Nasal interferon responses to community rhinovirus infections are similar in controls and children with asthma

Abstract

Background: Rhinovirus (RV) is the main cause of asthma exacerbations in children. Some studies reported that persons with asthma have attenuated interferon (IFN) responses to experimental RV infection compared with healthy individuals. However, responses to community-acquired RV infections in controls and children with asthma have not been compared.

Objective: To evaluate nasal cytokine responses after natural RV infections in people with asthma and healthy children.

Methods: We compared nasal cytokine expression among controls and children with asthma during healthy, virus-negative surveillance weeks and self-reported RV-positive sick weeks. A total of 14 controls and 21 patients with asthma were studied. Asthma disease severity was based on symptoms and medication use. Viral genome was detected by multiplex polymerase chain reaction. Nasal cytokine protein levels were determined by multiplex assays.

Results: Two out of 47 surveillance weeks tested positive for RV, illustrating an asymptomatic infection rate of 5%. A total of 38 of 47 sick weeks (81%) tested positive for the respiratory virus. Of these, 33 (87%) were positive for RV. During well weeks, nasal interleukin 8 (IL-8), IL-12, and IL-1β levels were higher in children with asthma than controls. Compared with healthy virus-negative surveillance weeks, IL-8, IL-13, and interferon beta increased during colds only in patients with asthma. In both controls and children with asthma, the nasal levels of interferon gamma, interferon lambda-1, IL-1β, IL-8, and IL-10 increased during RV-positive sick weeks. During RV infection, IL-8, IL-1β, and tumor necrosis factor-α levels were strongly correlated.

Conclusion: In both controls and patients with asthma, natural RV infection results in robust type II and III IFN responses.

Figure 1.

Histograms illustrating the monthly distribution of samples collected for well surveillance weeks (left panel) and self-reported sick weeks (right panel). RV-positive samples are shaded in gray. HCoV, human coronavirus; RSV, respiratory syncytial virus; RV, rhinovirus.

Figure 2.

Nasal fluid cytokine levels. Nasal fluid cytokine levels in controls and in children with asthma during well surveillance periods and RV-positive sick periods. RNA was tested for the virus using the Novaplex II RV16 Detection kit (Seegene, Walnut Creek, California). Cytokines were measured using Meso Scale Diagnostics multiplex biomarker assay kits and Meso Sector S600 reader (Rockville, Maryland) or Research and Development Luminex multiplex assays. Medians and interquartile range are illustrated. The asterisk indicates P <.05, Wilcoxon’s matched-pairs signed-rank test (for paired comparisons between well and RV samples), Mann-Whitney U test (for comparisons between controls and patients with asthma) or χ² Wilcoxon rank-sum test (for IL-13). One-way nonparametric analysis of variance (Kruskal-Wallis test) followed by the 2-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli to correct for multiple comparisons. IFN, interferon; IL, interleukin; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin.

Figure 3.

Relationship between asthma severity and nasal IFN levels. Nasal IFN-λ1 and IFN-γ levels during RV-positive sick periods in children with asthma according to asthma severity. Asthma severity was determined according to Asthma Expert Panel Report 3 and physician assessment. Sensitization to specific allergens was determined either by prick skin testing or serum fluorescence enzyme immunoassay. During the course of asthma management, immunoglobulin E levels were measured for 3 patients with moderate-to-severe persistent asthma. Abbreviation: IFN-γ, interferon gamma; IFN-λ1, interferon lambda 1; RV, Rhinovirus.

Figure 4.

Relationships between nasal fluid cytokine levels. Nasal fluid cytokine levels in controls and children with asthma during RV-positive sick periods. IL, interleukin; TNF, tumor necrosis factor.