NIAID Now | April 08, 2019
The common cold, a viral infection of the nose and throat, is one of the most common triggers of asthma attacks. Yet even among children with severe asthma, most colds do not lead to asthma attacks. In a new NIAID-funded study, researchers sought to answer a long-standing question: what differentiates a cold that leads to an asthma attack from a cold that is just a cold?
By analyzing nasal wash and blood samples from children with severe asthma, the researchers pinpointed characteristic changes in gene expression—the degree to which genes are turned on or off—that lead to asthma attacks. Their findings, reported online today in Nature Immunology, will inform future research to identify new strategies to treat asthma.
Investigators enrolled 208 children with severe asthma aged 6 to 17 years at nine clinical sites across the United States participating in NIAID’s Inner-City Asthma Consortium. All study participants received asthma care based on NIH guidelines. Over a six-month period, participants used a mobile app to record their cold and asthma symptoms. Within three days of the onset of cold symptoms, participants visited the clinic for a physical exam and collection of nasal wash and blood samples. They returned for a second clinic visit four to six days after cold onset.
During the study, 106 children experienced cold symptoms a total of 154 times, of which 47 led to an asthma attack requiring treatment with oral corticosteroids and 107 did not. The researchers analyzed and compared nasal washings from each child. Overall, they found that colds that led to an asthma attack demonstrated changes in gene expression levels in six gene “modules,” or families of genes that interact to produce specific biological functions. These gene modules are primarily associated with maintaining the function of the epithelium—the outermost layer of tissue lining the respiratory tract—and with responses of immune cells in close contact with the epithelium. Treatment of the attack with oral corticosteroids reduced gene expression levels in some of these modules to levels comparable to those observed in children who did not have an asthma attack, while others were not changed by this rescue therapy.
The researchers next divided the 47 instances of cold symptoms that led to an asthma attack into two groups: 33 in which researchers detected a cold-causing virus in nasal washings and 14 in which they did not. The absence of a virus likely indicates that the cold-like symptoms the children experienced were triggered by another cause, such as pollution, other irritants or allergens. By comparing the two groups, researchers identified distinct molecular changes that take place in asthma attacks that occur in the absence of a virus. Specifically, they found increased gene expression of kallikreins, a set of enzymes responsible for producing kinin molecules, notably bradykinin, which induces narrowing of the airways in asthma and dilates blood vessels. This finding suggests that drugs targeting kallikreins and/or bradykinin may hold potential for treatment of asthma attacks with a non-viral trigger. Such medications have already been developed to treat the rare disease hereditary angioedema, a disorder that results in recurrent attacks of severe swelling.
The study findings also provide insights into asthma attack risk factors. The researchers identified particular gene expression patterns present in samples taken at an initial study visit—before children began experiencing cold symptoms—that were associated with increased risk for an asthma attack.
Overall, the work provides a springboard for future research to better understand asthma attacks and identify prevention strategies and potential therapies. All study data and computer programming code are freely available for use by other researchers.
MC Altman et al. Transcriptome networks identify mechanisms of viral and non-viral asthma exacerbations in children. Nature Immunology DOI: 10.1038/s41590-019-0347-8 (2019).