Rhinovirus-Induced Cytokine Alterations With Potential Implications in Asthma Exacerbations: A Systematic Review and Meta-Analysis

Abstract

Background: Rhinovirus (RV) infections are a major cause of asthma exacerbations. Unlike other respiratory viruses, RV causes minimal cytotoxic effects on airway epithelial cells and cytokines play a critical role in its pathogenesis. However, previous findings on RV-induced cytokine responses were largely inconsistent. Thus, this study sought to identify the cytokine/chemokine profiles induced by RV infection and their correlations with airway inflammatory responses and/or respiratory symptoms using systematic review, and to determine whether a quantitative difference exists in cytokine levels between asthmatic and healthy individuals via meta-analysis.

Methods: Relevant articles were obtained from PubMed, Scopus, and ScienceDirect databases. Studies that compared RV-induced cytokine responses between asthmatic and healthy individuals were included in the systematic review, and their findings were categorized based on the study designs, which were ex vivo primary bronchial epithelial cells (PBECs), ex vivo peripheral blood mononuclear cells (PBMCs), and human experimental studies. Data on cytokine levels were also extracted and analyzed using Review Manager 5.4.

Results: Thirty-four articles were included in the systematic review, with 18 of these further subjected to meta-analysis. Several studies reported the correlations between the levels of cytokines, such as IL-8, IL-4, IL-5, and IL-13, and respiratory symptoms. Evidence suggests that IL-25 and IL-33 may be the cytokines that promote type 2 inflammation in asthmatics after RV infection. Besides that, a meta-analysis revealed that PBECs from children with atopic asthma produced significantly lower levels of IFN-β [Effect size (ES): -0.84, p = 0.030] and IFN-λ (ES: -1.00, p = 0.002), and PBECs from adult atopic asthmatics produced significantly lower levels of IFN-β (ES: -0.68, p = 0.009), compared to healthy subjects after RV infection. A trend towards a deficient production of IFN-γ (ES: -0.56, p = 0.060) in PBMCs from adult atopic asthmatics was observed. In lower airways, asthmatics also had significantly lower baseline IL-15 (ES: -0.69, p = 0.020) levels.

Conclusion: Overall, RV-induced asthma exacerbations are potentially caused by an imbalance between Th1 and Th2 cytokines, which may be contributed by defective innate immune responses at cellular levels. Exogenous IFNs delivery may be beneficial as a prophylactic approach for RV-induced asthma exacerbations.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=184119, identifier CRD42020184119.

Keywords: asthma; chemokine; cytokine; exacerbation; interferon; meta-analysis; rhinovirus; systematic review.

Figure 1

Flowchart showing the selection process of articles according to the PRISMA Statement. From the initial 1794 non-redundant articles, 34 articles reporting RV-induced cytokine responses in asthmatic and healthy individuals were included in the systematic review, with 18 of these further subjected to meta-analysis.

Figure 2

Forest plots of (A) IFN-β and (B) IFN-λ for ex vivo PBECs studies comparing adults with atopic asthma vs non-atopic healthy controls. (A) PBECs from adults with atopic asthma produced significantly lower levels of IFN-β (ES: -0.68, p = 0.009) than non-atopic healthy subjects after RV infection. (B) PBECs from adults with atopic asthma also produced lower levels of IFN-λ (ES: -1.13) compared to non-atopic healthy subjects after RV infection; however, the difference was not statistically significant (p = 0.230).

Figure 3

Forest plots of (A) IFN-β and (B) IFN-λ for ex vivo PBECs studies comparing children with atopic asthma vs non-atopic healthy controls. PBECs from children with atopic asthma produced significantly lower levels of (A) IFN-β (ES: -0.84, p = 0.030) and (B) IFN-λ (ES: -1.00, p = 0.002) compared to non-atopic healthy children after RV infection.

Figure 4

Forest plot of IFN-γ for ex vivo PBMCs studies comparing adults with atopic asthma vs non-atopic healthy controls. PBMCs from adults with atopic asthma produced lower levels of IFN-γ (ES: -0.56) compared with healthy adults after RV infection, and it was close to reaching statistical significance (p = 0.060).

Figure 5

Forest plot of (A) baseline and (B) post-infection IL-15 for adult atopic asthmatics vs non-atopic healthy adults experimentally infected with RV. (A) Atopic asthmatics had significantly lower levels of bronchial IL-15 at baseline compared to non-atopic healthy individuals (ES: - 0.69, p = 0.020). (B) Atopic asthmatics also had lower levels of bronchial IL-15 following experimental inoculation with RV compared to non-atopic healthy individuals (ES: -0.53), but the difference was not statistically significant (p = 0.640).

Figure 6

Forest plot of (A) baseline and (B) post-infection IL-8 for adult atopic asthmatics vs non-atopic healthy adults experimentally infected with RV. (A) At baseline, there was no significant difference in bronchial IL-8 levels between atopic asthmatics and non-atopic healthy adults. (B) After experimental RV infection, atopic asthmatics had higher levels of bronchial IL-8 (ES: 0.58) compared to non-atopic healthy individuals, and it was close to reaching statistical significance (p = 0.060).