Inflammatory Cytokine Profile Discriminates Invasive Pulmonary Fungal Infections From Bacterial Infections In Pediatric Hematology/Oncology Patients

Introduction:In recent years, due to the application of high-dose chemotherapy, immunosuppressants, corticosteroids, broad-spectrum antibiotics and stem cell transplantation techniques, the incidence of invasive fungal disease (IFD) greatly increased, with high mortality. Now common laboratory tests of fungal infections include the fungal culture and microbiological examination, the plasma (1,3)-β-D-glucan test(G test),the galactomannan test(GM test), fungal-specific nucleic acid detection and cryptococcus capsular antigen test. Howeve, all these tests have shortcomings, either low positive rate or poor sensitivity and specificity. There have been great efforts therefore to develop new surrogate markers for the diagnosis of IFD. Our previous studies showed that inflammatory cytokine profile plays an important role in diagnosis of bacterial infection, also was a helpful adjuvant approach for early and quick discrimination of gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Now we evaluated the quantification of inflammatory cytokines to assess its ability in discriminating invasive pulmonary fungal infections from bacterial infections. Study design:Retrospective studies.Methods:This study was performed at the Division of Hematology/Oncology, the Children’s Hospital of Zhejiang University School of Medicine in China, from December2012to February2013. Patients hospitalized in the department of hematology with invasive pulmonary fungal infections (IPFD) and bacterial infections were enrolled in this study. The healthy control samples were from children at the time of preoperative examination. Inflammatory cytokine levels, high-sensitivity C-reactive protein (hsCRP) and Procalcitonin (PCT) were measured.Results:A total of165cases of patients were enrolled, which were divided into IPFD group (n=56), pulmonary bacterial infection group (n=53) and control group (n=56), respectively.Three groups of patients showed no significantly difference in terms of age and gender. The median levels of hsCRP in three groups were23.5mg/L (1.0-160.0mg/L),82.5mg/L (7.0-160.0mg/L) and1.0mg/L (1.0-29.0mg/L), respectively. The levels of hsCRP in IPFD group, pulmonary bacterial infection group were significantly higher than that in healthy children (Both P values were0.000). The PCT levels in three groups were0.176ng/ml (0.038-3.270ng/ml),0.514ng/ml (0.053-7.060ng/ml), respectively. To compare with pulmonary bacterial infection patients, the level of PCT in IPFD patients decreased (P=0.000). IL-6, IFN-y levels in IPFD group were much higher than those in control group (median levels:IL-6,151.6pg/ml vs.2.5pg/ml, P=0.000; IL-10,21.0pg/ml vs.3.9pg/ml, P=0.000; IFN-γ,15.4pg/ml vs.4.6pg/ml, P=0.000, respectively). Meanwhile, to compare with control group, the levels of IL-6, IL-10and IFN-y were significantly higher in pulmonary bacterial infections group (median levels: IL-6,151.6pg/ml vs.2.5pg/ml, P=0.000; IL-10,21.0pg/ml vs.3.9pg/ml, P=0.000; IFN-γ,15.4pg/ml vs.4.6pg/ml, P=0.000, respectively). The IL-6and IL-10levels in pulmonary bacterial infection group showed sifnificantly higher than those in IPFD group (P=0.000).IL-10level in GPB was significantly elevated than that in IPFD group (median level:22.3pg/ml vs.5.3pg/ml, P=0.013). However, IL-6, IL-10and TNF-α levels in GNB increased significantly than those in IPFD group (median levels:IL-6,276.5pg/ml vs.37.0pg/ml, P=0.000; IL-10,16.4pg/ml vs.5.3pg/ml, P=0.000; TNF-α,2.7pg/ml vs.2.0pg/ml, P=0.010).The median levels of hsCRP, IL-6, IFN-γ in IPFD group before antifungal therapy were23.5mg/L,37.0pg/ml and11.4pg/ml, respectively, and returned to5.0mg/L,12.8pg/ml and9.0pg/ml, respectively, after infection was controlled. The median levels of PCT, hsCRP, IL-6, IL-10and IFN-γ in patients with pulmonary bacterial infections after antibiotic therapy decreased significantly (IL-6,151.6pg/ml vs.32.3pg/ml, P=0.000; IL-10,21.0pg/ml vs.4.9pg/ml, p=0.000; IFN-γ,15.4pg/ml vs.8.0pg/ml,P=0.001, respectively).There was correlation between PCT and IL-10(r=0.279, P=0.005). IL-4, IL-6and IL-10were related to hsCRP (r=0.235,0.319,0.376, P=0.002,0.000,0.000, respectively).The AUCs of IL-6and IL-10levels were0.783(P=0.000) and0.739(P=0.000), indicating IL-6was the most effective biomarker for predicting IPFD.Conclusion:Inflammatory cytokine profile was helpful in discrimination of invasive pulmonary fungal infections from bacterial infections in pediatric hematology/oncology patients. IL-6was the most useful biomark for fungal infection predication.