Rhinovirus-Induced Exacerbations of Asthma and COPD

Hershenson, Marc B.

Over the past decade, data from a birth cohort of highrisk infants with a positive family history of asthma (nicknamed the Childhood Origins of ASThma, or COAST) have shown that wheezing-associated illness with RV is the most important risk factor for asthma development [124, 125] . The relative risk of asthma development in infants with wheezing associated with rhinovirus infection was far higher than that of infants with allergen sensitization or RSV infection alone. Also, in infants hospitalized for respiratory infectionassociated wheezing, infection with RV was associated with asthma development [126] in contrast to respiratory syncytial virus (RSV), which was negatively associated [127] . Together, these data suggest two possibilities, either that RV infection causes asthma, or that RV infections may simply reveal a preexisting tendency for asthma. More recent data suggest that the latter is likely; prospective characterization of the COAST birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true [128] . Also, it was recently shown that children developing asthma by age seven had a lung function deficit and increased bronchial responsiveness as neonates [129] , suggesting that asthma precedes RV infection. If this is the case, then wheezingassociated illnesses due to rhinovirus are essentially viralinduced asthma exacerbations. Is it possible that, under the right circumstances, for example, the appropriate genetic background and allergen exposure, rhinovirus infection in early life modulates the immune response, increasing the likelihood of asthma development? A positive family is a known risk factor for asthma development, and it has recently been found that infants of mothers with asthma are more likely to have severe respiratory tract infections with RV [130] . To address this possibility, we infected baby mice with rhinovirus at 2 to 3 days of life. Unlike mature mice, rhinovirus-infected neonatal mice showed mucus metaplasia and airways hyperresponsiveness which lasted for one month after infection [131] . This is reminiscent of data from Washington University St. Louis in mature mice following infection with Sendai virus [132] . However, the finding of a developmental difference in response to rhinovirus, an infection that does not cause cytotoxic effects, warrants further investigation. Studies using neutralizing antibody and an IL-4 receptor knockout mouse showed that the effect of RV was dependent on IL-13. We also found increased production of IL-13 by invariant natural killer T (iNKT) cells.