Treatment and Prevention of Respiratory Syncytial Virus Lower Respiratory Tract Infection
Long-Term Effects on Respiratory Outcomes

ERIC A. F. SIMOES

Section of Infectious Diseases, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital, Denver, Colorado

	INTRODUCTION

TOP INTRODUCTION LONG-TERM BENEFIT OF ANTIVIRAL... LONG-TERM BENEFIT OF... LONG-TERM BENEFIT OF PREVENTION... DISCUSSION REFERENCES

The association between respiratory syncytial virus (RSV) bronchiolitis and asthma has been established for more than 30 yr. However, the question of causality remains unanswered: Does severe RSV lower respiratory tract infection (LRTI) cause long-term pulmonary morbidity or do factors that predispose a child to wheeze later in life also predispose the child to severe RSV LRTI? In several human studies (1), obstructive airway disease appears to occur up to 10 yr after an initial RSV infection. The Tucson Children's Respiratory Study showed an effect at 10 yr (5) but not by 13 yr (6). Hall and coworkers prospectively monitored 29 children who were hospitalized during infancy for RSV LRTI for 8 yr (7). Six children continued to have lower respiratory tract disease and six (21%) had persistently low oxyhemoglobin levels (Sa_O2) at follow-up. Sigurs and colleagues found that children who had experienced RSV LRTI were more likely to have asthma and recurrent wheeze for 7 yr (4). Weber and colleagues (8) determined in Gambia that RSV LRTI predisposed children to recurrent wheeze, but only for 2 yr; after 3 yr, there was no significant difference between RSV-infected children and control children with respect to wheezing episodes. Many of the patients in the Tucson study had only RSV upper respiratory tract infections and none were hospitalized (5, 6). Patients in the study by Sigurs and coworkers (4), Hall and colleagues (7), and those in the Gambia study (8) had severe RSV disease. The reason for the observed varying degree and length of long-term sequelae may lie in the differing degrees of severity of illness studied (mild versus severe), or differences in location (developed versus developing countries), or ecological differences in sensitizing allergens (desert versus temperate versus tropical), or other undetermined factors. It remains to be determined whether severe RSV LRTI causes the pulmonary sequelae observed in longitudinal studies (i.e., a cause-and-effect relationship) or whether inherent genetic or structural abnormalities that predispose a child to wheeze later in life also predispose the child to severe RSV LRTI. If causality exists, reducing severe RSV LRTI would reduce subsequent wheezing; if causality does not exist, reducing severe RSV LRTI would have no effect on subsequent wheezing. This is, therefore, a key clinical issue, which has been addressed in three sets of studies: antiviral therapy for RSV LRTI, antiinflammatory therapy for RSV LRTI, and prevention of RSV LRTI.

	LONG-TERM BENEFIT OF ANTIVIRAL THERAPY FOR SEVERE RSV LRTI

TOP INTRODUCTION LONG-TERM BENEFIT OF ANTIVIRAL... LONG-TERM BENEFIT OF... LONG-TERM BENEFIT OF PREVENTION... DISCUSSION REFERENCES

Ribavirin inhibits RSV replication during the active replication phase via a number of mechanisms (9). The first study to determine whether therapy for RSV LRTI with ribavirin would reduce long-term sequelae was reported by Krilov and coworkers (10). Thirty-three children who had received ribavirin for RSV LRTI in the 1986/1987 season and 67 age-matched control children who had not received ribavirin were monitored for 5 to 6 yr. Those in the ribavirin group had had more severe disease at presentation, but there was no between-group difference in long-term outcomes with respect to reactive airway disease (RAD) or pulmonary function.

Long and associates (11) enrolled 54 children who had participated in randomized trials of ribavirin therapy into a 9-yr follow-up study to assess the long-term effects of the antiviral agent. Twenty-eight of the children had been treated with ribavirin and 26 had been treated with placebo. There were no between-group differences with respect to any of the parameters evaluated, including recurrent LRTI, wheezing, and pulmonary function, suggesting no benefit of ribavirin therapy.

