An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study

Abstract

Background: Acute exacerbations of COPD are a major cause of morbidity, mortality and hospitalisation. Respiratory viruses are associated with the majority of exacerbations but a causal relationship has not been demonstrated and the mechanisms of virus-induced exacerbations are poorly understood. Development of a human experimental model would provide evidence of causation and would greatly facilitate understanding mechanisms, but no such model exists.

Methods: We aimed to evaluate the feasibility of developing an experimental model of rhinovirus induced COPD exacerbations and to assess safety of rhinovirus infection in COPD patients. We carried out a pilot virus dose escalating study to assess the minimum dose of rhinovirus 16 required to induce experimental rhinovirus infection in subjects with COPD (GOLD stage II). Outcomes were assessed by monitoring of upper and lower respiratory tract symptoms, lung function, and virus replication and inflammatory responses in nasal lavage.

Results: All 4 subjects developed symptomatic colds with the lowest dose of virus tested, associated with evidence of viral replication and increased pro-inflammatory cytokines in nasal lavage. These were accompanied by significant increases in lower respiratory tract symptoms and reductions in PEF and FEV1. There were no severe exacerbations or other adverse events.

Conclusion: Low dose experimental rhinovirus infection in patients with COPD induces symptoms and lung function changes typical of an acute exacerbation of COPD, appears safe, and provides preliminary evidence of causation.

Figure 1

Daily upper and lower respiratory tract scores. (A) Mean total upper respiratory tract symptom scores. Symptoms were significantly increased on days 5 – 10. * indicates p < 0.05 compared to baseline. (B) Lower respiratory tract symptom scores. Symptoms were significantly increased on days 7 – 14. * indicates p < 0.05 compared to baseline. Mean scores on days -6 to 0 were subtracted from post-inoculation scores for both upper and lower respiratory tract scores.

Figure 2

Individual lower respiratory tract symptoms. (A) Wheeze (p = 0.01). (B) Cough (p < 0.001). (C) Sputum production (p = 0.01). (D) Sputum quality (p = 0.19). (E) Shortness of breath (p = 0.82).

Figure 3

Daily and clinic spirometry measurements. (A) 3 day average of home-recorded PEF. There were significant falls in PEF on days 12 – 14 and 21 – 23. * indicates p < 0.05 compared to baseline. (B) FEV₁ measured in clinic. There was a significant fall in FEV₁ compared to baseline (p < 0.05).

Figure 4

Levels of IL-6 and IL-8 in nasal lavage. (A) Time course of IL-6. (B) Time course of IL-8. (C) Mean levels of IL-6 in nasal lavage when stable and at exacerbation. There was an increase in IL-6 at exacerbation but this was not significant (p = 0.054). (D) Mean levels of IL-8 when stable and at exacerbation. There was a significant increase in IL-8 at exacerbation (p = 0.046).

Figure 5

Viral load measured with measured with a real-time quantitative RT-PCR assay. Viral load was significantly increased above baseline on days 4 – 7. ** indicates p < 0.01. * indicates p < 0.05.