© 2007 American Thoracic Society DOI: 10.1165/rcmb.2007-0003ED
A Mechanistic Advance in Understanding RSV Pathogenesis, but Still a Long Way from TherapyVanderbilt University Medical Center, Nashville, Tennessee Respiratory syncytial virus (RSV) infection causes substantial morbidity at the extremes of age. In children under two years of age, RSV is the most common cause of emergency department visits and hospital admissions for wheezing (1, 2). Overall, RSV is the leading discharge diagnosis for infant hospital admissions in the United States, with a rate of 25.2 per 100,000 children and the most common cause of bronchiolitis worldwide (3). Although the expense of hospitalization for RSV is high, fortunately the mortality of RSV bronchiolitis is less than 1% in the developed world (4). In the United States, RSV causes nine times the mortality of influenza in the infant population. Lower respiratory tract RSV infection in infancy in outpatients significantly increased the odds of having wheezing up to age 11 in an outpatient population and more than quintupled (43% vs. 8%) the risk of asthma/recurrent wheeze at age 13 in infants who had been hospitalized with RSV bronchiolitis, compared to control subjects without infection (5, 6). Hospitalizations for RSV bronchiolitis peak between December and February each year in the United States (3). It is important to note that while bronchiolitis occurs in approximately 20% of children infected with RSV, the majority of RSV infections results in only mild upper respiratory tract symptoms as infection is almost universal at age 3 (7). Identifiable risk factors for more severe RSV infection in infants include age less than one year, bronchopulmonary dysplasia, congenital heart disease, prematurity, age less than three months at the start of the RSV season, having older siblings in the household, maternal smoking, and maternal asthma (7, 8). Although approximately half of infants who develop severe RSV disease will have identifiable risk factors, the other half are otherwise healthy full-term children (9). In the elderly, RSV is an important cause of asthma exacerbations, as approximately 7% of persons over 65 years of age have RSV detected in their respiratory secretions upon seeking care for worsening asthma symptoms (10). In addition, it has been estimated that in hospitalized elderly subjects, RSV has a similar mortality rate to influenza (10).
Unfortunately, treatment for RSV is currently suboptimal. There is no licensed RSV vaccine. Prophylactic use of RSV immune globulin, which contains high titers of anti-RSV antibody, has been beneficial in infants with high risk of developing severe bronchiolitis (11). Currently two such preparations are available. Palivizumab is a humanized monoclonal antibody that targets the RSV F protein (11). This product reduced RSV hospitalization by 55% in premature infants and those with bronchopulmonary dysplasia (11). Another preparation, RSV-IGIV, is pooled polyclonal human immunoglobulin obtained from donors who have high titers of RSV antibodies (11). Prophylactic administration of RSV-IGIV also significantly reduced hospitalization rates from RSV infection. However, a recent Cochrane Review concluded that there was no benefit from anti-RSV immune globulin in the postinfection treatment of RSV (11). Other specific treatments have not been conclusively proven to be useful. A recent meta-analysis of the broad spectrum antiviral agent ribavirin did not find that this agent significantly improved the duration of hospitalization, the need for mechanical ventilation, mortality from RSV infection, or long-term pulmonary function (12). Corticosteroids have also not been proven to be effective in a randomized-controlled fashion, nor have In this issue of the American Journal of Respiratory Cell and Molecular Biology (pp. 379–386), Davis and colleagues performed studies examining the effectiveness of the active metabolite of leflunomide, A77-1726, in reversing the decreased alveolar fluid clearance (AFC) that occurs with RSV infection in mice (15). Leflunomide is a drug used in the treatment of rheumatoid arthritis that was launched in the United States in 1998 (16). Three years ago, this group was the first to show that RSV infection reduced AFC two days after infection by almost 50% and also resulted in a loss of AFC sensitivity to amiloride inhibition (17). This inhibition of AFC led to a significant increase in lung water content that was associated with RSV-induced uridine triphosphate (UTP) production as measured in bronchoalveolar lavage (BAL) fluid (17). UTP acts on P2Y purinergic receptors on bronchoalveolar epithelial cells to decrease sodium transport across these cells (17). These authors hypothesized that a blunted ability to clear airway and alveolar fluid may be a component of RSV pathogenesis in that it could result in compromised gas exchange and decreased mucociliary clearance (17).
