Toward antiviral therapy/prophylaxis for rhinovirus-induced exacerbations of chronic obstructive pulmonary disease: challenges, opportunities, and strategies

Abstract

Chronic obstructive pulmonary disease (COPD) is a life-threatening lung illness characterized by persistent and progressive airflow limitation. Exacerbations of COPD contribute to the severity of this pathology and accelerate disease progression. To date, pharmacological treatment of both stable COPD patients and patients experiencing exacerbations is mainly symptomatic with bronchodilators and steroids as the mainstay of therapy. Bacteria trigger such exacerbations in a number of cases; hence, antibiotics might be included in the treatment as well. Several respiratory viruses are frequently detected in sputum from patients during COPD exacerbations. These include influenza viruses, respiratory syncytial virus, and, most often, rhinoviruses. In this review, we discuss the potential use of an anti-rhinovirus drug for the treatment and prophylaxis of rhinovirus-induced COPD exacerbations and the path forward toward the development and use of such a drug. Copyright © 2015 John Wiley & Sons, Ltd.

Figure 1

Viral pathogens during acute exacerbations 6, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 and stable chronic obstructive pulmonary disease (COPD) 6, 19, 20, 21. For each virus, the median and the range of the reported detection levels of viral RNA during acute exacerbation of COPD (red) and stable COPD (blue) are shown

Figure 2

Microbial involvement in chronic obstructive pulmonary disease exacerbations and (necessary) therapeutic interventions

Figure 3

Organization of the rhinovirus genome and polyprotein. The single‐stranded RNA genome encodes for four structural proteins {consisting of viral protein [VP1–4] and seven non‐structural proteins [comprising two proteases (2A and 3C), one polymerase (3D), one putative ring helicase/ATPase (2C), VPg, and two other proteins that, either cleaved or as a precursor, are involved in viral replication]}. The icosahedral virion consists of 60 monomers, and one monomer consists of four structural proteins VP1 (yellow), VP2 (orange), VP3 (blue), and VP4 (inside of the particle). On the right, an enlarged monomer is depicted (Protein Data Bank (PDB) file 1NCQ) 82. Pleconaril (cyan) interacts with a hydrophobic pocket beneath the canyon

Figure 4

Simplified scheme of an experimental influenza and rhinovirus infection. (A) Following experimental influenza infection in a healthy individual, viral RNA load (black) increased from day 1, peaked at day 2, and returned to baseline at day 8. Systemic symptoms (green) peaked at day 2 and resolved faster than the respiratory symptoms (red, peak at day 3). Treatment with neuraminidase inhibitors is recommended to start within 48 h after fever onset. Figure based on data from reference 71. (B) Rhinovirus infection of a chronic obstructive pulmonary disease patient resulted in a fast increase in upper respiratory tract symptoms (green, peak at day 3) and a slower and more prolonged increase in lower respiratory tract symptoms (red, peak at day 9). Viral RNA load (black) peaked at day 4 post‐infection. Blue box: suggested period of therapy initiation with an anti‐rhinovirus drug. Figure based on data from reference 36