The role of rhinovirus in asthma exacerbations

Rhinoviruses are a major cause of asthma exacerbations in children and adults. With the use of sensitive RT-PCR methods, respiratory viruses are found in approximately 80% of wheezing episodes in children and in approximately one half of such episodes in adults. Rhinovirus is a member of the family Picornaviridae, and acute rhinovirus infections occur predominantly in the upper airway. This virus has also been identified in the lower airway, and it might cause acute wheezing through the production of proinflammatory mediators with a resulting neutrophilic inflammatory response. Precisely how this process leads to increases in airway hyperresponsiveness and airway obstruction is not fully established. However, risk factors for wheezing with colds include asthma and atopy, extremes in age, and perhaps having a deficient TH1 response to rhinovirus. With the use of in vitro models and experimental inoculation studies, significant advances have led to a better understanding of the mechanisms by which rhinovirus infections cause asthma exacerbations. Advances in our understanding of this interaction might provide knowledge that could ultimately lead to specific treatment modalities to prevent and/or treat this significant burden of asthma exacerbations.     

Role of rhinovirus infections in asthma

Human rhinoviruses are not only the main pathogens responsible for the common cold, but are now recognized to have a major impact on asthma pathogenesis. There is evidence that rhinovirus infections play a role in asthma development, asthma exacerbations and, potentially, airway remodeling. Children who experience repeated rhinovirus-induced wheezing episodes in infancy have a significantly increased risk of developing asthma, even when compared to children who experience wheezing induced by respiratory syncytial virus. Rhinovirus is also the dominant virus type associated with acute exacerbations of asthma. The epithelial cell is the principal site of rhinovirus infection in both the upper and lower airways and there is strong evidence that virus-induced alterations of epithelial cell biology play a critical role in regulating clinical outcomes. This includes rhinovirus-induced epithelial generation of a variety of chemokines, cytokines and growth factors that likely play a role in viral modulation of airway inflammation. It has also become clear, however, that epithelial cells play an important role in the innate antiviral response to rhinovirus infection, raising the possibility that the relative induction of epithelial host innate antiviral responses versus proinflammatory responses may be one factor regulating the susceptibility of asthmatic subjects to virus-induced disease exacerbations. Recent evidence has also highlighted that rhinovirus infection induces epithelial production of a number of growth factors and other mediators that could contribute to the development and progression of airway remodeling processes in asthma. The current article reviews our current state of knowledge in these areas.     

Clinical effects of rhinovirus infections

Rhinovirus is the major cause of common cold and frequently associates with acute wheezing, otitis media, sinusitis, and pneumonia. High prevalence of rhinovirus in hospitalized children and adults has been documented recently. We screened children > or =1 month of age, hospitalized for any infection, for the presence of rhinoviruses and recruited 24 families with > or =2 children for a 3-week follow-up study. Rhinovirus was detected in 46 (28%) of 163 hospitalizations by study children. Most rhinovirus-positive children (85%) had respiratory symptoms. During the follow-up, rhinoviruses were detected in virtually all children and in one-half of adults in families with a rhinovirus-positive index child, but commonly also in families with a rhinovirus-negative index child. Melting temperature and sequence analysis revealed the transmission routes of the viruses and showed that several virus types could circulate in the families simultaneously. Our studies corroborate the major contribution of rhinovirus to hospitalization of children, most often because of wheezing. Young children with respiratory symptoms are major spreaders of rhinovirus in family setting.     

Genetic analysis of asthma exacerbations

BackgroundIdentifying genetic markers of susceptibility to exacerbations may improve patient management, decrease morbidity, and lead to drug development.ObjectivesTo assess whether genetic markers associated with severe asthma exacerbations in previous reports are associated with less severe events that do not require intensive care and intubation and to identify additional markers in candidate genes and throughout the genome.MethodsA total of 199 patients and 502 controls (individuals without an exacerbation) were identified from 4 clinical trials. We genotyped 51 markers from 17 genes previously reported to be associated with exacerbations; a whole genome scan was used to identify additional markers. Admixture analysis was conducted to characterize the presence of ancestral groups. The genetic marker effects were assessed by logistic regression for each study followed by a meta-analysis.ResultsSeveral coding variants in the IL4R gene had a genetic effect across 3 studies, including rs1805011 in IL4R (P < .0006). In addition, 3 markers in the IFNB1 gene showed evidence of association (P < .002) but only in the study with African Americans. Because these markers did not meet the prespecified multiplicity-adjusted significance level of P = .0002, we were unable to confirm previously published results for less severe events. The whole genome scan identified genes related to mast cell mediator release. The admixture analysis suggests that ancestry was best characterized by the presence of 3 ancestral groups.ConclusionWe were unable to confirm previously reported associations of genetic markers with asthma exacerbations. Although, in general, the patients studied had less severe asthma than patients in earlier reports, these results suggest involvement of similar pathways.Trial Registrationclinicaltrials.gov Identifiers: NTC00452699, NCT00452348, NTC00102765, NCT00843193.     

