Respiratory Syncytial Virus Infection and Recurrent Wheezing: A Complex Relationship
Article Outline
An association between viral lower respiratory tract infection in the first 2 years of life and episodes of recurrent wheezing, reactive airway disease, and pulmonary function abnormalities later in childhood has been established.1 A number of respiratory viruses have been implicated in this association, although repiratory syncytial virus (RSV) appears to be the virus most strongly linked with recurrent wheezing.2, 3 It is unclear whether subsequent wheezing occurs more commonly after RSV infection or whether this complication occurs with equal frequency after other viral respiratory tract infections (such as those caused by rhinovirus, influenza virus, parainfluenza virus, or human metapneumovirus).4, 5, 6 Whether the pathogenesis of subsequent airway obstruction is different after infection with different viruses, as suggested by the variable association with atopy, is not clear.7, 8 Variations on 3 basic theories have been proposed to explain the link between early RSV infection and subsequent asthma. One possibility, a causal relationship, is that changes induced by viral replication early in life alter the pattern of normal lung development in such a way that the infant is predisposed to subsequent episodes of wheezing. A second possibility, a triggering relationship, is that certain infants have a pre-existing aberration of either airway function or the immune response, and early viral infection serves as an initiating or triggering event to acute airway obstruction. Because of certain inconsistencies in these 2 proposals and clinical observations, Martinez proposed a third hypothesis, a more complex relationship.9 In this model, the response to a viral infection is a function of several factors: the genetic makeup of the infant, concomitant exposure to other environmental antigens, and the degree of maturation of the infant’s immune system and airway at the time of the infection. This theory proposes no single response to a viral infection, but rather the outcome is a function of several intrinsic and extrinsic factors.
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If viral lower respiratory tract infections can be a sufficient cause of asthma, prevention of infection should reduce the incidence of asthma. Alternatively, if viral lower respiratory tract infection acts to initiate the events leading to subsequent episodes of airway obstruction in a predisposed child, prevention of infection can be expected to reduce the wheezing associated with the acute illness, but will have only a modest or no impact on the incidence of asthma. Simoes et al report in this issue of The Journal about an industry-sponsored study addressing the effect of avoidance of RSV lower respiratory tract infection on recurrent wheezing. Infants who received prophylaxis with palivizumab were compared with a retrospectively selected cohort matched by gestational and postnatal age that did not receive prophylaxis.10 Children born prematurely at 1 of 27 sites in Europe or Canada were observed for 24 months starting at a mean age of 19 months and assessed for episodes of wheezing. Physician-diagnosed recurrent wheezing during the 24-month period of follow-up (from approximately 19 months until 43 months of age) was 8% in prophylaxis recipients and 16% in the comparator group. These data suggest that in this group of premature infants without chronic lung disease, a reduced rate of RSV infection correlated with a lower incidence of recurrent wheezing. If the findings are reproducible, these results will support the theory that avoidance of early RSV infection can reduce the risk of long-term pulmonary complications.
The prevalence of hospitalization attributable both to bronchiolitis and to asthma have increased in recent years.11, 12 Thus, the results of this study have important implications about the usefulness of passive immunoprophylaxis against long-term complications of RSV infection, and its design requires careful scrutiny. As discussed by the authors, there are substantial limitations to the study design and selection of subjects for both groups. No description is provided of the criteria used by physicians at the 27 sites to determine which infants were chosen to receive prophylaxis. Were the criteria the same for all sites? For both the prophylaxis and the comparator groups, little information is provided about the total number approached or who was not included for what reason. Although prophylaxis recipients had slightly lower mean birth weight (1.36 ± 0.44 kg versus 1.62 ± 0.51 kg) and were slightly more premature (29.9 ± 2.2 weeks versus 31.4 ± 2.5 weeks) than infants in the comparator groups, infants who did not receive prophylaxis had more risk factors for RSV infection (number of siblings, day care attendance, siblings in day care). Gestational age <32 weeks is a common threshold for administration of prophylaxis for most infants at most centers, and the presence of more risk factors in the comparator group that did not receive prophylaxis suggest a lack of consistency. In addition, families were aware of whether their child had received prophylaxis early in life both during the telephone contact and during the 6-month visits. This may have introduced bias when responding to questions about wheezing, although the investigator asking the questions was blinded.
The validity of any comparison between groups depends on the proper selection of control subjects. The authors correctly point out that a randomized, placebo controlled trial would not be ethically permissible because of the well-documented efficacy of palivizumab in reducing the risk of RSV hospitalization in premature infants.13 However, without prospective randomization, the possibility of unknowingly selecting control subjects with an increase in pathogenetic factors for the development of airway obstruction cannot be excluded. This is particularly true when the number of subjects enrolled is small. The authors of this study are senior investigators who have contributed numerous important insights toward our understanding of disease caused by RSV. However, the unavoidable questions about selection of infants with this study design mean that the conclusions are uncertain.
Approximately 3% of all infants in the first 12 months of life will be hospitalized because of RSV infection (>100,000 hospitalizations per year) and most of these infants will be previously healthy, term infants. Development of a live attenuated RSV vaccine with reverse genetics or a vectored vaccine holds the greatest promise for future control of disease.14 In the absence of a broadly useful antiviral agent for treatment or chemoprophylaxis, passive immunoprophylaxis remains the most important means of lowering the hospitalization rate and reducing the burden of RSV disease in infants who are at high risk. On the basis of preliminary results from a phase III trial, a second generation monoclonal antibody (motavizumab) appears to be as efficacious as palivizumab in reducing the risk of RSV hospitalization, but the cost of this intervention is likely to continue to restrict prophylaxis to those infants at greatest risk. The results reported here suggesting a possible reduction in recurrent wheezing after palivizumab use can be considered only as exploratory and do not justify any broadening of the existing recommendations for immunoprophylaxis.15
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PII: S0022-3476(07)00169-2
doi:10.1016/j.jpeds.2007.02.034
© 2007 Mosby, Inc. All rights reserved.
Refers to article:
- Palivizumab Prophylaxis, Respiratory Syncytial Virus, and Subsequent Recurrent Wheezing