A third study with long-term follow-up was conducted by Rodriguez and coworkers (12) in 24 ribavirin recipients and 11 placebo control subjects, 13 and 6 of whom, respectively, underwent pulmonary function testing (PFT). The investigators reported minimal improvement in respiratory outcome. There was no difference in reactive airway disease, wheezing, or pneumonia between the two groups for up to 7 yr. There was no between-group difference in results of methacholine challenge tests, but 0 of 6 placebo recipients had normal or mildly abnormal PFTs, compared with 6 of 13 ribavirin recipients (p = 0.04). Thus, these long-term follow-up studies showed no real difference in long-term outcomes with antiviral therapy.

In contrast, in a 1-yr retrospective study, Edell and colleagues (13) reported a significant reduction in the prevalence of RAD among 22 ribavirin-treated children compared with 19 children treated conservatively (59 versus 89%, p < 0.05). It is possible that therapy with ribavirin may affect the short-term outcome (14), although the studies by Long and colleagues (11) and Rodriguez and coworkers (12) that monitored patients initially randomized to the drug did not show this effect. Antiviral therapy appears to have no significant effect on long-term respiratory outcomes.

	LONG-TERM BENEFIT OF ANTIINFLAMMATORY THERAPY FOR SEVERE RSV LRTI

TOP INTRODUCTION LONG-TERM BENEFIT OF ANTIVIRAL... LONG-TERM BENEFIT OF... LONG-TERM BENEFIT OF PREVENTION... DISCUSSION REFERENCES

Although it is clear that RSV causes damage to the lungs, it is also recognized that the immune response plays a significant role in the pathogenesis of disease (15, 16). Cytokines and other mediators of inflammation released during acute infection play an important role during the acute phase of infection but may also have a more long-lasting effect on the respiratory tract owing to either immune or neural mechanisms (15). It is thus possible that reducing local inflammation at the time of acute infection would result in improved respiratory outcomes later. Two early studies (18, 19) that examined the effect of nebulized beclomethasone on persistent wheezing following bronchiolitis suggested improved lung function (18) as well as fewer episodes of subsequent asthma and obstructive episodes in treated patients (19). These studies did not, however, enroll patients at the time of hospitalization. Six more recent studies (20) with different designs, interventions, length of follow-up, and outcomes are summarized in Table 1. Some studies show that antiinflammatory therapy may provide short-term benefits (18) but, except for a study conducted in Finland (24), no long-term benefits have been observed. However, the studies that showed no benefits either were conducted in children with a mixture of etiologies (19, 20) or used short-term therapy for up to 2 wk after discharge from hospital (21, 25). The study in Finland (24), which included only children with RSV LRTI and examined the effect of nebulized therapy for the acute illness and 8 wk of follow-up antiinflammatory therapy, showed significant medium-term improvements in respiratory outcomes. This effect is similar to that seen in earlier studies (18, 19) and suggests that nebulized therapy with an inhaled corticosteroid may improve respiratory outcomes in the first few years after RSV LRTI. Longer term studies and those including pulmonary function testing are required.

	LONG-TERM BENEFIT OF PREVENTION OF SEVERE RSV LRTI

TOP INTRODUCTION LONG-TERM BENEFIT OF ANTIVIRAL... LONG-TERM BENEFIT OF... LONG-TERM BENEFIT OF PREVENTION... DISCUSSION REFERENCES

Currently, no licensed vaccines for the prevention of RSV LRTI are available. However, two immunoglobulin preparations have been effective in the prevention of severe RSV LRTI: RSV immunoglobulin (RSV-IGIV), a polyclonal antibody preparation (26, 27), and palivizumab, a humanized monoclonal antibody directed against the F protein of RSV (28).

The initial studies of RSV-IGIV were conducted about 10 yr ago, which has allowed us to assess the long-term effects of this prophylaxis on respiratory outcomes. In a large multicenter study designed to evaluate the prophylactic efficacy of intravenous RSV-IGIV, we administered RSV-IGIV every 4 wk during the RSV season in a dose of either 750 or 150 mg/kg to premature infants with or without bronchopulmonary dysplasia (BPD) or to infants with congenital heart disease (26). A third group of high-risk infants received no RSV-IGIV and served as control subjects. The results showed that only high doses of RSV-IGIV prevented severe RSV LRTI in these high-risk patients.

