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The treatment of bronchiolitis

M Yanney and H Vyas Arch. Dis. Child. 2008;93;793-798; originally published online 6 Jun 2008; doi:10.1136/adc.2007.128736

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Review

The treatment of bronchiolitis

M Yanney,1 H Vyas2
1

Sherwood Forest Hospitals Foundation Trust, Mansfield Road, Sutton-in-Ashfield, Nottinghamshire NG17 4JL, UK; 2 Nottingham University Hospitals, Queens Medical Centre Campus, Nottingham NG7 2UH, UK Correspondence to: Harish Vyas, Nottingham University Hospitals, Queens Medical Centre Campus, Nottingham NG7 2UH, UK; harish.vyas@nuh.nhs.uk Accepted 13 May 2008 Published Online First 6 June 2008

ABSTRACT Bronchiolitis is the commonest reason for hospital admission in infancy and the most frequent cause of acute respiratory failure in children admitted to paediatric intensive care units in the UK and North America. The respiratory syncytial virus accounts for most cases of bronchiolitis, however, new virus isolation techniques have led to the discovery of previously unrecognised viruses, including the human metapneumovirus and bocavirus which also play a significant role. The main developments in bronchiolitis management in recent years relate to the use of immunoprophylaxis; a number of other therapies such as the use of heliox are currently being investigated. Supportive therapy remains the mainstay of management with limited or no evidence of benefit for most other pharmacological treatments. This article summarises the current understanding of the different bronchiolitis phenotypes, with a brief description of outcomes and a review of the evidence for the various therapeutic interventions.

group than that typically affected by RSV.17 The human bocavirus discovered in 2005 is the most recently identified pathogen known to cause bronchiolitis.18 Other aetiological agents include adenovirus, influenza, parainfluenza, coronavirus and enterovirus.

CLINICAL FEATURES
Bronchiolitis is a clinical diagnosis. In the UK the term describes an illness in infants that begins as an upper respiratory tract infection (URTI) followed by signs of respiratory distress, a harsh cough, bilateral crepitations, air trapping and wheezing.19 In North America and other parts of Europe, acute bronchiolitis is used to describe children up to 2 years of age presenting with a wheezing illness associated with a URTI and may include children who would be considered to have viral induced wheeze in the UK. The differences in definition are important when evaluating the results of therapeutic interventions in clinical trials and when comparing data about incidence, morbidity, mortality and long-term outcomes between studies. Most children with bronchiolitis have a self-limiting illness and are managed conservatively at home. Infants with moderate or severe bronchiolitis who have marked difficulty breathing with hypoxia require hospital admission. There is no widely accepted validated scoring system to measure illness severity, however, factors found to be associated with more severe illness are listed in box 3.11 Mortality in infants who are otherwise healthy is less than 1% in patients admitted to an intensive care unit20 but is higher (,3.5%) in children with underlying conditions such as cardiac or chronic lung disease.21 Other groups at high risk of severe disease are preterm infants and children with congenital or acquired immunodeficiency as well as children with cystic fibrosis.22 Risk factors for bronchiolitis and for severe infection are listed in boxes 1 and 2. A subgroup of children requiring ventilation for RSV infection traditionally presumed to have bronchiolitis have recently been identified as having a different pattern of illness characterised by the radiological appearance of diffuse consolidation without hyperinflation as opposed to the classical appearance of gross hyperinflation without consolidation.23 This pattern of illness is more accurately described as RSV pneumonia and these children generally fulfil the clinical criteria of acute respiratory distress syndrome (ARDS). The distinction between the different clinical entities is important because the response to treatment and outcome may well be different for the two groups. One obvious difference is the prolonged length of ventilation in the group with pneumonia compared to those with bronchiolitis.
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Bronchiolitis is the most common reason for hospitalisation in infants and the most frequent cause of acute respiratory failure among paediatric intensive care unit (PICU) admissions in the UK.1 The respiratory syncytial virus (RSV) is responsible for about 5090% of all cases of bronchiolitis2 and results in approximately 20 000 hospital admissions annually in the UK.3 About 100 000 infants are admitted with bronchiolitis annually in the United States.4 Bronchiolitis occurs most commonly in infants aged between 2 and 6 months. Risk factors associated with bronchiolitis are listed in box 1 and groups at high risk of severe disease are listed in box 2. The option of passive immunisation to RSV has been the most significant addition to the management of bronchiolitis in recent years; supportive therapy otherwise remains the mainstay of treatment. This review summarises the current understanding of the bronchiolitis phenotypes and evaluates the evidence for various therapeutic interventions.

