Serum caspase-cleaved cytokeratin-18 fragment as a prognostic biomarker in hematological patients with febrile neutropenia.

The study aim was to determine the benefit of the measurement of serum caspase-cleaved cytokeratin-18 (CK-18) fragment as a prognostic marker of febrile neutropenia (FN) in hematological patients. The study population consisted of 86 consecutive patients with FN who received intensive chemotherapy for hematological malignancy at the adult hematology ward of Kuopio University Hospital. Twenty-three patients (27%) had acute myeloid leukemia, and 63 patients (73%) were autologous stem cell transplant recipients. Serum caspase-cleaved CK-18 fragment M30, C-reactive protein (CRP) and procalcitonin (PCT) were measured at the onset of FN (d0), on day 1 (d1), and on day 2 (d2). Eight patients (9%) developed severe sepsis, including three patients with septic shock. Eighteen patients (21%) had a blood culture-positive infection. Serum CK-18 fragment peaked on the first day after fever onset in patients with severe sepsis. Higher CK-18 level was associated with severe sepsis, intensive care unit treatment, and fatal outcome, but not with blood culture positivity. In ROC curve analysis, d1 serum CK-18 fragment predicted severe sepsis with an area under the curve (AUC) of 0.767, CRP with an AUC of 0.764, and PCT with an AUC of 0.731. On d2, the best predictive capacity was observed for CRP with an AUC of 0.832. The optimal cutoff of caspase-cleaved CK-18 fragment M30 for predicting severe sepsis was 205 U/L on d1. In hematological patients, serum CK-18 fragment was found to be a potential prognostic marker of severe sepsis at early stages of FN.

IGF2BP3 Associates with Proliferative Phenotype and Prognostic Features in B-Cell Acute Lymphoblastic Leukemia.

The oncofetal protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) belongs to a family of RNA-binding proteins involved in localization, stability, and translational regulation of target RNAs. IGF2BP3 is used as a diagnostic and prognostic marker in several malignancies. Although the prognosis of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved, a subgroup of patients exhibits high-risk features and suffer from disease recurrence. We sought to identify additional biomarkers to improve diagnostics, and we assessed expression of IGF2BP3 in a population-based pediatric cohort of B-ALL using a tissue microarray platform. The majority of pediatric B-ALL cases were positive for IGF2BP3 immunohistochemistry and were associated with an increased proliferative phenotype and activated STAT5 signaling pathway. Two large gene expression data sets were probed for the expression of IGF2BP3-the highest levels were seen among the B-cell lymphomas of a germinal center origin and well-established (KMT2A-rearranged and ETV6-RUNX1) and novel subtypes of B-ALL (e.g., NUTM1 and ETV6-RUNX1-like). A high mRNA for IGF2BP3 was associated with a proliferative "metagene" signature and a high expression of CDK6 in B-ALL. A low expression portended inferior survival in a high-risk cohort of pediatric B-ALL. Overall, our results show that IGF2BP3 shows subtype-specificity in expression and provides prognostic utility in high-risk B-ALL.

Plasma level of interleukin-18 and complicated course of febrile neutropenia in hematological patients after intensive chemotherapy.

In search of a biomarker for complicated course of febrile neutropenia (FN), plasma IL-18 was measured in 92 hematological patients after intensive chemotherapy at the beginning of FN (days 0-3). Complicated course was defined as blood culture positivity or septic shock. IL-18 varied according to background hematological malignancy and showed an inverse correlation with leukocyte count. IL-18 was not associated with complicated course of FN, defined as blood culture positivity or septic shock, in the whole study group, but an association was observed on d1 and d2 after the onset of FN in the subgroup of autologous stem cell transplant recipients with non-Hodgkin lymphoma.

Interleukin-1 receptor antagonist as a biomarker of sepsis in neutropenic haematological patients.

OBJECTIVE: The study aim was to compare the performance of interleukin-1 receptor antagonist (IL-1Ra) to C-reactive protein (CRP) and procalcitonin (PCT) in early prediction of the clinical course of febrile neutropenia. METHODS: The study population consisted of 86 consecutive patients with febrile neutropenia who received intensive chemotherapy for haematological malignancy between November 2009 and November 2012 at the adult haematology ward of Kuopio University Hospital. Twenty-three (27%) patients had acute myeloid leukaemia and 63 (73%) patients were autologous stem cell transplant recipients. IL-1Ra, CRP and procalcitonin were measured at the onset of fever (d0), on day 1 (d1) and on day 2 (d2). RESULTS: Eight patients developed severe sepsis, including three patients with septic shock. Eighteen patients had bacteraemia. After the onset of febrile neutropenia Youden´s indices (with their 95% confidence intervals) to identify severe sepsis were for IL-1Ra on d0 0.57 (0.20-0.71) and on d1 0.65 (0.28-0.78), for CRP on d0 0.41 (0.04-0.61) and on d1 0.47 (0.11-0.67) and for PCT on d0 0.39 (0.05-0.66) and on d1 0.52 (0.18-0.76). CONCLUSIONS: In haematological patients, IL-1Ra has a comparable capacity with CRP and PCT to predict severe sepsis at the early stages of febrile neutropenia.

