Viral Infections in Asthma: A Persistent Problem

Vol. 14 •Issue 9 • Page 44
Viral Infections in Asthma: A Persistent Problem

The Majority of Pathogens That Lead to Worse Asthma Control Are Upper Respiratory Infections

Viral infections are a common occurrence throughout life and could play roles as initiators, progression factors or exacerbants of lung inflammation and airway dysfunction. Identification of these potential roles could provide new tools to treat or prevent asthma.

Asthma is a prevalent medical problem that affects adults and children worldwide. About 5 percent of individuals are affected in the U.S., and the incidence of asthma is increasing, particularly allergic asthma.1

While the factors contributing to the development and persistence of asthma in childhood are unclear, the triggers of asthma exacerbations are better defined. These include environmental causes such as heat, cold and humidity, allergen inhalation and irritant exposure.

However, the predominant trigger of asthma exacerbations is respiratory viral infections. In addition, viral infections may contribute to more severe exacerbations than other triggers. Isolation of virus among patients in exacerbation has been associated with a higher hospital admission rate and length of hospital stay.2

This is a particularly intriguing fact: With the exceptions of some early childhood viral infections of the lower airways, the majority of pathogens that lead to worse asthma control are upper respiratory infections.

While we have no answers for this biologic disconnect, we will try to answer several important questions regarding viral infections in asthma, focusing on the mechanism in which airway inflammation in asthma is affected by viral infection (of the upper and lower airways) and the potential role of childhood infections in the development of asthma.


The epidemiologic evidence associating viral infection and asthma exacerbations is convincing. Beyond the readily apparent clinical association between a common cold and asthma, there’s evidence from molecular biological analysis of nasal cultures that implicate viral infection as causative. Viral pathogens have been identified by reverse transcriptase-polymerase chain reaction in approximately 85 percent and 50 percent of asthma exacerbations in adults and children, respectively.2-4

There are some critical distinctions between the type of infections and their relation to seasonal variation in adults and young children.5 Wheezing exacerbations that lead to hospital admission in children (less than 3 years old) peak in the winter, where this distribution has a milder peak in late fall for older children and adults.

The predominant viral pathogen isolated from infants (less than or 1 year old) is respiratory syncytial virus (RSV), accounting for nearly 60 percent of viral wheezing exacerbations in infants less than 6 months old. RSV directly infects the smaller conducting airways of the lung. More severe infection may be a risk factor for the development of obstructive lung disease later in life, notably asthma.

But there’s also a distinction to be drawn between wheezing in infancy/childhood and asthma that persists later in life. Wheezing frequently complicates respiratory infections in childhood in infants who aren’t atopic, the majority of whom won’t become asthmatic.

With the exception of influenza (A and B), a lower respiratory virus that’s found in about 15 percent of wheezing episodes, all other viral pathogens primarily infect upper airway mucosa in nature. (The lower airway infectivity of some viruses can be experimentally optimized.)

The most prevalent is rhinovirus, RV, of which there are more than 80 serotypes. RV accounts for more than 60 percent of asthma-associated viral infections in adults and has been studied extensively as a trigger for asthma exacerbations.6,7

Other upper respiratory viruses are adenovirus, parainfluenza, enteroviruses, coronaviruses and metapneumovirus. These pathogens are essentially similarly prevalent in adults and children.


Several clinical co-factors have been found to predispose patients with asthma to worsening control during viral infection and suggest a direct interaction between the immune/tissue responses to viral infection and asthmatic inflammation.8 These factors include allergen exposure, pre-existing lung disease and air pollution.

Allergen exposure is the best studied of the three. As approximately 80 percent of asthmatics are atopic, it isn’t surprising that exposure to allergen leads to worsened asthma control.

In addition, there appears to be a synergistic effect of concomitant viral infection and allergen exposure on exacerbation severity. Adult asthmatics in exacerbation with concomitant allergen exposure and viral infection were eight times more likely to be admitted to a hospital than atopic asthmatics with an exacerbation due to viral infection alone.9

These clinical findings have been paralleled in studies of experimental viral upper respiratory infection in atopics, where nasal challenge with virus and allergen leads to augmented release of proinflammatory mediators from eosinophils.10 While these findings aren’t universal, they support the notion that viral infection has a specific interaction with allergic inflammation.11

The manner in which upper respiratory infection leads to bronchoconstriction of the lower airways is an area of active research whose scope is beyond the current review. Major proposed contributors are neural control mechanisms that mediate a connection between upper airway infection and lower airway hyperresponsiveness, systemic immune responses to viral antigens, and alteration of lower airway inflammation.

While the direct connection between the latter and viral infection remains elusive, changes in asthmatic lower airway inflammation with viral infection have been well-described and help understand their contribution to loss of asthma control.


Chronic asthma leads to a stereotypic pattern of airway inflammation that’s particularly noted in the large and small conducting airways.12 The major characteristics are infiltration of eosinophils and lymphocytes into the epithelium and subepithelium. From an immunologic perspective, these cells are activated in response to an allergic stimulus, which can be seen in the setting of atopy (systemic allergic sensitization to antigen) or parasitic infection.

