- Email: [email protected]
The association between respiratory syncytial virus infection and reactive airway disease
Vol. 96 (2002) (SUPPLEMENT B), S25^S29
The association between respiratory syncytial virus infection and reactive airway disease G. PIEDIMONTE Departments of Pediatrics, Medicine, and Molecular/Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, U.S.A. Abstract Evidence has been accumulating that respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in infants may be linked to subsequent development of reactive airway disease (RAD) in childhood, and therefore researchintothe prevention of RSVLRTImayhaveimportantimplications for the prevention of RAD.This article reviews the epidemiological evidence linking RSVand RAD and some of the theories concerning cellular and molecular mechanisms of post-viral airwayinflammationin order to understand how RSV prophylaxis mayassistinreducing the occurrence of RSV LRTI and RAD. r 2002 Elsevier Science Ltd doi:10.1053/rmed.2002.1297, available online at http://www.idealibrary.com on
Keywords asthma; palivizumab; paediatrics; prevention.
INTRODUCTION Respiratory syncytial virus (RSV) is the most common cause of viral lower respiratory tract infection (LRTI) in infants (1) and several epidemiological studies have indicated that RSV LRTI early in life is associated with subsequent recurrent wheezing in many children. Thus, it has long been suspected that there is a link between RSVand reactive airway disease (RAD) (2^9). Since some risk factors for RAD, such as genetic predisposition, are relatively ¢xed, other factors, such as RSV LRTI, have become an important area of research because they may lend themselves to interventions that make it possible to reduce the incidence of RAD through prevention or elimination of the risk factor. The goal of this paper is to review the most recent epidemiological evidence linking early-life RSV LRTI to the development of RAD in childhood, to provide insight into some of the theories proposed to explain the RSV-RAD link, and to discuss the potential for reducing the incidence of RAD by preventing RSV infection.
EPIDEMIOLOGYOF RSV LRTI AND IT SEQUELAE Approximately half to two-thirds of children are infected with RSV during their ¢rst year of life (10), making this Correspondence should be addressed to: Prof.Giovanni Piedimonte MD, Batchelor Children’s Research Institute,1580 NW10th Avenue, Miami, FL 33136 U.S.A. Fax: +1305 2431262. Email: [email protected]
virus the most important respiratory pathogen in infancy. In addition, several retrospective studies have consistently shown a link between early-life RSV LRTI and development of RAD during childhood (Table 1), and more recently two well-controlled prospective studies con¢rmed that RSV was a major risk factor for development of recurrent wheezing and RAD during the ¢rst decade of life. Stein et al. conducted a study in a subset of the 1246 children born between 1980 and 1984 and enrolled in theTucson Children’s Respiratory Study in order to better understand the relationship between RSV LRTI contracted during the ¢rst 3 years of life and development of wheezing and atopy by age 13 (11). Parents completed questionnaires when children were 6, 8, 11 and 13 years of age. While 519 of these children had at least one LRTI during the ¢rst 3 years of life, 472 were actually tested for viruses and 207 of 472 had documented RSV LRTI. None of the children in the reference group had a LRTI during this period. Children with a history of RSV LRTI were 3?2 times more likely to have infrequent wheeze and 4.3 times more likely to have frequent wheeze by age 6 years (Table 2). The risk of wheeze decreased for each subsequent year up to age13, where the association was no longer statistically signi¢cant.The RSV group had signi¢cantly lower forced expiratory volume in one second (FEV1), but was also signi¢cantly more responsive to bronchodilation with albuterol than the reference group, suggesting that the decreased pulmonary function was caused by reversible dysregulation of the airway tone. In this study population, no link was found between RSV
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RESPIRATORY MEDICINE
Table 1. Retrospective studies showing a link between RSV infection and reactive airway disease (2^9). Study
Sims et al. (1978) (2) Pullan et al. (1982) (3) McConnochie et al. (1984) (4) Mok et al. (1984) (5) Carlsen et al. (1987) (6) Murray et al. (1992) (7) Osundwa (1993) (8) Noble et al. (1997) (9)
Number of subjects RSV/Controls
Length of follow-up (years)
Statistically signi¢cant di¡erence in outcomes between groups?