In a follow-up study published last year, Davis and colleagues reported that RSV infection not only increased UTP, but also adenosine triphosphate (ATP) in BAL fluid, and these increases could be blocked by pretreatment of mice with leflunomide, a pharmacologic inhibitor of de novo pyrimidine synthesis (18), Leflunomide administration by gavage for eight days before infection and then daily after infection reversed the RSV-induced inhibition of AFC and associated increase in lung water content, while an inhibitor of de novo purine synthesis, 6-mercaptopurine, did not (18). This improvement in AFC paralleled leflunomide's ability to significantly improve oxygenation in RSV-infected mice to the level of uninfected animals (18). In addition, leflunomide treatment reduced RSV-induced IFN- In the current study in this issue, Davis and colleagues administered the leflunomide metabolite A77-1726 intranasally one day after RSV infection of mice to determine if it might be useful as post-infection therapy (15). Under these conditions, on Day 2 after infection A77-1726 improved AFC and oxygenation while reducing lung water content, BAL nucleotide levels, and lung inflammation (15). Intranasal A77-1726 administered one day after infection also restored normal amiloride sensitivity to AFC the next day (15). A77-1726 did not reduce BAL lymphocytes and did not diminish viral clearance on Day 8 (15). A77-1726 administration also resulted in a transient reduction in proinflammatory cytokine levels (15). However, none of these effects were present when A77-1726 was administered systemically rather than intranasally (15).
This series of carefully performed studies by Davis and colleagues is most useful in that they provide clues to the mechanisms to RSV pathogenesis. Defining mechanisms of RSV-induced airway obstruction in humans has largely been deduced from intervention studies such as the ones involving Although leflunomide and its metabolite were useful in elucidating pathogenesis, their usefulness in the treatment of RSV airway disease is not clear and we would not recommend them at this point. First, as noted above, airway obstruction in humans may be more related to cellular obstruction than to decreased AFC and increased lung water seen in the mouse. Second, the study using leflunomide showed that outcomes were improved when it was given eight days before infection and A77-1726 led to benefit only when it was administered one day, and not two days, after infection (15, 18). The incubation period between infection and the onset of symptoms is four to six days (11). Therefore, by the time symptoms occur, the therapeutic window for A77-1726 administration to be useful would have already passed. Third, A77-1726 was administered intranasally to mice in a volume of 100 microliters so that it would reach the alveolar epithelium. This translates to a volume of 5 ml/kg, or 350 ml for a 70-kg person that would have to be distributed specifically to the RSV-infected epithelium, thus raising significant technical challenges. Fourth, lung toxicity has been reported in patients with rheumatoid arthritis who have been treated with this leflunomide. There have been a number of cases of interstitial lung disease associated with leflunomide administration (22, 23). Discerning a true cause-and-effect relationship is difficult given that interstitial disease can occur with rheumatoid arthritis, that patients may be taking other medication for rheumatoid arthritis that can cause interstitial lung disease (namely methotexate), and that patients with more severe rheumatoid disease and who therefore may be at greater risk for interstitial disease may be those who were more likely to be prescribed leflunomide. A population-based epidemiologic study examining a cohort of 62,734 patients with rheumatoid arthritis suggested there was not an elevated risk of interstitial lung disease with leflunomide usage among those persons with no previous methotrexate use and no history of interstitial lung disease (24). There was an increased relative risk (RR, 2.6; 95% confidence interval, 1.2–5.6) of interstitial disease associated with leflunomide usage in subjects with a history of methotrexate use and/or interstitial lung disease; however, these subjects were twice as likely to have been prescribed leflunomide as any other disease-modifying drug, presumably as a result of disease severity (24). To our knowledge, safety studies of leflunomide have not been performed in children under two years of age, the population at greatest risk for bronchiolitis. Davis and colleagues are to be congratulated for their seminal studies in describing a novel mechanism by which RSV causes disease. These studies provide a foundation for investigating the integrated host metabolic, physiologic, and immune responses in a mouse model of respiratory disease. Footnotes Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. References
Related articles in AJRCMB:
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
-agonists been conclusively shown to be effective in bronchiolitis (
, IL-1
