|Year : 2015 | Volume
| Issue : 3 | Page : 285-289
Asthma exacerbations: Understanding role of viral respiratory tract infections and possible treatment strategies
Kavita Sekhri1, Deepak Bhasin2
1 Department of Pulmonology and Critical Care Medicine, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Chandigarh, India
2 Medical Intensive Care Unit, Max Super Speciality Hospital, Mohali, Punjab, India
|Date of Web Publication||15-May-2015|
Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Sector 25, Panjab University, Chandigarh - 160 014
Source of Support: None, Conflict of Interest: None
Asthma is common, affecting around 500 billion people worldwide. It is a complex disease influenced by both genetic and environmental factors. Upper respiratory tract infections with viruses commonly precipitate severe and sustained asthma exacerbations (AEs). Exacerbations are responsible for the enormous amount of emotional and economic stress apart from imposing risk of hospitalization and even death. Hence, agents targeting these infections can contribute toward decreasing asthma morbidity and associated financial burden. Over the past years novel, pharmacological therapies are evolved for the treatment of asthma, but their exact role in exacerbations is still unclear. This article reviews the role of respiratory viral infections in AEs and discusses role of new therapeutic approaches to overcome it. Medline, Medscape, EMBASE, Cochrane database, Scopus and clinicaltrials.gov were searched using terms such as "asthma," "AE" and "viral respiratory infections." Journal articles published from 2000 to 2013 describing AEs were screened.
Keywords: Asthma, asthma exacerbations, viral respiratory infections, virus
|How to cite this article:|
Sekhri K, Bhasin D. Asthma exacerbations: Understanding role of viral respiratory tract infections and possible treatment strategies. Med J DY Patil Univ 2015;8:285-9
|How to cite this URL:|
Sekhri K, Bhasin D. Asthma exacerbations: Understanding role of viral respiratory tract infections and possible treatment strategies. Med J DY Patil Univ [serial online] 2015 [cited 2020 Jun 2];8:285-9. Available from: http://www.mjdrdypu.org/text.asp?2015/8/3/285/157063
| Introduction|| |
Asthma can be diagnosed at any age and throughout life, continuing dynamic association is seen between it and genetics, immune system, environmental factors or infections.  Asthma has increased to epidemic proportions and is estimated to affect 500 million people worldwide.  The natural history of asthma is marked by exacerbations that are the main cause of its morbidity.  Viral respiratory tract infections are an important trigger for exacerbations of asthma in both adults and children.  The typical viruses are known to cause exacerbations are rhinovirus (RV), respiratory syncytial virus, influenza, coronavirus and parainfluenza virus.  Limited current therapies for the treatment of virus-induced exacerbations highlight the need for alternative and novel therapies in the future. This article reviews the role of respiratory viral infections in asthma exacerbations (AEs) and potential new therapeutic approaches to overcome them.
| Asthma Exacerbation|| |
Several definitions of AE have been given by various groups like Global Initiative for Asthma or American Thoracic Society/European Respiratory Society. In 2011, National Institutes of Health institutes and other federal agencies proposed definition of AE as "worsening of asthma requiring the use of systemic corticosteroids (or for patients on a stable maintenance dose, an increase in the use of systemic corticosteroids) to prevent a serious outcome". 
| Viruses and Asthma|| |
Viral respiratory tract infections are associated with asthma in many ways. Viruses play a major role in causing wheezing episodes in early life leading to disease inception in infancy and acute exacerbations in established asthma. 
There is a bidirectional relationship between allergy and viral infections. Atopic state can modify the lower respiratory responses to viral infection, and viral infections can influence the development of allergen sensitization.  Viral respiratory infections and allergy synergistically increases the risk of AE in children.  Viral upper respiratory infections have been detected in 85% of childhood AEs and more than half of adult exacerbations, these are responsible for hospitalization. 
The major viruses associated with AEs are RV, which accounts for approximately 60% of all AE in all age groups.  Newer molecular techniques like polymerase chain reaction (PCR), Multiple PCR, sequencing, microarrays in virus detection have identified new classes of viruses such as metapneumoviruses, bocaviruses, new strains of coronaviruses and polyomaviruses some of which are associated with AEs.  RVs are members of Picornaviridae family, with single-stranded RNA and having more than 100 serotypes. Based on genetic sequence similarity they are divided into RV-A and RV-B groups. Recently, RV-C has been identified which is found to be more virulent and prone to cause AEs when compared to other RVs.  These RV-C group of viruses do not grow easily in standard tissue culture and are diagnosed only with newer molecular diagnostic techniques. 
| Mechanisms Underlying Exacerbation of Asthma|| |
Acute viral infections are found to be associated with alternations in airway physiology like increased airway responsiveness or abnormalities in airflow, lung volumes and gas exchange.  Bronchial epithelial cells (BECs), which form a pseudo stratified cubic epithelium are important defense mechanism against bacteria and viruses.  They are the principal cells involved in RV infection that initiate an immune response and allows viral entry and replication. It is seen that intercellular adhesion molecule-1 (ICAM-1) expression (site of attachment of majority of RV serotypes) is increased on respiratory BECs in asthma. This can explain the increased tissue susceptibility and complications in asthmatic patients. , Even RV infection itself can increase ICAM-1 expression through the interleukin (IL-1β) and nuclear factor-k-β production. 