It appears that what we have come to know as hay fever and asthma are likely a dysregulated immune response to essentially harmless antigens that develop in certain predisposed individuals, in which the immune system “sees” pollens, dust mites and pet antigens similarly to an invading parasite.

Specifically, CD4+ T cells are skewed to a phenotype that helps the growth of eosinophils and production of antigen-specific immunoglobulin E, which binds the surface of mast cells. These T cells, so-called T helper 2 (TH2) cells, secrete cytokines and chemical mediators that lead to two other critical findings in asthmatic bronchi, both of which specifically account for asthma symptoms: thickening of the bronchial smooth muscle that lines the airway and hypertrophy of the submucosal glands and epithelial goblet cells.

Together, these abnormalities contribute to airway narrowing that leads to wheeze — the former by increased smooth muscle contractility or “twitchiness,” the latter by increasing secretions into the airways.

Several cellular effects of viral infection appear to contribute directly to increased allergic inflammation in the airways of asthmatics. The systemic immune response to infection may be of an increased TH2 phenotype. Rhinovirus infection of atopic asthmatic peripheral leukocytes results in an increase TH2 cytokine release compared to normal controls.13 In the lungs, some investigators have found increased eosinophil infiltration after viral infection in asthmatic individuals.14 These studies suggest that there’s a specific effect of respiratory viral infection on allergic inflammation locally as well as systemically.

Other effects of viral infection on asthmatic inflammation highlight the central roles of epithelial cells and neural control mechanisms on the inflammatory milieu.8 As the interface between the environment and the immune system, the airway epithelium is poised to play a central role in regulating the immune response to infection, allergen or both.

Epithelial cells can be induced to release proinflammatory and immunomodulatory cytokines in response to viral infection such as CCL5, TNF-alpha, GM-CSF, IL-1beta and IL-8.15 A major contributor to inflammation that’s relevant to concomitant allergic inflammation and viral infection is IL-8. This neutrophil chemoattractant chemokine is identified in the sputum and bronchoalveolar lavage of RV-infected atopic asthmatics.7,16

While there’s good evidence from in vitro models that viral infection causes epithelial injury, evidence for a direct effect on supepithelial sensory and parasympathetic nerves is circumstantial. Yet a neural response must be postulated, at least in part, as many viral infections that lead to asthma exacerbation primarily infect the upper airways and cause lower airway inflammation and hyperresponsiveness, hallmarks of both chronic asthma and asthma exacerbations.


Viral infections and wheezing in infancy are closely associated.17,18 Asthma in infancy is unique in that the lung is only partially developed at birth. It will undergo a dramatic structural reorganization postnatally to increase alveolar number and surface area, reduce interstitial volume, and remodel the vascular system as the conversion from a secretory organ in the fluid-filled fetus to a highly efficient gas exchanger in the air-breathing neonate occurs.

The transformation is dramatic and appears to occur mainly over the first few years of life in humans.19 It’s highly regulated at the cellular level involving a complex interplay between proliferation, differentiation, migration, apoptosis, cell-cell interactions and cell-matrix interactions. Regulators include growth factors, hormones, environmental and mechanical factors.

The genetic components are slowly being unraveled with study of animal models.20,21 However, this transformation occurs largely in the absence of an acute inflammatory response even though a sophisticated innate immune defense system is evolving as the lung develops.22

An acute inflammatory response is elicited as a result of infection. Exact interactions between acute infection and lung development are limited, but viral pathogens are common and include RSV, rhinoviruses, parainfluenza viruses, metapneumoviruses and influenza viruses.

The relative role of pathogen (virus) vs. host (infant) factors in the susceptibility to wheezing are still under investigation.23 But it isn’t hard to imagine that activation of an acute inflammatory response onto the highly orchestrated lung developmental program could have a deleterious impact on lung structure and function, especially when later stages of the program depend on structural templates generated by specific events at earlier time periods.24

As one example, the inflammatory cytokine IL-1beta represses expression of fibulin-5 messenger RNA in rat interstitial fibroblasts.25 Fibulin-5 is a matrix molecule whose expression is key to the function of a well-known matrix molecule called elastin. Elastin regulates the formation of alveoli after birth and contributes to lung elasticity. Loss of fiblin-5 expression in the mouse lung leads to enlargement of airspaces and emphysema.26,27

Therefore, repression of fibulin-5 by inflammatory cytokines could impair formation of alveoli and lung elasticity. It isn’t yet known how well the lung can “repair” such a deficit later on.

Certainly there’s much to learn about the regulators of normal lung development and their interactions with inflammatory mediators, as well as host susceptibility factors that could predispose to infection.

Martin Joyce-Brady, MD, is director of the pulmonary care unit at Jewish Memorial Hospital and Rehabilitation Center in Boston, and associate professor of medicine at Boston University School of Medicine. Frédéric F. Little, MD, is assistant professor of medicine at Boston University School of Medicine.

For a list of references, please call Debra Yemenijian at (610) 278-1400, ext. 1153, or visit