Changes in the microbiological epidemiology of febrile neutropenia in autologous stem cell transplant recipients.

BACKGROUND: The aim of the study was to explore the incidence, microbiological etiology and outcome of febrile neutropenia among adult hematological patients following autologous stem cell transplantation (ASCT). METHODS: The study population consisted of patients who received ASCT between 1 December 2006 and 30 November 2012. The epidemiology was compared to a retrospective series covering eleven previous years at the same institution. Non-Hodgkin lymphoma (NHL) patients, who had been identified as a risk group in the retrospective study, received ciprofloxacin prophylaxis from January 2008. RESULTS: Altogether, 142 out of 178 of the included patients (80%) developed febrile neutropenia. The blood cultures were positive in 24 cases (17%). Of all bacteremia's, 88% were caused by Gram-positive and 12% by Gram-negative bacteria. The number of Gram-negative bacteremia were significantly lower in the prospective study compared to the retrospective study (3/142, 2.1% vs. 23/265, 8.7%, p = .01). Pseudomonas aeruginosa was prevalent in the retrospective series but not discovered in the present series. Enterococcus faecium was found more frequently in the prospective study (6/142, 4.2 vs. 2/265, 0.8%, p = .02). The infectious mortality among patients with febrile neutropenia was 4/142 (2.8%) in the present series and 9/265 (3.4%) in those who received ASCT in 1996-2006. CONCLUSION: Most patients who received ASCT developed febrile neutropenia and a minority had bacteraemia. In comparison to the earlier time period, the incidence of Gram-negative bacteraemias decreased, probably due to ciprofloxacin prophylaxis in NHL patients, but simultaneously the incidence of Enterococcus bacteraemias increased. Infectious mortality during febrile neutropenia was low in both series.

Biomarkers of neutropenic sepsis.

Neutropenic sepsis is a common clinical problem in hematological patients receiving intensive chemotherapy. Complications will develop in a minority of these patients. Biomarkers can be used for the recognition of infection as well as to estimate its severity and risk of complications and also to assess treatment response. Experience gained from other patient groups or sepsis patients treated in intensive care units cannot be directly extrapolated to hematological patients. Numerous biomarkers of infections have been investigated in hematological patients, but no optimal marker has been found. C-reactive protein is still the most commonly used biomarker in hematological patients, but procalcitonin may be a real challenger, although more studies are still needed.

Human plasma cell-free DNA as a predictor of infectious complications of neutropenic fever in hematological patients.

Neutropenic fever is common in patients receiving intensive chemotherapy for hematological malignancies. The clinical course may be aggravated by infectious complications like severe sepsis, septic shock or even death. We prospectively studied 100 patients with neutropenic fever and evaluated human plasma cell-free DNA (cfDNA) during the first 3 days after the onset of fever as a prognostic biomarker for complicated clinical course, defined as sepsis or septic shock. Complicated course was observed in 21 patients (21%). There were no significant differences in cfDNA levels between the patients with or without complications on any study day when all the patients were analyzed as one group. In subgroups according to hematological malignancy, patients with acute myeloid leukemia (AML) had lower cfDNA levels than patients with lymphoma. Among AML patients d0 cfDNA/leukocyte ratio and among lymphoma patients d0 cfDNA was associated with subsequent development of sepsis or septic shock. cfDNA deserves further studies in hematological patients with sepsis.

IL-10 combined with procalcitonin improves early prediction of complications of febrile neutropenia in hematological patients.