Hence, respiratory tract viruses can cause direct cytotoxic effect by damaging ciliated as well as nonciliated respiratory epithelial cells leading to necrosis, ciliostasis, loss of cilia and impairment of mucociliary clearance as well as by inducing the secretion of various cytokines and chemokines like in RV there is production of IL-1, IL-6, CXCL8/IL-8, Granulocyte macrophage colony stimulating factor, CCL5/RANTES and CXCL10/interferon (IFN)-inducible protein 10.  [Figure 1] These proinflammatory cytokines, monokines and inflammatory substances produced in airway epithelial cells may further affect the barrier function of these cells causing increased permeability to allergens resulting in recruitment and activation of immune cells. , There is infiltration of cells like neutrophils, lymphocytes and eosinophils in the airways either directly or by cytokines.  These further secrete various cytokines that results in antiviral effects but also contribute to airway inflammation and exacerbation of symptoms.  There is also an expression of toll-like receptors (TLRs) like TLR2, TLR3 and TLR4 on Lung epithelial cells, respiratory smooth muscle cells, macrophages and dendritic cells. Infection with respiratory viruses activates these TLRs thereby activating these cells to produce proinflammatory cytokines and mucus production. 
|Figure 1: Rhinovirus-induced release of different mediators from the Bronchial Epithelial Cells which results in airway hyperresponsiveness and remodeling. (interleukin, granulocyte macrophage colony stimulating factor) with permission from Elseiver 2005|
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There is an altered antiviral response in asthma. Allergic inflammation can suppress antiviral immunity as was shown by Gill et al.  The dendritic cells which are main contributor to immune defense show reduced production of IFN-α during respiratory viral infections. Dendritic cells can also have a role in allergic sensitization. Human RVs infection and allergic inflammation both induce epithelial cells to secrete thymic stromal lymphopoietin, which can induce various cells like dendritic cells to promote Th2 differentiation in turn enhancing allergic inflammation.  Subrata et al. demonstrated in 67 children suffering from AE to have decreased circulatory lymphocytes and increased expression of CCR2 chemokine receptor on monocytes and dendritic cells, which have potential to provoke inflammation. 
Impaired innate responses in asthmatic patients have been suggested to be associated with higher susceptibility to RV infection. Wark et al. demonstrated impairment of IFN-β in BECs, and contoli et al. showed deficient production of IFN-ë induced by RV in bronchoalveolar cells to be related to severity of RV-induced AEs. , Similarly Bullens et al. demonstrated a protective role of IFN-ë in asthma.  It was found that IFN-ë is negatively related to airway symptoms score, changes in lung function, virus load and markers of inflammation.  This leads to increased viral replication and delayed viral clearance in asthmatic epithelium. BEC also constitutively produce TGF-β, which is an immunosuppressive cytokine leading to suppression of host IFN responses to virus infection. Its concentration is found to decrease in asthma thereby enhancing the RV replication. 
Rhinovirus infects primarily the upper airways, but it is prone to spread to bronchi in asthma.  It has been found in patients of asthma that Rhinovirus is more commonly found in lower airways and such patients suffer from more prolonged illness due to this as compared to nonasthmatics. 
| Pathological Finding during Exacerbation|| |
Induced sputum is used to study cellular events during AE. But it does not provide a complete picture. Studies have shown bronchial eosinophilia in experimentally induced exacerbations.  However in severe cases of refractory asthma, neutrophils are involved rather than eosinophils and in these patients neutrophil counts are already high in a stable state so that no significant rise is seen during exacerbation. Bronchial biopsies from adult AE cases have shown increased eosinophils, neutrophils, CXC chemokines and chemokine receptors as compared to stable asthmatic controls. It was suggested by Botturi et al. that mixed Th1 and Th2 activation was hallmark of AEs. After viral infections, BEC switch their phenotype from tolerant to proinflammatory and attracts and activates immune cells including effector T cells. 
Mucus overproduction is one of the major symptoms of AE. MUC5AC and MUC5B are main mucin components which are responsible for viscoelastic properties of the mucus.  It's been experimentally demonstrated that MUC5AC production is increased in BECs in RV infection, and this is correlated to virus load in asthmatic subjects only and not in healthy volunteers. 
| Treatment Options|| |
Several interventions can be implemented to alter the history of the virus-induced AEs. Inhalational corticosteroid like budesonide therapy is found to decrease exacerbations by 25% in newly diagnosed mild persistent asthma.  This therapy effectively suppresses RV mediated induction of proinflammatory mediators like CCL5, CXCL8, Il-6, CXCL10 and fibroblast growth factor and vascular endothelial growth factor in BECs.  Combination therapy with budenoside and formoterol (long acting β2 agonist) has been demonstrated to be effective in decreasing AE and related hospitalization.  Broadly, mechanism underlying AEs can be targeted either by abolishing viral replication or by antagonizing TH 2 responses [Table 1].
