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Bronchiolitis is a common illness affecting young children. It is primarily a disease with respiratory distress, crepitation and expiratory wheeze associated with respiratory viral infections, including RSV, rhinovirus and parainfluenza viruses. RSV is one of the most important respiratory pathogens in infancy causing the majority of lower respiratory tract infections during the winter season. Almost all young children experience RSV infection at least once in the first two years of life, and >65% become infected during their first year, with the peak incidence for lower respiratory disease occurring between 2 and 7 months of age (1, 2). Hospitalization rates for RSV illness are 5-20 cases per 1000 infants <1 year of age (3, 4, 5). Mechanical ventilation is required in 7-21% of hospitalized infants with RSV bronchiolitis, with lower gestational age, requirement of neonatal oxygen supplementation and bronchopulmonary dysplasia as significant risk factors (6, 7, 8). Mortality in RSV-infected infants with lower respiratory tract symptoms is <1% (9). Reinfection with RSV occurs frequently and usually has a mild character with symptoms of uncomplicated upper respiratory tract infection (10). However, in our case RSV reinfection had caused the severe wheezing episode. Post-bronchiolitis wheeze occurs in about 42–71% of cases of RSV bronchiolitis. Post-bronchiolitis wheeze is characterized by recurrent episodes of wheeze during pre-school years (Fig.2).

 

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Figure 2 Number of days with respiratory wheeze per quarter following RSV LRTI. Parents recorded daily respiratory symptoms which were analysed per quarter. Infrequent wheeze (1-5 days/quarter) and frequent wheeze (>5 days/quarter) are distinguished. Data from Thorax. 2004Jun; 59(6):512-6

Most epidemiological studies do not find an association between post-bronchiolitis wheeze and the development of allergic asthma, although this issue is subject to debate in literature. It is generally assumed that wheezing episodes following RSV LRTI are associated with viral upper respiratory tract infections and not allergen exposure, in contrast to children who suffer allergic asthma (11).

The pathogenesis of post-bronchiolitis wheeze is not fully understood. Is it the virus-induced pathogenic effect on the airway epithelium which leaves these children with vulnerable lungs and wheezing episodes (serial hypothesis)? Or are these children born with small or vulnerable airways making them susceptible for both viral infections and wheezing episodes (parallel hypothesis)? This serial versus parallel hypothesis (Fig.3) is an important challenge in the attempts to understand the pathogenesis of post-bronchiolitis wheeze. Pre-existent morbidity has been shown to be a factor. The risk of having a wheezing illness is almost 4 times higher in children with pre-existent lung function abnormalities. The children whose initial values for lung volume at the end of tidal expiration were in the lowest third, even had an 10-16 fold increased risk (12). There is also evidence that several genetic phenotypes are of influence to disease severity and post-bronchiolitis symptoms. It was shown that disease severity is associated with a common single nucleotide polymorphism close to the IL-8 gene and an increased IL-8 production upon stimulation (13). Another such polymorphism has recently been found which clearly depicts early post-bronchiolitis wheezing and wheezing later in childhood as distinct pathophysiological entities. We found a significant overrepresentation of an IL-13 polymorphism in children with late wheezing, but this polymorphism was not associated with severe RSV LRTI (unpublished data). As such, these results support the concept that mechanisms underlying the development of severe RSV LRTI are to be studied separately from the pathophysiology of wheezing illness.

In addition to pre-existent factors, the immune response seems to be the major contributor to disease severity as is demonstrated in several studies. Especially in early infancy the immune system doesn’t seem able to elicit an appropriate Th1 immune response against the invading virus. Kristjansson found a local Th2 response and signs of eosinophils activation due to an elevated production of the Th2-type cytokine IL-4 (14).

Figure 3 Pathogenesis of post-bronchiolitis wheeze: serial vs. parallel hypothesis.

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Treatment
The treatment possibilities for RSV infection are very limited. An attempt to prevent RSV infection using formalin-inactivated RSV became a disastrous event, but researchers continue their search for a safe and effective vaccine. High-risk children can be given prophylaxis, by monthly administration of a monoclonal antibody against the RSV F-protein (passive immunization). Especially high-risk children who are younger than 6 months of age at the start of the RSV season should receive this therapy. Because of high costs, this type of prophylaxis can not be used for all infants.

Several therapies, including ribavirin, bronchodilatators, racemic epinephrine and corticosteroids are not recommended as standard therapies because of lack of benefit found in RCTs. In two different longitudinal studies intermittent inhaled corticosteroid therapy had no effect on the short- or long term benefit and had no disease modifying effect after the therapy was discontinued. There was also no significant difference between corticosteroid and control groups in the development of persistent wheezing (15, 16). Recently, Lehtinen and colleagues found that systemic steroids during the first episode of wheezing prevented post-bronchiolitis wheeze, but only when the initial bronchiolitic episode was caused by rhinovirus, and not by RSV (17). Use of montelukast, a leukotriene receptor antagonist, during RSV infection is another therapy which has been suggested to post-bronchiolitis wheeze. However, this study needs to be confirmed before it can be accepted as standard treatment. Taken together, there is no effective treatment for RSV bronchiolitis or an intervention that effectively prevents post-bronchiolitic symptoms.