P values/odds ratio
35/55 130/111 59/177 100/200 51/24 73/73 70/70 61/47
8 10 8 7 2 5.5 1 9^10
Yes Yes Yes Yes Yes Yes Yes Yes
Po0?02 Po0?001 Po0?0001 NA Po0?01 Po0?001 P=0?001 OR=3?59
Table 2. Risk of frequent wheeze in children who contracted RSV LRTI before 3 years of age (11). Frequent wheeze after 3 years of age LRTI Prior to 3 years of age RSV Reference group
Age 6 (n=68/669)
Age 8 (n=56/545)
Age11 (n=79/634)
Age13 (n=49/469)
4?3 (2?2^8?7)* 1?0
1?9 (0?9^4?2) 1?0
2?4 (1?3^4?6)** 1?0
1?4 (0?7^2?6) 1?0
*Pr0?001 **Pr0?01
and atopy, as measured by skin tests and serum IgE concentration. This study thus indicated that RSV infection contracted prior to 3 years of age is associated with a signi¢cantly increased risk of recurrent wheezing during the ¢rst decade of life. Another prospective study by Sigurs et al. compared 47 previously healthy infants hospitalized for RSV bronchiolitis with a reference population of 93 infants (12). The infants in the two groups were well matched for age, sex, family history of atopy or RAD, and living environment. RAD was de¢ned as three or more episodes of physician-diagnosed bronchial obstruction; recurrent wheezing was de¢ned as three or more episodes of self-reported bronchial obstruction; wheezing was de¢ned as any episode of bronchial obstruction. The allergic status was established using skin prick testing and titer of serum IgE antibodies. An important distinction between this study and the study by Stein et al. was that infants in the Sigurs et al. study were classi¢ed as having severe RSV infection requiring hospitalization, whereas the subjects in the Stein et al. study had not necessarily required hospitalization for their LRTI. Sigurs et al. found that by age 7, signi¢cantly more children in the RSV group (30%) had experienced RAD at some time than was true for children in the control group (3%). Furthermore, 23% of children in the RSV group had physician-diagnosed RAD at age 7 compared
with only 2% of children in the control group. The cumulative prevalence of wheezing was signi¢cantly greater in the RSV (68%) than in the control (34%) group. The current presence of any wheezing at age 7 was 38% in the RSV group and 2% in the control group (Figure 1). The only signi¢cant risk factor for RAD was RSV bronchiolitis, whereas when ‘any wheezing’ was considered, RSV bronchiolitis, family history of atopy, and male sex were risk factors. In multivariate analysis, the combination of RSV bronchiolitis and a family history was associated with the highest frequency of RAD. This study also found a link between RSV bronchiolitis and atopy, something that has not been found in similar studies. This di¡erence may be attributed to intrinsic factors, such as the genetic background, or to the severity of RSV disease in this study population, which contrasts with other studies involving infants with mild to severe RSVdisease.
MECHANISMS OF THE RSV-RAD LINK In attempting to reconcile various theories that have been proposed to explain how RSV generates airway in£ammation and hyperreactivity, we have suggested that interactions between neural and immune mechanisms may generate the acute response to RSV infection as well as recurrent in£ammation long after the infection has
THE ASSOCIATIONBETWEEN RSV INFECTION AND RAD
Figure 1. Risk for wheeze at 7 years for children who had prior severe RSV LRTI as infants (12). *P=0?003; **Po0?001; ***Po0?0001; zP=0?004.