To determine whether prophylaxis with RSV-IGIV of high-risk infants during the first year of life leads to improved respiratory outcomes, we monitored 13 children with BPD from our original group who had received RSV-IGIV and 26 age-matched control subjects with BPD who did not receive RSV-IGIV (29). The treatment and control groups were well matched with respect to parental smoking, number of children at home, and maternal asthma history, but they were not matched for a history of documented RSV infection. The treatment group had more boys (11 of 13 versus 12 of 26) and significantly more children with a cat at home (p < 0.005). Evaluation included questionnaires, PFTs, and skin tests. Children with BPD were selected because studies have shown that long-term survivors have ongoing respiratory sequelae. Bader and associates (30) found that children with BPD had evidence of airway obstruction, hyperinflation, and airway hyperreactivity at 10 yr compared with a control group.

The results of our study, recently reanalyzed, show that pulmonary function (FEV₁/FVC) was significantly better (p = 0.016) and airway conductance was marginally higher (p = 0.07) in the treatment group than in the control group. Airway hyperreactivity, as measured by PC₂₀ for methacholine, was similar in the two groups (p = 0.26), but there was significantly less atopy (as defined by one or more positive skin prick tests to 10 common allergens, p = 0.04) in the treatment group. In addition, in the last year, children in the treatment group were significantly less likely to have missed school (p = 0.006), had colds (p = 0.02), and had an asthma attack (p = 0.03). Marginal reductions were also seen in hospitalizations (p = 0.09) and the use of any asthma medications (p = 0.07).

RSV-IGIV and palivizumab are effective prophylactic agents for the prevention of RSV LRTI in children with BPD and/or prematurity, but their long-term impact on the development of asthma and recurrent wheezing is not known. The findings in a small group of children with BPD suggest that prophylaxis of RSV infections with RSV-IGIV may point to a possible long-term benefit in a selected group of patients. Palivizumab may also decrease the risk of asthma by preventing or blunting RSV LRTI. Large-scale prospective studies of palivizumab prophylaxis in children at high risk for asthma are warranted to confirm this association.

Clinical studies have shown that antiviral therapy appears to have no significant effect on reducing the long-term respiratory outcomes associated with RSV LRTI. Furthermore, reducing local inflammation at the time of acute infection with inhaled corticosteroid therapy improves respiratory outcomes only in the short term. Preliminary data suggest that preventing severe RSV disease may reduce the risk for development of reactive airway disease in selected populations. Research is ongoing to further elucidate the mechanisms involved.

	DISCUSSION

TOP INTRODUCTION LONG-TERM BENEFIT OF ANTIVIRAL... LONG-TERM BENEFIT OF... LONG-TERM BENEFIT OF PREVENTION... DISCUSSION REFERENCES

Sigurs: In my first follow-up study, the presence of indoor furred animals was protective against allergy. I thought it was a coincidence, but you found the same thing with cats.

Simoes: We did not find that cats were protective. I think there are other studies that have shown cats may be protective. Cats were a confounder in our study, as significantly more children in the RSV-IGIV group had cats at home than controls.

De Baets: A lot of studies are now looking at the children of farmers, and living on a farm also seems to be protective against development of allergic disease.

Piedimonte: Is it possible that cats generate some substance that might work as an adjuvant and modify the immunogenic characteristics of RSV proteins in specific environments, which, in turn, might modify the type of immune response to the virus?

Simoes: That is an interesting suggestion but a hypothesis that may be difficult to test in humans. The problem with cats in our study was that the effect that we saw in the RSV-IGIV group may have been explained purely by the increased number of cats in our study. In a multivariate analysis that analyzed risk factors and the presence of cats in the home, the effect of RSV-IGIV prophylaxis seen on pulmonary function tests as well as on atopy remained the single most important variable in the analysis after correcting for the imbalance in cats in the home. Although there was definitely a significant difference, I don't know if you can correct for a biological effect by statistics. So, I don't know the answer to your question. You may be right.

