Relationship of viral infections to wheezing illnesses and asthma

Abstract

Viral infections can influence both the development and the severity of asthma. In early life, viral infections can either increase or, remarkably, decrease the risk of subsequent asthma. In children and adults with existing asthma, viral respiratory infections frequently cause acute airway obstruction and wheezing. This article discusses the influence of viral infections on mechanisms of virus-induced airway inflammation in relationship to the development, persistence and severity of asthma.

Figure 1. Airway inflammation in asthma.

Asthma is a complex and interactive process involving many cell types, mediators and target-organ responses. Furthermore, the process can involve a progression from acute events (a) such as allergen-induced activation of mast cells to release pro-inflammatory cytokines and mediators, leading to acute bronchoconstriction and airway obstruction, to chronic inflammation (b) characterized by activation of T helper (T_H) 2 cells and macrophages, and recruitment and degranulation of eosinophils. The changes in the airway cause not only airflow obstruction but also an increase in airway responsiveness. Finally, in some subjects, there is a further progression of the inflammatory changes towards airway remodelling (c). The remodelling changes can lead to permanent alterations in the airway architecture such that obstructive events are irreversible. IgE, immunoglobulin E; IL-4, interleukin 4; T_H1, T helper 1 cells; TNF-α, tumour necrosis factor α.

Figure 2. Possible relationships between respiratory syncytial virus infection, wheezing in infancy, and asthma.

Respiratory syncytial virus (RSV) bronchiolitis is associated with an increased risk of recurrent wheezing and asthma in childhood, but the nature of this association has not yet been clearly defined. It is possible that this is a causal relationship, and that RSV bronchiolitis alters immune responses or lung development to promote allergy or asthma. Alternately, RSV infection could be an early stimulus for wheezing in children who have a predisposition for allergies and asthma. These possibilities are not mutually exclusive, and are currently under investigation in longitudinal clinical studies.

Figure 3. The 'hygiene hypothesis'.

According to this theory, the immune system at birth is immature and is skewed towards T helper (T_H) 2-like cytokine production. Certain stimuli, such as infections with helminths or viruses (contracted from siblings or peers in day care centres), can help immunological development towards a healthy balance of T_H1 and T_H2-like cytokine responses. In the absence of these stimuli (that is, children who do not have contact with other children, or who live in relatively 'sterile' urban environments), the immature T_H2-like pattern of cytokine production persists, leading to an increased risk of asthma and other atopic diseases. LPS, lipopolysaccharide.

Figure 4. Mechanisms of virus-induced airway inflammation.

Viral replication in airway epithelial cells induces the secretion of chemokines such as interleukin (IL)-8 and RANTES (regulated on activation, normal T cell expressed and secreted); (CCL5), which recruit mononuclear cells and neutrophils into the airway. The recruited leukocytes, together with pre-existing eosinophils in allergic airways, contribute to the inflammatory milieu through the secretion of additional cytokines and mediators. Epithelial cells that are damaged by viral infection or airway inflammation are shed and, together with transudated plasma proteins and secreted mucus, contribute to airway obstruction. IFN-γ, interferon γ; TNF-α, tumour necrosis factor α.