Our study observed that the levels of β2MG in patients with ARDS were elevated and were significantly higher in non-survivors than in survivors. A multivariate Cox proportional hazards analysis revealed that the β2MG level is an independent predictor for 28-day mortality in patients with ARDS, after adjusting for age, updated CCI, disorders of consciousness, septic shock, albumin level, cTnI level, PCT level, PT, lactic acid level, and PaO2/FiO2 ratio. To our knowledge, this is the first report suggesting that the serum β2MG level might have a predictive value for the outcomes of patients with ARDS.
As a low molecular-weight protein, β2MG is an ideal endogenous biomarker for estimating the glomerular filtration rate and AKI [8, 12] and is also associated with a number of clinical states. Several previous studies have shown that levels of serum β2MG are higher in patients with inflammatory bowel disease or systemic lupus erythematosus than in healthy controls, suggesting that it might also be a useful biomarker for the assessment of these autoimmune diseases [25, 26]. In addition, elevated levels of serum β2MG have been also observed in patients with haemato-oncological pathology and solid tumours despite their preserved renal function [15, 27]. Some research has suggested that β2MG is probably a general biomarker that reflects acute or chronic changes during inflammation and infection [28, 29]. Levels of serum β2MG are independently associated with major cardiovascular events in the general population as well as in patients with asymptomatic carotid atherosclerosis, patients with isolated systolic hypertension, and patients with acute heart failure who do not have severe renal insufficiency [10, 30-32]. Mao et al. reported that β2MG levels are associated with poor outcomes in patients with exacerbated chronic obstructive pulmonary disease [18].
ARDS is a clinical syndrome with extremely high mortality, characterized by severe hypoxemia and an overwhelming inflammatory response, accompanied by multiple organ dysfunctions. Kohanpour et al. stated that an increase in serum β2MG levels can occur with physical exercise under hypoxic conditions [33]. Hadzimuratovic et al. observed increased serum β2MG levels in neonatal asphyxia [34]. These findings suggest that elevated serum β2MG levels are associated with hypoxemia. Some studies have found that an increase in serum β2MG levels is also present during infectious diseases as well as in inflammatory responses [28, 29]. In our study, the serum β2MG levels were found to be elevated in patients with bacterial infection-induced ARDS. A rank correlation analysis revealed that the serum β2MG levels were negatively correlated with the PaO2/FiO2 ratio and positively correlated with the PCT and CRP levels. These correlations suggest that elevated serum β2MG levels during ARDS may be associated with hypoxemia and infection as well as with inflammation. In addition, ARDS is often accompanied by multiple organ dysfunctions, such as AKI and myocardial injury, which are significantly associated with a poor prognosis in patients with ARDS [35, 36]. Previous studies have shown that serum β2MG levels are correlated with renal injury [8, 12] as well as with cardiac function [32, 37, 38]. Both AKI and myocardial injury were present in approximately half of the patients in our cohort, and our correlation analysis revealed that the serum β2MG levels are positively correlated with AKI, NT-proBNP levels, and cTnI levels and are negatively correlated with the Ccr and left ventricular ejection fraction. An analysis conducted after stratification of the patients according to their Ccrs [39] showed that serum β2MG levels are also positively correlated with NT-proBNP levels in patients with a Ccr of > 60 mL/min. These conditions suggest that, in the case of ARDS caused by bacterial infection, severe hypoxemia, infection, and inflammatory responses, as well as the impairment of organ function, result in increased β2MG production and decreased renal filtration, ultimately leading to elevated serum β2MG levels, which are positively correlated with disease severity and sensitively predict an elevated risk of death.
The ROC curves generated from our data show that the predictive value of serum β2MG levels for patient outcome is superior to that of AKI and Ccr, which may additionally illustrate that the correlation between serum β2MG levels and mortality is not solely a consequence of renal impairment. Further comparison of these ROC curves showed that serum β2MG levels are not inferior to currently applied critical illness scores, such as the APACHE II score and SOFA score, for predicting 28-day mortality in patients with ARDS caused by bacterial infection. Therefore, the serum β2MG level may be an ideal screening tool that can be reliably and cost effectively measured.
We applied the updated CCI [19] to assess patient comorbidities, including coronary heart disease, congestive heart failure, cerebrovascular disease, diabetes mellitus, dementia, connective tissue disease, liver disease, and kidney disease, and found it was significantly associated with 28-day mortality in patients with bacterial infection-induced ARDS. This result is consistent with previous research [40]. We also found that the lactic acid level was an independent risk factor for 28-day mortality in patients with bacterial infection-induced ARDS. Lactic acid is directly produced by anaerobic glucose metabolism and is the product of pyruvate transformation through glycolysis. An acceleration of lactate synthesis may be observed under conditions of increased glucose uptake from circulation, of increased glycogenolysis and glycolysis owing to enhanced epinephrine secretion, of inhibition of pyruvate dehydrogenase or of glycogen synthesis during sepsis and, finally, during tissue hypoxia. Therefore, the lactic acid level is considered to be a sensitive biomarker, which can reflect the oxygen supply in cells and the perfusion of surrounding tissues in the early stage of disease, and can be used to assess disease severity and to predict the occurrence of and death risk from septic shock and multiple organ dysfunction syndrome [21, 41]. Demirel reported that the lactate level is a good predictor of in-hospital mortality in pneumonia cases [42]. During ARDS, owing to severe hypoxemia and varying degrees of tissue perfusion insufficiency, glucose anaerobic metabolism increases, resulting in increased lactic acid production, which indicates a poor prognosis [5, 6].
Severe hypoxemia is a characteristic manifestation of ARDS. The PaO2/FiO2 ratio is an integral part of the assessment of patients with ARDS and is an important criterion for severity grading in the Berlin standard [1]. Although some studies have found that the PaO2/FiO2 ratio is not a good prognostic factor for ARDS [4], as an important indicator of the severity of lung injury, however, most studies have shown that the decreased PaO2/FiO2 ratio is associated with increased mortality or failure of non-invasive MV in patients with ARDS [21, 43, 44]. Similarly, our study showed that the PaO2/FiO2 ratio was a protective factor for the prognosis of patients with ARDS.
There are some limitations to our study. First of all, this research was conducted in a single centre, which could have biased its results. Second, owing to the small sample size in this study, to avoid overfitting, only a limited number of clinical variables were entered into the Cox regression analysis, and it is possible that potentially relevant variables were not evaluated. Third, owing to the retrospective nature of this study, we could not simultaneously assay the levels of β2MG in the urine, and thus it was not possible to determine how much of the increase in serum β2MG levels can be attributed to renal injury and how much of the increased production is a consequence of the disease state. Fourth, although the ROC curve in our study showed predictive value for the outcome of patients with ARDS, we could not verify the applicability of this clinical indicator because of the small sample size. Future prospective studies will be necessary to identify and verify the prognostic value of serum β2MG levels in patients with ARDS caused by bacterial infection.