cleared. We focused our attention on the neural pathways in the airways and particularly the non-adrenergic non-cholinergic (NANC) system, which has an important role in the modulation of local in£ammatory and immune responses in the respiratory tract. The excitatory component of the NANC system (NANCe) is able to sense physical and chemical changes caused by airborne irritants at the level of the respiratory epithelium. Stimulated NANCe nerves release substance P and other peptide neurotransmitters, contributing to the early phase of the in£ammatory process and playing an important immunomodulatory role. We developed a model of RSV bronchiolitis in rats strain Fischer 344 (F-344), which is unique in that these rats mount a strong immune response and clear RSV from the lungs, much like the self-limiting disease process that occurs in immunocompetent children (13). In addition, the inoculation of weanling rats at 2 weeks of age allows for evaluation of the long-term e¡ects of early RSV infection (14). In this model, important developmental changes in the distribution of neurogenic in£ammatory responses across the respiratory tract were observed as the rats aged. In particular, the stronger in£ammatory response developing in the lower respiratory tract early in life may explain why RSV bronchiolitis tends to occur in infants, while RSV infection tends to present as an upper respiratory tract infection in older individuals. In the same model, we also found that prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV fusion (F) protein, prevents the acute neurogenic in£ammatory changes in the lower respiratory tract infected with RSV (15), and also protects against the development of long-term susceptibility to neurogenic-mediated in£ammation after the infection. Neurokinin (NK) receptors which mediate the biological
S27
e¡ects of NANCe nerves appear to be involved with the in£ammatory response to RSV, as this virus has been found to upregulate the gene encoding for the NK1 receptor subtype, which mediates the in£ammatory and immunomodulatory e¡ects of substance P (13,14). In contrast, RSV does not a¡ect the NK2 receptor subtype, which is expressed in airways smooth muscle ¢bres. Thus, air£ow obstruction during RSV infection appears to be more a function of mucosal in£ammatory oedema due to perturbation of NANCe system receptors, rather than a function of bronchial smooth muscle constriction. Prophylaxis with palivizumab, by opposing the penetration of infectious particles into the lower respiratory tract epithelium, inhibits the upregulation of the NK1 receptor gene and the associated in£ammatory e¡ects. Recent studies also suggest that RSV infection induces overexpression of NK1 receptors in T-lymphocytes subpopulations within the bronchiolar-associated lymphoid tissue (BALT).These NK1receptor-bearing lymphocytes ‘primed’ by the virus can be recruited into the airways following nerve stimulation by airborne irritants and can also be activated for the release of pro-in£ammatory cytokines. Another more recent study shows that nerve stimulation in RSV-infected airways promotes the release of leukotrienes from mucosal mast cells, which contributes to the exudative response to the virus (16). Recurrent activation of the NANCe system by irritants could then be responsible for new cycles of airway in£ammation and narrowing long after the acute RSV infection has cleared (Figure 2). Therefore, we have proposed that these neuro-immune interactions may link RSV infection in infants with RAD in children. If so, inhibiting RSV penetration or replication in the lower respiratory tract could signi¢cantly reduce the incidence of childhood RAD.
PREVENTION AND TREATMENTOF RSV DISEASE Currently, no satisfactory treatment is available for established RSV disease, and there is also little evidence to show that antiviral treatment reduces the risk for developing RAD later in life. Simoes reviewed four studies that looked at the e¡ect of ribavirin, which inhibits viral replication, on the long-term sequelae of RSV infection (17). Three controlled studies with long-term follow-up found that there were no di¡erences between ribavirintreated children and the placebo group in terms of the incidence of long-term sequelae, such as recurrent lower respiratory tract infection, wheezing, or RAD. One study did report a reduction in the prevalence of RAD, although it was a1-year study, which raises the possibility that the e¡ects of anti-viral therapy are only short-term. In the absence of safe and e¡ective options for the therapy or for the active prophylaxis of RSV disease, the
S28
RESPIRATORY SYNCYTIAL VIRUS
RESPIRATORY MEDICINE
SENSORY NERVES
IRRITANTS ALLERGENS MEDIATORS
SUBSTANCE P
NK 1 RECEPTORS
T Cells Cytokiness
PMNs Chemotaxis
Vessels
Oedema
Mast cells
LTs
Inflammation
Figure 2. Neuroin£ammatory and neuroimmune mechanisms in RSV-infected airways.