Nasal interferon responses to community rhinovirus infections are similar in controls and children with asthma

BackgroundRhinovirus (RV) is the main cause of asthma exacerbations in children. Some studies reported that persons with asthma have attenuated interferon (IFN) responses to experimental RV infection compared with healthy individuals. However, responses to community-acquired RV infections in controls and children with asthma have not been compared.ObjectiveTo evaluate nasal cytokine responses after natural RV infections in people with asthma and healthy children.MethodsWe compared nasal cytokine expression among controls and children with asthma during healthy, virus-negative surveillance weeks and self-reported RV-positive sick weeks. A total of 14 controls and 21 patients with asthma were studied. Asthma disease severity was based on symptoms and medication use. Viral genome was detected by multiplex polymerase chain reaction. Nasal cytokine protein levels were determined by multiplex assays.ResultsTwo out of 47 surveillance weeks tested positive for RV, illustrating an asymptomatic infection rate of 5%. A total of 38 of 47 sick weeks (81%) tested positive for the respiratory virus. Of these, 33 (87%) were positive for RV. During well weeks, nasal interleukin 8 (IL-8), IL-12, and IL-1β levels were higher in children with asthma than controls. Compared with healthy virus-negative surveillance weeks, IL-8, IL-13, and interferon beta increased during colds only in patients with asthma. In both controls and children with asthma, the nasal levels of interferon gamma, interferon lambda-1, IL-1β, IL-8, and IL-10 increased during RV-positive sick weeks. During RV infection, IL-8, IL-1β, and tumor necrosis factor-α levels were strongly correlated.ConclusionIn both controls and patients with asthma, natural RV infection results in robust type II and III IFN responses.     

Therapeutic strategies to reduce asthma exacerbations

Asthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled β?-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled β?-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled β?-agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti-IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations.     

EAACI position statement on asthma exacerbations and severe asthma

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult‐to‐treat asthma and severe treatment‐resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment‐resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult‐to‐control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult‐to‐control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.     

Clinical correlates of rhinovirus infection in preschool asthma

Background

Investigation of preschool asthma is important since not all children outgrow their illness during this age. Data are scarce on the role of rhinovirus (RV) infections in this patient group.

Objectives

To investigate the role of RV infections in preschool asthma: (i) susceptibility factors, (ii) clinical course, and (iii) medium-term outcome.

Methods

A total of 130 asthmatic children aged 4-6 years from the multinational PreDicta cohort were prospectively followed for a 12-month period. Allergy tests and a standard health questionnaire were carried out at study entry. Respiratory virus presence in nasopharyngeal washes was studied at illness visits and at 3 scheduled visits.

Results

At study entry, mean age of the children was 5.3 years. Of 571 visits, 54% were positive for any virus and 39% for RV. Patient characteristics were only assessed with RV infection due to low number of other viruses. The use of supplementary vitamin D was inversely associated with RV infection (P < .05). RV infection was associated with more severe course of acute illness in terms of more severe nighttime coughing, more sleep disturbances, and more days with runny nose (all P < .05). RV infection was also associated with more severe disease course during the 12-month follow-up in terms of more nights with awakenings and more days of exercise-related symptoms (both P < .05).

Conclusions

Vitamin D supplementation may have an anti-rhinovirus effect. Both short- and medium-term outcomes suggest RV infection to be an important clinical marker of instable preschool asthma.

     

Detection of viral, Chlamydia pneumoniae and Mycoplasma pneumoniae infections in exacerbations of asthma in children.

BACKGROUND: A high frequency of virus infections has been recently pointed out in the exacerbations of asthma in children. OBJECTIVES: To confirm this, using conventional and molecular detection methods, and expanding the study to younger children. STUDY DESIGN: One hundred and thirty-two nasal aspirates from 75 children hospitalized for a severe attack of asthma were studied (32 infants, mean age 9.1 months; and 43 children, mean age 5.6 years). According to the virus, a viral isolation technique, immunofluorescence assays (IFA) or both were used for the detection of rhinovirus, enterovirus, respiratory syncytial (RS) virus, adenovirus, coronavirus 229E, influenza and parainfluenza virus. Polymerase chain reaction (PCR) assays were used for the detection of rhinovirus, enterovirus, RS virus, adenovirus, coronavirus 229E and OC43, Chlamydia pneumoniae and Mycoplasma pneumoniae. RESULTS: Using IFA and viral isolation techniques, viruses were detected in 33.3% of cases, and by PCR techniques, nucleic acid sequences of virus, Chlamydia pneumoniae and Mycoplasma pneumoniae were obtained in 71.9% of cases. The combination of conventional and molecular techniques detects 81.8% of positive samples. Two organisms were identified in the same nasal sample in 20.4% of the cases. The percentage of detections was higher (85.9%) in the younger group than in the other (77%). The most frequently detected agents were rhinovirus (46.9%) and RS virus (21.2%). Using PCR rather than conventional techniques, the detection rates were increased 5.8- and 1.6-fold in rhinovirus and RS virus infections, respectively. The detection levels of the other organisms are as follows: 9.8, 5.1, 4.5, 4.5, 4.5, 3.7, and 2.2% for enterovirus, influenza virus, Chlamydia pneumoniae, adenovirus, coronavirus, parainfluenza virus, and Mycoplasma pneumoniae, respectively. CONCLUSION: These results confirm the previously reported high frequency of rhinovirus detection in asthmatic exacerbations in children. They also point out the frequency of RS virus detection, and emphasize the fact that PCR assays may be necessary to diagnose respiratory infections in asthma.