Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation

Abstract

Rationale: Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations.

Objectives: To evaluate experimental rhinovirus infection as a model of COPD exacerbation and to investigate the mechanisms of virus-induced exacerbations.

Methods: We used experimental rhinovirus infection in 13 subjects with COPD and 13 nonobstructed control subjects to investigate clinical, physiologic, pathologic, and antiviral responses and relationships between virus load and these outcomes.

Measurements and main results: Clinical data; inflammatory mediators in blood, sputum, and bronchoalveolar lavage; and viral load in nasal lavage, sputum, and bronchoalveolar lavage were measured at baseline and after infection with rhinovirus 16. After rhinovirus infection subjects with COPD developed lower respiratory symptoms, airflow obstruction, and systemic and airway inflammation that were greater and more prolonged compared with the control group. Neutrophil markers in sputum related to clinical outcomes and virus load correlated with inflammatory markers. Virus load was higher and IFN production by bronchoalveolar lavage cells was impaired in the subjects with COPD.

Conclusions: We have developed a new model of COPD exacerbation that strongly supports a causal relationship between rhinovirus infection and COPD exacerbations. Impaired IFN production and neutrophilic inflammation may be important mechanisms in virus-induced COPD exacerbations.

Figures

Figure 1.

Symptom scores and lung function during experimental rhinovirus infection. The time course for daily symptom scores is shown for (A) total daily upper respiratory tract (URT) symptoms, (B) total daily lower respiratory symptoms, and (C) breathlessness. (D) The time course of postbronchodilator peak expiratory flow as a percentage of baseline (all values represent means ± SEM). *P < 0.05 versus baseline; **P < 0.01 versus baseline; †P < 0.05, patients with chronic obstructive pulmonary disease (COPD) versus control subjects; ††P < 0.01, patients with COPD versus control subjects; †††P < 0.001, patients with COPD versus control subjects.

Figure 2.

Airway inflammatory cells and soluble mediators during experimental rhinovirus infection. Shown is the time course of (A) percentage neutrophils, (B) neutrophil elastase, and (C) IL-8 in induced sputum. (D and E) Lymphocytes and neutrophils, respectively, in bronchoalveolar lavage (BAL). All values represent means ± SEM. *P < 0.05 versus baseline; **P < 0.01 versus baseline; †P < 0.05, patients with chronic obstructive pulmonary disease (COPD) versus control subjects; ††P < 0.01, patients with COPD versus control subjects.

Figure 3.

Virus load in nasal lavage and sputum. The time course of virus load, measured by quantitative polymerase chain reaction, is shown in (A) nasal lavage and (B) sputum (values in both panels represent means ± SEM). *P < 0.005 versus baseline; **P < 0.01 versus baseline; ***P < 0.001 versus baseline; †P < 0.05, patients with chronic obstructive pulmonary disease (COPD) versus control subjects.

Figure 4.

Correlations between sputum virus load and inflammatory markers. Relationships between sputum virus load and inflammatory markers in subjects with chronic obstructive pulmonary disease (COPD) are shown. There were significant correlations between peak sputum virus load and (A) peak serum C-reactive protein (CRP), (B) peak sputum neutrophils, (C) peak sputum IL-8, (D) peak sputum neutrophil elastase (NE), (E) peak sputum IL-6, and (F) peak sputum tumor necrosis factor (TNF)-α.

Figure 5.

Interferon responses in bronchoalveolar lavage (BAL) cells. Cells obtained by BAL were infected ex vivo with rhinovirus 16 (RV) and (A) IFN-α, (B) IFN-λ, and (C) IFN-β were measured in supernatants 48 hours postinfection (all values represent means and SEM). *P < 0.05 versus filtered virus; **P < 0.01 versus filtered virus; †P < 0.05, patients with chronic obstructive pulmonary disease (COPD) versus control subjects. Results of comparisons between COPD and control groups are indicated above the relevant brackets.