BACKGROUND: Histamine-releasing factor (HRF) is implicated in allergic diseases. We previously showed its pathogenic role in murine models of asthma. OBJECTIVE: To present data analysis from three separate human samples (sera samples from asthmatic patients, nasal washings from rhinovirus (RV) infected individuals and sera samples from patients with RV-induced asthma exacerbation) and one mouse sample in order to investigate correlates of HRF function in asthma and virus-induced asthma exacerbations. METHODS: Total IgE and HRF-reactive IgE/IgGs as well as HRF in sera from patients with mild/moderate (MA) or severe asthma (SA) and healthy controls (HC) were quantified by enzyme-linked immunosorbent assay (ELISA). HRF secretion in culture media from RV-infected BEAS-2B human bronchial epithelial cells and in nasal washings from experimentally RV-infected subjects was analyzed by western blotting. HRF-reactive IgE/IgG levels in longitudinal serum samples from patients with asthma exacerbations were also quantified. RESULTS: HRF-reactive IgE and total IgE were higher in SA than in HC, whereas HRF-reactive IgGs (and IgG1) were lower in asthmatics vs. HC. In comparison to HRF-reactive IgE(low) asthmatics, HRF-reactive IgE(high) asthmatics had tendency to release more tryptase and prostaglandin D(2) upon anti-IgE stimulation of bronchoalveolar lavage (BAL) cells. RV infection induced HRF secretion from BEAS-2B cells, and intranasal RV infection of human subjects induced increased HRF secretion in nasal washes. Asthmatic patients had higher levels of HRF-reactive IgE at the time of asthma exacerbations associated with RV infection, compared with those after the resolution. This phenomenon was not seen in asthma exacerbations without viral infections. CONCLUSION: HRF-reactive IgE is higher in severe asthmatics. RV infection induces HRF secretion from respiratory epithelial cells both in vitro and in vivo. These results suggest the role of HRF in asthma severity and RV-induced asthma exacerbation.