Published ahead of print on June 15, 2006, doi:10.1165/rcmb.2006-0199TR
American Journal of Respiratory Cell and Molecular Biology. Vol. 35, pp. 513-518, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2006-0199TR
Role of Viral Infections in Asthma and Chronic Obstructive Pulmonary Disease
David Proud and
Chung-Wai Chow
Airway Inflammation Group and Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta; and Division of Respirology, Department of Medicine, University of Toronto, and Toronto General Hospital of the University Health Network, Toronto, Ontario, Canada
Correspondence and requests for reprints should be addressed to David Proud, Ph.D., Professor & Head, Department of Physiology & Biophysics, University of Calgary, HSC 1627, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1 Canada. E-mail: dproud{at}ucalgary.ca
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Abstract
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Substantial evidence implicates common respiratory viral infections in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Children who experience recurrent virally induced wheezing episodes during infancy are at greater risk for developing asthma. In addition, respiratory viral infections are a major trigger for acute exacerbations of both asthma and COPD. Despite the importance of viral infections in asthma and COPD, the mechanisms by which viruses predispose to, or cause exacerbations of, these diseases remain poorly understood. It is clear that viral infections lead to enhanced airway inflammation and can cause airways hyperresponsiveness. The epithelial cell is the principal site of viral infection in the airways and plays a central role in viral modulation of airway inflammation via release of a variety of cytokines, chemokines, and growth factors. The mechanisms by which viral infections modulate epithelial function, therefore, is a topic of intense investigation. The epithelium also contributes to the host innate defense response to viral infection by releasing products that are antiviral and/or can lead to increased recruitment of dendritic cells and lymphocytes. Some evidence supports a role for the epithelial cell in specific immunity, although the response of more conventional cells of the immune system to viral infections is likely the dominant factor in this regard. Although current therapies may help combat virally induced disease exacerbations, they are less than ideal. A better understanding of the mechanisms underlying viral modulation of these diseases, therefore, may lead to new therapeutic approaches.
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VIRAL INFECTIONS IN THE DEVELOPMENT OF ASTHMA
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Respiratory viral infections are the most common cause of episodic wheezing in young children. Initial studies focused on the role of respiratory syncytial virus (RSV) as the dominant pathogen associated with bronchiolitis, particularly during the winter months. Longitudinal studies demonstrated that RSV bronchiolitis increases the risk of recurrent wheezing and asthma in young children (1, 2). Although the Tucson Children's Respiratory Study has shown that this risk decreases progressively with age and is no longer significant by age 13 (2), other studies indicate that RSV bronchiolitis severe enough to cause hospitalization in infancy is still a risk factor for allergic asthma into adolescence (3). The observation that virtually all children are infected with RSV by age 2 yr, but that only a subset develop episodic wheezing, suggests two possible explanations. First, other pathogens may contribute to asthma development, and second, some children are somehow predisposed to develop recurrent wheezing and viral infections are simply the major trigger to modulate lower airway function.
There is now clear evidence that other viral types are also associated with bronchiolitis and wheezing. Although human metapneumovirus, influenza, and parainfluenza are all associated with episodes of wheezing (4–6), several recent studies indicate that the dominant pathogen besides RSV detected during such episodes, particularly in children older than 6 mo of age, is human rhinovirus (HRV) (5–8). It appears that HRV infections contribute more substantially to asthma development than was previously appreciated. Not only has it been reported that children hospitalized with HRV-induced bronchiolitis are at particularly high risk for subsequent development of asthma (9, 10), but, in a recent study, HRV-induced lower respiratory illness during infancy was the single most significant risk factor for subsequent development of childhood wheezing (8).
Our understanding of host-specific factors that determine susceptibility to develop asthma remains limited, but several risk factors have been associated with the development of childhood wheezing. These include reduced lung function (11), exposure to passive cigarette smoke, a maternal history of asthma and elevated serum IgE (12), allergic sensitization (13), genetic polymorphisms (14–16), variations in host immune responses (17, 18), and potential effects on lung development or remodeling (19). Finally, the ability of multiple virus types to predispose to the development of asthma also raises the possibility that additional, virus-specific factors may determine the ability of individual viruses to induce wheezing, and additional studies will be necessary to delineate these.
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VIRAL INFECTIONS AND EXACERBATIONS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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Acute exacerbations of asthma account for half of the total health care costs associated with this disease and lead to the deaths of some 5,000 Americans each year. Similarly, acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of hospitalizations and death, and account for 70% of health care costs for the disease (20). Moreover, exacerbation frequency is a major determinant of health status and quality of life for patients with COPD.