AETIOLOGY
New virus isolation techniques including the use of reverse transcription polymerase chain reaction (RT-PCR) have led to the identification of a number of previously unrecognised viruses which play a significant role in acute bronchiolitis besides RSV. Human metapneumovirus (hMPV) was identified as a significant respiratory pathogen in 2001.14 It causes a similar spectrum of illness to RSV and may be the second most common cause of bronchiolitis.14 15 HMPV co-infection with RSV is the cause of particularly severe bronchiolitis in some cases.15 16 Rhinovirus has also been shown to be a frequent cause of bronchiolitis in an older age
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Box 1 Environmental and other risk factors for bronchiolitis58
1. 2. 3. 4. Older siblings Nursery attendance Passive smoke, especially maternal Overcrowded household
available for use as immunoprophylaxis in infants at high risk of developing severe RSV bronchiolitis. The first to become available was intravenous RSV immunoglobulin (RSV-IG). The prophylactic administration of RSV-IG to high risk infants and young children was evaluated in a prospective, multicentre, blinded, randomised controlled trial involving 249 children.27 Subjects were randomly assigned to treatment groups which received high dose (750 mg/kg) or low dose (150 mg/kg) monthly infusions of RSV-IG, or to a control group that received no infusions. The investigators reported significantly fewer lower respiratory tract infections (LRTI) and hospitalisations and in addition reduced days in intensive care in children treated with high dose RSV-IG when compared with controls. Subjects in the low dose group were reported to have a significant reduction only in the number of days in intensive care. Disadvantages of RSV-IG include the need for intravenous administration of a large volume (15 ml/ kg) with its potential for fluid overload, a long duration of administration (24 h) and expense. The study found an increased incidence of adverse events in infants with cyanotic congenital heart disease, so RSV-IG is not recommended for this high risk group. The humanised monoclonal antibody (palivizumab) is an alternative form of passive immunisation which has largely superseded the use of RSV-IG. In a randomised, double blind, multi-centre trial (IMpact-RSV Trial), monthly palivizumab prophylaxis or placebo was administered to 1502 children by intramuscular injection over the 5 months of the RSV season.28 Palivizumab use was associated with a 55% reduction in RSVrelated hospitalisation (95% CI 38% to 72%), fewer days in hospital (placebo group: 62.6 days/100 children; palivizumab group: 36.4 days/100 children) and a lower incidence of intensive care admission (placebo group: 3%; palivizumab group: 1.3%; p = 0.026). Similar findings were reported in children with haemodynamically significant congenital heart disease.29 The main advantages of palivizumab over RSV-IG are its relative ease of administration and lack of interference with normal immunisations; its major disadvantage is its high cost. The benefits of palivizumab over RSV-IG have been assessed to outweigh any disadvantages by most clinicians and as a result it is preferred.30 A recent study of the healthcare utilisation of 190 prematurely born children with chronic lung disease found significantly increased respiratory morbidity and health service cost following RSV infection.31 In light of these data, the UK Department of Health advisory body on immunisations, the Joint Committee on Vaccination and Immunisation (JCVI), in 2005 revised its recommendations for the use of palivizumab prophylaxis; it was previously recommended only for children with chronic lung disease (CLD) who also required home oxygen but is now recommended for all children with CLD, even those not needing home oxygen. The groups recommended to receive palivizumab by the JCVI are: 1. Children under 2 years of age with chronic lung disease who have required supplementary oxygen for at least 28 days from birth or who are receiving home oxygen. 2. Infants less than 6 months of age who have a left to right shunt, haemodynamically significant congenital heart disease and/or pulmonary hypertension. 3. Children under 2 years of age with severe congenital immunodeficiency. Despite this there is a lack of an agreed approach in practice. Many clinicians do not prescribe palivizumab to infants with CLD who are not on home oxygen.
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PATHOPHYSIOLOGY
The pathological changes found in bronchiolitis were first described in autopsy specimens from infants dying of the condition and are presumed to be similar in those with a milder form of the illness who survive.24 The observed post mortem changes are those of acute inflammatory obstruction in the small airways. The virus colonises the respiratory tract epithelium and replicates causing epithelial necrosis and destruction of the cilia. The epithelial cell destruction triggers an inflammatory response with cellular infiltration with both neutrophils and lymphocytes and consequent oedema of the submucosa. There is also increased secretion of mucus from goblet cells, which combines with desquamated epithelial cells to form thick mucus plugs. The mucus plugs cause obstruction of the bronchioles, which results in both air trapping and lobular collapse to varying degrees. This leads to ventilation perfusion mismatch resulting in hypoxaemia.2 24

