Febrile neutropenia is a medical emergency that calls for a precocious diagnosis and the administration of antibiotics as soon as possible. The patient's clinical, microbiological and radiological data usually fail in revealing the origin of the fever. Even though it is known that PCT is also produced to some extent by leukocytes [18], studies have shown that PCT may be useful as a marker in neutropenic patients [7, 8, 12, 19, 20]. Al Nawas et al. (1996) have shown that PCT is increased in 25 patients with neutropenia and sepsis [8]. Giamarellos-Bourboulis et al., in a prospective study with 115 febrile neutropenic adults, revealed that PCT might be a useful diagnostic tool for the early detection of a systemic infection in this population [7].
In our study the following variables: sex, age, recentness of diagnosis versus re-incidence or non-responsiveness of disease, granulocyte and platelet count and hemoglobin concentration were similar between groups (p > 0.05). The rates of death related to the febrile event was shown to be strikingly different between both groups, with 11 deaths in group 1 (systemic infection) in contrast to only 2 deaths in group 2 (p = 0.009). As to the basal hemopathies, over 2/3 of all patients were suffering from some form of leukemia.
The most common causes of fever in our patients were FUO, followed by sepsis. The most frequently isolated microorganisms were Staphylococcus sp. followed by Enterobacter sp. and Klebsiella sp.
In spite of the sample size (n = 52) and of the single determination of PCT at the onset of fever, the increased values of PCT were able to indicate infection already on the first day of fever in group 1. These neutropenic patients with severe infection (diagnosed clinically and/or microbiologically) presented high concentrations of PCT, but CRP concentrations evinced no correlation with severe infection.
The mean PCT concentrations were statistically different between both groups already at the beginning of the febrile state, with PCT being much more elevated among patients with severe infection. This was not observed in the serum concentrations of CRP. For patients with neutropenia who did not have systemic infection (group2), that is, those who were diagnosed with FUO or localized infection presented low concentrations of PCT (0,08–2,15) that were highly significant (p = 0,0003) and CRP concentrations that did not greatly differ statistically from those found in group 1 (19,5–546,0) (p = 0,9198).
It can be seen in these cases that there is no correlation between PCT and CRP, that is, the variations in PCT concentration are not concomitant with the variations in CRP and the results further indicate that the PCT concentrations change more precociously than those of CRP in response to an infection. Also, there is no correlation between PCT versus PCR values in the group without systemic infection. Because PCT concentration changes more rapidly than CRP in response to infection (bacterial and/or fungal), a diagnostic decision can be taken more precociously, which would aid in speeding up choosing the therapeutic conduct.
It can be seen, from the ROC curve, that CRP cannot be used as a diagnostic or prognostic marker in febrile neutropenia. The area under the ROC curve for PCT is of 79% (CI between 67% and 91%), in contrast to 50% for CRP (CI between 34% and 67%) for diagnosing systemic infection in the groups studied.
Giamerellou et al. clearly showed in an important multicentre study concerning febrile neutropenia that PCT levels were elevated significantly in patients with severe sepsis compared to bacteremia (n = 158) [12]. A PCT cut-off value of 1.0 ng/mL could indicate bacteraemia, while severe sepsis could be shown with a level over 5.0 ng/mL. In this present study, the cut-off points used for PCT were 0.25 ng/mL; 0.5 ng/mL, 1.0 ng/mL and 2.0 ng/mL. Using values of 0.25 ng/mL, it was possible to discriminate between presence or absence of systemic infection with a sensitivity of 100% and a specificity of 30.8%. When the cut-off point used was of 0,49 ng/mL, the sensitivity and specificity obtained were of 85% and 50%, respectively. There were no satisfactory cut-off values for CRP.
The PCT ROC curves for evolution to death as a result of systemic infection limit an area under the curve statistically different than that expected by chance, whereas this is not the case for CRP. Furthermore, specifically for infection, one can see by means of the confidence intervals that there is a statistically significant difference between the PCT ROC curve and the CRP ROC curve. The main problem as to the determination of PCT is the ample variation of the results obtained that do not follow a Gaussian distribution, which thus makes it more difficult to determine a cut-off point with an optimum sensitivity and specificity adequate enough to indicate an infection. These data corroborate those obtained by Giamarellos-Bourboulis et al. (2001), who also found this distribution [7]. Even though a PCT concentration that fulfills adequate sensitivity and specificity and considering that a sensitivity of 73% has been proposed by other authors as satisfactory for PCT [7, 21], we could assume that concentrations of 0.49 ng/mL, or better 0.5 ng/ml, with 85% sensitivity and 50% specificity might be useful for the differential diagnosis between a disseminated infection (bacteremia, sepsis and its intermediate stages) and a non disseminated infection (FUO and localized infection).
Cut-off values of more than 2,0 ng/mL, which are suggested by the manufacturer for immunocompetent patients would increase the specificity to 96.2%, however, the sensitivity would drop to 53%, which would imply that a severe infection might not be considered in 1 of each 2 really infected patients. As the PCT concentrations rise, sensitivity decreases and specificity increases, to the point which leads us to assume that values >2.0 ng/mL in a single patient might indicate severe sepsis.
Using logistical regression, only PCT remained in the model as associated to the presence of severe infection. Thus, CRP concentration was not able to distinguish between presence or absence of a disseminated infection, perhaps because of the contribution of the basal malignant disease to the production of CRP [22]. Recently, Schuttrumpf et al. evaluated PCT plasma concentrations prospectively in 111 patients with a hemato-oncological condition with a CRP concentration >8 mg/L. Median CRP concentrations did not differ significantly between groups of patients with and without infection. However, PCT concentrations were higher in patients with infection than in those without infection and contributed significantly to the differential diagnosis of elevated CRP concentrations in patients with hemato-oncological conditions [23].
The prognostic significance of PCT has already been demonstrated in studies with immunocompetent adult patients in intensive care units [24] and in children with febrile neutropenia [25]. A recent study evaluated 49 children, who had 60 febrile episodes compared follow-up value of PCT with CRP in documenting the infection in neutropenic febrile patients. PCT and CRP levels were significantly higher in neutropenic febrile patients with infection than in control patients (P < 0.001). In sequential analyses of patients without documented infections, the median of PCT concentrations shows a tendency to fall after the 8th hour of onset of fever, whereas in patients with documented infections PCT concentrations fell after the 48th hour. This study suggests that PCT, when measured periodically, is a more useful diagnostic inflammation parameter in pediatric neutropenic-fever patients than CRP [26].
In our study, when we evaluated prognosis, its association with platelet count, even though significant from a statistical point of view, is not useful taking into account that it does not present a large increase of the probability of death as an outcome.
Although Giamarellou et al (2004) found a area under the ROC curve of 71%, very close to the one of these study, the present data suggest a lower cut-off value for PCT (0.5 ng/mL) could distinguish infected neutopenic febrile patients from those without severe systemic infection.
