© 2003 American Thoracic Society
Experimental Models of Rhinovirus-induced Exacerbations of AsthmaWhere to Now?Department of Respiratory Medicine National Heart and Lung Institute Imperial College London London, United Kingdom Asthma is responsible for a heavy burden of illness and its prevalence is increasing in most countries. The major burden of illness and health costs relates to acute exacerbations. Inhaled glucocorticoids are the mainstay of treatment. In persistent asthma, however, a dose producing almost maximal benefit (400 µg budesonide daily) reduces the frequency of severe exacerbations by only 40% (1). The same dose of beclomethasone in school-age children does not reduce exacerbation frequency (2). Reducing exacerbations is a large, unmet need in asthma therapy.
It is well established that respiratory virus infections are associated with the vast majority of asthma exacerbations, in the community and hospital, and in adults and children (3–5). Rhinoviruses account for around two thirds of viruses detected. Developing more effective therapies to prevent or treat exacerbations of asthma will require deeper understanding of the underlying cellular and molecular mechanisms. We have recently shown that asthmatic subjects are more susceptible to rhinovirus infections than normal individuals (6); one possible mechanism may involve impaired antiviral (interferon- Studies of experimental infection have considerably advanced our understanding of virus-induced asthma exacerbations. Rhinovirus infections have been shown to preferentially induce bronchial hyperreactivity and long-lasting airway narrowing in asthmatic volunteers, sputum markers of eosinophil activation, interleukin-8 and neutrophilia, bronchial infiltration with eosinophils and CD4 and CD8 lymphocytes, and activation of prostaglandin and leukotriene synthetic pathways, to name a few. Rhinovirus induction of nitric oxide has also been identified as a potential protective response to infection (8). A recent focus of studies of experimental infection has been the possibility of additive or synergistic interactions between agents provoking asthma exacerbations. An epidemiologic study indicated synergy between allergen exposure and virus infections in increasing the risk of asthma exacerbation (9). Another study demonstrated interactions between air pollution and virus infections (10). In this issue of the Journal (pp. 1174–1180), de Kluijver and colleagues report an attempt to reproduce the epidemiologic interaction between allergen exposure and rhinovirus infection in an experimental model (11). If successful, the investigators would then have a model with which to investigate the mechanisms of such an interaction and carry us another step forward. de Kluijver and colleagues (11) used repeated low-dose allergen/placebo exposure every day for 10 working days in the 2 weeks before rhinovirus/placebo infection, using a single dose of inhaled allergen that caused a 5% fall in FEV1 during a screening allergen challenge. The study was well designed, carefully controlled, intensive, and a testament to the dedication of both investigators and volunteers. The investigators were successful in inducing appropriate responses to low-dose allergen challenge—allergen exposure alone was associated with significant falls in FEV1 and PC20 histamine, and significant increases in exhaled nitric oxide and percent sputum eosinophils. The investigators were also successful in inducing expected responses to rhinovirus challenge alone—this was associated with significant increases in sputum neutrophils, sputum interleukin-8 and neutrophil elastase, and fall in FEV1. The investigators were unsuccessful in demonstrating any additive or synergistic interaction with the combined exposures of low-dose allergen followed by rhinovirus challenge, in terms of any of the clinical or inflammatory outcomes. This lack of success in demonstrating an additive or synergistic interaction between allergen exposure and rhinovirus infection in experimental models is not unprecedented. Avila and colleagues (12) were unsuccessful when using three high-dose nasal allergen challenges in the week preceding rhinovirus challenge. Surprisingly, allergen exposure was protective, both by delaying the onset and by shortening the duration of cold symptoms (12).
There are many reasons why both sets of investigators did not succeed in demonstrating positive interactions. One immunologic explanation is that allergen induced sufficient nitric oxide production to achieve a protective antiviral effect against subsequent viral infection. Evidence in support comes from human in vivo (8) and in vitro (13) studies, and also animal studies. Because neither de Kluijver and coworkers nor Avila and coworkers reported quantitative viral loads or duration of virus shedding, we cannot determine whether this mechanism played a role or not. Other immunologic mechanisms include the possibilities that prior allergen challenge induced antiinflammatory cytokines, such as interleukin-10, or antiviral cytokines, such as interferon-
For any of the above mechanisms, timing and dose of allergen exposure would be critical in determining the magnitude of nitric oxide, interleukin-10, interferon-
It is noteworthy that older seminal studies investigating allergen challenge (inhaled [14] or segmental [15]) during the acute phase of rhinovirus infection were able to demonstrate positive interactions in terms of physiologic responses (14) and airway inflammation (increase in bronchoalveolar eosinophils and tumor necrosis factor- A final possible explanation is that interactions between allergen exposure and rhinovirus infection may be greater in subgroups of asthmatic patients. Zambrano and coworkers recently demonstrated increased symptom severity, nasal wash markers of eosinophil activation, and exhaled nitric oxide in response to rhinovirus infection among asthmatic volunteers with high serum total IgE (371–820 IU/mL) compared with subjects who had low or normal IgE (29–124 IU/mL) (16). This could be an important observation because the asthmatics in whom the synergistic interaction was observed in the epidemiologic study also had high total serum IgE (geometric mean 253 kAU/l) (9). In conclusion, there are only a handful of centers around the world capable of undertaking studies such as that of de Kluijver and coworkers. It is hoped that these investigators will continue to discover important mechanisms and suggest further targets for development of new therapies for asthma exacerbations. Further studies are more likely to achieve success if the allergen exposure occurs during, rather than before, the infection. It may well be that the best model of allergen exposure is not artificial allergen challenge, but a naturally occurring challenge: volunteers returning once inoculated with virus to the place where they encounter the most allergen—their home. FOOTNOTES Conflict of Interest Statement: S.L.J. has received research grants from GlaxoSmithKline and Millennium Pharmaceuticals for research into respiratory infections and airway disease. He has also received honoraria for lectures at meetings or attendance at Advisory Boards from the following companies: GlaxoSmithKline, Novartis, Servier, Schering-Plough, and Abbott. REFERENCES
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