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Does Respiratory Syncytial Viral–induced Bronchiolitis Result from Helper T Cell Type 1/Type 2 Cytokine Imbalance?

Departments of Pediatrics and Medicine University of Wisconsin Medical School Madison, Wisconsin

The epidemiologic association of infantile respiratory syncytial viral (RSV) bronchiolitis with the subsequent development of recurrent wheezing and/or asthma has intrigued many clinicians and scientists for decades. Data pertaining to these associations have been difficult to interpret because of a number of methodological concerns. Two recent prospective studies, however, have been able to document that antecedent RSV infections are risk factors for both recurrent wheezing (1) and physician-diagnosed asthma (2). An interesting paradox is that almost all children have been infected with RSV by age 2 (3). Thus, the elucidation of genetic, environmental, epidemiologic, and immunologic factors that predispose certain individuals to the development of chronic lower respiratory tract sequelae after these infections has been the subject of intense study.

Studies of immunologic mechanisms have focused primarily on cytokine dysregulation, with an imbalance of helper T cell (Th) type 1/type 2 cytokine response patterns being a major area of investigation in both humans and animal models. The G (attachment) and F (fusion) proteins are the major surface glycoproteins of RSV against which neutralizing antibody is directed. Interestingly, in both murine and human in vitro experiments, it has been noted that the G protein elicits a predominantly Th2 immune response, whereas the F protein produces a predominantly Th1 response. In murine models, RSV infections are associated with the development of airway hyperresponsiveness and an augmented allergic airway response. In humans, reduced IFN- expression in peripheral blood mononuclear cells of infants with severe RSV disease has been observed (4) as has a diminished production of IFN- by mononuclear cells both during and months after RSV bronchiolitis in only those children who develop subsequent asthma (5). In contrast, analyses of IFN- levels obtained from upper airway secretions during episodes of viral-induced wheezing have demonstrated an increased level of this Th1 cytokine (6). Secretion of the so-called Th2 cytokine, interleukin (IL)-10, by mononuclear cells has also been evaluated in relationship to RSV-induced bronchiolitis resulting in hospitalization (7). During the convalescent phase (3 to 4 weeks after illness onset), IL-10 responses were significantly increased in patients as compared with healthy control subjects. At follow-up, 58% of the children had recurrent episodes of wheezing. IL-10 levels, measured during the convalescent phase, were significantly higher in patients who developed recurrent wheezing during the year after RSV bronchiolitis than in patients who did not. Interestingly, no association was found between IFN- responses, IL-4 responses, or the ratio of IFN- to IL-4 and recurrent wheezing. In relationship to other viral infections that produce upper and lower respiratory tract symptoms, the mean ratio of IFN- to IL-10 was significantly lower (due to lower IFN-) during RSV infections than during infections with other viruses; the cytokine ratio, however, did not differ between infants with or without wheeze during these illnesses, or between infants who were atopic or nonatopic based on parental histories (8). In contrast, messenger RNA analyses of secretions obtained from both the upper and lower airway in children with acute RSV bronchiolitis have not demonstrated any specific cytokine polarization patterns (9). These disparate findings emphasize the importance of conducting more detailed prospective evaluations in order to ascertain definitively the biologic and prognostic significance of cytokine dysregulation and viral infections in relationship to the development of childhood asthma.

To provide additional insight into these potential relationships, in this issue of AJRCCM (pp. 633–639), Legg and coworkers (10) report their examination of in vivo cytokine response profiles in high-risk babies (at least one atopic parent with asthma) during a documented RSV illness. Of the 28 infants with RSV-associated respiratory tract disease, 9 developed signs of acute bronchiolitis. During their acute illness, nasal lavage IL-4/IFN- and IL-10/IL-12 ratios were significantly elevated in infants who developed bronchiolitis as compared with infants who did not. Similar evidence for Th2-polarized responses was seen when mononuclear cell messenger RNA levels were evaluated: IL-18 levels were reduced and the IL-4/IFN- ratio was elevated. Because the balance between Th1 and Th2 cytokine responses could be potentially influenced by viral load, and because these same imbalances may affect viral clearance (10), an important advance of the observations of Legg and coworkers (10) was the evaluation of RSV F-protein levels in nasal lavage fluid. Interestingly, although viral load did not differ between the groups, the infants with bronchiolitis showed a trend toward impairment of viral clearance.

The results from this well designed study provide further evidence that alterations in Th1/Th2 cytokine response patterns are associated with the pathogenesis of RSV-induced bronchiolitis. As one might anticipate, however, additional questions emerge from the reported findings. Despite the exclusive enrollment of children at high risk of maintaining Th2 skewed responses during infancy, the two distinct respiratory phenotypes that emerged following RSV infection would suggest that children who display even greater Th2-polarized responses are more likely to develop more severe respiratory tract involvement. Unfortunately, what the study cannot address is whether the children with bronchiolitis developed this type of clinical response because of more severe (at birth) and/or persistent (during development) Th2 skewing, and/or whether the host response to the virus itself was different in these individuals and initiated an even greater immune deviation in Th1/Th2 balance. In other words, did the aberrant cytokine response precede or follow the infection? An equally important unanswered question is whether this type of Th2-skewed response is unique to RSV (8). For example, if these children developed bronchiolitis related to rhinovirus (11) or parainfluenza virus (12), would the same cytokine pattern have been seen? Or is the susceptible host response deviant only in response to a specific virus (13)? Finally, although genetic analyses were not reported by Legg and colleagues (10), polymorphisms in genes that regulate cytokine responses (14, 15) and disease severity (16) in relationship to RSV and/or other viruses, which include genes encoding for IL-4 and IL-4R, are now being described. The precise contribution of these and other genetic polymorphisms to the diversity of respiratory phenotypes, both acutely (bronchiolitis) and chronically (subsequent development of asthma), await further definition. The answers to these and other important questions await future results from the current study as well as a number of other birth cohort studies being conducted worldwide, which are focusing on genetic (cytokine dysregulation) and environmental (respiratory tract infections) risk factors relevant to the development of various childhood respiratory phenotypes, including asthma.

FOOTNOTES

Conflict of Interest Statement: R.F.L. has no declared conflict of interest.

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