PREVENTATIVE THERAPIES Vaccine

There is currently no vaccine available to prevent RSV infection, which is responsible for up to 90% of admissions with bronchiolitis. The first trials of a formalin-inactivated RSV vaccine in the 1960s induced a good IgG response in healthy volunteers but when assessed in clinical trials, the severity of subsequent infection was increased rather than decreased in those who had been immunised.25 26 Problems to be surmounted in the development of a vaccine include the need to induce immunity to multiple strains of the virus. A series of boosters would be required for a vaccine to be effective because natural infection with RSV does not prevent re-infection.

Immunoprophylaxis
The most significant progress in the management of bronchiolitis in recent years has been in the development of agents giving passive immunisation against RSV. Two products are currently

Box 2 Risk factors for severe respiratory syncytial virus disease and/or complications913
1. 2. 3. 4. 5. 6. 7. Prematurity (gestational age ,37 weeks) and low birth weight Age under 12 weeks Chronic lung disease (cystic fibrosis, broncho-pulmonary dysplasia and underlying lung anomalies) Congenital heart disease with left to right shunt Neurological diseases associated with hypotonia and pharyngeal incordination Immunocompromised state Congenital or anatomical defects of the airways

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Box 3 Clinical and radiographic findings associated with severe bronchiolitis illness11
c c c c c c

salbutamol.36 A Cochrane review of the use of adrenaline for bronchiolitis found some evidence that it was more effective than salbutamol or placebo when used in the outpatient setting but no evidence of benefit when used in inpatients.37

Ill or toxic general appearance Oxygen saturation ,95% Gestational age ,34 weeks Respiratory rate >70/min Atelectasis on chest x ray Age ,3 months

Methylxanthines
Uncontrolled trials of the use of methylxanthines such as theophylline and caffeine for infants with bronchiolitis-associated apnoea suggest they may be of some benefit in this subgroup of children.38 A randomised, double blind, placebo controlled trial of aminophylline in infants with severe bronchiolitis requiring intensive care is currently under way to determine if its use may reduce the need for respiratory support.39

TREATMENT
Children with bronchiolitis require hospital admission if they are hypoxic or are unable to maintain adequate hydration; those in high risk groups may require admission at an earlier stage of illness than otherwise healthy children. Supportive care with oxygen and nasogastric feeding (if fluid intake is inadequate) are the mainstays of treatment for children with mild or moderate bronchiolitis. Results from numerous studies on a range of other treatment options have been disappointing, with inconsistent findings or no evidence of benefit.

Antibiotics
The use of antibiotics in bronchiolitis has been the subject of a Cochrane review which unsurprisingly found no evidence to support their routine use.40 Antibiotics should be avoided unless there is strong suspicion or confirmation of secondary bacterial infection.

Corticosteroids
Despite the prominent role that inflammation plays in the pathogenesis of airway obstruction, trials of the use of corticosteroids have consistently failed to show any benefit. A systematic review of randomised controlled trials of systemic corticosteroids in acute bronchiolitis found no benefit in terms of length of hospital stay or of clinical scores.32 The most recent trial to confirm the lack of benefit of corticosteroids was a multi-centre randomised controlled trial which compared a single dose of oral dexamethasone with placebo in 600 children diagnosed with bronchiolitis in the A&E department. No significant difference was found in the rates of hospital admission, respiratory status after 4 h or later outcomes such as length of hospital stay, later medical consultations or admissions.33

