Understanding the asthmatic response to an experimental rhinovirus infection: Exploring the effects of blocking IgE

Abstract

Background: Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear.

Objective: Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection.

Methods: Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection.

Results: Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P < .01 for upper respiratory symptom tract scores and P < .001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days.

Conclusions: LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection.

Keywords: Asthma; IgE; allergy; anti-IgE; omalizumab; rhinovirus; viral infection.

FIG 1.

Study design diagrams. URTS and LRTS scores were recorded twice daily at home on diary cards by subjects participating in the Asthma/Control (A) and Anti-IgE (B) studies. The study designs for both trials were identical following rhinovirus inoculation. Physical examination, spirometry, FENO measurements, and sample collection (nasal washes and blood) were done on the study days marked by downward arrows before and following rhinovirus inoculation. Methacholine challenges were done on days 0, 4, and 21; IOS assessments were done on days 0, 4, 7, and 21; and tests for neutralizing antibody to RV-16 were done on days 0 and 21. Stars under the Anti-IgE study diagram indicate days when study drug (placebo or omalizumab) was administered.

FIG 2.

Symptom scores. Means and SEs are shown for URTS and LRTS scores. After adjustment for baseline symptoms, the AUC comparisons for URTS scores between groups over the first 4 days following inoculation were 10.5 (8.3) and 10.4 (7.0) for the asthmatics and control subjects, respectively (P = .88 [A]); and 10.0 (5.2) and 7.3 (6.6) for scores from the placebo- and omalizumab-treated asthmatics, respectively, (P = .17; [B]). The AUC comparisons for LRTS scores over the first 4 days (primary outcome) were 2.7 (4.3) and 1.0 (2.1) for the asthmatics and control subjects, respectively, (P = .42; [C]), and 2.1 (2.6) and 0.4 (1.8) for the placebo- and omalizumab-treated asthmatics, respectively,( P = .09; [D]). Regarding late symptoms, significant differences were observed over days 15 to 21 between groups in the Asthma/Control study for both URTS and LRTS scores. *P < .05; **P < .01; and ***P < .001. The differences for URTSs and LRTSs over days 15 to 21 between groups in the Anti-IgE study were not significant (P = .54 and 0.91, respectively). There were also no significant differences between the placebo- and omalizumab-treated groups in LRTS scores recorded on days 15, 16, and 17 (unadjusted or adjusted for scores on day 0) (P > .05 for all comparisons).

FIG 3.

Lung function changes (spirometry). By day 1, FEV₁ values declined by 3% and 0% from baseline (day 0) among the asthmatics and controls in the Asthma/Control study (A), respectively. They decreased by 5% and 3% among the asthmatics treated with placebo and omalizumab in the Anti-IgE study ([B] P < .04 and .05, respectively). Over the first 4 days in the Anti-IgE study, the percent change differences were significant between the placebo- and omalizumab-treated groups for the FEV₁/FVC ratio and FEF_25–75 measurements (D and F) and also early in the infection between groups over the first 2, 3, and 4 days after inoculation (P < .04, .03, and .02, respectively). By day 21, significant reductions from baseline (day 0) occurred in FEV1/FVC and FEF_25–75 among the asthmatics in the Asthma/Control study (§P < .05 for FEV₁/FVC and P < .02 for FEF_25–75 in panels C and E, respectively), but not among the controls or the asthmatic study groups in the Anti-IgE study (panels D and F).

FIG 4.

Blood eosinophil (A and B) and neutrophil (C and D) counts. Geometric mean values with SE bars are shown. *P < .05 by day 2 and day 3 as shown in panel A.

FIG 5.

Percentage of subjects who developed LRTSs over the first 4 days of the infection within each study group. ^#Number of those who developed LRTSs divided by the total number of subjects within each group. Shown in Fig E4, A-D are records from diary cards showing which subjects within each group reported LRTSs above their baseline.