Growing evidence implicates upper respiratory tract viral infections (URI) as the predominant risk factor associated with exacerbations of both asthma and COPD. There is a clear temporal relationship between outbreaks of URI and increases in hospitalizations for asthma exacerbations, with a marked peak in September (21, 22). Moreover, prospective studies using reverse transcription-polymerase chain reaction (RT-PCR) detected upper respiratory viruses in up to 60% of exacerbations in adults and in over 80% of exacerbations in children (23, 24). Although influenza, coronaviruses, parainfluenza, and RSV all contribute to exacerbations, the dominant pathogen detected was HRV. Similarly, recent studies indicate that about half of all COPD exacerbations are associated with viral infections, and that HRV is, again, the dominant viral pathogen (25, 26). Respiratory viral infections are associated with COPD exacerbations that are more frequent, severe, and have longer recovery times (25).
Despite overwhelming evidence linking respiratory viral infections with exacerbations of asthma and COPD, the specific pathways by which viruses induce disease exacerbations remain poorly understood. It is known that viral infections can lead to airway inflammation and, in subjects with asthma, increased airways responsiveness, perhaps via effects on neural control of airway function (27). Moreover, several studies have assessed whether responses to viral infection are altered in subjects with allergies or with asthma. No difference was observed in the frequency, duration, or severity of rhinovirus infections between subjects with asthma and those without asthma, but lower airway symptoms were more common in subjects with asthma (28). However, comparison of patients hospitalized with asthma exacerbations and subjects with stable asthma found sensitization and exposure to allergens to be an independent risk factor for hospitalization, suggesting that allergens and viruses act synergistically to exacerbate asthma (29). Studies of the interaction of experimental allergen exposure and experimental virus infection, however, have generated mixed results. Atopic subjects or subjects with asthma who have colds experience increased airway inflammatory responses to allergen provocation (30). By contrast, chronic low-dose allergen provocations did not alter subsequent lower airway responses to viral infection (31), and acute allergen challenge delayed onset and shortened the duration of common colds in the upper airways (32).
Although it remains possible that different viral types may induce disease exacerbations via variable mechanisms, it seems more likely that common aspects of viral pathogenesis dominate. Thus, although influenza and RSV are directly cytotoxic to the airway epithelium, HRV, the major pathogen associated with exacerbations of asthma and COPD, does not display overt cytotoxicity. In light of this, attention has focused on the concept that an overexuberant host response to viral infection may underlie disease exacerbations.
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ROLE OF THE EPITHELIUM IN VIRAL PROINFLAMMATORY RESPONSES IN THE AIRWAYS
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The airway epithelium is the primary target of inhaled pathogens and expresses receptors for several viral types. Indeed, in the case of HRV infections, the epithelial cell is, thus far, the only cell type in which virus has been detected in vivo. Moreover, in situ hybridization studies have clearly documented that HRV infections can spread to the lower airway epithelium (33). Thus, viral alterations of epithelial cell biology are likely to play a key role in enhancing airway inflammation in a manner that leads to disease exacerbations. In support of this concept, infection of human epithelial cells with HRV has been shown to lead to generation of a variety of proinflammatory chemokines, including IL-8 (CXCL8), ENA-78 (CXCL5), IP-10 (CXCL10), and RANTES (CCL5) (34–37), as well as cytokines, such as IL-1 , IL-6, GM-CSF, and IL-11 (38–41). Given that several of these products also are detected in airway secretions during HRV infections in vivo (35, 36, 42, 43), it is likely that they contribute to recruitment and activation of inflammatory cells during infections (Figure 1). The ability to induce proinflammatory cytokine production from epithelial cells is also shared by other viruses associated with exacerbations of asthma and COPD. For example, influenza infection has been shown to induce production of IL-6, IL-8, and RANTES (44), while RSV infection induces expression of a wide range of chemokine genes (45).
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Figure 1. Role of viruses in triggering exacerbations of asthma and COPD. Viral infection of the epithelium induces the generation of a variety of cytokines and chemokines, including IL-8, ENA-78 and IP-10, that can lead to the recruitment of inflammatory cells and a worsening of airway inflammation that could contribute to, or trigger, disease exacerbations. By contrast, virally infected epithelial cells also generate molecules that may contribute to host defense and antiviral response. For example, human -defensin 2 (HBD-2) can recruit immature dendritic cells and initiate a link between innate and specific immunity, while nitric oxide (NO) can have direct antiviral response and also suppress virally-induced chemokine production.