Ribavarin
Ribavarin is the only antiviral agent licensed for use in RSV bronchiolitis, but its use is associated with limited clinical benefit. A prospective, double blind multi-centre study was undertaken to assess the efficacy of early ribavarin intervention in mild RSV illness compared with placebo.41 Forty seven children with bronchopulmonary dysplasia or congenital heart disease were enrolled. Early administration of ribavarin (,72 h after onset of symptoms) was associated with improved oxygenation and clinical scores in 20 infants compared with 27 controls. In a later prospective controlled study, the Pediatric Investigators Collaborative Network on Infections in Canada conducted a subset analysis of 750 children with RSV LRTI enrolled in the 19931994 RSV database.42 They observed no significant benefit of ribavarin therapy in premature infants or infants with congenital heart disease or chronic lung disease with respect to a range of outcome measures including hospitalisation, duration of ventilation, stay in intensive care and mortality. A Cochrane review of randomised trials comparing ribavarin with placebo in infants with RSV LRTI found that ribavarin may reduce duration of mechanical ventilation and days of hospitalisation but concluded that it has not been shown to significantly reduce respiratory deterioration (treatment failure defined by pre-specified criteria leading to withdrawal from the study) or mortality.43 Trials of ribavarin have generally been inadequately powered to determine the outcome measures reliably. Ribavarin is currently only recommended for use in immunocompromised patients to reduce the duration of viral shedding.44

b2 Agonists
Evidence relating to the use of bronchodilators in bronchiolitis is inconclusive; most studies suggest they have no benefit and might be deleterious, while a few studies have found some clinical improvement. A systematic review of randomised controlled trials comparing bronchodilators with placebo in bronchiolitis concluded that bronchodilators produce a modest short-term improvement in clinical scores but no reduction in the rate or duration of hospitalisation; however, the definition of bronchiolitis used in some of the trials allowed inclusion of children with recurrent wheeze which will have biased the results in favour of bronchodilators.34

Adrenaline (epinephrine)
Adrenaline (epinephrine) has both a and b adrenergic action which may enhance its effectiveness in the management of bronchiolitis compared to other b2 agonists. A number of studies have evaluated its use in both inpatient and outpatient settings. A large multi-centre randomised double blind placebo controlled trial of its use in 194 infants found no difference in the length of hospital stay, and no significant changes in respiratory rate or respiratory scores.35 A smaller randomised controlled study of its use in 42 infants found it significantly improved oxygenation and reduced hospital admission compared to children treated with
Arch Dis Child 2008;93:793798. doi:10.1136/adc.2007.128736

MANAGEMENT OF RESPIRATORY FAILURE

Infants with bronchiolitis may need respiratory support for either recurrent apnoea or increased work of breathing with respiratory failure. About 2% of infants with bronchiolitis require respiratory support.4 Several modes of respiratory support have been used in the management of bronchiolitisassociated respiratory failure. Intermittent positive pressure ventilation (IPPV),45 continuous positive airway pressure (CPAP),46 negative extrathoracic pressure,47 high frequency oscillation ventilation48 and extracorporeal membrane oxygenation49 have all been used successfully, but none in the context of
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a randomised controlled trial. A helium/oxygen mixture (heliox) has been used in infants with bronchiolitis-related respiratory failure to see if it might improve clinical scores or reduce the need for mechanical ventilation.50 51 A prospective, randomised, double blind study of 20 infants with moderate to severe bronchiolitis found a significant difference in the modified Wood clinical asthma score after 1 h of heliox use.50 However, a multi-centre, randomised, double blind placebo controlled study of 39 infants with severe bronchiolitis found no difference in the need for intubation between subjects and controls following the use of heliox for at least 24 h.51 Exogenous surfactant is another adjunct that has been investigated for its use in severe bronchiolitis. A randomised controlled pilot study of the use of a bovine surfactant (Survanta) in nine ventilated infants with RSV bronchiolitis found a significant improvement in oxygenation at 60 h compared to 10 controls treated with air placebo.52 There was a significant reduction in lung compliance and a corresponding increase in respiratory resistance at 30 h in the placebo group but not the treatment group. These findings warrant further evaluation in a larger study.