REFERENCES

(1) Parrott, R. H., H. W. Kim, J. O. Arrobio, D. S. Hodes, B. R. Murphy, C. D. Brandt, E. Camargo, and R. M. Chanock. 1973. Epidemiology of respiratory syncytial virus infection in Washington, D.C. II. Infection and disease with respect to age, immunologic status, race and sex. Am. J. Epidemiol. 98:289.
(2) Glezen, W. P., L. H. Taber, A. L. Frank, and J. A. Kasel. 1986. Risk of primary infection and reinfection with respiratory syncytial virus. Am. J. Dis. Child 140:543.
(3) Karron, R. A., R. J. Singleton, L. Bulkow, A. Parkinson, D. Kruse, I. DeSmet, C. Indorf, K. M. Petersen, D. Leombruno, D. Hurlburt, M. Santosham, and L. H. Harrison. 1999. Severe respiratory syncytial virus disease in Alaska native children. RSV Alaska Study Group. J. Infect. Dis. 180:41.
(4) Shay, D. K., R. C. Holman, R. D. Newman, L. L. Liu, J. W. Stout, and L. J. Anderson. 1999. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA 282:1440.
(5) Glezen, W. P. 2004. The changing epidemiology of respiratory syncytial virus and influenza: impetus for new control measures. Pediatr. Infect. Dis. J. 23:S202-S206.
(6) Frankel, L. R., N. J. Lewiston, D. W. Smith, and D. K. Stevenson. 1986. Clinical observations on mechanical ventilation for respiratory failure in bronchiolitis. Pediatr. Pulmonol. 2:307.
(7) Tissing, W. J., H. A. van Steensel-Moll, and M. Offringa. 1993. Risk factors for mechanical ventilation in respiratory syncytial virus infection. Eur. J. Pediatr. 152:125.
(8) Flamant, C., F. Hallalel, P. Nolent, J. Y. Chevalier, and S. Renolleau. 2005. Severe respiratory syncytial virus bronchiolitis in children: from short mechanical ventilation to extracorporeal membrane oxygenation. Eur. J. Pediatr. 164:93.
(9) Thompson, W. W., D. K. Shay, E. Weintraub, L. Brammer, N. Cox, L. J. Anderson, and K. Fukuda. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179.
(10) Henderson, F. W., A. M. Collier, W. A. Clyde, Jr., and F. W. Denny. 1979. Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children. N. Engl. J. Med. 300:530.
(11) Pullan, C. R., and E. N. Hey. 1982. Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. Br. Med. J. (Clin. Res. Ed) 284:1665.
(12) Martinez, F. D., W. J. Morgan, A. L. Wright, C. J. Holberg, and L. M. Taussig. 1988. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N. Engl. J. Med. 319:1112.
(13) Hull, J., A. Thomson, and D. Kwiatkowski. 2000. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 55:1023.
(14) Kristjansson, S., S. P. Bjarnarson, G. Wennergren, A. H. Palsdottir, T. Arnadottir, A. Haraldsson, and I. Jonsdottir. 2005. Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local TH2-like response. J. Allergy Clin. Immunol. 116:805.
(15) Guilbert, T. W., W. J. Morgan, R. S. Zeiger, D. T. Mauger, S. J. Boehmer, S. J. Szefler, L. B. Bacharier, R. F. Lemanske, Jr., R. C. Strunk, D. B. Allen, G. R. Bloomberg, G. Heldt, M. Krawiec, G. Larsen, A. H. Liu, V. M. Chinchilli, C. A. Sorkness, L. M. Taussig, and F. D. Martinez. 2006. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N. Engl. J. Med. 354:1985.
(16) Bisgaard, H., M. N. Hermansen, L. Loland, L. B. Halkjaer, and F. Buchvald. 2006. Intermittent inhaled corticosteroids in infants with episodic wheezing. N. Engl. J. Med. 354:1998.
(17) Lehtinen, P., A. Ruohola, T. Vanto, T. Vuorinen, O. Ruuskanen, and T. Jartti. 2006. Prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema. J. Allergy Clin. Immunol.

Summary
We have described an infant with recurrent episodes of wheeze following RSV bronchiolitis. Pre-existent as well as virus-induced pathophysiological mechanisms have been discussed. It remains a challenge to identify children with persistent asthma among those who experience post-bronchiolitis wheeze. To date, no single treatment has convincingly been shown to be effective. The precise underlying mechanisms of post-bronchiolitis wheeze need to be unraveled before safe and effective preventive and treatment strategies can be developed.

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