only protection currently available for high-risk patients is represented by passive prophylaxis. The PREVENT study was a randomized, double blind, placebo-controlled trial that examined the e⁄cacy and tolerability of monthly prophylaxis with intravenous respiratory syncytial virus immune globulin (RSV-IGIV) (18). This study found that RSV-IGIV prophylaxis in high-risk children did reduce hospitalizations for lower respiratory tract infection. This prophylactic treatment was generally well tolerated, but had important drawbacks, including the requirement of monthly intravenous dosing and the administration of high £uid and protein loads to patients with underlying chronic lung disease. The IMpact-RSV study evaluated the safety and e⁄cacy of prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV fusion (F) protein, on 1502 children who were premature-born with or without chronic lung disease (CLD) (19). This trial was a randomized, double blind, placebo-controlled, 150 -day trial conducted at 139 sites in the United States of America, United Kingdom, and Canada. Children received either 5 monthly injections of palivizumab intramuscularly (15 mg kg1) or placebo. A 55% overall reduction in hospitalizations for RSV (10?6% placebo vs. 4?8% palivizumab) was observed. Children without CLD had a 78% reduction in RSV-related hospitalizations (8?1% vs. 1?8%), whereas children with CLD experienced a 39% reduction (12?8% vs. 7?9%). Palivizumab was very well tolerated and has the advantage of intramuscular administration. These exciting developments in the areas of RSV-RAD link and RSV prophylaxis beg the question: Can RSV immunoprophylaxis reduce the risk for development of RAD in childhood? In a study of 13 children with CLD who had received RSV-IGIV 5 to 9 years earlier, pulmonary function was signi¢cantly better in the treatment
group (Po0?016) than in matched controls (20). Furthermore, there was signi¢cantly less atopy (P=0?04) and a lower likelihood of RAD attacks (P=0?03) in children who were treated. Based on this preliminary evidence, Wenzel et al. suggested that RSV prophylaxis may have long-term bene¢t in reducing the risk of RAD. A prospective, multicentre case-controlled study is currently underway to examine the impact of palivizumab prophylaxis on the incidence and degree of reversible airway obstruction in premature children who developed RSV (21). A target of 300 children will be enrolled; 100 children who have received palivizumab prophylaxis will be compared with 100 children who have had documented RSV bronchiolitis and 100 controls. These children will be followed prospectively for 3 years using monthly telephone calls and scheduled visits at 6, 12, 24, and 36 months. The outcomes will include a respiratory questionnaire, history of wheezing, inventory of medications used, record of hospitalizations, and pharmacoeconomics evaluation. Results are expected late in 2003.
CONCLUSIONS While there has been much conjecture as to whether RSV LRTI causes long-term pulmonary sequelae such as RAD in children, or whether some underlying abnormality predisposes children to severe RSV LRTI and RAD, a body of evidence now exists suggesting that children with RSV infection early in life are more likely to subsequently su¡er from RAD. Preventing RSV may therefore have a positive impact on reducing the number of children who su¡er from RAD.Ongoing studies of RSV prophylaxis with agents such as palivizumab will help to clarify the bene¢cial e¡ect of RSV prevention on RAD.
REFERENCES 1. Centers for Disease Control and Prevention. Respiratory syncytial virus activityFUnited States, 1999-2000 season. MMWR Morb Mortal Wkly Rep 2000; 49:1091^1093 2. Sims DG, Downham MA, Gardner PS, et al. Study of 8 -year-old children with a history of respiratory syncytial virus bronchiolitis in infancy. Br Med J1978;1:11^14. 3. Pullan CR, Hey EN.Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy.Br Med J1982;284:1665^1669. 4. McConnochie KM, Roghmann, KJ. Bronchiolitis as a possible cause of wheezing in childhood: New evidence. Pediatrics 1984;74:1^10. 5. Mok JY, Simpson H. Outcome for acute bronchitis, bronchiolitis, and pneumonia in infancy. Arch Dis Child 1984;59:306 ^309. 6. Carlsen KH, Larsen S, Bjerve O, et al. Acute bronchiolitic predisposing factors and characterization of infants at risk. Pediatr Pulmonol 1987;3:153^160. 7. Murray M, Webb MS, O’Callaghan, et al. Respiratory status and allergy after bronchiolitis. Arch Dis Child 1992;67:482^ 487. 8. OsundwaVM, Dawod ST, Ehlayel M.Recurrent wheezing in children with respiratory syncytial virus (RSV) bronchiolitis. Arch Dis Child 1993; 152:1001^1003.
