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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.

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We compared biomarkers and their changes as predictors for bacteremia and severe sepsis during neutropenic fever after intensive chemotherapy in hematological patients. Serum C-reactive protein (CRP), semi-quantative procalcitonin, aminoterminal pro-brain natriuretic peptide (NT-proBNP), cortisol, lactate, plasma antithrombin and fibrinogen were measured daily from day 0 to day 3/day 4 in 89 neutropenic fever episodes of 65 hematological patients. The best predictors for bacteremia and gram-negative bacteremia were procalcitonin and its change, with odds ratios (ORs) and 95% confidence intervals of 2.63 (1.56-4.44) and 3.20 (1.77-5.80) for bacteremia and 4.14 (2.00-8.58) and 5.04 (2.18-11.63) for gram-negative bacteremia, respectively. For severe sepsis, the best predictors were CRP and fibrinogen, with ORs of 1.94 (1.07-3.52) and 1.92 (1.05-3.54). Factor analysis provided two predictive factors: procalcitonin-NT-proBNP-antithrombin factor predicted gram-negative bacteremia and CRP-fibrinogen predicted severe sepsis. Applying a combination of markers reflecting different aspects of infection might improve the recognition of risk for complications in patients with neutropenic fever.

There are no data on serum cortisol of hematological patients at the onset of neutropenic fever and its possible association with the severity of infection. The purpose of this study was to evaluate the association of serum cortisol with the level of C-reactive protein (CRP) and procalcitonin (PCT), widely used markers of infection and inflammation, and with the development of severe sepsis in this patient group. All clinical data were collected prospectively at the hematology ward of Kuopio University Hospital. Altogether, 69 hematological patients with 93 periods of neutropenic fever were included. Nineteen patients received therapy for acute myeloid leukemia, and 50 patients were autologous stem cell transplantation recipients. Each period of neutropenic fever was classified as severe sepsis or not. Serum cortisol, CRP, and PCT were determined at the onset of fever on day 0 and then at 8-9 a.m. on days 1-4. Level of serum cortisol correlated positively with maximal CRP level during days 0 to 4 in neutropenic fever periods without severe sepsis, but no correlation was observed in fever periods with severe sepsis. To conclude, the level of cortisol correlated with the severity of infection measured as maximal CRP or elevated PCT in fever periods without severe sepsis, but in fever periods with severe sepsis, the cortisol response was attenuated.

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., (© 2011 John Wiley & Sons A/S.)

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.).

Objective: To compare semi-quantitative procalcitonin with C-reactive protein in predicting bacteraemia in haematological patients with neutropenic fever., Methods: A total of 77 patients treated with intensive chemotherapy for haematological malignancy at Kuopio University Hospital were candidates for study entry. Eleven of these patients did not fulfil the criteria for neutropenic fever, and 66 patients were finally included. Nineteen patients had acute myeloid leukaemia and 47 had received high-dose chemotherapy supported by autologous stem cell transplant. Ninety neutropenic fever episodes in these 66 patients fulfilled the study entry criteria, with microbiological cultures, procalcitonin and C-reactive protein measurements available. Serum procalcitonin and C-reactive protein were analyzed at the onset of each neutropenic fever episode on day 0, and then daily from days 1 to 4., Results: Bacteraemia was observed in 21 episodes (23%) and the criteria for severe sepsis were fulfilled in 13 episodes (14%). Half of the bacteraemic episodes were caused by Gram-negative bacteria. The kinetics of procalcitonin and C-reactive protein were similar, with increasing levels for 2 to 4 days after the onset of fever. The procalcitonin level on days 1, 2, 3 and 4 was associated with bacteraemia and Gram-negative bacteraemia, but not with the development of severe sepsis. On day 1, a procalcitonin level above 0.5 ng/ml had a sensitivity of 57% and 70% and specificity of 81% and 77% to predict bacteraemia and Gram-negative bacteraemia, respectively., Conclusions: An elevated level of procalcitonin within 24 h after the onset of neutropenic fever predicts bacteraemia and Gram-negative bacteraemia in haematological patients.

Serum amino-terminal pro-brain natriuretic peptide (NT-proBNP) is considered as a prognostic marker in patients with severe sepsis or septic shock, but no data are available on NT-proBNP kinetics in hematological patients with neutropenic fever. Altogether 70 hematological patients with neutropenic fever were included in this prospective study. NT-proBNP and C-reactive protein (CRP) were determined at the beginning of the neutropenic fever (d0) and then daily up to 3-4 days. The median NT-proBNP (interquartile range) increased from 127 (57-393) ng/L on d0 to 542 (194-1385) ng/L on d4. The increment of CRP was from 35 (17-61) mg/L on d0 to 109 (56-109) mg/L on d2. Neither serial NT-proBNP nor CRP predicted development of severe sepsis, but NT-proBNP was significantly higher in patients with previous cardiovascular disease than in those without. NT-proBNP seemed to reflect cardiac distress, but it did not help to predict the development of severe sepsis in this patient group.

