The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. A randomized trial

Abstract

Rationale: Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-β. Exogenous IFN-β restores antiviral activity.

Objectives: To compare the efficacy and safety of inhaled IFN-β with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.

Methods: A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2-5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-β (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses.

Measurements and main results: A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse (mean change in six-item Asthma Control Questionnaire <0.5) and IFN-β treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset of more difficult-to-treat, Step 4-5 people with asthma (n = 27 IFN-β; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-β (P = 0.004).

Conclusions: Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-β is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the need for further, adequately powered, trials in this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).

Trial registration: ClinicalTrials.gov NCT01126177.

Keywords: innate immunity; respiratory virus; treatment.

Figures

Figure 1.

CONSORT flow diagram. ACQ = Asthma Control Questionnaire; mITT = modified intention-to-treat.

Figure 2.

Study design. During the pretreatment phase, patients responded to daily text messages inquiring about symptoms of cold. If the prespecified threshold for symptoms was reached, they visited the research unit within 24 hours to receive their first dose. Thereafter, patients received their daily treatment of IFN-β or placebo for a total of 14 days. The primary outcome, a validated shortened version of the Asthma Control Questionnaire (ACQ-6) (15), was completed during screening, before treatment began on Day 1, and 7 days later. For details of biologic samples collected, see Methods section and Table E1.

Figure 3.

Daily cold and asthma symptom scores in the modified intention-to-treat population. Symptoms (mean ± SEM) were analyzed in patients randomized to the placebo arm of the trial (n = 54–69) to avoid any effects of active treatment. (A) This showed that both cold (closed symbol) and asthma (open symbol) symptoms peaked at presentation, before treatment was initiated, and declined to baseline in a similar manner over a period of about 17 days. (B) There was a similar trend in the IFN-β group (n = 51–65). (C) At presentation there was a highly significant monotonic relationship (Spearman rank correlation = 0.48;P < 0.0001) between upper respiratory tract infection (cold) and asthma symptoms (n = 61).

Figure 4.

Effect of nebulized IFN-β on clinical outcomes. Analysis of the modified intention-to-treat population (A) showed that IFN-β treatment (n = 58) did not significantly affect the change in Asthma Control Questionnaire (ACQ-6) scores (LS mean ± SEM) at Day 8 (from treatment baseline) compared with placebo (n = 65). Further analysis of the subgroup with difficult-to-treat asthma (i.e., British Thoracic Society Step 4-5) (B) showed an increase (LS mean ± SEM) in ACQ-6 of 0.53 in the placebo group (n = 30) and a decrease of 0.10 in the IFN-β group (n = 24), a between-group difference of −0.63 (95% confidence interval [CI], −1.05 to −0.21; P= 0.004). In the whole modified intention-to-treat population, treatment with IFN-β (closed symbols) resulted in faster recovery of morning peak expiratory flow (PEF) (C), compared with placebo (open symbols) measured daily at home (P = 0.033 for area under the curve analysis; n = 56 for placebo; n = 58 for IFN-β; dashed linerepresents clinically relevant difference). This improvement was also seen in the British Thoracic Society Step 4-5 (D) subgroup of patients (P = 0.029 for area under the curve; n = 25 for placebo; n = 22 for IFN-β). Analysis of sputum (E) obtained on Day 4 from patients, in whom rhinovirus was detected in nasal lavage, showed a trend toward reduced rhinovirus load (P= 0.063) in IFN-β–treated patients (n = 9) compared with placebo (n = 14).

Figure 5.

Induction of innate immunity by IFN-β treatment. A more sustained rise (mean ± SEM) in serum concentrations of CXCL10 (A) was measured in patients treated with IFN-β (n = 58–65;closed symbols) when compared with those on placebo (n = 62–66; open symbols). Data were analyzed on the log scale via analysis of covariance, including Day 1 as a covariate (P = 0.037, 0.001, < 0.001, and < 0.001 for Days 4, 7, 10, and 13). By comparison with placebo (n = 25) treatment, the concentrations of CCL4 (B) in the sputum fluid phase measured on Day 7 was significantly (P = 0.035, data were log10 transformed and analyzed by unpaired ttest) lower in patients on IFN-β (n = 24) and there was a trend toward lower CXCL8 (P = 0.109) (C). Gene expression of antiviral biomarkers OAS1 (D), Mx1 (E), and CXCL10 (F) in sputum cells from patients treated with IFN-β (n = 16) was significantly higher when compared with placebo (n = 20) on Day 7 (P = 0.0003, 0.0001, and 0.0008 respectively). Data are from patients in the modified intention-to-treat population.

Figure 6.

Up-regulation of the type I IFN canonical pathway by IFN-β treatment. Analysis of circulating blood cell microarray data using Ingenuity Pathway Analysis software (Ingenuity Systems [www.ingenuity.com], Mountain View, CA) showed a significant up-regulation of elements (red) of the IFN-β signaling pathway at both Day 4 and Day 7 after correction for multiple testing using a Benjamini-Hochberg procedure. Data are from patients in the British Thoracic Society Step 4-5 modified intention-to-treat population.