THE ASSOCIATIONBETWEEN RSV INFECTION AND RAD
9. Noble V, Murray M, Webb MS et al. Respiratory status and allergy nine to 10 years after acute bronchiolitis. Arch Dis Child 1997; 76:315^319. 10. Moylett EH, Piedra PA. Respiratory syncytial virus infection: Diagnosis, treatment, and prevention. Hosp Med 1999; 35: 10 ^17. 11. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354:541^545. 12. Sigurs N, Bjarnason R, Sigurbergsson F, et al. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000; 161: 1501^1507. 13. Piedimonte G, Rodriguez MM, King KA, et al. Respiratory syncytial virus upregulates expression of the substance P receptor in rat lungs. Am J Physiol 1999;277 (Lung Cell Mol Physiol 21): L831^L840. 14. King KA, Hu C, Rodriguez MM, et al. Exaggerated neurogenic in£ammation and substance P receptor upregulation in RSV-infected weanling rats. Am J Respir Cell Mol Biol 2001;24:101^107. 15. Piedimonte G, King KA, Holmgren NL, et al. A humanized monoclonal antibody against respiratory syncytial virus (palivizumab) in-
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hibits RSV-induced neurogenic-mediated in£ammation in rat airways. Ped Res 2000;47: 351^356. 16. Wedde-Beer K, Hu C, Rodriguez MM, Piedimonte G. Leukotrienes mediate neurogenic in£ammation in lungs of young rats infected with respiratory syncytial virus. Am J Physiol (Lung Cell Mol Physiol) 2002;in press (10.1152/ajplung.00323.2001). 17. Simoes EAF.Treatment and prevention of respiratory syncytial virus lower respiratory tract infection. Long-term e¡ects on respiratory outcomes. Am J Respir Crit Care Med 2001;163:S14 ^S17. 18. The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997;99:93^99. 19. The IMpact-RSV Study group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531^537. 20. Wenzel SE, Gibbs R, Lehr M, et al. Asthma related clinical and physiologic outcomes in high risk children 5-9 years after prophylaxis with RSV-IGIV (abstract). Am J Respir Crit Care Med 2000;161:A898. 21. Protocol W00 -353, Abbott Laboratories, Abbott Park, IL.
The association between respiratory syncytial virus infection and reactive airway disease G. PIEDIMONTE Departments of Pediatrics, Medicine, and Molecular/Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, U.S.A. Abstract Evidence has been accumulating that respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in infants may be linked to subsequent development of reactive airway disease (RAD) in childhood, and therefore researchintothe prevention of RSVLRTImayhaveimportantimplications for the prevention of RAD.This article reviews the epidemiological evidence linking RSVand RAD and some of the theories concerning cellular and molecular mechanisms of post-viral airwayinflammationin order to understand how RSV prophylaxis mayassistinreducing the occurrence of RSV LRTI and RAD. r 2002 Elsevier Science Ltd doi:10.1053/rmed.2002.1297, available online at http://www.idealibrary.com on
Keywords asthma; palivizumab; paediatrics; prevention.
INTRODUCTION Respiratory syncytial virus (RSV) is the most common cause of viral lower respiratory tract infection (LRTI) in infants (1) and several epidemiological studies have indicated that RSV LRTI early in life is associated with subsequent recurrent wheezing in many children. Thus, it has long been suspected that there is a link between RSVand reactive airway disease (RAD) (2^9). Since some risk factors for RAD, such as genetic predisposition, are relatively ¢xed, other factors, such as RSV LRTI, have become an important area of research because they may lend themselves to interventions that make it possible to reduce the incidence of RAD through prevention or elimination of the risk factor. The goal of this paper is to review the most recent epidemiological evidence linking early-life RSV LRTI to the development of RAD in childhood, to provide insight into some of the theories proposed to explain the RSV-RAD link, and to discuss the potential for reducing the incidence of RAD by preventing RSV infection.
