ARTICLE

TOP ABSTRACT ARTICLE REFERENCES

Acute lower respiratory tract infections (ALRIs) in childhood are a major worldwide health problem, ranked first among conditions contributing to the global burden of disease in 1996 (1). Approximately 20-30% of ALRIs are viral in origin and 50% of these are attributed to respiratory syncytial virus (RSV), 13.9% to adenovirus, 7% to influenza, and approximately 5% to parainfluenza, with the remainder due to a variety of other viruses and a small percentage being due to more than one virus (2). Epidemiological studies have identified childhood infections as risk factors for the subsequent development of both asthma and chronic obstructive pulmonary disease (COPD), but much remains to be clarified as to the mechanisms involved in increasing this risk. The purpose of this presentation is to briefly review the role of childhood viral infections in the pathogenesis of adult obstructive lung disease.

Viruses are approximately 1/10 the diameter, 1/1,000 the volume, and much simpler in chemical composition than bacteria (3, 4). Their genome consists of only one type of nucleic acid, and this DNA or RNA can be either single or double stranded. The majority of viral respiratory infections are the result of infection with viruses that have a single-stranded RNA genome (3). This single strand of RNA is positively oriented (i.e., configured in the sense mode of host messenger RNA) in the rhinoviruses and coronaviruses, which account for the majority of the upper respiratory tract infections humans experience as the common cold. Viruses in which the single strand of RNA is negatively oriented (i.e., configured in the antisense mode of host messenger RNA) include influenza, parainfluenza, and respiratory syncytial viruses (3). These agents produce both upper and lower respiratory tract infections of varying severity and account for the bulk of lower respiratory tract viral infections in humans. Viruses that have a double-stranded DNA genome include several species that cause important respiratory tract infections. These include the herpes family of viruses, encompassing the cytomegalovirus and varicella zoster viruses, and the adenoviruses, which are a major cause of childhood bronchiolitis.

Viruses are obligate intercellular parasites that are well designed to enter cells and use the host nucleic acid- and protein-generating facilities to reproduce themselves. They attach to the host target cell by specific receptor-ligand interactions, enter the cell, and shed their envelope. The viral genome replicates itself, and the host protein-generating machinery is used to produce viral structural proteins. The newly produced genome and structural proteins are then packaged into complete viral particles, which are either shed from the host cell surface or released by lysis of the host cell. This cycle is repeated as the virus spreads from one target cell to the next.

An important determinant of the pathology produced in the respiratory tract is the host response to the viral particles. This response includes both the humoral and cellular arms of the immune system, which determine the nature of the inflammatory process generated in the infected tissue. In the case of common colds caused by rhinovirus and coronavirus, the host response accounts for the majority of the observed pathology (5). The lower respiratory tract disease produced by RSV infection is also generated primarily by the immune response (6), but the influenza virus and adenovirus, which are capable of lysing infected cells during the viral replicative cycle, can initiate an inflammatory response by directly damaging host tissue.

Naturally and experimentally induced episodes of viral respiratory tract infection are followed by the development of mild airway obstruction and bronchial hyperresponsiveness in children (7), adults (15, 16), and animals (17). These observations led naturally to the hypothesis that respiratory viral infections were important etiologic factors in the pathogenesis of both asthma and obstructive lung disease. The exact mechanism by which an acute episode of viral bronchitis and/ or bronchiolitis might contribute to the development of asthma and/or COPD has not been worked out. However, more recent thinking has been greatly influenced by the introduction of the concept that there are different types of helper T cell response. This hypothesis is based on the work of Mosmann and colleagues (21), who showed that the variation in cytokine profile produced during the immune response was regulated by subsets of CD4⁺ helper T cells. The response, which they described as the helper T cell type 2 (Th2) response, initiates an overproduction of interleukin (IL)-4, IL-5, and other cytokines that induce an inflammatory process in which there is increased production of IgE and attraction of eosinophils. This concept was taken up by investigators interested in asthma; they obtained evidence that the inflammatory reaction that underlies the lung tissue changes in asthma is the result of an excessive Th2-type immune response (25, 26).

