DENVER—Viral infections can exacerbate asthma in children and adults, and rhinovirus is responsible for most of these infections. But what is the mechanism behind virus-induced asthma? How is airway inflammation initiated in the presence of rhinovirus? And what is going on in the airways at a molecular level?

Two sessions at the 60th Anniversary Meeting of the American Academy of Asthma, Allergy and Immunology addressed these questions.[1,2]

RHINOVIRUS CAN INFECT THE LOWER AIRWAYS

There is a paradox involved in rhinovirus infection and the precipitation of asthma, said William W. Busse, MD, Head of the Allergy and Clinical Immunology Section at the University of Wisconsin Medical School in Madison.[1] “Rhinovirus is replicated primarily in the upper airways, but in patients with asthma, the consequences of these infections are felt primarily in the lower airways,” he explained. In addition, Dr. Busse noted, an asthma exacerbation associated with a viral respiratory infection can be quite severe, with rapid onset.

In past studies using experimental rhinoviruses, everyone inoculated with the virus developed a cold, but only some study participants experienced lower airway symptoms. No differences could be discerned to predict who would develop lower airway symptoms and who would not. Dr. Busse and others have pursued this question—specifically, if a person with allergies gets a cold, does the host response produce a reaction similar to asthma?

In 1989, Lemanske et al[3] studied 10 individuals with allergic rhinitis who were given rhinovirus 16. During the course of illness, histamine responsiveness increased in all patients, and eight of the 10 had late asthmatic reactions to ragweed antigen. The key observation was that both immediate and late-stage responses to antigen occurred during the illness, suggesting that the presence of a cold increased the likelihood of an inflammatory airway response. Again, rhinovirus in the upper airway caused profound changes in the lower airway.

Not everyone with asthma who gets a cold has lower airway exacerbations of their asthma, said Dr. Busse. The virus was similar among all subjects in that it produced a respiratory infection in everyone. So, who is at risk for an asthma exacerbation?

To explore whether host factors are involved in determining if colds lead to exacerbations, Parry and colleagues[4] performed a study in which individuals with allergies were given rhinovirus 16. They found that interferon gamma (IFN-gamma) levels affect the severity of rhinovirus infections. Dr. Busse, who coauthored the Parry study, explained that in nonasthmatic individuals, IFN-gamma levels increase in response to a respiratory infection. Some persons with asthma, however, have impaired IFN-gamma production, and this permits a more severe response with more inflammation and, therefore, greater airflow obstruction and airway responsiveness.

ATOPY AS A HOST FACTOR

Peter W. Heymann, MD, Professor of Pediatrics and Head of the Division of Pediatric Respiratory Medicine at the University of Virginia Health System in Charlottesville, looked at the role of atopy in the presence of asthma and rhinovirus infection in children.[1] After studying children who were admitted to the emergency department for wheezing, Dr. Heymann concluded that atopy and rhinovirus infection increase the risk of wheezing in children, especially during the spring and fall allergy seasons.

In studies of young adults with mild asthma who were given experimental rhinovirus infection, those with high immunoglobulin E (IgE) levels had more lower respiratory symptoms during the first four days of rhinovirus infection than did those with normal IgE levels. The most striking differences were observed in markers of inflammation, such as nasal eosinophil cationic protein levels, which were elevated in the high IgE group before infection and remained high afterwards. Dr. Heymann suggested that infection with rhinovirus in atopic individuals may “push them over the edge” and alter their immune response.

Levels of soluble intercellular adhesion molecule 1 (ICAM-1)—the main cell surface receptor for rhinovirus—were lower in the high IgE group, and these levels stayed low. Interestingly, Dr. Heymann observed that regulation of ICAM-1 was influenced by IFN-gamma, interleukin 1 (IL-1), and tumor necrosis factor alpha. Like Dr. Busse, he proposed a “suppressed IFN-gamma response in atopic patients that alters the response to rhinovirus and impairs viral clearance.”

INFLAMMATORY MECHANISMS

How does rhinovirus infection cause lower airway symptoms? asked James E. Gern, MD, Associate Professor of Pediatrics at the University of Wisconsin Medical School in Madison.[1,2] Epithelial cells initiate cellular inflammation in the airway by causing the synthesis of chemokines and activated mononuclear cells. “If you have those chemokines, you would expect to see inflammation in the lower airways,” said Dr. Gern. “When you see neutrophils in the lower airway (and this doesn’t happen in everyone), it tends to occur between four and seven days after [rhinovirus] inoculation.”

Agreeing that IFN-gamma is an important modulator in the clinical response to rhinovirus, Dr. Gern hypothesized that there may be factors that “turn on” IFN-gamma responses. Candidates for these responses include IL-12, -15, and -18—all prototypic IFN-gamma–inducing agents.

RSV AND ASTHMA

Cellular mechanisms underlying asthma exacerbations are similar to those linking respiratory syncytial virus (RSV) and asthma, according to data presented by Ray S. Peebles Jr, MD, Assistant Professor in the Allergy/Pulmonary and Critical Care Medicine Division of Vanderbilt University in Nashville, Tennessee. He studied the cytokine response to RSV infection in infants.[2]

Like rhinovirus, RSV produces an IFN-gamma response. Studies have shown that children with RSV bronchiolitis who later developed asthma had lower levels of IFN-gamma during both the acute and convalescent stages of illness, compared to children who did not develop asthma. There appears to be an underlying T helper 2 (TH2) response during the initial RSV infection that leads to more severe illness and the later development of asthma.

MOLECULAR MECHANISMS

Shyam Mohapatra, PhD, Associate Professor of Medicine and Medical Microbiology and Immunology at the University of South Florida in Tampa, has studied epithelial cells and mouse models to analyze gene expression in RSV and asthma.[2]

ICAM-1 expression is augmented when epithelial cells are infected with RSV. Dr. Mohapatra and colleagues examined ICAM-1 expression in four groups of mice: The first was a control group, the second was given RSV, the third underwent allergen sensitization, and the fourth was given both allergen and RSV.[5]

Eosinophil levels and ICAM-1 expression were increased in the mice who were given both allergen and RSV. In this study, the mice were infected with RSV several times. After three bouts of RSV, the mice had persistent airway hyperresponsiveness, a tremendous increase in macrophage inflammatory protein 1-alpha concentrations, persistent levels of RSV antigen load, and a TH2–like response.

MANY FACTORS TO CONSIDER

In a comprehensive review of rhinovirus and asthma,[6] Drs. Gern and Busse noted that “[Rhinovirus] infections induce a host of immunologic changes in the blood and airways, and some of these responses have been correlated with cold symptoms, changes in airway responsiveness, or lower airway symptoms.… It remains to be determined which of these factors participates in the pathogenesis of respiratory symptoms and which are merely indicators of an ongoing immune response.”

—Gale Jurasek