Cohen: I wonder if people don't naturally self-select when they decide to own a cat or live on a farm. Not that previous exposure to antigens can't somehow offer protection at times of future exposure, but the point is that many people who have cats and live on farms do so with the knowledge that they lack atopic responses to those triggers. So it may be just the opposite of what you propose.

Forster: Could you comment on the high incidence of atopy in your control group?

Simoes: We studied children with BPD, and these studies were started in the late 1980s, early 1990s. Hence, the BPD we saw was comparable to that described in the 1980's, where children with BPD had high attack rates of asthma and atopy. We don't see children with such severe BPD anymore because of surfactant, which was just being introduced when we were doing these studies. I think that the atopy may have been due to sensitization that occurred during the RSV infection. We defined atopy as a positive skin prick test to one of ten allergens compared to a histamine control. We did not do IgE testing.

Openshaw: I think the point about the possible effect of allergens on RSV is interesting. There is some in vitro evidence that some allergens may actually increase the infectivity of RSV. I also think there is very good evidence that respiratory epithelial permeability is increased by RSV disease, and therefore sensitization may occur to bystander inhaled allergens.

Götz: What would happen if you use ordinary IGIV instead of RSV-IGIV?

Simoes: IGIV has no preventive effect for RSV LRTI; you need high-titer (750 mg/kg) RSV IGIV to prevent RSV LRTI. At 150 mg/kg, however, even RSV-IGIV did not protect the lower respiratory tract, so I suspect that the long-term effect we saw with RSV-IGIV may not be seen with IGIV.

	Footnotes

Correspondence and requests for reprints should be addressed to Eric A. F. Simoes, M.D., DCH, Department of Pediatrics, Children's Hospital, Box B070, 1056 E. 19th Avenue, Denver, CO 80218. E-mail: eric.simoes{at}uchsc.edu

	References

TOP INTRODUCTION LONG-TERM BENEFIT OF ANTIVIRAL... LONG-TERM BENEFIT OF... LONG-TERM BENEFIT OF PREVENTION... DISCUSSION REFERENCES

1. Pullan CR, Hey EN. Wheezing, asthma, and pulmonary function 10 years after infection with respiratory syncytial virus in infancy. Br Med J 1982; 284: 1665-1669 .

2. Murray M, Webb MS, O'Callaghan C, Swarbrick AS, Milner AD. Respiratory status and allergy after bronchiolitis. Arch Dis Child 1992; 67: 482-487 [Abstract/Free Full Text].

3. Noble V, Murray M, Webb MS, Alexander J, Swarbrick AS, Milner AD. Respiratory status and allergy nine to 10 years after acute bronchiolitis. Arch Dis Child 1997; 76: 315-319 [Abstract/Free Full Text].

4. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. 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 [Abstract/Free Full Text].

5. Castro-Rodriguez JA, Holberg CJ, Wright AL, Halonen M, Taussig LM, Morgan WJ, Martinez FD. Association of radiologically ascertained pneumonia before age 3 yr with asthmalike symptoms and pulmonary function during childhood: a prospective study. Am J Respir Crit Care Med 1999; 159: 1891-1897 [Abstract/Free Full Text].

6. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, Wright AL, Martinez FD. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999; 354: 541-545 [Medline].

7. Hall CB, Hall WJ, Gala CL, MaGill FB, Leddy JP. Long-term prospective study in children after respiratory syncytial virus infection. J Pediatr 1984; 105: 358-364 [Medline].

8. Weber MW, Milligan P, Giadom B, Pate MA, Kwara A, Sadiq AD, Chanayireh M, Whittle H, Greenwood BM, Mulholland K. Respiratory illness after severe respiratory syncytial virus disease in infancy in The Gambia. J Pediatr 1999; 135: 683-688 [Medline].

9. Lugo RA, Nahata MC. Pathogenesis and treatment of bronchiolitis. Clin Pharm 1993; 12: 95-116 [Medline].

10. Krilov LR, Mandel FS, Barone SR, Fagin JC, Bronchiolitis Study Group. Follow-up of children with respiratory syncytial virus bronchiolitis in 1986 and 1987: potential effect of ribavirin on long term pulmonary function. Pediatr Infect Dis J 1997;16:273-276.