heart disease) out of 305 with bronchiolitis required PPV. This study suggests that, if started early, CPAP has the potential to be an effective mode of respiratory support for bronchiolitis. Soong et al55 similarly found nasal CPAP to be effective in 10 out of 11 children with impending respiratory failure from bronchiolitis; one child with immunodeficiency required intubation and ventilation after showing no improvement on nasal CPAP. It is postulated that CPAP works by keeping small airways open throughout the respiratory cycle. Paradoxically this reduces hyperinflation and air trapping and results in improved gas exchange.55 Studies have found CPAP to be relatively free of complications, although pneumothoraces can occur. Children with very severe bronchiolitis may still require intubation and mechanical ventilation, as CPAP may be less effective than PPV once exhaustion and respiratory failure have developed. There are no randomised trials comparing the use of CPAP with other modes of ventilatory support for bronchiolitis.

OUTCOME FOLLOWING BRONCHIOLITIS

The respiratory outcome following bronchiolitis has been extensively investigated and an association with subsequent reactive airway disease (RAD) has been found in most studies where this has been evaluated.5658 RSV is the commonest cause of bronchiolitis and has been found most frequently to have an association with RAD, although recent work suggests that rhinovirus may have an even stronger association.59 Results from controlled studies suggest the rate of wheezing following bronchiolitis is between 34% and 50% depending on the age at follow-up.57 58 Follow-up studies which have included lung function testing suggest that there may be persistent hyperinflation in the early years after bronchiolitis and increased airways resistance may still be evident after 10 years.57 The mechanism by which RSV or other aetiological agents cause reactive airways disease following bronchiolitis remains unclear. A number of hypotheses have been postulated: first that RSV infection damages the lung or alters host immunity resulting in RAD60; second, that RSV infection unmasks an inherent susceptibility to RAD61; or third, that host factors determine the pattern of the bronchiolitic illness and the frequency and severity of subsequent symptoms.62 Evidence to support the third hypothesis is provided by a recent prospective cohort study by Elphick et al.62 The effect of acute RSV illness on subsequent outcomes was evaluated in 56 infants with two different phenotypes of RSV LRTI and compared with 94 controls. The RSV infants were divided into those with bronchiolitis (RSVB) characterised by widespread crepitations with or without wheeze (n = 42) and those with wheeze alone (RSVW) (viral associated wheeze; n = 14). At 3 years of age, 37 of the RSV cohort (28 RSVB, nine RSVW) and 77 controls were assessed with a respiratory questionnaire and skin prick testing (SPT). Children with RSVW were significantly more likely to have wheezed most days in association with colds (odds ratio 42.0; 95% CI 3.5 to 501) compared to children with RSVB (odds ratio 9.9; 95% CI 1.0 to 101). There was no significant increase in allergic sensitisation on SPT in the RSV group as a whole when compared to controls; the numbers in the RSV subgroups were too small to draw conclusions about this in the different phenotypes.

Positive pressure ventilation

Positive pressure ventilatory support has been the mainstay of management for infants with bronchiolitis-associated respiratory failure since its introduction in the 1960s. Downes et al45 reported its use in a cohort of 86 children, 23 of whom had respiratory failure due to bronchiolitis, acute asthma or pneumonia. All 23 children with respiratory failure (including five infants with bronchiolitis), who would normally have been expected to progress to circulatory arrest, recovered after receiving mechanical ventilation. Retrospective studies by Outwater and Crone53 and Lebel et 54 al both confirmed the effectiveness of mechanical ventilation as respiratory support for infants with bronchiolitis-associated respiratory failure. Both studies excluded high risk infants with preceding lung disease, congenital heart disease or multiple congenital malformations but found that all previously well infants included in their studies (n = 77) survived to discharge with no clinically apparent respiratory sequelae.

