Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production

Abstract

Acute exacerbations are the major cause of asthma morbidity, mortality, and health-care costs and are difficult to treat and prevent. The majority of asthma exacerbations are associated with rhinovirus (RV) infection, but evidence supporting a causal relationship is weak and mechanisms are poorly understood. We hypothesized that in asthmatic, but not normal, subjects RV infection would induce clinical, physiologic, and pathologic lower airway responses typical of an asthma exacerbation and that these changes would be related to virus replication and impaired T helper 1 (Th1)/IL-10 or augmented Th2 immune responses. We investigated physiologic, virologic, and immunopathologic responses to experimental RV infection in blood, induced sputum, and bronchial lavage in 10 asthmatic and 15 normal volunteers. RV infection induced significantly greater lower respiratory symptoms and lung function impairment and increases in bronchial hyperreactivity and eosinophilic lower airway inflammation in asthmatic compared with normal subjects. In asthmatic, but not normal, subjects virus load was significantly related to lower respiratory symptoms, bronchial hyperreactivity, and reductions in blood total and CD8 ؉ lymphocytes; lung function impairment was significantly related to neutrophilic and eosinophilic lower airway inflammation. The same virologic and clinical outcomes were strongly related to deficient IFN-␥ and IL-10 responses and to augmented IL-4, IL-5, and IL-13 responses. This study demonstrates increased RV-induced clinical illness severity in asthmatic compared with normal subjects, provides evidence of strong relationships between virus load, lower airway virus-induced inflammation and asthma exacerbation severity, and indicates augmented Th2 or impaired Th1 or IL-10 immunity are likely important mechanisms.exacerbation ͉ respiratory viruses ͉ immunology ͉ human experimental virus infection A cute exacerbations are the major cause of asthma morbidity, mortality (1), and health-care costs (2). Inhaled steroids are associated with reduced risk of exacerbation (3); however, optimal therapy in adults reduces exacerbation frequency by only Ϸ40-50% (4, 5). In school-age children inhaled steroids were ineffective at reducing exacerbation frequency, duration, or severity (6), and in preschool children oral steroids are also reported ineffective (7). Current therapy is therefore of limited efficacy and new more effective therapies are urgently required. To identify targets for development of new treatments, better understanding of mechanisms of virus-induced asthma exacerbations is required.Virus infections are associated with 80-85% of pediatric (8, 9) and Ϸ75% of adult (10, 11) asthma exacerbations, and rhinoviruses (RVs) account for two-thirds of virus detections. Asthmatic individuals are more susceptible to naturally occurring RV infection than normal individuals in that lower respiratory tract symptoms and changes in peak expiratory flow (PEF) are more severe and of longer duration (12). We recently found increased RV...

Azithromycin for Acute Exacerbations of Asthma

“…18,19 Viral infection impairs antibacterial innate immune responses 20 and increases bacterial adherence to bronchial epithelium. 21 Thus, bacterial infections are more common and more severe in patients with asthma, viruses increase susceptibility to bacterial infection, and acute wheezing episodes in children younger than 3 years were associated with both bacterial and viral infection.…”

Activation of human basophils by combined toll‐like receptor‐ and FcεRI‐triggering can promote Th2 skewing of naive T helper cells

“…Although parasites can induce specific IgE and activate TLRs through pathogen-associated molecular patterns, chronic allergic inflammation may lead to activation of TLR by damage-associated molecular patterns [30,31]. In addition, certain viral and bacterial infections have been associated with asthma exacerbations [32,33], and the presence of endotoxin (TLR-4 ligand) was demonstrated in house dust, and was related to severity of allergic reactions against house dust mite [21], Our data indicate that activation of basophils may contribute to these processes by enhanced cytokine production when both specific IgE and TLR ligands are present.…”

Th2-associated immunity to bacteria in teenagers and susceptibility to asthma

“…The primary focus has been upon viruses, particularly rhinovirus [2,3], and bystander airway tissue damage during host-antiviral responses is widely believed to play a key role in driving wheezing disease pathogenesis towards chronicity. Considerably less attention has been paid to bacteria, with the exception of Staphylococcus aureus (SA) strains which produce soluble enterotoxins.…”