EPIDEMIOLOGYOF RSV LRTI AND IT SEQUELAE Approximately half to two-thirds of children are infected with RSV during their ¢rst year of life (10), making this Correspondence should be addressed to: Prof.Giovanni Piedimonte MD, Batchelor Children’s Research Institute,1580 NW10th Avenue, Miami, FL 33136 U.S.A. Fax: +1305 2431262. Email: [email protected]
virus the most important respiratory pathogen in infancy. In addition, several retrospective studies have consistently shown a link between early-life RSV LRTI and development of RAD during childhood (Table 1), and more recently two well-controlled prospective studies con¢rmed that RSV was a major risk factor for development of recurrent wheezing and RAD during the ¢rst decade of life. Stein et al. conducted a study in a subset of the 1246 children born between 1980 and 1984 and enrolled in theTucson Children’s Respiratory Study in order to better understand the relationship between RSV LRTI contracted during the ¢rst 3 years of life and development of wheezing and atopy by age 13 (11). Parents completed questionnaires when children were 6, 8, 11 and 13 years of age. While 519 of these children had at least one LRTI during the ¢rst 3 years of life, 472 were actually tested for viruses and 207 of 472 had documented RSV LRTI. None of the children in the reference group had a LRTI during this period. Children with a history of RSV LRTI were 3?2 times more likely to have infrequent wheeze and 4.3 times more likely to have frequent wheeze by age 6 years (Table 2). The risk of wheeze decreased for each subsequent year up to age13, where the association was no longer statistically signi¢cant.The RSV group had signi¢cantly lower forced expiratory volume in one second (FEV1), but was also signi¢cantly more responsive to bronchodilation with albuterol than the reference group, suggesting that the decreased pulmonary function was caused by reversible dysregulation of the airway tone. In this study population, no link was found between RSV
S26
RESPIRATORY MEDICINE
Table 1. Retrospective studies showing a link between RSV infection and reactive airway disease (2^9). Study
Sims et al. (1978) (2) Pullan et al. (1982) (3) McConnochie et al. (1984) (4) Mok et al. (1984) (5) Carlsen et al. (1987) (6) Murray et al. (1992) (7) Osundwa (1993) (8) Noble et al. (1997) (9)
Number of subjects RSV/Controls
Length of follow-up (years)
Statistically signi¢cant di¡erence in outcomes between groups?
P values/odds ratio
35/55 130/111 59/177 100/200 51/24 73/73 70/70 61/47
8 10 8 7 2 5.5 1 9^10
Yes Yes Yes Yes Yes Yes Yes Yes
Po0?02 Po0?001 Po0?0001 NA Po0?01 Po0?001 P=0?001 OR=3?59
Table 2. Risk of frequent wheeze in children who contracted RSV LRTI before 3 years of age (11). Frequent wheeze after 3 years of age LRTI Prior to 3 years of age RSV Reference group
Age 6 (n=68/669)
Age 8 (n=56/545)
Age11 (n=79/634)
Age13 (n=49/469)
4?3 (2?2^8?7)* 1?0
1?9 (0?9^4?2) 1?0
2?4 (1?3^4?6)** 1?0
1?4 (0?7^2?6) 1?0
*Pr0?001 **Pr0?01
and atopy, as measured by skin tests and serum IgE concentration. This study thus indicated that RSV infection contracted prior to 3 years of age is associated with a signi¢cantly increased risk of recurrent wheezing during the ¢rst decade of life. Another prospective study by Sigurs et al. compared 47 previously healthy infants hospitalized for RSV bronchiolitis with a reference population of 93 infants (12). The infants in the two groups were well matched for age, sex, family history of atopy or RAD, and living environment. RAD was de¢ned as three or more episodes of physician-diagnosed bronchial obstruction; recurrent wheezing was de¢ned as three or more episodes of self-reported bronchial obstruction; wheezing was de¢ned as any episode of bronchial obstruction. The allergic status was established using skin prick testing and titer of serum IgE antibodies. An important distinction between this study and the study by Stein et al. was that infants in the Sigurs et al. study were classi¢ed as having severe RSV infection requiring hospitalization, whereas the subjects in the Stein et al. study had not necessarily required hospitalization for their LRTI. Sigurs et al. found that by age 7, signi¢cantly more children in the RSV group (30%) had experienced RAD at some time than was true for children in the control group (3%). Furthermore, 23% of children in the RSV group had physician-diagnosed RAD at age 7 compared
with only 2% of children in the control group. The cumulative prevalence of wheezing was signi¢cantly greater in the RSV (68%) than in the control (34%) group. The current presence of any wheezing at age 7 was 38% in the RSV group and 2% in the control group (Figure 1). The only signi¢cant risk factor for RAD was RSV bronchiolitis, whereas when ‘any wheezing’ was considered, RSV bronchiolitis, family history of atopy, and male sex were risk factors. In multivariate analysis, the combination of RSV bronchiolitis and a family history was associated with the highest frequency of RAD. This study also found a link between RSV bronchiolitis and atopy, something that has not been found in similar studies. This di¡erence may be attributed to intrinsic factors, such as the genetic background, or to the severity of RSV disease in this study population, which contrasts with other studies involving infants with mild to severe RSVdisease.
