Cytokine expression in rhinovirus- vs. respiratory syncytial virus-induced first wheezing episode and its relation to clinical course

Abstract

Rhinovirus (RV) and respiratory syncytial virus (RSV) are common causes of bronchiolitis. Unlike an RSV etiology, an RV etiology is associated with a markedly increased risk of asthma. We investigated the cytokine profiles of RV- and RSV-induced first wheezing episode and their correlation with prognosis. We recruited 52 sole RV- and 11 sole RSV-affected children with a severe first wheezing episode. Peripheral blood mononuclear cells (PBMCs) were isolated during acute illness and 2 weeks later and stimulated in vitro with anti-CD3/anti-CD28. Culture medium samples were analyzed for 56 different cytokines by multiplex ELISA. Recurrences were prospectively followed for 4 years. In adjusted analyses, the cytokine response from PBMCs in the RV group was characterized by decreased expression of interleukin 1 receptor antagonist (IL-1RA), interleukin 1 beta (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) and increased expression of eosinophil chemotactic protein 2 (eotaxin-2), thymus- and activation-regulated chemokine (TARC), and epithelial-derived neutrophil-activating peptide 78 (ENA-78) in the acute phase and increased expression of fractalkine in the convalescent phase compared to those in the RSV group. An analysis of the change in cytokine expression between study points revealed an increased expression of fractalkine and IL-1β and decreased expression of I-309 (CCL1) and TARC in the RV group compared to those in the RSV group.. Considering hospitalization time, a significant non-adjusted group × cytokine interaction was observed in the levels of interferon gamma (IFN-γ), macrophage-derived chemokine (MDC), IL-1RA, and vascular endothelial growth factor (VEGF), indicating that a higher expression of cytokine was associated with shorter hospitalization time in the RSV group but not in the RV group. A significant interaction was also found in interleukin 6 (IL-6), but the cytokine response was not associated with hospitalization time in the RSV or RV group. In the RV group, increased expression of I-309 (CCL1) and TARC was associated with fewer relapses within 2 months, and decreased expression of interleukin 13 (IL-13) and increased expression of I-309 (CCL1) were associated with less relapses within 12 months. Differences in cytokine response from PBMCs were observed between RV- and RSV-induced first severe wheezing episode. Our findings also reveal new biomarkers for short- and medium-term prognosis in first-time wheezing children infected with RV or RSV.

Keywords: bronchiolitis; cytokine; respiratory syncytial virus; rhinovirus; wheezing.

Figure 1

Study flowchart. Patients with cytology data were included. ICU, intensive care unit; PBMC, peripheral blood mononuclear cell; RSV, respiratory syncytial virus; RV, rhinovirus.

Figure 2

Differences in cytokine expression levels at study entry and convalescent phases. Data are presented as median [the lower (Q1) and upper (Q3) quartiles, and data falling outside the Q1–Q3 range are plotted as outliers]. Cytokine concentrations are presented as pg/ml. In the difference in the cytokine expression, multiple significant differences were observed between virus groups (RV vs. RSV, all P <.05) (A–K).

Figure 3

The association between cytokine expression and recurrences at 2 and 12 months. Data are presented as median [the lower (Q1) and upper (Q3) quartiles, and data falling outside the Q1–Q3 range are plotted as outliers]. Cytokine concentrations are presented as pg/ml. Due to scarcity of the occurrence of relapses in the RSV group, only patients from the RV group were included in the analyses. In the association between cytokine expression and recurrences at 2 and 12 months, multiple significant differences were observed between virus groups (relapse vs. no-relapse, all P <.05) (A–D). An analysis of difference was excluded due to the small number of patients in the no-relapse group (n = 3). All data are shown in Supplementary Table S7 .