Continuous positive airway pressure

CPAP is another commonly used mode of respiratory support for infants with bronchiolitis-associated respiratory failure which has been employed since the 1970s. Criteria for its use vary widely between units. Its main advantages over IPPV are that it can be delivered non-invasively (via nasal prongs), thereby avoiding the complications associated with intubation, and can be used without the infants needing to be sedated. Uncontrolled studies suggest CPAP may be effective in bronchiolitis despite the pathophysiological process of the illness involving air trapping, which CPAP might be expected to make worse.46 55 Beasley and Jones46 first reported the use of CPAP for bronchiolitis in a cohort of 23 infants; 14 received nasal CPAP via a short nasal cannula and nine via an endotracheal tube (ET). All 23 infants showed clinical improvement with CPAP and survived to be discharged. One infant suffered a pneumothorax, which was drained. The authors noted that CPAP was started at an earlier stage in these infants, before the development of uncompensated respiratory failure, than was PPV in a previous cohort. In the 5 years before the authors began to use CPAP, 288 infants were admitted with bronchiolitis and 13 were managed with PPV. In the 5 years after its introduction, just two infants (both with congenital
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SUMMARY
Bronchiolitis is the commonest LRTI in infancy and is most frequently caused by the respiratory syncytial virus which
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occurs in predictable winter epidemics. A number of therapies have been evaluated for their use in the amelioration of symptoms during the acute illness with minimal evidence of benefit. Supportive therapy with oxygen and assistance with feeding remains the mainstay of treatment. A number of other therapies have been used to stave off the need for respiratory support in infants with impending respiratory failure, although the evidence for their use is limited. Once respiratory failure ensues, respiratory support can be successfully provided in a significant proportion of cases with CPAP if used at an early stage. For infants who go on to require mechanical ventilation, the mortality is low (less than 1%) in the absence of preceding lung disease, heart disease or immunodeficiency. The initial period following bronchiolitis is characterised by an increased prevalence of respiratory symptoms; a predisposition to reactive airways disease may last until early adolescence.
Competing interests: None.
22. 23. 24. 25. Stretton M, Ajizian S, Mitchell I, et al. Intensive care course and outcome of patients infected with respiratory syncytial virus. Pediatr Pulmonol 1992;13:14350. Tasker RC, Gordon I, Kiff K. Time course of severe respiratory syncytial virus infection in mechanically ventilated infants. Acta Paediatr 2000;89(8):93841. Aherne W, Bird T, Court SD, et al. Pathological changes in virus infections of the lower respiratory tract in children. J Clin Pathol 1970;23:718. Kim HW, Canchola JG, Brandt CD, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969;89:42234. Kapikian AZ, Mitchell RH, Chanock RM, et al. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS vaccine. Am J Epidemiol 1969;89:40521. Groothuis JR, Simoes E, Levin MJ, et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993;329(21):152430. 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(3):5317. Feltes TF, Cabalka AK, Meissner HC, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant heart disease. J Pediatr 2003;143:53240. Kimpen JL. Prevention and treatment of respiratory syncytial virus bronchiolitis and post bronchiolitis wheezing. Respir Res 2002;3(Suppl 1):S405. Greenough A, Alexander J, Burgess S, et al. Health care utilisation of prematurely born, preschool children related to hospitalisation for RSV infection. Arch Dis Child 2004;89(7):6738. Patel H, Platt R, Lozano JM, et al Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database Syst Rev 2004;(3):CD004878. Corneli HM, Zorc JJ, Mahajan P, et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med 2007;357:3319. Kellner JD, Ohlsson A, Gadomski AM, et al. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2000;(2):CD001266. Wainwright C, Altamirano L, Cheney M, et al. A multicenter, randomized, doubleblind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med 2003;349(1):2735. Menon K, Sutcliffe T, Klassen TP. A randomized trial comparing the efficacy of epinephrine with salbutamol in the treatment of acute bronchiolitis. J Pediatr 1995;126(6):10047. Hartling L, Wiebe N, Russell K, et al. Epinephrine for bronchiolitis. Cochrane Database Syst Rev 2004;(1):CD003123. Ramesh P, Samuels M. Are methylxanthines effective in preventing or reducing apnoeic spells in infants with bronchiolitis? Arch Dis Child 2005;90(3):3212. Royal Childrens Hospital Melbourne. The use of aminophylline in infants with bronchiolitis. http://www.rch.org.au/neonatal_rch/research.cfm?doc_id = 6944 (last updated 11 December 2006) (accessed 20 June 2008). Spurling GK, Fonseka K, Doust J. Antibiotics for bronchiolitis in children. Cochrane Database Syst Rev 2001;(1):CD005189. Groothuis JR, Woodin KA, Katz R, et al. Early ribavirin treatment of respiratory syncytial viral infection in high-risk children. J Pediatr 1990;117(5):7928. Law BJ, Wang EEL, MacDonald N, et al. Does ribavirin impact on the hospital course of children with respiratory syncytial virus (RSV) infection? An analysis using the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) RSV database. Pediatrics 1997;99(3):e7. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Cochrane Database Syst Rev 2007;(1):CD000181. Kneyber M, Moll H, de Groot R. Treatment and prevention of respiratory syncytial virus infection. Eur J Pediatr 2000;159:399411. Downes JJ, Wood DW, Striker TW, et al. Acute respiratory failure in infants with bronchiolitis. Anesthesiology 1968;29(3):42634. Beasley JM, Jones SEF. Continuous positive airway pressure in bronchiolitis. BMJ 1981;283:15068. Al-balkhi A, Klonin H, Marinaki K, et al. Review of treatment of bronchiolitis related apnoea in two centres. Arch Dis Child 2005;90:28891. Duval EL, Leroy PL, Gemke RJ, et al. High-frequency oscillatory ventilation in RSV bronchiolitis patients. Respir Med 1999;93(6):43540. Flamant C, Hallalel F, Nolent P, et al. Severe respiratory syncytial virus bronchiolitis in children: from short mechanical ventilation to extracorporeal membrane oxygenation. Eur J Pediatr 2005;164(2):938. Cambonie G, Milesi C, Fournier-Favre S, et al. Clinical effects of heliox administration for acute bronchiolitis in young infants. Chest 2006;129(3):67682. Liet JM, Millotte B, Tucci M, et al. Noninvasive therapy with helium-oxygen for severe bronchiolitis. J Pediatr 2005;147(6):81217. Tibby SM, Hatherill M, Wright SM, et al. Exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med 2000;162(4):12516. Outwater KM, Crone RK. Management of respiratory failure in infants with acute viral bronchiolitis. Am J Dis Child 1984;138:10715. Lebel MH, Gauthier M, Lacroix J, et al. Respiratory failure and mechanical ventilation in severe bronchiolitis. Arch Dis Child 1989;64(10):14317. Soong WJ, Hwang B, Tang RB. Continuous positive airway pressure by nasal prongs in bronchiolitis. Pediatr Pulmonol 1993;16:1636.