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Despite the important potential role of epithelial chemokine production in disease exacerbations, our understanding of the mechanisms by which virally induced chemokine production occurs remains limited. In the case of HRV infections, some products, such as IL-8, can be induced rapidly after viral exposure and do not seem to require viral replication (46). By contrast, other genes are not induced until several hours after infection and are absolutely dependent upon replicating virus (36). Little is known regarding early signaling events, although both phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways have been implicated in viral induction of chemokines (46–48). It has been suggested that late, replication-dependent chemokine production may be mediated via the generation the viral replication intermediate, double-stranded RNA, which mimics the production of such chemokines (36, 49). Although it is clear that viral induction of some cytokines and chemokines can occur via NF- B and/or interferon (IFN) regulatory factor–dependent transcriptional pathways (36, 50, 51), our understanding of the control of transcriptional and post-transcriptional regulation of epithelial cytokine and chemokine production in response to viral infection is limited and requires further study.
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IMMUNE AND HOST DEFENSE RESPONSES TO VIRAL INFECTION
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An important factor that may help determine susceptibility to virally induced disease exacerbations is the host immune and antiviral response to infection. Although the host defense to infection involves both innate and specific immunity, the innate response plays a particularly important role early after infection. In HRV infections, for example, antigen-specific humoral and cellular immune responses are usually not detectable until after the majority of symptoms have resolved.
As the initial site of viral infection, the epithelial cell contributes to the induction of the innate response in several ways (Figure 1). In addition to the release of cytokines and chemokines that can attract, and activate, cells of the immune system, epithelial cells can also produce human -defensin-2 (HBD-2) and HBD-3 in response to replicating virus (52). These defensins are chemotactic for immature dendritic cells expressing CCR6, as well as other cell types contributing to the immune response, and likely play an important role in linking innate and specific immunity (53). HBD-3 has also been reported to be able to inhibit influenza infection of epithelial cells by blocking membrane fusion (54).
Viral infection of epithelial cells also leads to increased expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) both in vitro and in vivo. NO appears to be an important component of the host antiviral response because it exerts direct antiviral activity against several viruses associated with exacerbations of asthma and COPD and also inhibits virally induced generation of several cytokines/chemokines from epithelial cells (55). Moreover, during experimental HRV infections in vivo, levels of epithelial iNOS induction correlate with levels of exhaled NO, and subjects with the highest levels of exhaled NO cleared virus more rapidly and had lower symptoms (56).
Type I interferons are also an important component of the innate immune response, as they induce numerous IFN-stimulated genes (ISGs) that collectively limit virus replication and spread. Type 1 interferons can be generated by several cell types. A recent report described marked impairment of rhinovirus-induced IFN- production in bronchial epithelial cells from subjects with asthma and suggested that this plays a role in increased susceptibility of subjects with asthma to lower airway disease (57). It must be noted, however, that there is also precedent for several viruses, including rhinovirus, to induce ISGs independently of IFN induction (36, 58).
Once significant viral replication occurs and newly synthesized viral particles are released in the airways, these particles can interact with other cell types, including monocytes/macrophages and dendritic cells, to stimulate the release of a variety of cytokines and chemokines that further contribute to the inflammatory milieu. Presumably, dendritic cells also initiate antigen presentation to T cells in the airways, although it also has been reported that HRV can inhibit the accessory function of dendritic cells (59). Epithelial cells also are likely to play a secondary role in immunomodulation as they express MHC class I and class II molecules, as well as numerous co-stimulatory molecules (60), and can internalize antigen and act in the context of class II MHC as antigen-presenting cells in vitro (61). They also can initiate T cell signaling and proliferation (62). Interestingly, intestinal epithelial cells infected with influenza have been shown to present viral antigens in the context of class I MHC to antigen-specific CD8+ cytotoxic T cells (63).
