Circulating markers of inflammation and infection as adjuncts to a clinical scoring system in predicting outcome in cancer patients with febrile neutropenia

Abstract

Infections remain the major cause of serious complications in cancer patients. Cancer patients receiving chemotherapy often develop febrile neutropenia and are at high risk for development of bacterial or fungal infections, which are the major cause of morbidity and mortality in these patients, with an overall in-hospital mortality rate of 9.5% in the USA. Febrile neutropenia is a life- threatening complication which can lead to septic shock and death, but the majority of patients can survive provided they receive appropriate management. Immediate hospitalisation with rapid administration of broad-spectrum antimicrobial agents is the standard management for these patients. However, in neutropenic patients, fever can be caused not only by infection, but also by non-infective causes. In this setting, there is a critical requirement for the development of strategies, such as the Talcott system and Multinational Association of Supportive Care in Cancer (MASCC) risk-index score, which enable early identification of patients at high risk for serious infective complications. The laboratory research presented in this dissertation was designed to: i) to compare the performance of a conventional ELISA procedure with the highly sensitive Bio-Plex® Suspension Bead Array System using a limited group of cytokines, namely IL-1β, IL-6 and IL-8; and ii) identify host-derived, systemic markers of inflammation or infection ( CRP, SAA, PCT, sTREM-1, HMGB-1, IL-1α, IL-1β, IL-6, IL-7, IL-8, IL-12, INF-γ, TNF, G-CSF, GM-CSF, and VEGF) which, either individually or in combination, can be used to distinguish between infective and non-infective causes of pyrexia in cancer patients, as well as to predict outcome in patients with chemotherapy-induced neutropenia. To fulfil these objectives, unthawed serum specimens from 48 patients recruited to an earlier study (Uys et al, 2007) were analysed. All patients had a histologically confirmed malignancy and had presented with febrile neutropenia, either with an oral temperature of >39°C in a single measurement, or > 38°C on two occasions within a 24 hour period lasting at least one hour, together with an absolute neutrophil count of ≤ 0.5 x 109 /L as a result of chemotherapy. The original study was approved by Ethics Committee of the University of Pretoria in November 2000, while approval for performance of the additional assay on the stored serum specimens as an extension of the original study was granted by the same committee in February 2010. Informed consent was obtained from all patients prior to enrolment in the original study. The results demonstrated that the Bio-Plex® Suspension Bead Array System and the conventional ELISA are well correlated, although the former has greater sensitivity. With respect to the second component of the study, all of the biomarkers tested were elevated in patients with FN. When these patients were classified into those at low- and high- risk for development of complications, (using clinical scores), IL-6, PCT and sTREM-1 demonstrated the best discriminatory potential. The sensitivity, specificity, positive predictive value (PPV), likelihood ratios and area under the ROC curve of each of these biomarkers was evaluated with respect to prediction of response to empiric antimicrobial therapy, resolution without complications, development of serious complications, and mortality. Soluble TREM-1, and to a lesser extent PCT, but not IL-6, predicted each of these events with reasonable accuracy, particularly with respect to the development of serious complications or death. Soluble TREM-1 and PCT, individually or in combination, hold promise as objective biomarkers which could be used to complement clinical prediction-making process in patients presenting with febrile neutropenia.