Blood Gene Expression Profiles for Early Identification of Sepsis in Children with Cancer and Episodes of Fever and Neutropenia

Abstract

Invasive bacterial infections are a leading cause of mortality in children with cancer and febrile neutropenia (FN). Clinical tools have been developed to predict sepsis in this population but the added value of comprehensive biomarkers such as RNA expression profiling remains unclear. This study aimed to determine the utility of transcriptome profiling for early sepsis identification in children with cancer and FN. Prospective, multicenter study conducted over three years in 6 hospitals in Chile in which children ≤ 18 years with cancer and FN were enrolled within 2 hours of fever onset, and blood samples obtained for blood culture and RNA expression profile analyses. Healthy age-matched controls (HC) were enrolled in parallel. A validated clinical scoring system was used to classify children in low and high-risk. Gene expression data was analyzed using linear regression and differential expressed genes were obtained with adjusted p-value < 0.05 and fold change > 2 in R environment. Modular analysis and quantitative gene set enrichment were used to identify pathways and network differences between groups. Data from 137 episodes of FN and in 34 healthy controls were analyzed. Median age was 8 (IQR: 6-12) years and 68 (50%) were male. The underlying diseases included hematological malignancies in 99 (72.3%) and solid tumor in 38 (27.7%) children. Of the137 episodes, 43 were classified as low risk -- and most (n=39; 91%) had a respiratory virus identified--, and 94 episodes were classified as high-risk. Of the high-risk episodes 22 developed sepsis, 20 of which had a positive blood culture. Pairwise comparisons identified 791significantly expressed genes between low-risk children and HC, while 991 genes were identified between children with sepsis and HC (Fig 1 A-B). The proportion of underexpressed genes was higher in children with sepsis (~70%) than in the low-risk group (~50%). Further, modular pathway analysis showed underexpression of inflammation, T and B-cell genes irrespective of the clinical classification, while interferon, monocyte, and neutrophil genes were overexpressed in the low-risk group but underexpressed in children with sepsis (Fig 1C). This study highlights the potential value of blood gene expression profiling for classifying children with cancer and FN according to their clinical risk classification. It also provides a deeper understanding of the pathways that are activated or suppressed in sepsis in this population.