Vol. 10 •Issue 4 • Page 42
RVI and Asthma
Pondering Precipitants to Exacerbations
By Robert L. Atmar, MD
Recent human clinical studies bring to light the possibility that respiratory viral infections could be a precipitant to asthmatic exacerbations. With increased understanding of the inflammatory mechanisms involved in the RVI-asthma interaction, specific strategies can attempt to interrupt the links between these two diseases.
Several epidemiological studies have noted an association between respiratory syncytial virus (RSV) infection and the subsequent development of recurrent wheezing or asthma. Most children are infected at least once by the age of 2, so simple infection doesn’t explain the observation. Instead, the severity of the clinical symptoms during infection (i.e., bronchiolitis or pneumonia) appears to play a role.
Several hypotheses have been proposed to explain the link, including:
• RSV infection of the lower respiratory tract leads to inflammation of these airways and somehow alters lung development or the sensitivity of the airways to allergen exposure. People without lower airway disease (and thus at lower risk for the development of asthma) would not undergo these changes.
• Severe RSV infection is a marker for people who are more likely to develop asthma. According to this hypothesis, an individual’s inability to limit the virus infection is a manifestation of the underlying immune defect that predisposes him/her to develop asthma.
• Severe RSV infection leads to an immune response that favors the development of allergic inflammation in susceptible individuals. Such T helper 2 (Th2)-like immune responses predominate in the newborn and are associated with the development of IgE antibody production and eosinophilic inflammation.
As the immune system matures, Th1-like responses become predominant. However, Th2-like responses persist in atopic individuals, possibly by expansion and maturation of these T cells in response to antigenic stimulation. One of the RSV viral proteins (the G protein) has been recognized to induce Th2-like immune responses, and it’s postulated that a severe RSV infection leads to an expansion of the Th2 immune response.
To date, insufficient data exists to determine which, if any, of the aforementioned hypotheses is correct. In addition, data from the Tucson Children’s Respiratory Study supports a seemingly contradictory hypothesis to the immune response: RVIs early in life may protect against the development of asthma later in childhood.1 (See ADVANCE’s March issue for more information about the Tucson Study.)
The investigators suggest that respiratory infections occurring after exposure to other children early in life stimulate Th1-like immune responses and earlier maturation of the immune system. The Th1-like responses inhibit Th2-like responses, decreasing the likelihood that Th2 cells would expand and favor the development of later allergic inflammatory responses. This “hygiene hypothesis” postulates that a decrease in infections early in childhood leads to an increase in allergic disorders.
There is a much clearer relationship between RVIs and the development of acute wheezing episodes in persons with pre-established asthma. Recent epidemiological studies have shown that in children, as many as 80 percent of acute wheezing episodes are associated with a concurrent RVI, while about half of acute wheezing episodes are associated in adults.
Wheezing exacerbations may occur following an RVI caused by any respiratory virus, but the most common infections are those caused by common cold viruses (rhinoviruses and coronaviruses). Influenza, RSV and parainfluenza viruses are less frequently identified precipitants of wheezing exacerbations in asthmatics, and adenoviruses are uncommon precipitants.
Experimental human infection with rhinoviruses has been used to further evaluate RVIs as asthmatic exacerbation precipitants. These studies show that following rhinovirus infection asthmatics have increased airway responsiveness to histamine, methacholine and allergen bronchoprovocation that lasts for one to two weeks. Interestingly, not all asthmatics develop increased airway responsiveness following rhinovirus infection.
Longitudinal cohort studies show asthma exacerbations are precipitated in an individual subject by some, but not all, RVIs. These observations suggest additional virus-specific and host-specific factors contribute to the occurrence and severity of wheezing episodes following an RVI.
Inflammation is one factor contributing to wheezing, and there appears to be a direct link between the inflammatory response to an RVI and the precipitation of an asthma exacerbation in a predisposed host.
Inflammation begins when respiratory viruses infect the respiratory epithelium. Follow ing infection, the epithelial cells produce a variety of cytokines and chemokines (e.g., interleukin-6, granulocyte macrophage-colony stimulating factor, interleukin-11, interleukin-8, RANTES) that promote airway inflammation and have been found in the respiratory secretions of infected individuals. The inflammatory mediators recruit neutrophils, eosinophils and monocyte/ macrophages to the affected area.
These inflammatory cells and their mediators are important contributors in the pathogenesis of an asthma exacerbation, as suggested by the positive cor-relation between their presence in respiratory secretions and the clinical manifestations of asthma, including wheez- ing and increased airway responsiveness.
Consequently, it is likely that the virus strain, the host’s immunity to that strain and the amount of ongoing bronchial inflammation are all contributing factors that determine an asthmatic’s response to an RVI.
PREVENTION & TREATMENT
This information has significant implications for the prevention of morbidity related to asthma. For example, if severe RSV infection contributes to asthma development, the prevention of serious RSV disease could prevent asthma.
Studies are under way to develop effective RSV vaccines that could be used in mothers (maternal immunization) or young children in order to decrease the morbidity and mortality associated with severe RSV infection. A similar benefit might be seen with the development of an effective antiviral for use in early RSV infection. An RSV-specific humanized monoclonal antibody (palivizumab) provides passive protection from RSV to premature infants (less than or equal to 35 weeks) and children less than 2 years of age who have bronchopulmonary dysplasia.
Another potential role for vaccines and antivirals is in the prevention of exacerbations in people with previously established asthma. Effective antivirals for the treatment of influenza (amantadine, rimantadine, zanamivir, oseltamivir) have been licensed, but the utility of these drugs in preventing asthma exacerbations is yet to be established.
Antivirals for other respiratory viruses (e.g., pleconaril for rhinovirus infections) are currently in clinical trials. Unfortunately, none of these antivirals has broad activity against all respiratory viruses. Thus, effective rapid diagnostic methods for specific RVI treatment will also be needed.
Researchers have developed effective immunization strategies for influenza. Annual immunization with inactivated influenza virus vaccine is currently recommended for asthmatics and is effective in disease prevention. A live, attenuated “nose-drop” influenza virus vaccine, with the advantage of not being administered by a shot, may be approved for clinical use soon. However, its safety in asthmatics remains to be established.
A different approach for preventing RVI-related asthma exacerbations is the use of anti-inflammatory agents to abrogate the virus-induced inflammatory response. Short bursts of systemic cortico-steroids are effective in decreasing the number and severity of asthma attacks in preschool children with upper respiratory tract infections. Yet, because of the side effects related to systemic corticosteroid use, more specific strategies to interrupt the pro-inflammatory effects are favored.
Further dissection of the interrelationships and interactions of the type of RVI, infection severity, the age when infected and other host-specific factors related to the immune system and the likelihood of asthma development is needed. REFERENCE
1. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. NEJM. 2000 Aug. 24;105:538-43.
Dr. Atmar is associate professor in the departments of medicine and molecular virology & microbiology at Baylor College of Medicine in Houston. He can be reached at [email protected].