Virus-induced airway hyperresponsiveness and asthma

Viral respiratory infections exert considerable influence on airway function and asthma in all age groups. In infancy, respiratory viruses such as RSV cause episodes of wheezing that may be recurrent but are largely transient. In addition, there are indications that early viral infections may be able to affect the development of the immune system and modify the subsequent risk of allergy and asthma. Finally, in children and adults with established asthma, common cold viruses such as RV frequently trigger acute symptoms of asthma. Antiviral agents would seem to be an obvious solution to virus-induced respiratory problems. However, current antiviral medications (e.g., rimantadine, ribavirin) have limited efficacy and must be started very early in the disease course to be effective. For prevention of RV infections, prophylactic use of topical IFN-α, soluble ICAM-1, or capsid-binding agents that prevent viral binding or uncoating has proven efficacy (184188). The clinical utility of these medications is limited, however, since they are generally ineffective if they are started after the onset of symptoms (189). Furthermore, IFN-α administered to patients with chronic respiratory diseases (including asthma) after close contact with people with upper respiratory symptoms does not prevent cold-related lower respiratory symptoms (190). Finally, the capsid-binding agents and soluble ICAM-1 specifically target RV, which account for about two-thirds of virus-induced asthma episodes, but have no effect on other viruses that can trigger asthma symptoms. Finding a broad spectrum antiviral agent with low cost and toxicity continues to present a major obstacle. There is now evidence that the immune response to respiratory viral infections, though critical to clear virus from the airway, also contributes to airway obstruction and respiratory symptoms. The mechanisms by which these changes occur appear to be associated with the ability of respiratory viruses to induce the production of pro-inflammatory cytokines and mediators. Some of these cellular and cytokine responses have been correlated with upper respiratory cold symptoms, changes in airway responsiveness, or lower airway symptoms (Table 3), although causal relationships have yet to be proven. Cur- rent data suggest that viral infections coordinately activate epithelial cells, endothelial cells, and leukocytes to cause airway edema, obstruction, and increased responsiveness (Figure 2). The epithelial cell is the host cell for respiratory viruses and is also the sentinel cell to initiate antiviral immune responses through the secretion of a broad array of cytokines, chemokines, and mediators. This early activation of epithelial cells and other resident airway cells stimulates changes in endothelial cell physiology: increased adhesion molecule expression to increase leukocyte recruitment, and increased vascular permeability, leading to edema and increased secretions. Granulocytes, macrophages, and T cells are activated by viruses and/or virus-induced cytokines, enhancing airway inflammation and obstruction and disrupting normal neural physiology in the lung to increase airway responsiveness. Finally, processes involved in the resolution of airway inflammation after viral infection include the lysis of virus-infected cells by cytotoxic lymphocytes, suppression of inflammation, mediated in part by cytokines such as transforming growth factor beta and IL-10, and the repair of airway structures with consequent airway remodeling. These processes may determine the nature of persistent changes in airway function after vital infections. This model suggests several opportunities, and a number of challenges, for the design of new therapeutic interventions for virus-induced asthma. The most effective treatment now used for virus-induced exacerbations of asthma is to prescribe a short 'burst' of oral corticosteroid early during the course of a vital respiratory infection (191). Despite proven efficacy in lessening lower airway consequences of viral respiratory infections in patients with asthma, systemic corticosteroids have little effect on common cold symptoms (120, 192), indicating that the mechanisms that cause upper versus lower respiratory symptoms associated with RV infection may be distinct. Use of systemic corticosteroids may be associated with side effects, and it is clearly desirable to develop more specific treatments that inhibit the pro-inflammatory effects of vital infections, while avoiding immunosuppression and corticosteroid-induced morbidity. In any case, since many of the cells, cytokines, and mediators unleashed by vital infections have overlapping inflammatory effects, it seems unlikely that therapeutic approaches aimed at inhibiting any one factor will reverse vital effects on airway function. With this in mind, several teams of investigators are working to define the intracellular mechanisms by which viruses activate cytokine genes, with the hope that viruses may trigger a common signaling pathway(s) that leads to the activation of multiple pro-inflammatory genes. If this is true, new therapies for virus-induced asthma could target this pathway. Another critical challenge is to determine why individuals with allergy and lower airway inflammation are so susceptible to the effects of respiratory viruses, such as RV, that cause mild disease in normal individuals. Is there a fundamental difference in the immune response to viruses in the presence of atopy? Alternatively, are the more severe clinical manifestations of respiratory viral infections in asthma a result of the different types of cells, or perhaps heightened activation state of the cells, in the asthmatic airway? With the answers to these questions will come a better appreciation of how airway inflammation is regulated in asthma and how best to treat this process when it is augmented by viral infection.