Limited data in humans suggest that patterns of cytokine induction may be related to the outcome of respiratory infections. Reduced peripheral blood mononuclear cell production of IFN- during RSV infection was observed in children who subsequently developed asthma (64). Mitogen-induced cord blood mononuclear cell production of IFN- also has been shown to be inversely related to the frequency of respiratory viral infections in infancy (17). Although it has been reported that IFN- levels are increased in nasal secretions during virally induced wheezing (65), a more recent study found that infections with RSV, influenza, or parainfluenza in early infancy are associated with a preferential production of TH2 cytokines, with IFN- being detected in only a modest proportion of subjects (66). In subjects experimentally inoculated with HRV, robust HRV-induced IFN- production from blood mononuclear cells was associated with lower levels of virus shedding (67). It has also been reported that subjects with asthma show reduced peripheral blood mononuclear cell production of IFN- in response to HRV stimulation compared with normal subjects (68). Although the physiologic relevance of examining peripheral blood responses to HRV is not clear, it is of interest that a higher ratio of IFN- to IL-5 mRNA in sputum cells during HRV infections was associated with lower symptoms and more rapid viral clearance (69).
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CURRENT AND POTENTIAL THERAPEUTIC APPROACHES
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In terms of control of childhood wheezing associated with viral infections, current drug therapies are less than ideal. Bronchodilators produce, at best, modest, short-term improvement in mild to moderate bronchiolitis, but do not affect rates or duration of hospitalization (70, 71). The role of corticosteroid therapy in virally induced childhood wheezing remains a topic of debate. Three months of inhaled corticosteroid therapy in wheezy infants did not lead to any improvement in lung function or symptoms compared with placebo (72). In addition, two recent studies have demonstrated that neither chronic administration of inhaled corticosteroids for two years, nor intermittent use of corticosteroids after wheezing episodes, was effective in preventing the development of chronic wheezing (73, 74). A meta-analysis of studies using systemic corticosteroids, however, led to the conclusion that these produced modest benefits (75). There may also be a useful role for leukotriene receptor inhibition in childhood asthma. A prospective, placebo-controlled trial in infants hospitalized for RSV bronchiolitis showed a small but significant inhibition of postbronchiolitis lower airway symptoms by montelukast (76). Moreover, montelukast was shown to reduce the number of virally induced asthma exacerbations in young children with intermittent asthma (77).
In adults, the use of corticosteroids, alone and in combination with long acting -agonists, or leukotriene receptor antagonists to maintain optimal asthma control, has proven efficacious in reducing numbers of asthma exacerbations, and the use of oral corticosteroids early in exacerbations helps prevent relapses. Similarly, there is mixed evidence regarding the ability of inhaled corticosteroids to reduce exacerbations of COPD (78, 79), but oral corticosteroids appear to hasten recovery from certain exacerbations (80). There have been no defined studies of the effects of these medications, however, in adults during asthma or COPD exacerbations of known viral origin. Corticosteroids have little efficacy in HRV-induced colds (81), and it is of interest that individuals with asthma who display prominent sputum neutrophilia, perhaps indicative of viral etiology, are poorly responsive to inhaled corticosteroids (82). Because of these limitations, alternative therapeutic approaches to virally induced airway disease continue to be sought.
An obvious alternative strategy is to use antiviral approaches. Influenza vaccine is clearly effective in preventing disease exacerbations induced by this virus during the winter months, but vaccination approaches have not been successful for RSV and are not feasible for HRV, give the large number of viral serotypes. Similarly, although neutralizing antibody prophylaxis for RSV-induced bronchiolitis is effective, cost factors limit the utility of this approach to patients at high risk for severe disease outcomes (83). Antiviral agents are available for influenza, and neuraminidase inhibitors have proven clinical efficacy in reducing development of disease. By contrast, while ribavirin treatment of infants with RSV bronchiolitis has been reported to reduce episodes of recurrent wheezing for the first year after treatment (84), other studies have found no reduction in asthma with longer periods of follow up (83). Antiviral agents targeted toward HRV also have been examined clinically. Both the novel capsid-binding inhibitor, pleconaril, and the 3C protease inhibitor, ruprintrivir, modestly reduce symptoms during HRV-induced colds (85, 86), but the ability of such compounds to modify viral exacerbations of asthma or COPD if given early in the cold have not yet been examined.
As we continue to gain greater insights into the mechanisms by which viral infections enhance production of specific proinflammatory cytokines, and into endogenous mechanisms of host defense, alternative therapeutic strategies may be derived. These could range from selective inhibitors of key virally induced signaling pathways in epithelial cells, to antagonists of specific chemokines that may play a key role in pathogenesis. Finally, enhancement of endogenous host antiviral pathways, or topical administration of drugs such as nitric oxide donors, may provide alternative approaches to reduce virally induced inflammation.
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Footnotes
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Originally Published in Press as DOI: 10.1165/rcmb.2006-0199TR on June 15, 2006
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Accepted in final form June 4, 2006
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Abstract
VIRAL INFECTIONS IN THE...