MECHANISMS OF THE RSV-RAD LINK In attempting to reconcile various theories that have been proposed to explain how RSV generates airway in£ammation and hyperreactivity, we have suggested that interactions between neural and immune mechanisms may generate the acute response to RSV infection as well as recurrent in£ammation long after the infection has
THE ASSOCIATIONBETWEEN RSV INFECTION AND RAD
Figure 1. Risk for wheeze at 7 years for children who had prior severe RSV LRTI as infants (12). *P=0?003; **Po0?001; ***Po0?0001; zP=0?004.
cleared. We focused our attention on the neural pathways in the airways and particularly the non-adrenergic non-cholinergic (NANC) system, which has an important role in the modulation of local in£ammatory and immune responses in the respiratory tract. The excitatory component of the NANC system (NANCe) is able to sense physical and chemical changes caused by airborne irritants at the level of the respiratory epithelium. Stimulated NANCe nerves release substance P and other peptide neurotransmitters, contributing to the early phase of the in£ammatory process and playing an important immunomodulatory role. We developed a model of RSV bronchiolitis in rats strain Fischer 344 (F-344), which is unique in that these rats mount a strong immune response and clear RSV from the lungs, much like the self-limiting disease process that occurs in immunocompetent children (13). In addition, the inoculation of weanling rats at 2 weeks of age allows for evaluation of the long-term e¡ects of early RSV infection (14). In this model, important developmental changes in the distribution of neurogenic in£ammatory responses across the respiratory tract were observed as the rats aged. In particular, the stronger in£ammatory response developing in the lower respiratory tract early in life may explain why RSV bronchiolitis tends to occur in infants, while RSV infection tends to present as an upper respiratory tract infection in older individuals. In the same model, we also found that prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV fusion (F) protein, prevents the acute neurogenic in£ammatory changes in the lower respiratory tract infected with RSV (15), and also protects against the development of long-term susceptibility to neurogenic-mediated in£ammation after the infection. Neurokinin (NK) receptors which mediate the biological
S27
e¡ects of NANCe nerves appear to be involved with the in£ammatory response to RSV, as this virus has been found to upregulate the gene encoding for the NK1 receptor subtype, which mediates the in£ammatory and immunomodulatory e¡ects of substance P (13,14). In contrast, RSV does not a¡ect the NK2 receptor subtype, which is expressed in airways smooth muscle ¢bres. Thus, air£ow obstruction during RSV infection appears to be more a function of mucosal in£ammatory oedema due to perturbation of NANCe system receptors, rather than a function of bronchial smooth muscle constriction. Prophylaxis with palivizumab, by opposing the penetration of infectious particles into the lower respiratory tract epithelium, inhibits the upregulation of the NK1 receptor gene and the associated in£ammatory e¡ects. Recent studies also suggest that RSV infection induces overexpression of NK1 receptors in T-lymphocytes subpopulations within the bronchiolar-associated lymphoid tissue (BALT).These NK1receptor-bearing lymphocytes ‘primed’ by the virus can be recruited into the airways following nerve stimulation by airborne irritants and can also be activated for the release of pro-in£ammatory cytokines. Another more recent study shows that nerve stimulation in RSV-infected airways promotes the release of leukotrienes from mucosal mast cells, which contributes to the exudative response to the virus (16). Recurrent activation of the NANCe system by irritants could then be responsible for new cycles of airway in£ammation and narrowing long after the acute RSV infection has cleared (Figure 2). Therefore, we have proposed that these neuro-immune interactions may link RSV infection in infants with RAD in children. If so, inhibiting RSV penetration or replication in the lower respiratory tract could signi¢cantly reduce the incidence of childhood RAD.
