Experimental Models of Rhinovirus-induced Exacerbations of Asthma: Where to Now?

Asthma is responsible for a heavy carrying capacity of illness and its prevalence is increasing in mostly countries. The major burden of illness and health take away froms 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) models the frequency of severe exacerbations at only 40% (1). The same dose of beclomethasone in school-age children does not resolve into exacerbation frequency (2). Reducing exacerbations is a large, unmet ne 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 sum of two units thirds of viruses detected. Developing more effective therapies to obstruct or treat exacerbations of asthma will require deeper understanding of the underlying cellular and molecular mechanisms. We have freshly shown that asthmatic subjects are more susceptible to rhinovirus infections than normal individuals (6); individual possible mechanism may involve impaired antiviral (Interferon-[gamma] and interleukin-12 production) immunity to rhinovirus (7) The latter observations, however, were made in vitro, and in vivo confirmation is required. In the continued absence of a nonprimate animal original of rhinovirus infection, investigators have used human experimental originals to investigate the mechanisms of rhinovirus-induced exacerbations of asthma.

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 offers sputum markers of eosinophil activation, interleukin-8 and neutrophilia, bronchial infiltration with eosinophils and CD4 and CD8 lymphocyte and activation of prostaglandin and leukotriene synthetic pathways, to name a not many Rhinovirus induction of nitric oxide has also been identified as a potential protective replication to infection (8).

A modern focus of studies of experimental infection has been the possibility of additive or synergistic interactions between agents provoking asthma exacerbations. An epidemiologic studious mood indicated synergy between allergen prospect and virus infections in increasing the risk of asthma exacerbation (9) Another reflection 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 imitate the epidemiologic interaction between allergen position and rhinovirus infection in an experimental gauge (11). If successful, the investigators would then have a protoplast with which to investigate the mechanisms of of the like kind an interaction and carry us another gradation forward.

de Kluijver and colleagues (11) used repeated low-dose allergen/placebo front 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 FEV^sub 1^ during a screening allergen challenge. The application of mind was well designed, carefully controll intensive, and a testament to the dedication of the two investigators and volunteers. The investigators were lucky in inducing appropriate responses to low-dose allergen challenge-allergen position alone was associated with significant falls in FEV^sub 1^ and PC^sub 20^ histamine, and significant increases in exhaled nitric oxide and percent sputum eosinophils. The investigators were also felicitous 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 FEV^sub 1^ The investigators were fruitless in demonstrating any additive or synergistic interaction with the combined exposing s of low-dose allergen followed on rhinovirus challenge, in terms of any of the clinical or inflammatory outcomes

This lack of succes in demonstrating an additive or synergistic interaction between allergen prospect and rhinovirus infection in experimental originals is not unprecedented. Avila and colleagues (12) were unavailing when using three high-dose nasal allergen challenges in the week preceding rhinovirus challenge. Surprisingly, allergen outlook was protective, both by delaying the charge and by shortening the duration of raw symptoms (12).

There are many reasons with what intent both sets of investigators did not succe in demonstrating positive interactions. united immunologic explanation is that allergen induced sufficient nitric oxide production to achieve a protective antiviral drift against subsequent viral infection. Evidence in support originates 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 part or not. Other immunologic mechanisms include the possibilities that prior allergen challenge induced antiinflammatory cytokines, similar as interleukin-10, or antiviral cytokines, in the same state [i]or[/i] condition as interferon-[gamma]. These mediators were not measured or finded in the reported studies.