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27.

28.

29.

30. 31.

REFERENCES
1. Paediatric Intensive Care Audit Network. PICANet Annual General Meeting. June 2006. http://www.picanet.org.uk/Documents/General/AGM_2006/ PICAnet%20bronchiolitis%202.pdf (accessed 20 June 2008). Hall CB. Respiratory syncytial virus. In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases. Philadelphia: WB Saunders, 1998:2084111. Handforth J, Friedland JS, Sharland M. Basic epidemiology and immunopathy of RSV in children. Paediatr Respir Rev 2000;1:21014. Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 19801996. JAMA 1999;282(15):14406. McConnochie KM, Roghmann KJ. Parental smoking, presence of older siblings and family history of asthma increase risk of bronchiolitis. Am J Dis Child 1986;140(8):80612. Holman RC, Curns AT, Cheek JE, et al. Respiratory syncytial virus hospitalizations among American Indian and Alaska native infants and the general United States infant population. Pediatrics 2004;114(4):e43744. Figueras-Aloy J, Carbonell-Estrany X, Quero J. Case-control study of the risk factors linked to respiratory syncytial virus infection requiring hospitalization in premature infants born at a gestational age of 3335 weeks in Spain. Pediatr Infect Dis J 2004;23(9):81520. Choudhuri JA, Ogden LG, Ruttenber AJ, et al. Effect of altitude on hospitalizations for respiratory syncytial virus infection. Pediatrics 2006;117(2):34956. Hall CB, Powell KR, MacDonald NE, et al. Respiratory syncytial viral infection in children with compromised immune function. N Engl J Med 1986;315(2):7781. MacDonald NE, Hall CB, Suffin SC, et al. Respiratory syncytial viral infection in infants with congenital heart disease. N Engl J Med 1982;307(7):397400. Shaw KN, Bell LM, Sherman NH. Outpatient assessment of infants with bronchiolitis. Am J Dis Child 1991;145(2):1515. Wang EE, Law BJ, Stephens D. Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. J Pediatr 1995;126(2):21219. Meissner HC. Selected populations at increased risk from respiratory syncytial virus infection. Pediatr Infect Dis J 2003;22(2 Suppl):S404. van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human metapneumovirus isolated from young children with respiratory tract disease. Nat Med 2001;7(6):71924. Foulongne VP, Guyon GM, Rodiere MM, et al. Human metapneumovirus infection in young children hospitalized with respiratory tract disease. Pediatr Infect Dis J 2006;25(4):3549. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350(5):44350. Jartti T, Makela MJ, Vanto T, et al. The link between bronchiolitis and asthma. Infect Dis Clin North Am 2005;19:66789. Allander T, Emerson SU, Engle RE, et al. Cloning of a human parvovirus by molecular screening of respiratory tract samples. Proc Natl Acad Sci U S A 2005;102(36):128916. Gardner PS. Virus infections and respiratory disease of childhood. Arch Dis Child 1968;43:62945. Behrendt CE, Decker MD, Burch DJ, et al. International variation in the management of infants hospitalised with respiratory syncytial virus. International RSV Study Group. Eur J Pediatr 1998;157:21520. Navas L, Wang E, De Carvalho V, et al. Improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children. Pediatric Investigators Collaborative Network on Infections in Canada. J Pediatr 1992;121(3):34854. 32. 33. 34. 35.