11. Long CE, Voter KZ, Barker WH, Hall CB. Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo. Pediatr Infect Dis J 1997; 16: 1023-1028 [Medline].

12. Rodriguez WJ, Arrobio J, Fink R, Kim HW, Milburn C. Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis. Ribavirin Study Group. Arch Pediatr Adolesc Med 1999; 153: 469-474 [Abstract/Free Full Text].

13. Edell D, Bruce E, Hale K, Edell D, Khoshoo V. Reduced long-term respiratory morbidity after treatment of respiratory syncytial virus bronchiolitis with ribavirin in previously healthy infants: a preliminary report. Pediatr Pulmonol 1998; 25: 154-158 [Medline].

14. Randolph AG, Wang EEL. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract. Cochrane Library 2000;3(CD000181): 1-11

15. Openshaw PJM. Potential mechanisms causing delayed effects of RSV infection. Am J Respir Crit Care Med 2001; 163: S10-S13 [Free Full Text].

16. Kimpen JLL. RSV and asthma: the role of monocytes. Am J Respir Crit Care Med 2001; 163: S7-S9 [Free Full Text].

17. Piedemonte G. Neural mechanisms and mechanisms of prevention of RSV sequelae: animal studies. Am J Respir Crit Care Med 2001; 163: S18-S21 [Free Full Text].

18. Maayan C, Itzhaki T, Bar-Yishay E, Gross S, Tal A, Godfrey S. The functional response of infants with persistent wheezing to nebulized beclomethasone dipropionate. Pediatr Pulmonol 1986; 2: 9-14 [Medline].

19. Carlsen KH, Leegaard J, Larsen S, Orstavik I. Nebulised beclomethasone dipropionate in recurrent obstructive episodes after acute bronchiolitis. Arch Dis Child 1988; 63: 1428-1433 [Abstract/Free Full Text].

20. Reijonen T, Korppi M, Kuikka L, Remes K. Anti-inflammatory therapy reduces wheezing after bronchiolitis. Arch Pediatr Adolesc Med 1996; 150: 512-517 [Abstract/Free Full Text].

21. Richter H, Seddon P. Early nebulized budesonide in the treatment of bronchiolitis and the prevention of postbronchiolitic wheezing. J Pediatr 1998; 132: 849-853 [Medline].

22. Fox GF, Everard ML, Marsh MJ, Milner AD. Randomised controlled trial of budesonide for the prevention of post-bronchiolitis wheezing. Arch Dis Child 1999; 80: 343-347 [Abstract/Free Full Text].

23. Van Woensel J, Kimpen JLL, Sprikkelman AB, Ouwehand A, van Aalderen WM. Long-term effects of prednisolone in the acute phase of bronchiolitis caused by respiratory syncytial virus. Pediatr Pulmonol 2000; 30: 92-96 [Medline].

24. Kajosaari M, Syvanen P, Forars M, Juntunen-Backman K. Inhaled corticosteroids during and after respiratory syncytial virus-bronchiolitis may decrease subsequent asthma. Pediatr Allergy Immunol 2000; 11: 198-202 [Medline].

25. Cade A, Brownlee KG, Conway SP, Haigh D, Short A, Brown J, Dassu D, Mason SA, Phillips A, Eglin R, Graham M, Chetcuti A, Chatrath M, Hudson N, Thomas A, Chetcuti PAJ. Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis. Arch Dis Child 2000; 82: 126-130 [Abstract/Free Full Text].

26. Groothuis JR, Simoes EAF, Levin MJ, Hall CB, Long CE, Rodriguez WJ, Arrobio J, Meissner HC, Fulton DR, Welliver RC, Tristram DA, Siber GR, Prince GA, Van Raden M, Hemming VG, Respiratory Syncytial Virus Immune Globulin Study Group. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993;329:1524-1530.

27. 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.

28. 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.

29. Wenzel SE, Gibbs R, Lehr M, Park N, Simoes EAF. 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 .

30. Bader D, Ramos AD, Lew CD, Platzker AC, Stabile MW, Keens TG. Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia. J Pediatr 1987; 110: 693-699 [Medline].