PREVENTION AND TREATMENTOF RSV DISEASE Currently, no satisfactory treatment is available for established RSV disease, and there is also little evidence to show that antiviral treatment reduces the risk for developing RAD later in life. Simoes reviewed four studies that looked at the e¡ect of ribavirin, which inhibits viral replication, on the long-term sequelae of RSV infection (17). Three controlled studies with long-term follow-up found that there were no di¡erences between ribavirintreated children and the placebo group in terms of the incidence of long-term sequelae, such as recurrent lower respiratory tract infection, wheezing, or RAD. One study did report a reduction in the prevalence of RAD, although it was a1-year study, which raises the possibility that the e¡ects of anti-viral therapy are only short-term. In the absence of safe and e¡ective options for the therapy or for the active prophylaxis of RSV disease, the
S28
RESPIRATORY SYNCYTIAL VIRUS
RESPIRATORY MEDICINE
SENSORY NERVES
IRRITANTS ALLERGENS MEDIATORS
SUBSTANCE P
NK 1 RECEPTORS
T Cells Cytokiness
PMNs Chemotaxis
Vessels
Oedema
Mast cells
LTs
Inflammation
Figure 2. Neuroin£ammatory and neuroimmune mechanisms in RSV-infected airways.
only protection currently available for high-risk patients is represented by passive prophylaxis. The PREVENT study was a randomized, double blind, placebo-controlled trial that examined the e⁄cacy and tolerability of monthly prophylaxis with intravenous respiratory syncytial virus immune globulin (RSV-IGIV) (18). This study found that RSV-IGIV prophylaxis in high-risk children did reduce hospitalizations for lower respiratory tract infection. This prophylactic treatment was generally well tolerated, but had important drawbacks, including the requirement of monthly intravenous dosing and the administration of high £uid and protein loads to patients with underlying chronic lung disease. The IMpact-RSV study evaluated the safety and e⁄cacy of prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV fusion (F) protein, on 1502 children who were premature-born with or without chronic lung disease (CLD) (19). This trial was a randomized, double blind, placebo-controlled, 150 -day trial conducted at 139 sites in the United States of America, United Kingdom, and Canada. Children received either 5 monthly injections of palivizumab intramuscularly (15 mg kg1) or placebo. A 55% overall reduction in hospitalizations for RSV (10?6% placebo vs. 4?8% palivizumab) was observed. Children without CLD had a 78% reduction in RSV-related hospitalizations (8?1% vs. 1?8%), whereas children with CLD experienced a 39% reduction (12?8% vs. 7?9%). Palivizumab was very well tolerated and has the advantage of intramuscular administration. These exciting developments in the areas of RSV-RAD link and RSV prophylaxis beg the question: Can RSV immunoprophylaxis reduce the risk for development of RAD in childhood? In a study of 13 children with CLD who had received RSV-IGIV 5 to 9 years earlier, pulmonary function was signi¢cantly better in the treatment
group (Po0?016) than in matched controls (20). Furthermore, there was signi¢cantly less atopy (P=0?04) and a lower likelihood of RAD attacks (P=0?03) in children who were treated. Based on this preliminary evidence, Wenzel et al. suggested that RSV prophylaxis may have long-term bene¢t in reducing the risk of RAD. A prospective, multicentre case-controlled study is currently underway to examine the impact of palivizumab prophylaxis on the incidence and degree of reversible airway obstruction in premature children who developed RSV (21). A target of 300 children will be enrolled; 100 children who have received palivizumab prophylaxis will be compared with 100 children who have had documented RSV bronchiolitis and 100 controls. These children will be followed prospectively for 3 years using monthly telephone calls and scheduled visits at 6, 12, 24, and 36 months. The outcomes will include a respiratory questionnaire, history of wheezing, inventory of medications used, record of hospitalizations, and pharmacoeconomics evaluation. Results are expected late in 2003.
CONCLUSIONS While there has been much conjecture as to whether RSV LRTI causes long-term pulmonary sequelae such as RAD in children, or whether some underlying abnormality predisposes children to severe RSV LRTI and RAD, a body of evidence now exists suggesting that children with RSV infection early in life are more likely to subsequently su¡er from RAD. Preventing RSV may therefore have a positive impact on reducing the number of children who su¡er from RAD.Ongoing studies of RSV prophylaxis with agents such as palivizumab will help to clarify the bene¢cial e¡ect of RSV prevention on RAD.
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THE ASSOCIATIONBETWEEN RSV INFECTION AND RAD
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