2. 3. 4. 5.

36.

6.

37. 38. 39.

7.

8. 9. 10. 11. 12.

40. 41. 42.

43.

44. 45. 46. 47. 48. 49.

13. 14.

15.

16.

17. 18.

50. 51. 52.

19. 20.

53. 54. 55.

21.

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Review
56. 57. 58. 59. 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(9178):5415. Noble V, Murray M, Webb MS, et al. Respiratory status and allergy nine to 10 years after bronchiolitis. Arch Dis Child 1997;76:31519. Sims DG, Downham MA, Gardner PS, et al. Study of 8 year old children with a history of respiratory syncytial virus bronchiolitis in infancy. BMJ 1978;1:1114. Kotaniemi-Syrjanen A, Vaiionpaa R, Reijonen TM, et al. Rhinovirus-induced wheezing in infancy--the first sign of childhood asthma? J Allergy Clin Immunol 2003;111(1):6671. 60. 61. 62. Piedimonte G, Rodriguez M, King K, et al. Respiratory syncytial virus upregulates expression of the substance P receptor in rat lungs. Am J Physiol 1999;277:L83140. Young S, OKeeffe P, Arnott J, et al. Lung function, airway responsiveness and respiratory symptoms before and after bronchiolitis. Arch Dis Child 1995;72:1624. Elphick HE, Ritson S, Rigby AS, et al. Phenotype of acute respiratory syncytial virus induced lower respiratory tract illness in infancy and subsequent morbidity. Acta Paediatr 2007;96(2):3079.

4th Fred J Epstein International Symposium on New Horizons in Pediatric Neurology, Neurosurgery and Neurofibromatosis
1519 March 2009, Eilat, Israel A symposium for paediatric neurologists, neurosurgeons, neuroradiologists, neuropathologists, neurooncologists, neurogeneticists, neuroscientists, perinatologists and paediatricians The symposium will provide an update in the diagnoses and management of diseases of the nervous system in infants and children that may be treated surgically. An emphasis will be placed on joint, rather than parallel sessions, with both neurological and neurosurgical approaches. The faculty is comprised of recognised leaders in their respective fields. Special attention will be given to controversial issues of common interest in patient management, new surgical-neuroradiological techniques and oncological options. The conference will be conducted in English. Conference organisers are: Shlomi Constantini, Israel; Shaul Harel, Israel; Rick Abbott, USA; Susan Bressman, USA; Kathy Epstein, USA; Roger J Packer, USA; Shlomo Shinnar, USA. For more information please contact the Secretariat: Target Conferences Ltd, PO Box 29041, Tel Aviv 61290, Israel; Tel: +972 3 5175150; Fax: +972 3 5175155; Email: newhorizons@targetconf.com; Website: www.fredhorizons.com.

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