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.