Monitoring procalcitonin in febrile neutropenia: what is its utility for initial diagnosis of infection and reassessment in persistent fever?

BACKGROUND: Management of febrile neutropenic episodes (FE) is challenged by lacking microbiological and clinical documentation of infection. We aimed at evaluating the utility of monitoring blood procalcitonin (PCT) in FE for initial diagnosis of infection and reassessment in persistent fever. METHODS: PCT kinetics was prospectively monitored in 194 consecutive FE (1771 blood samples): 65 microbiologically documented infections (MDI, 33.5%; 49 due to non-coagulase-negative staphylococci, non-CNS), 68 clinically documented infections (CDI, 35%; 39 deep-seated), and 61 fever of unexplained origin (FUO, 31.5%). RESULTS: At fever onset median PCT was 190 pg/mL (range 30-26'800), without significant difference among MDI, CDI and FUO. PCT peak occurred on day 2 after onset of fever: non-CNS-MDI/deep-seated-CDI (656, 80-86350) vs. FUO (205, 33-771; p<0.001). PCT >500 pg/mL distinguished non-CNS-MDI/deep-seated-CDI from FUO with 56% sensitivity and 90% specificity. PCT was >500 pg/ml in only 10% of FUO (688, 570-771). A PCT peak >500 pg/mL (1196, 524-11950) occurred beyond 3 days of persistent fever in 17/21 (81%) invasive fungal diseases (IFD). This late PCT peak identified IFD with 81% sensitivity and 57% specificity and preceded diagnosis according to EORTC-MSG criteria in 41% of cases. In IFD responding to therapy, median days to PCT <500 pg/mL and defervescence were 5 (1-23) vs. 10 (3-22; p = 0.026), respectively. CONCLUSION: While procalcitonin is not useful for diagnosis of infection at onset of neutropenic fever, it may help to distinguish a minority of potentially severe infections among FUOs on day 2 after onset of fever. In persistent fever monitoring procalcitonin contributes to early diagnosis and follow-up of invasive mycoses.

1,3-Beta-D-glucan antigenemia for early diagnosis of invasive fungal infections in neutropenic patients with acute leukemia.

BACKGROUND: Invasive fungal infections (IFIs) are life-threatening complications in neutropenic patients with hematological malignancies. Because early diagnosis of IFI is difficult, new noninvasive, culture-independent diagnostic tools are needed to improve clinical management. Recent studies have reported that detection of 1,3-beta-D-glucan (BG) antigenemia may be useful for diagnosis of IFI. The aim of the present prospective study was to evaluate the usefulness of monitoring BG in patients undergoing chemotherapy for acute leukemia. METHODS: BG antigenemia was measured by a colorimetric assay twice weekly in the absence of fever and daily in the presence of fever. IFIs were classified according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. RESULTS: During 190 consecutive neutropenic episodes (median duration, 22 days; range, 7-113 days) in 95 patients, 30 proven or probable IFIs (13 aspergillosis, 15 candidiasis, and 2 mixed IFIs) were diagnosed. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of 2 consecutive BG values > or =7 pg/mL for diagnosis of proven or probable IFI was 0.63 (95% confidence interval, 0.44-0.79), 0.96 (95% confidence interval, 0.89-0.98), 0.79 (95% confidence interval, 0.57-0.92), 0.91 (95% confidence interval, 0.84-0.95), and 0.89, respectively. The time interval between onset of fever as first sign of IFI and BG antigenemia was significantly shorter than the time to diagnosis of IFI by clinical, microbiological, radiological, and/or histopathological criteria (P < .001). BG values >50 pg/mL were observed in only 2 patients, both of whom experienced failure of antifungal therapy. CONCLUSION: Monitoring of BG antigenemia is a useful noninvasive method for early diagnosis of IFI in patients with acute leukemia.

Macrophage migration inhibitory factor (MIF) in meningococcal septic shock and experimental human endotoxemia.

Macrophage migration inhibitory factor (MIF) is a mediator of innate immunity and important in the pathogenesis of septic shock. Lipopolysaccharide (LPS) and tumor necrosis factor (TNF) alpha are reported to be inducers of MIF. We studied MIF and cytokines in vivo in patients with meningococcal disease, in human experimental endotoxemia, and in whole blood cultures using a newly developed sensitive and specific enzyme-linked immunosorbent assay. Twenty patients with meningococcal disease were investigated. For the human endotoxemia model, 8 healthy volunteers were intravenously injected with 2 ng/kg Escherichia coli LPS. Whole blood from healthy volunteers was incubated with LPS or heat-killed meningococci. Macrophage migration inhibitory factor concentration in blood was increased during meningococcal disease and highest in the patients presenting with shock compared with patients without shock. Plasma concentration of MIF correlated with disease severity, the presence of shock and with the cytokines interleukin (IL) 1beta, IL-10, IL-12, and vascular endothelial growth factor, but not with TNF-alpha. MIF was not detected in blood in experimental endotoxemia, nor after stimulation of whole blood with LPS or meningococci, although high levels of TNF-alpha were seen in both models. In conclusion, MIF is increased in patients with meningococcal disease and highest in the presence of shock. Macrophage migration inhibitory factor cannot be detected in a human endotoxemia model and is not produced by whole blood cells incubated with LPS or meningococci.

Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis.

BACKGROUND: Identification of new therapeutic targets remains an imperative goal to improve the morbidity and mortality associated with severe sepsis and septic shock. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, has recently emerged as a critical mediator of innate immunity and experimental sepsis, and it is an attractive new target for the treatment of sepsis. METHODS: Circulating concentrations of MIF were measured in 2 clinical trial cohorts of 145 pediatric and adult patients who had severe sepsis or septic shock caused predominantly by infection with Neisseria meningitidis or other gram-negative bacteria, to study the kinetics of MIF during sepsis, to analyze the interplay between MIF and other mediators of sepsis or stress hormones (adrenocorticotropic hormone and cortisol), and to determine whether MIF is associated with patient outcome. RESULTS: Circulating concentrations of MIF were markedly elevated in 96% of children and adults who had severe sepsis or septic shock, and they remained elevated for several days. MIF levels were correlated with sepsis severity scores, presence of shock, disseminated intravascular coagulation, urine output, blood pH, and lactate and cytokine levels. High levels of MIF were associated with a rapidly fatal outcome. Moreover, in meningococcal sepsis, concentrations of MIF were positively correlated with adrenocorticotropic hormone levels and negatively correlated with cortisol levels and the cortisol:adrenocorticotropic hormone ratio, suggesting an inappropriate adrenal response to sepsis. CONCLUSIONS: MIF is markedly and persistently up-regulated in children and adults with gram-negative sepsis and is associated with parameters of disease severity, with dysregulated pituitary-adrenal function in meningococcal sepsis, and with early death.