Rhinovirus is implicated in the majority of AEs but due to its antigenic diversity and more than 100 serotypes, creation of an effective respiratory syncytial virus (RSV) vaccine is extremely difficult. The only vaccines available are against influenza virus.  Vaccination against pandemic HINI influenza is recommended in asthmatics as asthma is recognized to be one of the comorbid factors in HINI pandemic. However, there is a dispute regarding the benefit of vaccination in AEs.
Nowadays, certain ligands are used as adjuvant in the development of vaccines. Monophosphoryl lipid A is a derivative of bacterial lipopolysaccharide which when incorporated with RSV virosomes demonstrated an increase Th1 response and production of IFN-γ in animals. 
As there is reduced induction of IFNα, IFNβ, IFN-ë in asthmatics the role of IFN therapy in AE seems to be promising. Recently, trial of inhaled IFN-β in adult atopic asthmatics showed reduced rates of AE and improved lung function. It has been suggested that IFN-β acts by reducing virus replication thereby reducing inflammation and by antagonizing TH 2 responses induced by allergens.  Advantage of developing IFN therapy is that it can treat all virus-induced asthma attacks instead of just those caused by specific virus. 
Toll like receptor 7/8 agonists
It has been found that TLR7 agonist R848 (imiquinod) reduces eosinophilic inflammation and impairment of lung function and hence may be useful in treating allergic diseases like asthma.  Recently, Drake et al. demonstrated dose-dependent relaxation of methacholine-contracted human airways in vitro with TLR7 agonist imiquinod. 
The humanized antiIgE mab omalizumab has shown a reduction in both number and duration of AEs in adult allergic asthma.  In a recent study conducted on 767 patients, it was shown that addon omalizumab in uncontrolled severe asthma is associated with a significantly decreased risk of hospitalization or emergency visits as compared to no add-on omalizumab group. 
Mepolizumab, anti-IL-5 mAb reduces blood eosinophil counts as IL-5 is required for maturation and differentiation of eosinophils. Studies are conducted, which demonstrate that mepolizumab is an effective and well-tolerated treatment that reduces the risk of AEs in patients with severe eosinophilic asthma. 
Lebrikizumab (anti-IL-13) demonstrated decrease in the rate of exacerbations in "high TH 2" subgroup than in the placebo group.  Palivizumab and motavizumab are used for immunoprophylaxis in RSV. Palivizumab has been licensed for use in humans whereas motavizumab is not yet licensed. Fi6 v3 and PN-SIA28 mabs are being investigated against Group 1 and 2 influenza A virus. 
AMG157 is another fully humanized monoclonal antibody developed against thymic stromal lymphopoietin. It is being studied for its potential as a treatment for asthma. 
Macrolide antibiotics have distinct immunomodulatory effects. They decrease excessive production of cytokines in viral infections and hence may reduce virus-related exacerbations.  There are studies demonstrating decreased IL-6, IL-8 and ICAM-1 expression in BECs or increased type I and III IFN's after clarithromycin and azithromycin administration respectively. , Another macrolide antibiotic bafilomycin A 1 has been shown to inhibit the production of IL-6, IL-8, and ICAM-1 in human tracheal epithelial cells in RV14 infection.  This provides a rationale for their use in AEs.
AZISAST trial, a randomized double-blind placebo controlled trial conducted in Belgium in patients with exacerbation prone severe asthma revealed that azithromycin causes significant reduction in the rate of severe exacerbations and (Lower Respiratory Tract Infection)LRTI requiring treatment with antibiotics. However, this was reported only in the subgroup of noneosinophilic severe asthma patients. There is a need for further research to exactly establish their role in the management of AEs or they can be employed in set of patients according to inflammatory phenotype. 
| Patient Education|| |
Last but not the least; nowadays self-management is greatly emphasized. The patient's ability to assess the risk for AE can go a long way to reducing asthma morbidity. There are self-management programs educating about self-monitoring including written action plan and regular medical review. 
| Conclusion|| |
As viral infections can trigger severe episodes of AEs, development of antiviral medications can have a major impact on the reduction of severity and frequency of such episodes. Current options for the treatment of AEs are limited. But with the development of experimental human and murine models of virus induced AEs, opportunities have been created to better understand the complex mechanisms which provokes asthma and to identify new targets for novel therapies. Even virus-induced exacerbations can be used as criteria to characterize asthma phenotypes so that interventions could be tailored to suit the specific type.  Ongoing extensive studies of immunologic, virologic and physiological measures in the lower respiratory tract during viral infections in asthmatics are a road towards the development of targeted therapy. Hence, future goal should be to develop personalized therapy for individual patients.
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