Early diagnosis of complicated course in febrile neutropenia is cumbersome due to the non-specificity of clinical and laboratory signs of severe infection. This prospective study included 100 adult hematological patients with febrile neutropenia after intensive chemotherapy at the onset of fever (d0) and for 3 days (d1-d3) thereafter. The study aim was to find early predictors for complicated course of febrile neutropenia, defined as bacteremia or septic shock. Interleukin 6 (IL-6), interleukin 10 (IL-10), procalcitonin (PCT) and C-reactive protein (CRP) all predicted complicated course of febrile neutropenia on d0, but only PCT was predictive throughout the study period. For IL-10 on d0-1 with cut-off 37 ng/L, sensitivity was 0.71, specificity 0.82, positive predictive value 0.52 and negative predictive value 0.92. For PCT on d0-1 with cut-off 0.13 µg/L, the respective measures were 0.95, 0.53, 0.36, and 0.98. For the combination of IL-10 and PCT on d0-1 with the same cut-offs, specificity improved to 0.85 and positive predictive value to 0.56. In conclusion, the present study confirms the high negative predictive value of PCT and provides new evidence for IL-10 as an early predictor for complicated course of febrile neutropenia in hematological patients. Combining IL-10 with PCT improves the early prediction for complicated course of febrile neutropenia.

Plasma copeptin in the assessment of febrile neutropenia.

Copeptin, the surrogate marker of arginine vasopressin (AVP), has been suggested to be a useful biomarker in monitoring sepsis reflecting hemodynamic imbalance and stress state. This prospective study conducted at a hematology ward in a Finnish University Hospital aimed to investigate whether plasma copeptin predicts the development of complicated course of neutropenic fever (bacteremia or need for treatment at intensive care unit) in 100 hematological patients experiencing their first neutropenic fever episode after intensive chemotherapy for hematological malignancy. Contrary to study presumptions, not elevated copeptin but the lack of a proper initial increase of plasma copeptin (<0.02 ng/mL from day 0 to day 1) predicted blood culture positive sepsis (p=0.023) and gram-negative bacteremia (p=0.045). No correlation was observed with plasma sodium, blood pressure or evaluated osmolality. Plasma copeptin correlated inversely with the same day pentraxin 3 on day 0-day 2 (all p-values <0.001) and with C-reactive protein on day 1 (p=0.015). In conclusion, copeptin did not correlate with disease severity, but the lack of a proper initial increase was associated with bacteremic complications of febrile neutropenia in hematological patients. The findings suggest the possibility of central dysregulation of AVP release and do not support the use of copeptin as a biomarker of septic complications in this patient group.

High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients.

We evaluated pentraxin 3 as a marker for complications of neutropenic fever in 100 hematologic patients receiving intensive chemotherapy. Pentraxin 3 and C-reactive protein were measured at fever onset and then daily to day 3. Bacteremia was observed in 19 patients and septic shock in 5 patients (three deaths). In comparison to C-reactive protein, pentraxin 3 achieved its maximum more rapidly. Pentraxin 3 correlated not only with the same day C-reactive protein but also with the next day C-reactive protein. High pentraxin 3 on day 0 was associated with the development of septic shock (P=0.009) and bacteremia (P=0.046). The non-survivors had constantly high pentraxin 3 levels. To conclude, pentraxin 3 is an early predictor of complications in hematologic patients with neutropenic fever. High level of pentraxin 3 predicts septic shock and bacteremia already at the onset of febrile neutropenia. (ClinicalTrials.gov Identifier: NCT00781040.).

Pentraxin 3 predicts complicated course of febrile neutropenia in haematological patients, but the decision level depends on the underlying malignancy.

OBJECTIVES: This study aimed at assessing the cut-off levels for pentraxin 3 (PTX3) in predicting complications of neutropenic fever (bacteraemia, septic shock) in haematological patients. METHODS: A prospective study during 2006-2009 was performed at haematology ward in Kuopio University Hospital. A patient was eligible for the study if having neutropenic fever after intensive therapy for acute myeloid leukaemia (AML) (n = 32) or non-Hodgkin lymphoma (NHL) (n = 35). Blood cultures were taken, and maximal PTX3 and C-reactive protein (CRP) were evaluated during d0 to d3 from the beginning of fever onset. RESULTS: The level of PTX3 was associated with both the underlying malignancy and the presence of complications, with highest level in NHL patients with complicated course of febrile neutropenia and lowest in AML patients with non-complicated course. The cut-off level of PTX3 to predict complications was ten-fold in patients with NHL (115 µg/L) in comparison with patients with AML (11.5 µg/L). In combined analysis based on separate cut-offs, PTX3 predicted complications of febrile neutropenia with sensitivity of 0.86, specificity of 0.83, positive predictive value of 0.57 and negative predictive value of 0.96. CONCLUSIONS: PTX3 was superior to CRP in predicting complicated course of febrile neutropenia, but only when the effect of the underlying malignancy had been taken into account.