Association Of Interleukin-6 Levels With Morbidity And Mortality in Patients With Coronavirus Disease 2019(COVD-19) Ⅱ
Apr 08, 2024
RESULTS
Demographics, clinical characteristics, and laboratory findings: A total of 66 patients diagnosed with coronavirus were included in this study. The median age was 63 years (range 31-92 years). In total31 patients were females (47.0 %). By April 9, 2020,56patients were discharged, 8 patients died, and 2 patients continued hospitalization. The length of hospital stay was 32 (range 21-43) days. Table 1 shows that common comorbidities included hypertension (24 patients, 36.4%), diabetes (14 patients, 21.2 %), and cardiovascular disease (11 patients, 16.7 %). There were 3 moderate.46 severe, and 17 critical cases. Patients were classified into elevated and normal groups according to the normal range of serum IL-6 concentrations (<10 pg/mL). The median serum l-6 concentration in the elevated group was 30.00 pg/mL, while that in the normal group was 1.77 pg/mL. Compared with patients with normal serum IL-6 levels, patients with elevated serum IL-6 levels were older and the proportion of critical cases was significantly higher. The interval from onset to admission in the elevated group was significantly shorter than that in the normal group. while no difference in hospital stay was found between the 2 groups. There were more patients in the elevated group with a history of cerebrovascular disease than in the normal group. The lowest pulse oxygen saturation(SpO,)documented during hospital stay in the elevated group was significantly lower than that in the normal group. In the laboratory findings on admission, the platelet count was significantly decreased, while serum concentrations of creatinine,cTnl, procalcitonin, and C-reactive protein were all significantly increased in patients with elevated I-6 levels, compared to those in patients with normal IL-6 levels.
Correlation between serum I-6 concentrations and other variables: As demonstrated by Spearman's correlation (Table 2), serum IL-6 concentrations were positively correlated with age, urea, creatinine, cTnNT-proBNP, C-reactive protein, and procalcitonin. Positive correlations with lL-6 were also found for white blood cell count and neutrophil counts. In addition, serum IL-6 concentrations were negatively correlated with the lowest SpO, documented during a hospital stay, lymphocyte counts, and platelet counts. Complications and outcomes in patients with different serum I-6 levels: As described in Table 3worse outcomes and higher incidences of complications were observed in patients with elevated serum IL-6levels compared with those in the normal groupComplications, including acute cardiac injury, cardiacinsufficiency, and ARDS, occurred more frequently in patients with elevated IL-6 levels than in those with normal levels. In comparison to the normal group, the incidence of critical cases and deaths in the elevated group was significantly higher, and more patients in the elevated group received mechanical ventilationThe median time to death was 3(1-37) days after the detection of serum IL-6 levels in the dead cases. Predictive value of serum I-6 concentrations for outcomes: Logistic regression analysis for associations between serum IL-6 levels and outcomes is shown in Table 4. Univariate analysis (Model 1) revealed that serum -6 levels were associated with critical illness and mortality. After adjusting for age, and sex. comorbidities, and procalcitonin(Model 4), serumIL-6 levels were still independently associated with critical illness. In multivariate logistic regression models (Models 2 to 4), after age, sex, comorbidities, and procalcitonin levels were adjusted hierarchically and serum IL-6 concentration remained an independent predictor of fatal outcome. In contrast, no significant association with disease severity or outcome was found for C-reactive protein, a classical inflammation marker that was routinely determined. The predictive value of serum IL-6 concentrations for a fatal outcome was further evaluated using the ROC curve (Fig. 1). After optimization, the threshold of serum IL-6 concentrations for predicting death was 26.09 pg/mL, with a sensitivity of 87.5 % and a specificity of 77.6 %(area under the curve 0.887.95 % CI0.767-1.000.P<0.001)
DISCUSSION
The present study illustrates the correlations between serum IL-6 levels, complications, and outcomes in patients with COVID-19. We report 3 major findings in this study. First, patients with elevated serum IL-6 levels had a higher incidence of critical illness, complications including heart injury and ARDS, use of mechanical ventilation, and fatal outcomes. Second, serum IL-6 concentration was positively correlated with biomarkers for cardiac and kidney injuries. Third, elevated serumI-6 concentration was an independent predictor of data! outcome in patients with COVID-19. In the present study, elevated serum IL-6 levels were associated with decreased oxygen saturation, increased disease severity, and frequent use of mechanical ventilation. indicating that serum IL-6 might reflect the severity of inflammation and lung lesions and could have predictive value in patients with COVID-19. There were several confounding factors associated with serum IL-6 levels which may influence disease severity and outcomes such as age and bacterial infection. A close relationship between serum IL-6 levels and age was observed in the present study, and a similar relationship has been previously reported in patients without infectious disease (20), indicating a possible inherent relationship between age and inflammation. In addition, ascending serum IL-6 levels may be associated with bacterial infections. A previous study on pneumonia revealed an association between bacterial infection and increased serum IL-6 levels (21). Our data also showed significant positive correlations between serum I-6 levels and indices of bacterial infection, such as neutrophil count and procalcitonin.
