driven pro-inflammatory cascades. Here, we aimed to identify molecular biomarkers of disease severity by measuring the serum levels of inflammatory mediators in a Brazilian cohort of patients with COVID-19 and healthy controls (HCs). Critically ill patients in the intensive care unit were defined as such by dependence on oxygen supplementation (93% intubated and 7% face mask), and computed tomography profiles showing ground-glass opacity pneumonia associated to and high levels of D-dimer. Our panel of mediators included HMGB1, ATP, tissue factor, PGE(2), LTB4, and cys-LTs. Follow-up studies showed increased serum levels of every inflammatory mediator in patients with COVID-19 as compared to HCs. Originally acting as a transcription factor, HMGB1 acquires pro-inflammatory functions following secretion by activated leukocytes or necrotic tissues. Serum levels of HMGB1 were positively correlated with cys-LTs, D-dimer, aspartate aminotransferase, and alanine aminotransferase. Notably, the levels of the classical alarmin HMGB1 were higher in deceased patients, allowing their discrimination from patients that had been discharged at the early pulmonary and hyperinflammatory phase of COVID-19. In particular, we verified that HMGB1 levels above 125.4 ng/ml is the cutoff that distinguishes patients that are at higher risk of death. In conclusion, we propose the use of serum levels of HMGB1 as a biomarker of severe prognosis of COVID-19.Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Pneumonia and acute respiratory distress syndrome are the major complications of coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 infection can activate innate and adaptive immune responses and result in massive inflammatory responses later in the disease. These uncontrolled inflammatory responses may lead to local and systemic tissue damage and co-infections due to intensive care unit environment. This scenario makes it difficult to administer direct treatment of the disease. It is necessary to investigate inflammatory biomarkers that precociously distinguish the worst prognosis.WHAT QUESTION DID THIS STUDY ADDRESS? We aimed to identify molecular biomarkers of disease severity in a Brazilian cohort of patients with COVID-19 by measuring the serum levels of inflammatory mediators as high mobility group box 1 (HMGB1), ATP, tissue factor, PGE2, LTB4, and cys-LTs at different phases of the disease.WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our work confirms HMGB1 as an important endogenous danger signal during COVID-19 and provides evidence that high levels of HMGB1 in the circulation of patients with severe COVID-19 orchestrates the acute and persistent mediators storm, in association with several other mediators. Indeed, we demonstrated that HMGB1 distinguishes patients that are at higher risk of death during the early hyperinflammatory phase.HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The results suggest that the alarmin HMGB1 could be a severity biomarker for COVID-19, useful to distinguish patients that are at higher risk of death, and a potential target for innovative therapeutic strategies leading to a direct treatment for severe COVID-19.