Objectives: Vascular endothelial growth factor (VEGF) is considered to be of importance in patients with sepsis. No data are available on VEGF kinetics in haematological patients with neutropenic fever., Methods: Forty-two haematological patients were included into this prospective study. Median age was 57 yr (range 18-70). Fifteen patients received therapy for acute myeloid leukaemia and 27 patients received autologous stem cell transplantation for haematological malignancy. Laboratory samples for the determination of C-reactive protein (CRP) and VEGF were collected at the start of fever (d0) and then daily., Results: The median serum VEGF concentrations were low in all study patients. In patients with severe sepsis (n = 5) the median VEGF on d0 was higher than in septic patients without signs of hypoperfusion or hypotension (n = 37) (77 pg/mL vs. 52 pg/mL, P = 0.061). Also on d1 the median VEGF concentration was higher in patients with severe sepsis (82 pg/mL vs. 56 pg/mL, P = 0.048). There were no statistically significant differences in CRP values on any day during the study period between patients with severe sepsis and those without. Time from d0 to the peak VEGF concentration (mean 1.02, SE 0.18 d) was shorter than that to the peak CRP concentration (mean 1.93, SE 0.15 d) (P = 0.002)., Conclusion: Compared to CRP, serum VEGF was a more rapid indicator for sepsis in our haematological patients with neutropenic fever. Those with severe sepsis had higher VEGF concentrations than those without on d0 and d1 after the onset of fever. Further studies on VEGF are warranted in haematological patients.

The objective of this study was to evaluate etiology and consequences of neutropenic fever in AML patients. Two hundred and ninety neutropenic periods following chemotherapy in 84 AML patients were retrospectively evaluated. Neutropenic fever was found in 280 periods (97%). Severe sepsis developed in 35 occasions (13%) and 9 patients (11%) died due to severe sepsis. In 165 episodes with neutropenic fever (59%), the potential causative organism was found in blood cultures. Gram-negative bacteria were more commonly found in patients who developed severe sepsis (40% vs. 23%, p = 0.03). CRP after 2 - 3 days from start with fever was higher in patients with severe sepsis (190 mg/L vs. 96 mg/L, p < 0.001) but the rise in CRP rather coincided than preceded with the development of severe sepsis. Severe sepsis is associated with significant mortality in AML patients. Earlier methods than CRP are needed to predict development of severe sepsis.

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. [ABSTRACT FROM AUTHOR]

Objective. Elevated levels of a cell surface glycoprotein, soluble cluster of differentiation 14 (sCD14), have been observed in patients with sepsis. Only scarce data are available on sCD14 in hematological patients with chemotherapy-induced febrile neutropenia. The study aim was to investigate sCD14 as an early biomarker in febrile neutropenia after intensive chemotherapy to detect a rapidly deteriorating clinical course early enough to avoid serious infectious complications. Patients and Methods. This prospective study included 87 adult hematological patients at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The study endpoints were septic shock, severe sepsis, and positive blood culture findings. sCD14 was analyzed from day 0 to day 2, and its prognostic capacity was compared to that of C-reactive protein and procalcitonin. Results. Plasma level of sCD14 predicted the development of septic shock on day 1 (p=0.001) and day 2 but not the development of severe sepsis or blood culture positivity in hematological patients with chemotherapy-induced febrile neutropenia. Conclusions. Soluble CD14 did not predict an overall complicated course at the early stages of febrile neutropenia. However, it was helpful in predicting the progression of the clinical course of neutropenic fever to septic shock. [ABSTRACT FROM AUTHOR]

Asymmetric dimethylarginine (ADMA) has been recognized as an independent prognostic factor for sepsis mortality in intensive care units. No data are available on kinetics or prognostic value of ADMA in hematological patients. We evaluated the ability of ADMA to act as a predictor for complicated course of febrile neutropenia, defined as bacteremia and/or septic shock in adult hematological patients receiving intensive chemotherapy. This prospective study included 87 adult hematological patients with febrile neutropenia after an intensive chemotherapy for acute myeloid leukemia (AML) or after an autologous stem cell transplantation (ASCT). Plasma ADMA and serum C-reactive protein (CRP) levels were measured from the onset of fever (d0) and for 2 days (d1–d2) thereafter. The levels of ADMA were stable or had only minimal changes during the study period. There was no difference between the levels at any time-point in patients having complicated course compared to those without it. On the other hand, CRP levels were significantly higher on d1 (p = 0.016) in patients with bacteremia and/or septic shock than in those without. ADMA was not able to differentiate hematological patients with a complicated course from those without complications. Elevated ADMA levels are probably associated with organ dysfunction, which is rare in this group of patients, of whom about 95% can be successfully managed at the hematology ward. [ABSTRACT FROM PUBLISHER]

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 fi rst 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. [ABSTRACT FROM AUTHOR]

Elevated plasma lactate and impaired lactate clearance have been associated with poor outcome in patients with severe sepsis. No data are available on the kinetics or prognostic value of plasma lactate in haematological patients with neutropenic fever. A total of 70 haematological patients with 94 episodes of neutropenic fever were included into this prospective study during the period 2006–2008. The median age of the patients was 56 (range 18–70) y. Nineteen patients received therapy for acute myeloid leukaemia and 51 patients received autologous stem cell transplantation. At the onset and on days 1, 2, and 3 of each neutropenic fever episode, plasma lactate and serum C-reactive protein were determined. Criteria for severe sepsis were fulfilled in 13 neutropenic episodes. An elevated plasma lactate level was infrequent at the start of neutropenic fever (5%). There was no association of lactate level with the development of severe sepsis. Two patients died of septic shock, 1 patient with an exceptionally high and increasing level of lactate and the other patient with a normal lactate level. An elevated plasma lactate level at the start of neutropenic fever is not common and does not indicate severe sepsis, but high lactate and an impaired lactate decrease may signify a fatal course in neutropenic fever. [ABSTRACT FROM AUTHOR]