To evaluate the independent predictive value of IL-6, age, and procalcitonin levels
were adjusted using multivariate logistic regression. The results showed that serum I-6 concentration was independently related to critical illness and was an independent predictor of fatal outcomes. Serum IL-6 levels might also be related to complications associated with COVID-19. Our data showed significant positive correlations with ofIL-6 with several biomarkers for kidney function and cardiac injury, such as urea, creatinine, cTnl, and NT-proBNPAs described in Table 3, the incidence of several complications, such as ARDS, acute cardiac injury. and cardiac insufficiency were significantly higher in patients with elevated levels of serum IL-6 than in those with normal l-6 concentrations. Heart injuries in COVID-19 might be caused by several factors, such as virus invasion, and systemic inflammation. It has been reported that the invasion sites of SARS-coronavirusSARS-CoV)correspond to the presence of angiotensin-converting enzyme 2(ACE2)(22), which is abundantly expressed in the lung and small intestine (23).ACE2 is also expressed in the endothelium and smooth muscles of the vasculature in the heart(24).SARS.CoV RNA was detected in autopsied human hearts obtained from patients infected with SARS-CoV, and macrophage infiltration was observed in these infected hearts (25).
However, there is no histological evidence supporting the direct impairment of the SARS-CoV-2 on cardiomyocytes(26). Systemic infammation under pathophysiological conditions might also cause heart damage. It has been reported that some circulating cytokines, including IL-1,1L-4, 1L-6, 1L-8, and 1L-18which are related to inflammatory cardiac pathologies. are involved in cardiac dysfunction (27). Our results also found correlations between I-6 and cardiac injury or cardiac dysfunction, suggesting a possible role of inflammation in heart injury in COVID-19 patients. The optimal cutoff value of IL-6 for mortality prediction in the present study was 26.09 pg/which was similar to that reported in other studies. For instance,1L-6 >25 pg/mL was reported to be an important risk factor for severe COVID-19 and/or in-hospital mortality (28). Severe complications were more likely to occur in COVlD patients with IL-6 levels >32.1pg/mL based on a study population of 140 patients with mild to severe diseases (29). In addition, IL-6 is a potential biomarker for the progression of COVID-19(30). Monoclonal antibodies targeting the IL-6 pathway have been used in the treatment of COVID-19, which might block the inflammatory storms. For example. tocilizumab, a monoclonal antibody that blocks -6 receptors, has shown encouraging clinical results in COVID-19 treatment(7). Detection of serum IL-6 levels after admission should be necessary for patients with COVID-19, which could help to identify patients at high risk and provide guidance for immune-modulating therapies.
As a retrospective study on severe diseases 1-6 was not routinely determined for all patients. Only a small portion of patients received measurements of IL-6 within the frst week after admission, and most of the measurements were not performed on admission. Serum I-6 levels determined within the frst week after admission were used for the analysis. In addition, other important cytokines involved in systemic inflammation such as lL-10 were not determined at the same time. In conclusion, in patients with COVID-19, elevated serum IL-6 levels were associated with critical illness. use of mechanical ventilation, and complications including heart injury and ARDS. Serum concentration was an independent predictor of fatal outcomes. The optimal cutoff value of IL-6 for mortality prediction was 26.09 ng/mL. Our study suggests that detection of serum IL-6 levels after admission should be necessary in COVID-19 patients.
Acknowledgments This work was supported by the National Natural Science Foundation of China (grant numbers 8157045081900455).
Conflict of interest None to declare
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