[HTML][HTML] Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients

L Chen, X Long, Q Xu, J Tan, G Wang, Y Cao… - Cellular & molecular …, 2020 - nature.com
L Chen, X Long, Q Xu, J Tan, G Wang, Y Cao, J Wei, H Luo, H Zhu, L Huang, F Meng…
Cellular & molecular immunology, 2020nature.com
COVID-19 is a disease with heterogeneous clinical appearances. Most patients are
asymptomatic or exhibit mild to moderate symptoms; approximately 15% progress to severe
pneumonia and about 5% are eventually admitted to the intensive care unit (ICU) due to
acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure. ICU
patients respond poorly to currently available treatments and exhibit a high mortality rate. 1–
3 Inadequate identification of the determinants of fatal outcomes is one of the major …
COVID-19 is a disease with heterogeneous clinical appearances. Most patients are asymptomatic or exhibit mild to moderate symptoms; approximately 15% progress to severe pneumonia and about 5% are eventually admitted to the intensive care unit (ICU) due to acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure. ICU patients respond poorly to currently available treatments and exhibit a high mortality rate. 1–3 Inadequate identification of the determinants of fatal outcomes is one of the major obstacles to the improvement of the outcomes in severe COVID-19 patients. A previous study reported a scoring system (COVID-GRAM) which accurately predicted the occurrence of critical illness in hospitalized COVID-19 patients. 4 Damage-associated molecular patterns (DAMPs), or alarmins, are a number of molecules, released by stressed cells undergoing microbial infection or sterile injury, that act as danger signals to promote and exacerbate the inflammatory response. 5, 6 Of note, the serum level of S100A8/A9 and HMGB1 was found to be correlated with both the severity of pathogen-associated tissue damage and excessive cytokine storm. 7 Despite the hypothesis that S100A8/A9 and HMGB1 are significantly involved in COVID-19, so far, no study has yet tried to substantiate the hypothesis. In this study, we aimed to define the role of S100A8/A9 and HMGB1 in progression to a fatal outcome and develop clinically relevant risk strata for COVID-19 patients. A total of 121 patients were enrolled in this retrospective study, of which 40 patients were in ICU and 81 patients in general wards at enrollment (Table S1). ICU Patients had much higher COVID-GRAM risk scores in comparison to those in general wards. Complications, including ARDS, sepsis, septic shock, secondary infection, acute renal injury, acute cardiac injury or failure, were more frequent in CCOVID-19 patients admitted to ICU. As of the cutoff date of April 30, 2020, most of non-ICU patients (96.3%) had been discharged alive, while 82.5% of ICU patients had died in ICU.
COVID-19 patients treated in general wards had significantly elevated level of S100A8/A9 (P= 0.033) but not HMGB1 (P> 0.9999) as compared to healthy controls, suggesting that S100A8/A9 is a more sensitive alarmin than HMGB1 in response to SARS-CoV-2 infection. However, both S100A8/A9 and HMGB1 were significantly elevated extracellularly in ICU-admission patients compared to non-ICU patients, or in fatal outcomes patients compared to alive patients (Fig. 1 a–d), indicating that significant elevation of S100A8/A9 and HMGB1 was associated with high mortality. We further examined the Spearman’s correlation between the serum S100A8/A9 or HMGB1 levels and clinical manifestations in COVID-19 patients. First of all, either serum levels of S100A8/A9 or HMGB1 at admission were positively correlated with peak CT score and oxygen demand, which is indicative of the severity of acute lung injury and ARDS (Fig. 1 e, f and S1a, b). Moreover, the degree of organic impairment, as evaluated by the MCP classification, NT-proBNP level, cTn I level, and AKI stage were well correlated with the serum levels of S100A8/A9 or HMGB1 (Fig. S1c–j). The level of peak D-dimer significantly was elevated as the serum S100A8/A9 or HMGB1 increased (Fig. 1 g, h). On the other hand, the ratio of neutrophils to lymphocytes was positively correlated with the serum S100A8/A9 but not with HMGB1, suggesting S100A8/A9 plays a more important role in the substantial reduction of the peripheral lymphocytes. The serum S100A8/A9 was strongly correlated with the qSOFA score, 8 a quick indicator of …
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