Intensive serial biomarker profiling for the prediction of neutropenic Fever in patients with hematologic malignancies undergoing chemotherapy: a pilot study

Abstract

Neutropenic fever (NF) is a life-threatening complication of myelosuppressive chemotherapy in patients with hematologic malignancies and triggers the administration of broad-spectrum antimicrobials. The ability to accurately predict NF would permit initiation of antimicrobials earlier in the course of infection with the goal of decreasing morbid complications and progression to septic shock and death. Changes in the blood level of inflammatory biomarkers may precede the occurrence of NF. To identify potential biomarkers for the prediction of NF, we performed serial measurements of nine biomarkers [C-reactive protein (CRP), protein C, interleukin (IL)-6, IL-8, IL-10, IL-1β, tumor necrosis factor-α, monocyte chemotactic protein-1, and intercellular adhesion molecule-1] using a multiplex ELISA array platform every 6-8 hours in patients undergoing myelosuppressive chemotherapy for hematologic malignancies. We found that the blood levels of IL-6 and CRP increased significantly 24 to 48 hours prior to the onset of fever. In addition, we showed that frequent biomarker monitoring is feasible using a bedside micro sample test device. The results of this pilot study suggest that serial monitoring of IL-6 and CRP levels using a bedside device may be useful in the prediction of NF. Prospective studies involving a larger cohort of patients to validate this observation are warranted. This trial is registered at ClinicalTrials.gov (NCT01144793).

Keywords: C-reactive protein; acute leukemia; interleukin-6; neutropenic fever.

Conflict of interest statement

Conflict of interests: the authors have no potential conflict of interests to disclose. This pilot study was a collaboration between Stanford University School of Medicine/Stanford Cancer Institute and Theranos, Inc, and no funding was received from Theranos for its implementation or conduct.

Figures

Figure 1.

Scatter plots of the proximal and distal fold-changes for each biomarker. Each point represents data from an individual patient. The mean value (horizontal line) is shown. *P

Figure 2.

Time course of body temperature, interleukin (IL)-6 and C-reactive protein (CRP) levels. Data are shown starting from the time of baseline measurement (5-7 days prior to fever onset) to the time of fever. Day 0 corresponds to the day of study enrollment. Red arrow indicates the time of fever. Black arrow indicates the time when the fold-change cut-off is crossed. The number under the green line refers to the time difference in days between these two values. The dotted horizontal lines in the IL-6 and CRP graphs indicate the baseline Searchlight measurements prior to onset of fever. Refer to Results and Discussion for details.

Figure 3.

Plot of C-reactive protein levels measured using the Searchlight assay versus the Theranos micro sample test. Each data point represents an individual blood sample collected from one of the six fully evaluable patients in this study. The Pearson’s correlation coefficient (r) is shown.