DISCUSSION
In diseases where inflammation is at the forefront, there is an increase in the production of proinflammatory cytokines associated with the increase of oxidative stress mediators. Thiol/disulphide homeostasis is also one of the oxidative stress markers [12, 20]. The impaired thiol/disulphide balance plays a role in the formation of most inflammatory diseases such as diabetes mellitus, cardiovascular diseases, rheumatoid arthritis, chronic renal failure, cancer, Alzheimer’s disease and Parkinson’s disease [21]. PCT is a specific marker that is used in the diagnosis of inflammatory and infectious cases, and it is released from c cells [22, 23]. High PCT levels are associated with the severity of the infection and they can also be used to monitor the patients with severe infections, sepsis and multiple organ dysfunction syndrome (MODS). For all the reasons stated above, PCT is considered to be a reliable marker in the differential diagnosis of bacterial and non-bacterial inflammation [15, 24]. CRP is a biochemical marker that is secreted as an acute phase reactant after the cytokines are released in almost all microbial infections and inflammatory conditions [14].
Despite the widespread use of CRP and PCT as inflammatory markers and their occasionally inconsistent results, PCT has become prominent as a diagnostic and prognostic marker in the recent studies on febrile neutropenic patients with systemic infections [25]. A meta-analysis performed by Wu et al. has evaluated the possibility of using CRP and PCT for the early diagnosis in the febrile neutropenic patients with severe infections [26]. Despite PCT and CRP, the severity of the infection and the risk of mortality still cannot be predicted accurately. Therefore, new biomarkers are being searched [27, 28].
In the study conducted by Wenneras et al., PCT and CRP values were found to be above the normal range in all febrile neutropenic patients with proven or unproven infections and severe inflammation. PCT values were measured to be higher in infected patients as the strongest parameter. CRP was again recorded to be slightly higher in infected patients [3]. Similarly, in the study carried out by Ruokonen et al., PCT values measured in the patients with infections or with bacteremia were found to be higher than in patients with fewer of unknown origin in neutropenic patients [29]. The data of our study also provided similar results in febrile neutropenic patients in terms of PCT and CRP. In our study, disulphide/native thiol ratio was found to be higher in the patients with febrile neutropenia when compared to the control group, while the disulphide, native thiol, total thiol and native thiol/total thiol values were measured to be lower.No difference was recorded between the two groups in terms of disulphide/total thiol ratio.
Mortality rates in the patients with febrile neutropenia were found to be at different rates ranging from 4% to 24% in the literature [30-32]. The mortality rate in our study was approximately 25%. In the literature, Massaro et al. reported that PCT was not a good marker for predicting mortality [33-35], although there are some studies that have indicated that PCT may show short-term mortality when used as an early prognostic biomarker in oncologic emergencies. In certain studies on febrile neutropenia, CRP has been shown to have no significance in predicting the mortality [27, 28]. In another study, the relationship between mortality and CRP was found to be stronger in the patients with the febrile neutropenic disease, especially bacteremia, than in those who died from non-infectious causes [36]. In our study, disulphide/native thiol, disulphide/total thiol, and PCT values were measured to be higher in dying patients while the mean values of native thiol, total thiol, and native thiol/total thiol were recorded to be lower in the same group. There was no difference between dying and surviving patients in terms of disulphide and CRP values. PCT values were found to be compatible with the studies in the literature in terms of predicting the mortality. High values of disulphide/native thiol, disulphide/total thiol and low values of native thiol, total thiol and native thiol/total thiol may be used as valuable markers for the prediction of mortality in febrile neutropenia together with PCT.
Risk classifications are used for deciding which patients will have outpatient treatment, and to prevent serious complications infebrile neutropenic patients, [37, 38]. The MASCC score is a risk management-based scoring system with sensitivityof 71% and positive predictive value of 91%, which has been shown to be reliable in numerous studies for the management of febrile neutropenia and is widely used in clinical practices. Early discharge and outpatient treatment of the low-risk patients in febrile neutropenia according to MASCC score increase the quality of life and decrease nosocomial infections. MASCC score has been shown to be a cost-effective and safe method that can be used for identifying the patients with low risk [16, 17, 39]. Although there have been many studies in the literature showing the relationship between MASCC and PCT and CRP, there is no study that compares MASCC with thiol/disulphide homeostasis parameters. Combariza et al reported that the combination of MASCC risk score and mean CRP value successfully diagnosed the high mortality risk in the patients with neutropenic fever within the first 5 days [40]. Uys et al. indicated in their study that PCT and CRP values were significantly associated with the risk classification (strongest correlation) in the low-risk and high-risk patients according to MASCC risk score [41]. In the study carried out by Ahn et al., the combination of high-risk MASCC score and PCT elevation was found to be a strong predictor for the detection of bacteremia and septic shock [42]. PCT and CRP levels were found to be high in our study in high-risk patients according to MASCC risk score, which is compatible with the literature. In addition to the literature, high-risk patients were found to have high levels of disulphide/native thiol, while native thiol and total thiol levels were lower. There was no difference between disulphide, disulphide/total thiol and native thiol/total thiol values between high-risk and low-risk patients according to the MASCC risk score. Although there are different studies investigating the correlation between MASCC and PCT and CRP, our study is the first research indicating the correlation between thiol/disulphide homeostasis and MASCC risk score.
Although the majority of febrile neutropenic episodes are thought to result from a bacterial infection, it is difficult to determine the cause of febrile neutropenia because of the relatively poor diagnostic performance of the blood cultures [43]. In a study carried out by Viscoli et al., The frequency of bacteremia in febrile neutropenia was detected to be 29% [44]. In the literature, there are also the studies showing high PCT and CRP levels in the patients with positive blood cultures [45-47]. In our study, PCT and CRP values were found to be high in the patients with positive culture results, which is similar to the data in the literature. There was no significant relationship between thiol/disulphide homeostasis parameters and culture results.
To the best of our knowledge our study is the first research analyzing the relationship between thiol/disulphide homeostasis parameters and PCT and CRP and the MASSC scoring system in the patients diagnosed with febrile neutropenia. We observed that thiol/disulphide homeostasis parameters are significantly different amongst different prognostic groups of febrile neutropenia and we believe that with further studies these markers may be used in the prognostic evaluation of febrile neutropenic patients presenting to the emergency department.