The commonest form of childhood bronchiolitis is the result of RSV infection and several investigators have provided evidence consistent with those infections being associated with a Th2-type immune response. Strannegard and coworkers (27) have reported that children who develop high anti-RSV antibody titers in the postbronchiolitis period are more likely to become sensitized to environmental antigens and develop asthma. Animal studies by Hussell and coworkers (28) also show that the introduction of the RSV G protein into the lower respiratory tract via a viral vector induces a Th2 response. Interestingly, they also found that this Th2 response was modulated by a population of CD8⁺ cells and made the interesting suggestion that vaccines designed to enhance CD8⁺ T cell recognition might avoid Th2 disease. These and other suggestions concerning the mechanism by which a childhood viral infection initiates the asthmatic state are currently under active investigation.

Tabachnik and Levison (29) reported that 30% of individuals who develop childhood asthma and become symptom free as adolescents enter the asthmatic state as adults. They also reported that many adults with a history of childhood bronchiolitis who did not have symptomatic asthma demonstrated bronchial hyperresponsiveness when challenged. On the basis of this evidence, they suggest that the famous pediatric dictum that children "outgrow their asthma" is based on the fact that they outgrow their pediatricians rather than their disease. Macek and colleagues (30) reported a study of the development of persistent steroid-resistant asthma in the postbronchiolitic period. They monitored a large group of children after an episode of bronchiolitis in their clinic in Slovenia and found, like many others, that most children recover from acute bronchiolitis uneventfully. A smaller group developed a wheezing illness postinfection, and in most cases this asthma-like syndrome responded to appropriate therapy. However, a subset of the latter group failed to respond to adequate therapy and developed persistent steroid-resistant asthma. When they investigated this group of children by bronchoscopy and biopsy, they were able to demonstrate the presence of the adenoviral capsid protein in the lower airways of the majority of these children and were able to culture adenovirus from the lung in some cases.

Viral infections can persist after an episode of acute replicating viral infection by several mechanisms. In the case of herpesvirus, the genome persists in the cells of the posterior root ganglia of sensory nerves, where it can be intermittently induced to replicate complete herpesviruses, which then migrate down the nerves to produce the familiar herpetic eruptions in the skin of the dermatome supplied by the infected nerves. Adenovirus, on the other hand, persists in a latent form in which viral proteins are produced without replication of a complete virus. The possibility that latent adenoviral infections of this type are capable of amplifying cigarette smoke- induced lung inflammation to account for COPD has been a major focus of our more recent work (31).

Matsuse and colleagues were able to show that adenoviral E1A DNA persists in human lungs from patients with COPD compared with patients of similar age, sex, and smoking history who do not have COPD (31). Elliott and coworkers showed that airway epithelial cells produced the E1A protein in lungs from human cigarette smokers (32). Liu and Green (38) showed that the E1A adenoviral protein is capable of acting as an ubiquitous amplifier of many host genes by attaching to the DNA-binding sites of transcription factors. Our studies of E1A-transfected airway epithelial cells have shown that the E1A-positive cells produce excess inflammatory cytokines (IL-8) (33) and surface adhesion molecules (ICAM-1) (34) when challenged in vitro and that this involves the NF-B transcription factor (35). Vitalis and colleagues (36) developed an animal model of adenoviral infection in the guinea pig by depositing human adenovirus 5 in the nose, where it was aspirated into the lungs. They used a plaque assay to show that viral replication occurred in the guinea pig lung for several days after the nasal inoculation and demonstrated that the animals seroconverted to the infecting agent. In situ hybridization was used to show that viral DNA was in the nucleus of the airway epithelial cells during the acute infection, and the polymerase chain reaction (PCR) was used to demonstrate that this viral DNA persisted in the lower respiratory tract weeks after the acute infection had cleared. It is interesting that this latent infection was associated with a persistent bronchiolitis in these animals even though the animals did not appear sick and ate and drank normally. Subsequent studies showed that those animals with a latent infection showed a greater response to a single dose of cigarette smoke than did control animals who did not have a latent viral infection, suggesting that the latent viral infection is capable of amplifying the cigarette smoke-induced inflammatory response (37).

An important difference between asthma and COPD is that the former shows a favorable response to steroid therapy whereas the latter does not. The work of Macek and coworkers in humans (30) and of Vitalis and colleagues in animals (37) is of interest. Macek and coworkers found evidence of persistent adenoviral infection in asthmatic children who had a viral illness before the development of steroid-resistant asthma. The observation by Vitalis and colleagues that latent adenoviral infection was associated with a low-grade peripheral lung inflammation is also of interest, because the airway lesions showed mucous plugging and cellular infiltration similar to that seen in the asthmatic state (37). The possibility that latent adenoviral infection might lead to a chronic low-level inflammatory process in the peripheral lung that is steroid resistant is currently under active investigation.