In this study, we found that the serum FGF21 level at baseline was greater in ICU patients who had sepsis and ARDS than in those who had sepsis alone. Furthermore, non-survivors in the Sepsis + ARDS group had persistently increasing levels of FGF21 during their ICU stays, but survivors in the Sepsis + ARDS group had persistently declining levels. Notably, our Cox proportional hazards model indicated that an increase in the serum level of FGF21 from the baseline was a significant risk factor for 28-day mortality in the Sepsis + ARDS group. To our best knowledge, this is the first study to identify the prognostic value of dynamic changes in the serum level of FGF21 in patients with sepsis and ARDS.
Previous studies demonstrated that the serum level of FGF21 was greater in adults and newborns who had sepsis [22, 23]. Our previous study demonstrated that the serum level of FGF21 was positively associated with serum inflammation biomarkers, including PCT, CRP, IL-6, and TNFα [23]. Patients with sepsis and ARDS have a greatly increased inflammatory state. Thus, it is not surprising that the serum level of FGF21 was greater in patients with sepsis and ARDS.
Elevation of inflammatory and anti-inflammatory biomarkers can occur concurrently during the early phase of sepsis [24]. Previous studies reported that FGF21 had anti-inflammatory effects during sepsis [25]. The present study, which compared patients with sepsis alone vs. sepsis and ARDS, identified much higher levels of serum FGF21 and pro-inflammatory factors (PCT, CRP, IL-6, and TNFα) in the Sepsis + ARDS group. This suggests a more intense interaction between pro-inflammatory and anti-inflammatory factors in patients who have sepsis and ARDS.
Immune cells function in the early stage of ARDS, so the focused biomarkers for ARDS in this stage are inflammatory cytokines, such as IL-1β and TNF-α which are mainly related to exudation and migration of inflammatory. However, the anti-inflammatory cytokines also play a critical role in this stage and should not be ignored. Besides it is also critical to identify novel biomarkers for late stage of ARDS which is not well investigated currently. FGF21 has anti-inflammatory and anti-oxidative stress effects [18,19,20,21]. This motivated our interest in the relationship between the dynamics changes of FGF21 and the prognosis of ARDS during sepsis in the present research.
In this study, we found that FGF21 is a promising prognostic biomarker for differentiating non-survivors and survivors among patients with Sepsis + ARDS (Table 1). Our analysis of disease progression in patients with sepsis and ARDS indicated the non-survivors had continuously increased serum levels of FGF21, and this was accompanied by persistent increases in the levels of multiple pro-inflammatory cytokines. In contrast, the survivors had gradually decreased levels of FGF21 and of pro-inflammatory cytokines. The presence of higher levels of pro- and anti-inflammatory biomarkers in the non-survivors is consistent with the presence of increased physiological stress.
Because the dynamic changes of pro- and anti-inflammatory markers appeared to be of vital importance in the progression of patients with sepsis and ARDS, we were interested in the following question: Which parameters can be used to predict the mortality of patients with sepsis and ARDS? Thus, we used Cox regression analysis to assess the prognostic value of biomarkers that were measured at admission to the ICU, at the peak of shock, and before death (non-survivors) or before ICU discharge (survivors). Our measurements at admission indicated that increased FGF21, LAC, and SOFA score were associated with poor prognosis in patients with sepsis and ARDS. This result is consistent with results from our previous study [23].
Our measurements at the peak time of shock (typically 1 week after ICU admission) indicated that the level of FGF21 at the peak did not show significant difference, but the percentage increase in the FGF21 from baseline (ΔFGF21%2–1) value had a much greater HR (15.269 [95% CI 1.622–143.712] vs. 1.247 [95% CI 1.096–1.418]). In other words, based on measurements at baseline and the peak of shock, we identified the percentage increase of FGF21 as the best predictor of poor prognosis in patients with sepsis and ARDS. The FGF21 at the peak may serve as a good predictor with enlarged sample size. The large changes in the serum level of FGF21 from admission to the peak of shock reflect the dynamics of pro- and anti-inflammatory factors in patients with sepsis and ARDS.
We also analyzed the relationship of the final clinical measurements (before death or ICU discharge) with patient prognosis. We found that the ΔFGF21%3–1, ΔLAC%3–1, and ΔSOFA3–1, and CRP1 were significant prognostic factors. Notably, ΔFGF21%3–1 was best predictor of poor prognosis (HR = 25.760 [95% CI 1.482–447.610]). This confirms that a large increase in the serum level of FGF21, either between the first and second measurements or between the first and third measurements, was strongly associated with 28-day mortality in patients with sepsis and ARDS. At the physiological level, this may be attributed to the anti-inflammation, anti-apoptotic, and anti-oxidative effect of FGF21 during sepsis.