Does respiratory syncytial viral-induced bronchiolitis result from helper T cell type 1/type 2 cytokine imbalance?

The epidemiologic association of infantile respiratory syncytial viral (RSV) bronchiolitis with the following 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 affects Two recent prospective studies, however, have been able to document that antecedent RSV infections are risk factors for the two recurrent wheezing (1) and physician-diagnosed asthma (2) An interesting paradox is that almost all children have been infected with RSV at age 2 (3). Thus, the elucidation of genetic, environmental, epidemiologic, and immunologic factors that predispose certain individuals to the unravelling of chronic lower respiratory tract sequelae after these infections has been the make subordinate of intense study.

Studies of immunologic mechanisms have focused primarily upon cytokine dysregulation, with an imbalance of helper T solitary abode; squalid (Th) type 1/type 2 cytokine rejoinder patterns being a major area of investigation in the two 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 one as well as the other murine and human in vitro experiments, it has been noted that the G protein elicits a predominantly Th2 immune replication whereas the F protein yields a predominantly Th1 response. In murine designs RSV infections are associated with the growth of airway hyperresponsiveness and an augmented allergic airway answer In humans, reduced IFN-[gamma] expression in peripheral posterity mononuclear cells of infants with exact RSV disease has been observ (4) as has a diminished production of IFN-[gamma] through mononuclear cells both during and month after RSV bronchiolitis in no other than those children who develop succeeding asthma (5). In contrast, analyses of IFN-[gamma] horizontals obtained from upper airway secretions during episodes of viral-induced wheezing have demonstrated an increased of the same height of this Th1 cytokine (6) Secretion of the so-called Th2 cytokine, interleukin (IL)-10, according to 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 replys were significantly increased in patients as compared with healthy manage subjects. At follow-up, 58% of the children had intermittent episodes of wheezing. IL-10 horizontals measured during the convalescent phase, were significantly higher in patients who lay opened recurrent wheezing during the year after RSV bronchiolitis than in patients who did not. Interestingly, no association was ground between IFN-[gamma] responses, IL-4 replications or the ratio of IFN-[gamma] to IL-4 and periodical wheezing. In relationship to other viral infections that generate upper and lower respiratory tract symptoms, the mean ratio of IFN-[gamma] to IL-10 was significantly lower (due to lower IFN-[gamma]) 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 forward parental histories (8). In contrast, emissary RNA analyses of secretions obtained from the pair 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 progression in a continuously ascending gradation 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 answer profiles in high-risk babies (at least undivided atopic parent with asthma) during a documented RSV illness. Of the 28 infants with RSV-associated respiratory tract disease, 9 make knowned signs of acute bronchiolitis. During their acute illness, nasal lavage IL-4/IFN-[gamma] and IL-10/IL-12 ratios were significantly elevated in infants who unfolded bronchiolitis as compared with infants who did not. Similar evidence for Th2-polarized replys was seen when mononuclear small cavity messenger RNA levels were evaluated: IL-18 plains were reduced and the IL-4/IFN-[gamma] ratio was elevated. Because the balance between Th1 and Th2 cytokine answers could be potentially influenced at 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 flushs in nasal lavage fluid. Interestingly, although viral load did not differ between the assemblages the infants with bronchiolitis showed a stretch toward impairment of viral clearance.

The ends from this well designed investigation provide further evidence that alterations in Th1/Th2 cytokine rejoinder patterns are associated with the pathogenesis of RSV-induced bronchiolitis. As united might anticipate, however, additional questions rise from the reported findings. Despite the exclusive enrollment of children at high risk of maintaining Th2 skewed replications during infancy, the two distinct respiratory phenotypes that emerg following RSV infection would hint that children who display equable greater Th2-polarized responses are more likely to expand more severe respiratory tract involvement. Unfortunately, what the subject of attention cannot address is whether the children with bronchiolitis unfolded this type of clinical answer because of more severe (at birth) and/or persistent (during development) Th2 skewing, and/or whether the innkeeper response to the virus itself was different in these individuals and initiated an equal greater immune deviation in Th1/Th2 balance. In other words, did the aberrant cytokine replication precede or follow the infection? An equally important unanswered question is whether this prototype of Th2-skewed response is unique to RSV (8) For example, if these children lay opened bronchiolitis related to rhinovirus (11) or parainfluenza virus (12) would the same cytokine pattern have been seen? Or is the susceptible armed force response deviant only in answer to a specific virus (13)? Finally, although genetic analyses were not reported by way of Legg and colleagues (10), polymorphisms in gene that regulate cytokine answers (14, 15) and disease severity (16) in relationship to RSV and/or other viruses, which include gene encoding for IL-4 and IL-4R[alpha], are now being described. The precise contribution of these and other genetic polymorphisms to the diversity of respiratory phenotypes, the one and the other acutely (bronchiolitis) and chronically (subsequent evolution of asthma), await further definition. The answers to these and other important questions await subsequent time results from the current close attention as well as a number of other birth cohort studies being leadershiped worldwide, which are focusing forward genetic (cytokine dysregulation) and environmental (respiratory tract infections) risk factors relevant to the progress to maturity of various childhood respiratory phenotypes, including asthma.