Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production.
09 Sep 2008-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 105, Iss: 36, pp 13562-13567
TL;DR: Increased RV-induced clinical illness severity in asthmatic compared with normal subjects is demonstrated, evidence of strong relationships between virus load, lower airway virus-induced inflammation and asthma exacerbation severity is provided, and indicates augmented Th2 or impaired Th1 or IL-10 immunity are likely important mechanisms.
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-γ 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.
Citations
More filters
Woolcock Institute of Medical Research1, University of Cape Town2, University of Manitoba3, Laval University4, Federal University of Bahia5, Harvard University6, Helsinki University Central Hospital7, Kagoshima University8, Erasmus University Rotterdam9, University of Wisconsin-Madison10, McMaster University11, University of Pisa12, University of Southern Denmark13, Universidade Federal de Santa Catarina14, University of Costa Rica15, Boston Children's Hospital16, The Chinese University of Hong Kong17, University of British Columbia18
TL;DR: The changes include a revised asthma definition, tools for assessing symptom control and risk factors for adverse outcomes, and updated strategies for adaptation and implementation of GINA recommendations.
Abstract: Over the past 20 years, the Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many national guidelines. However, uptake of existing guidelines is poor. A major revision of the GINA report was published in 2014, and updated in 2015, reflecting an evolving understanding of heterogeneous airways disease, a broader evidence base, increasing interest in targeted treatment, and evidence about effective implementation approaches. During development of the report, the clinical utility of recommendations and strategies for their practical implementation were considered in parallel with the scientific evidence.This article provides a summary of key changes in the GINA report, and their rationale. The changes include a revised asthma definition; tools for assessing symptom control and risk factors for adverse outcomes; expanded indications for inhaled corticosteroid therapy; a framework for targeted treatment based on phenotype, modifiable risk factors, patient preference, and practical issues; optimisation of medication effectiveness by addressing inhaler technique and adherence; revised recommendations about written asthma action plans; diagnosis and initial treatment of the asthma-chronic obstructive pulmonary disease overlap syndrome; diagnosis in wheezing pre-school children; and updated strategies for adaptation and implementation of GINA recommendations.
657 citations
TL;DR: There is evidence that deficiencies in antiviral activity and the integrity of the airway epithelial barrier could make individuals with asthma more likely to have severe viral respiratory infections of the lower airway, and thus increase the risk of exacerbation.
641 citations
TL;DR: The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions, which initiates multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses.
Abstract: The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions. It initiates multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses. The interaction between respiratory viruses and airway epithelial cells results in production of antiviral substances, including type I and III interferons, lactoferrin, β-defensins, and nitric oxide, and also in production of cytokines and chemokines, which recruit inflammatory cells and influence adaptive immunity. These defense mechanisms usually result in rapid virus clearance. However, respiratory viruses elaborate strategies to evade antiviral mechanisms and immune responses. They may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms. In addition, they can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones. Finally, by inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, they favor lung damage and further impair host antiviral mechanisms.
564 citations
Cites background from "Rhinovirus-induced lower respirator..."
...tion of chronic airway diseases such as asthma (36, 179)....
[...]
[...]
TL;DR: Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways, and is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness.
Abstract: Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways. Airway remodeling in asthmatic patients involves a wide array of pathophysiologic features, including epithelial changes, increased smooth muscle mass, increased numbers of activated fibroblasts/myofibroblasts, subepithelial fibrosis, and vascular changes. Multiple cytokines, chemokines, and growth factors released from both inflammatory and structural cells in the airway tissue create a complex signaling environment that drives these structural changes. However, recent investigations have changed our understanding of asthma from a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Several reports have suggested that asthma primarily develops because of serious defects in the epithelial layer that allow environmental allergens, microorganisms, and toxins greater access to the airway tissue and that can also stimulate the release of mediators from the epithelium, thus contributing to tissue remodeling. Lung-resident fibroblasts and smooth muscle cells have also been implicated in the pathogenesis of airway remodeling. Remodeling is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness. Asthmatic subjects experience an accelerated decrease in lung function compared with healthy subjects, which is proportionally related to the duration and severity of their disease.
476 citations
TL;DR: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo and relate to exacerbation severity, which is a novel therapeutic approach for asthma exacerbations.
Abstract: Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays ...
473 citations
Cites background or methods from "Rhinovirus-induced lower respirator..."
...In Vitro Studies Human bronchial epithelial cells (BECs) (Lonza, Basel, Switzerland) were either infected with RV16 or treated with media for 24 hours (28)....
[...]
...We recruited nonsmoking patients with mild or moderately severe asthma and nonsmoking, nonatopic healthy volunteers aged 18–55 years and without a recent viral illness or serum neutralizing antibodies to rhinovirus 16 (RV16) at screening....
[...]
...As previously reported (25), lower respiratory symptom scores were corrected for baseline symptoms and the effects of the bronchoscopy (see Figure E2)....
[...]
...lavage and BAL samples as described previously (25)....
[...]
...Cell type 2 cytokine production in BAL fluid in response to nonspecific ex vivo stimulation has previously been reported to be increased in asthma and also to be related to the severity of the asthma exacerbation following subsequent rhinovirus challenge (25)....
[...]
References
More filters
TL;DR: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.
Abstract: Objective: To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. Design: Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. Subjects: 108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. Setting: Southampton and surrounding community. Main outcome measures: Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. Results: Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 1/min. The most commonly identified virus type was rhinovirus. Conclusions: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children. Key messages Key messages In this study common cold viruses were found in 80-85% of reported exacerbations of asthma in children Rhinoviruses, which cause most common colds, accounted for two thirds of viruses detected Analysis of diary cards also showed large numbers of similar but less severe episodes that may also be viral in origin
1,889 citations
"Rhinovirus-induced lower respirator..." refers background or methods in this paper
...Standard RV PCR (PerkinElmer 9600 GeneAmp) was performed from 2 l of cDNA (7, 8)....
[...]
...Virus infections are associated with 80–85% of pediatric (8, 9) and 75% of adult (10, 11) asthma exacerbations, and rhinoviruses (RVs) account for two-thirds of virus detections....
[...]
TL;DR: In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids, the addition of formoterol to budesonid therapy or the use of a higher dose of budesonide may be beneficial.
Abstract: Background The role of long-acting, inhaled β2-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. Methods After a four-week run-in period of treatment with budesonide (800 μg twice daily), 852 patients being treated with glucocorticoids were randomly assigned to one of four treatments given twice daily by means of a dry-powder inhaler (Turbuhaler): 100 μg of budesonide plus placebo, 100 μg of budesonide plus 12 μg of formoterol, 400 μg of budesonide plus placebo, or 400 μg of budesonide plus 12 μg of formoterol. Terbutaline was permitted as needed. Treatment continued for one year; we compared the frequency of exacerbations of asthma, symptoms, and lung function in the four groups. A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days. Results T...
1,519 citations
"Rhinovirus-induced lower respirator..." refers background in this paper
...Inhaled steroids are associated with reduced risk of exacerbation (3); however, optimal therapy in adults reduces exacerbation frequency by only 40–50% (4, 5)....
[...]
...886 A, R Completed 60 22 F 400 h(5)g(2)b(3)3t(2)d(4) 101 6....
[...]
...64 A, R Baseline 62 22 F 355 h(5)c(2) 136 3....
[...]
...1d) in the asthmatic subjects [13 (5, 25)] compared with normal subjects [2 ( 1, 7)], P 0....
[...]
...794 A Completed 53 22 F 212 h(5) 118 7....
[...]
TL;DR: A causal link between deficient interferon-β, impaired apoptosis and increased virus replication is demonstrated, suggesting a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.
Abstract: Rhinoviruses are the major trigger of acute asthma exacerbations and asthmatic subjects are more susceptible to these infections. To investigate the underlying mechanisms of this increased susceptibility, we examined virus replication and innate responses to rhinovirus (RV)-16 infection of primary bronchial epithelial cells from asthmatic and healthy control subjects. Viral RNA expression and late virus release into supernatant was increased 50- and 7-fold, respectively in asthmatic cells compared with healthy controls. Virus infection induced late cell lysis in asthmatic cells but not in normal cells. Examination of the early cellular response to infection revealed impairment of virus induced caspase 3/7 activity and of apoptotic responses in the asthmatic cultures. Inhibition of apoptosis in normal cultures resulted in enhanced viral yield, comparable to that seen in infected asthmatic cultures. Examination of early innate immune responses revealed profound impairment of virus-induced interferon-beta mRNA expression in asthmatic cultures and they produced >2.5 times less interferon-beta protein. In infected asthmatic cells, exogenous interferon-beta induced apoptosis and reduced virus replication, demonstrating a causal link between deficient interferon-beta, impaired apoptosis and increased virus replication. These data suggest a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.
1,112 citations
TL;DR: In this paper, the authors show deficient induction of interferon-λs by rhinovirus in primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus induced asthma exacerbation and virus load in experimentally infected human volunteers.
Abstract: Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-λs by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.
927 citations
"Rhinovirus-induced lower respirator..." refers background or methods or result in this paper
...In the asthmatic group there was a significant inverse correlation between the maximum fall in PEF and CD4 IFN- production (c) and significant positive correlations between CD4 IL-4 (d), IL-5 (e), and IL-13 ( f) production and total chest symptom score....
[...]
...We observed that both IFN- (Fig....
[...]
...We found blood and BAL IFN- and IL-10 responses were associated with protection from RV-induced illness (lower virus loads, reduced symptoms, and less severe reduction in lung function), whereas the Th2 cytokines IL-4, IL-5, and IL-13 all were associated with more severe virus-induced asthma symptoms....
[...]
...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....
[...]
...We recently found increased RV replication and impaired IFN responses to ex vivo RV infection in primary bronchial epithelial cells from asthmatic compared with normal subjects (13, 14)....
[...]